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Leukocytes rapidly lose their surface receptors for TNF and IL-1 upon exposure to various stimuli in vitro. We sought to determine by FACS analysis changes in the expression of TNF receptors (TNFR) and type II IL-1R on circulating monocytes and granulocytes during endotoxemia in vivo, and the role of endogenous TNF in these changes. Twelve healthy subjects received an i.v. injection with LPS (2 ng/kg), directly preceded by a 30-min infusion of either a recombinant human dimeric TNFR type II-IgG fusion protein (TNFR:Fc; 6 mg/m2; n = 6) or vehicle (n = 6). LPS administration was associated with decreases in the expression of types I and II TNFR and type II IL-1R on both monocytes and granulocytes. Treatment with TNFR:Fc completely neutralized LPS-induced TNF activity (p < 0.0001 vs LPS only), modestly blunted the decrease in monocyte TNFR (p < 0.05), but did not influence reduced expression of granulocyte TNFR or monocyte/granulocyte type II IL-1R. In separate experiments, rTNF added to whole blood reduced cellular type I and type II TNFR expression by an effect on the type I TNFR; TNF did not (monocytes) decrease or only marginally (granulocytes) decreased type II IL-1R expression. LPS induces down-modulation of monocyte and granulocyte receptors for TNF and IL-1 in humans in vivo. TNF is involved in reduced monocyte TNFR expression during endotoxemia.

Background: Topotecan has been shown in previous studies to be a specific inhibitor of topoisomerase I, a nuclear enzyme required for DNA replication and transcription., Purpose: Our objectives in this phase I clinical trial were to determine the maximum tolerated dose, dose-limiting toxic effects, and recommended phase II dose of topotecan and to define the pharmacokinetics of topotecan in humans., Methods: Forty-three patients with advanced, incurable solid tumors were treated. Doses ranged from 0.5 to 2.0 mg/m2 daily for five days [corrected], with treatment cycles repeated initially every 28 days. Following the identification of the standard maximum tolerated dose, further dose escalations were attempted by following topotecan cycles with recombinant granulocyte colony-stimulating factor (rG-CSF)., Results: The maximum tolerated dose without rG-CSF for patients without prior cytotoxic therapy was 1.75 mg/m2 daily. The maximum tolerated dose for previously treated patients was 1.50 mg/m2 daily. The dose-limiting toxic effect was myelosuppression, with granulocytopenia being most commonly observed. Use of rG-CSF did not permit topotecan dose intensification, since thrombocytopenia and fatigue rapidly emerged as dose-limiting toxic effects. Plasma half-lives of topotecan (lactone form) were approximately 10 and 100 minutes for distribution and elimination phases, respectively., Conclusions: The doses of topotecan recommended for use in phase II clinical trials in solid tumors are 1.5 and 1.25 mg/m2 daily in previously untreated and previously treated patients, respectively. Based on observed rates of recovery from myelosuppression, treatment should be possible on a 21-day cycle. Dose intensification was not possible with the use of rG-CSF; however, rG-CSF may be a useful addition to the regimens of those few patients who experience either prolonged granulocytopenia or neutropenic sepsis or those who are not able to receive their second treatment cycle by day 21.

The primary complex like Ghon was observed in a child's clinical roentgenographic study. C.S., white, male, 6 years old, was born in Curitiba (PR), Brazil and living in Guaratingueta (SP), Brazil, developed "common cold", bimodal diary fever, chills, shake and sweats. Dyspnea, cough with general lymphadenopathy. Foot and right shoulder arthralgias. Six months ago visited a cave, equitation practice, dog and cat contacts and no transfusion, frontal sweats, fever (38.4 degrees C). T.A. was 8/6, tachycardia in generalized lymphadenopathy. Cardiopulmonary system was normal, mesogastric tumoral mass, hepatosplenomegaly and no ascites. Bone marrow with eosinophilia; nodule demonstrated presence of P. brasiliensis, hypoalbuminemia; hyperglobulinemia; anemia; leukocytosis with eosinophilia. Immunodiffusion with exoantigen 43 kd of P. brasiliensis was 1/32. Primary complex like Ghon was observed in interstitial pneumonia followed by mediastinal and mesogastric mass (35 to 40 days). Clavicular osteolytic lesions (45 to 60 days) appeared during paracoccidioidomycosis therapy. Recovery was observed 2 months after treatment of acute infantile paracoccidioidomycosis.