As neuroinflammation is an early event in the pathogenesis of Alzheimer' s disease, new selective antiinflammatory drugs could lead to promising preventive strategies. We evaluated the safety, tolerability, pharmacokinetics and pharmacodynamics of CHF5074, a new microglial modulator, in a 12-week, double-blind, placebo-controlled, parallel groups, ascending dose study involving 96 MCI patients. Subjects were allocated into three successive study cohorts to receive ascending, titrated doses of CHF5074 (200, 400 or 600 mg/day) or placebo. Vital signs, cardiac safety, neuropsychological performance and safety clinical laboratory parameters were assessed on all subjects. Plasma samples were collected throughout the study for measuring drug concentrations, soluble CD40 ligand (sCD40L) and TNF-α. At the end of treatment, cerebrospinal fluid (CSF) samples were optionally collected after the last dose to measure drug levels, β- amyloid1-42 (Aβ42), tau, phospho-tau181, sCD40L and TNF-α. Ten patients did not complete the study: one in the placebo group (consent withdrawn), two in the 200-mg/day treatment group (consent withdrawn and unable to comply) and seven in the 400-mg/day treatment group (five AEs, one consent withdrawn and one unable to comply). The most frequent treatment-emergent adverse events were diarrhea, dizziness and back pain. There were no clinically significant treatmentrelated clinical laboratory, vital sign or ECG abnormalities. CHF5074 total body clearance depended by gender, age and glomerular filtration rate. CHF5074 CSF concentrations increased in a dose-dependent manner. At the end of treatment, mean sCD40L and TNF-α levels in CSF were found to be inversely related to the CHF5074 dose (p=0.037 and p=0.001, respectively). Plasma levels of sCD40L in the 600-mg/day group were significantly lower than those measured in the placebo group (p=0.010). No significant differences between treatment groups were found in neuropsychological tests but a positive dose-response trend was found on executive function in APOE4 carriers. This study shows that CHF5074 is well tolerated in MCI patients after a 12-week titrated treatment up to 600 mg/day and dose-dependently affects central nervous system biomarkers of neuroinflammation.

CHF5074 has been shown to inhibit brain β-amyloid deposition and attenuate memory deficits in different transgenic mice models of Alzheimer disease. We evaluated the safety, pharmacokinetics, and pharmacodynamics of 3 ascending dose regimens of CHF5074 (200, 400, and 600 mg/d for 14 d) in a double-blind, placebo-controlled, parallel group study involving 48 healthy subjects. Plasma, urine, and cerebrospinal fluid (CSF) samples were collected for measuring drug and main metabolite concentrations and potential biomarkers of pharmacodynamic activity (β-amyloid1-40, β-amyloid1-42, soluble CD40 ligand, and tumor necrosis factor-α). All subjects completed the study, and no serious or severe adverse events were reported. The maximum tolerated dose was close to 600 mg/d with mild diarrhea being the most frequent adverse event at this dose. CHF5074 reached peak plasma levels 2 to 3 hours after drug administration and then was slowly eliminated (t(1/2z)=30 h) in the urine as glucoronide. Systemic exposure to the drug appeared to be dose-proportional with a 2-fold accumulation ratio at steady state. Metabolite plasma levels peaked at 4 to 5 hours and accounted for about 25% of the parent compound. Drug levels in the CSF were dose-proportional. The drug dose-dependently lowered the levels of the soluble CD40 ligand, a marker of microglia activation, in both plasma and CSF samples.

One hundred twenty-five granulocyte transfusions were given concurrently with amphotericin B to 31 granulocytopenic patients with acute leukemia during a four year period. Twenty-six patients had culture-documented, and 5 had presumed fungal infections; pulmonary infiltrates were present in 26 patient courses. Eight patients developed pulmonary deterioration temporally related to therapy with amphotericin, granulocyte transfusions, or both. One event occurred following amphotericin alone. Three additional reactions occurred in alloimmunized patients with antibodies to human leukocyte antigens (HLA) who received random donor granulocytes, which may indicate a potential mechanism for the pulmonary reactions. Two reactions potentially represent an adverse interaction between amphotericin and granulocytes, but these were reversible and were not unlike reactions expected with each modality alone. Our data fail to document a specific detrimental interaction between granulocyte transfusions and amphotericin beyond the reactions associated with each modality, and the data suggest that other clinical factors, particularly infection and alloimmunization, also contribute to pulmonary decompensation. We nevertheless recommend great care and attention be given to administering these modalities in the setting of severely ill patients.

Immune globulin, prepared as a chemically and enzymatically unmodified solution in 10 percent maltose at pH 4.25, was administered intravenously, at a dose of 0.4 g per kg per day for five consecutive days, to seven alloimmunized patients who had acute nonlymphocytic leukemia. All patients had an approximately threefold rise in IgG level. Five patients showed no change in lymphocytotoxic antibody (LCTAb) activity and no response to random donor platelets that were administered after the immune globulin. The activity of LCTAb either disappeared or diminished after immune globulin infusion in two patients, and they had borderline acceptable corrected count increments 1 hour after transfusion of pooled random-donor platelet transfusions. Because of the diminished LCTAb activity, the improvements in response to pooled random-donor platelet transfusions cannot be ascribed to the administration of immune globulin. High-dose intravenous immune globulin has not been shown to be effective in reversing the effects of alloimmunization.