FIGURE 53-2 Cytokine—cell interactions. Macrophages, T cells, B cells, and marrow stem cells interact via several cytokines (IL-1, IL-2, IL-3, IL-4, IFN [interferon]-g GM-CSF, and G-CSF) in response to a bacterial or a foreign antigen challenge.

marrow damage (e.g., moderately severe aplastic anemia or tumor infiltration of the marrow). The neutropenia of AIDS patients receiving zidovudine also can be partially or completely reversed. Filgrastim is routinely used in patients undergoing PBSC collection for stem cell transplantation. It promotes the release of CD34+ progenitor cells from the marrow, reducing the number of collections necessary for transplant. Moreover, filgrastim-mobilized PBSCs appear more capable of rapid engraftment. PBSC-transplanted patients require fewer days of platelet and red blood cell transfusions and a shorter duration of hospitalization than do patients receiving autologous bone marrow transplants.

Filgrastim is administered by subcutaneous injection or intravenous infusion over at least 30 minutes at doses of 1—20 mg/kg/day. The usual starting dose in a patient receiving myelosuppressive chemotherapy is 5 mg/kg/day. The distribution and clearance rate from plasma (t1/2 ~3.5 hours) are similar for both routes of administration. As with GM-CSF therapy, filgrastim given daily after hematopoietic stem cell transplantation or intensive cancer chemotherapy increases granulocyte production and shortens the period of severe neutropenia. Frequent blood counts should be obtained to determine the effectiveness of the treatment and guide dosage adjustment. In patients who received intensive myelosuppressive cancer chemotherapy, daily administration of G-CSF for 14—21 days or longer may be necessary to correct the neutropenia. With less intensive chemotherapy, fewer than 7 days of treatment may suffice. In AIDS patients on zidovudine or patients with cyclic neutropenia, chronic G-CSF therapy often is required.

Adverse reactions to filgrastim include mild-to-moderate bone pain in patients receiving high doses over a protracted period, local skin reactions following subcutaneous injection, and rare cutaneous necrotizing vasculitis. Patients with a history of hypersensitivity to proteins produced by E. coli should not receive the drug. Marked granulocytosis, with counts >100,000/mL, can occur in patients receiving filgrastim over a prolonged period of time. Mild-to-moderate splenomegaly has been observed in patients on long-term therapy.

Pegylated recombinant human G-CSF pegfilgrastim (neulasta) is generated by conjugation of a polyethylene glycol moiety (20 kDa) to the W-terminal Met residue of the G-CSF glycoprotein produced in E. coli. The clearance of pegfilgrastim by glomerular filtration is minimized, thus making neutrophil-mediated clearance the primary route of elimination. Consequently the circulating t1/2 of pegfilgrastim is longer than that of filgrastim, allowing for more sustained duration of action and less frequent dosing. The recommended dose for pegfilgrastim is 6 mg administered subcutaneously.

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Diabetes 2

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