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Chapter: Pharmaceutical Biotechnology: Fundamentals and Applications - Hematopoietic Growth Factors

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AIDS - Pharmaceutical Biotechnology

Patients infected with HIV often have neutropenia, anemia, and/or thrombocytopenia. These hematolo-gic abnormalities may occur as a direct result of HIV infection, as secondary effects of comorbid conditions, or because of chronic myelosuppressive therapy.

AIDS

 

Patients infected with HIV often have neutropenia, anemia, and/or thrombocytopenia. These hematolo-gic abnormalities may occur as a direct result of HIV infection, as secondary effects of comorbid conditions, or because of chronic myelosuppressive therapy. Antiviral therapy must be interrupted in up to half of the patients because of drug-induced neutropenia (Foote and Welch, 1999; Welch and Foote, 1999).


Filgrastim

 

Filgrastim has been approved in Australia, Canada, the European Union, and Japan for use in patients with HIV infection for the reversal of clinically significant neutropenia and for the subsequent maintenance of adequate neutrophil counts during treatment with antiviral and/or other myelosup-pressive medications when other options to manage neutropenia are inappropriate. A phase III study reported the effect of filgrastim on the incidence of severe neutropenia in patients with advanced HIV infection and its effect on the prevention of infectious morbidity (Kuritzkes et al., 1998). Two hundred and fifty-eight patients enrolled in the 24-week study, and 201 completed it. Filgrastim was administered daily at 1 m/kg and adjusted up to 10 mg/kg/day or intermittently at 300 mg daily 1 to 3 days per week. Patients in a control group received filgrastim only if severe neutropenia (defined as a neutrophil count < 0.5 109/L) devel-oped. Both daily and intermittent administration of filgrastim lowered the incidence of bacterial infec-tion rates compared with patients in the control group. Overall, filgrastim-treated patients developed 31% fewer bacterial infections than did control patients. Use of filgrastim produced significant reductions in the risk of severe bacterial infections and the number of days of hospitalization.

 

rhEPO

 

A randomized, double-blind, placebo-controlled study in 63 patients with AIDS treated with zidovu-dine showed that the addition of rhEPO three times a week reduced the number of transfusions of packed red blood cells and the number of units of packed red blood cells (Fischl et al., 1990). A significantly higher rate of increase in hematocrit was observed in patients treated with rhEPO when their native EPO concentra-tions were less than 500 IU/L.

Various additional dosing regimens of filgrastim have been used alone or in combination with rhEPO to reverse the dose-limiting hematologic toxicity of ganciclovir or zidovudine (Miles et al., 1991).

 

Anemia

Anemia, a low number of red blood cells, a decreased volume of red blood cells, or a reduced hemoglobin concentration, has many causes. The symptoms of anemia may include fatigue, dizziness, headache, chest pain, shortness of breath, and depression. Anemia is associated with increases in illness and death in patients with chronic renal failure, cancer, or HIV infection. Use of an erythro-poietic factor has many advantages for patients with anemia associated with cancer, chemotherapy, or renal failure.

rhEPO

 

In a phase III study of 333 patients with anemia and end-stage renal disease, epoetin alfa increased the hematocrit and eliminated the need for red blood cell transfusions in nearly all patients (Eschbach et al., 1989). The response was dose dependent, evident within 2 weeks, and maximal at 6 to 10 weeks of dosing.

 

In patients with cancer receiving chemotherapy, rhEPO increases hemoglobin values and decreases the need for blood transfusions (Abels et al., 1991). In patients with HIV/AIDS, rhEPO increased hemoglo-bin levels even when administered concomitantly with zidovudine therapy (Henry et al., 1992).

 

Darbepoetin Alfa

Darbepoetin alfa was designed by introducing five amino acid changes into the primary sequence of EPO to create two extra consensus N-linked carbohydrate sites (Egrie et al., 2003; Elliott et al., 2004). Because of its increased carbohydrate content and sialic acid changes, darbepoetin alfa has a threefold longer serum half-life in animal models compared with rhEPO, which was substantiated in a double-blind, randomized, crossover trial in humans (Macdougall et al., 1999). The area-under-the-serum-concentration-time curve was significantly greater for darbepoetin alfa compared with rhEPO, and volume of distribu-tion was similar for both products. The peak concentration of darbepoetin alfa administered sub-cutaneously was about 10% of that after intravenous administration, and bioavailability was approxi-mately 37% by the subcutaneous route. The longer half-life of darbepoetin alfa may confer a clinical advantage over rhEPO by allowing less frequent dosing when treating patients for anemia of chronic renal failure or anemia associated with cancer or chemotherapy or both.

 

Thrombocytopenia

 

Oprelvekin is licensed for use for the prevention of severe thrombocytopenia and the reduction of platelet transfusions after chemotherapy. In a placebo-con-trolled trial of women receiving chemotherapy for breast cancer, oprelvekin 25 or 50 mg/kg produced dose-related increases in mean platelet counts and a reduction in chemotherapy-induced thrombocytope-nia (Tepler et al., 1996).

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