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biopharmaceuticals biochemistry and biotecnology - Walsh G.

Walsh G. biopharmaceuticals biochemistry and biotecnology - John Wiley & Sons, 2003. - 572 p.
ISBN 0-470-84327-6
Download (direct link): biochemistryandbiotechnology2003.pdf
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Chronic disease and cancer chemotherapy
Anaemia often becomes a characteristic feature of several chronic diseases, such as rheumatoid arthritis. In most instances this can be linked to lower than normal endogenous serum EPO levels (although in some cases, a deficiency of iron or folic acid can also represent a contributory factor). Several small clinical trials have confirmed that administration of EPO increases haematocrit and serum haemoglobin levels in patients suffering from rheumatoid arthritis. A satisfactory response in some patients, however, required high-dose therapy, which could render this therapeutic approach unattractive from a cost:benefit perspective.
272 BIOPHARMACEUTICALS
Table 6.9. Some non-renal applications of EPO (refer to text for details)
Treatment of anaemia associated with chronic disease Treatment of anaemia associated with cancer/chemotherapy Treatment of anaemia associated with prematurity To facilitate autologous blood donations before surgery To reduce transfusion requirements after surgery To prevent anaemia after bone marrow transplantation
Severe, and in particular chronic, infection can also sometimes induce anaemia ó which is often made worse by drugs used to combat the infection, e.g. anaemia is evident in 8% of patients with asymptomatic HIV infection. This incidence increases to 20% for those with AIDS-related complex and is greater than 60% for patients who have developed Kaposiís sarcoma. Up to one-third of AIDS patients treated with zidovudine also develop anaemia. Again, several trials have confirmed that EPO treatment of AIDS sufferers (be they receiving zidovudine or not) can increase haematocrit values and decrease transfusion requirements.
Various malignancies can also induce an anaemic state. This is often associated with decreased serum EPO levels, although iron deficiency, blood loss or tumour infiltration of the bone marrow can be complicating factors. In addition, chemotherapeutic agents administered to this patient group often adversely affect stem cell populations, thus rendering the anaemia even more severe.
Administration of EPO to patients suffering from various cancers/receiving various chemotherapeutic agents yielded encouraging results, with significant improvements in haematocrit levels being recorded in approximately 50% of cases. In one large US study (2000 patients, most receiving chemotherapy) s.c. administration of an average of 150IU EPO/kg, three times weekly, for 4 months, reduced the number of patients requiring blood transfusions from 22% to 10%. Improvement in the sense of well-being and overall quality of life was also noted. The success rate of EPO in alleviating cancer-associated anaemia has varied in different trials, ranging from 32% to 85%.
The EPO receptor is expressed not only by specific erythrocyte precursor cells but also by endothelial, neural and myeloma cells. Concern has been expressed that EPO, therefore, might actually stimulate growth of some tumour types, particularly those derived from such cells. To date, no evidence (in vitro or in vivo) has been obtained to support this hypothesis.
Additional non-renal applications
Babies, especially babies born prematurely, often exhibit anaemia, which is characterized by a steadily decreasing serum haemoglobin level during the first 8 weeks of life. While multiple factors contribute to development of anaemia of prematurity, a lower than normal serum EPO level is a characteristic trait. In vitro studies indicate that BFU-E and CFU-E cells from such babies are responsive to EPO, and several pilot clinical trials have been initiated. Administration of 300-600 IU EPO/kg/week generally was found to enhance erythropoiesis and reduced the number of transfusions required by up to 30%.
Patients who have received an allogeneic bone marrow transplant characteristically display depressed serum EPO levels for up to 6 months post-transplantation. Administration of EPO thus seems a logical approach to counteract this effect. Several clinical studies have validated
HAEMOPOIETIC GROWTH FACTORS 273
this approach, observing accelerated erythropoiesis, resulting in attainment of satisfactory haematocrit levels within a shorter period post-transplant.
Tolerability
In general, rhEPO is well tolerated. The most pronounced adverse effects appear to be associated with its long-term administration to patients with end-stage renal failure. Particularly noteworthy is an increase in blood pressure levels in some patients and the increased risk of thromboembolic events (a thromboembolic event, i.e. a thromboembolism, describes the circumstance where a blood clot forms at one point in the circulation but detaches, only to become lodged at another point; Chapter 9).
Most short-term applications of EPO are non-renal related, and generally display very few side-effects; i.v. administration can sometimes prompt a transient flu-like syndrome, while s.c. administration can render the site of injection painful. This latter effect appears, however, to be due to excipients present in the EOP preparations, most notably the citrate buffer. EPO administration can also cause bone pain, although this rarely limits its clinical use.
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