Section XI - Drugs Acting on the Blood and the Blood-Forming docx

Section XI. Drugs Acting on the Blood and the Blood-Forming Organs Overview The short life span of mature blood cells requires their continuous replacement, a process termed hematopoiesis. New cell production must be responsive to both basal needs and situations of increased demand. For example, red blood cell production can vary over more than a fivefold range in response to anemia or hypoxia. White blood cell production increases dramatically in response to a systemic infection, and platelet production can increase severalfold when platelet destruction results in thrombocytopenia. The regulation of hematopoiesis is complex and involves cell–cell interactions within the microenvironment of the bone marrow as well as both hematopoietic and lymphopoietic growth factors. A number of these hormonelike glycoproteins now have been identified and characterized, and, using recombinant DNA technology, their genes have been cloned and the proteins produced in quantities sufficient for use as therapeutic agents. Clinical applications now are being developed, ranging from treatment of primary hematological diseases to uses as adjunctive agents in the treatment of severe infections and in the management of patients who are undergoing chemotherapy or marrow transplantation. Hematopoiesis also requires adequate supplies of minerals, both iron and copper, and a number of vitamins, including folic acid, vitamin B 12 , pyridoxine, ascorbic acid, and riboflavin. Deficiencies of these minerals and vitamins generally result in characteristic anemias and, less frequently, a general failure of hematopoiesis. Therapeutic correction of a specific deficiency state depends on the accurate diagnosis of the anemic state and knowledge as to the correct dose, the use of these agents in various combinations, and the expected response. This chapter deals with the growth factors, vitamins, minerals, and drugs that affect the blood and blood-forming organs. Hematopoietic Growth Factors History Modern concepts of hematopoietic cell growth and differentiation developed beginning in the 1950s with the work of Jacobsen, Ford, and others (Jacobsen et al. , 1949 ; Ford et al. , 1956 ). These investigators demonstrated the role that cells from the spleen and marrow play in the restoration of hematopoietic tissue in irradiated animals. In 1961, Till and McCulloch were able to show that individual hematopoietic cells could form macroscopic hematopoietic nodules in the spleens of irradiated mice. Their work led to the concept of colony-forming stem cells. It also led to the subsequent proof that stem cells present in human bone marrow are pluripotent—that is, they give rise to granulocytes, monocytes, lymphocytes, megakaryocytes, and erythrocytes. The role of growth factors in hematopoiesis was elucidated by Bradley, Metcalf, and others using bone marrow culture techniques (Bradley and Metcalf, 1966). Individual growth factors were isolated (Metcalf, 1985; Moore, 1991), and the target cells of these factors characterized. The pluripotent stem cell gives rise to committed progenitors, which can be identified as single colony- forming units, and to cells that are increasingly differentiated. The existence of a circulating growth factor that controls erythropoiesis was first suggested by experiments carried out by Paul Carnot in 1906 (Carnot and Deflandre, 1906). He observed an increase in the red cell count in rabbits injected with serum obtained from anemic animals and postulated the existence of a factor that he called hemapoietine. However, it was not until the 1950s that Reissmann (1950), Erslev (1953), and Jacobsen and coworkers (1957) defined the origin and actions of the hormone, now called erythropoietin. Subsequently, extensive studies of erythropoietin were carried out in patients with anemia and polycythemia, culminating in 1977 with the purification of erythropoietin from urine by Miyake and colleagues. The gene that encodes the protein was subsequently cloned and expressed at a high level in a mammalian cell system (Jacobs et al. , 1985 ; Lin et al. , 1985 ), producing a recombinant hormone that is indistinguishable from human urinary erythropoietin. Similarly, complementary DNA and genomic clones for granulocyte, macrophage, and, most recently, megakaryocyte colony-stimulating factors have been isolated and sufficient quantities of biologically active growth factors produced for clinical investigation (Kawasaki et al. , 1985 ; Lee et al. , 1985 ; Wong et al. , 1985 ; Yang et al. , 1986 ; Lok et al. , 1994 ; de Sauvage et al. , 1994 ). Growth Factor Physiology Steady-state hematopoiesis involves the production of more than 200 billion (2 x 10 11 ) blood cells each day. This production is under delicate control, and, with increased demand, the rate can increase severalfold. The hematopoietic organ also is unique in that several mature cell types are derived from a much smaller number of pluripotent stem cells that are formed in early embryonic life. These stem cells are capable of both maintaining their own number and differentiating under the influence of cellular and humoral factors [stem cell factor (SCF), Flt3 ligand (FL), interleukin-3 (IL-3), and granulocyte/macrophage colony-stimulating factor (GM-CSF)] to produce a variety of hematopoietic and lymphopoietic cells. Stem cell differentiation can be described as a series of steps that produce so-called burst-forming units (BFU) and colony-forming units (CFU) for each of the major cell lines (Quesenberry and Levitt, 1979). Although these early progenitors (BFU and CFU) are not morphologically recognizable as precursors of a specific cell type, they are capable of further proliferation and differentiation, increasing their number by some 30-fold. Subsequently, colonies of morphologically distinct cells form under the control of an overlapping set of additional growth factors (G-CSF, M-CSF, erythropoietin, and thrombopoietin). Proliferation and maturation of the CFU for each cell line can further amplify the resulting mature cell product by another 30-fold or more, resulting in greater than 1000 mature cells produced for each committed stem cell (Lajtha et al. , 1969 ). Hematopoietic and lymphopoietic growth factors are produced by a number of marrow cells and peripheral tissues. The growth factors are glycoproteins and are active at very low concentrations, usually on more than one committed cell lineage. Most show synergistic interactions with other factors, as well as "networking," wherein stimulation of a cell lineage by one growth factor induces the production of additional growth factors. Finally, growth factors generally exert actions at several points in the processes of cell proliferation and differentiation and in mature cell function (Metcalf, 1985). Some of the overlapping effects of the more important hematopoietic growth factors are illustrated in Figure 54–1 and listed in Table 54–1. Figure 54–1. Sites of Action of Hematopoietic Growth Factors in the Differentiation and Maturation of Marrow Cell Lines. A self-sustaining pool of marrow stem cells differentiates under the influence of specific hematopoietic growth factors to form a variety of hematopoietic and lymphopoietic cells. Stem cell factor (SCF), ligand (FL), interleukin-3 (IL-3), and granulocyte/macrophage colony-stimulating factor (GM-CSF), together with cell–cell interactions in the marrow, stimulate stem cells to form a series of burst-forming units (BFU) and colony-forming units (CFU): CFU-GEMM, CFU-GM, CFU-Meg, BFU-E, and CFU-E (GEMM, granulocyte, erythrocyte, monocyte, and megakaryocyte; GM, granulocyte and macrophage; Meg, megakaryocyte; E, erythrocyte). After considerable proliferation, further differentiation is stimulated by synergistic interactions with growth factors for each of the major cell lines—granulocyte colony-stimulating factor (G-CSF), monocyte/macrophage-stimulating factor (M- CSF), thrombopoietin, and erythropoietin. Each of these factors also influences the proliferation, maturation, and, in some cases, the function of the derivative cell line (seeTable 54–1). Erythropoietin While erythropoietin is not the sole growth factor responsible for erythropoiesis, it is the most important regulator of the proliferation of committed progenitors (BFU-E and CFU-E). In its absence, severe anemia is invariably present. Erythropoiesis is controlled by a highly responsive feedback system in which a sensor in the kidney can detect changes in oxygen delivery to increase the secretion of erythropoietin, which then stimulates a rapid expansion of erythroid progenitors. Erythropoietin is produced primarily by peritubular interstitial cells of the kidney under the control of a single gene on human chromosome 7. The gene product is a protein containing 193 amino acids, of which the first 27 are cleaved during secretion (Jacobs et al. , 1985 ; Lin et al. , 1985 ). The final hormonal peptide is heavily glycosylated and has a molecular weight of approximately 30,000 daltons. Once released, erythropoietin travels to the marrow, where it binds to a receptor on the surface of committed erythroid progenitors and is internalized. With anemia or hypoxemia, renal synthesis rapidly increases by 100-fold or more, serum erythropoietin levels rise, and marrow progenitor cell survival, proliferation, and maturation are dramatically stimulated. This finely tuned feedback loop can be disrupted at any point—by kidney disease, marrow damage, or a deficiency in iron or an essential vitamin. With an infection or an inflammatory state, erythropoietin secretion, iron delivery, and progenitor proliferation are all suppressed by inflammatory cytokines. Recombinant human erythropoietin (epoetin alfa), produced using a mammalian cell line (Chinese hamster ovary cells), is virtually identical to endogenous hormone. Small differences in the carbohydrate portion of the molecule do not appear to affect the kinetics, potency, or immunoreactivity. Currently available preparations of epoetin alfa include EPOGEN and PROCRIT, supplied in single-use vials of from 2000 to 10,000 U/ml for intravenous or subcutaneous administration. When injected intravenously, epoetin alfa is cleared from plasma with a half-life of 10 hours. However, the effect on marrow progenitors is sufficiently sustained that it need not be given more often than three times a week to achieve an adequate response. No significant allergic reactions have been associated with the intravenous or subcutaneous administration of epoetin alfa, and antibodies have not been detected, even after prolonged administration. Therapeutic Uses Recombinant erythropoietin therapy can be highly effective in a number of anemias, especially those associated with a poor erythropoietic response. As first shown by Eschbach and coworkers in 1987, there is a clear dose-response relationship between the epoetin alfa dose and the rise in hematocrit in anephric patients, with eradication of their anemia at higher doses. Epoetin alfa also has been shown to be effective in the treatment of anemias associated with surgery, AIDS, cancer chemotherapy, prematurity, and certain chronic inflammatory illnesses. Anemia of Chronic Renal Failure Patients with the anemia of chronic renal disease are ideal candidates for epoetin alfa therapy. The response in predialysis, peritoneal dialysis, and hemodialysis patients is dependent on severity of the renal failure, the erythropoietin dose and route of administration, and iron availability (Eschbach et al. , 1989 ; Kaufman et al. , 1998 ; Besarab et al. , 1999 ). The subcutaneous route of administration is preferred over the intravenous, since absorption is slower and the amount of drug required is reduced by 20% to 40%. Iron supply is especially critical. Adequate iron stores, as reflected by an iron saturation of transferrin of at least 30% and a plasma ferritin greater than 400 g/l, must be maintained, usually by repeated injections of iron dextran (see"Therapy with Parenteral Iron"). The patient must be closely monitored during therapy, and the dose of epoetin alfa must be adjusted to obtain a gradual rise in the hematocrit, over a 2- to 4-month period, until a final hematocrit of 33% to 36% is reached. Treatment to hematocrit levels greater than 36% is not recommended. A study of patients treated to hematocrits above 40% showed a higher incidence of myocardial infarction and death (Besarab et al. , 1998 ). Furthermore, the drug should never be used to replace emergency transfusion in patients who need immediate correction of a life-threatening anemia. It is currently recommended that the patient be started on a dose of 80 to 120 U/kg of epoetin alfa, given subcutaneously, three times a week. It can be given on a once-a-week schedule, but considerably more drug is required for an equivalent effect. If the response is poor, the dose should be progressively increased. The final maintenance dose of epoetin alfa can vary from as little as 10 U/kg to more than 300 U/kg, with an average close to 75 U/kg, three times a week, in most patients. Children under the age of 5 years generally require a higher dose. Resistance to therapy is commonly seen in the patient who develops an inflammatory illness or becomes iron deficient, so that close monitoring of general health and iron status is essential. Less common causes of resistance include occult blood loss, folic acid deficiency, carnitine deficiency, inadequate dialysis, aluminum toxicity, and osteitis fibrosa cystica secondary to hyperparathyroidism. The most common side effect of epoetin alfa therapy is aggravation of hypertension, seen in 20% to 30% of patients and most often associated with a too-rapid rise in hematocrit. Blood pressure control usually can be attained by either increasing antihypertensive therapy or ultrafiltration in dialysis patients or by reducing the epoetin alfa dose to slow the hematocrit response. An increased tendency to vascular access thrombosis in dialysis patients also has been reported, but this remains controversial. Anemia in AIDS Patients Epoetin alfa therapy has been approved for the treatment of HIV-infected patients, especially those on zidovudine therapy (Fischl et al. , 1990 ). Excellent responses to doses of 100 to 300 U/kg, given subcutaneously three times a week, generally are seen in patients with zidovudine-induced anemia. In the face of advanced disease, marrow damage, and elevated serum erythropoietin levels (greater than 500 IU/L), therapy is less effective. Cancer-Related Anemias Epoetin alfa therapy, 150 U/kg three times a week or 450 to 600 U/kg once a week, can reduce the transfusion requirement in cancer patients undergoing chemotherapy. It also has been used to treat patients with multiple myeloma, with improvement in both their anemia and sense of well-being. Here again, a baseline serum erythropoietin level may help to predict the response. Surgery and Autologous Blood Donation Epoetin alfa has been used perioperatively to treat anemia and reduce the need for transfusion. Patients undergoing elective orthopedic and cardiac procedures have been treated with 150 to 300 U/kg of epoetin alfa once daily for the 10 days preceding surgery, on the day of surgery, and for 4 days after surgery. As an alternative, 600 U/kg can be given on days –21, –14, and –7 prior to surgery, with an additional dose on the day of surgery. This can correct a moderately severe preoperative anemia, hematocrit 30% to 36%, and reduce the need for transfusion. Epoetin alfa also has been used to improve autologous blood donation (Goodnough et al. , 1989 ). However, as a routine, the potential benefit is small while the expense is considerable. Patients treated for 3 to 4 weeks with epoetin alfa (300 to 600 U/kg twice a week), are able to donate only 1 or 2 more units than untreated patients, and most of the time this goes unused. Still, the ability to stimulate erythropoiesis for blood storage can be invaluable in the patient with multiple alloantibodies to homologous red blood cells. Other Uses Epoetin alfa has been designated an orphan drug by the United States Food and Drug Administration (FDA) for the treatment of the anemia of prematurity and patients with myelodysplasia. In the latter case, even very high doses of more than 1000 U/kg 2 to 3 times a week have had limited success. The possible use of very high dose therapy in other hematological disorders, such as sickle cell anemia, is still under study. Highly competitive athletes have used epoetin alfa to increase their hemoglobin levels ("blood doping") and improve performance. Unfortunately, this misuse of the drug has been implicated in the deaths of several athletes, and it should be discouraged. Myeloid Growth Factors The myeloid growth factors are glycoproteins that stimulate the proliferation and differentiation of one or more myeloid cell lines. They also enhance the function of mature granulocytes and monocytes. Recombinant forms of several of the growth factors have now been produced, including GM-CSF (Lee et al. , 1985 ), G-CSF (Wong et al. , 1985 ), IL-3 (Yang et al. , 1986 ), M-CSF or CSF-1 (Kawasaki et al. , 1985 ), SCF (Huang et al. , 1990 ), and, most recently, thrombopoietin (Lok et al. , 1994; de Sauvage et al. , 1994 ; Kaushansky et al. , 1994 ; Table 54–1). The myeloid growth factors are produced naturally by a number of different cells including fibroblasts, endothelial cells, macrophages, and T cells (Figure 54–2). They are active at extremely low concentrations. GM-CSF is capable of stimulating the proliferation, differentiation, and function of a number of the myeloid cell lineages (Figure 54–1). It acts synergistically with other growth factors, including erythropoietin, at the level of the BFU. GM-CSF stimulates the CFU- GEMM (granulocyte/erythrocyte/macrophage/megakaryocyte), CFU-GM, CFU-M, CFU-E, and CFU-Meg (megakaryocyte) to increase cell production. It also enhances the migration, phagocytosis, superoxide production, and antibody-dependent cell media toxicity of neutrophils, monocytes, and eosinophils. Figure 54–2. Cytokine–Cell Interactions. Macrophages, T cells, B cells, and marrow stem cells interact via several cytokines [IL (interleukin)-1, IL-2, IL-3, IL-4, IFN (interferon)- , GM-CSF, and G-CSF] in response to a bacterial or a foreign antigen challenge. SeeTable 54–1 for the functional activities of these various cytokines. The activity of G-CSF is more focused. Its principal action is to stimulate the proliferation, differentiation, and function of the granulocyte lineage. It acts primarily on the CFU-G, although it can also play a synergistic role with IL-3 and GM-CSF in stimulating other cell lines. G-CSF enhances phagocytic and cytotoxic activities of neutrophils. Unlike GM-CSF, G-CSF has little effect on monocytes, macrophages, and eosinophils. At the same time, G-CSF reduces inflammation by inhibiting IL-1, tumor necrosis factor, and interferon gamma. Granulocyte/Macrophage Colony-Stimulating Factor (GM-CSF) Recombinant human GM-CSF (sargramostim) is a 127–amino acid glycoprotein produced in yeast. Except for the substitution of a leucine in position 23 and variable levels of glycosylation, it is identical to endogenous GM-CSF. While sargramostim, like natural GM-CSF, has a wide range of effects on cells in culture, its primary therapeutic effect is the stimulation of myelopoiesis. The initial clinical application of sargramostim was in patients undergoing autologous bone marrow transplantation. By shortening the duration of neutropenia, transplant morbidity was significantly reduced without a change in long-term survival or risk of inducing an early relapse of the malignant process (Brandt et al. , 1988 ; Rabinowe et al. , 1993 ). The role of GM-CSF therapy in allogeneic transplantation is less clear. The effect of the growth factor on neutrophil recovery is less pronounced in patients receiving prophylactic treatment for graft-versus-host disease (GVHD), and studies have failed to show a significant effect on transplant mortality, long-term survival, the appearance of GVHD, or disease relapse. However, it may improve survival in transplant patients who exhibit early graft failure (Nemunaitis et al. , 1990 ). It also has been used to mobilize CD34- positive progenitor cells for peripheral blood stem cell collection for transplantation following myeloablative chemotherapy. Sargramostim has been used to shorten the period of neutropenia and reduce morbidity in patients receiving intensive chemotherapy (Gerhartz et al. , 1993 ). It also will stimulate myelopoiesis in some patients with cyclic neutropenia, myelodysplasia, aplastic anemia, or AIDS-associated neutropenia (Groopman et al. , 1987 ; Vadhan-Raj et al. , 1987 ). Sargramostim (LEUKINE) is administered by subcutaneous injection or slow intravenous infusion at a dose of 125 to 500 g/m 2 per day. Plasma levels of GM-CSF rise rapidly after subcutaneous injection and then decline, with a half-life of 2 to 3 hours. When given intravenously, infusions should be maintained over 3 to 6 hours. With the initiation of therapy, there is a transient decrease in the absolute leukocyte count secondary to margination and sequestration in the lungs. This is followed by a dose-dependent, biphasic increase in leukocyte counts over the next 7 to 10 days. Once the drug is discontinued, the leukocyte count returns to baseline within 2 to 10 days. When GM-CSF is given in lower doses, the response is primarily neutrophilic, while at larger doses, monocytosis and eosinophilia are observed. Following bone marrow transplantation or intensive chemotherapy, sargramostim is given daily during the period of maximum neutropenia until a sustained rise in the granulocyte count is observed. Frequent blood counts are essential to avoid an excessive rise in the granulocyte count. The dose may be increased if the patient fails to respond after 7 to 14 days of therapy. However, higher doses are associated with more pronounced side effects, including bone pain, malaise, flulike symptoms, fever, diarrhea, dyspnea, and rash. Patients can be extremely sensitive to GM-CSF, demonstrating an acute reaction to the first dose, characterized by flushing, hypotension, nausea, vomiting, and dyspnea, with a fall in arterial oxygen saturation due to sequestration of granulocytes in the pulmonary circulation. With prolonged administration, a few patients may develop a capillary leak syndrome, with peripheral edema and both pleural and pericardial effusions. Granulocyte Colony-Stimulating Factor (G-CSF) Recombinant human G-CSF (filgrastim, NEUPOGEN) is a 175–amino acid glycoprotein produced in Escherichia coli. Unlike natural G-CSF, it is not glycosylated and carries an extra N-terminal methionine. The principal action of filgrastim is the stimulation of CFU-G to increase neutrophil production (Figure 54–1). It also enhances the phagocytic and cytotoxic functions of neutrophils. Filgrastim has been shown to be effective in the treatment of severe neutropenia following autologous bone marrow transplantation and high-dose chemotherapy (Lieschke and Burgess, 1992). Like GM-CSF, filgrastim shortens the period of severe neutropenia and reduces morbidity secondary to bacterial and fungal infections. When used as a part of an intensive chemotherapy regimen, it can decrease the frequency of both hospitalization for febrile neutropenia and interruptions in the chemotherapy protocol. G-CSF also has proven to be effective in the treatment of severe congenital neutropenias. In patients with cyclic neutropenia, G-CSF therapy, while not eliminating the neutropenic cycle, will increase the level of neutrophils and shorten the length of the cycle sufficiently to prevent recurrent bacterial infections (Hammond et al. , 1989 ). Filgrastim therapy can improve neutrophil counts in some patients with myelodysplasia or marrow damage (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 now routinely used in the patient undergoing peripheral blood stem cell (PBSC) collection and a stem cell transplant. It encourages 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 a dose of 1 to 20 g/kg per day. A usual starting dose in a patient receiving myelosuppressive chemotherapy is 5 g/kg per day. The distribution and clearance rate from plasma (half-life of 3.5 hours) are similar for both routes of administration. A continuous 24-hour intravenous infusion can be used to produce a steady-state serum concentration of the growth factor. As with GM-CSF therapy, filgrastim given daily following bone marrow transplantation or intensive chemotherapy will increase granulocyte production and shorten the period of severe neutropenia. Frequent blood counts should be obtained to determine the effectiveness of the treatment. The dosage may need to be adjusted according to the granulocyte response, and the duration of therapy will depend on the specific application. In marrow transplantation and intensive chemotherapy patients, continuous daily administration for 14 to 21 days or longer may be necessary to correct the neutropenia. With less intensive chemotherapy, fewer than 7 days of treatment may be needed. In AIDS patients on zidovudine or patients with cyclic neutropenia, chronic G-CSF therapy often will be required. Adverse reactions to filgrastim include mild to moderate bone pain in those patients receiving high doses over a protracted period, local skin reactions following subcutaneous injection, and, rarely, a cutaneous necrotizing vasculitis. Patients with a history of hypersensitivity to proteins produced by E. coli should not receive the drug. Marked granulocytosis, with counts greater than 100,000/ l, can occur in patients receiving filgrastim over a prolonged period of time. However, this is not associated with any reported clinical morbidity or mortality and rapidly resolves once therapy is discontinued. Mild to moderate splenomegaly has been observed in patients on long-term therapy. The therapeutic roles of other growth factors still need to be defined. M-CSF may play a role in stimulating monocyte and macrophage production, though with significant side effects, including splenomegaly and thrombocytopenia. Because of their primary effect on primitive marrow precursors, IL-3 and FL may be used in combination with GM-CSF and G-CSF. Administration of IL-3 followed by GM-CSF has been shown to give a greater neutrophil response than GM-CSF alone (Ganser et al. , 1992 ). This combination also may be more effective in promoting the release of marrow CD34+ stem cells in patients undergoing stem cell pheresis. SCF, IL-1, IL-6, IL-9, and IL-11 need to be studied alone and in combination with each other, as well as with both GM-CSF and G-CSF. The combination of IL-3 followed by GM-CSF also needs to be studied in protocols that include the reinfusion of harvested stem cells for their growth-promoting activity. Thrombopoietin The cloning and expression of a recombinant human thrombopoietin, a cytokine that selectively stimulates megakaryocytopoiesis, is another major milestone in the development of hematopoietic growth factors as therapeutic agents (Lok et al. , 1994 ; de Sauvage et al. , 1994 ; Kaushansky et al. , 1994). If future clinical trials live up to the early promise of the demonstrated ability of this new cytokine to increase rapidly the platelet count in animals (Harker, 1999), the combined use of thrombopoietin with G-CSF or GM-CSF together with erythropoietin will have a great impact in the treatment of primary hematological diseases and the anemia, neutropenia, and thrombocytopenia associated with high-dose chemotherapy. In a study of a small number of patients with gynecological cancers receiving carboplatin (Vadhan-Raj et al. , 2000 ), recombinant human thrombopoietin (rHuTPO) therapy reduced the duration of severe thrombocytopenia as well as the need for platelet transfusions. Larger, randomized, controlled trials are now under way to define fully the clinical merits and safety of rHuTPO. The optimal dose and schedule of administration in various clinical settings also need to be worked out. Both rHuTPO and pegylated recombinant human megakaryocyte growth and development factor (PEG-rHyMGDF) give delayed platelet responses. Following a single bolus injection, platelet counts show a detectable increase by day 4 and a peak response by 12 to 14 days. The platelet count then returns to normal over the next 4 weeks. The peak platelet response follows a log-linear dose response. Platelet activation and aggregation are not affected, and patients are not at increased risk of thromboembolic disease, unless the platelet count is allowed to rise to very high levels. These kinetics need to be taken into account when planning therapy in a chemotherapy patient. Drugs Effective in Iron Deficiency and Other Hypochromic Anemias Iron and Iron Salts Iron deficiency is the most common cause of nutritional anemia in human beings. It can result from inadequate iron intake, malabsorption, blood loss, or an increased requirement, as with pregnancy. When severe, it results in a characteristic microcytic, hypochromic anemia. However, the impact of iron deficiency is not limited to the erythron (Dallman, 1982). Iron also is an essential component of myoglobin; heme enzymes such as the cytochromes, catalase, and peroxidase; and the metalloflavoprotein enzymes, including xanthine oxidase and the mitochondrial enzyme - glycerophosphate oxidase. Iron deficiency can affect metabolism in muscle independently of the effect of anemia on oxygen delivery. This may well reflect a reduction in the activity of iron- dependent mitochondrial enzymes. Iron deficiency also has been associated with behavioral and learning problems in children and with abnormalities in catecholamine metabolism and, possibly, heat production (Pollit and Leibel, 1982; Martinez-Torres et al. , 1984 ). Awareness of the ubiquitous role of iron has stimulated considerable interest in the early and accurate detection of iron deficiency and in its prevention. History Iron has been used in the treatment of illness since the Middle Ages and the Renaissance. However, it was not until the sixteenth century that iron deficiency was recognized as the cause of "green sickness," or chlorosis, in adolescent women. Sydenham subsequently proposed iron as a preferred therapy over bleedings and purgings, and in 1832, the French physician Pierre Blaud recognized the need to use adequate doses of iron to successfully treat chlorosis. Blaud's nephew later distributed the "veritable pills of Blaud" throughout the world. The treatment of anemia with iron followed the principles enunciated by Sydenham and Blaud until the end of the nineteenth century. At that time the teachings of Bunge, Quincke, von Noorden, and others cast doubt on their treatment of chlorosis. The dose of iron employed was reduced, and the resulting lack of efficacy brought discredit on the therapy. It was not until the third and fourth decades of the twentieth century that the lessons taught by the earlier physicians were relearned. The modern understanding of iron metabolism began in 1937 with the work of McCance and Widdowson on iron absorption and excretion and Heilmeyer and Plotner's measurement of iron in plasma. Then in 1947, Laurell described a plasma iron transport protein that he called transferrin. Hahn and coworkers (1943) were the first to use radioactive isotopes to quantitate iron absorption and define the role of the intestinal mucosa to regulate this function. In the next decade, Huff and associates (1950) initiated isotopic studies of internal iron metabolism. The subsequent development of practical clinical measurements of serum iron, transferrin saturation, plasma ferritin, and red cell protoporphyrin permitted the definition and detection of the body's iron store status and iron-deficient erythropoiesis. Iron and the Environment Iron exists in the environment largely as ferric oxide or hydroxide or as polymers. In this state, its biological availability is limited unless it is solubilized by acid or chelating agents. For example, to meet their needs, bacteria and some plants produce high-affinity chelating agents that extract iron from the surrounding environment. Most mammals have little difficulty in acquiring iron; this is explained by an ample iron intake and perhaps also by a greater efficiency in absorbing iron. Human beings, however, appear to be an exception. Although total dietary intake of elemental iron in human beings usually exceeds requirements, the bioavailability of the iron in the diet is limited. [...]... of the recent nature of blood loss, but iron supply is nonetheless limiting erythropoiesis More difficult is the differentiation of true iron deficiency from iron-deficient erythropoiesis due to inflammation In the latter condition, the stores of iron are actually increased, but the release of iron from reticuloendothelial cells is blocked; the concentration of iron in plasma is decreased, and the. .. lb), and 2.0 ml (100 mg of iron) for other patients Iron dextran should be injected only into the muscle mass of the upper outer quadrant of the buttock using a z-track technique (displacement of the skin laterally prior to injection) However, local reactions, including long-continued discomfort at the site of injection and local discoloration of the skin, and the concern about malignant change at the. .. which then acts as a methyl group donor for the conversion of homocysteine to methionine This folate–cobalamin interaction is pivotal for normal synthesis of purines and pyrimidines and, therefore, of DNA The methionine synthetase reaction is largely responsible for the control of the recycling of folate cofactors; the maintenance of intracellular concentrations of folylpolyglutamates; and, through the. .. between the therapeutic action desired and the toxic effects Prophylaxis and mild nutritional iron deficiency may be managed with modest doses When the object is the prevention of iron deficiency in pregnant women, for example, doses of 15 to 30 mg of iron per day are adequate to meet the 3- to 6-mg daily requirement of the last two trimesters When the purpose is to treat iron-deficiency anemia, but the. .. including the severity of anemia, the ability of the patient to tolerate and absorb medicinal iron, and the presence of other complicating illnesses Therapeutic effectiveness can be best measured from the resulting increase in the rate of production of red cells The magnitude of the marrow response to iron therapy is proportional to the severity of the anemia (level of erythropoietin stimulation) and the. .. with the response of an iron-deficiency anemia to iron therapy Intrinsic disease of the marrow can, by decreasing the number of red cell precursors, blunt the response Inflammatory illnesses suppress the rate of red cell production, both by reducing iron absorption and reticuloendothelial release and by direct inhibition of erythropoietin and erythroid precursors Continued blood loss can mask the response... elemental iron) also is available Ferrous fumarate (FEOSTAT, others) contains 33% iron and is moderately soluble in water, stable, and almost tasteless Ferrous gluconate (FERGON, others) also has been successfully used in the therapy of iron-deficiency anemia The gluconate contains 12% iron Polysaccharide–iron complex (NIFEREX, others), a compound of ferrihydrite and carbohydrate, is another preparation with... greater nutritional significance is the bioavailability of iron in food (Hallberg, 1981) Heme iron is far more available, and its absorption is independent of the composition of the diet Heme iron, which constitutes only 6% of dietary iron, represents 30% of iron absorbed Nevertheless, it is the availability of the nonheme fraction that deserves the greatest attention, since it represents by far the largest... B12-dependent methylmalonyl CoA mutase reaction, a step in propionate metabolism, is related to the abnormality However, other evidence suggests that the deficiency of methionine synthetase and the block of the conversion of methionine to S-adenosylmethionine is more likely to be responsible (Scott et al., 1981) Nitrous oxide (dinitrogen monoxide; N2O), used for anesthesia (seeChapter 14: General Anesthetics),... general terms After acidification and partial digestion of food in the stomach, its content of iron is presented to the intestinal mucosa as either inorganic iron or heme iron These fractions are taken up by the absorptive cells of the duodenum and upper small intestine, and the iron is transported either directly into the plasma or stored as mucosal ferritin Absorption appears to be regulated by two . ferritin, and red cell protoporphyrin permitted the definition and detection of the body's iron store status and iron-deficient erythropoiesis. Iron and the Environment Iron exists in the environment. Section XI. Drugs Acting on the Blood and the Blood- Forming Organs Overview The short life span of mature blood cells requires their continuous replacement, a process. pheresis. SCF, IL-1, IL-6, IL-9, and IL-11 need to be studied alone and in combination with each other, as well as with both GM-CSF and G-CSF. The combination of IL-3 followed by GM-CSF also needs