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بسم الله الرحمن الرحيم
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YazdanpanahSBMU
1. Agents Used in Anemias
2. Hematopoietic Growth Factors
Dr. Yazdanpanah
Pharmacology/Toxicology Dept.
Shaheed Beheshti School of Pharmacy
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YazdanpanahSBMU
Outline• Introduction
1. Agents used in Anemia• Iron• Folic acid• Vitamin B12
2. Hematopoietic Growth Factors• Erythropoietin• Myeloid Growth factors• Megakaryocyte Growth factors
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YazdanpanahSBMU
Introduction
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Hematopoiesis– Production from undifferentiated stem cells of circulating
erythrocytes, platelets and leukocytes
– Requires 3 essential nutrients and hematopoietic growth factors
– Blood cells play roles in• Oxygenation of tissues
• Coagulation
• Protection against infections
• Tissue repair
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YazdanpanahSBMU
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YazdanpanahSBMU
Deficiency of functional blood cells
• Anemia
• Thrombocytopenia
• Neutropenia
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YazdanpanahSBMU
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YazdanpanahSBMU
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The pale hand of a woman with severe anemia (right) in comparison to the normal hand of her
husband (left).
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YazdanpanahSBMU
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YazdanpanahSBMU
1. Agents Used in Anemias
1.1 Iron
1.2 Vitamin B12
1.3 Folic acid
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YazdanpanahSBMU 2. Hematopoietic Growth
Factors
2.1 Erythropoietin
2.2 Myeloid growth factors
2.3 Megakaryocyte growth factors
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YazdanpanahSBMU
1. Agents Used in Anemias
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YazdanpanahSBMU
IRON
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YazdanpanahSBMU 1.1 IRON: Basic Pharmacology
• Iron forms the nucleus of the iron-porphyrin heme ring
• Iron deficiency
– The most common cause of chronic anemia– Leads to pallor, fatigue, exertional dyspnea, etc.– Cardiovascular adaptations to chronic anemia
– Formation of small erythrocytes with insufficient hemoglobin: microcytic hypochromic
anemia 19
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The protein's α and β subunits are in red and blue, and the iron-containing heme groups in green.
Structure of human hemoglobin
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YazdanpanahSBMU 1.1 IRON : Pharmacokinetics
• Free inorganic iron: extremely toxic
• An elaborate system for regulating iron absorption, transport and storage
• Iron reclaimed from catalysis of hemoglobin
• Only a small amount of iron lost from the body
• Iron deficiency can develop if …
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YazdanpanahSBMU 1.1 IRON : Pharmacokinetics:
Absorption
• Average diet: 10-15 mg elemental iron daily
• Absorption of 5-10% of iron
• Absorption in duodenum and proximal jejunum
• Increase in iron absorption in response to:• Low iron stores• Increased iron requirements
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YazdanpanahSBMU 1.1 IRON : Pharmacokinetics:
Absorption and Transport
• Iron in foods– Meat– Vegetables and grains
• Iron crosses the luminal membrane of the
intestinal mucosal cell by 2 mechanisms
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Figure 33-1. Absorption, transport, and storage of iron 25
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YazdanpanahSBMU 1.1 IRON : Pharmacokinetics:
Storage
• Storage in:
– Intestinal mucosal cells– Macrophages in liver, spleen, bone– In parenchymal liver cells
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YazdanpanahSBMU 1.1 IRON : Pharmacokinetics:
Elimination
• No mechanism for excretion
• Losses account for no more than 1 mg of iron per day
• Regulation of iron balance
• achieved by changing intestinal absorption and storage of iron, in response to the body's needs
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YazdanpanahSBMU
1.1 IRON : Clinical Pharmacology
1. Indications
• Treatment or prevention of iron deficiency anemia
• Iron deficiency– Increased iron requirements– Inadequate iron absorption– Blood loss
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YazdanpanahSBMU
1.1 IRON : Clinical Pharmacology
2. Treatment with Oral iron therapy
Drugs as ferrous salts
200 – 400 mg of elemental iron
For 3-6 months after cause correction
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YazdanpanahSBMU
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YazdanpanahSBMU 1.1 IRON : Clinical Pharmacology 2. Adverse effects with Oral iron therapy
• Nausea, epigastric discomfort, abdominal cramps,
constipation, and diarrhea
• Usually dose-related, can often be overcome by lowering the daily dose of iron or by taking the tablets immediately after or with meals
• Some patients have less severe gastrointestinal adverse effects with one iron salt than another
• Patients taking oral iron develop black stools31
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YazdanpanahSBMU
1.1 IRON : Clinical Pharmacology 3. Treatment with parenteral iron therapy
– Reserved for patients with documented iron deficiency who:
• unable to tolerate or absorb oral iron • for patients with extensive chronic blood loss who cannot be
maintained with oral iron alone:
– patients with various postgastrectomy conditions and previous
small bowel resection
– inflammatory bowel disease
– advanced chronic renal disease
– malabsorption syndromes32
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YazdanpanahSBMU
3. Treatment with parenteral iron therapy
– Iron dextran (IV, deep IM)• Hmw and Lmw forms
• Advantages of IV administration• Adverse effects
– Hypersensitivity reaction to the dextran: anaphylaxis» A small test dose
– Iron-sucrose (IV) – sodium ferric gluconate complex (IV)
• Advantages to HMW??
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1.1 IRON : Clinical Pharmacology
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YazdanpanahSBMU 1.1 IRON : Clinical Toxicity
1. Acute toxicity– Almost exclusively in young children (10 Tabs =
Death)– Treatment:
• Whole bowel irrigation• Deferoxamine
2. Chronic toxicity (hemochromatosis)– Deposition of excess iron in heart, liver, etc.– Leads to organ failure and death– Treatment: intermittent phlebotomy,
deferoxamine, deferasirox34
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YazdanpanahSBMU
Vitamin B12
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YazdanpanahSBMU
A cofactor for several essential biochemical reactions
Deficiency: Anemia, GI symptoms and neurologic abnormalities
Cause of deficiency: Inadequate supply in the diet: unusual Inadequate absorption of dietary vitamin:
relatively common and easily treated
1.2. Vitamin B12
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YazdanpanahSBMU
A porphyrin-like ring with a central cobalt atom attached to a nucleotide
1.2. Vitamin B12: Chemistry
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YazdanpanahSBMU
Extrinsic and intrinsic factors
Active forms of vitamin in humans Deoxyadenosylcobalamin, methylcobalamin
Cyanocobalamin, Hydroxocobalamin: convert to active forms
Chief dietary source: Meats, eggs, dietary products
1.2. Vitamin B12: Chemistry
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YazdanpanahSBMU
Average diet: 5 – 30 mcg daily
1-5 mcg: usually absorbed
Store primarily in liver (3000 - 5000 mcg)
Normal daily requirement: 2 mcg
Absorbed in the distal ileum after complex with IF By highly-specific receptor-mediated transport system
1.2. Vitamin B12: Pharmacokinetics
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YazdanpanahSBMU
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YazdanpanahSBMU
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YazdanpanahSBMU
Deficiency:
Malabsorption of vitamin due to
1. Lack of IF
2. Loss or malfunction of the specific absorptive mechanism
Nutritional deficiency: strict vegetarians
Transport to cells bound to transcobalamin I, II, III
Excess: transport to liver for storage
1.2. Vitamin B12: Pharmacokinetics
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YazdanpanahSBMU1.2. Vitamin B12: Pharmacodynamics
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YazdanpanahSBMU
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YazdanpanahSBMU1.2. Vitamin B12: Pharmacodynamics
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YazdanpanahSBMU
The most common causes of deficiency:
Pernicious anemia
Gastrectomy
Conditions affecting distal ileum
malabsorption syndrome inflammatory bowel disease or small bowel resection
1.2. Vitamin B12: Clinical Pharmacology
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YazdanpanahSBMU
Clinical manifestation of Vitamin deficiency:
Neurologic syndrome Megaloblastic Macrocytic anemia
Leukopenia, Thrombocytopenia, Hypercelluar bone marrow with an accumulation of
megaloblastic erythroid cells
Megaloblastic anemia: Vitamin B12 or Folic acid deficiency
1.2. Vitamin B12: Clinical Pharmacology
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YazdanpanahSBMU
Almost all cases of deficiency: Malabsorption of the vitamin
Treatment: Parenteral injection of vitamin
Most patients: require life-long treatment Hydroxocobalamin, Cyanocobalamin 100 -1000 mcg IM for 1-2 weeks (100-100 mcg IM once a
month for life)
Oral doses of 1000 mcg of vitamin in pernicious anemia
1.2. Vitamin B12: Clinical Pharmacology
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YazdanpanahSBMU
Folic Acid
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YazdanpanahSBMU
Reduced forms of folic acid required for essential biochemical reactions that provide precursors for the synthesis of amino acids, purines, and DNA
Folate deficiency: not uncommon
The deficiency easily corrected by administration of folic acid
The folate deficiency: Anemia Implicated as a cause of congenital malformations in newborns May play a role in vascular disease
1.3. Folic Acid
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• The average diet in the USA: 500-700 µg daily
• Pregnant women absorb as much as 300-400 µg of folic acid daily
• Various forms of folic acid present in a wide variety of plant and animal tissues– The richest sources: yeast, liver, kidney, and green
vegetables
• Normally, 5-20 mg of folates stored in the liver and other tissues
1.3. Folic Acid: Pharmacokinetics
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• Excreted in the urine and stool
• Destroyed by catabolism
• Serum levels fall within a few days when intake diminished
• Body stores relatively low and daily requirements high
• Folic acid deficiency and megaloblastic anemia:• within 1-6 months after stopping the intake of folic acid
1.3. Folic Acid: Pharmacokinetics
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• Unaltered folic acid readily and completely absorbed in the proximal jejunum
• Dietary folates consist primarily of polyglutamate
forms of N5-methyltetrahydrofolate
• Before absorption, all but one of the glutamyl residues of the polyglutamates hydrolyzed
– by the enzyme α-1-glutamyl transferase ("conjugase")
within the brush border of the intestinal mucosa
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llustration of the brush border membrane of small intestinal villi
Duodenum with brush border
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• The monoglutamate N5-methyltetrahydrofolate transported into the bloodstream by
– both active and passive transport – widely distributed throughout the body
• Inside cells, N5-methyltetrahydrofolate converted to tetrahydrofolate by the demethylation reaction that requires vitamin B12
1.3. Folic Acid: Pharmacokinetics
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• Megaloblastic anemia from folate deficiency:
• microscopically indistinguishable from the anemia caused by vitamin B12 deficiency
• Folate deficiency does not cause the characteristic neurologic syndrome seen in vitamin B12 deficiency
• Folate status
• assays for serum folate • assays for red blood cell folate
1.3. Folic Acid: Clinical Pharmacology
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• Folic acid deficiency • often caused by inadequate dietary intake of folates
• Development of folic acid deficiency:– Alcohol dependence and liver disease– Pregnant women and hemolytic anemia– Malabsorption syndromes– Renal dialysis– Drugs ??
• Maternal folate deficiency • Occurrence of fetal neural tube defects (spina bifida)
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• Parenteral administration rarely necessary
• Oral folic acid well absorbed even in patients with malabsorption syndromes
• A dose of 1 mg folic acid orally daily sufficient to:
– reverse megaloblastic anemia– restore normal serum folate levels– replenish body stores of folates
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• Therapy should be continued until the underlying cause of the deficiency removed or corrected
• Therapy may be required indefinitely for patients with malabsorption or dietary inadequacy
• Folic acid supplementation to prevent folic acid deficiency should be considered in high-risk patients including:
– pregnant women– hemolytic anemia– liver disease– patients on renal dialysis
1.3. Folic Acid: Clinical Pharmacology
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Folic Acid Supplementation
• From 1998, all products made from enriched grains in the USA were required to be supplemented with folic acid
• Epidemiologic studies show a strong correlation between maternal folic acid deficiency and the incidence of NTDs such as anencephaly
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Folic Acid Supplementation • Supplemented grains with folic acid
• associated with a significant (30–75%) reduction in NTD rates
• The reduction in NTDs is dose-dependent
• Supplementation of grains in the USA with higher levels of folic acid could result in an even greater reduction in the rate of NTDs
• Rates of other types of congenital anomalies (heart and orofacial) have fallen after supplementation
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2. Hematopoietic Growth Factors
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2. Hematopoietic Growth Factors
• Glycoprotein hormones that regulate the proliferation and differentiation of hematopoietic progenitor cells in the bone marrow
• The first growth factors to be identified were called colony-stimulating factors
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2. Hematopoietic Growth Factors
2.1 Erythropoietin
2.2 Myeloid growth factors
2.3 Megakaryocyte growth factors
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Erythropoietin
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• A 34-39 kDa glycoprotein • Recombinant human erythropoietin (rHuEPO,
epoetin alfa)
• IV administration: serum half-life of 4-13 hours in patients with chronic renal failure
• Darbepoetin alfa:• A twofold to threefold longer half-life
• Methoxy polyethylene glycol epoetin ??
2.1. Erythropoietin: Chemistry and pharmacokinetics
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• Stimulates erythroid proliferation and differentiation by interacting with specific erythropoietin receptors on red cell progenitors
• Induces release of reticulocytes from the bone marrow
• Endogenous erythropoietin primarily produced in the kidney– In response to tissue hypoxia, more erythropoietin produced results
in correction of the anemia
2.1. Erythropoietin: Pharmacodynamics
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• Normally, an inverse relationship exists between the hematocrit or hemoglobin level and the serum erythropoietin level
• Exception: anemia of chronic renal failure
Erythropoietin levels usually lowMost likely to respond to treatment with exogenous
erythropoietin
• In most primary bone marrow disorders and most nutritional and secondary anemias• Endogenous erythropoietin levels are high
2.1. Erythropoietin: Pharmacodynamics
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• Consistently improve the hematocrit and hemoglobin level • Usually eliminate the need for transfusions• Reliably improve quality of life indices
1. For patients with anemia of chronic renal failure
– Oral or parenteral iron
– Folate supplementation
2.1. Erythropoiesis-stimulating agents: Clinical Pharmacology
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2. Useful for the treatment of anemia due to
Primary bone marrow disorders and secondary anemias including patients with:
• aplastic anemia and other bone marrow failure states
• myeloproliferative and myelodysplastic disorders
• multiple myeloma
• the anemias associated with chronic inflammation, AIDS, and myelosuppresive cancer chemotherapy
2.1. Erythropoietin: Clinical Pharmacology
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3. Other uses • used successfully to offset the anemia produced by
zidovudine treatment in patients with HIV infection and in the treatment of the anemia of prematurity
• can also be used to reduce the need for transfusion in high-risk patients undergoing elective, noncardiac,
nonvascular surgery; to accelerate erythropoiesis after phlebotomies for autologous transfusion for elective
surgery; or for treatment of iron overload
2.1. Erythropoietin: Clinical Pharmacology
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The most common adverse effects– hypertension and thrombotic complications
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Myeloid growth factors
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• Recombinant human G-CSF (rHuG-CSF; filgrastim)
• Recombinant human GM-CSF (rHuGM-CSF; sargramostim)
• Pegfilgrastim: – much longer serum half-life than recombinant G-CSF
2.2. Myeloid growth factors: Chemistry and pharmacokinetics
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• Stimulate proliferation and differentiation by interacting with specific receptors found on various myeloid progenitor cells
G-CSF– Stimulates proliferation and differentiation of progenitors
already committed to the neutrophil lineage
– Activates the phagocytic activity of mature neutrophils and prolongs their survival in the circulation
– A remarkable ability to mobilize hematopoietic stem cells (increase their concentration in peripheral blood)
• Use of peripheral blood stem cells rather than bone marrow stem cells for autologous and allogeneic hematopoietic stem cell transplantation
2.2. Myeloid growth factors: Pharmacodynamics
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GM-CSF
– broader biologic actions than G-CSF
– stimulates proliferation and differentiation of granulocytic progenitor cells, erythroid progenitors and megakaryocyte progenitors
– stimulates the function of mature neutrophils
– acts together with interleukin-2 to stimulate T-cell proliferation
– locally active factor at the site of inflammation
– mobilizes peripheral blood stem cells (significantly less efficacious than G-CSF) 79
2.2. Myeloid growth factors: Pharmacodynamics
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• G-CSF and pegfilgrastim
• used more frequently (better tolerated)• cause bone pain
• GM-CSF
• cause more severe side effects, particularly at higher doses
– fever, malaise, arthralgias, myalgias, etc.
2.2. Myeloid growth factors: Toxicity
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Megakaryocyte growth factors
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• Interleukin-11 (IL-11) • A 65-85 kDa protein• The half-life: 7-8 hours: sc injection
• Oprelvekin• recombinant form of interleukin-11
• Peptide agonists of thrombopoietin receptor– Romiplostim: sc route
– Eltrombopag: oral route
2.3. Megakaryocyte growth factors: Chemistry and pharmacokinetics
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2.3. Megakaryocyte growth factors: Pharmacodynamics
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IL-11
• Acts through a specific cell surface cytokine receptor to stimulate the growth of multiple lymphoid and myeloid cells
• Acts synergistically with other growth factors
• to stimulate the growth of primitive megakaryocytic progenitors• increases the number of peripheral platelets and neutrophils
Romiplostim
• high affinity for the thrombopoietin receptor
• a dose-dependent increase in platelet count
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• The most common adverse effects of interleukin-11
– Fatigue, headache, dizziness, and cardiovascular effects
• The cardiovascular effects: anemia, dyspnea transient atrial arrhythmias
• Hypokalemia
• All of these adverse effects appear to be reversible
2.3. Megakaryocyte growth factors: Toxicity
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