DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

SECTION IV
INFLAMMATION. IMMUNOMODULATION, AND HEMATOPOIESIS
1086 therapeutic trial with copper is appropriate. Daily doses up to
0.1 mg/kg of cupric sulfate have been given by mouth, or 1-2 mg per
day may be added to the solution of nutrients for parenteral administration.
The daily U.S. Recommended Daily Allowance (RDA) of copper
ranges from 1,300 μg for nursing women to 200 μg for infants
0-6 months of age.
Pyridoxine
Harris and associates first described pyridoxine-responsive
anemia in 1956. Subsequent reports suggested that the
vitamin might improve hematopoiesis in up to 50% of
patients with either hereditary or acquired sideroblastic
anemia. These patients characteristically have impaired
hemoglobin synthesis and accumulate iron in the perinuclear
mitochondria of erythroid precursor cells, so-called
ringed sideroblasts. Hereditary sideroblastic anemia is
an X-linked recessive trait with variable penetrance
and expression that results from mutations in the erythrocyte
form of δ-aminolevulinate synthase. Affected
men typically show a dual population of normal red cells
and microcytic, hypochromic cells in the circulation. In
contrast, idiopathic acquired sideroblastic anemia and
the sideroblastic anemias associated with a number of
drugs, inflammatory states, neoplastic disorders, and
preleukemic syndromes show a variable morphological
picture. Moreover, erythrokinetic studies demonstrate a
spectrum of abnormalities, from a hypoproliferative
defect with little tendency to accumulate iron to marked
ineffective erythropoiesis with iron overload of the
tissues (Solomon and Hillman, 1979).
Oral therapy with pyridoxine is of proven benefit in correcting
the sideroblastic anemias associated with the antituberculosis
drugs isoniazid and pyrazinamide, which act as vitamin B 6
antagonists.
A daily dose of 50 mg of pyridoxine completely corrects the
defect without interfering with treatment, and routine supplementation
of pyridoxine often is recommended (see Chapter 56). In contrast,
if pyridoxine is given to counteract the sideroblastic abnormality
associated with administration of levodopa, the effectiveness of levodopa
in controlling Parkinson’s disease is decreased. Pyridoxine
therapy does not correct the sideroblastic abnormalities produced by
chloramphenicol or lead.
Patients with idiopathic acquired sideroblastic anemia generally
fail to respond to oral pyridoxine, and those individuals who
appear to have a pyridoxine-responsive anemia require prolonged
therapy with large doses of the vitamin, 50-500 mg per day.
Unfortunately, the early enthusiasm for treatment with pyridoxine
was not reinforced by results of later studies. Moreover, even when
a patient with sideroblastic anemia responds, the improvement is
only partial because both the ringed sideroblasts and the red-cell
defect persist, and the hematocrit rarely returns to normal.
Nonetheless, in view of the low toxicity of oral pyridoxine, a therapeutic
trial with pyridoxine is appropriate.
As shown in studies of normal subjects, oral pyridoxine in a
dosage of 100 mg three times daily produces a maximal increase in
red-cell pyridoxine kinase and the major pyridoxal phosphate–dependent
enzyme glutamic-aspartic aminotransferase (Solomon and Hillman,
1978). For an adequate therapeutic trial, the drug is administered for at
least 3 months while the response is monitored by measuring the reticulocyte
index and the hemoglobin concentration. The occasional patient
who is refractory to oral pyridoxine may respond to parenteral administration
of pyridoxal phosphate. However, oral pyridoxine in doses of
200-300 mg per day produces intracellular concentrations of pyridoxal
phosphate equal to or greater than those generated by therapy with the
phosphorylated vitamin.
Riboflavin
Pure red-cell aplasia that responded to the administration
of riboflavin was reported in patients with protein
depletion and complicating infections. Lane and associates
induced riboflavin deficiency in humans and
demonstrated that a hypoproliferative anemia resulted
within a month. The spontaneous appearance in
humans of red-cell aplasia due to riboflavin deficiency
undoubtedly is rare, if it occurs at all. It has been
described in combination with infection and protein
deficiency, both of which are capable of producing a
hypoproliferative anemia. However, it seems reasonable
to include riboflavin in the nutritional management
of patients with gross, generalized malnutrition.
B 12
, Folic Acid, and
the Treatment of
Megaloblastic Anemias
Vitamin B 12
and folic acid are dietary essentials (Varela-
Moreiras et al., 2009). A deficiency of either vitamin
impairs DNA synthesis in any cell in which chromosomal
replication and division are taking place. Because tissues
with the greatest rate of cell turnover show the most
dramatic changes, the hematopoietic system is especially
sensitive to deficiencies of these vitamins. An early sign
of deficiency is megaloblastic anemia. Abnormal macrocytic
red blood cells are produced, and the patient
becomes severely anemic. Recognized in the 19th century,
this pattern of abnormal hematopoiesis, termed pernicious
anemia, spurred investigations that ultimately led
to the discovery of vitamin B 12
and folic acid. Even today,
the characteristic abnormality in red blood cell morphology
is important for diagnosis and as a therapeutic guide
following administration of the vitamins.
History. The discovery of vitamin B 12
and folic acid is a dramatic
story that started >180 years ago and includes two discoveries that
won the Nobel Prize. The first descriptions of what must have been
megaloblastic anemias came from the work of Combe and Addison,
who published a series of case reports beginning in 1824. It still is