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Biomedical subjects

C D Fitch

Publications and source records attributed to C D Fitch.

At least 37 records · Page 2Linked to original sources
PubMed1984

Lack of effect of vitamin E therapy on the anemia of patients receiving hemodialysis.

We conducted a prospective, randomized, double-blind therapeutic trial of vitamin E as an erythropoietic agent in a group of patients with chronic renal failure who were undergoing chronic hemodialysis. Sixteen patients received 400 IU of vitamin E (d-alpha-tocopheryl acetate) by mouth twice daily and 19 patients received a placebo twice daily for 20 wk. The serum vitamin E concentration increased from 1.3 to 2.6 mg/dl in the treated group and decreased from 1.3 to 1.1 in the placebo group. For the treated group the initial hematocrit was 24.8 +/- 3.0 (mean +/- SD) and the final hematocrit was 25.8 +/- 3.8. For the placebo group the initial hematocrit was 24.9 +/- 3.0 and the final hematocrit was 23.5 +/- 2.7. The treated group received a total of 40 blood transfusions, and the placebo group received a total of 35 blood transfusions. Thus, vitamin E had no effect on the anemia or transfusion requirements of patients undergoing chronic hemodialysis for chronic renal failure.

Anemia↗
PubMed1984

Serum concentrations of alpha-tocopherol after ingestion of various vitamin E preparations.

The rat-fetal-resorption test currently is used to assess the biological activity of vitamin E compounds. Previous studies in humans, however, suggest that rat assays underestimate the potency of free tocopherol relative to the acetate ester form and of RRR-alpha-tocopheryl acetate relative to all-rac-alpha-tocopheryl acetate. Therefore, we studied the serum concentrations of alpha-tocopherol after ingestion of RRR-alpha-tocopheryl acetate, all-rac-alpha-tocopheryl acetate, RRR-alpha-tocopherol, RRR-alpha-tocopheryl succinate, and RRR-alpha-tocopheryl acetate plus apple pectin by each of 20 adult human subjects. Measurements were made at 0, 8, 24, and 48 h after ingestion of 800 IU of the various preparations. The results at 24 h were representative of the differences observed. The mean increase in concentration of alpha-tocopherols (mg/g lipid) in 24 h was 71.2% after RRR-alpha-tocopherol, 63.3% after RRR-alpha-tocopherol acetate, and 41.2% after RRR-alpha-tocopherol succinate. Animal assay data do not correlate with data from studies of absorption and retention in serum of alpha-tocopherols ingested by humans.

Adult↗
PubMed1984

Iron is sequestered as ferritin in macrophages in skeletal muscle of vitamin E-deficient rabbits.

Weanling rabbits were fed a purified diet with or without vitamin E supplementation to evaluate the abnormal sequestration of iron in skeletal muscle associated with vitamin E deficiency. A severe myopathy developed in unsupplemented rabbits within 3 to 4 weeks. At this time, the concentration of soluble nonheme iron in biceps femoris muscles had increased from 2.1 +/- 0.4 microgram/g wet weight (mean +/- SD) for six control rabbits to 4.3 +/- 1.4 for 10 vitamin E-deficient rabbits, and total nonheme iron had increased from 5.0 +/- 1.2 to 8.4 +/- 3.3. Soleus muscles had even greater increases in total and soluble nonheme iron concentrations. Intramuscular injection of iron-dextran caused large increases in total and soluble nonheme iron in noninjected muscle of vitamin E-deficient rabbits, which further exaggerated the difference between the two groups. By radioimmunoassay using an antibody to rabbit liver ferritin, the concentration of ferritin in biceps femoris muscles increased from 0.47 +/- 0.18 microgram/g wet weight for seven control rabbits to 6.34 +/- 1.70 for 14 vitamin E-deficient rabbits. Uptake of intravenously injected transferrin-bound iron into muscle of vitamin E-deficient rabbits was not increased in a short term experiment (6 h), but radioiron did accumulate in muscle in a long term experiment (6 days). There was no trapping of heat-damaged erythrocytes, no phagocytosis of intravenously injected carbon particles, and no erythrophagocytosis in muscle. An immunohistological staining method designed to detect ferritin in tissue sections stained muscle from normal rabbits very scantily but intensely stained macrophages in the muscle of vitamin E-deficient rabbits.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1984

Ferriprotoporphyrin IX: a mediator of the antimalarial action of oxidants and 4-aminoquinoline drugs.

Ferriprotoporphyrin IX (FP) is released from hemoglobin by oxidative denaturation or by proteolytic degradation. FP added exogenously to cells or released intracellularly is a lytic toxin. Chloroquine enhances the accumulation of exogenous FP in cellular membranes and potentiates its lytic effect. Menadione is an example of an oxidant drug that denatures hemoglobin, releases FP intracellularly, and thereby lyses cells. Chloroquine increases the accumulation of FP in the membranes of menadione-treated erythrocytes and enhances the hemolysis induced by menadione. Intraerythrocytic malaria parasites release FP from hemoglobin by proteolytic degradation, but they ordinarily survive the exposure either because FP interacts with a soluble intracellular substance, which renders it nontoxic, or because FP is sequestered in an innocuous, insoluble form in malaria pigment. Chloroquine binds tightly to FP, diverts it away from the soluble detoxifying substance in malaria parasites, and delays its sequestration into malarial pigment. Malaria parasites exposed to chloroquine while degrading hemoglobin accumulate a chloroquine-FP complex, which is sufficiently toxic to kill them. FP has a detergent-like effect on biological membranes which may account for its lytic toxicity.

Aminoquinolines↗
PubMed1983

Fasting modulates creatine entry into skeletal muscle in the mouse.

[14C]-Creatine entry into skeletal muscle of mice is inhibited by feeding creatine or by fasting. Plasma creatine specific activity after an i.p. injection of [14C]-creatine is decreased by feeding creatine and increased by fasting. These results indicate that creatine enters muscle via a saturable process that is modulated by fasting.

Animals↗
PubMed1983

Mode of action of antimalarial drugs.

Chloroquine, quinine, quinacrine and related drugs are effective antimalarial agents only against parasites that degrade haemoglobin. This fact prompted an examination of the role of ferriprotoporphyrin IX (FP), a product of haemoglobin degradation, in the mode of action of chloroquine. FP was identified as a high affinity drug receptor of malaria parasites by showing that it has the appropriate affinity for chloroquine, with a dissociation constant on the order of 10(-8) M, and specificity for amodiaquine, quinacrine, quinine and mefloquine. Moreover, FP and its complex with chloroquine impair the ability of cell membranes to maintain cation gradients, and they lyse normal erythrocytes, Plasmodium berghei and P. falciparum. The amount of FP required for lysis is less than 0.1% of the haem in erythrocytic haemoglobin. Recently, evidence has been obtained that FP in the parasite forms transient, non-toxic complexes with cytoplasmic haem binders and that FP in this form can interact with chloroquine. Thus, chloroquine and related drugs may act as antimalarial agents by shunting FP away from natural haem binders and into toxic drug-FP complexes. In addition FP released from haemoglobin, either spontaneously or by oxidant drugs, may contribute to haemolysis and protection against malaria in patients with Heinz body haemolytic anaemias.

Anemia, Hemolytic↗
PubMed1983

Diverse membrane-active agents modify the hemolytic response to ferriprotoporphyrin IX.

Because ferriprotoporphyrin IX (ferriheme, FP) is a lytic agent that can be released by degradation or oxidative denaturation of hemoglobin, we measured the hemolytic responses of human erythrocytes to FP alone or to FP in combination with various membrane-active agents. Suspensions of erythrocytes (0.5%) incubated at pH 7.4 and 37 degrees C were hemolyzed by FP alone in concentrations of 10 microM or greater. Preincubation of the erythrocytes with nonhemolytic concentrations of chloroquine, mefloquine, quinine, calcium, lanthanum or manganese potentiated the hemolytic response to FP. For example, hemolysis in the presence of 5 microM FP was 5%; in the presence of 5 microM FP and 20 microM chloroquine, hemolysis exceeded 80%. For 5 microM FP, maximal potentiation was obtained with 20 microM chloroquine, 200 microM quinine or 1 mM calcium. Paradoxically, with 5 microM FP and a high concentration of chloroquine (1 mM), hemolysis did not exceed the base-line value of 5%. In addition, all of the agents that individually potentiated the hemolytic response to 5 microM FP also inhibited hemolysis when used in combination with 5 microM chloroquine and 5 microM FP. Detailed studies of calcium showed that it inhibited the increase in osmotic fragility, which was induced by FP and chloroquine, without inhibiting the increase in binding of [14C]chloroquine to erythrocytes treated with FP. These results can be rationalized by proposing that the structure of the erythrocyte membrane at the time of exposure to FP and membrane-active agents determines whether the hemolytic response will be potentiated or inhibited.

Adult↗
PubMed1983

Intracellular ferriprotoporphyrin IX is a lytic agent.

Human erythrocytes were treated with menadione to oxidatively denature hemoglobin and release ferriprotoporphyrin IX (ferriheme, FP) intracellularly. The high affinity of FP for chloroquine was used to detect its release. After incubation for 1 hr at 37 degrees C and pH 7.4 with 0.5 mM menadione, erythrocytes bound 14C-chloroquine with an apparent dissociation constant of 10(-6)M. Untreated erythrocytes did not bind chloroquine with high affinity. At a chloroquine concentration in the medium of 2 microM, for example, menadione-treated erythrocytes bound 70 mumole chloroquine/kg and untreated erythrocytes bound 13.4 mumole/kg. The intracellular location of FP released by menadione was verified by finding that Tween 80 did not prevent chloroquine binding. By contrast, Tween 80 inhibited the binding of chloroquine to erythrocytes treated with extracellular FP. The hemolytic response to menadione was characteristic of the hemolytic response to FP. Thus, 5 microM chloroquine caused hemolysis to increase to 60% from baseline values of 5% in experiments using erythrocytes treated either with 0.5 mM menadione or with 5 microM FP; and, in both cases, the potentiating effect of chloroquine was inhibited by 1 microM mefloquine or 10 microM quinine. Higher concentrations of menadione caused hemolysis in the absence of chloroquine. We conclude that FP released by menadione exists intracellularly in a form that is accessible to bind chloroquine and to express its lytic activity.

Anemia, Hemolytic↗
PubMed1982

Ferriprotoporphyrin IX binding substances and the mode of action of chloroquine against malaria.

Bovine serum albumin and preparations of cell sap from malaria parasites and normal erythrocytes were tested for ability to protect cellular membranes against the toxicity of ferriprotoporphyrin IX (FP) and a chloroquine-FP complex. Suspensions of Plasmodium berghei (approximately 7 X 10(6) parasites per ml, isolated from saponin-lysed, infected erythrocytes) were used as a test system. Toxicity was monitored by measuring changes in turbidity of these suspensions at 700 nm. Parasite cell sap (0.56 mg protein per ml) and albumin (1 mg per ml) completely prevented the toxicity of 40 micrometers FP. Erythrocyte cell sap (8.6 mg of hemoglobin per ml). Provided only partial protection from 40 micrometers FP. Neither the cell sap preparations nor albumin eliminated the toxicity of a chloroquine-FP complex formed from 20 micrometers chloroquine and 40 micrometers FP. These observations suggest that the cell sap preparations contain FP binding substances and that the mode of action of chloroquine may be to shunt FP away from a nontoxic complex with these substances and into a toxic chloroquine-FP complex.

Animals↗
PubMed1982

The antimalarial drug mefloquine binds to membrane phospholipids.

The new antimalarial drug mefloquine bound with high affinity (Kd approximately 3 X 10-7 M) to membrane lipids of normal mouse erythrocytes and of erythrocytes infected either with chloroquine-susceptible or chloroquine-resistant Plasmodium berghei. Approximately 80 nmol of mefloquine was bound per mg of total lipid. Mefloquine also bound to purified phospholipids with high affinity (Kd approximately 3 X 10-7 M). Phosphatidylinositol and phosphatidylserine bound 300 to 400 nmol of mefloquine per mg. Phosphatidylcholine and phosphatidylethanolamine bound approximately 100 nmol of mefloquine per mg. Mefloquine did not bind to hemoglobin with high affinity, but it bound to free ferriprotoporphyrin IX with a Kd of approximately 3 X 10-7 M. In comparison with mefloquine, chloroquine did not bind effectively to purified phospholipids, although it is known to bind with high affinity to free ferriprotoporphyrin IX. Greater binding to phospholipids may account for the superiority of mefloquine in the treatment of chloroquine-resistant malaria.

Animals↗
PubMed1982

Lysis of Plasmodium falciparum by ferriprotoporphyrin IX and a chloroquine-ferriprotoporphyrin IX complex.

Ferriprotoporphyrin IX (FP) and a chloroquine-FP complex lysed isolated Plasmodium falciparum parasites as judged by decreases in the turbidity of parasite suspensions and by ultrastructural changes. Exposure of parasite suspensions to 50 microM FP or to a complex formed from 50 microM FP and 20 MicroM chloroquine reduced the number of identifiable parasites and caused swelling and loss of internal detail in those that were identifiable. The amount of lysis was dose-dependent over the range of 10 to 50 microM FP. Formation of a chloroquine-FP complex reduced, but did not eliminate, the toxicity of FP. Since there is evidence indicating that a chloroquine-FP complex forms when chloroquine-susceptible parasites are exposed to chloroquine, we suggest that accumulation of this complex may account for the chemotherapeutic effect of chloroquine against P. falciparum.

Chloroquine↗
PubMed1981

Hemin lyses malaria parasites.

Malaria parasites isolated from mouse erythrocytes are lysed by ferriprotoporphyrin IX chloride (hemin) or by a chloroquine-hemin complex in amounts that could be produced by release of less than 0.1 percent of the heme in erythrocytic hemoglobin. This effect of hemin may explain the protection against malaria provided by thalassemia and other conditions causing intracellular denaturation of hemoglobin. The toxicity of the chloroquine-hemin complex may explain the selective antimalarial action of chloroquine.

Animals↗
PubMed1981

Biochemical and ultrastructural changes in skeletal muscle induced by a creatine antagonist.

To evaluate the essentiality of creatine and phosphocreatine for the maintenance of the ultrastructure of skeletal muscle, chicks were fed a creatine antagonist, beta-guanidinobutyric acid (beta-GBA), as 2% of a Chow diet. Chicks fed beta-GBA exhibited growth retardation and weakness, and they accumulated large amounts of a monosubstituted guanidino compound, presumably beta-GBA, in their skeletal muscles. After 2 wk, there was a 74% decrease in the uptake of [14C]-1-creatine into pectoralis muscles of chicks fed beta-GBA. After 2 wk there as a significant decrease in phosphocreatine concentrations in pectoralis muscles from 20.1 +/- 2.8 mumoles per g wet weight (mean +/- S.D.) for 8 control chicks to 16.5 +/- 2.5 for 7 chicks fed beta-GBA. Selected fibers of the pectoralis and gastrocnemius muscles of chicks fed beta-GBA exhibited ultrastructural abnormalities including loss of thick and thin filaments, disruption of the Z band, dilated mitochondria, and dilated and displaced sarcoplasmic reticulum. The pectoralis muscles of chicks given 6% creatine in addition to 2% beta-GBA in the diet accumulated little beta-GBA, maintained normal phosphocreatine concentrations, and exhibited no significant ultrastructural abnormalities. These findings are the first experimental evidence that high concentrations of phosphocreatine are essential for the maintenance of the ultrastructural integrity of skeletal muscle.

Animals↗
PubMed1981

Progressive neuropathologic lesions in vitamin E-deficient rhesus monkeys.

A consistent group of progressive central and peripheral nervous system lesions developed in seven rhesus monkeys maintained on a vitamin E-deficient diet for 30 to 33 months. These lesions were absent from vitamin E-supplemented monkeys. The principal neuropathologic alteration was loss of sensory axons in the posterior columns, sensory roots, and peripheral nerves. Morphologic and morphometric studies indicated that the distal segments of the axons were affected most severely and large-caliber myelinated fibers are selectively involved. Swollen, dystrophic axons (spheroids) occurred infrequently. Degeneration and phagocytosis of small numbers of neuronal perikarya were observed in the dorsal root ganglia and the anterior horns. The number of affected neurons was not proportional to the number of affected axons. Accumulation of lipopigment was evident in neuronal perikarya and CNS endothelial cells. The nervous system lesion were usually accompanied by a chronic necrotizing myopathy. The neuropathologic lesions in vitamin E-deficient monkeys are compared with those in vitamin E-deficient rats and in humans with low serum vitamin E concentrations. A similar type of sensory axonopathy is associated with chronic deficiency of vitamin E in these three species.

Animals↗
PubMed1981

Sequestration of the chloroquine receptor in cell-free preparations of erythrocytes infected with Plasmodium berghei.

When mouse erythrocytes infected with Plasmodium berghei were preincubated with [14C]chloroquine and then lysed by hypotonic shock, chloroquine remained bound to the resulting cell-free preparation. In an isotonic medium at pH 7.4 and 25 degrees C, chloroquine was bound to the cell-free preparation with an apparent dissociation constant of 1.8 x 10(-7) M. The bound [14C]chloroquine could be displaced by nonradioactive chloroquine, amodiaquine, quinacrine, and mefloquine, as would be predicted from knowledge of the specificity of ferriprotoporphyrin IX for antimalarial drugs. Also, as predicted, primaquine did not displace the [14C]chloroquine. The ability of these cell-free preparations to bind chloroquine with high affinity decreased rapidly with incubation at 37 degrees C and became undetectable within 1 h; at 4 degrees C the decrease occurred more slowly. This behavior of the endogenous receptor-chloroquine complex was duplicated by an exogenous ferriprotoporphyrin IX-chloroquine complex loaded into cell-free preparations of erythrocytes infected with P. berghei. These findings support the hypothesis that ferriprotoporphyrin IX is the endogenous chloroquine receptor of P. berghei and indicate that it can be sequestered rapidly in a form that is inaccessible to chloroquine.

Animals↗
PubMed1981

Mechanism of hemolysis induced by ferriprotoporphyrin IX.

Incubation of a 0.5% suspension of washed, normal mouse erythrocytes with ferriprotoporphyrin IX (FP) at 37 degrees C and pH 7.4 caused potassium loss, swelling, increased susceptibility to hypotonic lysis, and finally hemolysis. Hemolysis was not inhibited by incubation in the dark, malonyldialdehyde was not produced, and various free radical scavengers had no effect on the hemolysis. Only the sulfhydryl compounds, cysteine, dithiothreitol, and mercaptoethanol protected erythrocytes from FP. Potassium loss reached 90% within 30 min of exposure to 5 microM FP. This amount of FP caused greater than 50% hemolysis within 2.5 h. Sucrose (0.1 M) completely prevented hemolysis but had no effect on potassium loss. Likewise, reducing the temperature from 37 to 25 degrees C greatly retarded hemolysis but had no effect on potassium loss. These observations indicate that FP impairs the erythrocyte's ability to maintain cation gradients and induces hemolysis by a colloid-osmotic mechanism.

Animals↗
PubMed1980

Contractile characteristics of skeletal muscles depleted of phosphocreatine.

The contractile characteristics of skeletal muscle were evaluated after phosphocreatine depletion was accomplished by feeding weanling female rats a ground Chow diet containing 1% of beta-guanidino-propionic acid for 10 weeks. Except for a slight decrease in initial strength and a 30% decrease in wet weight, phosphocreatine depleted plantaris muscles exhibited no abnormalities. By contrast, phosphocreatine depleted soleus muscles exhibited several significant abnormalities. In an isometric twitch, the rise time was prolonged from 57 +/- 6 ms (mean +/- S.D.) for 6 control rats to 87 +/- 6 for 6 phosphocreatine depleted rats, the amplitude was decreased from 264 +/- 11 g per g wet weight of muscle to 163 +/- 9, and the half-relaxation time was prolonged from 61 +/- 6 ms to 85 +/- 8. In addition the maximum velocity of shortening was reduced from 3 to 2 muscle lengths per second, the maximum isometric tension was reached at a lower frequency of synchronous stimulation (30 versus 50 HZ), the initial strength was reduced from 1,065 +/- 76 g per g wet weight of muscle to 752 +/- 69, and the isometric endurance was increased from 340 +/- 16 s to 973 +/- 95. The molecular basis for these effects of phosphocreatine depletion on the contractile characteristics of soleus muscles remains to be elucidated.

Animals↗