The preparation and gamma-scintigraphic evaluation of the in vivo distribution patterns in dogs of a series of structurally related hydantoins labeled with the positron emitting, 20.4 min half-life radionuclide, carbon-11 are described. Carbon-11 labeled HCN was collected in water or aqueous Me2SO containing carrier KCN following cyclotron bombardment of 99% N2-1% H2 gas mixture with 22 MeV protons for 1 hr at 25-35 muA. Five 11C-labeled 5,5-dialkylhydantoins, three [11C]diarylhydantoins, five [11C]-5-alkyl-5-phenylhydantoins, and five [11C]spirohydantoins were prepared by heating generally under pressure, a mixture of 11C-labeled KCN, which was produced by isotopic exchange with carrier KCN, the corresponding aldehyde or ketone, and excess (NH4)2CO3 in aqueous ethanol or Me2SO solvent. The 11C-labeled hydantoins were dissolved in 1-1.5% aqueous NaOH for intravenous administration to dogs. Total synthesis time was 70-106 min and 1-59 mCi of final product was available for conducting serial in vivo imaging for up to 2 hr or more with the gamma-scintillation camera. Carbon-11 activity from all compounds showed initial blood-pool distribution with variable concentration of activity in the brain, lungs, liver, and kidney. All of the 11C-labeled diarylhydantoins, and most having one phenyl substituent, and one having a hexamethylene moiety showed initial accumulation of 11C activity in brain. Carbon-11 labeled 5,5-diphenylhydantoin (dilantin) showed the greastest qualitative accumulation of activity in the brain. Those 11C-labeled hydantoins having a carboxyl substituent showed prominent renal concentration and urinary excretion of activity. Most 11-c-labeled hydantoins showed a progressive homogenous whole body distribution of activity in all cellular tissues of the body. The relatively uniform distribution of activity in cellular tissues and slow excretion from the body support the thesis that the pharmacologic action of the hydantoins is related to physical effects on biomembranes rather than to specific chemical interactions with cell constituents.
1. Patients with polycythemia vera may be classified according to their erythropoietic pattern. Erythropoiesis is abnormally increased in all classes. Class I is characterized by normal red cell lifespan. Class II is characterized by shortened red cell lifespan; in Class IIa the shortened red cell survival is related to splenic sequestration of RBC; in Class IIb the markedly shortened red cell survival is predominantly related to intramedullary hemolysis. Class III is characterized by extramedullary erythropoiesis. Patients in Classes I and IIa are in relatively earlier phases of their disease and frequently are found to develop red cell kinetics of Class III as their disease progresses. Conversely, patients in Classes IIb and III are generally late in the course of their disease and have previous hematologic findings that suggest that they originally had the red cell kinetic patterns of Classes I and IIa.
2. As the duration of their disease increases, patients with polycythemia vera generally have a progressive shortening of red cell lifespan which is incompletely compensated by a progressive decrease in circulating red cell volume. However, total blood volume remains elevated since the plasma volume increases. These changes occur whether or not the patient receives radiation therapy. Similar changes may occur in white cell and platelet production and functional survival. It is suggested that the natural history of the disease may be characterized by progressive emergence of hematopoietic cell clones which have a selective advantage for reproduction associated with altered functional survival.
3. The results suggest the potential usefulness of iron, and occasionally of splenectomy, in selected polycythemic patients with myeloid metaplasia (Class III) and anemia, dependent upon the presence of the frequent finding of iron deficiency or the occasional finding of splenic sequestration of red cells in excess of splenic erythropoiesis.
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