Therapy of newly emerging mutant viral disorders and role in bioterrorism.
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Antibodies, Viral↗
Biomedical subjects
C M Ambrus
Publications and source records attributed to C M Ambrus.
Umbilical cord blood transplantation.
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Blood Banks↗
Treatment of lead poisoning with an immobilized chelator comparison with conventional therapy.
Lead poisoning is a global public health problem. In pregnant women it may result in developmental delays of the fetus, in children it my produce learning disability. Available chelators are nephrotoxic when eliminated as lead-chelator complexes. For safe removal of lead from the body we developed a "Lead-Hemopurifier" (L-HP), a device with an immobilized chelator. In vitro, applied to lead solutions, this device reduced the lead concentration. Applied to dogs with lead intoxication, Lead-HP-s removed lead from the blood; this was continuously replaced by lead from the bones until the skeleton was cleared from lead deposit. Treatment of lead poisoning in dogs with Lead-HP-s compared favorably with Versenate treatment of children with lead toxicity. This report demonstrates the in vivo efficiency and safety of this new detoxfication method. Methods to induce lead poisoning in dogs and procedures to identify lead released from skeletal deposits are described.
Animals↗
Thromboembolic disease susceptibility related to red cell membrane fluidity in patients with polycythemia vera and effect of phlebotomies.
Thromboembolic disorders are frequent complications in polycythemia vera. In addition to thrombocytosis with hyperaggregability, leukocytosis, and high hematocrit, hyperviscosity syndrome, a new component, is described in the pathophysiology of this phenomenon. There is decreased red cell membrane fluidity with decreased deformability which increases the susceptibility to microvascular occlusion and also increases the chance of disseminated intravascular coagulation (DIC). Periodic phlebotomies improved the hematologic picture in these patients and results in the removal of the "stiff" red cells with an increased production of young red cells, greater membrane fluidity, deformability and less chance of microvascular occlusion.
Aged↗
Hormone-replacement therapy and coagulation.
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Blood Coagulation Factors↗
Treatment of aluminum overload using a cartridge with immobilized desferrioxamine.
Intravenous desferrioxamine (DFO) is the method commonly used to treat aluminum toxicity. This laboratory has developed a hollow fiber device with immobilized DFO, an "Aluminum DFO-HP" (DFO-HP), for the purpose of removing aluminum without the chelator (DFO) entering the blood. With Food and Drug Administration approval, a polysulfone DFO-HP, placed in the extracorporeal circuit in series with the patient's customary dialyzer, was tested for its safety and ability to remove aluminum in patients with ESRD who had aluminum overload. During treatment with this device, no toxic reactions, side effects, or hematologic or clinical laboratory changes were seen other than those associated with dialysis. Average aluminum clearance with the DFO-HP device was 25.3 mL/min with a range of 7.2 to 52.4 mL/min, whereas aluminum clearance with the F-60 polysulfone high-flux dialyzer was 8.4 mL/min. Aluminum clearance of the cuprophane dialyzers in series with the DFO-HP was negligible. The amount of aluminum removed over a 2-h treatment with DFO-HP ranged from 94 to 628 micrograms, which corresponded to 32 to 199% of the initial aluminum in the circulation before that particular treatment. The excess 99% was provided from aluminum released from tissue sites into the circulation throughout the duration of the treatment. It is expected that, because of the efficiency and safety of the DFO-HP device, the time presently needed for aluminum depletion using intravenous DFO will be greatly shortened and the potential toxicity of intravenous DFO will be eliminated.
Aluminum↗
Potentiation of thrombolytic therapy by enzyme combinations and with aspirin or pentoxifylline.
Radioactively labeled human fibrin clots were placed into veins of Macaca arctoides monkeys. Thrombolysis was recorded by the disappearance of radioactivity and by angiography. Streptokinase (SK) and urokinase (UK) induced thrombolysis was potentiated by low dose aspirin (ASA) and pentoxifylline (PE). Studies on the mechanisms of action revealed that PE inhibits platelet aggregation, releases tissue plasminogen activator (t-PA) from the endothelium, increases red cell deformability and inhibits white cell adhesion. Thrombolysis by pro-urokinase (pro-UK) was potentiated by low dose SK probably because of streptokinase-plasmin activation of pro-UK to UK. Platelet aggregation inhibitory effects, disaggregation of platelet aggregate inducing effects, and the t-PA releasing activity of PE was demonstrated in patients with obstructive cardiovascular disease. Pharmacodynamic studies suggested that PE metabolites one and five are most effective from this point of view. These metabolites are currently studied in combination with thrombolytic enzymes.
Animals↗
Studies on tumor induced angiogenesis.
Methods were developed to test angiogenic response to human tumor implants and various biologic agents in the cornea of rabbits and non-human primates (Macaca arctoides). Crude PDGF preparations were found to have significant angiogenic effect. Purified, recombinant PDGF preparations were also effective inhibitors (e.g. pentoxifylline (Px) (which also were found to release PgI2 and t-PA) inhibited human tumor implant induced angiogenesis and reduced spontaneous metastases in 3 transplantable murine tumors (Furth-Columbia Wilms' tumor in Furth-Wistar rats, C-1300 neuroblastoma in A/J mice and HM-Kim mammary carcinoma in Wistar rats) but not in the NIH adenocarcinoma in Balb/c mice. Sodium diethyldithiocarbamate (DDTC), a metal complexing agent with special affinity to copper and anti-thyroid as well as, immune stimulating activity was shown to be anti-angiogenic and to potentiate the effect of Px. The anti-fibrinolytic agents epsilon amino caproic acid (EACA) and tranaxamic acid (t-AMCHA) were anti-angiogenic. DDTC and Px were synergistic from this point of view.
Adenocarcinoma↗
Prevention and treatment of osteoporosis. One of the most frequent disorders in American women: a review.
This review summarizes basic pathophysiology, epidemiology, classification and theories on the etiology of osteoporoses. Diagnostic, preventative and therapeutic aspects are discussed including the use of hormones and hormone analogues (estrogen, progestins, calcitonins, anabolic steroids), calcium, fluoride, bisphosphonates, vitamins D and their metabolites and the recently proposed "coherence therapy". Reference is made to new compounds under study including imidazoquinazolinones, methylxanthines and benzothiophenes.
Calcitonin↗
Studies on tumor induced angiogenesis.
Methods were developed to test the angiogenic response to human tumor implants and various biologic agents in the cornea of rabbits and non-human primates (Macaca arctoides). Human malignant melanoma tissue and crude platelet derived growth factor (PDGF) preparations had significant angiogenic effects. Purified, recombinant PDGF preparations were also effective initiators. Hemorheologic agents which also inhibit platelet aggregation [e.g. pentoxifylline (Px) (Trental) (also found to release PgI2 and tissue plasminogen activator (t-PA)] inhibited human tumor implant-induced angiogenesis. Sodium diethyldithiocarbamate (DDTC), a metal complexing agent with special affinity to copper and anti-thyroid as well as immune stimulating activity, was shown to be anti-angiogenic and to increase the effect of Px. The anti-fibrinolytic agents epsilon amino caproic acid (EACA) and tranexamic acid (t-AMCHA) were anti-angiogenic.
Animals↗
Changes in the fibrinolysin system in infantile and adult respiratory distress syndrome (ARDS), caused by trauma and/or septic shock in patients and in experimental animals.
Five hundred premature infants were treated on a randomized double-blind basis with human plasminogen or placebo. We found that in premature infants plasminogen levels are low; thus, defense against intra-alveolar fibrin deposition during birth trauma is reduced. A significant decrease in the incidence of respiratory distress syndrome-hyaline membrane disease and death was seen in the treated infants. Infants with established respiratory distress syndrome were treated with human plasmin or placebo. A significant decrease in death rate was found in the treated infants. Decreased plasminogen and anti-thrombin III (AT-III) levels were found in patients with adult respiratory distress syndrome and/or septic shock. These levels returned to normal within 14 days in survivors, but remained depressed in those who died. It was thought that these parameters may have diagnostic and predictive values. In experimental animals, injection of E. coli endotoxin or oleic acid produced an adult respiratory distress syndrome type phenomenon. This was also accompanied by decreases in plasminogen levels, with recovery in the survivors. It is suggested that plasminogen and anti-thrombin III should be explored as auxiliary therapeutic agents in adult respiratory distress syndrome.
Adult↗
Erythrocyte filterability in normal and high-risk pregnancy.
Erythrocyte filterability was studied longitudinally in normal pregnancy and in certain categories of high-risk pregnancy. Study subjects included ten normal controls, 12 insulin-dependent diabetics, eight gestational diabetics, and five essential hypertensives. Our results indicate that erythrocyte filterability remains relatively stable over the course of normal gestation. We noted no differences between controls and essential hypertensives or gestational diabetics, although a favorable effect of insulin therapy was suggested in gestational diabetics. Erythrocyte filterability and mean arterial blood pressure were not related. Insulin-dependent diabetics demonstrated a significantly elevated and widely varying erythrocyte filterability, and individual patient trends correlated well with outcome. Fibrinogen levels in diabetics rose precipitously and were significantly higher than normal throughout gestation. Fibrinogen levels paralleled changes in erythrocyte filterability, with the two parameters positively correlated. Mean glucose control had no influence on filterability. We conclude that in the diabetic pregnancy, varying erythrocyte filterability is related to altered fibrinogen metabolism and may contribute to perinatal morbidity.
Diabetes Mellitus, Type 1↗
Extracorporeal enzyme reactors for depletion of phenylalanine in phenylketonuria.
Multitubular enzyme reactors with immobilized enzymes were developed to achieve depletion of circulating substrate by extracorporeal means. To act as prototypes, reactors were prepared with immobilized L-phenylalanine ammonia-lyase, an enzyme that metabolizes phenylalanine to trans-cinnamic acid and ammonia without the need for a coenzyme. We report the first application of phenylalanine ammonia-lyase reactors in an extracorporeal circulation system in a patient with phenylketonuria. A phenylalanine level of 1.82 mmol/L (for the last 6 years) decreased to 1.24 mmol/L after 5.5. hours of treatment, without the enzyme entering the circulation. Total phenylalanine depletion from blood and tissue stores was estimated at 1800 mg. The hemodialysis-like procedure proved to be without side effects, specific for phenylalanine, and suitable in the management of pregnant women with phenylketonuria and late-onset hyperphenylalaninemia. The extracorporeal use of enzyme reactors for temporary enzyme replacement represents a new, safe, and effective therapeutic modality.
Adult↗
Mechanism of the potentiation of thrombolysis by pentoxifylline (Trental).
Streptokinase induced thrombolysis of radioactive labeled human fibrin clots was potentiated by simultaneous treatment with pentoxifylline (Trental). This appears to be due in part to the prevention of platelet aggregation on the clot. In addition, release of t-PA and PgI2 from the endothelium and increases in red cell deformability may also play a role.
Animals↗
Effect of imidazoquinazolinones on tumor cells in the circulation.
Of several imidazoquinazolinones, Anagrelide was found to be the most effective compound to inhibit platelet aggregation and to increase circulation time of intravenously injected tumor cells resulting in metastasis formation.
Animals↗
Red cell flexibility and platelet aggregation in patients with chronic obstructive vascular disease (COAD) and study of therapeutic approaches.
The red blood cell flexibility was studied in the blood of twenty patients with severe peripheral vascular disease and twenty matched controls. Patients exhibited significantly less red cell flexibility than controls. In both groups there was an inverse relationship between age and red cell flexibility. No correlation was found between red cell flexibility and sex or smoking history. Pentoxifylline, a xanthine derivative which inhibits phosphodiesterases and platelet aggregation, was found to increase red cell flexibility. This effect of the drug was greater on red cells with imparied flexibility than on normal cells. Various prostaglandins by contrast were found to decrease red cell flexibility, this could be compensated for by pentoxifylline. Forty patients with COAD were treated intravenously with PgE1. Significant inhibition of platelet aggregation and clinical improvement was noticed. It is suggested that combinations of PgE1 and pentoxifylline should be explored in clinical studies.
Adult↗
The role of fibrinolysis in the therapy of peripheral vascular disease.
In vivo thrombolytic studies in stumptailed monkeys indicated that pentoxifylline potentiates thrombolysis induced by urokinase activated human plasmin. Pentoxifylline as well as prostaglandin E1 released plasminogen activators and activated the fibrinolysin system. From this point of view pentoxifylline and prostaglandin E1 synergized with each other. Pentoxifylline potentiated the thrombolytic effect of prostaglandin E1 in vivo.
Alprostadil↗
Studies on the management and prevention of vasoocclusive crisis in sickle cell disease.
In vitro deformability of red blood cells from SS-genotype patients in vasoocclusive crisis of sickle cell disease was significantly improved by the in vitro addition of the xanthine derivative pentoxifylline (Trental). Monkeys transfused with discarded sickle cell crisis blood showed aggregation of red cells and platelets on metal screens inserted into arterio-venous anastomoses. This phenomenon could be prevented by pretreatment of the animals with 24 mg/kg of pentoxifylline. The possible mechanisms of action are discussed.
3',5'-Cyclic-AMP Phosphodiesterases↗