Biomedical subjects

C H Ts'ao

Publications and source records attributed to C H Ts'ao.

At least 19 recordsLinked to original sources

PubMed2000

Effects of unfractionated heparin, low-molecular-weight heparin, and heparinoid on thromboelastographic assay of blood coagulation.

Thromboelastography (TEG) has been used increasingly as an intraoperative hemostasis monitoring device. Low-molecular-weight heparins are given increasingly to reduce the development of antibodies against the heparin-platelet factor 4 complex, and heparinoids are given to patients who have developed the antibody. We studied the effect of unfractionated heparin, a low-molecular-weight heparin (enoxaparin sodium [Lovenox]), and a heparinoid (danaparoid sodium [Orgaran]) on blood clotting assayed with TEG (TEG clotting) in vitro and the efficacy of protamine sulfate and heparinase for reversing the effect. Heparin, enoxaparin, and danaparoid all caused a dose-dependent inhibition of TEG clotting of normal blood. Concentrations of enoxaparin and danaparoid that totally inhibited TEG clotting only minimally prolonged the activated partial thromboplastin time. While inhibition of TEG clotting by heparin and enoxaparin was reversed by protamine sulfate and heparinase, inhibition by danaparoid was reversed only by heparinase. Abnormal TEG clotting was observed in patients receiving enoxaparin whose plasma level of the drug was more than 0.1 antiXa U/mL. However, the degree of TEG abnormality did not always coincide with plasma levels of the drug.

Antibodies↗

PubMed1999

Mechanism of captopril toxicity to a human mammary ductal carcinoma cell line in the presence of copper.

Captopril (D-3-mercapto-2-methylpropanoyl-L-proline) is an angiotensin converting enzyme (ACE) inhibitor, used widely in the treatment of hypertension and congestive heart failure. Captopril also inhibits proliferation of a variety of cell types, including several lacking ACE and renin acitvity. We have previously demonstrated that human mammary ductal carcinoma cells are among the cell types whose mitotic activity is inhibited by captopril. In those cells, captopril also reduces estrogen receptor (ER) and increases progesterone receptor (PR) concentrations. The present study evaluated the mechanism of captopril's antiproliferative action in an ER/PR-negative human mammary ductal carcinoma cell line, Hs578T. Cells grown in a 10% serum medium showed negligible changes in the presence of captopril alone. However, in the presence of subphysiologic concentrations of copper salts or copper-loaded ceruloplasmin, captopril caused a dose-dependent reduction in cell number, thymidine incorporation and mitochondrial dehydrogenase activity. In contrast, iron salts and iron-saturated transferrin had no effect on captopril activity. Catalase and horseradish peroxidase nullified the cytotoxic effects of captopril/Cu++, whereas H2O2 mimicked those effects. These data are consistent with the notion of a copper-catalyzed oxidation of captopril, leading to the generation of H2O2 as the cytotoxin to this clinically important cell type.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1998

Stability of plasma for add-on PT and APTT tests.

We conducted studies to determine at what time point an add-on prothrombin time (PT) or activated partial thromboplastin time (APTT) test can be honored on specimens that have been received in the laboratory hours earlier without yielding results with clinically significant differences from those if the test had been performed on the original unstored plasma. PT and APTT tests were performed on blood samples from 20 healthy subjects, 30 patients receiving warfarin, and 30 patients receiving heparin anticoagulation therapy. The tests were performed on plasma prepared initially after the samples were obtained. The same tests were assayed on plasma that had been left on spun-down blood cells at room temperature for 2, 4, and 8 hours. We found that the PT of the majority of plasma samples from healthy subjects and from patients receiving oral anticoagulant therapy tended to become shorter on storage. However, the difference in PT values was small and had no clinical significance. In most cases, the APTT values for the stored plasma from healthy subjects tended to increase with time. Except in one specimen in which the 8-hour add-on APTT was 1.2 seconds longer than the APTT result for the original sample, all others had APTT results less than 1.2 seconds longer than the original values. In patients receiving heparin, the differences in APTT values between the initial and add-on tests were larger than those observed for healthy subjects. However, those differences are not beyond what we would accept for duplicate checks for heparinized samples with high APTT values. Unlike samples from healthy subjects, there was no obvious trend of time-related prolongation of the APTT in heparinized plasma. These results led us to believe that within an 8-hour period and with plasma on spun-down cells at room temperature, add-on tests for PT and APTT could be performed with results similar to what would be obtained from testing unstored samples.

Anticoagulants↗

PubMed1995

Annexin I in female rabbit reproductive organs: varying levels in relation to maturity and pregnancy.

The level of annexin I, a 36 kDa calcium-dependent phospholipid-binding protein (36 kDa PLBP) in the reproductive organs of young, mature, and pregnant rabbits was determined immunologically with antibodies raised against purified rabbit lung annexin I. In the cytosolic fractions of the ovary, fallopian tube, uterus, and placenta, annexin I was the only major immunoreactive protein. The reproductive organs appeared to have higher annexin I levels than most nonreproductive organ tissues, except the lung and the spleen which were also rich in annexin I. A small amount of annexin I and a nearly equal amount of its hydrolytic product, a 33 kDa polypeptide, were detected in the amniotic fluid between 21 and 27 days gestation. Structural similarity of annexin I in the reproductive organs and in the lung was suggested by their identical isoelectric point values. Annexin I in the ovary of adult rabbits was 70% higher than that in the respective organ of immature rabbits. The uterus of pregnant rabbits had about 84% higher annexin I contents than that of the nonpregnant rabbits. The placenta had more annexin I per mg cytosolic protein than either the ovary or the uterus during pregnancy. The high concentration of annexin I in the reproductive organs may reflect specific functions of these organs in the reproductive years and during the reproductive cycle.

Amniotic Fluid↗

PubMed1994

Captopril inhibits proliferation of human lung fibroblasts in culture: a potential antifibrotic mechanism.

The angiotensin converting enzyme (ACE) inhibitor captopril, a free-thiol compound used widely as an antihypertensive agent, also inhibits radiation-induced pulmonary fibrosis in rats (Ward et al., Int J Radiat Oncol Biol Phys 19:1405, 1990). In an attempt to clarify the antifibrotic mechanism of captopril in vivo, the present study examined the effect of the drug on proliferation of human lung fibroblasts in culture. Captopril produced a drug dose-dependent reduction in fibroblast proliferation and 3H-thymidine incorporation during a 24-72-hr incubation. This cytostatic action of captopril was not the result of cytotoxicity as assessed by trypan blue exclusion, or by 51Cr or lactate dehydrogenase (LDH) release. Fibroblasts stimulated to proliferate by basic FGF were more sensitive to the antimitotic effect of captopril than were unstimulated cells. The ability of captopril to inhibit 3H-thymidine incorporation was not reversed by exogenous angiotensin 2, and was not mimicked by the nonthiol ACE inhibitor lisinopril. These data indicate that the cytostatic effect of captopril was not attributable to ACE inhibition. Penicillamine, a thiol compound with virtually no ACE inhibitory activity, also reduced fibroblast 3H-thymidine incorporation, indicating that the antimitotic action of captopril may represent a nonspecific sulfhydryl effect. This study suggests that the antifibrotic activity of captopril in irradiated lung may result in part from a direct inhibition of fibroblast proliferation, particularly in fibroblasts responding to mitogenic stimuli.

Angiotensin II↗

PubMed1992

Radiation pneumotoxicity in rats: modification by inhibitors of angiotensin converting enzyme.

The present study determined whether inhibitors of angiotensin converting enzyme (ACE) can ameliorate radiation-induced pulmonary endothelial dysfunction and pulmonary fibrosis in rats sacrificed 2 months after a range of single doses of 60Co gamma rays to the right hemithorax. Four indices of pulmonary endothelial function were monitored: right lung ACE and plasminogen activator (PLA) activity, and prostacyclin (PGI2) and thromboxane (TXA2) production. Hydroxyproline (HP) content served as an index of pulmonary fibrosis. Rats consumed either control powdered chow or feed containing one of five modifying agents continuously after irradiation. The modifiers included three ACE inhibitors: Captopril, CL242817, and CGS13945, respectively, a thiol, a thioacetate, and a nonthiol compound. All of the ACE inhibitors are analogues of proline. Two additional modifiers were tested: penicillamine, a thiol with no ACE inhibitory activity; and pentoxifylline, a vasodilator that is neither a thiol nor an ACE inhibitor. Radiation produced a dose-dependent decrease in lung ACE and PLA activity, and an increase in PGI2 and TXA2 production and in HP content. All ACE inhibitors attenuated the radiation-induced suppression in lung ACE and PLA activity. All thiol or thioacetate compounds ameliorated the radiation-induced increase in PGI2, TXA2, and HP. The two agents that were both thiols and ACE inhibitors (Captopril and CL242817) spared all of the radiation reactions, while the compound that was neither a thiol nor an ACE inhibitor (pentoxifylline) spared none of the reactions. These data suggest a novel application for ACE inhibitors in general, and for Captopril in particular, as modifiers of radiation pneumotoxicity.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1990

Captopril reduces collagen and mast cell accumulation in irradiated rat lung.

The angiotensin converting enzyme inhibitor captopril ameliorates radiation-induced pulmonary endothelial dysfunction in rats. The present study determined whether captopril also reduces collagen (hydroxyproline) accumulation in the lungs of rats sacrificed 2 months after a range of single doses (0-30 Gy) of 60Co gamma rays to the right hemithorax. Captopril was administered in the feed at a regimen of 0, 25, or 50 mg/kg/day continuously after irradiation. Mast cell counts also were obtained from lungs of all animals exposed to 30 Gy. In rats receiving no captopril, there was a radiation dose-dependent increase in right lung hydroxyproline (HP) content and in HP concentration per g wet weight. Captopril produced a drug dose-dependent suppression in this radiation-induced HP accumulation. At a dose of 50 mg/kg/d, captopril reduced the slope of the radiation dose response curve for lung HP content by a factor of 1.7, and completely prevented the increase in HP concentration. At an isoeffect level of 550 micrograms HP per right superior lobe, this dose of captopril exhibited a DRF of 1.7 +/- 0.2. In rats exposed to 30 Gy, moreover, the number of mast cells per mm2 of alveolar cross-sectional surface area decreased from 105 +/- 8 to 100 +/- 7 and 59 +/- 5 in the groups given 0, 25 or 50 mg/kg/d of captopril, respectively, (vs none in sham-irradiated rats). These data are the first to demonstrate that the ACE inhibitor captopril might provide a novel intervention in the pathogenesis of radiation fibrosis.

Animals↗

PubMed1990

Stimulation of radiation-impaired plasminogen activator release by phorbol ester in aortic endothelial cells.

Ionizing radiation has been reported to affect the fibrinolytic activity of exposed tissue. With cultured bovine aortic endothelial cells, radiation suppresses the release of plasminogen activator to the conditioned media, with a concomitant increase in intracellular plasminogen activator. Thus study was undertaken to determine whether radiation-impaired plasminogen activator release can be modified by phorbol ester. We exposed cultured bovine aortic endothelial cells to a sterilizing dose of 10 Gy of gamma-rays and found the treatment led to cell injury, as evidenced by an increased release of prelabeled chromium, and to a reduction of plasminogen activator in the conditioned media with elevated intracellular plasminogen activator in irradiated cells. Phorbol ester enhanced plasminogen activator activity in both sham-irradiated and irradiated endothelial cells. It was interesting to note that the increased plasminogen activator in phorbol ester-stimulated sham-irradiated cells was largely retained inside the cell, while it was released to the conditioned media in irradiated cells. Apparently, altered plasminogen activator activity of radiation-sterilized endothelial cells can be modified by exogenous stimuli.

Animals↗

PubMed1990

Hematin: effects on hemostasis.

Extensive studies performed over the past 6 years have shown that a degradation product of hematin produces a unique coagulopathy, characterized by thrombocytopenia with platelet degranulation, alteration in the function of numerous clotting and fibrinolytic proteins, and reversible changes in endothelial cells. With the use of degraded hematin, it can be demonstrated that platelet aggregation is stimulated, that platelet adhesion to endothelial cells is enhanced, that the dissociation of factor VIII: C from von Willebrand factor is inhibited, and that the binding of the factor VII/von Willebrand factor complex to platelets is impaired. Even freshly reconstituted solutions of sorbitol-stabilized hematin affect hemostasis and induce thrombophlebitis, presumably because of in vivo degradation of the hematin. Recently, a new formulation of hematin, heme arginate, has been shown to be extraordinarily stable and to have virtually no effects on coagulation. This review compares and summarizes the effects of these various hematin compounds on hemostasis.

Arginine↗

PubMed1989

Monocrotaline-induced cardiopulmonary injury in rats. Modification by the neutrophil elastase inhibitor SC39026.

Rats were killed after 6 weeks of continuous ingestion of the pneumotoxic alkaloid monocrotaline (2.2 mg/kg/day), the neutrophil elastase inhibitor SC39026 (60 mg/kg/day), or both. Pulmonary reactions were evaluated by light and electron microscopy. Lung endothelial function was monitored by angiotensin converting enzyme (ACE) activity, plasminogen activator (PLA) activity, and prostacyclin (PGI2) and thromboxane (TXA2) production. Lung hydroxyproline content was measured as an index of interstitial fibrosis. Cardiac right ventricular hypertrophy was determined by the right ventricle to the left ventricle plus septum weight ratio (RV/LV + S). Rats receiving SC39026 alone did not differ significantly from untreated control animals with respect to any of the quantitative endpoints, although rarefaction of Type I pneumocytes was observed in the electron micrographs of these animals. Monocrotaline-treated rats, in contrast, developed a significant increase in RV/LV + S, and exhibited pulmonary edema, inflammation, fibrosis, and muscularization and occlusive mural thickening of the pulmonary small arteries and arterioles. These monocrotaline-induced structural changes were accompanied by decreased lung ACE and PLA activities, and increased PGI2 and TXA2 production, and by an increase in lung hydroxyproline content. Cotreatment with SC39026 ameliorated the monocrotaline-induced pulmonary vascular wall thickening and the cardiac right ventricular hypertrophy. These data suggest that inappropriate neutrophil elastase activity contributes to monocrotaline pulmonary vasculopathy and hypertension. On the other hand, cotreatment with SC39026 had no significant effect on the severity of the monocrotaline-induced lung inflammatory reaction, the pulmonary endothelial dysfunction, or the increase in lung hydroxyproline content.

Animals↗

PubMed1989

Monocrotaline pneumotoxicity in mice.

Lung injury induced in rats by the pyrrolizidine alkaloid monocrotaline is a well-documented model of pulmonary hypertension. To our knowledge, however, monocrotaline-induced cardiopulmonary injury has rarely been described and has never been quantitated in mice. In the present study, adult male mice received 2.4, 4.8, or 24.0 mg monocrotaline/kg body weight/day in the drinking water continuously for 6 weeks. These doses represent 1, 2, and 10 times the severely pneumotoxic regimen in rats. Pulmonary endothelial function was monitored by right lung angiotensin converting enzyme (ACE) activity, plasminogen activator (PLA) activity, and prostacyclin (PGI2) and thromboxane (TXA2) production. Light and electron microscopy were performed on the left lungs. Cardiac right ventricular hypertrophy was evaluated by the right ventricle to left ventricle plus septum weight ratio (RV/LV + S). Monocrotaline-treated mice exhibited a dose-dependent decrease in lung ACE and PLA activities and an increase in PGI2 and TXA2 production, indicative of endothelial dysfunction. However, these responses were significant only after the highest monocrotaline dose. Light and electron microscopy revealed dose-dependent pulmonary inflammatory and exudative reactions. Unlike previous studies in rats, however, monocrotaline-treated mice developed relatively little lung fibrosis, cardiomegaly, or right ventricular hypertrophy, and no occlusive medial thickening of the pulmonary arteries, even at the highest dose level. These and previous data indicate that there are quantitative biochemical and qualitative morphological differences between mice and rats with respect to monocrotaline pneumotoxicity. Furthermore, in monocrotaline-treated mice (but not in rats) there appears to be a dissociation between lung endothelial dysfunction and inflammation on the one hand, and pulmonary hypertension and fibrosis on the other.

Animals↗

PubMed1989

Radiation-induced endothelial dysfunction and fibrosis in rat lung: modification by the angiotensin converting enzyme inhibitor CL242817.

The purpose of this study was to evaluate the angiotensin converting enzyme (ACE) inhibitor CL242817 as a modifier of radiation-induced pulmonary endothelial dysfunction and pulmonary fibrosis in rats sacrificed 2 months after a single dose of 60Co gamma rays (0-30 Gy) to the right hemithorax. CL242817 was administered in the feed continuously after irradiation at a regimen of 60 mg/kg/day. Pulmonary endothelial function was monitored by lung ACE activity, plasminogen activator (PLA) activity, and prostacyclin (PGI2) and thromboxane (TXA2) production. Pulmonary fibrosis was evaluated by lung hydroxyproline (HP) content. Lung ACE and PLA activities decreased with increasing radiation dose, and cotreatment with CL242817 significantly ameliorated both responses. CL242817 dose-reduction factors (DRF) were 1.3-1.5 for ACE and PLA activity. Lung PGI2 and TXA2 production increased with increasing radiation dose, and CL242817 almost completely prevented both radiation responses. The slope of the radiation dose-response curves in the CL242817-treated rats was essentially zero, precluding calculation of DRF values for PGI2 and TXA2 production. Lung HP content also increased with increasing radiation dose, and CL242817 significantly attenuated this response (DRF = 1.5). These data suggest that the ability of ACE inhibitors to ameliorate radiation-induced pulmonary endothelial dysfunction is not unique to captopril [Ward et al., Int. J. Radiat. Oncol. Biol. Phys. 15, 135-140 (1988)], rather it is a therapeutic action shared by other members of this class of compounds. These data also provide the first evidence that ACE inhibitors exhibit antifibrotic activity in irradiated rat lung.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1988

Changes in venous blood lactate, venous blood gases, and somatosensory evoked potentials after tourniquet application.

The effects of inflation of a 7-cm tourniquet applied to the upper arm of eight volunteers on venous lactate, venous blood gases, and ulnar nerve somatosensory evoked potentials (SSEPs) were investigated. The inflation pressure was 100 mmHg over the systolic pressure. Venous blood samples for lactate and blood gas determinations were withdrawn before tourniquet inflation; immediately and at 2, 5, 10, 15 min after tourniquet deflation; and additionally at 30, 45, and 60 min after deflation in the last four volunteers. SSEP stimulating surface electrodes were placed over the ulnar nerve at the wrist. Recording electrodes were placed over the ipsilateral ulnar groove of the elbow, Erb's point, and on the contralateral cortex. Averaged responses were acquired before inflation of the tourniquet, every 5-10 min during tourniquet inflation, and every 5-10 min for 45-60 min after tourniquet deflation. The tourniquet was inflated for 36 +/- 11 min. After deflation of the tourniquet, postdeflation pain and paresthesias were felt by five volunteers; these occurred at 30-120 s after deflation and lasted for 75-120 s. The postdeflation pains were characterized as burning, cramping, paresthesias, buzzing, or severe expansion of the hand. The venous blood lactate levels were significantly elevated for 10 min, and the time course of its change did not correlate with reperfusion pain. The PO2 and O2Hb saturation in venous blood were significantly elevated for 10-15 min after deflation. The elevated lactate and PO2 levels in the presence of a restored blood flow probably result from continued anaerobic muscle metabolism secondary to capillary closure from the tourniquet-induced ischemia.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1988

Split-dose sparing of gamma-ray-induced pulmonary endothelial dysfunction in rats.

The purpose of this study was to determine whether radiation-induced pulmonary endothelial dysfunction exhibits split-dose sparing. Rats were sacrificed 2 months after a range of 60Co gamma-ray doses (0-40 Gy) delivered to the right hemithorax in either a single fraction or in two equal fractions separated by 24 h. Pulmonary angiotensin converting enzyme (ACE) activity, plasminogen activator (PLA) activity, and prostacyclin (PGI2) and thromboxane (TXA2) production served as indices of lung endothelial function. There were dose-dependent decreases in ACE and PLA activity and increases in PGI2 and TXA2 production after both single and split-dose exposures. The D2-D1 values determined from the two-fraction minus single-fraction isoeffective doses were 3.9 Gy for ACE activity, 7.2 Gy for PLA activity, 4.8 Gy for PGI2 production, and 4.7 Gy for TXA2 production. Thus these data demonstrate that over the present range of radiation doses approximately 4-7 Gy is repairable as subeffective endothelial damage during the 24-h interval between fractions. These values agree with previously published estimates of split-dose sparing in mouse lung based on lethality and breathing rate assays.

Animals↗

PubMed1988

Cellular and extracellular plasminogen activator and inhibitor in an experimental tumour.

We determined plasminogen activator (PA) and PA inhibitor (PAI) activities in the intra- and extracellular compartments of an experimental pancreatic ascites tumour with indirect and direct functional assays, and partially characterized these activities on SDS-polyacrylamide gels coupled with fibrin and reverse fibrin autography. Intact tumour cells caused lysis of plasminogen-rich but not plasminogen-free fibrin clots, and the extent of lysis of the former was related to tumour cell count. Direct assay of PA with a synthetic substrate yielded an equivalent of 109 urokinase units per 10(9) tumour cells. No PAI activity was demonstrated in tumour cells with functional assays. Contrary to tumour cells, cell-free ascitic fluids caused no lysis of fibrin clots. Instead, it inhibited tumour cell- and urokinase-induced, but not plasmin-induced, clot lysis in a dose-dependent fashion. Although functional assays failed to demonstrate PA in ascitic fluid and PAI in tumour cells, both activities were detected in electrophoresed samples of cell lysates and fluids by fibrin and reverse fibrin autography. In tumour cells, a mixture of tissue-type PA (tPA) and urokinase-type PA (uPA) were present. In the fluid, uPA together with two other PAs with greater molecular weights than tPA were detected.

Animals↗

PubMed1986

Monocrotaline-induced cardiopulmonary damage in rats: amelioration by the angiotensin-converting enzyme inhibitor CL242817.

Pulmonary injury induced by the plant alkaloid monocrotaline is partially prevented by the angiotensin-converting enzyme (ACE) inhibitor captopril. CL242817 [(S-[R*,S*])-1-([3-acetylthio]-3-benzoyl-2-methyl-propionyl)- L-proline] is a new orally active ACE inhibitor under evaluation as an antihypertensive agent. To determine whether CL242817 also can modify monocrotaline-induced pulmonary injury, male rats were divided into four groups: control; CL242817 (60 mg/kg/day, po); monocrotaline (2.4 mg/kg/day, po); or monocrotaline plus CL242817, and were sacrificed after 6 weeks of continuous treatment. Rats receiving monocrotaline alone exhibited occlusive medial thickening of the pulmonary arteries, cardiomegaly, and right ventricular hypertrophy. Electron micrographs of monocrotaline-treated lung revealed degeneration of both endothelial and Type I epithelial cells, as well as marked interstitial hypercellularity and fibrosis. Hydroxyproline (collagen) content of monocrotaline-treated lung also increased significantly, confirming the fibrosis observed in the electron micrographs. These structural changes were accompanied by decreased lung ACE and plasminogen activator (PLA) activities, indicative of pulmonary endothelial dysfunction. Concomitant CL242817 treatment ameliorated all anatomic manifestations of monocrotaline injury, particularly the right ventricular hypertrophy, pulmonary arterial occlusion, epithelial degeneration, and interstitial fibrosis. CL242817 also significantly prevented the monocrotaline-induced increase in lung hydroxyproline content. In contrast, concomitant CL242817 did not significantly influence the suppressed lung ACE and PLA activities in monocrotaline-treated rats. CL242817 alone produced retarded weight gain, decreased heart weight relative to body weight, decreased lung hydroxyproline content and ACE activity, and increased serum ACE activity and plasma AII concentration. Thus CL242817 resembles captopril, both in its ability to ameliorate monocrotaline-induced pulmonary injury in rats, and in many of its side effects.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1985

Metabolic and morphologic effects of the antimicrobial agent nitrofurantoin on human erythrocytes in vitro.

We have reported previously that the antimicrobial nitrofurantoin stimulates superoxide production and methemoglobin formation from HbO2 as an isolated hemeprotein and in hemolysates [M. Dershwitz and R. F. Novak, J. biol. Chem. 257, 75 (1982); M. Dershwitz and R. F. Novak, J. Pharmac. exp. Ther. 222, 430 (1982)]. The production of hydrogen peroxide and methemoglobin by nitrofurantoin has been determined in normal erythrocytes in vitro. Hydrogen peroxide production increased 5-fold during a 20-hr incubation in the presence of 840 microM nitrofurantoin, while methemoglobin content increased to over 20% of the total hemoglobin concentration of the cells. Consequent metabolic and morphologic alterations also occurred. Concomitant with nitrofurantoin-stimulated hydrogen peroxide production were time- and concentration-dependent decreases in cellular levels of GSH and ATP, as well as alterations in red cell morphology. Significant differences in GSH and ATP levels between control and nitrofurantoin-treated erythrocytes occurred after 12 hr and proceeded maximally from 18 to 21 hr. After a 21-hr incubation, 840 microM nitrofurantoin caused the cellular GSH and ATP levels to fall 65 and 75%, respectively, while controls exhibited only 29 and 43% decreases in ATP and GSH levels, respectively. Studies on the concentration dependence of such decreases demonstrated that the EC50 values for depletion of GSH and ATP were similar in blood obtained from an individual donor. The EC50 values varied from approximately 10 microM to 100 microM among the various donors whose blood was studied. Incubation of normal red cells with nitrofurantoin also resulted in an increased conversion of red cells to echinocytes as observed by scanning electron microscopy. These metabolic effects, coupled with increased oxidative stress via hydrogen peroxide generation, lend support to the mechanism for nitrofurantoin-induced hemolysis in erythrocytes compromised by certain enzyme deficiencies which result in low basal levels of GSH or diminished rates of GSH synthesis.

Adenosine Triphosphate↗

PubMed1985

The bleeding time as a preoperative screening test.

To examine the benefit of determination of the bleeding time as a preoperative screening test, the medical records of all patients who had a prolonged bleeding time during a six-month period were reviewed. At Northwestern Memorial Hospital, where the bleeding time test is part of the presurgical panel, 1,941 bleeding time determinations were performed during six months. Prolonged bleeding times were recorded in 110 preoperative patients, of whom 83 (75 percent) had bleeding risk factors, including drug ingestion, thrombocytopenia, and azotemia. In these patients, the bleeding time ranged unpredictably from 10 to more than 20 minutes. However, of the 27 patients without apparent risk factors, only two had bleeding times of more than 20 minutes. This small number probably does not justify the routine use of the test in all preoperative patients. Rather, the test should be used selectively for those subjects who, on the basis of history or laboratory evidence, are suspected of being at risk of hemorrhage. Moreover, even in these patients, prolongation of the bleeding time may not always be associated with excessive surgical blood loss.

Aspirin↗