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L Eddy

Publications and source records attributed to L Eddy.

13 recordsLinked to original sources
PubMed2001

Bioavailability and pharmacokinetic features of etoposide in childhood acute lymphoblastic leukemia patients.

The bioavailability and pharmacokinetic characteristics of etoposide were studied in 12 relapsed B-lineage acute lymphoblastic leukemia (ALL) patients after both intravenous (i.v.) infusion and oral administration. Following a 1 hour i.v. infusion of 50 mg/m2 etoposide, the elimination half-life ranged from 49.8 min to 509.4 min (mean +/- SD = 218.6 +/- 134.7 min), the MRT ranged from 71.8 to 734.9 min (mean +/- SD = 315.4 +/- 194.3 min) and the systemic clearance of etoposide ranged from 15.7 to 38.0 ml/min/m2 (mean +/- SD = 24.1 +/- 7.0 ml/min/m2). The AUC ranged from 2234.9 to 5427.0 microM.min) (mean +/- SD = 3827.8 +/- 1069.5 microM.min) and Vc ranged from 2026.9 to 13,505.2 ml/m2 (mean +/- SD = 6825.4 +/- 3278.5 ml/m2). The maximum plasma etoposide levels ranged from 6.0 to 28.4 microM (mean +/- SD = 13.6 +/- 6.3 microM). The bioavailability of oral etoposide was determined by comparing the AUC following i.v. infusion to the AUC following oral administration in the same patient. The overall bioavailability (mean +/- SD) was 60.6 +/- 22.4% (ranged from 17.6% to 91.2%). The elimination half-life following oral administration (mean +/- SD) was 209.8 +/- 196.3 min (ranged from 51.0 to 794.2 min). The time required to reach the maximum plasma etoposide concentration was 145.4 +/- 118.7 min (ranged from 23.7 to 396.9 min). To our knowledge, this is the first report concerning the bioavailability of etoposide in pediatric leukemia patients. All of the other pharmacokinetic properties of etoposide in pediatric B-lineage ALL leukemia patients reported here were similar to those described previously.

Administration, Oral↗
PubMed1991

Comparative cardiotoxicity of doxorubicin and a morpholino anthracycline derivative (KRN8602).

The toxicities of doxorubicin (DXR) and 3'-deamino-3'-morpholino-13-deoxy-10-hydroxycarcminomycin (KRN8602) were compared in perfused rat heart preparations. In addition, their toxicities in isolated myocytes as well as their abilities to cause oxidation of intracellular reduced glutathione (GSH) were evaluated. Finally, their capacities to initiate oxygen consumption and lipid peroxidation in isolated microsomes were determined. DXR caused a dramatic decrease in left ventricular pressure in the perfused hearts and a leak of lactic acid dehydrogenase (LDH) from isolated myocytes. These effects were not observed with KRN8602 at comparable concentrations although KRN8602 caused oxidation of GSH to oxidized glutathione (GSSG) in the myocytes. Both anthracyclines caused an increase in oxygen consumption and lipid peroxidation in isolated microsomes although these effects were more pronounced with KRN8602. The results of these experiments demonstrate that, despite the high capacity to redox cycle and to generate oxygen-derived oxidants, KRN8602 exhibited no measurable cardiotoxicity. The findings are consistent with a view that, if the formation of such oxidants is central to the cardiotoxicity of DXR, these substances must be formed in cellular compartments, e.g. plasma membranes, where the morpholino derivative (KRN8602) does not accumulate.

Animals↗
PubMed1990

The reduction of ferryl myoglobin by ergothioneine: a novel function for ergothioneine.

In this paper, we demonstrate that ergothioneine (ES), a naturally occurring thiolhistidine, reduces ferrylmyoglobin (MbIV) to MbIII when the former (ferryl species) is produced by exposing either deoxy MbII or MbIII to H2O2. The reduction of MbIV to MbIII by ES yields the disulfide of ES which the addition of GSH promptly reduces back to ES. The addition of ES (100 microM) in the perfusion buffer of Langendorff rat heart preparations exposed to a brief period of ischemia prevents the myocardial damage (lactate dehydrogenase release) which accompanies reperfusion. The results of these experiments support a view that ES and its redox couple GSH might function in a Mb redox cycle.

Animals↗
PubMed1990

Detection of ferryl myoglobin in the isolated ischemic rat heart.

Reflectance spectroscopy was utilized to monitor the oxidation states of myoglobin (Mb) in isolated, buffer-perfused rat hearts. Hearts were subjected to 30 min global, no-flow ischemia, followed by reperfusion under anoxic conditions. The addition of Na2S to the buffer at reperfusion permitted the detection of ferryl myoglobin (MbIV) as its sulfmyoglobin derivative. The accumulation of MbIV was prevented by addition of ascorbic acid (1 mM), ergothioneine (2 mM), or desferal (1 mM) to the buffer prior to ischemia. Ascorbate and other agents have been previously shown to serve as one-electron reductants of MbIV. We propose that during the early phases of ischemia, deoxymyoglobin is oxidized to MbIV by residual H2O2. It also seems reasonable that the peroxidative activity of Mb(IV), during oxygenated reperfusion, might lead to cellular damage if this hypervalent form of Mb is not reduced.

Animals↗
PubMed1990

Reduction of ferrylmyoglobin in rat diaphragm.

The oxidation of myoglobin was monitored by transmission spectroscopy in isolated, superfused preparations of rat diaphragms. In its deoxygenated form, during anoxia, myoglobin was oxidized by adding hydrogen peroxide (1.0 mM) to its ferryl form (FeIV). On the other hand, peroxide-induced formation of ferrylmyoglobin was not observed when the perfusate contained oxygen. Ferrylmyoglobin was visualized after its derivatization with Na2S to form sulfmyoglobin. Depending on the time of addition, ascorbate (4.0 mM) or ergothioneine (2.0 mM) either prevented the formation of or dissipated ferrylmyoglobin. These agents are known to be reductants of this hypervalent form of myoglobin. In addition to providing the first demonstration of ferrylmyoglobin in skeletal muscle, these observations are consistent with the concept that oxidation of myoglobin to hypervalent states might be an important event in the initiation of muscle damage associated with anoxia and reoxygenation. The rapid reduction of myoglobin would prevent peroxidatic alterations of essential cellular constituents by ferrylmyoglobin.

Animals↗
PubMed1989

Mechanisms of reoxygenation injury in myocardial infarction: implications of a myoglobin redox cycle.

The addition of ascorbate to ischemic rat hearts prevents the myocardial damage associated with reoxygenation. H2O2 oxidizes myoglobin (Mb+2) to higher oxidation states (Mb+4 and Mb+5) which are rapidly reduced by ascorbate. It is proposed that the operation of a myoglobin redox cycle, in which H2O2 causes the two-electron oxidation of myoglobin, is a critical determinant of reperfusion injury. Conversely, the reduction of myoglobin, in one-electron steps, may represent an essential protective mechanism against such injury in the heart.

Animals↗
PubMed1985

Infarct-size limitation--real or artifactual. Studies with flurbiprofen using a reperfusion model.

With the use of tetrazolium staining and risk-zone analysis, flurbiprofen has previously been shown to limit infarct size at 6 hr but not at 24 hr following coronary embolization in the dog heart. This study was designed to assess whether this delay in the development of a histologically defined infarct was real or an artifact arising from the effect of the drug on tetrazolium staining characteristics. With the use of a closed-chest bead-embolization model with a capability for reperfusion, hearts were made ischemic for 4 hr by injecting a 2.5 mm bead attached to a silk thread through a special cannula into the coronary vasculature. Immediately following occlusion, radioactive microspheres (141Ce) were administered to define the zone at risk of infarction. Hearts were divided into treatment (flurbiprofen, 1 mg/kg every 6 hr, N = 7) and control (saline, N = 7) groups. Following 4 hr of ischemia, the ischemic area was reperfused by withdrawing the thread and attached bead. Twenty hours later, the hearts were removed and transverse sections (3 mm) were prepared. The area of necrosis was visualized by tetrazolium staining and the risk zone by microsphere autoradiography. In control hearts, 24.7 +/- 5.0% of the zone at risk deteriorated to necrotic tissue; in the flurbiprofen-treated hearts, 17.4 +/- 4.3% of the risk zone became necrotic (NS, p greater than 0.10). Thus, despite earlier findings, these results suggest that the apparent delay in the development of tissue injury may be artifactual.

Animals↗
PubMed1979

Neonatal sepsis.

A review of neonatal sepsis, based on 30 recent cases is presented. After analyzing their personal experiences, the authors review the etiopathogeny (higher incidence in small-for-date, preterm, postterm and in some macrosomic newborns; predominance of gram-negative germs), the importance of early diagnosis, and correct treatment, adapting the antibiotherapy to the bacteriological flora of the location at the time of treatment.

Humans↗