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Biomedical subjects

S M Pond

Publications and source records attributed to S M Pond.

At least 19 recordsLinked to original sources
PubMed1995

Gastric emptying in acute overdose: a prospective randomised controlled trial.

OBJECTIVE: To test the hypothesis that administration of activated charcoal is as efficacious and safe as the combination regimen of gastric emptying plus charcoal in adults after acute oral overdose. DESIGN: Prospective randomised controlled trial, with subjects presenting on odd-numbered dates allocated to the emptied group (E), and those on even-numbered dates to the not-emptied group (NE). SETTING: Princess Alexandra Hospital, Brisbane (a tertiary referral hospital), which serves an adult urban community, between 4 January 1988 and 11 June 1990. SUBJECTS: Consecutive patients (13 years or older) who presented to the Emergency Department after ingesting an overdose of one or more compounds able to be adsorbed by activated charcoal. INTERVENTIONS: All patients received charcoal by the oral or nasogastric route. Those in the E group also had gastric emptying by ipecac-induced emesis or gastric lavage. OUTCOME MEASURES: Clinical course during the first six hours after treatment began, length of hospital stay, complications. RESULTS: 876 patients were eligible for the study. There were no significant differences between the E and NE groups in age and sex distribution, severity of the overdose or other characteristics, except the mean interval between presentation and administration of charcoal (91 min [SD, 52] for E group and 55 [SD, 41] for NE group; P = 0.0001). There were no significant differences between the E and NE groups in outcome, even when the groups were stratified for severity of the overdose or into subgroups that presented sooner or later than one hour after ingestion. CONCLUSIONS: Gastric emptying can be omitted from the treatment protocol for adults after acute oral overdose.

Adolescent↗
PubMed1995

Evaluation and comparison of the TDxII, Stratus, and OPUS digoxin assays.

Three automated immunoassays for digoxin in serum were evaluated--Abbott TDxII, Baxter Stratus, and Behring OPUS. The accuracy and precision of the assays were assessed by weighed-in controls and an external quality control program. Coefficients of variation of all methods in serum were < or = 10% at weighed-in concentrations of digoxin of 1 and 2.5 micrograms/L. Accuracy relative to weighed-in concentrations of 1 and 2.5 micrograms/L ranged from 98 to 126% for all methods. Comparative results from patient samples showed little difference between the TDxII and Stratus and a greater difference observed between the TDxII and OPUS assays. The detection of digoxin-free samples containing digoxin-like immunoreactive substances (DLIS) in neonatal cord blood, pregnant patients, and liver and renal recipients by each assay was then assessed. The TDxII exhibited the highest incidence of DLIS. This is evident in neonatal cord blood in which 40.4% of samples tested positive. In comparison, the extent of DLIS detected by Stratus was less and OPUS exhibited no DLIS in any of the groups studied. A case study of a patient treated with anti-digoxin Fab fragments (Digibind) also was included for analysis by each method. Fourteen hours after Digibind administration, the TDxII registered a digoxin concentration of 49.5 micrograms/L compared with 3.73, 1.80, and 2.49 micrograms/L for Stratus, OPUS, and ultrafiltered TDxII methods, respectively. The results indicate that to determine the concentration of digoxin after the administration of Digiband, the OPUS or fluorescence polarization immunoassay (FPIA)-ultrafiltered samples by TDxII are the assays of choice.

Adult↗
PubMed1995

Effects of specific antibody Fab fragments on desipramine pharmacokinetics in the rat in vivo and in the isolated, perfused liver.

Drug-specific antibody fragments, which can reverse tricyclic antidepressant toxicity in rats, represent a potential clinical treatment for tricyclic antidepressant overdose in humans. To delineate the pharmacokinetic mechanisms, we studied the effects of a high-affinity, drug-specific Fab fragment on desipramine (DMI) disposition in rats and on DMI kinetics in the isolated, perfused rat liver. These studies were performed at high DMI and Fab doses, with Fab administered at the time of peak DMI toxicity, to simulate the treatment of overdose. Rats received 20 mg/kg DMI intravenously over 30 min followed in 10 min by DMI-specific ovine polyclonal Fab (DMI-Fab) or nonspecific human Fab (control-Fab) (1.1 g/kg; molar Fab-to-DMI ratio, 0.34) intravenously over 20 min. The serum DMI concentration increased by 50-fold 5 min after DMI-Fab administration. The mean area under the serum concentration-time curve increased by more than 3-fold. The steady-state volume of distribution was decreased by 90% and total body clearance was decreased by 70% after DMI-Fab administration compared with control-Fab. Renal clearance increased by 72% after DMI-Fab and total renal excretion of DMI increased by 7-fold due to the much higher serum DMI concentration. Ninety-four percent of DMI-Fab excretion and 87% of DMI excretion occurred in the first 12 h. The percent of DMI bound in urine was markedly increased by DMI-Fab (87.1 vs. 19.1%), as was the molar ratio of DMI to DMI-Fab in urine (0.75 vs. 0.08). Isolated rat livers were perfused with DMI alone, DMI and DMI-Fab or DMI and control-Fab.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Sensitive high-performance liquid chromatographic assay with ultraviolet detection of methadone enantiomers in plasma.

Methadone is being prescribed increasingly as an analgesic in palliative medicine. R-Methadone has been shown to be responsible for most of the pharmacological activity of this drug. Despite that in most countries it is administered as the racemate. Few assay methods for the enantiomers are available; e en fewer can determine accurately the low concentrations of enantiomers required to undertake pharmacokinetic studies in patients taking the drug in analgesic doses. We present here an HPLC method used to determine concentrations of the specific enantiomers of methadone as low as 5.0 ng/ml with adequate precision and accuracy. The mean R/S ratio of the plasma concentrations was 0.80 +/- 0.05 (n = 3 samples) in one patient taking 25-27.5 mg daily and 1.21 +/- 0.12 (n = 6 samples) in another taking 10-20 mg daily. In the second patient, concentrations of the enantiomers ranged between 5.8 and 25.9 ng/ml. Tricyclic antidepressants did not interfere with the assay but dextropropoxyphene did. Its presence could be detected by dual wavelength monitoring.

Adult↗
PubMed1994

The effects of aging and nutritional state on hypoxia-reoxygenation injury in the perfused rat liver.

During liver transplantation, donor livers are subject to hypoxia and reoxygenation. Recently, because of a shortage of suitable donors, the livers of older donors have been used for transplantation. In this study, we examined the influence of aging and nutritional state on hepatic intracellualr pH (pHi) and the susceptibility of the rat liver to hypoxia-reoxygenation injury. Perfused livers from fasted and fed, young (2-3 months) and aged (24-28 months) male Wistar rats were compared during 30 min of nitrogen hypoxia followed by 20 min of reoxygenation. Under control conditions, pHi was significantly lower and glucose release higher in livers from fed young rats (7.24 +/- 0.04, 3.4 +/- 1.8 mumol/min/g) than in those from fasted young (7.33 +/- 0.04, 0.0 +/- 1.3), fasted aged (7.32 +/- 0.03, -0.1 +/- 0.5), and fed aged rats (7.29 +/- 0.06, 0.9 +/- 1.0). In all groups, pHi fell by approximately 0.15 U during hypoxia. Lactate dehydrogenase (LDH) release from the livers of fed young livers was unaffected by hypoxia-reoxygenation as was that from the livers of fed aged rats, despite features that would be expected to predispose to injury (reduced glucose output and more alkaline pHi). In contrast, livers from fasted young and aged rats had substantially increased LDH release and reduced bile flow during hypoxia. There were no age-related differences in these parameters, but, during reoxygenation, LDH release was significantly less in the aged livers. These results indicate that the livers of fed rats are resistant to hypoxia-reoxygenation injury and that aging does not increase the susceptibility of the liver to injury in the fasted state.

Aging↗
PubMed1994

Nonlinear relationship between circulating concentrations of reduced haloperidol and haloperidol: evaluation of possible mechanisms.

In patients taking haloperidol (HP), circulating concentrations of reduced haloperidol (RHP increase disproportionately to the dose or concentration of the parent drug. In the current study, we tested the hypothesis that the nonlinearity is due to preferential saturation of the reoxidation of RHP to HP, and two factors that could amplify the nonlinearity-concentration-dependent binding of RHP by plasma proteins, or by red blood cells. In 25 patients with schizophrenia who were taking HP, the unbound fraction of HP (0.085 +/- 0.016) and RHP (0.244 +/- 0.026) in plasma, and the blood:plasma ratio for each compound were independent of their concentration. Thus, saturable binding of RHP to plasma proteins or red blood cells can be excluded. HP reductase and RHP oxidase activity were measured in human liver cytosol and microsomal fractions, respectively. Because ketone reductase-catalysed formation of RHP is stereospecific, we examined each enantiomer of RHP separately. The Vmax for the oxidation of the S(-) and R(+) RHP enantiomers in four livers was 0.23 +/- 0.15 and 0.60 +/- 0.32 mumol/g protein per min (mean +/- SD), respectively. The Km was 110 +/- 40 and 70 +/- 10 microM, respectively. In contrast, HP reductase activity displayed greater capacity and was not saturable. The rate of production of RHP at a HP concentration of 122 microM (the limit of HP solubility) in the same livers was 2.6 +/- 0.7 mumol/g protein per min. Despite the observed nonlinearity between the enzymatic pathways in vitro, RHP concentrations in vivo are 2-3 orders of magnitude lower than the Km for oxidation of each enantiomer of RHP.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1994

Quantitative analysis of two pyridinium metabolites of haloperidol in patients with schizophrenia.

OBJECTIVE: A pyridinium metabolite (HPP+) of the neuroleptic drug haloperidol has been identified in rats and in the urine of patients. The purpose of this study was to measure the steady-state blood and plasma concentrations and daily urinary excretion of HPP+ in patients treated with haloperidol. METHODS: HPP+ was measured by HPLC with fluorescence detection. The chromatograms also revealed the presence of a previously unknown pyridinium species, which was identified in urine by liquid chromatography/mass spectrometry/mass spectrometry as 4-(4-chlorophenyl)-1-4-(4-fluorophenyl)-4-hydroxybutylpyridinium (RHPP+). Concentrations of RHPP+ were then measured by HPLC. RESULTS: The steady-state concentrations of HPP+ or RHPP+ in blood and plasma from 34 patients were virtually identical. The plasma concentrations of each metabolite were related to the daily dose of haloperidol and to its plasma concentrations. Nonlinearity in the elimination of RHPP+ was suggested by the increase in the ratio between RHPP+ and HPP+ plasma concentrations with dose or steady-state concentrations of haloperidol. The concentrations of RHPP+ in plasma and urine generally exceeded those of HPP+; the ratio between them in plasma ranged from 0.9 to 14.1. The daily urinary excretion of HPP+ and RHPP+ accounted for 0.40% +/- 0.18% and 2.3% +/- 1.4% of the haloperidol dose, respectively. The renal clearance of each species was 4.5 +/- 2.5 and 11.3 +/- 5.3 L/hr, respectively. CONCLUSIONS: The presence of these pyridinium species in humans raises the concern that they may be neurotoxic in a manner similar to the dopaminergic pro-neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.

Adult↗
PubMed1994

Comparison of high-performance liquid chromatography and monoclonal fluorescence polarization immunoassay for the determination of whole-blood cyclosporin A in liver and heart transplant patients.

Conflicting conclusions have been drawn from comparisons of high-performance liquid chromatography (HPLC) and the Abbott Diagnostics monoclonal fluorescence polarization immunoassay (mFPIA) for cyclosporin. The aim of this study was to compare whole blood cyclosporin A (CsA) concentrations measured by both mFPIA and HPLC in liver and heart transplant patients. One hundred and twenty-four liver and 62 heart transplant patient samples were assayed by both methods. Assay imprecision for both methods during the studies was < 7% over the range 150-800 micrograms/L. At an HPLC-determined concentration of 100 micrograms/L, mFPIA overestimated CsA by 60% (liver) and 77% (heart). At 300 micrograms/L, the overestimation was 40% (liver) and 45% (heart). On this basis, the mFPIA is not interchangeable with HPLC.

Antibodies, Monoclonal↗
PubMed1994

Effects of gender and pregnancy on hepatocellular uptake of palmitic acid: facilitation by albumin.

The human serum albumin (HSA)-dependent unbound clearance (Clu) of [3H]palmitic acid (PA) by hepatocyte suspensions isolated from immature and mature male and female and pregnant female rats was studied. The Clu values obtained experimentally were compared with the predictions of a noncompartmental diffusion-reaction (Bass-Pond) theory for the cellular uptake of protein-bound ligands. In all groups, as the concentration of HSA (Ca) was increased, there was a striking increase in Clu. These enhancement factors were predicted by the theory. Adult females had higher Clu values at high Ca values than males or immature females. Furthermore, at high Ca values, Clu in pregnant animals was twice as high as in the nonpregnant animals and four times as high as in the aged-matched males. The absolute values of Clu obtained experimentally in both pregnant and nonpregnant females exceeded the maximal predictions of the theory, using reasonable values of all of the parameters. Thus, according to current data on the physicochemical characteristics of the uptake system, the study demonstrates that some specialized process exists to facilitate hepatocellular uptake of fatty acid from albumin, and that it is potentiated by the female sex hormones.

Aging↗
PubMed1994

Prevention of paraquat toxicity in suspensions of alveolar type II cells by paraquat-specific antibodies.

1. The herbicide, paraquat, is accumulated by the energy-dependent polyamine uptake pathway of alveolar type II cells. There it undergoes redox cycling that results in an amplified production of toxic reactive oxygen species and depletion of NADPH and other reducing equivalents. These processes account for the lung being the major target organ for paraquat toxicity. 2. We postulated that paraquat-specific antibodies would inhibit the uptake of the herbicide by type II cells and prevent its toxicity. Accordingly, we examined the effects of paraquat-specific monoclonal antibodies and Fab fragments on the uptake, efflux and cytotoxicity of 50 microM paraquat in suspensions of alveolar type II cells isolated from the rat. 3. The uptake of paraquat was linear over 40 min. Over this time, the uptake rate was inhibited significantly (% inhibition, 73-89) by IgG (25 or 50 microM) or Fab fragments (50 or 100 microM). 4. The apparent efflux rate of paraquat, studied over 16 h, was increased significantly from 0.12 h-1 for the control cells in medium to 0.17 h-1 by paraquat-specific Fab fragments but was unaffected by the specific IgG. 5. Cytotoxicity was determined by measuring the release of 51Cr from the cells. The cytotoxicity of 50 microM paraquat was decreased significantly (percent decrease, 56-80%) in the presence of specific antibodies. 6. These studies in vitro suggest some potential for immunotherapy in selected cases of paraquat poisoning.

Animals↗
PubMed1993

Polyclonal amanitin-specific antibodies: production and cytoprotective properties in vitro.

The amanitins found in several mushroom species are responsible for many deaths every year. Based on its successful application to cardiac glycoside overdose, immunotherapy could be applicable to amanitin toxicity. Therefore, we produced polyclonal amanitin antibodies by immunizing rabbits with a novel conjugate of alpha-amanitin. Purified antibodies had an average association constant for alpha-amanitin of 1.3 x 10(9) M-1. A partially protective effect of the antibodies against amanitin toxicity in vitro in Chang cells was evident at a molar ratio of antibody binding sites to alpha-amanitin of 4:1. Together with reported studies in vivo, these investigations indicate the potential of immunotherapy for amanitin poisoning.

Amanitins↗
PubMed1993

Experience with 732 acute overdose patients admitted to an intensive care unit over six years.

OBJECTIVE: To determine the outcome in patients with acute overdose requiring admission to the Intensive Care Unit (ICU). DESIGN: Prospective survey of all overdose admissions to an ICU over a six-year period ending January 1991. SETTING: Tertiary referral adult teaching hospital. PATIENTS: 732 consecutive patients with acute overdose. OUTCOME MEASURES: Death rate, use and duration of mechanical ventilation, type of compound taken and compounds associated with a fatal outcome. RESULTS: The 732 patients represented 13.8% of all admissions and 6% of the available ICU bed-days. Comparison with all admissions to the Emergency Department for acute overdose over a 27-month period ending April 1990 indicated that 22% of these patients were admitted to the ICU. Among the patients admitted to the ICU, tricyclic antidepressants, benzodiazepines and alcohol were the most frequently used compounds. More than one compound had been taken by 46.8% of the patients. Mechanical ventilation was required in 79.5% of the patients and 14 (2%) died. CONCLUSIONS: Acute overdose is a common cause of admission to the ICU but has a mortality rate of only 2%. In contrast to the overdoses taken by survivors, patients taking fatal overdoses are more likely to have taken a large dose of a single drug, or a non-medicinal compound.

Adult↗
PubMed1993

Calibration of albumin-fatty acid binding constants measured by heptane-water partition.

Most measurements of binding affinity of albumin for long-chain fatty acids are based on heptane-water partition. In this method, equilibrium partition of fatty acid between heptane and an albumin-containing buffer is calibrated using the partition ratio between heptane and buffer in the absence of protein. In the current study, we used a variety of techniques to examine potential problems with this approach. Hydrophobic impurities in commercial [3H]palmitate preparations were incompletely removed by standard purification techniques. These impurities contributed from 5% of the total radioactivity in the heptane phase at low albumin concentrations (5 microM) to 62% at higher albumin concentrations (500 microM), thus confounding determination of binding affinity. These were identified by gas chromatography/mass spectroscopy as radio-labeled glycerol monopalmitate and monostearate. When albumin was not present, the partition ratio was similar to values reported by others. However, our results varied by a factor of four (265-1,119) depending on how the solutions were prepared. Although a true equilibrium partition must not depend on starting conditions, the partition ratio after 24-72 h was > 2x as large when tracer [3H]palmitate was added to the heptane phase than when it was added to the aqueous phase. Results also depended on the relative volumes of heptane and buffer used, approaching a maximum of 1,445 +/- 112 for very low heptane/buffer volume ratios. Much of this variability was due to hydrophilic impurities in [3H]palmitate, which ranged from 0.2 to 1.2% in commercial lots down to 0.1-0.5% after alkaline ethanol extraction and < 0.05% after thin-layer chromatography (TLC).(ABSTRACT TRUNCATED AT 250 WORDS)

Calibration↗
PubMed1992

The influence of pH on the interaction of lipophilic anthracyclines with bovine serum albumin. Quantitative characterization by measurement of fluorescence quenching.

We have investigated the interaction of the lipophilic anthracyclines 4'-iodo-4'-deoxydoxorubicin (IDX) and 4-demethoxy-daunorubicin (DDN) with bovine serum albumin by the quantitation of fluorescence quenching. The protein binding of IDX was extremely sensitive to the pH of the solution in which the complex was formed and paralleled the effect of pH on dimerization of the drug. The effect of pH on the protein binding and self-association of DDN was less extensive. Both compounds exhibited curvilinear Scatchard plots indicating apparent cooperativity in the binding process. Because of the self-association of the drugs in aqueous solution, we attempted to resolve this cooperativity in terms of the preferential binding of the dimer to the acceptor. However, we found that similar Scatchard plots could be simulated by using slightly erroneous estimates of the fluorescence yield of the complex, rendering any such analysis inconclusive. Consequently, the relationship between acceptor concentration and the fraction of ligand bound was considered to be fitted adequately in terms of a single acceptor site per albumin molecule. The pH dependence of the association constants for bovine serum albumin was described best by the hydrophobic interaction of neutral drug monomer with a binding site with titratable affinity. We postulate that the pH-dependent binding of some anthracyclines with albumin may lead to their enhanced uptake, relative to that of non-target organs, into tumours with an acidotic extracellular milieu.

Doxorubicin↗