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S M Pond

Publications and source records attributed to S M Pond.

At least 73 records · Page 4Linked to original sources
PubMed1992

Competition between paraquat and putrescine for uptake by suspensions of rat alveolar type II cells.

Paraquat and the structurally similar polyamines, such as putrescine and spermidine, are accumulated actively and selectively by the alveolar type II cells via the polyamine uptake system. We report the uptake kinetics of paraquat and putrescine and their mutual inhibition in freshly isolated rat type II cell suspensions. The uptake of paraquat by type II cells exhibited saturation kinetics and could be inhibited in a concentration-dependent manner by putrescine. By applying enzyme kinetic analysis to our experimental data it was demonstrated that the uptake of paraquat or putrescine is inhibited in a partially competitive manner by the respective inhibitor. Thus, we postulate that the polyamine uptake pathway in type II cells for paraquat and putrescine has two separate sites, one for each substrate, and that binding of one leads to a conformational change in the other.

Animals↗
PubMed1992

Stereospecific reduction of haloperidol in human tissues.

In the current study, we have examined the catalytic activity and stereospecificity of haloperidol (HP) reductase activity in the cytosolic fractions of human brain and liver and in whole blood. The reductase activity was NADPH-dependent and inhibited by menadione, features typical of the ketone reductases (EC 1.2.1). The Vmax in the brain was about 4-fold higher than in the liver. Moreover, the reaction was stereospecific in that only the S(-) enantiomer was detected in brain and blood and 99.2 +/- 0.1% of the reduced HP (RHP) produced in the liver was S(-). The potential clinical implications of our results are unknown because until now all binding and pharmacodynamic studies with RHP have been performed with the racemate.

Adolescent↗
PubMed1992

Severe botulism after eating home-preserved asparagus.

OBJECTIVE: To present a case of adult botulism acquired in Queensland. CLINICAL FEATURES: After eating home-preserved asparagus, a 33-year-old man presented with internal and external ophthalmoplegia, bilateral facial nerve palsies, and descending muscle weakness culminating in a sudden respiratory arrest. Electrophysiological testing demonstrated normal nerve conduction velocities and an incremental response of evoked motor potentials on repetitive stimulation, confirming the clinical diagnosis of botulism. INTERVENTION AND OUTCOME: Treatment with trivalent antitoxin, oral treatment with vancomycin and supportive mechanical ventilation for four weeks resulted in complete clinical recovery. Plasmapheresis was also used but its contribution to the patient's improvement is dubious. CONCLUSIONS: Although botulism is rare in Australia, clinicians should be aware of the clinical presentation and the rapidity of confirmation of the diagnosis by electrophysiological testing. Patients should be nursed in an intensive care setting. Regular testing of vital capacity should be performed to determine the need for mechanical ventilation.

Adult↗
PubMed1992

Axial tissue diffusion can account for the disparity between current models of hepatic elimination for lipophilic drugs.

An assumption of previous models of hepatic elimination is that there is negligible axial diffusion in the liver. We show, by construction of a stochastic model and analysis of published data, that compounds which are readily diffusible and partitioned into hepatocytes may undergo axial tissue diffusion. The compounds most likely to be affected by axial tissue diffusion are the lipophilic drugs for which the cell membranes provide little resistance and which are highly extracted, thereby creating steep concentration gradients along the sinusoid at steady state. This phenomenon greatly modifies the availability of the compound under conditions of altered hepatic blood flow and protein binding. For moderately diffusible compounds, these relationships are similar to those predicted by the simplistic venous-equilibrium model. Hence, the paradoxical ability of the venous-equilibrium model to describe the steady-state kinetics of lipophilic drugs such as lidocaine, meperidine, and propranolol may be finally resolved. The effects of axial tissue diffusion and vascular dispersion on hepatic availability of drugs are compared. Vascular dispersion is of major importance to the availability of poorly diffusible compounds, whereas axial tissue diffusion becomes increasingly dominant for highly diffusive and partitioned substances.

Computer Simulation↗
PubMed1992

Determination of haloperidol and reduced haloperidol in the plasma and blood of patients on depot haloperidol.

We developed a sensitive HPLC assay to measure haloperidol (HA) and its metabolite, reduced haloperidol (RH), in plasma and whole blood. The conditions under which HA might be converted to RH during collection and analysis of blood were examined. Provided the blood was kept at 0 degrees C, erythrocyte ketone reductase activity was insignificant. The solid phase extraction method did not generate RH. We studied ten patients taking 25-400 mg/month of HA decanoate and one patient for 4 weeks after the daily oral dose of 120 mg HA was ceased. In the patients on depot HA, the plasma and blood concentrations of HA were not significantly different (P greater than 0.1). For the first time, RH was detected in plasma patients on depot drug, but only in three cases. In contrast, RH was present in the blood of eight of these patients. The accumulation of RH in red blood cells was also evident in the patient on oral HA, in whom the mean ratio of RH concentrations in whole blood to plasma was 3.6 +/- 1.1. Plasma concentrations of HA correlated highly with total neuroleptic activity measured by a radioreceptor assay. Compared to plasma, analysis of concentrations of HA and RH in blood has the advantages of greater sensitivity, of using smaller volumes of blood and of avoiding the efflux of HA and RH during separation of plasma and red cells.

Chromatography, High Pressure Liquid↗
PubMed1992

Quantitation of paraquat in biological samples by radioimmunoassay using a monoclonal antibody.

We have developed a sensitive and specific radioimmunoassay for the quantitative determination of paraquat in plasma, urine, and bronchoalveolar lavage fluid using a monoclonal antibody. The synthesis of the iodinated paraquat tracer is novel and less complicated than a previously reported method. Regardless of the type of biological sample analyzed, the sensitivity of the assay was 0.46 ng/ml in a 200-microliters aliquot. The results correlated well with those of another assay performed in a separate laboratory. Paraquat concentrations were determined in plasma and in urine of a dog over several days after the intravenous administration of 7.48 mg paraquat cation/kg and in bronchoalveolar lavage fluid obtained 34 hr after the 2-hr infusion was discontinued. Concentrations of paraquat measured ranged from 14.1 to 0.03 micrograms/ml in plasma and 2034 to 0.36 micrograms/ml in urine. Concentrations of paraquat in plasma obtained at various times after the ingestion of paraquat by three patients ranged from 51.0 to 0.010 micrograms/ml.

Animals↗
PubMed1992

Uptake of palmitate by hepatocyte suspensions: facilitation by albumin?

Albumin-dependent uptake of unbound [3H]palmitic acid by hepatocytes isolated from female rat livers was studied and the experimental results compared with the predictions of a noncompartmental diffusion-reaction theory for the cellular uptake of protein-bound ligands. The outright theoretical predictions involve values for the parameters of the system, some newly measured (hepatocyte radii and the rate constant for the dissociation of palmitate-albumin complex) and some taken from the literature (diffusion coefficients and the equilibrium association constant for the palmitate-albumin complex). The measured unbound clearance of [3H]palmitic acid, defined as the initial uptake velocity divided by the unbound [3H]palmitic acid concentration in the medium, was enhanced 6.6-fold as the concentration of human serum albumin was increased from approximately 5 to 480 microM. This enhancement factor was predicted by the theory, according to which the enhancement reflects codiffusion of bound ligand across the unstirred layer adjacent to the cell membrane and, therefore, an increased delivery of unbound ligand to the cell surface. In contrast, the absolute magnitude of the unbound clearance was consistent with the theory only for the lowest published value for the equilibrium association constant, 15 microM-1. For higher published values (62 and 94 microM-1), the magnitude of the unbound clearance observed experimentally was severalfold higher than that predicted by the theory. If in fact the association constant exceeds 30 microM-1, the data would imply that an albumin-dependent facilitation mechanism exists which enhances the availability of palmitate to the cell over and above the enhancement predicted by the diffusion-reaction theory.

Animals↗
PubMed1992

Management of theophylline overdose patients in the intensive care unit.

In a retrospective survey of all adults admitted to the Intensive Care Unit with acute theophylline poisoning over the last five years, we identified 38 patients (6.8% of all admissions for poisoning), two of whom died. Thirty-five (92%) had taken a sustained-release preparation. Eight patients had grand mal seizures and six developed arrhythmias (ventricular fibrillation, 3; atrial fibrillation, 2; supraventricular tachycardia, 1). Severe vomiting was present in 34 (89%) and proved to be a serious obstacle to the administration of enteral charcoal. The vomiting was controlled by intravenous metoclopramide in seventeen patients (50%), but the remaining seventeen required mechanical ventilation with sedation and muscle relaxation for the effective delivery of nasogastric charcoal. Importantly, in nine (24%), the serum theophylline concentration continued to rise despite enteral charcoal. Charcoal haemoperfusion was used in seven (18%). We present an algorithm for the management of severe, acute theophylline poisoning.

Absorption↗
PubMed1992

Reversal of desipramine toxicity in rats using drug-specific antibody Fab' fragment: effects on hypotension and interaction with sodium bicarbonate.

The effect of drug-specific antibody Fab' fragment on desipramine (DMI) toxicity was studied in anesthetized rats to determine 1) whether DMI-induced hypotension can be reversed, and 2) whether the effect of this Fab' fragment can be enhanced by the concurrent administration of hypertonic NaHCO3. DMI (60 mg/kg) was administered i.p. to produce marked hypotension. Antitricyclic antidepressant (TCA) Fab' (molar Fab'/DMI ratio = 0.11) or control Fab' was administered 15 min later as a 10 min i.v. infusion. The mean arterial pressure was higher at the end of anti-TCA Fab' infusion than after control Fab' (58 +/- 8 vs. 17 +/- 7 mm Hg, P less than .001). In a second protocol, DMI (30 mg/kg) was administered to prolong QRS duration. Anti-TCA Fab' alone (molar Fab'/DMI ratio = 0.09) and NaHCO3 alone both reduced QRS prolongation compared to control treatment, and combined therapy was more effective than either one alone. In both protocols, anti-TCA Fab' markedly increased the total DMI concentration and the bound fraction of DMI in serum, but did not alter the unbound DMI concentration. In the low DMI dose protocol, anti-TCA Fab' also reduced the cardiac DMI concentration. Concurrent treatment with anti-TCA Fab' and NaHCO3 substantially increased urinary DMI and anti-TCA Fab' excretion compared to treatment with anti-TCA Fab' alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Placebo-controlled, double-blind study of the effects of proglumide in the treatment of schizophrenia.

A double-blind, placebo-controlled, randomized study was performed to determine whether proglumide added to ongoing neuroleptic medication was efficacious in the treatment of 32 patients with persistent positive and negative schizophrenic symptoms. Patients treated with both proglumide and placebo showed a significant improvement over the 8 weeks of the study, but no significant difference between the patients taking proglumide and those taking placebo could be demonstrated. In addition, proglumide had no effect on plasma homovanillic acid concentrations or neuroleptic drug activity. The results suggest that, at least for the dose of proglumide used in this study (15 mg/day), the addition of this particular cholecystokinin antagonist does not potentiate the antipsychotic efficacy of neuroleptic medication in patients with persistent schizophrenic symptoms.

Adult↗
PubMed1991

Identification of potentially neurotoxic pyridinium metabolite in the urine of schizophrenic patients treated with haloperidol.

Evidence that the parkinsonian inducing agent MPTP is biotransformed to a pyridinium species that selectively destroys nigrostriatal neurons in humans and subhuman primates has prompted studies to evaluate the metabolic fate of the structurally related neuroleptic agent haloperidol. With the aid of a highly sophisticated atmospheric pressure ionspray HPLC/MS/MS assay, unambiguous evidence has been obtained for the presence of the haloperidol pyridinium species in extracts of urine obtained from haloperidol-treated patients and in extracts of NADPH-supplemented human liver microsomal incubation mixtures containing haloperidol. The potential significance of the formation of this putative neurotoxic pyridinium species is considered.

Adult↗
PubMed1991

Cloning and analysis of a cDNA encoding a human liver carboxylesterase.

A human liver carboxylesterase (CE)-encoding cDNA has been cloned using synthetic oligodeoxyribonucleotides (oligos) based on the known amino acid (aa) sequences of rabbit and rat liver CEs. The oligos hybridize specifically to DNA encoding liver CEs. The longest cDNA obtained from screening several cDNA libraries encodes about 80% of the protein and translates into an aa sequence which has a high degree of similarity with the sequences of liver CEs from other species. On hybridization to mRNA isolated from human liver, the cDNA gave a single band of about 2.0 kb consistent with its encoding a protein of less than 68 kDa. DNA obtained from a number of human livers and probed with the CE cDNA gave identical hybridization patterns. These patterns were moderately complex by comparison with published data.

Amino Acid Sequence↗
PubMed1991

Extracorporeal techniques in the treatment of poisoned patients.

The role of haemodialysis, haemoperfusion and haemofiltration in the management of poisoned patients is reviewed in light of 15 years' clinical experience. During haemodialysis, blood is pumped across a semipermeable membrane (dialysis) through which the compound diffuses and, during haemoperfusion, through a cartridge that contains activated charcoal to which the compound is adsorbed. During haemofiltration, the constituents of blood that have a relative molecular mass which is below the cut-off point of the hollow fibre membrane (usually less than 40,000) are extracted. Haemofiltration is indicated particularly for aminoglycoside toxicity. The clearance by these three procedures depends on the physicochemical characteristics and kinetics of the toxic compound. In general, if a compound is adsorbed by charcoal, the clearance by haemoperfusion will be higher than that achieved by haemodialysis. Similarly, if a compound is amenable to removal by haemodialysis, its clearance will be greater than that achieved by haemofiltration. The indications for extracorporeal elimination depend on the clinical severity and complications of the overdose, the characteristics of the individual patient and the nature, dose and plasma concentrations of the toxic substance. It is generally accepted that extracorporeal elimination is worthwhile if it increases total body clearance by 30% or more. It has little or no value for intoxication caused by chloroquine, flecainide, methotrexate, paraquat, quinine, and tricyclic antidepressants. The complications of extracorporeal elimination which are encountered most frequently are: hypotension; blood loss; haematomas; metabolic disequilibria; mechanical problems such as air embolism; and, in the case of haemoperfusion, hypocalcaemia, thrombocytopenia and leukopenia. In practice, the compounds for which extracorporeal elimination is used most frequently are the alcohols, lithium and salicylate (haemodialysis) and theophylline (haemofiltration).

Adult↗
PubMed1991

Determination of the in vivo antigen-antibody affinity constant from the redistribution of desipramine in rats following administration of a desipramine-specific monoclonal antibody.

Quantitative expressions have been derived to determine the affinity constant for the in vivo interaction of an antigen with its elicited monoclonal antibody by analysing the redistribution of antigen following antibody administration. Using this method, the intrinsic binding constant for the interaction of subtoxic doses of DMI in rats with anti-TCA was found to be about two orders of magnitude less than the value obtained in vitro. The disparity is probably due to the presence of endogenous ligands for the antibody.

Animals↗