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Biomedical subjects

S M Pond

Publications and source records attributed to S M Pond.

At least 109 records · Page 6Linked to original sources
PubMed1988

Creation of a carotid-jugular fistula for repeated hemoaccess in a canine model.

We have developed a method to obtain access to the arterial circulation in the dog, which can be used for repeated hemoperfusion, hemodialysis, and for pharmacokinetic studies. Hemoaccess is achieved by the surgical creation of a carotid-jugular fistula. Using the fistula, which is internal and autogenous, has overcome the problems of thrombosis, dislodgement, and infection, which are associated with external shunts. Blood flow rates of between 70 and 100 ml/min in 12-kg dogs were obtained through a hemodialysis pump. The surgical techniques are described in detail so that other investigators can avail themselves of the methodology.

Animals↗
PubMed1988

Large scale production and purification of paraquat and desipramine monoclonal antibodies and their Fab fragments.

We describe the rapid, large scale purification of Fab fragments from mouse monoclonal antibodies. Antibodies against two clinically important and often fatal toxins, paraquat and desipramine, were isolated from mouse ascites fluid by preparative high performance hydroxylapatite (HPHT) or ion exchange (DEAE) high performance liquid chromatography. A competitive inhibition ELISA was used to determine the cross-reactivity of the antibody with analogs of the antigens. Papain digests of the IgGs were subjected to further HPHT followed by Sephadex G-100 chromatography to yield homogeneous Fab fragment preparations. The high purity of these preparations, demonstrated by SDS polyacrylamide gel electrophoresis, has only been achieved previously by affinity chromatography. Intrinsic association constants for the intact IgG and the Fab fragment--antigen interactions, determined by competitive inhibition ELISA, were similar. This indicates that antigen-binding activity was conserved during the production and purification of the Fab fragments.

Animals↗
PubMed1988

Comparison of paraquat-specific murine monoclonal antibodies produced by in vitro and in vivo immunization.

The techniques of in vitro and in vivo immunization have been used to produce murine hybridomas secreting anti-paraquat IgM and IgG antibodies, respectively. The monoclonal antibodies from these IgM-secreting and IgG-secreting cell lines have been purified by HPLC and characterized by ELISA for their affinities to eliciting antigen and cross-reactivity. Both antibody preparations exhibited high selectivity and similar affinities for paraquat. There was only a minor degree of interaction with a range of paraquat analogs that differed in the nature and position of group substituents.

Animals↗
PubMed1988

Ultrastructure of canine lung during the proliferative phase of paraquat toxicity.

The herbicide paraquat induces irreversible progressive pulmonary fibrosis in human beings and animals. The mechanisms of the fibrosis are still unresolved. There is histological and ultrastructural evidence that an early destructive phase followed by a proliferative phase occurs in the lungs post paraquat-exposure. In this study, lungs obtained from a dog 7 days following intravenous administration of paraquat (12 mg paraquat dichloride per kg bodyweight) are compared with lungs obtained from a normal dog. Examination included gross post mortem inspection, histology, transmission electron microscopy (TEM) and scanning electron microscopy (SEM). Comparison of the TEM of the paraquat affected canine lung with the normal showed: alveolar collapse; detachment of alveolar epithelial cells from the basement membrane; alteration of the type II alveolar cell morphology; infiltration of granulocytes and erythrocytes into both the interstitium and alveolar air spaces; and fibroblasts associated with collagen fibrils. The SEM of the paraquat-exposed canine lung, reported here for the first time, demonstrated irregular, alveolar walls with type I alveolar epithelial cell detachment, and erythrocyte and alveolar macrophage infiltration. These findings suggest that the detachment of alveolar epithelial cells and the alveolar macrophage play a significant role in paraquat-induced pulmonary fibrosis.

Animals↗
PubMed1988

Nonlinear intestinal first-pass metabolism of salicylamide in dogs after portacaval transposition.

The dose-dependent first-pass metabolism and pharmacokinetics of salicylamide (SAM) were studied at four dose levels in dogs before and after portacaval transposition. Four minutes after each p.o. dose, a tracer dose of [14C]SAM was given i.v. to determine clearance and bioavailability. Over the dosage range studied pretransposition, 5 to 40 mg/kg, bioavailability increased from 0.24 +/- 0.14 (mean +/- S.D.) to 0.76 +/- 0.20 (P less than .05). Clearance decreased from 3.4 +/- 1.0 to 0.6 +/- 0.11 liter/min (P less than .01) and half-life increased from 5.0 +/- 1.2 to 23.5 +/- 6.1 min (P less than .01). Over the dosage range studied post-transposition, 1.5 to 20 mg/kg, bioavailability increased from 0.31 +/- 0.09 to 0.99 +/- 0.08. Clearance and half-life had the same values and showed the same dose-dependence as in the normal dogs. The amount of SAM removed by the intestine during first-pass remained constant at about 1 mg/kg over the dose range given to the post-transposition animals. Therefore, although more easily saturable than the liver, the intestine plays an important role in first-pass metabolism of low p.o. doses of SAM. In contrast to previous results in the normal dog, the p.o. coadministration of sodium sulfate did not reduce the bioavailability of SAM in transposed dogs. This indicates that the nonlinear intestinal first-pass metabolism of SAM is not due to the depletion of the cosubstrate precursor, inorganic sulfate.

Administration, Oral↗
PubMed1987

The effects of differential induction of cytochrome P-450, carboxylesterase and glutathione S-transferase activities on malathion toxicity in mice.

The organophosphorous pesticide malathion is metabolized by three hepatic enzyme systems: the microsomal cytochrome P-450-dependent monooxygenase system, the microsomal carboxylesterases, and the cytosolic glutathione S-transferases. We produced differential induction of these three enzyme systems in mice with phenobarbital and 2(3)-tert-butyl-4-hydroxyanisole (BHA) and examined the effects of the induction on the inhibition of acetylcholinesterases by malathion. Phenobarbital not only significantly induced hepatic microsomal cytochrome P-450 (p less than 0.05) but also increased microsomal carboxylesterase activity (p less than 0.05). BHA not only increased the activity of microsomal carboxylesterases (p less than 0.05) but also substantially increased cytosolic glutathione S-transferase activity (p less than 0.05). Despite the differential effects of phenobarbital and BHA on the three enzyme systems, neither agent protected the mice against malathion toxicity.

Animals↗
PubMed1987

Concurrent intravenous administration of a labeled tracer to determine the oral bioavailability of a drug exhibiting Michaelis-Menten metabolism.

The theoretical accuracy of concurrent administration of labeled intravenous tracer and oral doses to estimate the bioavailability of drugs exhibiting Michaelis-Menten kinetics was determined by computer simulation. The simulation model consisted of sampling and hepatic compartments with elimination occurring by hepatic metabolism according to the venous equilibration model. The relationships between error in bioavailability estimation and dose, metabolic activity (Vmax), first-order absorption rate constant (ka), and volume of distribution (V) and the fraction of the dose absorbed were examined. Error was hypothesized to be relatively low when conditions result in a relatively constant value of clearance after oral dosing or when the concentration-time curves after intravenous and oral dosing are similar. The results were consistent with these hypotheses and, under most conditions, error was less than 15%. The effects, on error, of altering the intravenous tracer dose input and having a lag time in absorption of drug from the oral dose were also determined. In general, accuracy was improved by delaying administration of the iv tracer for a time equal to 50% of the oral dose peak time or by administering the tracer dose by constant-rate infusion from the time of oral dosing to the peak time. Lag time in absorption of the oral dose was shown to often result in overestimates in bioavailability of greater than 50%.

Administration, Oral↗
PubMed1987

Repeated hemoperfusion and continuous arteriovenous hemofiltration in a paraquat poisoned patient.

Prompt hemodialysis or hemoperfusion can be of value during the first 24 hours after paraquat ingestion particularly when the patient has developed acute renal failure. However, many cases of paraquat poisoning occur in areas where hemoperfusion facilities are unavailable. In contrast, continuous arteriovenous hemofiltration (CAVH) could be instituted easily. We have measured the removal of paraquat from the body by CAVH in a 46 year old male cane farmer who ingested 70 ml, 20% paraquat and died twelve days later from pulmonary fibrosis. Renal failure developed rapidly. Concentrations of paraquat were measured by an indirect competitive ELISA using a murine paraquat monoclonal IgG antibody. Hemoperfusion was performed daily for five days, beginning 78 hours post-ingestion. By 180 hours, when the patient was in respiratory failure, hemoperfusion was replaced with CAVH which was continued for 46 hours. During this time interval, 1.1 mg paraquat was recovered in the hemofiltrate and 1.56 mg paraquat in the urine. The extraction of paraquat by the hemofilter was close to 100%. The plasma clearance of paraquat across the hemofilter was 6.1 ml/min and the renal clearance was 8.2 ml/min. The mean hemoperfusion clearance of paraquat was 50 ml/min and the total amount of paraquat removed by the 34 hours of hemoperfusion was 9 mg. Because of the relative ease with which CAVH can be performed, its low cost, compared to that of hemoperfusion or hemodialysis, and the continuous nature of the procedure, CAVH may be worth considering in paraquat poisoning. It could be used particularly in those patients who have developed renal failure or while patients are being prepared for hemoperfusion.

Hemofiltration↗
PubMed1986

Serum formate concentrations in methanol intoxication as a criterion for hemodialysis.

To evaluate the utility of serum formate concentrations, four patients were studied after ingestion of a methanolic copying fluid. All patients were initially intoxicated. Twelve to twenty-four hours later, signs and symptoms included nausea, abdominal pain, hypokalemia, acidosis (three patients), and pathologic ocular findings (two patients). All patients were treated with ethanol and folate. The two patients with ocular signs and acidosis had high serum formate concentrations (75 and 55 mg/dL, respectively). One of the two patients had a high methanol concentration (222 mg/dL) and required hemodialysis; the other patient did not (methanol concentration, 24 mg/dL). In the other two patients without ocular signs, initial formate concentrations were undetectable (limit of detection, 0.5 mg/dL); however, one patient required hemodialysis because the methanol concentration was 72 mg/dL. Formate is the mediator of ocular injury and acidosis. In these patients formate concentrations correlated with the clinical condition but methanol concentrations did not.

Acidosis↗
PubMed1986

Amatoxin poisoning in northern California, 1982-1983.

Twenty-two patients who ate mushrooms containing hepatotoxic amatoxins were treated during the fall and winter seasons of 1982 and 1983. All patients were treated with intensive supportive care and repeated oral doses of activated charcoal. In two patients fulminant hepatic failure developed and they died. One patient in whom encephalopathy developed had an orthotopic liver transplant and survived. Liver biopsy specimens obtained from five patients during the acute illness showed centrilobular hemorrhagic necrosis. The hepatic histopathology in a biopsy specimen from a 5-year-old boy eight weeks after mushrooms were eaten showed bands of fibrosis and islands of hepatocytes suggestive of early cirrhosis. Radioimmunoassay for amanitins, done on the serum from all patients, detected the toxins in only three, probably because most of the specimens were obtained 24 hours or more after the ingestion. This series, with a mortality rate of 9%, illustrates the outcome in patients who receive intensive supportive care and provides a background on which success of specific treatments should be judged.

Adolescent↗
PubMed1986

Extrahepatic extraction of salicylamide in dogs.

Extrahepatic conjugation may be an important mechanism for the metabolism of many phenolic compounds. We have observed dose-dependent sulfoconjugation of salicylamide (SAM) in the lung, kidney and forelimb of dogs during steady-state infusions. The lungs alone accounted for more than one-half the total elimination at the lowest infusion rate (0.3 microgram/min/kg). The limbs appeared to play an important secondary role in SAM elimination whereas the kidneys made only a minor contribution to total elimination. At the highest infusion rate (500 micrograms/min/kg), extrahepatic extraction approached zero and elimination by the three extrahepatic sites fell to less than 31% of total elimination. Dose-dependent elimination at the three extrahepatic sites was responsible for most of the dose dependence observed in these studies. Extrahepatic extraction was insensitive to plasma inorganic sulfate. Clearance significantly, but only slightly, increased on coinfusing sodium sulfate at a rate that increased plasma inorganic sulfate from one-sixth (after depletion by SAM infusion) to two times normal.

Animals↗
PubMed1985

Theophylline overdose: acute single ingestion versus chronic repeated overmedication.

Currently available guidelines for managing theophylline intoxication do not distinguish between acute single ingestion and chronic repeated overmedication and do not reliably predict which patients should undergo hemoperfusion. Although hemoperfusion is widely recommended when serum concentrations exceed 40-60 mg/l, many patients with acute overdose tolerate much higher levels without serious toxicity. Because manifestations of toxicity might be dependent on the chronicity of the overdose, the authors retrospectively compared the clinical features of 15 patients with chronic repeated overmedication with those of 27 patients suffering acute single overdose. Patients suffering chronic repeated overmedication developed seizures (7/15) and serious arrhythmias (4/15) with serum levels of 28-70 mg/l. By contrast, only one of 19 patients suffering acute single overdose with peak levels less than 100 mg/l had seizures, and only two of 19 with levels less than 100 mg/l had serious arrhythmias. However, of the eight single-overdose patients with levels over 100 mg/l, seven had seizures and three had serious arrhythmias. Single-overdose patients were easily recognized by the presence of hypotension, hypokalemia, and low serum bicarbonate, features not present in chronic-type patients. Thus, while patients with theophylline overdose caused by chronic repeated overmedication frequently develop seizures and arrhythmias with serum levels of 40-70 mg/l, those with acute single ingestion are highly unlikely to suffer serious complications unless serum levels exceed 100 mg/l. Management of the intoxication, especially selection of patients for hemoperfusion, should be based on whether the overdose is caused by an acute single ingestion or chronic repeated overmedication.

Acute Disease↗
PubMed1985

Altered methadone pharmacokinetics in methadone-maintained pregnant women.

We studied the influence of human pregnancy on the maternal disposition and effects of methadone. Nine healthy pregnant women who had been on p.o. methadone maintenance for at least 2 months were studied between 20 and 34 weeks of gestation (phase I), 35 and 40 weeks (phase II), 1 to 4 weeks post partum (phase III) and 8 to 9 weeks post partum (phase IV). Two subjects who breast-fed their infants had plasma and breast milk samples collected simultaneously. With or without normalization for dose and body weight, trough plasma concentrations of methadone were significantly lower and total or unbound methadone clearances greater during pregnancy than after delivery. Plasma protein binding of methadone was lower during pregnancy but the difference was only statistically significant between phases I and IV. The greater ratios of urinary excretion of the major metabolites to total and unbound methadone areas under the curve during pregnancy suggests that methadone metabolism was enhanced. The ratios of concentrations of methadone in milk to plasma were constant in two subjects, 0.32 +/- 0.06 and 0.61 +/- 0.07, respectively. Some of the women reported symptoms of methadone withdrawal during pregnancy, even when the daily methadone dose did not change. Because of the lower plasma methadone concentrations, increased methadone doses may be required during pregnancy to achieve methadone maintenance.

Adult↗
PubMed1985

Dose-dependent sulfoconjugation of salicylamide in dogs: effect of sulfate depletion or administration.

The effects of plasma inorganic sulfate concentrations on the dose-dependent kinetics of salicylamide (SAM) were examined in the dog. Decreasing plasma sulfate concentrations from 0.9 mM to less than 0.3 mM significantly decreased clearance of a small dose of SAM (5 mg/kg) to the sulfate conjugate. Infusing sodium sulfate to prevent the decrease in plasma inorganic sulfate concentration that follows a p.o. 20-mg/kg dose of SAM did not increase SAM elimination. However, sodium sulfate given p.o. decreased SAM bioavailability, which suggests a local effect of sulfate on intestinal first-pass metabolism of SAM. These data show some dependence of SAM metabolism on plasma inorganic sulfate concentrations, but only when they are markedly reduced.

Animals↗
PubMed1985

Combined hepatic and renal injury in alcoholics during therapeutic use of acetaminophen.

Combined hepatocellular injury and renal tubular necrosis developed in five alcoholic patients who were receiving acetaminophen therapeutically. Two patients were taking doses prescribed by a physician. The hepatitis was characterized by extremely high serum transaminase values that were maximal on admission. Two patients died, and autopsy disclosed hepatic centrizonal necrosis and acute renal tubular necrosis. The three who survived had clinical features typical of acute tubular necrosis. All five had measurable concentrations of acetaminophen in plasma, although measurements were requested on admission only in two patients. When an alcoholic presents with combined hepatic and renal insufficiency, acetaminophen should be considered as a possible inciting agent. This diagnosis should be considered when serum transaminase levels are markedly elevated and when renal failure is due to acute tubular necrosis.

Acetaminophen↗