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Biomedical subjects

G Randall Bond

Publications and source records attributed to G Randall Bond.

10 recordsLinked to original sources
PubMed2004

Use of vasopressin in a canine model of severe verapamil poisoning: a preliminary descriptive study.

OBJECTIVES: The purpose of this preliminary study was to evaluate the effect of arginine vasopressin (AVP) administration in a model of shock induced by calcium channel antagonist overdose and to determine endogenous serum AVP concentrations in calcium channel antagonist-induced shock. METHODS: This was a controlled, randomized laboratory investigation based on a previously described canine model of verapamil toxicity. After induction of verapamil toxicity, animals in both the control and the experimental groups (n = 6 each) received a continuous infusion of verapamil. Experimental animals received an escalating dose of AVP, while control animals received an equal volume of 0.9% saline infusion. The hemodynamic end point was return of mean arterial pressure (MAP) to within 20% of baseline. Surviving animals were killed after 60 minutes. RESULTS: In the treatment group, administration of low-dose AVP (4 mU/kg/min) resulted in further declines in cardiac index and heart rate. No significant change was noted in MAP with low-dose AVP. A slight increase in MAP was noted with both escalating doses of AVP and equivalent volumes of normal saline. By the end of the 60-minute antidote/saline phase, the MAPs of the saline control group and the AVP experimental group were similar. The primary hemodynamic end point was not achieved in either the AVP or the saline control arm. Mean baseline serum AVP concentration in control animals was 5.8 pg/mL, increasing to 225 pg/mL during the toxicity phase. CONCLUSIONS: In an animal model of verapamil-induced shock, endogenous AVP levels increased nearly 40-fold compared with baseline levels. Escalating doses of exogenous AVP worsened cardiac index and failed to return MAP to within 20% of baseline.

Animals↗
PubMed2003

Massive venlafaxine overdose resulted in a false positive Abbott AxSYM urine immunoassay for phencyclidine.

CASE REPORT: A 13-yr-old girl overdosed on 48 x 150 mg venlafaxine (Effexor XR). She was taking venlafaxine regularly for depression. Her only other medications included topical Benzamycin and pyridoxine 50 mg daily for acne. The Abbott AxSYM assay was positive only for phencyclidine, but GC/MS did not confirm the presence of phencyclidine. Toxilab identified only one substance, confirmed by GC/MS as venlafaxine. A serum sample obtained 3 h after her ingestion revealed a venlafaxine concentration of 24460 ng/mL and an O-desmethylvenlafaxine concentration of 3930 ng/mL, confirming the massive acute overdose (therapeutic range of venlafaxine and O-desmethylvenlafaxine together is 250-750 ng/mL). Urine spiked with 4.2 mg/mL ofvenlafaxine and 0.7 mg/mL of O-desmethylvenlafaxine was interpreted as positive with the Abbott AxSYM fluorescent polarized immunoassay for phencyclidine (readout of 28 ng/mL). CONCLUSION: Venlafaxine may cause a false positive Abbott AxSYM phencyclidine assay when present in very high concentrations. Physicians should be aware of this potential reaction when interpreting urine drug immunoassays.

Adolescent↗
PubMed2003

Mitigation of pennyroyal oil hepatotoxicity in the mouse.

OBJECTIVES: Pennyroyal oil ingestion has been associated with severe hepatotoxicity and death. The primary constituent, R-(+)-pulegone, is metabolized via hepatic cytochrome P450 to toxic intermediates. The purpose of this study was to assess the ability of the specific cytochrome P450 inhibitors disulfiram and cimetidine to mitigate hepatotoxicity in mice exposed to toxic levels of R-(+)-pulegone. METHODS: 20-g female BALB/c mice were pretreated with either 150 mg/kg of cimetidine intraperitoneal (IP), 100 mg/kg of disulfiram IP, or both. After one hour, mice were administered 300 mg/kg of pulegone IP and were killed 24 hours later. Data were analyzed using ANOVA. Post-hoc t-tests used Bonferroni correction. RESULTS: There was a tendency for lower serum glutamate pyruvate transaminase in the disulfiram and cimetidine groups compared with the R-(+)-pulegone group. The differences were significant for both the cimetidine and the combined disulfram and cimetidine groups compared with the R-(+)-pulegone group. Pretreatment with the combination of disulfiram and cimetidine most effectively mitigated R-(+)-pulegone-induced hepatotoxicity. CONCLUSIONS: Within the limitations of a pretreatment animal model, the combination of cimetidine and disulfiram significantly mitigates the effects of pennyroyal toxicity and does so more effectively than either agent alone. These data suggest that R-(+)-pulegone metabolism through CYP1A2 appears to be more important in the development of a hepatotoxic metabolite than does metabolism via CYP2E1.

Animals↗
PubMed2003

The difficulty of risk assessment for hepatic injury associated with supra-therapeutic acetaminophen use.

We examined historical and laboratory features to identify patients who do not experience hepatic injury when presenting with a history of repeated supra-therapeutic acetaminophen use by performing a retrospective, double cohort comparison over almost 5 y. One cohort included patients suffering severe hepatic injury after supra-therapeutic acetaminophen ingestion; the control cohort included all patients in a geographically limited population with repeated supra-therapeutic acetaminophen ingestion who did not experience severe hepatic injury. Demographics, baseline health, medications, ethanol consumption, acetaminophen dosage, reason for excessive acetaminophen dosing, acetaminophen concentration at presentation, presentation and peak hepatic enzymes, N-acetylcysteine (NAC) treatment, highest measured AST and outcome were abstracted from 1114 possible patient contacts. Twenty two of these met all inclusion criteria. Ten suffered severe hepatic injury, 12 did not. The actual acetaminophen dose consumed over a period of time was difficult to establish, but the historic quantity ingested exceeded 20 g in the majority of patients in both groups. High ethanol use was common in both groups. All patients who ultimately suffered severe liver injury presented with some injury. No patient who presented without some injury suffered severe injury. None of these patients were treated with NAC. Two patients who presented with minor injury (1 of whom received NAC), did not progress to severe injury. Future investigations of the cause of liver injury in patients exposed to supra-therapeutic doses of acetaminophen will require larger patient numbers. The lack of injury in similarly exposed patients underscores the peril of attempting to assess the role of risk factors without an appropriate control group. Our experience suggests history is unlikely to be clinically useful in predicting risk of injury. Future risk assessment studies should focus on objective presentation features like presence or absence of injury or serum acetaminophen levels.

Acetaminophen↗
PubMed2002

The role of activated charcoal and gastric emptying in gastrointestinal decontamination: a state-of-the-art review.

Gastrointestinal decontamination has been practiced for hundreds of years; however, only in the past few years have data emerged that demonstrate a clinical benefit in some patients. Because most potentially toxic ingestions involve agents that are not toxic in the quantity consumed, the exact circumstances in which decontamination is beneficial and which methods are most beneficial in those circumstances remain important topics of research. Maximum benefit from decontamination is expected in patients who present soon after the ingestion. Unfortunately, many overdose patients present at least 2 hours after taking a medication, when most of the toxin has been absorbed or has moved well into the intestine, beyond the expected reach of gastrointestinal decontamination. Decontamination probably does not contribute to the outcome of many such patients, especially those without symptoms. However, if absorption has been delayed or gastrointestinal motility has been slowed, activated charcoal may reduce the final amount absorbed. The use of activated charcoal in these cases may be beneficial and is associated with few complications. Therefore, administration of activated charcoal is recommended as soon as possible after emergency department presentation, unless the agent and quantity are known to be nontoxic, the agent is known not to adsorb to activated charcoal, or the delay has been so long that absorption is probably complete. The use of gastric emptying in addition to activated charcoal has generated intense debate. Several large comparative studies have failed to demonstrate a benefit of gastric emptying before activated charcoal. Because complications of such 2-step decontamination include a higher rate of intubation, aspiration, and ICU admission, gastric emptying in addition to activated charcoal cannot be considered the routine approach to patients. However, there are several infrequent circumstances in which the data are inadequate to accurately assess the potential benefit of gastric emptying in addition to activated charcoal: symptomatic patients presenting in the first hour after ingestion, symptomatic patients who have ingested agents that slow gastrointestinal motility, patients taking sustained release medications, and those taking massive or life-threatening amounts of medication. These circumstances represent only a small subset of ingestions. In the absence of convincing data about benefit or lack of benefit of gastric emptying for these patients, individual physicians must act on a personal valuation: Is it better to use a treatment that might have some benefit but definitely has some risk or not to use a treatment that has any risk unless there is proven benefit?

Absorption↗
PubMed2002

American Academy of Clinical Toxicology practice guidelines on the treatment of methanol poisoning.

EPIDEMIOLOGY: Almost all cases of acute methanol toxicity result from ingestion, though rarely cases of poisoning have followed inhalation or dermal absorption. The absorption of methanol following oral administration is rapid and peak methanol concentrations occur within 30-60minutes. MECHANISMS OF TOXICITY: Methanol has a relatively low toxicity and metabolism is responsible for the transformation of methanol to its toxic metabolites. Methanol is oxidized by alcohol dehydrogenase to formaldehyde. The oxidation of formaldehyde to formic acid is facilitated by formaldehyde dehydrogenase. Formic acid is converted by 10-formyl tetrahydrofolate synthetase to carbon dioxide and water. In cases of methanol poisoning, formic acid accumulates and there is a direct correlation between the formic acid concentration and increased morbidity and mortality. The acidosis observed in methanol poisoning appears to be caused directly or indirectly by formic acid production. Formic acid has also been shown to inhibit cytochrome oxidase and is the prime cause of ocular toxicity, though acidosis can increase toxicity further by enabling greater diffusion of formic acid into cells. FEATURES: Methanol poisoning typically induces nausea, vomiting, abdominal pain, and mild central nervous system depression. There is then a latent period lasting approximately 12-24 hours, depending, in part, on the methanol dose ingested, following which an uncompensated metabolic acidosis develops and visualfunction becomes impaired, ranging from blurred vision and altered visual fields to complete blindness. MANAGEMENT: For the patient presenting with ophthalmologic abnormalities or significant acidosis, the acidosis should be corrected with intravenous sodium bicarbonate, the further generation of toxic metabolite should be blocked by the administration of fomepizole or ethanol and formic acid metabolism should be enhanced by the administration of intravenous folinic acid. Hemodialysis may also be required to correct severe metabolic abnormalities and to enhance methanol and formate elimination. For the methanol poisoned patient without evidence of clinical toxicity, the first priority is to inhibit methanol metabolism with intravenous ethanol orfomepizole. Although there are no clinical outcome data confirming the superiority of either of these antidotes over the other, there are significant disadvantages associated with ethanol. These include complex dosing, difficulties with maintaining therapeutic concentrations, the need for more comprehensive clinical and laboratory monitoring, and more adverse effects. Thus fomepizole is very attractive, however, it has a relatively high acquisition cost. CONCLUSION: The management of methanol poisoning includes standard supportive care, the correction of metabolic acidosis, the administration of folinic acid, the provision of an antidote to inhibit the metabolism of methanol to formate, and selective hemodialysis to correct severe metabolic abnormalities and to enhance methanol and formate elimination. Although both ethanol and fomepizole are effective, fomepizole is the preferred antidote for methanol poisoning.

Ethanol↗