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Biomedical subjects

Geoffrey K Isbister

Publications and source records attributed to Geoffrey K Isbister.

At least 37 records · Page 2Linked to original sources
PubMed2005

Pharmacologically distinct cardiovascular effects of box jellyfish (Chironex fleckeri) venom and a tentacle-only extract in rats.

Using a recently developed technique to extract jellyfish venom from nematocysts, the present study investigated the in vivo cardiovascular effects of Chironex fleckeri venom and tentacle extract (devoid of nematocysts). In anaesthetised rats, venom (10 microg/kg, i.v.) produced a transient pressor response (23+/-4 mmHg) followed, in two of five animals, by cardiovascular collapse. Tentacle extract (100 microg/kg, i.v.) produced a more prolonged hypertensive effect (31+/-3 mmHg) without cardiovascular collapse. Prazosin (50 microg/kg, i.v.) did not have any significant effect on the cardiovascular effects produced by venom. However, prazosin significantly attenuated the pressor response produced by tentacle extract. Ketanserin (1 mg/kg, i.v.) did not have any significant effect on the cardiovascular response of the anaesthetised rat to venom (10 microg/kg, i.v.; 25+/-1 mmHg). Sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE) was performed to compare the two jellyfish samples used in the present study. In addition to ensuring reproducibility of future studies and allow comparison with previous research. We show, for the first time, that a pure venom sample extracted from C. fleckeri nematocysts and a tentacle extract have cardiovascular effects in the anaesthetised rat which are different and pharmacologically distinct.

Animals↗
PubMed2005

The in vivo cardiovascular effects of the Irukandji jellyfish (Carukia barnesi) nematocyst venom and a tentacle extract in rats.

Envenoming by Carukia barnesi may produce life-threatening Irukandji syndrome. There is little published on the activity of C. barnesi venom. This is the first study to investigate the in vivo cardiovascular effects of C. barnesi venom and a tentacle extract (devoid of nematocysts). Venom (50 microg/kg or 100 microg/kg, i.v.) produced a pressor response (42+/-3 and 44+/-6 mmHg, respectively; n=4) and increase in heart rate (31+/-5 and 13+/-2 bpm, respectively; n = 4) in anaesthetised rats. These changes were not dose-dependent and were followed by cardiovascular collapse in one of four rats receiving 50 microg/kg and three of four animals receiving 100 microg/kg. Prazosin (50 microg/kg, i.v.) significantly attenuated the venom (50 microg/kg, i.v.)-induced pressor response (-8+/-3 mmHg; P < 0.05; n = 4) and tachycardia (-9+/-4 bpm; P < 0.05; n = 4). Tentacle extract (100 microg/kg; i.v.) produced a pressor response (51+/-12 mmHg; n = 3) and an increase in heart rate (35+/-1 bpm; n = 3) in anaesthetised rats, with no subsequent cardiovascular collapse. The results of this study are consistent with the effects shown by humans envenomed by C. barnesi which are postulated to be a result of catecholamine release. We show, for the first time, that C. barnesi tentacle extract, free of nematocyst material, produces cardiovascular effects which are distinct from those caused by venom derived from isolated nematocysts.

Adrenergic alpha-Antagonists↗
PubMed2005

The in vivo cardiovascular effects of an Australasian box jellyfish (Chiropsalmus sp.) venom in rats.

Using a new technique to extract venom from the nematocysts of jellyfish, the in vivo cardiovascular effects of Chiropsalmus sp. venom were investigated in anaesthetized rats. Chiropsalmus sp. venom (150 microg/kg, i.v.) produced a transient hypertensive response (44+/-4 mmHg; n=6) followed by hypotension and cardiovascular collapse. Concurrent artificial respiration or pretreatment with Chironex fleckeri antivenom (AV, 3000 U/kg, i.v.) did not have any effect on the venom-induced hypertensive response nor the subsequent cardiovascular collapse. The cardiovascular response of animals receiving venom after the infusion of MgSO4 (50-70 mM @ 0.25 ml/min, i.v.; n=5) alone, or in combination with AV (n=5), was not significantly different from rats receiving venom alone. Prior administration of prazosin (50 microg/kg, i.v.; n=4) or ketanserin (1 mg/kg, i.v.; n=4) did not significantly attenuate the hypertensive response nor prevent the cardiovascular collapse induced by venom (50 microg/kg, i.v.). In contrast to previous work examining C. fleckeri venom, administration of AV alone, or in combination with MgSO4, was not effective in preventing cardiovascular collapse following the administration of Chiropsalmus sp. venom. This indicates that the venom of the two related box jellyfish contain different lethal components and highlights the importance of species identification prior to initiating treatment regimes following jellyfish envenoming.

Animals↗
PubMed2005

Acute tetrodotoxin-induced neurotoxicity after ingestion of puffer fish.

This study documents the effects of puffer-fish poisoning on peripheral nerve. Excitability measurements investigated membrane properties of sensory and motor axons in four patients. The median nerve was stimulated at the wrist, with compound muscle potentials recorded from abductor pollicis brevis and compound sensory potentials from digit 2. Stimulus-responses, strength-duration time constant (tau(SD)), threshold electrotonus, and current-threshold relations were recorded. The urine of each patient tested positive for tetrodotoxin. Compared with controls, axons were of higher threshold, compound muscle action potentials and compound sensory nerve action potentials were reduced in amplitude, latency was prolonged, and tau(SD) was reduced. In recovery cycles, refractoriness, superexcitability, and late subexcitability were decreased. Threshold electrotonus of motor axons exhibited distinctive abnormalities with less threshold decline than normal on depolarization and greater threshold increase on hyperpolarization (p < 0.0005 for each patient). The changes in excitability were reproduced in a mathematical model by reducing sodium (Na(+)) permeabilities by a factor of two. This study confirms that the neurotoxic effects of puffer-fish poisoning can be explained by tetrodotoxin blockade of Na(+) channels. It demonstrates the ability of noninvasive nerve excitability studies to detect Na(+) channel blockade in vivo and also the utility of mathematical modeling to aid interpretation of altered excitability properties in disease.

Action Potentials↗
PubMed2005

Phospholipase A2-dependent effects of the venom from the New Guinean small-eyed snake Micropechis ikaheka.

The New Guinean small-eyed snake (Micropechis ikaheka) is a cause of life-threatening envenoming. Previous studies on M. ikaheka venom have indicated the presence of neurotoxins as well as myotoxins. This study examined the in vitro myotoxic effects of M. ikaheka venom and the efficacy of a polyvalent antivenom in neutralizing these effects. Venom (50 microg/ml) produced a slowly developing contracture and inhibition of direct twitches of the chick biventer cervicis nerve-muscle preparation in the presence of tubocurarine (10 microM). Myotoxicity was confirmed by subsequent histological examination of tissues. This myotoxicity was prevented by the prior addition of polyvalent snake antivenom (30 U/ml). However, the addition of antivenom (30 U/ml) 1 h after venom administration failed to reverse or prevent the further inhibition of direct twitches. In addition, venom (1-10 microg/ml) produced concentration-dependent contractions of the guinea-pig isolated ileum. These effects were dependent on phospholipase A2 (PLA2) activity of the venom as evidenced by the ability of the PLA2 inhibitor 4-bromophenacyl bromide (4-BPB; 1.8 mM) to prevent this activity. This study indicates that M. ikaheka venom causes significant myotoxicity and that polyvalent snake antivenom may be a potential treatment for the myotoxic effects in patients envenomed by this species.

Acetophenones↗
PubMed2005

The population pharmacokinetics of citalopram after deliberate self-poisoning: a Bayesian approach.

Defining the pharmacokinetics of drugs in overdose is complicated. Deliberate self-poisoning is generally impulsive and associated with poor accuracy in dose history. In addition, early blood samples are rarely collected to characterize the whole plasma-concentration time profile and the effect of decontamination on the pharmacokinetics is uncertain. The aim of this study was to explore a fully Bayesian methodology for population pharmacokinetic analysis of data that arose from deliberate self-poisoning with citalopram. Prior information on the pharmacokinetic parameters was elicited from 14 published studies on citalopram when taken in therapeutic doses. The data set included concentration-time data from 53 patients studied after 63 citalopram overdose events (dose range: 20-1700 mg). Activated charcoal was administered between 0.5 and 4 h after 17 overdose events. The clinical investigator graded the veracity of the patients' dosing history on a 5-point ordinal scale. Inclusion of informative priors stabilised the pharmacokinetic model and the population mean values could be estimated well. There were no indications of non-linear clearance after excessive doses. The final model included an estimated uncertainty of the dose amount which in a simulation study was shown to not affect the model's ability to characterise the effects of activated charcoal. The effect of activated charcoal on clearance and bioavailability was pronounced and resulted in a 72% increase and 22% decrease, respectively. These findings suggest charcoal administration is potentially beneficial after citalopram overdose. The methodology explored seems promising for exploring the dose-exposure relationship in the toxicological settings.

Adolescent↗
PubMed2005

Neurotoxic marine poisoning.

Marine poisoning results from the ingestion of marine animals that contain toxic substances and causes substantial illness in coastal regions. Three main clinical syndromes of marine poisoning have important neurological symptoms-ciguatera, tetrodotoxin poisoning, and paralytic shellfish poisoning. Ciguatera is the commonest syndrome of marine poisoning and is characterised by moderate to severe gastrointestinal effects (vomiting, diarrhoea, and abdominal cramps) and neurological effects (myalgia, paraesthesia, cold allodynia, and ataxia), but is rarely lethal. Tetrodotoxin poisoning and paralytic shellfish poisoning are less common but have a higher fatality rate than ciguatera. Mild gastrointestinal effects and a descending paralysis are characteristic of these types of poisoning. In severe poisoning, paralysis rapidly progresses to respiratory failure. Diagnosis of all types of marine poisoning is made from the circumstances of ingestion (type of fish and location) and the clinical effects. Because there are no antidotes, supportive care, including mechanical ventilation in patients with severe paralysis, is the mainstay of treatment.

Animals↗
PubMed2005

Antipsychotic poisoning in young children: a systematic review.

The aim of this review was to determine the spectrum and severity of effects of unintentional antipsychotic poisoning in children. A computerised literature search of MEDLINE (1966 to February 2005) and EMBASE (1980 to February 2005) was undertaken. The Internet was searched using URL: www.google.com. The proceedings of the North American Congress of Clinical Toxicology (NACCT) and the European Association of Poisons Centres and Clinical Toxicologists (EAPCCT) were hand searched. All cases of unintentional antipsychotic (all classes) poisoning in children aged 0-6 years were included. The data extracted included the age, weight, antipsychotic, dose, clinical effects, treatment and outcomes. The toxic dose was estimated as the lowest dose causing objective adverse effects.Sixty-eight reports were identified. Few contained all of the required information. Most of the case series included multiple antipsychotics with limited information on individual drugs or all ages with limited paediatric information. For most antipsychotics the ingestion of one tablet caused symptoms that were sometimes severe and usually lasted from 1 to 3 days. Extrapyramidal symptoms (EPS) were often delayed for up to 12-24 hours. Chlorpromazine caused CNS depression, hypotension and miosis; EPS and cardiac effects were rare, and the toxic dose was estimated to be 15 mg/kg. Haloperidol caused drowsiness (rarely coma) and over one-half of patients had neuromuscular effects (mainly EPS), with a toxic dose estimated at 0.15 mg/kg. Thioridazine caused CNS depression and potentially cardiac effects, with a toxic dose of 1.4 mg/kg. Atypical antipsychotics caused significant CNS depression (except risperidone); EPS were less common. Toxic doses were clozapine 2.5 mg/kg, olanzapine 0.5 mg/kg and aripiprazole 3 mg/kg. EPS responded to anticholinergic drug treatment. In summary, unintentional antipsychotic ingestion in children can cause severe effects that last 1-3 days, often with one tablet. Children potentially ingesting a toxic dose or who are symptomatic should be considered for assessment in hospital. Most cases resolve with good supportive care. Toxic doses are only estimates that are based on limited data and should be used with caution until prospective studies are undertaken.

Antipsychotic Agents↗
PubMed2005

Hyperbaric oxygen for carbon monoxide poisoning : a systematic review and critical analysis of the evidence.

Poisoning with carbon monoxide (CO) is an important cause of unintentional and intentional injury worldwide. Hyperbaric oxygen (HBO) enhances CO elimination and has been postulated to reduce the incidence of neurological sequelae. These observations have led some clinicians to use HBO for selected patients with CO poisoning, although there is considerable variability in clinical practice. This article assesses the effectiveness of HBO compared with normobaric oxygen (NBO) for the prevention of neurological sequelae in patients with acute CO poisoning. The following databases were searched: MEDLINE (1966 to present), EMBASE (1980 to present), and the Controlled Trials Register of the Cochrane Collaboration, supplemented by a manual review of bibliographies of identified articles and discussion with recognised content experts. All randomised controlled trials involving people acutely poisoned with CO, regardless of severity, were examined. The primary analysis included all trials from which data could be extracted. Sensitivity analysis examined trials with better validity (defined using the validated instrument of Jadad) and those enrolling more severely poisoned patients. Two reviewers independently extracted from each trial, including information on the number of randomised patients, types of participants, the dose and duration of the intervention, and the prevalence of neurological sequelae at follow-up. A pooled odds ratio (OR) for the presence of neurological symptoms at 1-month follow-up was calculated using a random effects model. Bayesian models were also investigated to illustrate the degree of certainty about clinical effectiveness. Eight randomised controlled trials were identified. Two had no evaluable data and were excluded. The remaining trials were of varying quality and two have been published only as abstracts. The severity of CO poisoning varied among trials. At 1-month follow-up after treatment, sequelae possibly related to CO poisoning were present in 242 of 761 patients (36.1%) treated with NBO, compared with 259 of 718 patients (31.8%) treated with HBO. Restricting the analysis to the trials with the highest quality scores or those that enrolled all patients regardless of severity did not change the lack of statistical significance in the outcome of the pooled analysis. We found empiric evidence of multiple biases that operated to inflate the benefit of HBO in two positive trials. In contrast, the interpretation of negative trials was hampered by low rates of follow-up, unusual interventions for control patients and inclusion of less severely poisoned patients. Collectively, these limitations may have led negative trials to overlook a real and substantial benefit of HBO (type II error). There is conflicting evidence regarding the efficacy of HBO treatment for patients with CO poisoning. Methodological shortcomings are evident in all published trials, with empiric evidence of bias in some, particularly those that suggest a benefit of HBO. Bayesian analysis further illustrates the uncertainty about a meaningful clinical benefit. Consequently, firm guidelines regarding the use of HBO for patients with CO poisoning cannot be established. Further research is needed to better define the role of HBO, if any, in the treatment of CO poisoning. Such research should not exclude patients with severe poisoning, have a primary outcome that is clinically meaningful and have oversight from an independent data monitoring and ethics committee.

Carbon Monoxide Poisoning↗
PubMed2004

The efficacy of two antivenoms against the in vitro myotoxic effects of black snake (Pseudechis) venoms in the chick biventer cervicis nerve-muscle preparation.

Neurotoxicity is rarely seen following human systemic envenoming by Australasian black snakes (genus Pseudechis) with myotoxicity being the most prominent feature following bites by some species. This study investigated the in vitro myotoxicity of venoms from seven species of Australasian Pseudechis and determined the efficacy of CSL black and tiger snake antivenoms. All Pseudechis venoms (10 microg/ml) significantly inhibited direct twitches of the chick biventer cervicis nerve-muscle preparation (p<0.05, one-way ANOVA). Prior addition of black snake antivenom (5 U/ml) prevented the inhibitory effects of all Pseudechis venoms (p<0.05, one-way ANOVA), except Pseudechis butleri. Prior addition of tiger snake antivenom (5 U/ml) prevented the venom-induced reduction in direct twitches to Notechis scutatus venom and all Pseudechis venoms (p<0.05, one-way ANOVA), with the exception of Pseudechis australis and Pseudechis colletti venoms. Black or tiger snake antivenom (5 U/ml) added 1 h after the addition of venom inhibited further reduction of direct twitches by N. scutatus and most Pseudechis venoms, but did not significantly restore twitch height. PLA2 activity was found in all venoms with the following rank order: Pseudechis porphyriacus>P. australis>Pseudechis papuanus>P. butleri>Pseudechis guttatus> or =Pseudechis pailsii>P. colletti>N. scutatus. The results of the present study suggest that Australasian Pseudechis venoms possess variable myotoxic activity. The ability of black or tiger snake antivenom to prevent or inhibit further venom-induced effects varied across the genus.

Animals↗
PubMed2004

Mouse spider bites (Missulena spp.) and their medical importance. A systematic review.

OBJECTIVE: To determine the clinical significance of definite bites by mouse spiders (Actinopodidae: Missulena spp.) from published case reports/series and museum records. DATA SOURCES: A computerised literature search of MEDLINE and EMBASE was undertaken. All cases reported to major Australian museums and reports from venom researchers working with mouse spiders were also reviewed. Textbooks on clinical toxinology were searched and further reports of cases were located. STUDY SELECTION: All cases of definite spider bites where the spider was collected and identified by an expert as a mouse spider were included. DATA EXTRACTION: All reports were evaluated and the following data extracted: patient demographics (age, sex, geographical location, season), bite site, local and systemic effects, and hospital attendance. Clinical effects were classified into three groups: severe neurotoxic envenoming, local neurotoxic effects or mild systemic effects, and minor local effects. DATA SYNTHESIS: Forty definite bites were identified from around Australia, with only one case of severe envenoming (a 19-month-old child). Local neurotoxic effects occurred in six cases and minor systemic effects in five. There was no evidence of envenoming in most bite victims, and the rate of severe envenoming was 2.5% (95% CI, 0-13%). There were no recorded deaths. CONCLUSIONS: In most cases, bites by mouse spiders cause only minor or moderate effects. Severe envenoming is rare and far less common than for funnel-web spider bites. Mouse spider bites do not appear to be a major medical problem.

Adult↗
PubMed2004

Bites by Australian mygalomorph spiders (Araneae, Mygalomorphae), including funnel-web spiders (Atracinae) and mouse spiders (Actinopodidae: Missulena spp).

A number of mygalomorph spiders cause bites in Australia, including the funnel-web spiders (Hexathelidae, Atracinae: Hadronyche and Atrax) and mouse spiders (Actinopodidae: Missulena). There is ongoing debate about the significance of bites by mouse spiders and the frequency of severe envenoming by funnel-web spiders. We conducted a prospective cohort study of definite spider bites with expert spider identification and include the analysis of mygalomorph spiders here. Subjects were recruited prospectively from February 1999 to April 2003 from patients presenting to participating hospitals or contacting a state poison information centre. Forty-nine cases of bites by mygalomorph spiders were included: 16 were by funnel-web spiders, 13 by mouse spiders and 20 by other trapdoor spiders (Families Idiopidae and Nemesiidae). Of the 49 bites, 45 (92%) occurred on distal limbs (hands and feet). Local effects included severe pain (53%), puncture marks (61%) and bleeding (27%), local redness (33%). Itchiness did not occur. The following were highly statistically associated with mygalomorph spider bites compared to all other spiders (p<0.0001) circumstances (gardening at the time (likelihood ratio (LR) 7.9) and distal limb bites (LR 2.0)) and early clinical features (presence of puncture marks OR bleeding (2.3), or severe pain (2.0)). Of 16 funnel-web spider bites, there were 10 cases with minor local effects, four with moderate envenoming (non-specific systemic or local neurotoxicity) and two with severe envenoming requiring antivenom. In addition to local effects, mouse spider bites caused local paraesthesia in three cases, local diaphoresis in one case and non-specific systemic effects in five cases, but not severe envenoming. True trapdoor spider bites caused only minor effects. The data from a mixed species sample of funnel-web spiders confirms previous observations suggesting that only a small proportion of funnel-web bites cause severe effects. Mouse spider bites are unlikely to cause major envenoming but the clinical effects are consistent with neurotoxic venom and are more severe than the trapdoor spiders.

Animals↗
PubMed2004

Clinical consequences of spider bites: recent advances in our understanding.

Spider bite continues to be a controversial subject worldwide and attribution of clinical effects to different spiders is problematic because of poor case definition and paucity of clinical evidence. The effects of medically important spiders are sometimes underestimated and simultaneously there is misattribution of effects to harmless spider groups. The majority of suspected spider bites present as skin lesions or necrotic ulcers where the history of a spider bite must be confirmed. To be a definite spider bite, the patient must immediately observe the spider and there be evidence of the bite, such as pain. Important groups of spiders worldwide include the widow spiders (latrodectism), recluse spiders (loxoscelism) and some mygalomorph spiders including the Australian Funnel web spider. Most spiders only cause minor effects, including a large number of groups that have been implicated in necrotic arachnidism.

Animals↗
PubMed2004

The in vivo cardiovascular effects of box jellyfish Chironex fleckeri venom in rats: efficacy of pre-treatment with antivenom, verapamil and magnesium sulphate.

Using a new technique to extract venom from the nematocysts, the efficacy of CSL box jellyfish antivenom (AV) and adjunct therapies, verapamil and magnesium sulfate (MgSO(4)), were investigated against the in vivo cardiovascular effects of Chironex fleckeri venom in anaesthetised rats. C. fleckeri venom (30 microg/kg; i.v.) produced a transient hypertensive response followed by hypotension and cardiovascular collapse within 4 min of administration. Prophylactic treatment of anaesthetised rats with CSL box jellyfish AV (3000 U/kg; i.v.) did not have any effect on the venom-induced pressor response, but prevented cardiovascular collapse in four out of 10 animals. Administration of verapamil (20mM@0.25 ml/min; i.v.) either alone or in combination with AV, did not have any effect on the C. fleckeri venom-induced pressor response nor the consequent hypotension or cardiovascular collapse of animals. However, the administration of verapamil negated the partially protective effects of AV. Concurrent artificial respiration of animals with the above treatments did not attenuate the C. fleckeri venom-induced cardiovascular effects. MgSO(4) (0.05-0.07M@0.25 ml/min; i.v.) alone did not have any effect on the venom-induced pressor response nor the consequent cardiovascular collapse of animals. However, although combined AV and MgSO(4) administration could not inhibit the transient pressor effect following the administration of C. fleckeri venom, it prevented cardiovascular collapse in all animals. We show for the first time, the cardiovascular effects of a C. fleckeri venom sample free of tentacular contamination and the potential of MgSO(4) as an adjunct therapy for the treatment of potentially fatal C. fleckeri envenomings.

Animals↗