Acute and long-term effects of exposure to sodium monofluoroacetate (1080) in sheep.

Acute and long-term effects of a single, relatively high oral dose (0.25 and 0.30 mg/kg) of sodium monofluoroacetate (1080) on the survival and productivity of sheep were evaluated to establish a better understanding of 1080 poisoning and identify more specific changes diagnostic of toxicosis. In survivors, clinical signs of acute 1080 toxicosis such as salivation and lethargy were generally very mild. Fasted animals were more prone to 1080 toxicity. In animals that died, more severe signs, including tachypnoea, dyspnoea, and tremors occurred for 15-20 min prior to death. 1080 concentrations were highest in the blood > heart > skeletal muscle > liver. 1080 could not be detected in any of these organs of the animals that survived. Serum citrate concentrations were elevated for 4 days after dosing. No clinical or biochemical abnormalities were found in any animal after 4 days. Histopathological lesions were most marked in the heart and lung with inflammation, necrosis, and scattered foci of fibrous tissue in the myocardium, pulmonary oedema and inflammation of the lung. No adverse long-term effects on general health or reproductive performance were observed in any sheep that survived the first 4 days following exposure to 1080. The most reliable diagnostic indicators of 1080 exposure in sheep were measurement of its residues in blood, skeletal muscle and ruminal contents, increased serum citrate concentration, elevated heart rate, and characteristic electrocardiograph changes (up to 4 days after exposure). Death from 1080 is most likely to occur within 96 h, and animals that survived this period appeared normal.

The trophic effects of gastrin on fundic neuroendocrine cells of the rat stomach.

The histomorphological effect of multidose administration of 6 mg/kg pentagastrin b.d. for 5 weeks, and 1000 mg/kg sodium bicarbonate b.d. for 13 weeks, on the rat fundic mucosa has been examined. Sodium bicarbonate induced a significant hypergastrinaemia (plasma gastrin concentrations were 370.5 pg/ml in the control versus 642.6 pg/ml in sodium bicarbonate-treated rats after 13 weeks, P less than 0.01). Both treatment regimens induced fundic neuroendocrine cell hyperplasia. The cellular proliferation that occurred following hypergastrinaemia of endogenous or exogenous origin suggests that systemic gastrin concentrations play a major role in the control of fundic neuroendocrine cell populations.

The in vitro effect of amrinone on thromboxane B2 synthesis in human whole blood.

Thromboxane B2 production in vitro in human whole blood was inhibited at pharmacological levels of amrinone. There was no observed effect on prostacyclin production as measured by 6-ketoprostaglandin F1 alpha levels. The biochemical basis for the inhibition of platelet aggregation by amrinone and the inter-relationships between arachidonic acid metabolism, c-AMP and Ca2+ levels are discussed.

A comparison of the effects of three positive inotropic agents (amrinone, milrinone and medorinone) on platelet aggregation in human whole blood.

Amrinone, milrinone and medorinone inhibit platelet aggregation in human whole blood. They are particularly potent inhibitors of arachidonic acid induced aggregation, inhibiting by 50% (IC50) at concentrations of 1.5 microM (milrinone), 7.5 microM (medorinone) and 48 microM (amrinone). Each drug was less potent at inhibiting ADP and collagen-induced aggregation. The rank order for inhibition of arachidonic acid - induced aggregation correlated well with the rank order of cyclic AMP phosphodiesterase inhibition for these drugs when compared to the response of a reference cAMP phosphodiesterase inhibitor (CI-930) and a reference cGMP phosphodiesterase inhibitor (M & B 22948). Since inhibition of platelet aggregation in vitro occurred at clinically relevant concentrations, it is evident that these agents have potentially beneficial antithrombotic properties.

Frusemide/amiloride combination ('Frumil') in heart failure: an open, multi-centre study in general practice.

A total of 95 patients seen in general practice with oedema associated with heart failure took part in an open study of the efficacy and tolerability of a combination tablet containing 40 mg frusemide and 5 mg amiloride. The study was of 3-months' duration and patients received a dosage of 1 to 2 tablets once daily. Efficacy was assessed by physicians' scores for ankle, leg and lumbosacral oedema and pulmonary crepitations, body weight and physicians' global clinical impression. In addition, patients recorded their symptom severity in study diaries during the first 7 days of therapy, and the day before each trial visit. On the basis of the physicians' overall impression of response to therapy, 89 (93.7%) of the patients were graded as 'excellent', 'good' or 'adequate' responders. Improvement in severity scores for oedema, crepitations and body weight also followed this pattern, although certain symptoms were mild or absent in some patients at recruitment. Nine patients were withdrawn from the study, 4 due to drug-related adverse effects. There was no evidence of any consistent change in serum potassium levels or other clinical chemistry, liver function tests or haematology during the study.

The effect of ciprofibrate on gastric secretion in the rat.

The potential of ciprofibrate to inhibit gastric secretion has been investigated in the rat. A significant gastric antisecretory effect was observed following a single oral administration of 300 and 500 mg kg-1 and following a single intraduodenal dose of 100, 300 and 500 mg kg-1. The toxicological significance of this finding is discussed in the light of a spate of recent publications linking changes in gastric morphology with hypergastrinaemia produced as a secondary effect of inhibition of acid secretion.

Modification by monoamine oxidase inhibitors of the analgesic, hypothermic and toxic actions of morphine and pethidine in mice.

A single injection of phenelzine 100 mg kg-1 given 18 h before, decreased the analgesia and hypothermia induced by morphine, but potentiated the analgesic and hypothermic effects of pethidine, when the analgesics were administered either intraperitoneally, or intracerebroventricularly. The modification of pethidine analgesia and hypothermia, but not morphine analgesia, was antagonized by methysergide (10 mg lg-1, s.c.). The LD50 of pethidine, but not that of morphine, was 30-40% lower in mice treated with phenelzine tranylcypromine or iproniazid 6 h before the test. The increased lethality of a single dose of pethidine induced by phenelzine was also prevented by methysergide. Pretreatment of mice with 100 mg kg-1 phenelzine was followed by a significant rise in both brain tryptophan and 5-hydroxytryptamine (5-HT) concentrations which lasted for 24 h. Therefore, the changes in pethidine effects could have been due to raised brain tryptophan and 5-HT concentrations.

Persistence of sodium monofluoroacetate in livestock animals and risk to humans.

1. Sodium monofluoroacetate (1080), a vertebrate pesticide widely used in New Zealand, was administered orally to sheep and goats at a dose level of 0.1 mg kg-1 body weight to assess risk to humans of secondary poisoning from meat. Blood, muscle, liver, and kidney were analysed for 1080 residues. 2. The plasma elimination half-life was 10.8 h in sheep and 5.4 h in goats. Concentrations of 1080 in muscle (0.042 microgram g-1), kidney (0.057 microgram g-1), and liver (0.021 microgram g-1) were substantially lower than those in plasma (0.098 microgram ml-1) at 2.5 h after dosing. 3. Only traces of 1080 (< 0.002 to 0.008 microgram g-1) were found in sheep tissues after 96 hours. 4. Livestock are normally excluded from areas where 1080 is being used for pest control, reducing the risk of secondary poisoning. Even with accidental exposure to a sublethal dose 1080 would not persist in tissues for more than a few days because it is cleared rapidly from the body. Therefore the occurrence of 1080 in meat intended for human consumption is highly unlikely.

Persistence of sodium monofluoroacetate in rabbits and risk to non-target species.

1. Sodium monofluoroacetate (1080), a vertebrate pesticide used in New Zealand, was administered orally to rabbits at two dose levels (sub-lethal and lethal) to determine how long 1080 would persist in plasma, liver, kidney, and muscle so that the risk of consumption of meat from lethally or sub-lethally poisoned rabbits by non-target species could be assessed. 2. The plasma elimination half-life in rabbits receiving a sub-lethal dose was 1.1 h. Retention of 1080 in tissue was greater in rabbits dosed with a lethal dose than in those that received a sub-lethal dose. Irrespective of the dose level, concentration of 1080 in muscle, kidney, and liver was substantially lower than in the plasma. 3. Poisoning of dogs is possible because of their extreme susceptibility to 1080. Poisoning of birds is less likely. The risk of secondary poisoning is reduced as the concentration of 1080 declines in putrefying carcasses.

The relationship between the pharmacokinetics of amrinone in the marmoset and platelet effects.

The pharmacokinetic characteristics of amrinone have been studied in six female marmosets following oral administration of 1, 12.5, 25, 50 and 75 mg.kg-1 and an intravenous dose of 1mg.kg-1. The mean plasma AUC0 infinity was determined at each dose level; the values obtained were 2.5, 18.7, 33.9, 103 and 312 micrograms.h.ml-1 for the oral doses of 1, 12.5, 25, 50 and 75 mg.kg-1 respectively and 1.9 micrograms.h.ml-1 for the intravenous dose of 1mg.kg-1. Mean maximum observed plasma concentrations were 0.6, 7.1, 11.7, 23.7 and 40.0 micrograms.ml-1 respectively following oral doses. Over the range 1 to 50 mg.kg-1 the AUC0 infinity was linear; at 75 mg.kg-1 the AUC0 infinity was disproportionately greater. Elimination appeared to be first order over the dose range 1 to 50 mg.kg-1 and the t1/2 in the marmoset was approximately 1 to 3 hours over this dose range. The plasma levels achieved are discussed in relation to the observed effects on the platelet population in this species following chronic administration at high dose levels.

Behavioural, biochemical, and pathological responses of possums (Trichosurus vulpecula) poisoned with phosphorus paste.

AIM: To investigate the behavioural, biochemical and pathological responses of possums following poisoning with phosphorus paste, in order to assess the implications for the welfare of possums. METHODS: After ingestion of phosphorus paste by wild-caught possums (18 high dose, nine low dose, and 12 non-poisoned controls), behavioural observations were made at 15-min intervals for 24 h or until death. Serum biochemistry, and gross and microscopic pathology were assessed at 3-hourly intervals in a further 21 possums. RESULTS: Possums that ingested phosphorus paste developed an abnormal posture (high incidence of crouching after 4-8 h), mild congestion of the gastric mucosa, and elevated levels of creatine kinase (CK) in serum after 3-6 h. Retching was observed in 67% possums, and 44% vomited at least once. Possums were prostrate from about 18 h after eating the poison, and the response to handling, an indicator of consciousness, was lost at about 24 h, followed by death at 25 h. CONCLUSION: The main welfare concern was the possibility of discomfort or pain caused by the congestion of the gastric mucosa, as indicated by the crouched posture adopted by poisoned possums. Retching and vomiting may also have caused pain and distress. The degree of pain or discomfort would depend on the degree of congestion of the gastric mucosa, which was typically mild, and on the duration and severity of retching and vomiting, which were typically short and mild. Possums remained conscious until 1 h before death, implying that they were able to experience pain and distress from the effects of ingestion of phosphorus for almost the entire period of illness, which lasted for approximately one day.

The plasma pharmacokinetics of iophenoxic and iopanoic acids in goat.

1. The comparative plasma pharmacokinetics of two organic iodine-containing compounds were evaluated in the goat for their suitability as markers in wildlife studies. 2. After oral administration of a single dose, the plasma elimination half-life for iopanoic acid was considerably more rapid (t1/2 of 1-2 days) than that of iophenoxic acid (t1/2 of 81 days). 3. Similar peak plasma concentrations were obtained after administration of iophenoxic acid (1.5 mg/kg) and iopanoic acid (25 mg/kg); however, the AUC0----infinity for iopanoic acid at doses of 25, 50, and 100 mg/kg were 201 +/- 39, 604 +/- 225, and 1292 +/- 721 (micrograms h/ml +/- SD), respectively, which were less than the value of 36,600 +/- 6387 for the oral administration of iophenoxic acid at 1.5 mg/kg. 4. Iophenoxic acid was chosen as a suitable marker because of its persistence at detectable concentrations in the plasma for 5 months.

The in vitro effect of amrinone on platelet aggregation in human whole blood.

Amrinone was found to inhibit platelet aggregation in human whole blood in a dose dependent manner, and at physiological levels of the drug. Statistically significant drug-related decreases in aggregation were observed with collagen, ADP and arachidonic acid. Inhibition of aggregation was most marked with arachidonic acid, where greater than 90% inhibition was achieved at a drug concentration of 25 mugml-1. The aggregation profiles presented indicate that amrinone inhibits aggregation primarily through inhibition of thromboxane A2 synthesis.

Nicotinic acid enhances the production of 6-ketoprostaglandin F1 alpha in human whole blood in vitro.

The effect of nicotinic acid on the synthesis of arachidonic acid metabolites in human whole blood has been examined by stimulation with exogenous and endogenous arachidonic acid substrate. In both cases there was an increase in the production of 6-ketoprostaglandin F1 alpha which was statistically significant at 10 micrograms ml-1 (p less than 0.01) and 100 micrograms ml-1 (p less than 0.001) with endogenous arachidonic acid. This increase is markedly enhanced at nicotinic acid levels of 1000 and 2000 micrograms ml-1 following stimulation with exogenous arachidonic acid (p less than 0.01).

The importance of pharmacokinetic and receptor studies in drug safety evaluation.

The importance of pharmacokinetic and receptor studies in the preclinical and clinical safety evaluation of candidate drugs is reviewed with reference to a number of recently developed drugs. Different aspects of the relationships between pathways of metabolism, pharmacokinetics, receptor interactions, and drug toxicity are illustrated. The failure of animal toxicity studies to predict drug toxicity in humans, due to species differences in metabolism and pharmacokinetics, is illustrated by reference to the anti-inflammatory antiviral terpenoid carbenoxolone, the antiasthmatic candidate drug FPL 52757, and the cardiotonic drug amrinone. The false prediction of adverse effects in man from toxicity manifested in experimental animals, due to species differences in pharmacokinetics or receptor activities, is exemplified with reference to the antiepileptic valproic acid, the hypolipidemic drug ciprofibrate, the antipeptic ulcer drug, omeprazole, and the progestogen lynestrenol. Finally, the importance of adequate, repeat-dose, clinical pharmacokinetic studies in patients as distinct from healthy volunteers to evaluate any effect of the disease state, in the elderly and the young to examine the effects of age, and in sufficiently large populations to detect genetic anomalies and idiosyncrasies is illustrated by reference to the anti-rheumatoid drug benoxaprofen, the antiangina drug perhexiline, and the diuretic tienilic acid.

Pharmacokinetics of antipyrine, warfarin and paracetamol in the brushtail possum.

The plasma pharmacokinetics of antipyrine, warfarin and paracetamol have been studied in the Australian brushtail possum (Trichosurus vulpecula). The plasma elimination half-lives (t1/2) were 1.2 h for antipyrine, 11.9 h for warfarin and 5.2-12.9 h for paracetamol. Our data indicate that the clearance of these three xenobiotics in the possum is similar to that reported in eutherian mammals. There was no dose-dependent increase in paracetamol plasma t1/2 over the dose range 100-1000 mg kg(-1), indicating a lack of capacity saturation. This observation may in part explain the unusual resistance of the possum to the hepatotoxic effect of high doses of paracetamol.

Development of antidotes for sodium monofluoroacetate (1080).

Baits containing sodium monofluoroacetate (1080) are commonly used in New Zealand during feral pest control operations. However, each year, a number of domestic dogs are unintentionally killed during these control operations, and a suitable antidote to 1080 intoxication is required. The primary toxic mechanism of 1080 is well known. However, as with other pathologies where energy deprivation is the main effect of intoxication, the cascade of effects that arises from this primary mechanism is complex. At present, putative antidotes for 1080 are generally unable to address the primary mechanism of intoxication but such agents may be able to control the cascade of secondary effects, which can result during intoxication. Part of the reason for this is that targeting the cascade can provide a longer window of time for antidote success. We have undertaken studies that identified some of the central nervous system (CNS) and systemic pathophysiological cascades caused by 1080 intoxication. Using this information we designed antidotes, on the basis of preventing different steps in this cascade. In the chicken model targeting systemic changes, in particular reducing effects of nitric oxide derivatives generated in cardiac muscle, proved successful in reducing fatality associated with 1080. In rats and sheep, targeting the CNS with a number of compounds including: glutamate; calcium and dopamine antagonists; gamma amino butyric acid agonists, and astressin-like compounds reduced fatalaties. However, to be successful in the rat and sheep model a given antidote needed to move quickly from systemic circulation across the blood brain barrier and into the CNS. The work also suggests ways in which specific biomarkers of 1080 exposure may be developed with respect to different species.