Taking stock: UK national antidote availability increasing, but further improvements are required.

BACKGROUND: A 2010/2011 audit of the Royal College of Emergency Medicine (RCEM) National Poisons Information Service (NPIS) UK guidelines on antidote availability demonstrated variable stocking of antidotes for the management of poisoned patients; the guidelines were updated and republished in 2013. AIM: To assess if antidote stocking has improved since the 2010/2011 audit and introduction of the 2013 guidelines. METHODS: Questionnaires were sent to Chief Pharmacists at all 215 acute hospitals in England, Wales and Northern Ireland in October 2014. Data were collected on the timing of availability (category A antidotes should be available immediately, category B within 1 h and category C can be held supraregionally) and stock levels. RESULTS: 169 (78.6%) responses were received. Atropine, calcium gluconate and flumazenil (category A) were the only antidotes available in all hospitals within the recommended time and stock levels. Forty-one (24.3%) hospitals held every category A antidote; this increased to 81 (47.9%) for those holding at least one cyanide antidote and all other category A antidotes. The proportion of hospitals stocking category A/B antidotes within the recommended time increased for 20 (90.9%) category A/B antidotes. Fomepizole (category B) availability increased to 62.1% of hospitals from 11.4% in 2010/2011. Other than penicillamine (63.3% hospitals), there was poor availability (2.4%-36.1%) of category C antidotes. CONCLUSIONS: Availability of category A and B antidotes has improved since the 2010/2011 audit and 2013 guidelines. However, there remains significant variability particularly for category C antidotes. More work is required to ensure that those treating poisoned patients have timely access to antidotes focusing particularly on category C antidotes.

Two-generation reproduction and developmental neurotoxicity study with sodium chlorite in the rat.

The potential for sodium chlorite to produce reproductive toxicity, developmental neurotoxicity and alterations in hematology and thyroid hormones was evaluated in Sprague-Dawley rats administered sodium chlorite in the drinking water continuously for two generations. The F(0) generation animals (30 of each gender per group) and F(1) generation animals (25 of each gender per group) selected to rear the F(2) generation were allowed free access to drinking water containing 0, 35, 70 or 300 ppm sodium chlorite for a 10-week prebreed period, through mating for males and through mating, gestation and lactation for females. These drinking water concentrations corresponded to sodium chlorite doses of approximately 4, 8 and 30 mg kg(-1) day(-1) for males and 5, 10 and 39 mg kg(-1) day(-1) for females, respectively. Evaluations included standard reproductive and postnatal indices, sperm morphology and motility, estrous cyclicity, a functional observational battery, motor activity, auditory startle, swim maze, hematology, serum thyroid hormone analyses and histopathology of reproductive and nervous system tissues. Sodium chlorite resulted in a decrease in water consumption in all groups and a decrease in food consumption and body weights in the 70 and 300 ppm groups. There was no evidence of reproductive toxicity. Pup body weight was decreased in the 300 ppm group and small delays were observed in the time to preputial separation and vaginal opening. Mild anemia and mild methemoglobinemia were observed for animals in the 300 ppm group. Thyroid hormone levels were not affected by treatment. Changes to the nervous system were limited to small decreases in amplitude of auditory startle response for postnatal day (PND) 25 pups in the 70 and 300 ppm groups and a small decrease in absolute brain weight for PND 11 pups in the 300 ppm group. These effects were considered to be of questionable neurotoxicological significance. Based on the results of this study, the no-observed-effect level (NOEL) for effects on reproduction and thyroid hormones is 300 ppm. The no-observed-adverse-effect levels (NOAEL) for hematological toxicity and neurotoxicity are considered to be 70 and 300 ppm, respectively.

Sucralose: assessment of teratogenic potential in the rat and the rabbit.

The teratogenic potential of sucralose was examined following gavage administration to pregnant rats and rabbits during organogenesis. Groups of 20 mated rats were dosed on days 6-15 of gestation inclusive at 500, 1000 or 2000mg/kg/day; groups of 16 to 18 inseminated rabbits were dosed on days 6 to 19 of gestation inclusive at 175, 350 or 700mg/kg/day following preliminary studies at higher doses. Concurrent control groups received vehicle alone. Rats were killed on day 21 and rabbits on day 29 of gestation. Foetuses were evaluated at necropsy and after processing for possible soft tissue and skeletal alterations. There was no evidence of teratogenicity for either species. The only observed response to treatment in rats was a slight increase in water intake. Some adult rabbits receiving 700mg/kg/day exhibited marked gastrointestinal disturbance, also seen at higher doses in preliminary studies. Gastrointestinal effects such as these occur non-specifically in response to high doses of poorly absorbed compounds, and in the present study were considered to be responsible for two maternal deaths and four abortions. Full evaluation of rabbit foetuses in the main study (up to 700mg/kg/day) and necropsy of foetuses in a preliminary study with pregnant animals (up to 1000mg/kg/day) showed no evidence of adverse foetal response to sucralose. These teratology studies in both pregnant rodent and non-rodent animal models demonstrate that maternal consumption of high levels of sucralose during the period of organogenesis has no effect on normal foetal development in the rat or rabbit.

Contribution of glutamate receptors to spontaneous and stimulus-evoked discharge in afferent fibers innervating hair cells of the Xenopus lateral line organ.

The relative contributions of NMDA (N-methyl-D-aspartate) and non-NMDA glutamate receptors to spontaneous and stimulus-evoked transmission at the hair cell/afferent fiber synapse were determined in the Xenopus laevis lateral line organ. The non-NMDA receptor antagonist, CNQX (6-cyano-7-nitroquinoxaline-2,3-dione), reversibly reduced both spontaneous and stimulus-evoked discharge rate with an EC(50) of 0.5 microM. NMDA receptor antagonism with the combination of chlorokynurenic acid (100 microM) and elevated magnesium (1.1 mM), or elevated magnesium alone, blocked responses to NMDA without significantly altering spontaneous or stimulus-evoked discharge rate or the responses to kainate. All non-NMDA receptor agonists tested increased discharge rate at low concentrations and, at higher concentrations, increased, then suppressed discharge rate. The EC(50)s were: domoic acid (2.4 mcM)

Calcitonin gene-related peptide suppresses hair cell responses to mechanical stimulation in the Xenopus lateral line organ.

The presence of calcitonin gene-related peptide (CGRP) in the efferent fibers of virtually every hair cell organ studied suggests it may serve some fundamental but heretofore unknown role in control of hair cell function. We examined the effects of CGRP on spontaneous and stimulus-evoked discharge patterns in an in vitro preparation of the lateral line organ of Xenopus laevis. Discharge patterns were determined by sinusoidally displacing the cupula with a glass micropipette driven with a piezoelectric device while recording afferent fiber activity. All afferent fibers had characteristic frequencies of 16-32 Hz. Responses synchronized to cupular displacements as small as 20 nm. CGRP suppressed responses of the lateral line organ to displacement while increasing spontaneous discharge rate. In the presence of CGRP, stimulus-response curves were shifted 10 dB toward higher displacement levels. The suppression of stimulus-evoked responses suggests a function for CGRP as an efferent neurotransmitter that is similar to that of cholinergic efferent transmission in other hair cell organs. The 10 dB shift toward larger displacements makes it comparable in magnitude with the effects of electrical stimulation of efferents in the mammalian cochlea. This suggests a significant role for CGRP in efferent modulation of the output of this mechanosensory organ.

Pharmacological characterization of the CGRP receptor in the lateral line organ of Xenopus laevis.

Calcitonin gene-related peptide (CGRP) is a neurotransmitter candidate colocalized with acetylcholine in efferent fibers innervating hair cell organs. We have used the Xenopus laevis lateral line organ to investigate the responses of a hair cell organ to the CGRP family of peptides. Two isoforms of CGRP, r alpha-CGRP and r beta-CGRP, and a human analog of alpha-CGRP, h(Tyro) alpha-CGRP, produced dose-dependent increases in afferent nerve fiber discharge rate with EC50 values of approximately 1 microM. Rate increases were 31.2, 18.9, and 10.3%, respectively. The peptide fragment rCGRP8-37 a selective CGRP1 receptor antagonist, competitively inhibited the response to r alpha-CGRP. Diacetoamidomethyl cysteine CGRP (r[Cys(ACM)2,7]alpha-CGRP), a CGRP2 agonist, did not change discharge rate. Rat amylin did not increase rate until very high concentrations, and then the change was less than 7%. Rat adrenomedullin produced no increase in rate. Responses to r alpha-CGRP developed after metamorphosis. No change in spontaneous discharge rate was observed until postmetamorphic day 6, and then it was only a fraction of the maximal response. This response progressively increased until postmetamorphic day 28, when it reached its maximal value. The most straightforward interpretation of our results is that the effect of CGRP is mediated by the CGRP1 receptor and that CGRP, of the peptides presently known to exist in the CGRP family, is the most likely endogenous peptide mediating these effects.

Intravenous reproductive and developmental toxicity studies of cimadronate (YM175), a novel bisphosphonate, in rats and rabbits.

Cimadronate (YM175) is a novel bisphosphonate with potent inhibitory activity on bone resorption under development for the treatment of tumor-induced hypercalcemia, metastatic bone disease and osteoporosis. We conducted intravenous reproductive toxicity and teratology studies (Segment I, II and III) of this compound in rats and teratology study in rabbits. The test compound was dissolved in physiological saline, which was also given as the vehicle control. Rats were administered at a dosage of 0.06, 0.16 and 0.62 mg/kg/day in the male Segment I study. Dose levels in the other studies in rats including the female Segment I were 0.16, 0.31 and 0.62 mg/kg/day. In the Segment I study, no treatment-related abnormalities were observed in reproductive parameters or fetuses. In the Segment II study, slightly retarded fetal ossification was noted at 0.31 mg/kg/day or more, but the incidence of malformation did not increase. In the Segment III study, death of the dams and abnormal tooth growth of offspring were observed at 0.16 mg/kg/day or more. Further Segment III study showed that the no toxic effect level was 0.003 mg/kg/day. In the rabbit teratology study, dose levels were 0.01, 0.025 or 0.05 mg/kg/day. No toxic effects on pregnant females or their litters were observed at up to 0.05 mg/kg/day.