In vitro assessment of the dermal penetration potential of sodium fluoroacetate using a formulated product.

This paper presents experimental data on the skin absorption of sodium fluoroacetate from a formulated product using an in vitro approach and human skin. Sodium fluoroacetate is a pesticide, typically applied in formulation (1080) for the control of unwanted vertebrate invasive species. It has been assigned a Skin Notation by the ACGIH, and other international workplace health regulatory bodies, due to its predicted ability to permeate intact and abraded human skin. However, there is a distinct lack of experimental data on the skin absorption of sodium fluoroacetate to support this assignment. This study found that sodium fluoroacetate, as a formulated product, permeated the human epidermis when in direct contact for greater than 10 hr. A steady-state flux (Jss) of 1.31 ± 0.043 µg/cm2/hr and a lag time of 6.1 hr was calculated from cumulative skin permeation data. This study provides important empirical evidence in support of the assignment of a Skin Notation.

Prospective evaluation of fexapotide triflutate injection treatment of Grade Group 1 prostate cancer: 4-year results.

PURPOSE: This study was undertaken to determine the safety and efficacy of fexapotide triflutate (FT) 2.5 mg and 15 mg for the treatment of Grade Group 1 prostate cancer. METHODS: Prospective randomized transrectal intraprostatic single injection FT 2.5 mg (n = 49), FT 15 mg (n = 48) and control active surveillance (AS) (n = 49) groups were compared in 146 patients at 28 U.S. sites, with elective AS crossover (n = 18) to FT after first follow-up biopsy at 45 days. Patients were followed for 5 years including biopsies (baseline, 45 days, and 18, 36, and 54 months thereafter), and urological evaluations with PSA every 6 months. Patients with Gleason grade increase or who elected surgical or radiotherapeutic intervention exited the study and were cumulatively included in the data analysis. Percentage of normal biopsies in baseline focus quadrant, tumor grades, and volumes; and outcomes including Gleason grade in entire prostate as well as treated prostate lobe, interventions associated with Gleason grade increase and total incidence of interventions were assessed. RESULTS: Significantly improved long-term clinical outcomes were found after 4-year follow-up, with percentages of patients progressing to interventions with and without Gleason grade increase significantly reduced by FT single treatment. Results in the FT 15-mg group were superior to the FT 2.5-mg dose group. There were no drug-related serious adverse events (SAEs). CONCLUSIONS: FT showed statistically significant long-term efficacy in the treatment of Grade Group 1 patients regarding clinical and pathological progression. FT 15 mg showed superior results to FT 2.5 mg. There were no drug-related SAEs; FT injection was well tolerated.

Fexapotide triflutate: results of long-term safety and efficacy trials of a novel injectable therapy for symptomatic prostate enlargement.

PURPOSE: These studies were undertaken to determine if fexapotide triflutate 2.5 mg transrectal injectable (FT) has significant long-term (LT) safety and efficacy for the treatment of benign prostatic hyperplasia (BPH). METHODS: Two placebo controlled double-blind randomized parallel group trials with 995 BPH patients at 72 sites treated 3:2 FT:placebo, with open-label FT crossover (CO) re-injection in 2 trials n = 344 and long-term follow-up (LF) 2-6.75 years (mean 3.58 years, median 3.67 years; FT re-injection CO mean 4.27 years, median 4.42 years) were evaluated. 12 months post-treatment patients elected no further treatment, approved oral medications, FT, or interventional treatment. Primary endpoint variable was change in Symptom Score (IPSS) at 12 months and at LF. CO primary co-endpoints were 3-year incidence of (1) surgery for BPH in FT treated CO patients versus patients crossed over to oral BPH medications and (2) surgery or acute urinary retention in FT-treated CO placebo patients versus placebo patients crossed over to oral BPH medications. 28 CO secondary endpoints assessed surgical and symptomatic outcomes in FT reinjected patients versus conventional BPH medication CO and control subgroups at 2 and 3 years. RESULTS: FT injection had no significant safety differences from placebo. LF IPSS change from baseline was higher in FT treated patients compared to placebo (median FT group improvement - 5.2 versus placebo - 3.0, p < 0.0001). LF incidence of AUR (1.08% p = 0.0058) and prostate cancer (PCa) (1.1% p = 0.0116) were both reduced in FT treated patients. LF incidence of intervention for BPH was reduced in the FT group versus oral BPH medications (8.08% versus 27.85% at 3 years, p < 0.0001). LF incidence of intervention or AUR in placebo CO group with FT versus placebo CO group with oral medications was reduced (6.07% versus 33.3% at 3 years, p < 0.0001). 28/28 secondary efficacy endpoints were reached in LF CO re-injection studies. CONCLUSIONS: FT 2.5 mg is a safe and effective transrectal injectable for LT treatment of BPH. FT treated patients also had reduced need for BPH intervention, and reduced incidence of PCa and AUR.

Inhibiting Inducible Nitric Oxide Synthase in Enteric Glia Restores Electrogenic Ion Transport in Mice With Colitis.

BACKGROUND & AIMS: Disturbances in the control of ion transport lead to epithelial barrier dysfunction in patients with colitis. Enteric glia regulate intestinal barrier function and colonic ion transport. However, it is not clear whether enteric glia are involved in epithelial hyporesponsiveness. We investigated enteric glial regulation of ion transport in mice with trinitrobenzene sulfonic acid- or dextran sodium sulfate-induced colitis and in Il10(-/-) mice. METHODS: Electrically evoked ion transport was measured in full-thickness segments of colon from CD1 and Il10(-/-) mice with or without colitis in Ussing chambers. Nitric oxide (NO) production was assessed using amperometry. Bacterial translocation was investigated in the liver, spleen, and blood of mice. RESULTS: Electrical stimulation of the colon evoked a tetrodotoxin-sensitive chloride secretion. In mice with colitis, ion transport almost completely disappeared. Inhibiting inducible NO synthase (NOS2), but not neuronal NOS (NOS1), partially restored the evoked secretory response. Blocking glial function with fluoroacetate, which is not a NOS2 inhibitor, also partially restored ion transport. Combined NOS2 inhibition and fluoroacetate administration fully restored secretion. Epithelial responsiveness to vasoactive intestinal peptide was increased after enteric glial function was blocked in mice with colitis. In colons of mice without colitis, NO was produced in the myenteric plexus almost completely via NOS1. NO production was increased in mice with colitis, compared with mice without colitis; a substantial proportion of NOS2 was blocked by fluoroacetate administration. Inhibition of enteric glial function in vivo reduced the severity of trinitrobenzene sulfonic acid-induced colitis and associated bacterial translocation. CONCLUSIONS: Increased production of NOS2 in enteric glia contributes to the dysregulation of intestinal ion transport in mice with colitis. Blocking enteric glial function in these mice restores epithelial barrier function and reduces bacterial translocation.

Administração repetida de doses não tóxicas de monofluoroacetato de sódio não protege contra a intoxicação por este composto em ovinos / Repeated administration of non-toxic doses of sodium monofluoroacetate does not protect against poisoning by this compound in sheep

Com o objetivo de avaliar se repetidas doses não tóxicas de monofluoroacetato de sódio (MFA) induzem resistência à intoxicação por essa substância, 18 ovinos foram distribuídos aleatoriamente em dois grupos experimentais de nove animais cada. Os ovinos do Grupo 1 ingeriram doses crescentes não letais de MFA por seis períodos: 0,05mg/kg por 5 dias; 0,08mg/kg por 4 dias; 0,08mg/kg por 4 dias; 0,1mg/kg por 3 dias; 0,1mg/kg por 3 dias e 0,25mg/kg por 3 dias. Entre o primeiro e o segundo período de administração e entre o segundo e o terceiro período os animais não receberam o MFA por 10 dias consecutivos; entre o terceiro e o quarto período e dentre os demais períodos de administração, os ovinos permaneceram 15 dias sem ingerir o MFA. Quinze dias após o último período de administração os ovinos foram desafiados com a dose única de 1mg/kg de MFA. O Grupo 2 não foi adaptado a ingestão de MFA, estes ovinos receberam dose única de 1mg/kg de MFA no mesmo período em que o G1 foi desafiado. No desafio sete ovinos do Grupo 1 apresentaram sinais clínicos da intoxicação e um ovino se recuperou. No Grupo 2 todos os animais manifestaram quadro clínico da intoxicação por MFA, no entanto, dois ovinos se recuperaram. Os coeficientes de mortalidade foram de 66,6 por cento para o Grupo 1 e de 77,7 por cento para o Grupo 2. Os resultados deste trabalho sugerem que a administração repetida de doses não tóxicas de MFA não protege contra a intoxicação aguda por este composto, portanto, outras alternativas para a profilaxia da intoxicação por plantas que contêm MFA deverão ser pesquisadas, principalmente a utilização intraruminal de bactérias que hidrolisam MFA.

With the objective to assess whether repeated non-toxic doses of sodium monofluoroacetate (MFA) induce resistance to poisoning by this compound, 18 sheep were randomly divided into two experimental groups of nine animals each. Sheep from Group 1 ingested non-lethal increasing doses of MFA for six periods: 0.05mg/kg for 5 days; 0.08mg/kg for 4 days; 0.08mg/kg for 4 days; 0.1mg/kg for 3 days; 0.1mg/kg for 3 days and 0.25mg/kg for 3 days. Between the first and second period of administration and between the second and third period the animals did not receive MFA for 10 consecutive days, between the third and fourth period and during the remaining periods of administration the sheep were left 15 days without ingesting MFA. Group 2 was not adapted to the ingestion of MFA and received a single dose of 1mg/kg of MFA at the same time that Group 1 was challenged. After challenge, seven sheep of Group 1 showed clinical signs of poisoning and one sheep recovered. In Group 2, all animals showed clinical signs of poisoning by MFA, however two sheep recovered. The mortality rate was 66.6 percent in Group 1 and 77.7 percent for Group 2. These results suggest that repeated administration of non-toxic doses of MFA does not protect against acute poisoning by this compound; therefore other alternatives of prophylaxis for poisoning by plants containing MFA should be searched, mainly the use of intraruminal bacteria that hydrolyze MFA.

Importância da intoxicação por Amorimia pubiflora (Malpighiaceae) em bovinos em Mato Grosso: reprodução experimental da intoxicação em ovinos e bovinos / The importance of poisoning by Amorimia pubiflora (Malpighiaceae) in cattle in Mato Grosso: experimental reproduction of the poisoning in sheep and cattle

No município de Colniza, Mato Grosso, a principal limitação para expansão pecuária é a ocorrência de "morte súbita" em bovinos, com registros de mortalidade próxima a 50% dos animais. Em visitas realizadas em áreas de ocorrência do problema, nos anos de 2004, 2011 e 2012, constatou-se que havia coincidência entre a ocorrência de "mortes súbitas" no rebanho e a presença de Amorimia pubiflora nas pastagens. As mortes ocorrem durante todo ano, porém acentuam-se no início do período das chuvas, quando há maior quantidade de brotação nas áreas de pastoreio. A intoxicação foi reproduzida em ovinos e bovinos através da administração de folhas jovens coletadas em dois períodos do ano, e, em ovinos, através de folhas maduras e dos frutos. Nos ovinos que morreram, as primeiras manifestações clínicas foram observadas entre 34min e 17h34min após a administração da planta e a evolução clínica foi de 3min a 15h20min, com uma fase final superaguda de 3 a 21min. As principais alterações clínicas encontradas foram taquicardia, evidenciação da jugular, tremores musculares, apatia e relutância à movimentação. Todos os sinais acentuavam-se após a movimentação. A fase final superaguda foi caracterizada por relutância para caminhar, cifose, tremores e contrações musculares generalizadas, principalmente de membros, cabeça e pescoço. Notou-se também taquipneia com respiração abdominal, decúbito esternal e rapidamente lateral ou quedas em decúbito lateral, opistótono, nistagmo e cianose de mucosa oral, seguidos de morte. As folhas jovens, independentemente do período da coleta, foram mais tóxicas; causaram a morte de ovinos a partir de 2g/kg e de um bovino que ingeriu 3g/kg. Já as folhas maduras revelaram-se tóxicas e causaram morte na dose de 20g/kg e os frutos ocasionaram a morte de um ovino que ingeriu 5g/kg. Concluímos que monofluoracetato de sódio (MFA), encontrado na concentração de 0,015% nas folhas em brotação de A. pubiflora, é o princípio tóxico responsável pela "morte súbita" causada por Amorimia pubiflora. Esse estudo mostra a importância de A. pubiflora para a região Centro-Oeste do Brasil, principalmente para a pecuária bovina do município de Colniza, MT. Essa planta é tóxica, também, para ovinos e o quadro clínico é similar ao descrito para bovinos.

In the county of Colniza, Mato Grosso, the main limitation for livestock production is the occurrence of "sudden death" in cattle, which affects in some farms up to 50% of the herd. In visits to some of the farms where the problem occurred, in 2004, 2011 and 2012, the presence of Amorimia pubiflora on the pastures was associated with the occurrence of "sudden deaths" in cattle. The deaths occurred throughout the year, however more frequently at beginning of the rainy season, when A. pubiflora sprouts in the grazing areas. The poisoning was experimentally reproduced in sheep and cattle by the administration of young leaves of the plant collected during two seasons, and in sheep by the administration of mature leaves and fruits. In the sheep that died, the first clinical signs were observed between 34min and 17h34min after the administration of the plant, and the clinical course varied from 3min to 15h20min, with a final peracute phase of 3 to 21 minutes. The main clinical signs were tachycardia, engorgement of the jugular veins, muscle trembling, apathy and reluctance to move, which were more evident when the animals were moved. The peracute final phase was characterized by generalized tremors and muscle contractions mainly of limbs, head and neck, respiratory distress and abdominal respiration, sternal and quick lateral recumbence or falling to the ground with peddling movements, opisthotonus, nystagmus, nystagmus and cyanosis of the oral mucosa, followed by death. The young leaves of A. pubiflora, independent of the collection period, were more toxic and caused death of sheep and cattle after ingestion of 2g/kg and 3g/kg respectively. Mature leaves caused death at the dose of 20g/kg, and the fruits at 5g/kg. The young leaves contained 0.015% of sodium monofluoracetate which is responsible for clinical signs of the "sudden death". These findings show the importance of Amorimia pubiflora for cattle raising in Midwestern Brazil. The plant is toxic also for sheep causing a clinical picture similar to that reported in cattle poisoned by monofluoracetate-containing plants.

Astrocytes promote peripheral nerve injury-induced reactive synaptogenesis in the neonatal CNS.

Neonatal damage to the trigeminal nerve leads to "reactive synaptogenesis" in the brain stem sensory trigeminal nuclei. In vitro models of brain injury-induced synaptogenesis have implicated an important role for astrocytes. In this study we tested the role of astrocyte function in reactive synaptogenesis in the trigeminal principal nucleus (PrV) of neonatal rats following unilateral transection of the infraorbital (IO) branch of the trigeminal nerve. We used electrophysiological multiple input index analysis (MII) to estimate the number of central trigeminal afferent fibers that converge onto single barrelette neurons. In the developing PrV, about 30% of afferent connections are eliminated within 2 postnatal weeks. After neonatal IO nerve damage, multiple trigeminal inputs (2.7 times that of the normal inputs) converge on single barrelette cells within 3-5 days; they remain stable up to the second postnatal week. Astrocyte proliferation and upregulation of astrocyte-specific proteins (GFAP and ALDH1L1) accompany reactive synaptogenesis in the IO nerve projection zone of the PrV. Pharmacological blockade of astrocyte function, purinergic receptors, and thrombospondins significantly reduced or eliminated reactive synaptogenesis without changing the MII in the intact PrV. GFAP immunohistochemistry further supported these electrophysiological results. We conclude that immature astrocytes, purinergic receptors, and thrombospondins play an important role in reactive synaptogenesis in the peripherally deafferented neonatal PrV.

Electrophysiological study of infant and adult rats under acute intoxication with fluoroacetamide.

A study was conducted of acute intoxication of infant and adult Wistar rats with fluoroacetamide (FAA), an inhibitor of oxidative metabolism. FAA was administered orally to adult rats at 1/2 LD(50) and subcutaneously to infant rats at LD(100) or 1/10 LD(50). Electrocardiogram (ECG), respiration and motor activity were registered for 7 days. Clinical analysis of ECG and the heart rate variability (HRV) was carried out to assess the state of the vegetative nervous system. In adult rats, FAA caused marked disturbances in the activity of cardiovascular and respiratory systems, including the development of a potentially lethal acute cor pulmonale. Conversely, there were no significant changes of cardiac function and respiration in infant rats; they died because of extreme emaciation accompanied by retardation of development. In adult rats, bursts of associated cardiac and respiratory tachyarrhythmia, as well as regular high amplitude spasmodic sighs having a deca-second rhythm were observed. In both infant and adult rats, FAA caused short-term enhancement of humoral (metabolic) and sympathetic activities, followed by a gradual and stable predominance of parasympathetic influence on HRV. Under conditions of FAA inhibition of the tricarboxylic acid cycle, the observed physiological reactions may be explained by activation of alternative metabolic pathways. This is also supported by a lack of ontogenetically caused inhibition of spontaneous motor activity in infant rats poisoned with FAA, which highlights the significance of the alternative metabolic pathways for implementation of deca-second and minute rhythms and a lack of a rigid dependence of these rhythms upon activity of neuronal networks.

Determination of fluoroacetic acid in water and biological samples by GC-FID and GC-MS in combination with solid-phase microextraction.

A novel procedure has been developed for determination of fluoroacetic acid (FAA) in water and biological samples. It involves ethylation of FAA with ethanol in the presence of sulfuric acid, solid-phase microextraction of the ethyl fluoroacetate formed, and subsequent analysis by GC-FID or by GC-MS in selected-ion-monitoring mode. The detection limits for FAA in water, blood plasma, and organ homogenates are 0.001 microg mL(-1), 0.01 microg mL(-1), and 0.01 microg g(-1), respectively. The determination error at concentrations close to the detection limit was less than 50%. For analysis of biological samples, the approach has the advantages of overcoming the matrix effect and protecting the GC and GC-MS systems from contamination. Application of the approach to determination of FAA in blood plasma and organ tissues of animals poisoned with sodium fluoroacetate reveals substantial differences between the dynamics of FAA accumulation and clearance in rabbits and rats.

Variabilidade clínica na determinação da dose tóxica oral em intoxicação experimental por fluoroacetato de sódio em gatos / Clinical variability in the determination of oral toxic dosis in the experimental intoxication with sodium fluoroacetate in cats

O fluoroacetato de sódio (FAS) ou composto 1080 é um potente rodenticida utilizado no controle de roedores e predadores manúferos. Sua utilização está proibida por lei em diversos países devido à sua alta toxicidade, mas no Brasil há evidências do uso ilegal e sem critérios causando intoxicações, principalmente em crianças e animais domésticos. O FAS age por meio do seu metabólito tóxico, o fluorocitrato, no bloqueio do ciclo de Krebs com consequente diminuição da produção de energia do organismo, provocando principalmente manifestações clínicas neurológicas e cardíacas. No presente estudo compararam quatro doses orais tóxicas do fluoroacetato de sódio, descritas em gatos, na literatura, observando-se o aparecimento dos sinais clínicos predominantes da intoxicação, as diferenças entre as doses quanto a variabilidade clínica em relação ao período de latência para o aparecimento dos sinais clínicos e sua respectiva intensidade. A dose oral tóxica que melhor caracterizou o quadro clínico da intoxicação por FAS em gatos, sem causar a letalidade aguda, foi de 0,4Smg/kg. As diferenças entre as manifestações clínicas foram dose-dependentes e em ordem crescente de intensidade, caracterizando-se como sinais leves (dose 1: 0,3mg/kg), leves a moderados (dose 2: 0,4mg/kg), moderados a graves (dose 3: 0,45mg/ kg) e graves (dose 4: 0,5mg/kg). Houve também variabilidade clínica individual entre animais intoxicados com a mesma dosagem do tóxico.

The sodium monofluoroacetate (FAC) or compound 1080 is a potent rodenticide used for a rodents and vertebrate pest control. lt was prohibited in many countties because of its high toxicity, but in Brazil exist evidences of ilegal use causing the intoxication in children and domestic animals. The fluoroacetate metabolite, fluorocitric acid, blocks body energy production by inhibit the Krebs cycle, resulting in neurological and cardiacs signs. ln the present study, four group of oral toxic dosis of the FAC were compared in cats. The best oral toxic dose for clinical signs presentation, without cause acute lethality, was 0,45mg/kg. The clinical variability was dosis dependent and its intensity , in crescent order, was: light signs (dose 1: 0,3mg/kg), light to moderate (dose 2: 0,4mg/kg), moderate to severe (dose 3: 0,45mg/ kg) and severe (dose 4: 0,5mg/kg). There was individual clinical variability between animals that received the same oral toxic dose.

Neurotoxic effects of alpha-fluoro-beta-alanine (FBAL) and fluoroacetic acid (FA) on dogs.

In order to clarify the mechanism of the neurotoxicity of 5-FU and/or its masked compounds, we studied the effects of alpha-fluoro-beta-alanine (FBAL) and fluoroacetic acid (FA) on the formation of vacuolar changes in the dog cerebrum, using the dosage of 3.0 mg/kg/day of FBAL-HCl (FBAL x HCl) and 0.03 mg/kg/day of FA-Na (FA x Na), respectively. These 2 compounds were selected because they are the metabolites of 5-FU claimed to be responsible for the neurotoxic effects of 5-FU and/or its masked compounds, and we wanted to confirm their effects. Tegafur-uracil mixture (UFT) was used as a positive control drug for the formation of vacuolar changes in the dog cerebrum. All compounds were orally administered daily for 3 months to beagle dogs. Each study group consisted of 3 males. Neurotoxic signs such as hyperesthesia and/or excitement, as well as convulsions, were observed in both FBAL x HCl and FA x Na groups; these toxic signs were also found in the UFT group. Slight loss of body weight gain and of food consumption was observed in the FBAL x HCl and UFT groups. Neuropathologically, vacuolar changes were detected in several areas of the dog cerebrum following administration of FBAL x HCl, FA x Na or UFT. In terms of morphology, the neuropathological effects of these 2 drugs were very similar to those induced by UFT. In conclusion, we clearly showed that FBAL is one of the main substances that cause neurotoxic signs and neuropathological changes in dogs intoxicated by 5-FU or its masked compounds. Moreover, FA might be considered to be a causative factor in addition to FBAL.

Acute inhalation toxicity study of 2-fluoroacetamide in rats.

One of the most potent rodenticides is 2-fluoroacetamide (2-FA). Toxicity of this chemical is well documented. However, its inhalation toxicity data is not available in the literature. Hence, acute inhalation toxicity study was carried out by exposing male and female rats to aerosols of 2-FA at different concentrations for 4 h in a dynamically operated whole body inhalation exposure chamber. During and after the inhalation exposure the rats were less active, and showed mild tremors and convulsions. At higher concentrations the rats died after 2-3 days. The estimated 4-h LC50 for male and female rats was 136.6 and 144.5 mg.m-3 respectively. Exposure to 0.7 LC50 for 4 h duration showed an increase in the liver weight of male and female rats 7 days after exposure. Various haematological and biochemical variables determined were within the normal limits. However, histological findings showed injured lung as indicated by desquamation and necrosis of the epithelium of the respiratory tract. Marked hypertrophy of hepatocytes displaying strong acidophilic granulated cytoplasm was observed. Focal dilatation of renal proximal tubules in kidney with cytoplasmic vacuolation, and irregularly placed pyknotic nuclei were seen. The present study shows that 2-FA is a highly toxic chemical through the inhalation route based on the LC50 value. Consequently necessary precautions should be taken during its handling.

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.

Evaluation of potential antidotes for sodium fluoroacetate in mice.

Pathogenesis in fluoroacetate poisoning is multifactorial. Biochemically it is characterized by lethal synthesis of fluorocitrate, causing hypocalcemia, and energy deficiency through blockade of the TCA cycle. Calcium gluconate (CaG) was chosen to antagonize hypocalcemia, while sodium alpha kelogluterate (NaKG) and sodium succinate (NaSuc) were selected as potential antidotes to revive the TCA cycle. Effectiveness of each of these antidotes individually and in certain combinations was tested in mice exposed to lethal doses (15 mg/kg ip) of sodium fluoroacetate (NaFAC). Antidotal treatments were administered at 15 min, 4 h, 10 h, 24 h, and 36 h after NaFAC. All 3 of the antidotes alone, as well as a combination of CaG with NaKG, were ineffective in reducing mortality in mice after NaFAC. On the other hand, a combination of CaG (130 mg/kg) with NaSuc (240 mg/kg) was effective if the 2 solutions were either injected at separate sites or mixed in the same syringe just prior to injection. Similar solutions, if mixed for 24 h or longer before administrations, were ineffective. Increasing the dose of NaSuc to 360 or 480 mg/kg with CaG (130 mg/kg) was unrewarding. These results indicate that CaG in combination with 240 mg NaSuc/kg offer a promising therapy modality in NaFAC intoxication. Additional studies involving biochemical parameters and other species are needed to confirm the efficacy and mechanism(s) of action of this combination.

Sodium fluoroacetate poisoning.

We observed a case of poisoning with sodium fluoroacetate, and extremely lethal rodenticide that has had relatively strict controls placed on its use. The case was unusual in the very long time the rodenticide had been present in the home, the mild nature of the poisoning, and the remarkably delayed onset of serious central nervous system symptoms. It demonstrates the need for even stronger controls on the use of sodium fluoroacetate.