Liver tumor formation in female rat induced by fluopyram is mediated by CAR/PXR nuclear receptor activation.

Fluopyram is a broad spectrum fungicide targeting plant pathogenic fungi (eg. white dot, black mold, botrytis). During the general toxicity evaluation of fluopyram in rodents, the liver was identified as a target organ (hepatomegaly and liver hypertrophy were observed in all studies). At the end of the guideline carcinogenicity study, an increased incidence of hepatocellular adenomas and carcinomas was observed in female Wistar rats following exposure to the highest fluopyram dose evaluated (1500ppm). Short-term mechanistic studies (3, 7 or 28days of exposure) were conducted in the female rat to identify the initial key events responsible for the tumor formation and to establish thresholds for each of the early hepatic changes. Increased expression of constitutive androstane receptor (CAR) and pregnane X receptor (PXR) inducible genes was recorded after each exposure period. Further confirmation of CAR/PXR activation was provided by increased activity of specific Phase I enzymes (PROD/BROD respectively). Increased hepatocellular proliferation (measured by Ki67) was observed after each exposure period with the greatest proliferative response occurring after 3days of treatment. In these studies, dose responses and clear thresholds were established for gene expression, enzyme activity and cell proliferation. Furthermore, these early hepatic changes were shown to be reversible following compound withdrawal. Other modes of action for liver tumor formation such as DNA damage, cytotoxicity and peroxisome proliferation were excluded during the investigations. In conclusion, fluopyram is a threshold carcinogen and the resultant hepatocellular carcinomas in the female rat are due to hepatocellular proliferation mediated by CAR/PXR activation.

Thyroid tumor formation in the male mouse induced by fluopyram is mediated by activation of hepatic CAR/PXR nuclear receptors.

Fluopyram, a broad spectrum fungicide, caused an increased incidence of thyroid follicular cell (TFC) adenomas in males at the highest dose evaluated (750ppm equating to 105mg/kg/day) in the mouse oncogenicity study. A series of short-term mechanistic studies were conducted in the male mouse to characterize the mode of action (MOA) for the thyroid tumor formation and to determine if No Observed Effect Levels (NOELs) exist for each key event identified. The proposed MOA consists of an initial effect on the liver by activating the constitutive androstane (Car) and pregnane X (Pxr) nuclear receptors causing increased elimination of thyroid hormones followed by an increased secretion of thyroid stimulating hormone (TSH). This change in TSH secretion results in an increase of TFC proliferation which leads to hyperplasia and eventually adenomas after chronic exposure. Car/Pxr nuclear receptors were shown to be activated as indicated by increased activity of specific Phase I enzymes (PROD and BROD, respectively). Furthermore, evidence of increased T4 metabolism was provided by the induction of phase II enzymes known to preferentially use T4 as a substrate. Additional support for the proposed MOA was provided by demonstrating increased Tsh ß transcripts in the pituitary gland. Finally, increased TFC proliferation was observed after 28days of treatment. In these dose-response studies, clear NOELs were established for phase 2 liver enzyme activities, TSH changes and TFC proliferation. Furthermore, compelling evidence for Car/Pxr activation being the molecular initiating event for these thyroid tumors was provided by the absence of the sequential key events responsible for the TCF tumors in Car/Pxr KO mice when exposed to fluopyram. In conclusion, fluopyram thyroid toxicity is mediated by activation of hepatic Car/Pxr receptors and shows a threshold dependent MOA.

Pharmacokinetics of colchicine in pediatric and adult patients with familial Mediterranean fever.

This study sought to determine the appropriate starting dose of colchicine in children aged 2 to 4 years with familial Mediterranean fever (FMF) based on steady-state pharmacokinetics in pediatric patients with FMF from 2 to less than 16 years and adult patients with FMF from 16 to 65 years. Outpatients received colchicine for 90 days starting with a fixed dose for 14 days (blood sampling days 14 and 15). After starting doses of colchicine (0.6 mg/day [2 to less than 4 years], 0.9 mg/day [from 4 to less than 6 years], 0.9 mg/day [from 6 to less than 12 years], 1.2 mg/day [from 12 to less than 16 years], and 1.2 mg/day [from 16 to less than 65 years]), the observed steady-state pharmacokinetic parameters were comparable across age groups, despite the higher doses of colchicine on a mg/kg/day basis in the younger age groups. An exception occurred with once-daily colchicine, whereby mean Cmax for colchicine was higher in patients 4 to less than 6 years (9.4 ng/mL) compared with the younger and older age groups (6.1-6.7 ng/mL). Mean AUC0?24h values in children 2 to less than 4, 6 to less than 12, and 12 to less than 16 years were similar to those in adults. However, mean AUC0?24h values in children 4 to less than 6 years were 25 percent higher than those observed in adults. The results show that the recommended starting dose for children 2-4 years and 4-6 years should be 0.6 mg/day (half the US adult dose). Children aged 6 to less than 12 years should receive 0.9 mg/day (i.e. three-quarters of the US adult dose). The safety of colchicine in children 2 to less than 4 years was comparable to that in older children and adults.

A multi-institutional randomized controlled trial comparing first-generation transrectal high-resolution micro-ultrasound with conventional frequency transrectal ultrasound for prostate biopsy.

Objectives: To study high-frequency 29 MHz transrectal side-fire micro-ultrasound (micro-US) for the detection of clinically significant prostate cancer (csPCa) on prostate biopsy, and validate an image interpretation protocol for micro-US imaging of the prostate. Materials and methods: A prospective randomized clinical trial was performed where 1676 men with indications for prostate biopsy and without known prostate cancer were randomized 1:1 to micro-US vs conventional end-fire ultrasound (conv-US) transrectal-guided prostate biopsy across five sites in North America. The trial was split into two phases, before and after training on a micro-US image interpretation protocol that was developed during the trial using data from the pre-training micro-US arm. Investigators received a standardized training program mid-trial, and the post-training micro-US data were used to examine the training effect. Results: Detection of csPCa (the primary outcome) was no better with the first-generation micro-US system than with conv-US in the overall population (34.6% vs 36.6%, respectively, P = .21). Data from the first portion of the trial were, however, used to develop an image interpretation protocol termed PRI-MUS in order to address the lack of understanding of the appearance of cancer under micro-US. Micro-US sensitivity in the post-training group improved to 60.8% from 24.6% (P < .01), while specificity decreased (from 84.2% to 63.2%). Detection of csPCa in the micro-US arm increased by 7% after training (32% to 39%, P < .03), but training instituted mid-trial did not affect the overall results of the comparison between arms. Conclusion: Micro-US provided no clear benefit over conv-US for the detection of csPCa at biopsy. However, it became evident during the trial that training and increasing experience with this novel technology improved the performance of this first-generation system.

Acute isopropyl alcohol intoxication. Diagnosis and management.

Alcohol intoxication (methyl, ethyl, isopropyl, and ethylene glycol) is treated frequently in emergency room and intensive care units. Although high morbidity and mortality rates exist, effective therapies for methyl alcohol and ethylene glycol (ethyl alcohol blocking and hemodialysis) and ethyl and isopropyl alcohol (hemodialysis) are available. Prompt and accurate clinical and laboratory differentiation is needed to optimize these therapies. This review presents clinical, pharmacologic, and management data, contrasts important aspects in differential diagnosis, and suggests an appropriate approach to management of isopropyl alcohol intoxication.

Phosphorus trichloride toxicity. Preliminary report.

A railroad accident in Somerville, Massachusetts, led to spillage of phosphorus trichloride liquid. Attempted clean-up with water led to the liberation of phosphorus trichloride, phosphoric acid, hydrochloric acid, and phosphorus oxides. Seventeen people exposed to this mixture were studied. Patients experienced eye irritation, lacrimination, nausea, vomiting, and dyspnea. Six patients had transient elevation of lactic dehydrogenase. Although all patients had normal chest roentgenographic findings, pulmonary function tests showed statistically significant decreases in vital capacity (p = 0.02), maximal breathing capacity (p = 0.02), forced expiratory volume in one second (p = 0.02), and maximal expiratory flow rate at 25 percent of vital capacity (p = 0.05) in those closest to the accident site. Further, patients exposed for less than one and a half hours had significantly greater maximal expiratory flow rates at 25 percent of vital capacity when compared with patients who had been exposed longer (p = 0.02). In seven patients, repeated pulmonary function tests one month later showed improvement, suggesting strongly that the acute effects may have been due to phosphorus trichloride toxicity.

Camphor toxicity.

Camphor is present in several over-the-counter compounds of questionable use and therefore may be ingested by small children. Because seizures may follow ingestion of certain amounts, appropriate treatment is needed, including the use of anticonvulsants.

Mothball toxicity.

Accidental mothball ingestion is very common in children. Mothballs consist either of naphthalene or paradichlorobenzene, the toxicities of which are very different. This article focuses on the management of mothball ingestion with reference to these major ingredients.

Boric acid toxicity.

Although boric acid was widely used therapeutically in the past and resulted in significant toxicity, the past few years have seen a decline in its usage. Ninety-nine per cent boric acid powder is now being used as a household pesticide. Physicians therefore should be aware of the potential for boric acid toxicity.

A 12-week clinical trial determining the efficacy of synthetic conjugated estrogens, A (SCE), in the treatment of vasomotor symptoms in menopausal women.

OBJECTIVE: To compare the clinical effects of a new oral synthetic conjugated estrogens, A (SCE), versus placebo in a clinically relevant population on the reduction in the mean number of moderate to severe vasomotor symptoms. DESIGN: A total of 120 healthy pre- and postmenopausal women (72 active, 48 placebo) were enrolled into a randomized, placebo-controlled, double-blind, multi-center clinical trial. Women of all races were enrolled, using minimal inclusion and exclusion criteria. Each subject received either orally administered SCE, in doses of 0.3 mg, 0.625 mg or 1.25 mg per day, or placebo. Analysis of variance was performed on the primary efficacy variable (change from baseline to weeks 4, 8, and 12 in the mean number of moderate to severe vasomotor symptoms). RESULTS: Changes in moderate to severe vasomotor symptoms in the intent to treat population showed statistically significant differences between the active and placebo treatments at week 4 (P < .022), week 8 (P < .010), and week 12 (P < .010). By week 12, the mean percentage reduction in moderate to severe vasomotor symptoms was 81%, from an average baseline of 96.8, to 16.5 hot flashes per week for the active treatment group. The overall incidence of expected estrogen-related adverse effects was modest. Laboratory tests and vital sign measurements did not reveal clinically significant changes or abnormalities from screening to the final visit in either treatment group. CONCLUSIONS: The results of this study confirm the efficacy and safety of SCE in the treatment of moderate to severe vasomotor symptoms in menopausal women. In addition, the study also demonstrated that the use of more liberal entry criteria did not materially affect the efficacy outcome.

The emergency management of caustic ingestions.

Controversial therapeutic issues in patients with caustic ingestions concern the reliability of symptoms and signs in predicting esophageal injury, the appropriate use of endoscopy in evaluating esophageal damage, and the use of steroids in preventing late strictures. The conclusions of this review are: The majority of pediatric caustic ingestions involve a "lick and taste" whereas adolescents and adults often ingest substantial quantities. Oral burns and dysphagia are sensitive predictors of esophageal injury; however, esophageal injury may occur in the absence of the findings. Household bleach and nonphosphate detergents represent a low risk of injury whereas button batteries greater than 20 mm in diameter and Clinitest tablets represent high risk. Endoscopy should be an elective rather than emergency procedure and should be undertaken in all symptomatic patients, and in asymptomatic patients when history indicates substantial ingestion. Steroid therapy should be considered only for patients who have deep or circumferential esophageal burns.

Superwarfarin poisoning.

Superwarfarins consist of two classes of compounds, the 4-hydroxycoumarins and the indandiones. These compounds have replaced warfarin as an anticoagulant rodenticide. This article is a summary of the clinical effects produced by accidental and deliberate ingestions of superwarfarins. Most accidental ingestions occur in childhood and result in a benign outcome. Deliberate overdoses usually involve repeated ingestions of large quantities of superwarfarins that have resulted in prolonged laboratory evidence of interference with clotting; serious bleeding has been rare. This article suggests an approach to the management of patients with accidental and deliberate anticoagulant rodenticide ingestions.

Acute valproic acid toxicity at therapeutic concentrations.

A previously healthy nonepileptic 11-year-old girl presented with confusion and disorientation after an acute ingestion of valproic acid. Her serum concentration of valproic acid was 39.6 mcg/ml, a range normally considered "therapeutic" in the control of seizures. She recovered without sequelae despite the subsequent attainment of higher valproic acid concentrations.

Multiaxial orthotic hip joint for squatting and cross-legged sitting with hip-knee-ankle-foot-orthosis.

In view of the importance of squatting and cross-legged sitting in the activities of daily living in Asian and African countries, a multiaxial orthotic hip joint has been developed which when fitted to a Hip-Knee-Ankle-Foot-Orthosis (HKAFO) can permit the user to squat and sit cross-legged. The design consists of a modified ball and socket joint.

Intravenous hydrocarbon abuse.

The case of a man who injected turpentine intravenously in an attempt to kill himself is reported. The patient developed immediate pulmonary edema and hypoxia, followed later by cellulitis at the site of injection. Although only one death to date has been attributed to this form of chemical abuse, extensive local reactions, pulmonary involvement, central nervous system depression, and febrile reactions should be anticipated, and such patients should be admitted to the hospital. Patients should be observed for local reactions and myonecrosis around the site of injection, especially as these occur 12-24 hours later.

Severe hyperphosphatemia, hypocalcemia, acidosis, and shock in a 5-month-old child following the administration of an adult Fleet enema.

We report the case of a 5-month-old girl who was given an adult Fleet enema by her mother because of her concern that the baby was constipated. Within minutes the child became extremely ill. She developed shock, hyperphosphatemia, hypocalcemia, and acidosis. This case is presented to demonstrate that life-threatening events may result after the injudicious use of enemas in children.

Delayed diagnosis of coin ingestion in children.

Diagnosis of coin ingestion with esophageal impaction may be delayed if appropriate history is lacking. This delay may lead to mistreatment and complicate management. A series of illustrative cases are reported and relevant literature is reviewed. Guidelines for radiographic evaluation of potential ingestions are provided.

Cocaine toxicity in an infant following intranasal instillation of a four percent cocaine solution.

An 11-week-old infant experienced toxicity following the intranasal instillation of a four percent cocaine solution in preparation for an examination to rule out choanal stenosis. The child recovered fully but required the use of anticonvulsants and admission to the hospital. To our knowledge, this is the first case report where cocaine toxicity was experienced following this routine practice. We present our case and a review of the literature involving other instances where there have been complications with the use of topical cocaine. This report should alert the medical community to the potential complications of using topical cocaine for its anesthetic properties.

Ventricular tachycardia associated with non-freon aerosol propellants.

A previously well 2-year-old child presented with seizures and ventricular tachycardia shortly after playing with an aerosol can of a well-known proprietary deodorant. She required intensive care and survived without sequelae. The propellants used in this product were isobutane, n-butane, and propane. The propellants have been thought to be safer than the previously used Freons, which were known to be cardiotoxic and neurotoxic. Significant exposure was confirmed by the detection of n-butane and isobutane in the patient's serum. We conclude that unintentional exposure to non-Freon aerosol propellants in a nonconfined space can be hazardous to children. Aerosol cans should be considered to represent toxic hazards and should be kept out of reach of children.

Lidocaine overdose: another preventable case?

Physicians who prescribe viscous lidocaine preparations should be aware of the adverse effects and the high risk for overdose in pediatric patients. Owing to altered pharmacokinetics (increased absorption, decreased clearance, and prolonged half-life), doses that are innocuous for adults may present a significant potential toxic hazard in children. Lidocaine should not be used to treat painful mouth lesions in children until further safety data are available. Benzocaine may be considered as a safe alternative to lidocaine. Its low incidence of side effects makes it a safer choice for infants and children. If no other choices are appropriate, then very specific instructions should be given to parents. The amount, frequency, maximum daily dose, and mode of administration should be clearly communicated (eg, cotton pledget to individual lesions, one-half dropper to each cheek every four hours, or 20 minutes before meals). They should never be prescribed on a "PRN" basis.