Effects of three infusion fluids with different sodium chloride contents on steady-state serum concentrations of bromide in dogs.

Potassium bromide overdose (bromism) in the management of canine epilepsy has been known. However, a protocol to reduce bromide concentrations rapidly has not been previously established. The effects of three infusion fluids with different chloride contents on the steady-state serum concentrations of bromide in beagles were determined. After stabilization of the serum bromide concentrations, seven dogs were infused with saline (Na+ 154 mmol/L; Cl- 154 mmol/L), lactated Ringer's (Na+ 131 mmol/L; Cl- 110 mmol/L), or maintenance solutions (Na+ 35 mmol/L; Cl- 35 mmol/L) at a rate of 2 or 10 ml kg-1  hr-1 for 5 hr. Serum and urine were collected hourly, and the bromide concentrations were measured. When saline and lactated Ringer's solutions were infused at a rate of 10 ml kg-1  hr-1 for 5 hr, serum bromide concentrations were decreased by 14.24% and urine bromide concentrations by 17.63%, respectively. Of all compositions of infusion fluids, only sodium and chloride contents were associated with the decreased serum concentrations and the increased renal clearance of bromide. In summary, saline and lactated Ringer's solutions reduced serum bromide concentrations in a sodium chloride-dependent manner in dogs were found when infused at 10 ml kg-1  hr-1 for 5 hr.

THE ESTROGENS / CHROMIUM INTERACTION IN THE NITRIC OXIDE GENERATION.

The interaction of estrogens with environmental toxins in free radicals generation: reactive oxygen species (ROS) or reactive nitrogen species (RNS) which participates in cancerogenesis is not yet recognized. Chromium(VI) is widely present in environment. One of its toxicity pathway is free radicals generation. Estrogens have the ability to scavenge free radicals, but may also act as prooxidants. Both chromium(VI) and estrogens are classified by International Agency for Research on Cancer (IARC) as carcinogens, so synergistic effect seems very dangerous. The interaction of chromium and estrogens in ROS generation are partly described but there are no reports on estrogen/chromium interaction on nitric oxide (NO) generation. The aim of the study was to examine the interaction of chromium(VI) and 17-p-estradiol (E2) on NO level in human blood as well as the role of E2 metabolites: 4-hydroxyestradiol (4-OHE2) and 16a-hydroxyestrone (16α-OHE1) in these processes. The NO level was estimated with the diagnostic kit (Nitric Oxide Colorimetric Detection Kit from Arbor Assays) in human blood in vitm. The results showed that Cr(VI) in used concentration (0.5; 1.0 and 5.0 gg/mL) decreases significantly NO level in blood, acting antagonistically to E2 and 4-OHE2. Estrogens (E2, 4-OHE2 and 16α-OHEI) do not protect against inhibiting effect of Cr(VI) on nitric oxide generation in blood because after combined exposure the decreased production of NO in blood was noted. In conclusion, presented results provide the information about the character of estrogen/Cr(VI) interaction in NO level in human blood. It is important knowledge for cardio protected effect e.g., hormone replacement therapy in environmental or occupational exposure to Cr(VI), chromium supplementation, also important for cancer risk evaluation.

A randomised trial of a medium-chain TAG diet as treatment for dogs with idiopathic epilepsy.

Despite appropriate antiepileptic drug treatment, approximately one-third of humans and dogs with epilepsy continue experiencing seizures, emphasising the importance for new treatment strategies to improve the quality of life of people or dogs with epilepsy. A 6-month prospective, randomised, double-blinded, placebo-controlled cross-over dietary trial was designed to compare a ketogenic medium-chain TAG diet (MCTD) with a standardised placebo diet in chronically antiepileptic drug-treated dogs with idiopathic epilepsy. Dogs were fed either MCTD or placebo diet for 3 months followed by a subsequent respective switch of diet for a further 3 months. Seizure frequency, clinical and laboratory data were collected and evaluated for twenty-one dogs completing the study. Seizure frequency was significantly lower when dogs were fed the MCTD (2·31/month, 0-9·89/month) in comparison with the placebo diet (2·67/month, 0·33-22·92/month, P=0·020); three dogs achieved seizure freedom, seven additional dogs had ≥50 % reduction in seizure frequency, five had an overall <50 % reduction in seizures (38·87 %, 35·68-43·27 %) and six showed no response. Seizure day frequency were also significantly lower when dogs were fed the MCTD (1·63/month, 0-7·58/month) in comparison with the placebo diet (1·69/month, 0·33-13·82/month, P=0·022). Consumption of the MCTD also resulted in significant elevation of blood ß-hydroxybutyrate concentrations in comparison with placebo diet (0·071 (sd 0·035) v. 0·053 (sd 0·028) mmol/l, P=0·028). There were no significant changes in serum concentrations of glucose (P=0·903), phenobarbital (P=0·422), potassium bromide (P=0·404) and weight (P=0·300) between diet groups. In conclusion, the data show antiepileptic properties associated with ketogenic diets and provide evidence for the efficacy of the MCTD used in this study as a therapeutic option for epilepsy treatment.

Comparison of the Biological Impacts of the Fluoride Compounds by Graphical Risk Visualization Map Technique.

Various fluoride compounds are widely used in industry. The present risk assessment study was conducted using a series of inorganic binary fluorides of the type XFn, where X(n) = Na(+), K(+), Li(+), Mg(2+), Ca(2+), Sr(2+), Ba(2+), Al(3+), Nd(3+), La(3+), Ce(3+), Sm(3+), Gd(3+), Y(3+), Yb(2+), and Zn(2+). The aqueous solutions of these salts were orally administrated to 16 experimental groups (one for each of the salts tested). The levels of fluoride, N-acetyl-ß-D-glucosaminidase in cumulative 24-h urine samples and creatinine clearance were measured to assess possible acute renal damages. The levels of fluoride, alanine aminotransferase, and aspartate aminotransferase were also determined in serum samples to assess possible acute hepatic damages. The results reveal that sodium fluoride (NaF), potassium fluoride (KF), and zinc fluoride tetrahydrate (ZnF2 (.)4H2O) can carry the fluoride ion into the bloodstream and that it is excreted via urine more readily than the other compounds tested. These fluorides were assigned the highest risk impact factor. Most of the rare earth fluorides are insoluble in water while those groups 2 and 13 of the periodic table are slightly soluble, so that they do not have a significant negative risk. These findings suggest that the biological impact of fluoride depends on the accompanying counter ion and its solubility. The risk map obtained in the present study shows that the graphical visualization map technique employed is a valuable new tool to assess the toxicological risk of chemical compounds.

Pharmacokinetics of bromide in adult sheep following oral and intravenous administration.

OBJECTIVE: To determine the pharmacokinetics of bromide in sheep after single intravenous (IV) and oral (PO) doses. PROCEDURE: Sixteen Merino sheep were randomly assigned to two treatment groups and given 120 mg/kg bromide, as sodium bromide IV or potassium bromide PO. Serum bromide concentrations were determined by colorimetric spectrophotometry. RESULTS: After IV administration the maximum concentration (Cmax ) was 822.11 ± 93.61 mg/L, volume of distribution (Vd ) was 0.286 ± 0.031 L/kg and the clearance (Cl) was 0.836 ± 0.255 mL/h/kg. After PO administration the Cmax was 453.86 ± 43.37 mg/L and the time of maximum concentration (Tmax ) was 108 ± 125 h. The terminal half-life (t½ ) of bromide after IV and PO administration was 387.93 ± 115.35 h and 346.72 ± 94.05 h, respectively. The oral bioavailability (F) of bromide was 92%. No adverse reactions were noted in either treatment group during this study. The concentration versus time profiles exhibited secondary peaks, suggestive of gastrointestinal cyclic redistribution of the drug. CONCLUSIONS AND CLINICAL RELEVANCE: When administered PO, bromide in sheep has a long half-life (t½ ) of approximately 14 days, with good bioavailability. Potassium bromide is a readily available, affordable salt with a long history of medical use as an anxiolytic, sedative and antiseizure therapy in other species. There are a number of husbandry activities and flock level neurological conditions, including perennial ryegrass toxicosis, in which bromide may have therapeutic or prophylactic application.

[Certain toxicodynamic and toxicokinetic features of combined subchronic intoxication with hexavalent chromium and nickel].

Repeated intraperitoneal injections of nickel and chromium (VI) into rats appeared to demonstrate that the combined subchronic toxicity can be additive or vary (mostly to subadditivity) in accordance with effect on which they are evaluated. With moderate general toxic effects, the studied combination has marked genotoxicity with additive effect. The studies demonstrated reciprocal influence of nickel and chromium on accumulation of the second metal in some organs (especially, in spleen), but not on its renal excretion.

Serum bromide concentrations following loading dose in epileptic dogs.

OBJECTIVE: To determine serum bromide concentrations following an oral loading dose in dogs. METHODS: Retrospective review of clinical records of dogs suffering from seizures that were treated with bromide. A loading dose of 600 mg/kg potassium bromide was administered orally in 17 to 48 hours together with a maintenance dose of 30 mg/kg/day. Blood samples were collected within 24 hours after completing the protocol and serum bromide concentrations were determined by ultra-violet gold chloride colorimetric assay. RESULTS: Thirty-eight dogs were included in the study. The median age was 3 (range, 0 · 2 to 10) years and bodyweight 21 · 8 (3 · 45 to 46 · 2) kg. The median serum bromide concentration was 1 · 26 (0 · 74 to 3 · 6) mg/mL. Thirty-two dogs (84 · 2%) had serum bromide concentrations within the therapeutic interval (1 to 3 mg/mL). The serum concentration in five dogs (13 · 2%) was just under the minimal therapeutic value and in one dog (2 · 6%) it exceeded the maximal therapeutic value (3 · 6 mg/mL). CLINICAL RELEVANCE: Following this oral loading dose protocol, serum bromide concentrations reach the therapeutic range in the majority of dogs. This indicates that the suggested protocol is effective in achieving therapeutic concentrations rapidly in epileptic dogs.

Compounding errors in 2 dogs receiving anticonvulsants.

Two cases that involve drug compounding errors are described. One dog exhibited increased seizure activity due to a compounded, flavored phenobarbital solution that deteriorated before the expiration date provided by the compounder. The other dog developed clinical signs of hyperkalemia and bromine toxicity following a 5-fold compounding error in the concentration of potassium bromide (KBr).

Control of the misuse of bromide in horses.

Bromide is a sedative hypnotic. Due to its potential use as a sedative or calmative agent in competition horses, a method to control bromide is needed. Colorimetric method had been employed in the authors' laboratory from 2003 for the semi-quantification of bromide in equine plasma samples. However, the method was found to be highly susceptible to matrix interference, and was replaced in 2008 with a more reliable inductively coupled plasma-mass spectrometry (ICP/MS) method. Equine plasma was protein-precipitated using trichloroacetic acid, diluted with nitric acid, and then submitted directly to ICP/MS analysis. Since bromide is naturally occurring in equine plasma, a threshold is necessary to control its misuse in horses. Based on population studies (n = 325), a threshold of 90 µg/mL was proposed (with a risk factor of less than 1 in 10 000). Using the ICP/MS screening method, equine plasma samples with bromide greater than 85 µg/mL would be further quantified using the more accurate ICP/MS standard addition method. Confirmation of bromide was achieved by gas chromatography-mass spectrometry (GC-MS), with the bromide detected as its pentafluorobenzyl derivative. A sample is considered positive if its plasma bromide concentration exceeds the threshold (90 µg/mL) plus the measurement uncertainty of the quantification method (8 µg/mL at 99% 1-tailed confidence level) and its presence is confirmed using the GC-MS method. Following oral administration of potassium bromide (60 g each) to two geldings, plasma bromide levels peaked after approximately 2 hours at about 300 µg/mL, and then remained above the threshold for 8 and 13 days respectively.

What is your diagnosis? Marked hyperchloremia in a dog.

A 5-year-old neutered male Cavalier King Charles Spaniel was evaluated for a 3-week history of progressive paresis. The dog had been receiving potassium citrate capsules to acidify urine for the past 2 years because of an earlier history of urolithiasis. Results of neurologic examination, spinal cord radiography, and magnetic resonance imaging of the skull and spinal cord revealed no lesions that could have accounted for the neurologic signs. The main abnormalities on a clinical chemistry profile were marked hyperchloremia (179 mmol/L, reference interval 108-122 mmol/L) and an anion gap of -50.4 mmol/L (reference interval 16.3-28.6 mmol/L). Because of the severe hyperchloremia, serum bromide concentration was measured (400 mg/dL; toxic concentration >150 mg/dL; some dogs may tolerate up to 300 mg/dL). Analysis of the potassium citrate capsules, which had been compounded at a local pharmacy, yielded a mean bromide concentration of 239 mg/capsule. Administration of the capsules was discontinued and there was rapid resolution of the dog's neurologic signs. This case of extreme bromide toxicity, which apparently resulted from inadvertent use of bromide instead of citrate at the pharmacy, illustrates the importance of knowing common interferents with analyte methodologies and of pursing logical additional diagnostic tests based on clinical and laboratory evidence, even when a patient's history appears to rule out a potential etiology.

Determination of bromide in canine plasma using ion chromatography.

A new ion chromatographic procedure has been developed and validated for the determination of bromide in canine plasma. Following a simple dilution, samples were separated on a Metrosep A Supp 5 column. The mobile phase was an isocratic mixture of 2.2 mM Na(2)CO(3), 1.0 mM NaHCO(3), and 1% acetonitrile, with a flow-rate of 0.7 ml/min. The procedure produced a linear curve over the concentration range of 50-2500 microg/ml. The development of the assay permitted the determination of therapeutic levels after oral administration of potassium bromide to dogs being treated for epilepsy.

Pharmacokinetics of potassium bromide in adult horses.

OBJECTIVE: To determine the pharmacokinetics of potassium bromide (KBr) in horses after a single and multiple oral doses. ANIMALS: Twelve adult Standardbred and Thoroughbred mares. PROCEDURE: Horses were randomly assigned into two treatment groups. In Part 1 of the study, horses were given a single oral dose of 120 mg/kg KBr. Part 2 of the study evaluated a loading dose of 120 mg/kg KBr daily by stomach tube for 5 days, followed by 40 mg/kg daily in feed for 7 days. Serum concentrations of bromide were determined by colorimetric spectrophotometry following drug administration to permit determination of concentration versus time curves from which pharmacokinetic parameters could be calculated. Treated horses were monitored twice daily by clinical examination. Serum concentrations of sodium, potassium and chloride ions and partial pressures of venous blood gases were determined. RESULTS: Maximum mean serum bromide concentration following a single dose of KBr (120 mg/kg) was 284 +/- 15 microg/mL and the mean elimination half-life was 75 +/- 14 h. Repeated administration of a loading dose of KBr (120 mg/kg once daily for 5 days) gave a maximum serum bromide concentration of 1098 +/- 105 microg/mL. The administration of lower, maintenance doses of KBr (40 mg/kg once daily) was associated with decreased serum bromide concentrations, which plateaued at approximately 700 microg/mL. Administration of KBr was associated with significant but transient changes in serum potassium and sodium concentrations, and possible changes in base excess and plasma bicarbonate concentrations. High serum concentrations of bromide were associated with an apparent increase in serum chloride concentrations, when measured on an ion specific electrode. CONCLUSIONS AND CLINICAL RELEVANCE: A loading dose of 120 mg/kg daily over 5 days and maintenance doses of approximately 90-100 mg/kg of KBr administered once daily are predicted to result in serum bromide concentrations consistent with therapeutic efficacy for the management of seizures in other species. The clinical efficacy of this agent as an anticonvulsant medication and/or calmative in horses warrants further investigation.

Calcimimetics as an adjuvant treatment for familial hypophosphatemic rickets.

BACKGROUND AND OBJECTIVES: The treatment for X-linked hypophosphatemia (XLH) with phosphate and calcitriol can be complicated by secondary hyperparathyroidism and nephrocalcinosis. Furthermore, vitamin D and phosphate stimulate FGF23 production, the pathogenic factor causing XLH. We investigated in XLH patients: 1) whether treatment with the calcimimetic agent, cinacalcet, will block the rise in parathyroid hormone (PTH) caused by phosphate administration; and 2) whether treatment with oral phosphate and calcitriol increases FGF23 levels. DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS: Eight subjects with XLH were given a single oral dose of phosphate, followed the next day by combined treatment with phosphate and cinacalcet. Serum measurements of ionized calcium (Ca), phosphate, creatinine, intact PTH, 1,25(OH)(2)D, FGF23, and tubular threshold for phosphate/glomerular filtration rate (TP/GFR) were assessed in response to short-term treatment with phosphate and cinacalcet and compared with long-term administration of phosphate and calcitriol. RESULTS: Oral phosphate load increased serum phosphate, decreased ionized calcium, and increased PTH. Twenty-four hours later, FGF23 significantly increased and 1,25(OH)(2)D decreased. The concomitant administration of phosphate and cinacalcet resulted in further decrease in serum Ca(2+) but suppression of PTH and greater increase in serum phosphate and TP/GFR. Chronic treatment with phosphate and calcitriol resulted in a smaller increment in serum phosphate and high serum FGF23. CONCLUSIONS: Traditional therapy of XLH with phosphate and calcitriol elevates FGF23 and has the potential to stimulate PTH. Short-term treatment with cinacalcet suppresses PTH, leading to increase in TP/GFR and serum phosphate. Thus, long-term clinical studies are needed to investigate whether cinacalcet may be a useful adjuvant in the treatment of XLH, allowing the use of lower doses of phosphate and calcitriol.

Hypokalemic sensory overstimulation.

This report describes 2 generations of a family with symptoms of sensory overstimulation that exhibit a potassium sensitivity similar to that seen in hypokalemic periodic paralysis. The sensory overstimulation is characterized by a subjective experience of sensory overload and a relative resistance to lidocaine local anesthesia. The sensory overload is treatable with oral potassium gluconate, with onset of the therapeutic effect in approximately 20 minutes. The effect of potassium is reminiscent of its effect in the channelopathies underlying hypokalemic periodic paralysis, and the resistance to lidocaine applied peripherally suggests a peripheral sensory localization to the abnormality. The phenotype overlaps with that of attention deficit disorder, raising the possibility of subtypes of attention deficit disorder that have a peripheral sensory cause and novel forms of therapy.

A new graduated dosing regimen for phosphorus replacement in patients receiving nutrition support.

BACKGROUND: Hypophosphatemia is a common metabolic complication in patients receiving specialized nutrition support. We changed our previously reported dosing algorithm because the low dose no longer appeared to be effective at increasing serum phosphorus concentrations. The purpose of this study was to evaluate the safety and efficacy of a revised weight-based phosphorus-dosing algorithm in critically ill trauma patients receiving specialized nutrition support. METHODS: Seventy-nine adult trauma patients with hypophosphatemia (serum phosphorus concentration < or = 0.96 mmol/L) receiving nutrition support received an IV dose of phosphorus on day 1 according to the serum concentration of phosphorus: 0.73-0.96 mmol/L (0.32 mmol/kg, low dose), 0.51-0.72 mmol/L (0.64 mmol/kg, moderate dose), and < or = 0.5 mmol/L (1 mmol/kg, high dose). The IV phosphorus bolus dose was administered at 7.5 mmol/hour. Generally, patients with a serum potassium concentration <4 mmol/L received potassium phosphate and patients with a serum potassium concentration > or = 4 mmol/L received sodium phosphate. Patients who still had hypophosphatemia on day 2 were dosed using the new dosing algorithm by the nutrition support service according to that day's serum concentration of phosphorus, or empirically by the trauma service. RESULTS: Of the 79 patients studied, 57 were male and 22 were female with a mean age of 44.8 +/- 20.6 years. Mean Injury Severity Scores and APACHE-II scores were 27.1 +/- 11.6 and 15.2 +/- 6.8, respectively. There was no difference in baseline characteristics among the 3 dosing groups. Of the 79 patients, 34 received the low dose, 30 received the moderate dose, and 15 received the high dose of phosphorous. Mean serum phosphorous concentrations on day 2 were significantly increased in the moderate-dosed group (0.64 +/- 0.06 to 0.77 +/- 0.22 mmol/L, p < .05) and high-dosed group (0.38 +/- 0.06 to 0.93 +/- 0.32 mmol/L, p < .01), respectively, when compared with day 1. Mean serum phosphorus concentrations were normal in all 3 groups on day 3. Serum concentrations of magnesium, sodium, and potassium, as well as arterial pH, were stable across the study. Mean concentrations of ionized calcium were not significantly different in any of the 3 dosing groups across the study period. CONCLUSIONS: This weight-based phosphorus-dosing algorithm is safe for use in critically ill patients receiving nutrition support. The moderate and severe-dose regimens effectively increase serum phosphorus concentrations.

A streamlined method to predict hepatic clearance using human liver microsomes in the presence of human plasma.

INTRODUCTION: Human liver microsomal incubations are often used to predict the metabolic lability of new chemical entities. The clearance values are scaled-up from in vitro data and mathematically corrected for plasma protein binding, or in some cases the free fraction ratio of plasma to microsomes, using well-established scaling methods such as the well-stirred model. This can be time consuming for multiple compounds since it requires separate experiments to determine in vitro lability, and free fraction. METHODS: We attempted to streamline clearance predictions by combining experiments into one. Firstly, we combined the free fraction experiments into one free fraction ratio by measuring the partitioning of compound between plasma and microsomes, and by applying this experimental ratio to clearance predictions found that it performed at least as well as free fractions determined separately. We also incubated compounds with plasma added to the incubation mixture and compared the predicted clearances to values determined using traditional mathematical protein binding corrections. RESULTS: Consistently, incubations with added plasma resulted in CL predictions closer to literature values than incubations only mathematically corrected for protein binding. For example, incorporating plasma into a ketamine incubation resulted in a CL value of 15.1 mL/min/kg, compared with a value of 10.2 using mathematical binding corrections. The literature value is 16.4 mL/min/kg. DISCUSSION: This work characterizes this new method and compares it to the traditional microsomal incubation method using several literature compounds, and suggests that streamlining the methods may generate quality data faster and with less resource investment.

Pharmacokinetics of potassium bromide in adult horses.

OBJECTIVE: To determine the pharmacokinetics of potassium bromide (KBr) in horses after single and multiple oral doses. ANIMALS: Twelve adult Standardbred and Thoroughbred mares. PROCEDURE: Horses were randomly assigned to two treatment groups. Group 1 horses were given a single oral dose of 120 mg/kg potassium bromide. Part 2 of the study evaluated a loading dose of 120 mg/kg KBr daily by stomach tube for 5 days, followed by 40 mg/kg daily in feed for 7 days. Serum concentrations of KBr were measured to construct concentration versus time curves and to calculate pharmacokinetic parameters. Treated horses were monitored twice daily by clinical examination. Serum concentrations of sodium, potassium and chloride ions and partial pressures of venous blood gases were determined. RESULTS: Maximum mean serum concentration following a single dose of KBr (120 mg/kg) was 423 +/- 22 microg/mL and the mean elimination half-life was 75 +/- 14 h. Repeated administration of a loading dose of KBr (120 mg/kg once daily for 5 d) gave a maximum serum concentration 1639 +/- 156 microg/mL. The administration of lower, maintenance doses (40 mg/kg once daily) was associated with decreased serum bromide concentrations, which plateaued at approximately 1000 microg/mL. Administration of KBr was associated with significant but transient changes in serum potassium and sodium concentrations, and possible changes in base excess and plasma bicarbonate concentrations. High serum concentrations of bromide were associated with an apparent increase in serum chloride concentrations, when measured on an ion specific electrode. CONCLUSIONS: and clinical relevance Loading doses of 120 mg/kg daily over 5 d and maintenance doses of approximately 90 mg/kg of KBr administered once daily resulted in serum bromide concentrations consistent with therapeutic efficacy for the management of seizures in other species. The clinical efficacy of this agent as an anticonvulsant medication and/or calmative in horses warrants further investigation.