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[Significance of bromide levels in evaluation of the hemato-encephalic barrier during acute viral meningitis].

INTRODUCTION: Inflammatory diseases of the CNS are associated with increased permeability of blood-brain barrier due to vasculitis of cerebral blood vessels leading to regional ischaemia and necrosis. Many substances pass easily from the serum into the CSF through inflamed and damaged blood-brain barrier. Bromide partition test is one of the parameters for evaluation of the blood-brain barrier integrity during CNS inflammatory diseases. As early as 1929 Walter published a monograph on blood-brain barrier accentuating the value of bromide partition test for evaluation of the functional status of blood-brain barrier. In healthy individuals bromide partition test usually ranges from 2.9-3.5. In most patients with TB meningitis bromide partition test remains below 1.6 while it is usually higher in patients with serous meningitis of other aetiologies. However, the low bromide partition test may associate also some other viral and other serous meningitides accompanied with severe lesions of the blood-brain barrier, resulting in increased passage of sodium bromide from the serum into the CSF, so that the serum/CSF ratio is lower. The aim of th study was to calculate and analyze the results of bromide partition test in patients with acute viral meningitis and hyperproteinorachia above 0.70 g/l and to calculate and analyze the results of bromide partition test in patients with TB and parasitic meningitis. The results of bromide patirion tests were compared with results of other parameters for evaluation of the blood-brain barrier function. METHOD: Titration method was used to determine the serum sodium bromide and CSF ratio. Sodium bromide oxidation into sodium bromate was the principle, where addition of potassium iodide is followed by release of equivalent amount of elementary iodide. Iodide is titrimetrically evidenced with thyosulphate, with starch as an indicator. In addition to bromide partition test functional condition of blood-brain barrier was also evaluated by albumin coefficients, albuminorachia and total proteinorachia. RESULTS: In 6 of 30 patients (20%) with acute viral meningitis the bromide partition ratio was below 1.6, suggesting severe damage of blood-brain barrier in these patients: albumin coefficients exceeded 16.7 (mean = 24.7), albuminorachia was over 0.90 (mean = 1.38 g/l), and total proteinorachia over 3.0 g (mean = 3.1 g/l). The aetiology was confirmed in all patients: lymphocyte choriomeningitis virus in 5, COX B1 in one. Values of bromide partition test were higher on follow-up examination, and values of other parameters decreased, suggesting restitution of blood-brain barrier. The results are given in Table 1. Most severe damage of blood-brain barrier was evidenced in patients with lymphocyte choriomeningitis. Parameters for evaluation of functional condition of blood-brain barrier in patients with lymphocyte choriomeningitis and TB meningitis with most severe damage of the barrier, were compared. The results are given in Table 2. No differences between the compared parameters were found, i.e. no difference in the severity of blood-brain damage. Bromide patition test values were below 1.6 in all patients with TB meningitis and in 3 of 5 patients with parasitic meningitis. DISCUSSION: Numerous studies have shown that bromide patition test value during TB meningitis was usually below 1.6. This is probably due to hypersensitivity reaction of the meninges to tuberculin which is located intrathecally and leads to blood-brain barrier damage. Use of antituberculous drugs does not affect the bromide partition test values in early stages of the disease. In all of our 15 patients with TB meningitis the bromide partition test values were below 1.6, coinciding with reference reports. However, we also measured bromide partition test values below 1.6 in 6 (20%) of 30 patients with acute viral meningitis with proteinorachia above 0,70 g/l (ABSTRACT TRUNCATED).

Acute Disease↗
PubMed1992

NTP Toxicology and Carcinogenesis Studies of Methyl Bromide (CAS: 74-83-9) in B6C3F1 Mice (Inhalation Studies).

Methyl bromide is widely used as a fumigant and pesticide. Toxicology and carcinogenesis studies were conducted by exposing groups of male and female B6C3F1 mice to methyl bromide (99.8% pure) by inhalation 6 hours per day, 5 days per week, for 14 days, 6 weeks, 13 weeks, or 2 years. Six-week and 13-week inhalation toxicity studies in F344/N rats were conducted concurrently with the mouse studies. Hematology parameters were measured during the 6-week, 13-week, and 2-year studies. Quantitative neurobehavioral testing was performed during the 14-day, 13-week and 2-year studies. Genetic toxicology studies were conducted for gene mutation induction in Salmonella typhimurium and for induction of sister chromatid exchanges in mouse bone marrow cells and of micronuclei from peripheral blood erythrocytes. 14-Day Studies: Groups of five B6C3F1 mice of each sex were exposed to 0, 12, 25, 50, 100, or 200 ppm methyl bromide by inhalation 6 hours per day, 5 days per week for 2 weeks. Only four female mice and one male mouse survived 10 exposures at 200 ppm. No deaths occurred at the lower doses. Neurobehavioral effects including trembling and paralysis were noted in all groups, but were most pronounced in the three highest dose groups. Red urine was noted in the mice exposed to 200 ppm. 13-Week Studies : Groups of 10 mice of each sex were exposed to 0, 10, 20, 40, 80, or 120 ppm methyl bromide by inhalation 6 hours per day, 5 days per week for 13 weeks. Additional groups of eight to 17 mice were concurrently exposed for neurobehavioral and genetic toxicology studies. The final mean body weight of males exposed to 120 ppm was significantly (12%) lower than that of the controls. Four of 24 males exposed to 120 ppm died during the study. Groups of 10 rats of each sex were exposed to 0, 30, 60, or 120 ppm methyl bromide by inhalation 6 hours per day, 5 days per week for 13 weeks. Additional groups of eight rats were concurrently exposed for neurobehavioral studies. Final mean body weights of rats exposed to 120 ppm were 12% lower than those of the controls for males and 13% lower for females. No rats died as a result of methyl bromide exposure during the studies. Special 6-Week Target Organ Toxicity Studies: Neither the 14-day nor the 13-week studies provided strong evidence for specific organ toxicity. Six-week studies were therefore conducted to identify target organs for the 2-year studies. Groups of 20 rats and mice of each sex were exposed to methyl bromide by inhalation for 6 hours per day, 5 days per week for 6 weeks at a dose of 160 ppm. Mortality rates exceeded 50% in the male mice after eight exposures, in female mice after six exposures, and in male rats after 14 exposures. Only the female rat group survived 30 exposures with less than 50% mortality. The study identified the brain, kidney, nasal cavity, heart, adrenal gland, liver, and testis as the primary organs to examine for toxicity in the 2-year methyl bromide inhalation studies. 2-Year Studies: Groups of 70 B6C3F1 mice of each sex were exposed to methyl bromide by inhalation at 0, 10, 33, or 100 ppm for 6 hours per day, 5 days per week for up to 103 weeks. Additional groups of 16 mice were included for neurobehavioral evaluations throughout the 2-year studies. By 20 weeks (139 days), 27 males and 7 females exposed to 100 ppm had died and methyl bromide exposure was discontinued for the remaining mice in this dose group. Ten female mice from the 100 ppm group predesignated for the 15-month interim evaluation were killed on schedule and all other high-dose animals were allowed to live to term (24 months) for evaluation of chronic toxicity and carcinogenicity. Clinical signs indicative of neurotoxicity, including tremors, abnormal posture, tachypnea, and hind leg paralysis, persisted in these high-dose mice until the end of the studies. Final mean body weights of surviving 100 ppm males and females were markedly lower (33% and 31%) than those of the controls. Neurobehavioral changes occurred in male and female mice initially exposed to 100 ppm methyl bromide, with more prnitially exposed to 100 ppm methyl bromide, with more pronounced changes observed in males. In general, these animals were less active and manifested a heightened sensitivity in the startle response than mice in other dose groups. Exposure to methyl bromide was not carcinogenic under the conditions of these studies. However, there was an increase in the incidence of several nonneoplastic lesions in the brain, heart, bone (sternum), and nose. Degenerative changes in the cerebellum and cerebrum occurred in males and females exposed to 100 ppm. Myocardial degeneration and cardiomyopathy were observed in the hearts of mice exposed to 100 ppm. An increased incidence of sternal dysplasia was seen in treated animals, particularly in those exposed to 100 ppm. An increased incidence of olfactory epithelial necrosis and metaplasia within the nasal cavity was seen in the mice exposed to 100 ppm, particularly males. Genetic Toxicology: Methyl bromide was positive for induction of gene mutations in Salmonella typhimuriumstrain TA100, with and without exogenous metabolic activation; negative results were obtained with TA98 in this assay. In vivo, methyl bromide induced sister chromatid exchanges in bone marrow cells and micronuclei in peripheral erythrocytes of female mice exposed by inhalation for 14 days. No significant increase in either sister chromatid exchanges or micronuclei was observed in male or female mice exposed to methyl bromide by inhalation for 4, 8, or 12 weeks. Conclusions: Under the conditions of these 2-year inhalation studies, methyl bromide caused degenerative changes in the cerebellum and cerebrum, myocardial degeneration and cardiomyopathy, sternal dysplasia, and olfactory epithelial necrosis and metaplasia. Toxic effects persisted although exposure to methyl bromide in the 100 ppm group terminated after 20 weeks. There was no evidence of carcinogenic activity of methyl bromide in male or female B6C3F1 mice exposed to 10, 33, or 100 ppm. Synonym: Bromomethane

Journal Article↗
PubMed1998

Therapeutic serum drug concentrations in epileptic dogs treated with potassium bromide alone or in combination with other anticonvulsants: 122 cases (1992-1996).

OBJECTIVE: To determine therapeutic serum drug concentrations in epileptic dogs treated with potassium bromide. DESIGN: Retrospective study. ANIMALS: 122 dogs with major motor epilepsy. PROCEDURE: Medical histories were collected for epileptic dogs treated with potassium bromide with or without phenobarbital sodium or primidone, from which serum was submitted for bromide analysis from May 1992 to May 1996 to the Therapeutic Drug Monitoring Program at Cornell University's College of Veterinary Medicine. A therapeutic response (improved seizure control) was defined as a > or = 50% reduction in seizure frequency following initiation of bromide treatment. Serum bromide and phenobarbital concentrations and therapeutic outcome were determined for all dogs. RESULTS: 72% of epileptic dogs had a > or = 50% reduction in seizure frequency following initiation of treatment with potassium bromide. Discontinuation of barbiturate treatment was possible in 19% of those dogs originally treated with phenobarbital or primidone. Of those dogs continued on bromide and phenobarbital, 45% maintained seizure control with serum phenobarbital concentrations < 20 micrograms/ml. Significantly higher serum bromide concentrations were required when dogs were initially or eventually treated with bromide alone (mean bromide concentration, 1,906 micrograms/ml) compared with dogs treated with potassium bromide along with a barbiturate (mean bromide concentration, 1,621 micrograms/ml). CLINICAL IMPLICATIONS: When dogs are treated with bromide and phenobarbital, a reasonable therapeutic range for serum bromide concentrations is 810 to 2,400 micrograms/ml, and for bromide treatment alone, the range is 880 to 3,000 micrograms/ml. When phenobarbital is used in combination with bromide, a reasonable therapeutic range for serum phenobarbital concentrations is 9 to 36 micrograms/ml, although in some dogs treated with bromide, phenobarbital can eventually be discontinued.

Animals↗
PubMed2002

Characterization of propargyl bromide transformation in soil.

Propargyl bromide is being investigated for its potential as a soil fumigant. Characterization of the fate of propargyl bromide in soil is important in determining both efficacy and the threat of environmental contamination. These experiments investigated some of the factors affecting the rate of propargyl bromide degradation in soil and quantified some of the products formed as a result of propargyl bromide degradation in four soils of differing composition and at three initial propargyl bromide concentrations. In all soils at all initial propargyl bromide concentrations, equimolar formation of Br- was observed during propargyl bromide degradation, but little propargyl alcohol (product of hydrolysis) was formed. The apparent first-order degradation coefficient (k) increased with decreasing initial propargyl bromide concentration in all soils, but the mass degraded per unit time increased with increasing propargyl bromide concentration. The rate of propargyl bromide degradation increased with increasing soil organic matter content, and the k value was correlated to the organic carbon content of the soil (correlation coefficient > 0.97 for all concentrations). Repeated application of propargyl bromide did not increase the rate of propargyl bromide degradation in soil. Addition of Br- did not affect the rate of propargyl bromide transformation in soil, so accumulation of Br- in the soil is not expected to impede propargyl bromide degradation.

Alkynes↗
PubMed2002

Comparative microvascular exchange kinetics of [(77)Br]bromide and (99m)Tc-DTPA in humans.

The plasma clearance curves of small hydrophilic solutes comprise three exponentials, consistent with a three-compartmental distribution model. A previous comparison between inulin and diethylene triamine penta-acetic acid (DTPA) suggested that these three compartments are in series, the first being plasma and the second and third representing compartments within the extravascular space. Moreover, whilst the total distribution volumes of these two indicators were similar, the volume of the second compartment was higher for DTPA. The purpose of the current study was to investigate whether a solute smaller than DTPA, namely bromide, fits the hypothesis that the second space volume is an inverse function of the size of the solute. Two groups of subjects were studied: group A comprised eight patients undergoing routine diagnostic arteriography and group B, eight patients referred for routine measurement of glomerular filtration rate plus two normal volunteers. (99m)Tc-DTPA and sodium [(77)Br]bromide were intravenously administered simultaneously. In group A, frequent arterial samples were obtained up to 40 min after injection, and antecubital venous samples 30 s after each arterial sample. In group B, frequent venous samples were obtained up to 280 min after injection. Volume measurements based on bromide were corrected for erythrocyte bromide accumulation. In both subject groups, the normalised venous concentration ratio of bromide to DTPA, corrected for red cell bromide uptake, was significantly less than unity in the earliest blood samples, being 0.56 (SD 0.08) at 1 min, consistent with faster diffusion of bromide from plasma to interstitial fluid. Furthermore, the extraction fraction of bromide from plasma to interstitial fluid in the forearm was about 0.6, higher than that of DTPA (about 0.5) in spite of red cell bromide accumulation which equilibrated with plasma bromide within 20 s and resulted in a red cell to plasma concentration ratio of 0.51 (0.09). Nevertheless, the net extraction fractions of the two solutes approached asymptotic values with identical time courses over 20-25 min. The total volume of distribution of bromide in group B was 22.5 (3.8) litres, which was higher than that of DTPA, 18.0 (2.8) litres ( P<0.001). It was assumed that this difference was the result of intracellular bromide accumulation. After correction for this, the combined volume of the first and second spaces was significantly higher for bromide, at 13.9 (2.9) litres, than for DTPA, 12.3 (2.0) litres ( P<0.05), but the volume of the third space, 4.1 (2.8) litres, was less compared with DTPA, for which it was 5.8 (2.2) litres ( P<0.05). The proportion of the total space occupied by the first and second spaces was also higher for bromide, 0.78 (0.14), than for DTPA, for which it was 0.69 (0.09; P<0.05). These data are consistent with a three-in series-compartmental model of solute distribution in which the volume of the second space is an inverse function of solute molecular size while the volume of the third is a positive function of solute size.

Bromides↗
PubMed1995

Tiotropium bromide (Ba 679 BR), a novel long-acting muscarinic antagonist for the treatment of obstructive airways disease.

Tiotropium bromide (Ba 679 BR) is a novel potent and long-lasting muscarinic antagonist that has been developed for the treatment of chronic obstructive airways disease (COPD). Binding studies with [3H]tiotropium bromide in human lung have confirmed that this is a potent muscarinic antagonist with equal affinity for M1-, M2- and M3-receptors and is approximately 10-fold more potent than ipratropium bromide. Tiotropium bromide dissociates very slowly from lung muscarinic receptors compared with ipratropium bromide. In vitro tiotropium bromide has a potent inhibitory effect against cholinergic nerve-induced contraction of guinea-pig and human airways, that has a slower onset than atropine or ipratropium bromide. After washout, however, tiotropium bromide dissociates extremely slowly compared with the dissociation of atropine and ipratropium bromide. Measurement of acetylcholine (ACh) release from guinea-pig trachea shows that tiotropium bromide, ipratropium bromide and atropine all increase ACh release on neural stimulation and that this effect is washed out equally quickly for the three antagonists. This confirms binding studies to transfected human muscarinic receptors which suggested that tiotropium bromide dissociates slowly from M3-receptors (on airway smooth muscle) but rapidly from M2 autoreceptors (on cholinergic nerve terminals). Clinical studies with inhaled tiotropium bromide confirm that it is a potent and long-lasting bronchodilator in COPD and asthma. Furthermore, it protects against cholinergic bronchoconstriction for > 24 h. This suggests that tiotropium bromide will be a useful bronchodilator, particularly in patients with COPD, and may be suitable for daily dosing. The selectivity for M3- over M2-receptors may also confer a clinical advantage.

Acetylcholine↗
PubMed2004

Tiotropium bromide. A review of its use as maintenance therapy in patients with COPD.

Tiotropium bromide (Spiriva) is a long-acting anticholinergic bronchodilator that maintains bronchodilation for at least 24 hours, allowing once-daily administration. The active moiety is the tiotropium cation (tiotropium); tiotropium bromide 22.5 micrograms is equivalent to 18 micrograms of tiotropium cation. Greater improvements in lung function from baseline (primary endpoint mean trough FEV(1)) were observed with inhaled tiotropium 18 micrograms once daily than with placebo in 6-month and 1-year randomized, double-blind trials in patients with COPD. Tiotropium improved lung function (trough FEV(1) response) more effectively than ipratropium bromide (ipratropium) 40 micrograms four times daily in 1-year clinical trials, and was at least as effective as salmeterol 50 micrograms 12-hourly in 6-month trials. Preliminary data suggest that tiotropium alone or in combination with once-daily formoterol has a greater bronchodilator effect than twice-daily formoterol in patients with COPD. Improvements in patients' perception of health-related quality of life (HR-QOL) or dyspnea were greater with tiotropium than with placebo or ipratropium, and were similar to those with salmeterol. Reductions in the frequency and severity of acute exacerbations and in the use of rescue medication were also greater with tiotropium than with ipratropium or placebo. There was no evidence of tachyphylaxis with tiotropium during 1-year clinical trials. Inhaled tiotropium was generally well tolerated in clinical trials. Apart from dry mouth, the type and incidence of adverse events with tiotropium were similar to those with ipratropium, salmeterol or placebo in patients with COPD. In conclusion, inhaled tiotropium 18 micrograms once daily improved lung function, dyspnea, and HR-QOL, and decreased the incidence of acute COPD exacerbations and the use of rescue medication relative to placebo or ipratropium in clinical trials in patients with COPD. Tiotropium was at least as effective as salmeterol in terms of bronchodilator efficacy and improvements in dyspnea or HR-QOL. With the exception of dry mouth, the tolerability profile of tiotropium was similar to that with placebo, ipratropium, or salmeterol. Consequently, inhaled tiotropium is likely to be a valuable option for first-line, long-term maintenance therapy in the management of bronchoconstriction in patients with symptomatic COPD. Tiotropium bromide has a quaternary ammonium structure and acts as an anticholinergic bronchodilator; the active moiety is the tiotropium cation (tiotropium). A 22.5 micrograms dose of tiotropium bromide provides 18 micrograms of tiotropium. Orally inhaled tiotropium bromide antagonizes the muscarinic M(1), M(2), and M(3) receptors located in airway smooth muscle, reversing vagally mediated bronchoconstriction. Receptor binding assays and in vitro tests indicate that tiotropium bromide is kinetically selective for M(1) and M(3) receptors over the M(2) receptor, unlike ipratropium bromide, which is nonselective. Animal and in vitro studies showed that tiotropium bromide was more potent ( approximate, equals 20-fold) than ipratropium bromide in displacing [(3)H]N-methylscopolamine (NMS) from muscarinic receptors, and had a more sustained protective effect (>70% inhibition) against NMS binding. Tiotropium bromide was a more potent inhibitor of bronchial contraction than atropine ( approximate, equals 23-fold), and had a slower onset and markedly longer duration of action than atropine or an equipotent dose of ipratropium bromide. Aerosol particle penetration is improved with tiotropium, without delaying mucus clearance from the lungs. Tiotropium 4.5-36 micrograms once daily for 4 weeks increased mean trough and average FEV(1) and FVC and mean PEFR values from baseline compared with placebo, with no evidence of tachyphylaxis. Improvements in trough FEV(1) from baseline with tiotropium 4.5-36 micrograms were not dose dependent. Based on a lack of dose response, the optimal once-daily tiotropium dosage is 18 micrograms. Steady-state trough FEV(1) values are achieved within 48 hours of commencing tiotrochodilation (for >/=24 hours) and an attenuation of the nocturnal decline in FEV(1) that were unaffected by timing of the daily tiotropium dose were seen in randomized, double-blind, placebo-controlled studies in patients with stable COPD. The drug improved static and dynamic lung hyperinflation (evidenced by reduced trapped air volume and increased tidal volume and end-of-exercise inspiratory capacity), and improved exertional dyspnea (during activities of daily living and exertion) and exercise tolerance compared with placebo in randomized, double-blind studies. In patients with stable COPD, improved sleep-related oxygen desaturation that was unaffected by the timing of the daily dose was seen with tiotropium but not with placebo. Clinically significant treatment-related disorders of conduction or rhythm, or changes in heart rate were not observed with tiotropium in this patient group. Mean maximal plasma concentrations (C(max)) were observed within 5 minutes of inhalation of a single dose of tiotropium 18 micrograms in patients with COPD. Plasma drug levels declined to minimum concentrations (C(min)) within 1 hour of treatment in healthy volunteers. Mean steady-state C(max) concentrations (16 ng/L) were achieved after 2-3 weeks of once-daily inhaled tiotropium 18 micrograms in elderly patients with COPD; tiotropium does not appear to accumulate once steady-state has been achieved.The estimated absolute bioavailability of tiotropium at steady state in healthy volunteers was approximately 20-25%, and approximately 72% of the drug is bound to plasma proteins. Excretion of tiotropium is predominantly renal (through active secretion by the kidneys), although in vitro studies suggest that cytochrome P450 (CYP) oxidation (possibly involving CYP2D6 and CYP3A4 enzymes) may have a minor role. In patients with COPD, renal excretion of the unchanged drug at 24 hours (Ae(24)) was approximately 7%. The mean plasma elimination half-life after single or multiple doses in healthy volunteers and elderly patients with COPD was approximately 5-6 days. The renal clearance and urinary excretion of tiotropium decrease with increasing age; however, these changes are not considered to be clinically significant. Because of altered steady-state C(max), C(min), area under the concentration-time curve, and Ae(24) values, caution is required with tiotropium administration in patients with moderate-to-severe renal impairment. The pharmacokinetics of tiotropium in patients with severe renal or hepatic impairment have not been studied. Tiotropium does not interact with drugs such as cimetidine or ranitidine, which are also eliminated by active renal secretion. Orally inhaled tiotropium bromide has been evaluated as a bronchodilator for the management of patients with COPD in randomized, double-blind 6-month and 1-year trials, and in several shorter studies. In clinical trials, COPD was diagnosed according to the American Thoracic Society guidelines. The bronchodilator effect was expressed as the trough FEV(1) response (the mean change in FEV(1) from baseline measured 1 hour prior to and immediately before a scheduled dose), and was the primary endpoint in all but two clinical trials. The bronchodilator effect with tiotropium 18 micrograms once daily was superior to that with placebo in several well designed trials in patients with COPD. Moreover, greater improvements in mean peak and average FEV(1) responses occurred with tiotropium but not with placebo. Mean trough, peak, and average FVC responses, and weekly mean morning and evening PEFR values were also improved to a greater extent with tiotropium than with placebo. Tiotropium demonstrated a greater bronchodilator effect than ipratropium bromide (hereafter referred to as ipratropium when used at approved dosages) 40 micrograms four times daily in two 1-year trials in patients with COPD. Mean peak and average FEV(1), mean trough FVC responses, and weekly mean morning and evening PEFR values were also increased to a greater extent with tiotropium than with ipratropium. In one of the two 6-month trials that compared the efficacy of tiotropium with that of inhaled salmeterol 50 micrograms twice daily, greater improvements from baseline in mean trough, peak, and average FEV(1) and FVC responses were seen with tiotropium than with salmeterol. Increases in weekly mean evening, but not morning, PEFR values were generally greater with tiotropium than salmeterol. In the second trial, improvement in the primary endpoint (mean trough FEV(1) response from baseline) with tiotropium or salmeterol was similar, although peak and average responses were superior with tiotropium. Preliminary results from a 6-week crossover study in patients with COPD suggested that tiotropium alone or in combination with once-daily formoterol improved mean trough and average FEV(1) and trough FVC values from baseline to a greater extent than twice-daily formoterol. More patients achieved a clinically important improvement (increase of >/=1 unit) in the transitional dyspnea index focal score (a measure of dyspnea-related impairment) with tiotropium than with placebo in the 1-year trials. Tiotropium was superior to ipratropium in 1-year trials, and was at least as effective as salmeterol in 6-month trials, in achieving a clinically important improvement in focal scores. Tiotropium recipients experienced fewer COPD exacerbations than placebo or ipratropium recipients and had fewer and shorter COPD-related hospitalizations compared with placebo recipients. Unlike salmeterol, tiotropium lengthened the time to onset of the first exacerbation and decreased the number of exacerbations compared with placebo in two 6-month trials. Similar proportions of tiotropium, salmeterol, and placebo recipients required COPD-related hospitalizations. (ABSTRACT TRUNCATED)

Bronchodilator Agents↗
PubMed2004

Metabolism of bromide and its interference with the metabolism of iodine.

The present knowledge about the metabolism of bromide with respect to its goitrogenic effects, including some conclusions drawn from our recent research on this subject, is reviewed. Firstly, the biological behavior of bromide ion is compared with that of chloride and iodide. Secondly, the details about distribution and kinetics of bromide ions in the body and in 15 different organs and tissues of the rat are given. Significant correlation between the values of the steady-state concentration of bromide in the respective tissue and of the corresponding biological half-life was found in most tissues examined. A remarkably high concentration of radiobromide was found in the skin, which represents, due to its large mass, the most abundant depot of bromide in the body of the rat. Thirdly, the effects of excessive bromide on the rat thyroid are summarized, along with the interference of exogenous bromide with the whole-body metabolism of iodine. It is suggested that high levels of bromide in the organism of experimental animals can influence their iodine metabolism in two parallel ways: by a decrease in iodide accumulation in the thyroid and skin (and in the mammary glands in lactating dams), and by a rise in iodide excretion by kidneys. By accelerating the renal excretion of iodide, excessive bromide can also influence the pool of exchangeable iodide in the thyroid. Finally, our recent results concerning the influence of high bromide intake in the lactating rat dam on iodine and bromide transfer to the suckling, and the impact of seriously decreased iodine content and increased bromide concentration in mother's milk on the young are discussed. We must state, however, that the virtue of the toxic effects of excessive bromide on the thyroid gland and its interference with the biosynthesis of thyroid hormones, as well as the exact mechanism of bromide interference with postnatal developmental processes remains to be elucidated.

Animals↗
PubMed1980

Control and virus-transformed baby hamster kidney cells resistant to ethidium bromide. I. Characterization and the respiratory enzymes.

Cell lines resistant to ethidium bromide have been developed from cultured mammalian BHK21/C13 cells and these same cells transformed by Rous sarcoma virus (C13/B4). Cells resistant to 2 micrograms ethidium bromide per milliliter have been cloned. One clone of the control and one of the virus-transformed cell lines has been employed for characterization. The resistant cells, in the presence of 2 micrograms ethidium bromide/ml, grow at approximately the same rate as the untreated parental cells. The control cells possess a "normal" karyotype (44 chromosomes), while the corresponding ethidium bromide mutant has a reduced chromosome number of 41 and a number of translocations. The mitochondria displayed morphological alterations compared to the parental lines during the transition phase prior to the isolation of the ethidium bromide-resistant cells. The mitochondria of the ethidium bromide-resistant mutants appear somewhat enlarged with a normal morphology. The effect of ethidium bromide on selected respiratory enzymes in normal and virus-transformed ethidium bromide-resistant baby hamster kidney cells was determined. Ethidium bromide-resistant cells exhibited a depressed level of cytochrome aa3. This depression could not be reversed by growth in ethidium bromide-free media. Ethidium bromide-resistant cells possessed the same cytochrome b, c, and c1 levels per cell as their corresponding parental lines. Purified mitochondria isolated from virus-transformed ethidium bromide-resistant cells exhibited a depression in cytochrome oxidase-specific activity, while the ethidium bromide-resistant control cells did not. All cell lines studied showed a depression in NADH-ferricyanide and NADH-cytochrome c reductase-specific activities relative to their parental BHK21/C13 cells. No increase was observed in virus-transformed ethidium bromide-resistant cells. Ethidium bromide-resistant control cells exhibited a two-fold increase in oligomycin-insensitive adenosine triphosphatase activity relative to their parental cells. All of the cell lines studied possessed equivalent oligomycin-sensitive adenosine triphosphatase-specific activity except for the virus-transformed, dye-resistant mutant, whose activity was increased.

Adenosine Triphosphatases↗