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Kinetic behavior of thallium in the rat. Accelerated elimination of thallium owing to treatment with potent diuretic agents.

1. In acute experiments anesthetized rats were treated with a subthreshold dose of 204Tl+, given intravenously in order to study the elimination kinetics of Tl+. Thallium disappeared from whole blood by means of two different half-lives (5 and 196 min, respectively), whereas VDbeta amounted to 1400 ml. The same kinetic parameters were found after chronic exposure to toxic amounts of Tl+. 2. After chronic exposure to thallium (10 or 30 ppm in the drinking water), the distribution of thallium over various organs proved non-specific. However, a pronounced accumulation was found in the renal medulla. 3. In view of the importance of the renal route in the elimination of Tl+ from the body and also because of the established accumulation of the toxic metal in the kidney, the influence of potent diuretic agents like furosemide and ethacrynic acid on the excretion of Tl+ was studied. The enhanced excretion of water and ions (Na+, K+, Cl-) was accompanied by a significantly accelerated excretion of thallium ions. High doses of ethacrynic acid (25 mg/kg) proved particularly powerful in this respect. Between the enhanced excretion of thallium and potassium ions a significant correlation was obvious, thus supporting the well-known similarity in the behaviour of these ions. The marked increase in renal elimination of thallium upon intensive diuretic treatment may be useful in the management of thallotoxicosis.

Animals

Thallium-205 and proton nuclear magnetic resonance investigation of the complexation of thallium by the ionophores monensin and nigericin.

A thallium-205 and proton nuclear magnetic resonance study of the ionophores monensin and nigericin is reported. Evidence is presented for the simultaneous existence of two forms of monensin free acid in chloroform solution, one containing a water molecule in the central cavity and one with a water molecule on the periphery, linking the ends of the monensin molecule by hydrogen bonding. There appear to be three structurally different monensin complexes of thallium, two in the salt form and one in the acid form. In free nigericin acid, both terminal hydroxyl moieties hydrogen bond to the terminal carboxylic acid oxygens; in the Na+ salt, the binding of one of the carboxylate oxygens to the metal ion allows but one of the terminal OH's to hydrogen bond strongly. Thallium-205 chemical shifts and spin-lattice relaxation times in the title complexes are discussed and compared to those in ionophores studied previously.

Anti-Bacterial Agents

Toxicity and accumulation of thallium in bacteria and yeast.

Thallium sulphate inhibited microbial growth, with Bacillus megaterium KM more sensitive to the metal than Saccharomyces cerevisiae and Escherichia coli. Inhibition of B. megaterium KM and S. cerevisiae, but not of E. coli, was alleviated by increasing the potassium concentration of the medium; inhibition of respiration of S. cerevisiae, but not of E. coli, was similarly alleviated. Thallium was rapidly bound, presumably to cell surfaces, by S. cerevisiae and E. coli, and was progressively accumulated by energy-dependent transport systems (probably concerned primarily with potassium uptake) with both organisms. Thallium uptake kinetics suggested more than one transport system operated in yeast, possibly reflecting a multiplicity of potassium transport systems. Apparent Km and Ki values for competitive inhibition of thallium uptake by potassium indicated S. cerevisiae to have a higher affinity for thallium uptake than for potassium, while E. coli had a transport system with a higher affinity for potassium than for thallium. The likely systems for thallium transport are discussed. A mutant of E. coli with tenfold decreased sensitivity to thallium was isolated and apparently effected surface binding of thallium in amounts equivalent to the wild type organism, but showed no subsequent uptake and accumulation of the metal from buffer, even though it was able to accumulate potassium to normal intracellular concentrations during growth.

Bacillus megaterium

Thallium loading in owls and other birds of prey in Denmark.

Due to previous findings of increased concentrations of the rodenticid, thallium, in free-living Danish carnivores, thallium analysis has been carried out on material from 77 owls and birds of prey. Thallium was found in 2/3 of the birds and in 10% the concentration was so high that the load of thallium may have caused the death of the birds. The load of thallium in birds of prey was lower than concentrations found in carnivores, probably because poisoning caused by direct intake of thallium baits placed for rodent control does not seem to occur among birds of prey. From the investigation of this limited number of birds, it is not possible to tell if thallium did have any influence on the maintenance of a healthy population of birds of prey, but the large number of thallium loaded birds also justify the restrictions in the sue of thallium which were given from the 1st of July, 1975.

Animals

The effect of Prussian blue and sodium-ethylenediaminetetraacetic acid on the faecal and urinary elimination of thallium by the dog.

After oral administration of sublethal doses of thallium (lower than 10 mg/kg) to dogs, 75.5 +/- 3.9 per cent of the dose was eliminated from the body--47 per cent faecal and 28 per cent urinary. Cumulative excretion reached 50 and 70 per cent after 10 and 25 days respectively, and was almost complete after 75 days. This was slightly lower at higher doses. The total body-burden of thallium, calculated from the cumulative excretion, decreased exponentially for at least the first 40 days with a half-time (T 1/2) of 6.5 days. Oral doses of Prussian blue after 10 days resulted in an acceleration of the thallium elimination from the body (T 1/2 2.5 days), an increase of the faecal (49 per cent) and a decrease of the urinary excretion (18 per cent). Nevertheless, the cumulative faecal and urinary thallium excretion was not influenced. Minor transitory influences of Prussian blue on the faecal thallium excretion could be observed up to day 26. After 40 days, Prussian blue could no longer influence the faecal thallium excretion. At no time did sodium-ethylenediaminetetraacetic (Na2EDTA) acid significantly change faecal or urinary thallium excretion.

Administration, Oral

[On heavy-metal poisoning, especially by thallium (author's transl)].

Only thallium poisoning is still of clinical significance among heavy-metal intoxications. Among 1800 cases of poisoning there were 15 caused by thallium, 3 by lead and 1 by iron (none by arsenic or mercury). Among thallium poisonings, 13 were due to suicide, one ending fatally, and two of homicide. Thallium can be demonstrated in urine even after haemodialysis and forced diuresis. As more and more rat poisons contain coumarine derivatives instead of thallium, the number of cases of thallium poisoning is likely to decrease.

Adolescent

Serial exercise thallium myocardial perfusion scanning and exercise electrocardiography in the diagnosis of coronary artery disease.

Serial exercise thallium-201 myocardial perfusion scanning (exercise and 4-hour redistribution) was compared to rest and exercise electrocardiography (ECG) for the detection of coronary artery disease in 125 patients with known or suspected coronary artery disease. All patients underwent coronary arteriography and 108 were found to have significant coronary artery lesions. The serial exercise thallium scan was significantly more sensitive than rest and exercise ECG in detecting coronary artery disease (94% v. 83% P less than 0.01). The sensitivity of a reversible thallium perfusion scan abnormality and a positive exercise ECG for detecting exercise induced myocardial ischaemia in coronary artery disease was similar (69% v. 63%). The exercise thallium scan complemented the exercise ECG, and the sensitivity of the combined test was significantly greater than the exercise ECG alone (84% v. 63% P less than 0.001). The specificity for coronary artery disease of the exercise ECG was 65% and that of the exercise thallium-201 myocardial perfusion scan was 82% (P = NS). Thallium-201 myocardial perfusion scanning complements the rest and exercise ECG in the non-invasive detection of coronary artery disease.

Adult

[Thallium intoxication treated by hemodialysis, forced diuresis and antidote (author's transl)].

Mode of action and toxicity of thallium and former treatment of thallium intoxication are described. A case of thallium poisoning with a lethal dose of thallous sulfate which was successfully treated by hemodialysis, forced diuresis and antidote is reported. 43 percent of the thallium could be eliminated by continuous hemodialysis during 72 hours and forced diuresis within the third and seventh day after ingestion of the poison. The dialysance of thallium was 111,1 ml/min with a blood flow of 200 ml/min. Later damage can be prevented by early maximal elimination of thallium.

Adenosine Triphosphatases

Thallium as an industrial poison (review of literature).

The presented reports on cases of occupational thallium poisoning clearly demonstrate that the possibility of their occurrence in industrial plants is very real. The number of such intoxications is much higher than that of non-industrial poisonings, but this is predominantly due to the less pronounced clinical picture and to the fact that specific tests for thallium are not performed. As a result, these cases partly escape registration altogether and partly are wrongly diagnosed. Thallium and its compounds belong to the first class of poisons, their dangerousness being enhanced by their easy permeability through the skin. Industrial thallium poisoning can be either acute or chronic, but in all cases, it is characterized by a long duration and severity of its course. Strict hygienic demands on the organization of the technological process and the measures of protection of persons working with thallium are indispensable. Compulsory examination of the urine of those working with thallium for the presence of this substance should also be introduced.

Adult

Thallium-induced achondroplasia in chicken embryos and the concept of critical periods during development.

Achondroplasia was induced in chicken embryos by in ovo application of 0.6 mg/egg thallium sulfate. The critical (sensitive) period for production of achondroplasia began on day 5 of incubation and ended at the start of HH stage 35 (8.5 days). The end of the critical period was accurately timed and found to be 205-207 hours of incubation and to coincide with a 66% decrease in growth rate of the embryos. Treatment resulted in reduced tibial growth one day later, tibial angulation two days later, and chrondrocytic necrosis four days later. The last was therefore not the cause of the angulation. Tibias were taken from thallium-treated and control donor embryos of various ages and grafted to the chorioallantoic membranes of treated and control host embryos of various ages during and outside the critical period and achondroplastic changes induced in grafted tibias exposed to thallium while on the chorioallantoic membrane. The critical period was extended into day 10 of incubation in such grafted tibias. Tibias maintained for seven days in organ culture were achondroplastic if pretreated with thallium at seven or eight days of incubation but not at ten days. Exposure of as little as 0.5 hour was sufficient to elicit micromelia when the tibias were grafted or organ cultured. Thallium therefore rapidly binds to skeletal tissues during a critical period of embryonic development but this critical period may be extended when tibias are removed from the embryo.

Abnormalities, Drug-Induced

Acute cardiovascular toxicity of thallium (I) ions.

The acute cardiovascular toxicity of thallium (I)-ions was studied in anesthetized rats and also in some isolated preparations. In pentobarbital-anesthetized rats, intravenously applied Tl2SO4 (range 3 to 100 mg/kg) caused a significant, dose-dependent decrease in mean arterial blood pressure and heart rate. In spontaneously beating guinea pig isolated atria, thallium (I)-ions (10(-5) to 10(-3) M) caused a concentration-dependent decrease in frequency, which was not influenced by atropine, cocaine, or by considerable changes in the potassium concentration of the medium. A direct influence of Tl+ on the sinus node is presumed. Thallium decreases contractile force probably as a result of its negative chronotropic properties, since the amplitude of contraction remained uninfluenced in electrically driven atria. Thallium (I)-ions were readily taken up by the guinea pig isolated atria. At a bath concentration of 5 times 10(-5) M Tl+ a tissue/medium ratio of approximately 45 was achieved. Probably, an exchange against cellular potassium takes place. Relaxation of vascular smooth muscle by Tl+ was demonstrated both in isolated aortic strips (rabbit) and in the isolated perfused rabbit ear preparation. Both the vascular smooth muscle relaxation and the decrease in heart rate would explain the acute hypotensive effect of thallium.

Animals

Myocardial imaging with intravenously injected thallium-201 in patients with suspected coronary artery disease: analysis of technique and correlation with electrocardiographic, coronary anatomic and ventriculographic findings.

Myocardial imaging was performed after intravenous injection of thallium-201 at rest in 50 patients with suspected coronary artery disease and the results were compared with electrocardiographic, ventriculographic and coronary arteriographic findings. The thallium-201 myocardial images were of good quality and compared favorably with images previously obtained with intracoronary particle injection. Myocardial to background ratios averaged 2:1, a considerable improvement over ratios reported with potassium-43. There was complete intra- and interobserver agreement in the interpretation of images in 90 and 82 percent of cases, respectively. Major disagreement occurred in less than 5 percent of cases. Overall, 15 (30 percent) had an abnormal, 10 patients (20 percent) a borderline abnormal and 25 patients (50 percent) a normal myocardial image. Of patients with electrocardiographic Q waves, 91 percent had an image defect. Of 39 patients without Q waves, 13 percent had an image defect. All 30 patients with a normal or borderline abnormal thallium-201 image had a normal ventricular contraction pattern. All patients with a segmental ventriculographic abnormality had an image defect. In all cases, the area of electrocardiographic or ventriculographic abnormality corresponded to the area of the thallium-201 image defect. The systolic ejection fraction was depressed (0.49 +/- 0.18 [mean +/- standard deviation]) in patients with an image defect compared with that in patients with a normal image (0.64 +/- 0.06, P less than 0.005). Coronary arterial lesions were present and usually of high grade in all patients with an abnormal image; however, the presence of high grade coronary stenosis or occlusion as such correlated with image defects only to the extent that prior myocardial infraction was associated. Thus, satisfactory myocardial images at rest appear to be obtained with intravenously administered thallium-201 and electrocardiographic, ventriculographic and coronary arteriographic data suggest that image defects denote regions of prior myocardial infarction.

Coronary Angiography

Thallium intoxication treated with long-term hemodialysis, forced diuresis and Prussian blue.

A 56-year-old woman, who ingested 2 g of thallium sulfate, was successfully treated with long-term hemodialysis for 200 hours during ten days, combined with forced diuresis and Prussian blue. The effect of the artificial kidney dialysis was determined by repeated analysis of the thallium concentration in the dialysis bath and in blood samples. During the first 120 hours of hemodialysis, 143 mg of thallium was eliminated via the artificial kidney and 110 mg via the urinary tract. The present case of acute thallium intoxication is the first in which long-term hemodialysis has been used in the acute phase together with forced diuresis and Prussian blue. The data obtained are compared to those obtained from cases treated with hemodialysis in the past. It is concluded that treatment with hemodialysis should be considered as an important supplement to treatment with forced diuresis and Prussian blue in cases of thallium intoxication.

Antidotes

Thallium 201 myocardial imaging in patients with pulmonary hypertension.

The appearance of the right ventricular myocardium on thallium 201 myocardial perfusion images was evaluated in patients with chronic pulmonary hypertension and compared to patients without pulmonary hypertension. Four groups of patients were studied: 1) eight normals, 2) five patients with angiographically documented coronary artery disease and normal pulmonary artery pressures, 3) ten patients with moderate to severe pulmonary parenchymal or vascular disease and documented pulmonary hypertension and 4) eight patients with chronic left ventricular dysfunction and pulmonary hypertension discovered during cardiac catheterization. The right ventricular free wall was visualized on the thallium 201 myocardial perfusion image in only one of eight normals (group 1) and in only one of the five patients with coronary artery disease (group 2) and measured 0.5 cm and 0.9 cm in thickness, respectively. In patients with documented pulmonary hypertension the right ventricle was visualized on low contrast thallium 201 myocardial perfusion image in all patients. The apparent right ventricular free wall thickness measured from the ungated thallium 201 myocardial perfusion images was 1.7 +/- 0.3 cm in group 3 and 1.5 +/- 0.2 cm in group 4. Right ventricular hypertrophy was detected by electrocardiography in only five of ten patients in group 3 and only one of eight patients in group 4. Thallium 201 myocardial perfusion imaging appears to be a useful technique for assessing the effects of chronic pulmonary hypertension on the right ventricular myocardium.

Chronic Disease

Thallium-201 scintigraphy in unstable angina pectoris.

Thallium-201 scintigraphy was performed during the pain free period in 98 patients with unstable angina. Scintiscans were positive in 39 patients, questionable in 27 patients and normal in 32 patients. Eighty-one patients responded favorably to treatment (group I). Seventeen patients had complicated courses (group II) and despite maximal treatment with propranolol either developed infarction (six patients) or continued to have angina necessitating coronary surgery (11 patients). In group I during the pain free period 26 of 81 patients had positive thallium-201 scans, whereas 20 patients had an abnormal ECG at that time; during angina 18 patients had transient ECG changes. In group II during the pain free period 13 of 17 patients had positive scans, whereas two patients had abnormal ECG at that time; during angina 12 patients showed transient ECG changes. The sensitivity to recognize group II was 76% for thallium-201 scintigraphy, 11% for ECG during the pain free period; 70% for ECG during angina; 94% for the combination of either positive scans or abnormal ECG. Thus, 1) positive thallium-201 scans occur in patients with unstable angina, 2) positive scans can be obtained during the pain free period, 3) thallium-201 scans are more frequently positive in patients with complicated course.

Angina Pectoris

Usefulness and limitations of thallium-201 myocardial scintigraphy in delineating location and size of prior myocardial infarction.

In order to evaluate the usefulness of thallium-201 (201TI) myocardial scintigraphy in delineating the location and size of prior myocardial infarction, 32 patients were evaluated at a mean of 7 +/- 2 months after infarction with a 12-lead ECG, resting 201TI myocardial scintigram, biplane left ventriculogram and coronary angiograms. From the left ventriculogram, asynergy was quantified as percent abnormally contracting segment (% ACS), the percent of end-diastolic circumference which was either akinetic or dyskinetic. Using a computerized planimetry system, we expressed 201TI perfusion defects as a percentage of total potential thallium uptake. Of 21 patients with ECG evidence of prior transmural infarction, a 201TI defect was present in 20 (95%), and angiographic asynergy was present in all 21 (100%). The site of prior infarction by ECG agreed with the 201TI defect location in 24 of 32 patients (75%) and with site of angiographic asynergy in 23 of 32 patients (72%). Scintigraphic defects were present in only four of 10 patients (40%) with ACS less than or equal to 6%, but scintigraphic defects were found in 20 to 22 patients (91%) with ACS greater than 6% (p less than 0.01). Thallium defect size correlated marginally with angiographic left ventricular ejection fraction (r = -0.60) but correlated closely with angiographic % ACS (r = 0.80). Thallium defect size was similar among patients with one-, two-, or three-vessel coronary artery disease (greater than or equal to 70% stenosis), but thallium defect size was larger in patients with electrocardiographic evidence of transmural infarction (p less than 0.01) or pulmonary capillary wedge pressure greater than 12 mm Hg (p less than 0.001). Thus, resting 201TI myocardial scingigraphy is useful in localizing and quantifying the extent of prior myocardial infarction, but is insensitive to small infarcts (ACS less than 6%).

Angiocardiography

[Diagnosis of coronary artery disease: value and limitations of non-invasive methods. (Ecg, thallium perfusion scintigraphy, radionuclide angiography) (author's transl)].

In order to compare the three non-invasive exercise tests Ecg, Thallium myocardial perfusion imaging and radionuclide angiography in the diagnosis of coronary artery disease, the results of these tests in a consecutive series of 30 patients and 14 controls were analyzed. In all 88 symptom-limited exercise tests a significantly higher double product (heart rate x systolic blood pressure, mm Hg/min) was reached on a treadmill test (for Ecg and Thallium scintigraphy) as compared to the supine bicycle ergometer exercise (for radionuclide angiography: 243.1 +/- 61.1 vs. 215.2 +/- 46.5 x 10(2) (p less than 0.01). Considering all 132 diagnostic tests the overall sensitivity for rest/exercise Ecg was 67%, for Thallium scans 77%, for both combined 83% and for the ejection fraction response to exercise determined by radionuclide angiography 97%. If only the exercise response was considered, the corresponding sensitivity values were 60% (Ecg), 47% (Thallium scans), 70% (both tests combined) and 97% (radionuclide angiography). The specificity for coronary artery disease was determined to be 79% for Ecg, 86% for Thallium scintigraphy, 64% for Ecg/Thallium scans and 71% for radionuclide angiography. The most common reason for a false-positive result in all tests was found to be the diagnosis of cardiomyopathy, whereas most false-negative results were seen in patients with single vessel right coronary artery disease. Based on these results, the clinical implications of the three non-invasive tests in the diagnosis of coronary artery disease are discussed.

Adult

Thallium-201 myocardial imaging in anomalous left coronary artery arising from the pulmonary artery. Applications before and after medical and surgical treatment.

Thallium-201 myocardial imaging was performed on six patients with an anomalous left coronary artery arising from the pulmonary artery. Initial images in three children (aged 4 months, 12 months and 2 1/2 years, respectively) demonstrated anterolateral perfusion defects in agreement with the electrocardiographic localization of infarction. Repeat imaging in two patients 2 to 3 months later, after clinical improvement with anticongestive therapy, demonstrated a reduction in the perfusion defect. In 3 other patients (aged 16, 16 and 20 years, respectively) thallium-201 scans performed during exercise stress demonstrated normal myocardial perfusion 7 to 15 years after operation (ligation of anomalous left coronary in two, ligation plus bypass graft in one). Thallium-201 imaging appears to be helpful in monitoring changes in myocardial perfusion before and after medical or surgical treatment of an anomalous left coronary artery, and may shed light on the pathophysiology of the defect. A possible practical limitation of thallium-201 imaging in this condition is the difficulty of imaging subendocardial infarction.

Adolescent