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The interactions of gallium (Ga) with the ligands, EDTA, NTA, phosphate, lactate, MOPS, TRIS and HEPES are investigated using both 71Ga and 1H nmr measurements. Both EDTA and NTA form strong complexes with gallium, which have a 1:1 stoichiometry. In alkaline solution the tetrahedral Ga(OD)4- competes strongly with EDTA in complex formation. In the lactate complex, there are probably three lactates per gallium present. The phosphate complexes of gallium are difficult to characterize on the basis of this investigation. The buffers, MOPS, TRIS, and HEPES, do not interact with gallium significantly. The ability of the ligands to bind gallium correlates well with their ability to inhibit gallium incorporation by L1210 leukemic cells.
The sharpness and reproducibility of the gallium melting point were studied and the melting temperature of gallium in terms of IPTS-68 was determined. Small melting-point cells designed for use with thermistors are described. Nine gallium cells including three levels of purity were used in 68 separate determinations fo the melting point. The melting point of 99.99999% pure gallium in terms of IPTS-68 is found to be 29.771(4) +/- 0.001(4) degree C; the melting range is less than 0.0005 degree C and is reproducible to +/- 0.0004 degree C.
The mechanism of ionic gallium-67 localization in inflammatory lesions was studied. Human polymorphonuclear leukocytes (PMN) had higher Ga-67 uptake than lymphocytes, whereas red blood cells had no affinity for Ga-67. Uptake by PMN showed temperature dependence, was independent of Ga-67 concentrations, and was not inhibited by metabolic inhibitors. However, its binding to PMN could be removed by trypsin but not by neuraminidase. These results are consistent with the hypothesis that the plasma membrane serves as a diffusion barrier and Ga-67 only binds to the surface of the PMN plasma membrane. When this membrane's permeability barrier was disrupted, as in heat-killed PMN, Ga-67 uptake increased markedly. Experimental abscesses were induced with E. coli or turpentine in rabbits. Twenty-four hours after i.v. injection, only 20% of Ga-67 in abscesses was in fractions containing intact PMN, cell debris or bacteria; the remainder was in a soluble, non-cellular fraction (2,500-g supernatant).
The kinetics of 67Ga accumulation in experimental inflammatory exudates were studied. In six rabbits with S. aureus induced abscesses, serial samples of exudate and blood were obtained at 1, 2, 4, 24 and 48 hrs after intravenous injection of 67Ga. The accumulation of 67Ga in the inflammatory exudate was slow with an accumulation half-time of 5.5 hrs. The concentration of 67Ga in the abscesses approached that of blood 48 hrs after injection. Analysis of the distribution of 67Ga in the inflammatory exudate revealed that the portion of 67Ga in the cellular fraction (1,600 xg pellet) correlated best with the number of non-viable polymorphonuclear leukocytes (PMN) (r = 0.81). Its correlation with total number of PMN and bacteria was r = 0.69 and r = 0.35, respectively. Autoradiographic studies confirmed that the majority of 67Ga in the cellular fraction of the exudate was associated with non-viable PMN's.
Administration of gallium nitrate to rats resulted in the formation of renal precipitates which occluded tubular lumina. When analyzed with a combination of scanning electron microscopy and x-ray energy spectrometry, these precipitates were found to contain gallium complexed with calcium and phosphate. Injection of gallium nitrate also resulted in hypercalciuria, although serum calcium levels remained unaltered. Administration of an osmotic diuretic, isosorbide, prior to gallium treatment resulted in the formation of fewer renal precipitates and histopathologic changes than in the nondiuresed animals. Diuresis did not alter gallium serum pharmacokinetics, the 24 hour cumulative renal excretion of gallium or the extent of the drug-induced hypercalciuria. However, isosorbide pretreatment significantly reduced the urinary concentrations of both gallium and calcium. The data presented indicate that diuresis reduces the severity of gallium-induced renal lithiasis and subsequent renal accumulation of gallium by diluting the urinary concentration of gallium and calcium thereby lowering the incidence of interaction of these two elements within the kidney tubule.
The use of gallium radionuclides in nuclear medicine dates back to the late 1940s, following the observation in toxicologic studies that gallium tended to localize to a high degree at sites of osteogenic activity. Initial attempts in the early 1950s to use 72Ga for clinical diagnosis and therapy of malignant bone lesions were unproductive. However, the basic information gained then in the preclinical and clinical investigations was quite instrumental in generating the present-day use of gallium radionuclides as effective radiopharmaceutical agents. Although initial clinical trials of 72Ga were unproductive, subsequent studies with 68Ga and 67Ga, together with advances in nuclear medical instrumentation, resulted in the identification of gallium radionuclides as effective tumor- and abscess-localizing agents. A major factor in the recognition of the peculiar biologic properties of gallium radionuclides was the existence of a carrier (stable isotope) effect. Also, it appears from basic studies of the mechanism(s) of the uptake of gallium in tumor tissue that the biodistribution of gallium involves many essential biologic processes. The future use of gallium radionuclides may, therefore, actually very well fall more into the field of basic biologic investigations rather than into the field of nuclear medical diagnosis.
The physiologic disposition of pharmacologic doses of gallium was studied in control dogs and dogs with spontaneous lymphosarcoma. Gallium 67 (67Ga) was administered iv with carrier gallium added at a dose of 8 mg/kg. About 50% of the injected dose was excreted in the urine by 48 hours (mostly in the first 12 hr), whereas negligible amounts were excreted in bile. The distribution of 67Ga in normal tissues was similar in control and tumor-bearing dogs. The tissue-to-plasma concentrations of gallium were considerably greater than 1 in the kidney cortex, bone marrow, bone, small intestine, and liver 6-72 hours after administration of the drug. At comparable time periods, tissue-to-plasma ratios of gallium were less than 1 in skeletal muscle and brain. In dogs with lymphosarcoma there was neither selective uptake nor selective retention of gallium in comparison to most normal tissues. In fact, several normal tissues, particularly kidney cortex and bone marrow, concentrated gallium greatly in excess of tumors. Qualitatively similar findings were obtained in a dog with malignant melanoma. These findings were contrary to what one would predict from reports showing that carrier-free 67Ga is selectively concentrated in various human and animal tumors. This indicates the need for more extensive studies of the physiologic disposition of pharmacologic (antitumor) doses of gallium in humans and appropriate animal models.
Pharmacokinetic studies were conducted in 8 patients with disseminated neoplasms refractory to conventional chemotherapy, who received gallium nitrate at doses of 300 to 600 mg/m2 intravenously in a phase I clinical trial. Gallium concentrations in biological fluids were determined colorimetrically. In patients with normal renal function, gallium showed a biphasic plasma disappearance with an initial half-life (t1/2) of 0.5 to 1.8 hr (mean 1.0) and a terminal t1/2 of 10.5 to 50.4 hr (mean 25.1). Gallium was distributed in total body water and often localized in some body compartment as evidenced by a volume of distribution ranging from 0.25 to 2.53 L/kg (mean 1.19). The total drug clearance from the plasma was 0.13 to 1.00 ml/kg/min (mean 0.65) in patients with normal renal function. Cumulative urinary excretion of gallium was 15% to 72% (mean 35%) of the administered dose in 24 hr (it fell to 23% in 8 days in a patient with acute oliguric renal failure). Gallium kinetics are altered in patients with acute renal dysfunction and in patients who have received multiple doses of gallium or other metal chemotherapy.
Gallium-67 scanning was evaluated in 100 patients with proved carcinoma of the lung. It was valuable in separating primary from secondary lung tumors, determining the extent of contralateral hilar or mediastinal lymph node involvement, and detecting distant organ metastases. In addition to multiplane whole-body Ga-67 tomographic scanning, colloid liver scans, bone scans, and computerized axial tomography scans of the brain were obtained to determine the presence of distant metastasis. The gallium scan detected 11 of 12 occult metastases and identified 7 of 7 liver, 9 of 14 brain, 4 of 4 soft tissues, 1 of 4 contralateral lung, and 9 of 11 bone metastases. The whole-body gallium scan accurately detected or excluded extrathoracic metastatic disease in 11 of 12 patients examined postmortem within three months of a gallium scan. An approach is recommended using gallium scanning along with chest roentgenograms for clinical staging and preoperative evaluation of patients with carcinoma of the lung. Specific organ scans should be reserved for the occasional symptomatic patient with a negative gallium scan or for clarification of an indeterminate gallium scan.
The role of polymorphonuclear leukocytes (PMN) and bacteria in the accumulation of gallium-67 in inflammatory lesions was studied using an animal model. A plastic practice golf ball was implanted in the subcutaneous tissue of the abdominal wall of rabbits, and sterile or bacterial inflammation was induced inside the ball. Gallium accumulated in the inflammatory exudates induced by either sterile casein or Staphylococcus aureus. Two rabbits were made agranulocytic by prior treatment with myleran before the injection of S. aureus and gallium. These also accumulated gallium, although in one agranulocytic rabbit there were no PMN in the inflammatory exudate. Analysis of the inflammatory exudates showed that most of the gallium was in the noncellular fraction (2,500-g supernatant) in both sterile and bacteria-induced inflammation. The results indicate that gallium accumulates in the inflammatory lesions, even in the absence of either PMN or bacteria.
Angiotensin-converting enzyme assays and gallium-scan results were obtained from 27 patients with biopsy-proven, clinically active sarcoidosis. Twenty-three of these patients had elevated converting enzyme levels, and 22 had positive gallium-scan results. Three of four patients with normal or borderline-elevated levels of angiotensin-converting enzyme also had positive gallium-scan results. Of 156 nonsarcoid patients (pulmonary and other diseases), 27 were found to have elevated serum converting enzyme levels, and 25 of these had negative gallium-scan results. These results indicate that the combination of an assay of angiotensin-converting enzyme and gallium scan increases diagnostic specificity from 83% to 99% without sacrificing sensitivity. We conclude that the concurrent use of angiotensin-converting enzyme assay and gallium scan is of value in the diagnosis of sarcoidosis.
Gallium has been shown to accumulate in metabolically active tissue including sites of infection. The purpose of this study was to evaluate gallium scanning in cholecystitis. Ten patients with cholecystitis were studied using conventional gallium scanning techniques. Five patients with acute cholecystitis showed intense gallium accumulation in the gallbladder area. One of five patients with chronic cholecystitis showed significant accumulation in the gallbladder. The limitations of this method are mainly the need for serial scanning to rule out gallium accumulation in the hepatic flexure of the colon and also the failure to detect consistently a chronically diseased fibrotic gallbladder. We conclude that gallium scanning of the gallbladder is an important adjunctive study in the evaluation of cholecystitis.
Two hundred and twenty-two patients presented with clinical suspicion of an abdominal or pelvic abscess. Abscesses tend to locate in the perihepatic spaces or the pelvis, and these areas can easily be examined by ultrasound, using the liver or the urinary bladder as acoustic windows. Thirty-eight of 42 abdominal abscesses, and 32 of 33 pelvic abscesses were correctly diagnosed and located by ultrasound, giving a sensitivity of 93.3%. Of the 145 patients without abscesses, 143 were correctly excluded, giving a specificity of 98.6%. Thirty of these patients also underwent gallium 67 examination. This detected all 7 true negatives and all 10 abscesses, 1 of which was missed by ultrasound. Of the remaining 13 patients with positive gallium results, 10 had nonspecific uptake in diffuse inflammatory conditions, and 3 were false positives with uptake in bowel or in a surgical wound. In those patients with nonspecific gallium uptake, ultrasound was valuable in documenting the absence of an abscess cavity. Conversely, gallium detected a left subphrenic abscess missed by ultrasound. For reasons of economy, speed, and high sensitivity, we believe that ultrasound should be the initial screening procedure for patients with clinical suspicion of abdominal or pelvic abscess. Gallium should be reserved for patients with equivocal ultrasound results of those with septic foci not revealed by ultrasound.
Imaging of the chest cage with gallium-67 (67Ga) citrate is relatively easier to perform and interpret than imaging of the abdomen, because normally pulmonary concentration is low after 48 hr and physiologic accumulation in bones and breast can be recognized by its distribution. Modern scintillation detectors, particularly large field cameras with multiple pulse-height analyzers, give substantially better gallium images than those available in the past. Because of the nonspecific affinity of gallium through neoplastic and inflammatory processes, its value in the differential diagnosis of pulmonary diseases is limited. However, based on the literature and our own observations in over 1100 patients with established diagnosis of a variety of pulmonary diseases, we feel that the judicious use of 67Ga in selected patients is helpful in answering specific questions. These include preoperative evaluation of hilar and mediastinal involvement in pulmonary neoplasms, differential diagnosis of pulmonary infarctions and bacterial pneumonias, evaluation of pulmonary infiltrates regarding infectious etiology, follow-up of sarcoidosis on corticosteroid treatment, assessment of inflammatory activity in interstitial fibrosis and, in selected cases, early detection of neoplastic and inflammatory diseases before radiography becomes abnormal, such as diffuse carcinomatosis and Pneumocystis carinii infection. Potential large-scale application of pulmonary gallium imaging could be found in the screening of subjects exposed occupationally to noxious dust and in long-term serial follow-up of pulmonary tuberculosis patients for treatment response and reactivation. However, it remains to be seen whether gallium imaging statistically provides essential additional information in these indications when compared to cheaper conventional techniques.
Cerebral scans were obtained on 30 "stroke" patients first with 99mTc pertechnetate and subsequently with 67Ga citrate. Of the 26 patients with abnormal 99mTc static scans, 17 (65%) showed the same abnormality in gallium citrate scans also. In 4 patients with positive technetium flow studies but negative static scans, no abnormality was seen in the scans obtained after gallium citrate injection. In none of the patients was the relative concentration of radioactivity in the lesion greater in the gallium image than in the technetium image. This study proves the nonspecificity of gallium citrate and thus its inability to differentiate cerebral tumor from cerebral infarction just on the basis of localization of gallium.
The usefulness of gallium-67-citrate scanning and lymphangiography in the detection of iliac and paraaortic lymph node involvement was evaluated in 53 patients with Hodgkin's disease and non-Hodgkin's lymphomas who subsequently underwent laparotomy. Our data suggest that the overall accuracies of the two procedures in this regard are comparable. Although in this anatomic area the gallium scan tends to underestimate the presence of disease (higher false-negative rate), the false-negative rate is quite low. The false-negative rate with lymphangiography is lower than with scanning but it tends to overestimate the presence of disease (higher false-positive rate). It was concluded that gallium scanning should be an integral part of the staging of lymphomas and a schema for their clinical staging based on the use of gallium scanning early in the diagnostic sequence is proposed.
The application of flameless atomic absorption spectrophotometry to the quantitation of gallium in urine, serum and tissues is described. The method can be used to detect gallium concentrations as low as 100--200 ppb in fluids and tissues. Significant interference with the gallium atomization signal was caused by CaCl2; however, the interference could be completely prevented by using the chelating agent EDTA. This method makes feasible the quantitative determination of the pharmacokinetic parameters of gallium administration as an anticancer drug in animals and humans.