DMSA and DMPS--water soluble antidotes for heavy metal poisoning.
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meso-2,3-Dimercaptosuccinic acid: chemical, pharmacological and toxicological properties of an orally effective metal chelating agent.
The primary purpose of this article is to summarize the recent investigations dealing with the pharmacology and toxicology of meso-2,3-dimercaptosuccinic acid, an orally effective chelating agent. The need for a better chelating agent for treating young children and pregnant women with lead intoxication has been apparent for some time. Preclinical and clinical evidence now indicate that meso-2,3-dimercaptosuccinic acid, an Orphan Drug, shows the most promise for being effective in this regard. It has an extracellular distribution that may be responsible for its low toxicity compared to other dithiols. No attempt has been made to compare it in a rigorous and thorough manner with other chelating agents. That has not been the purpose of this review. The advantages of meso-DMSA, however, compared to CaNa2EDTA for the treatment of lead intoxication, have been outlined. Significant advances have been made recently in elucidating the structures of the metal chelates of DMSA. There is a striking difference between the structures of the lead chelate of meso-DMSA and those of racemic-DMSA. The former chelates by coordination of one sulfur and one oxygen atom with Pb. The latter can form chelates via the two sulfur atoms or via one oxygen and one sulfur atom. Solubility of the lead chelates depends on the ionization of the noncoordinated thiol and carboxylic acid groups. Bimane derivatization, HPLC, and fluorescence, as well as gas chromatography can be used for analysis of DMSA in biological fluids. The acid dissociation constants for meso- and racemic-DMSA have been summarized from the literature as have the formation constants of some of the DMSA chelates. DMSA is biotransformed to a mixed disulfide in humans. By 14 hr after DMSA administration (10 mg/kg), only 2.5% of the administered DMSA is excreted in the urine as unaltered DMSA and 18.1% of the dose is found in the urine as altered forms of DMSA. Most altered DMSA in the urine is in the form of a mixed disulfide. It consists of DMSA in disulfide linkages with two molecules of L-cysteine. One molecule of cysteine is attached to each of the sulfur atoms of DMSA. The remaining 10% of the altered DMSA was in the form of cyclic disulfides of DMSA. So far, the mixed disulfide has been found in human but not in rabbit, mouse, or rat urine. Apparently there are species differences in how organisms metabolize meso-DMSA.(ABSTRACT TRUNCATED AT 400 WORDS)
Animals↗
Renal hyperconcentration of 99mTc-HEDP in experimental acute tubular necrosis.
The effect of transient renal ischemia on renal concentration and distribution of 99mTc-HEDP, 99mTc-DMSA, and 99mTc-DTPA was compared in rabbits with acute tubular necrosis. Scintigrams were obtained after injection in normal rabbits or ones with unilateral or bilateral ischemia. 99mTc-HEDP concentration in ischemic tissue was 8 to 18 times normal 1--4 hours after injection, and the resulting images delineated the morphological changes in the ischemic kidneys more accurately than those obtained with DMSA or DTPA. Calcium concentration in the ischemic kidneys increased sixfold. 99mTc-HEDP may be useful in evaluation of renal failure secondary to tubular injury.
Acute Kidney Injury↗
Pharmacodynamics of stannous chelates administered with 99mTc-labeled chelates.
The pharmacodynamics of several tin compounds were studied in healthy rabbits, rabbits with myocardial infarcts, and isolated myocardial tissue. The results showed that tin chelates of pyrophosphate, HEDP, DTPA, and glucoheptonate are very unstable in vivo, giving rise to free stannous ions. These ions localize mainly in bone, with the rest being primarily excreted in the urine. They also concentrate more in infarcted than in normal myocardium; there they enter the mitochondria. The supernatant of homogenates contains bound and free fractions, demonstrating a subcellular distribution pattern similar to that of calcium ions. Tin chelates have different pharmacodynamics from the corresponding 99mTc chelates.
Animals↗
Delayed scanning with DMSA: a simple index of relative renal plasma flow.
Relative renal uptake of 99mTc-dimercaptosuccinic acid (DMSA) was compared with the relative effective renal plasma flow (ERPF) to each kidney. In 25 patients with serum creatinine less than or equal to 2.0 mg/dl, there was excellent agreement when the regions of interest were assigned by a computer. In 10 patients with serum creatinine greater than 2.0 mg/dl, agreement was poor. A 24-hour image is sufficient to obtain such data. In patients with renal failure, this technique may give inaccurate results due to high tissue background activity; moreover, since it reflects the current functioning status of the kidney, it should not be used to predict recoverable function in patients with acute or unstable renal disease.
Acute Kidney Injury↗
97Ru-DMSA for delayed renal imaging.
Dimercaptosuccinic acid (DMSA) was labeled with 97Ru both with and without the addition of SnCl.2H2O. The tin-containing preparation was found to induce higher cortical deposition of 97Ru-DMSA than the tin-free preparation. Visualization of the renal cortex was excellent 4 to 48 hours after injection in normal dogs with renal insufficiency. It is concluded that 97Ru-(Sn+2)-DMSA is a potentially useful renal imaging agent when delayed scintigraphy is necessary because of decompensaton of the kidneys.
Animals↗
Complete and partial ureteral obstruction: evaluation of renal effects with P-31 MR spectroscopy and Tc-DMSA scintigraphy.
Phosphorus-31 magnetic resonance (MR) spectroscopy was used to study the effects of partial and complete ureteral obstruction on the porcine kidney; results were compared with renal tubular function as determined with technetium-99m dimercaptosuccinic acid (DMSA) scintigraphy. Twenty-seven pigs were used: nine as sham-operated controls, six with partial ureteral obstruction, and 12 with complete ureteral obstruction. P-31 MR spectra and Tc-DMSA scintiscans were obtained weekly over 3 weeks. Partial obstruction caused no significant change in P-31 MR spectra, whereas Tc-DMSA scintiscans showed a 74% decrease in tubular function by the end of 3 weeks. Complete obstruction caused a 43% reduction in the mean adenosine triphosphate (ATP) to inorganic phosphate (Pi) ratio, which paralleled the 96% decrease in Tc-DMSA uptake over 3 weeks. The difference in ATP/Pi ratios between control and completely obstructed kidneys was significant (P less than .01) at 2 and 3 weeks after ligation. These results indicate that radionuclide Tc-99m DMSA uptake is very sensitive to the pathophysiologic changes in renal tubular function, while the organ average cellular bioenergetic state (ATP/Pi) is not as strongly affected.
Adenosine Triphosphate↗
Soft-tissue tumors: diagnosis with Tc-99m (V) dimercaptosuccinic acid scintigraphy.
PURPOSE: To assess the potential of technetium-99m (V) dimercaptosuccinic acid (DMSA) scintigraphy for diagnosis of soft-tissue tumors. MATERIALS AND METHODS: Tc-99m (V) DMSA scintigraphy was performed in 76 patients with histologic proof of soft-tissue tumors. In 57 of these patients, gallium-67 citrate scintigraphy was performed within 2 weeks after Tc-99m (V) DMSA scintigraphy. RESULTS: Uptake of Tc-99m (V) DMSA was clearly detected in almost all sarcomas, metastatic carcinomas, highly recurrent benign tumors (ie, extra-abdominal desmoids and tenosynovial giant cell tumors), superficial and deep hemangiomas, and granulomatous soft-tissue lesions but was not found in other benign solid tumors of soft tissue. Uptake of Ga-67 citrate was clearly detected in all inflammatory lesions and metastatic carcinomas, eight of 14 sarcomas (57%), and two of 10 highly recurrent benign tumors (20%) but was not found in hemangiomas or benign soft-tissue tumors. CONCLUSION: Low-grade malignant and highly recurrent benign lesions, which often recur after surgery, were detected more accurately with Tc-99m (V) DMSA scintigraphy than with Ga-67 citrate scintigraphy.
Adolescent↗
Pneumonitis after inhalation of mercury vapours.
A 43-year-old man presented to hospital with pneumonia but only after discharge from hospital did he admit to deliberate prior inhalation of mercury. His pulmonary involvement appeared to resolve almost completely with antibiotics and supportive care. Nevertheless, persisting elevated urinary excretion of mercury required two courses of chelation therapy. No serious systemic sequelae were observed.
Administration, Inhalation↗
[Relative renal function based on DMSA uptake corrected for volume: normalized relative renal function].
OBJECTIVE: Relative renal function (RRF) quantification based on dimercaptosuccinic acid (DMSA) uptake is an established method for determining differential renal function. An abnormal kidney size may lead to an alteration in its RRF value, although it has no dysfunction. Therefore, it is useful to correct RRF values taking into account relative renal volumes, thus obtaining the normalized relative renal function (NRRF). The feasibility of the method used for volume correction, differences with respect to usual quantification and different normality intervals were studied. MATERIAL AND METHODS: A total of 187 DMSA renal scintigraphies (130 children and 57 adults) were studied. RRF was quantified and volume corrected to obtain NRRF. Patients were classified as normal or pathological using various normality intervals for NRRF. A second classification was performed depending on how the diagnostic changed after volume correction. RESULTS: An increase of pathological diagnosis was observed after volume correction, mainly in children. Using an intermediate estimation for the normality interval, 53% of the initially pathological diagnosis for children may be caused simply by different renal volumes. CONCLUSIONS: NRRF provides complementary information to RRF and helps to distinguish between a smaller kidney and a really hypofunctioning one in cases with abnormal RRF.
Adolescent↗
Efforts to control the errant products of a targeted in vivo generator.
Alpha-particle immunotherapy by targeted alpha-emitters or alpha-emitting isotope generators is a novel form of extraordinarily potent cancer therapy. A major impediment to the clinical use of targeted actinium-225 (225Ac) in vivo generators may be the radiotoxicity of the systemically released daughter radionuclides. The daughters, especially bismuth-213 (213Bi), tend to accumulate in the kidneys. We tested the efficacy of various pharmacologic agents and the effect of tumor burden in altering the pharmacokinetics of the 225Ac daughters to modify their renal uptake. Pharmacologic treatments in animals were started before i.v. administration of the HuM195-225Ac generator. 225Ac, francium-221 (221Fr), and 213Bi biodistributions were calculated in each animal at different time points after 225Ac generator injection. Oral metal chelation with 2,3-dimercapto-1-propanesulfonic acid (DMPS) or meso-2,3-dimercaptosuccinic acid (DMSA) caused a significant reduction (P < 0.0001) in the renal 213Bi uptake; however, DMPS was more effective than DMSA (P < 0.001). The results with DMPS were also confirmed in a monkey model. The renal 213Bi and 221Fr activities were significantly reduced by furosemide and chlorothiazide treatment (P < 0.0001). The effect on renal 213Bi activity was further enhanced by the combination of DMPS with either chlorothiazide or furosemide (P < 0.0001). Competitive antagonism by bismuth subnitrate moderately reduced the renal uptake of 213Bi. The presence of a higher target-tumor burden significantly prevented the renal 213Bi accumulation (P = 0.003), which was further reduced by DMPS treatment (P < 0.0001). Metal chelation, diuresis with furosemide or chlorothiazide, and competitive metal blockade may be used as adjuvant therapies to modify the renal accumulation of 225Ac daughters.
Actinium↗
Vesicoureteric reflux: the evolution of the understanding of the anatomy and the development of radiology.
Vesicoureteric reflux is now recognized to be a disease which is different in boys and girls and known to be associated with renal parenchymal abnormalities in the fetus. Understanding the anatomy and reviewing the development of the radiologic investigation of vesicoureteric reflux helps put in context conclusions reached from recent clinical and laboratory studies, on which new insights into vesicoureteric reflux have been based.
Animals↗
Tubular dysfunction in proliferative lupus nephritis.
We prospectively studied renal tubular function during 11 consecutive exacerbations of proliferative glomerulonephritis in 8 patients with systemic lupus erythematosus (SLE). We found a rise in the fractional excretion of beta 2-microglobulin (p less than or equal to 0.05) and dimercaptosuccinic acid (DMSA; p less than or equal to 0.02) during the exacerbations. These changes coincided with a fall in the glomerular filtration rate (p less than or equal to 0.02). Since fractional excretion of beta 2-microglobulin and DMSA can be considered as markers for tubular function, their rise during exacerbation and their fall (p less than or equal to 0.01) to control values during remission indicate that tubular dysfunction frequently occurs during active proliferative glomerulonephritis in SLE and can be influenced by immunosuppressive treatment. As no correlation was found between the different tubular function studies and the activity index of tubulointerstitial abnormalities in the renal biopsy, it is suggested that tubular function studies are probably a more sensitive indicator of tubulointerstitial disease than this activity index.
Adolescent↗
Value of urinary endothelin-1 in patients with primary vesicoureteral reflux.
By using a radioimmunoassay specific for endothelin-1 (ET-1), we measured urinary excretion of ET-1-like immunoreactivity (LI) in 63 spot urine samples of 48 patients with primary vesicoureteral reflux (VUR). And also, urinary excretion of N-acetyl-beta-D-glucosaminidase (NAG), beta 2-microglobulin (beta-2-MG), microalbumin (Alb) and creatinine (Cr) were measured. There was no significant correlation in any of the pairs ET-1 and NAG, ET-1 and beta 2-MG, and ET-1 and Alb. Comparing the grade of reflux according to the International Classification with urinary ET-1, urinary ET-1/Cr levels in patients with grade 2, 3 and 4 VUR were higher than normal, and the ratio of more than normal urinary ET-1/Cr increased in proportion to the grade of reflux, but it conversely decreased in grade 5. In conclusion, urinary ET-1 may be an indicator of renal tubular injury in patients with primary VUR, and its meaning may be different from conventional urinary parameters.
Acetylglucosaminidase↗
Clinical value of DMSA planar and single photon emission computed tomography as an initial diagnostic tool in adult women with recurrent acute pyelonephritis.
Routine DMSA scintigraphy, ultrasound (US) of the kidney, intravenous pyelography (IVP) and voiding cystoureterography (VCU) were performed in 27 consecutive adult women with recurrent acute pyelonephritis (APN) during a 12-month follow-up. Both planar and single photon emission computed tomography (SPECT) images were obtained for DMSA scan. DMSA scans were repeated in those patients with abnormal initial scan. DMSA-SPECT showed normal findings in 2, single renal cortical detect (RCD) in 9 and multiple RCD in 16 (including nonvisualization in 2). Of the 11 kidneys with normal findings or single RCD on DMSA-SPECT, only 1 (9%) showed vesicoureteral reflux (VUR) on VCU (grade I). A large proportion of those with multiple RCDs showed abnormal findings on IVP (44%, 7/16), US (38%, 6/16) or VCU (31%, 5/16); 63% in any of these three studies. 5 of 6 patients with VUR had multiple RCDs on DMSA-SPECT, and 3 of these 5 showed no abnormality on IVP or US. 7 patients who needed other managements besides initial standard antibiotic treatment had multiple RCDs on DMSA-SPECT. 15 normal women were also studied and showed normal DMSA-SPECT, US and IVP, in all cases. Follow-up DMSA-SPECT was done in 16 patients (7 with single RCD, 9 with multiple RCD). All 7 patients with single RCD showed improvement, in those with multiple RCDs improvement was observed in 2, no change in 7 on follow-up studies. We conclude: (1) DMSA-SPECT is a useful initial diagnostic tool in adult women with recurrent APN to identify patients who need more extensive radiological studies.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Dissociation of selective renal venous plasma endothelin-1 activity and corresponding plasma renin activity in a patient with hypertension, severe stenosis of unilateral renal artery and ipsilaterally decreased renal function.
Plasma endothelin-1 (ET-1)-like immunoreactivity in selective renal venous blood and peripheral venous blood was measured and compared with plasma renin activity and aldosterone level in a 26-year-old woman with suspected renovascular hypertension due to stenosis of the left renal artery. Although there was no significant step-up in plasma renin activity between the right and the left renal vein, left/right ratio of plasma ET-1 in the renal vein was 2.18. This case suggests that ET-1 may be one of the hypertensive mechanisms of suspected renovascular hypertension in addition to the renin-angiotensin system.
Adult↗
Renal infarction in a severely hypertensive patient with lupus erythematosus and antiphospholipid antibodies.
Systemic lupus erythematosus (SLE) patients, specially those with antiphospholipid antibodies, have a high incidence of arterial and venous thrombotic manifestations. However, renal infarction has been rarely reported in these patients. The case of a young female with renal infarction, diagnosed by renal arteriography and scintigraphy, and arterial hypertension (AH) is described. In subsequent years she also suffered several cerebrovascular accidents with important neurological sequelae. No evidence of systemic disease was observed at this time. Fourteen years after the renal infarction a diagnosis of SLE was established. Despite therapy with prednisone, acetylsalicylic acid, azathioprine and antihypertensive drugs the progression of the neurological disease led to death. The sudden appearance of severe AH in a young woman with a renal infarction should alert the clinician about a possible underlying renal artery thrombosis in association with SLE and antiphospholipid antibodies.
Adult↗
A case of renovascular hypertension with marked polyuria after percutaneous transluminal renal angioplasty.
A 43-year-old female patient with hypertension was diagnosed as having one-kidney renovascular hypertension with dysfunction of the contralateral kidney, and percutaneous transluminal renal angioplasty was carried out. Marked polyuria was observed during the 2- to 72-hour postoperative period. During the 12- to 18-hour period of polyuria, the urine volume was 8.9 liters/6 h, which was 62% of the glomerular filtration, and was accompanied by high fractional excretion of sodium and of potassium and a high urine beta 2-microglobulin level. The mechanism of polyuria in this case is discussed.
Adult↗