Trends in Shortages of Lead Chelators From 2001 to 2022.

OBJECTIVE: The study aims to describe drug shortages affecting lead chelators in the United States from 2001 through 2022. METHODS: Drug shortage data were retrieved from the University of Utah Drug Information Service from January 1, 2001, through December 31, 2022. Shortages of first- and second-line lead chelators were analyzed. Drug class, formulation, administration route, shortage reason, shortage duration, generic status, single-source status, and presence of temporally overlapping shortages were examined. Total shortage months, percentages of study period on shortage, and median shortage durations were calculated. RESULTS: Thirteen lead chelator shortages were reported during the study period. Median duration was 7.4 months and the longest shortage (24.8 months) involved calcium disodium edetate. Calcium disodium edetate and dimercaprol had the greatest number of shortages, 4 each, and 61.5% of shortages involved parenteral medications. Median shortage duration was 14.2 months for parenteral agents and 2.2 months for non-parenteral agents. All shortages involved generic, single-source products. Supply/demand and manufacturing problems were the most common shortage reasons provided. Overlapping shortages occurred for 3.7% of the study period. Median shortage duration increased from 3 to 11 months in the second half of the study period, and 61.5% of shortages occurred in the second half of the study period. CONCLUSIONS: All chelators experienced multiple shortages, which became increasingly frequent and prolonged over time. Concurrent shortages occurred, potentially hampering substitution between different agents. Health care stakeholders must build supply chain resilience and develop guidelines regarding how to modify chelation therapy based on shortage conditions.

Succimer chelation does not produce lasting reductions of blood lead levels in a rodent model of retained lead fragments.

Retained lead fragments from nonfatal firearm injuries pose a risk of lead poisoning. While chelation is well-established as a lead poisoning treatment, it remains unclear whether chelation mobilizes lead from embedded lead fragments. Here, we tested whether 1) DMSA/succimer or CaNa2EDTA increases mobilization of lead from fragments in vitro, and 2) succimer is efficacious in chelating fragment lead in vivo, using stable lead isotope tracer methods in a rodent model of embedded fragments. DMSA was > 10-times more effective than CaNa2EDTA in mobilizing fragment lead in vitro. In the rodent model, succimer chelation on day 1 produced the greatest blood lead reductions, and fragment lead was not mobilized into blood. However, with continued chelation and over 3-weeks post-chelation, blood lead levels rebounded with mobilization of lead from the fragments. These findings suggest prolonged chelation will increase fragment lead mobilization post-chelation, supporting the need for long-term surveillance in patients with retained fragments.

Antagonistic effectiveness of Anacardium occidentale leaf extract on lead-acetate exposure-induced hepatorenal toxicity in rats.

Lead (Pb) poisoning is an environmental substance that accumulates in the hepato-renal tissue, which is hazardous to health, while Anacardium occidentale L. is a tropical herb used to treat oxidative stress and inflammatory diseases. The aim of this study was to investigate the antagonistic effect of Anacardium occidentale leaf extract on lead acetate exposure-induced hepatorenal toxicity in rats. Thirty-six adult Wistar rats were split into six equal groups (n = 6). Group I served as a control, and groups II and III were administered lead acetate (50 mg/kg) and Anacardium occidentale leaf extract (400 mg/kg), respectively, while rats in groups IV-VI were administered Anacardium occidentale (L) extract (200 mg/kg and 400 mg/kg) and 10 mg/kg of Succimer, respectively, and were then administered lead acetate (50 mg/kg). When compared to the group I, rats administered lead acetate showed an increase in hepatic enzymes, urea, creatinine, MDA, TNF-α, and IL-1ß (p < 0.001) levels and decreased levels of SOD, CAT, and GSH, whereas Anacardium occidentale prevented the increase in hepatorenal function parameters, oxidative stress, and inflammatory markers (TNF-α and IL-1ß) induced by lead acetate. Rats administered only lead acetate had a marked increase in hepatic Pb concentration, severe hepatic steatosis, and renal glomerulus degeneration. However, treatment with Anacardium occidentale extract and succimer decreases the Pb concentration, oxidative stress, and inflammation, and also reduces histological liver steatosis and glomerular cytoarchitecture deterioration in the kidney. The results of this study revealed that Anacardium occidentale extract protects against lead acetate-induced liver and kidney toxicity by decreasing oxidative stress and inflammation.

Chelation during sequential pregnancies: A case report with a twist.

This report summarizes chelation management of lead poisoning occurring during sequential pregnancies. Several aspects make this case unusual; firstly recurrent lead poisoning, secondly treatment with succimer, the use of which is very rarely reported in pregnancy, and thirdly the presence of co-existent vitamin D deficiency and hyperparathyroidism, both potential contributors to bone lead release.

Synergic fabrication of succimer coated titanium dioxide nanomaterials delivery for in vitro proliferation and in vivo examination on human aortic endothelial cells.

The probable nanotoxicity to human health and the environment is a significant challenge for the sustainable application of nanomaterials in medicine. The cytototoxical effect of succimer (meso-2,3-dimercaptosuccinic acid-DMSA) coated titanium dioxide (DMSA-TiO2) with cultured human aortic endothelial cells (HAoECs) was assessed in this investigation. Our findings have shown that DMSA-TiO2 can be accumulated in HAoECs and dispersed in a cytoplasm on the culture medium. DMSA-cytotoxicity TiO2 effects were dose-responsive, and the concentrations were of little toxicity, and MTT stain testing showed that they had only 0.02 mg ml-1. Meanwhile, the lactate dehydrogenase biomarker was not considerably more remarkable than the biomarker from untreated (control) cells (free DMSA-TiO2). Though, also without any apparent signs of cell damage, the endocrine functions for prostacyclin I-2 and endothelin-1 and the urea transporter functions were modified. In addition, in vitro endothelial tube development has been shown that HAoECs could induce angiogenesis even with small amounts of DMSA-TiO2 (0.01 and 0.02 mg ml-1). Further, we have examined the in vivo toxicity and biochemical parameter by animal model. Furthermore, in vivo assessments designated that the resulting DMSA-TiO2 presented synergistic activities of angiogenesis activity. Overall, these findings show the cytotoxicity of DMSA-TiO2 and could induce adverse effects on normal endothelial cells.

Efficacy and expenses of succimer vs. d-penicillamine plus garlic in the treatment of lead poisoning: a retrospective cross-sectional study.

PURPOSE: Lead Poisoning is a major health problem in Iran. We aimed to compare efficacy of a standard regimen (Succimer) with that of a low-priced combination of D-penicillamine and Garlic in outpatients with lead poisoning. METHODS: In this retrospective cross-sectional study, year-long clinical files of outpatients with lead poisoning in two referral toxicology clinics in Mashhad, Iran were reviewed. A total of 79 patients (all men), received either Succimer or a combination of D-penicillamen plus garlic (DPN + Gar), for 19 and 30 days, respectively. Clinical and laboratory data, including blood lead level (BLL), were analyzed and treatment expanses were compared between the two regimens. RESULTS: Of 79 male patients, 42 were treated by DPN + Gar and 37 received Succimer. Mean BLL of DPN + Gar group before treatment (965.73 ± 62.54 µg/L) was higher than that of the Succimer group (827.59 ± 24.41) (p < 0.001). After treatment, BLL in both groups significantly reduced to 365.52 ± 27.61 µg/L and 337.44 ± 26.34 µg/L, respectively (p < 0.001). The price of a 19-day treatment with Succimer was approximately 28.6 times higher than a one-month course of treatment with garlic plus DPN. None of the treatments caused serious side effects in the patients. CONCLUSION: Combination therapy with DPN + Gar is as effective as Succimer in Pb poisoning, while treatment with Succimer is significantly more expensive.

Systematic Assessment of the Adsorption of 99mTc-Radiopharmaceuticals onto Plastic Syringes.

The phenomenon of adsorption of several 99mTc-radiopharmaceuticals onto disposable syringes is common knowledge and can reach a level of up to 50%, with the result being inadequate dosing. The resulting underdosing has a substantial influence on the quality of imaging, especially in pediatric patients. Therefore, we aimed to establish a standardized in vitro assessment to investigate the adsorption of several 99mTc-radiopharmaceuticals on various brands of syringes. Methods: The 99mTc-radiopharmaceuticals were prepared according to manufacturer instructions. For the assessment, the disposable syringes (n = 3) were filled to one third of capacity with the 99mTc preparation and incubated for 30 min at room temperature. The syringes were emptied into evacuated vials, and the radioactivity of the syringes was measured before and after they were emptied. Furthermore, the dilution effect of 99mTc preparations was studied. We used 2 different brands of syringes and systematically examined 99mTc-pertechnetate, 99mTc-butedronate, 99mTc-oxidronate, 99mTc-medronate, 99mTc-tetrofosmin, 99mTc-sestamibi, 99mTc(V)-dimercaptosuccinic acid, and 99mTc-succimer. Additionally, 99mTc-succimer was retested with 5 brands of syringes. Results: 99mTc-pertechnetate, 99mTc-phosphonates, and 99mTc(V)-dimercaptosuccinic acid showed no significant adsorption. The measured radioactive retention of 2%-5% was equivalent to the determined dead volume. Using 99mTc-tetrofosmin, we found a slight but significant adsorption of 4%-7%. The 99mTc-sestamibi preparation showed a nonsignificant retention of 3%-5%. However, when the 99mTc-sestamibi was diluted 1:10 with saline, the adsorption rate increased to 9%-13%. 99mTc-succimer displayed different adsorption levels depending on the brand of syringe and the preparation technique. The adsorption of 99mTc-succimer, prepared from kits according to the instructions, did not exceed 15%. The 1:10 saline dilution of a 99mTc-succimer kit preparation, as well as an in-house preparation, demonstrated a radioactive syringe adsorption rate of more than 30%. Conclusion: The results revealed the significance of syringe adsorption of radiopharmaceuticals in the prevention of underdosing. Therefore, a quality assurance assessment is recommended before the introduction of new brands of plastic syringes or routine application of diluted or in-house radiopharmaceuticals.

A comparative study of edetate calcium disodium and dimercaptosuccinic acid in the treatment of lead poisoning in adults.

BACKGROUND: We evaluated the efficacy of two antidotes, edetate calcium disodium (CaNa2EDTA) and dimercaptosuccinic acid (DMSA), for the treatment of lead poisoning in adults. METHODS: Thirty-seven patients with blood lead concentrations >40 µg/dL and positive CaNa2EDTA lead mobilization were randomized to receive 1050 mg/m2/day of oral DMSA (n = 21) or 500 mg/m2/day of intravenous CaNa2EDTA (n = 16) over two five-day courses separated by a 10-day rest period. Efficacy of treatment was evaluated by blood lead assays on the first day of the two courses and 14 days after the end of treatment and baseline CaNa2EDTA lead mobilization test and 14 days after the end of treatment. RESULTS AND CONCLUSION: Both treatments significantly reduced the prevalence of clinical symptoms, blood lead levels and CaNa2EDTA lead mobilization and were well tolerated. DMSA had a greater impact on reducing blood lead concentrations (p = .005) and CaNa2EDTA on lead mobilization (p = .04). Comparison of equimolar doses showed that CaNa2EDTA was more effective than DMSA (p < .001).

Modeling the effect of succimer (DMSA; dimercaptosuccinic acid) chelation therapy in patients poisoned by lead.

CONTEXT: Kinetic models could assist clinicians potentially in managing cases of lead poisoning. Several models exist that can simulate lead kinetics but none of them can predict the effect of chelation in lead poisoning. Our aim was to devise a model to predict the effect of succimer (dimercaptosuccinic acid; DMSA) chelation therapy on blood lead concentrations. MATERIALS AND METHODS: We integrated a two-compartment kinetic succimer model into an existing PBPK lead model and produced a Chelation Lead Therapy (CLT) model. The accuracy of the model's predictions was assessed by simulating clinical observations in patients poisoned by lead and treated with succimer. The CLT model calculates blood lead concentrations as the sum of the background exposure and the acute or chronic lead poisoning. The latter was due either to ingestion of traditional remedies or occupational exposure to lead-polluted ambient air. The exposure duration was known. The blood lead concentrations predicted by the CLT model were compared to the measured blood lead concentrations. RESULTS: Pre-chelation blood lead concentrations ranged between 99 and 150 µg/dL. The model was able to simulate accurately the blood lead concentrations during and after succimer treatment. The pattern of urine lead excretion was successfully predicted in some patients, while poorly predicted in others. CONCLUSIONS: Our model is able to predict blood lead concentrations after succimer therapy, at least, in situations where the duration of lead exposure is known.

Modelling dimercaptosuccinic acid (DMSA) plasma kinetics in humans.

CONTEXT: No kinetic models presently exist which simulate the effect of chelation therapy on lead blood concentrations in lead poisoning. OBJECTIVE: Our aim was to develop a kinetic model that describes the kinetics of dimercaptosuccinic acid (DMSA; succimer), a commonly used chelating agent, that could be used in developing a lead chelating model. MATERIAL AND METHODS: This was a kinetic modelling study. We used a two-compartment model, with a non-systemic gastrointestinal compartment (gut lumen) and the whole body as one systemic compartment. The only data available from the literature were used to calibrate the unknown model parameters. The calibrated model was then validated by comparing its predictions with measured data from three different experimental human studies. RESULTS: The model predicted total DMSA plasma and urine concentrations measured in three healthy volunteers after ingestion of DMSA 10 mg/kg. The model was then validated by using data from three other published studies; it predicted concentrations within a factor of two, representing inter-human variability. CONCLUSIONS: A simple kinetic model simulating the kinetics of DMSA in humans has been developed and validated. The interest of this model lies in the future potential to use it to predict blood lead concentrations in lead-poisoned patients treated with DMSA.

Management of Lead Encephalopathy with DMSA After Exposure to Lead-Contaminated Moonshine.

BACKGROUND: Lead encephalopathy is a severe manifestation of lead poisoning that can present with altered mental status and seizures and has been associated with illicit moonshine consumption. Lead encephalopathy has traditionally been treated using dimercaprol (British anti-Lewisite, BAL) and calcium disodium ethylenediaminetetraacetic acid (CaNa2EDTA). CASE REPORT: We describe a patient with lead encephalopathy related to lead-contaminated moonshine consumption, who was treated using dimercaptosuccinic acid (DMSA) due to a national shortage of CaNa2EDTA. A 66-year-old woman presented to a hospital with headache, irritability, and altered mental status. On hospital day 16, she was found to have a whole blood lead concentration of 148.2 µg/dL and a 24-h urine lead concentration of 232 µg/day. Due to a national shortage of CaNa2EDTA, the patient was given one dose of BAL and then started on DMSA via nasogastric tube. She dramatically improved over 4 days and was subsequently transitioned to oral DMSA and outpatient treatment. One day prior to discharge, her whole blood lead concentration was 47.2 µg/dL and her mental status was normal. DMSA was used in lieu of CaNa2EDTA to treat the patient with lead encephalopathy. The patient subsequently experienced clinical improvement and declining whole blood level concentrations. CONCLUSION: Further prospective studies are needed to compare the efficacy of DMSA versus CaNa2EDTA in patients with lead encephalopathy.

Assessment of 99mTc-succimer residual activity using inert nonreactive syringes.

UNLABELLED: It has been widely reported that (99m)Tc-succimer adsorbs to plastic syringes significantly (up to 50%), often resulting in a lower administered dose than intended or inaccurate dosing. This adsorption rate is especially problematic in the pediatric population. To improve (99m)Tc-succimer dosing, we compared the adsorption of (99m)Tc-succimer with 2 types of syringes: silicone-coated syringes with nonlatex rubber on the plunger and inert nonreactive syringes with no silicone coating and no rubber on the plunger. METHODS: (99m)Tc-succimer kits were compounded according to the manufacturer's instructions. (99m)Tc-succimer doses (37-185 MBq) were drawn into 3-mL (silicone-coated or inert nonreactive) syringes in a 1-mL volume. Thirty min, 1 h, 2 h, and 4 h later, the syringes were assayed in a dose calibrator and assayed again after being emptied and rinsed with saline. In addition, we examined the data collected from 129 (99m)Tc-succimer doses administered in a pediatric department, in which 52 were dispensed in silicone-coated syringes and 77 were dispensed in inert nonreactive syringes. The doses were assayed immediately before and after injection. The syringes were flushed with normal saline. RESULTS: The labeling efficiency of the (99m)Tc-succimer kits was more than 95%. Residual activity left in the inert nonreactive syringes was 0.73% (SD, ±0.18%), which was significantly lower than the activity left in the silicone-coated syringes, 20.9% (SD, ±5.6%; P < 0.0001). The extent of adsorption did not change significantly between 30 min and 4 h of incubation. The clinical data showed that the residual activity was 30.6% (SD, ±12.5%) from doses dispensed in silicone-coated syringes and 6.38% (SD, ±2.95%) from doses dispensed in inert nonreactive syringes (P < 0.001). CONCLUSION: The inert nonreactive syringes had significantly less residual of (99m)Tc-succimer than silicone-based syringes, making it possible to accurately administer calculated doses of (99m)Tc-succimer to pediatric patients.

Evaluation of 99mTc-succimer dosing in pediatric patients.

UNLABELLED: Balancing image quality with radiation dose is a goal with every diagnostic procedure requiring radiation. Our institution compared the dosing of (99m)Tc-labeled succimer, commonly referred to as dimercaptosuccinic acid ((99m)Tc-DMSA), to pediatric patients using 2 methods of calculation, body surface area (BSA, the method we used from 2009 to 2010) and body weight (BW, the method we used in 2011). METHODS: A retrospective study was conducted in a 230-bed inpatient, tertiary-care academic pediatric hospital to obtain objective data on patients under the age of 17 y who received a renal nuclear medicine procedure with (99m)Tc-DMSA using a 300,000-count parallel image and four 150,000-count pinhole images. Data collection included patient age, sex, height, weight, calculated activity, assayed activity, administered activity, residual syringe activity, imaging time, and notable patient or equipment factors affecting the procedure. RESULTS: Calculated activities based on BSA were higher than calculated activities based on BW. (99m)Tc-DMSA adsorption to the plastic syringes was significant, with a range of 3%-82%. Because of the adsorption, an average of 23.7 MBq (SD, ±31 MBq) was added to the patients' calculated dose when the order was placed. Therefore, assayed activities were significantly higher than calculated activities in both groups. Administered activity correlations to BSA and BW calculations were 0.75 and 0.83, respectively. Administered activities from BSA and BW groups were outside the American College of Radiology (ACR)-recommended guidelines 59% and 45% of the time, respectively. Overall, children less than 2 y old were above the ACR recommendations 80% of the time. There was a poor correlation between administered activity and total imaging time (r = 0.23). Average imaging time overall for 5 planar views was 14.8 min (±7.1 min). Patients receiving less than the ACR-recommended administered activities (<1.85 MBq/kg) had an average increase in imaging time of 4.5 min (±3.4 min). CONCLUSION: The activity administered to patients was significantly affected by the amount of (99m)Tc-DMSA activity adsorbed to the syringe. Syringe residual should be considered when standardizing (99m)Tc-DMSA imaging protocols and calculating patient dose. Although (99m)Tc-DMSA adsorption was variable, the administered activities correlated with calculated activities. In all but one of our patients, the total imaging time was far less than recommended by the ACR and European Association of Nuclear Medicine guidelines. The study indicates that using the BW calculation of 3.7 MBq/kg resulted in a range of administered activity of 1.85-2.59 MBq/kg. (99m)Tc-DMSA dosing of 3.7 MBq/kg for pinhole imaging should be appropriate for most studies.

Chelation in metal intoxication.

Chelation therapy is the preferred medical treatment for reducing the toxic effects of metals. Chelating agents are capable of binding to toxic metal ions to form complex structures which are easily excreted from the body removing them from intracellular or extracellular spaces. 2,3-Dimercaprol has long been the mainstay of chelation therapy for lead or arsenic poisoning, however its serious side effects have led researchers to develop less toxic analogues. Hydrophilic chelators like meso-2,3-dimercaptosuccinic acid effectively promote renal metal excretion, but their ability to access intracellular metals is weak. Newer strategies to address these drawbacks like combination therapy (use of structurally different chelating agents) or co-administration of antioxidants have been reported recently. In this review we provide an update of the existing chelating agents and the various strategies available for the treatment of heavy metals and metalloid intoxications.

Developmental lead exposure induces tactile defensiveness in rhesus monkeys (Macaca mulatta).

BACKGROUND: Tactile defensiveness in children is associated with difficult social relations, emotional dysregulation, and inattention. However, there are no studies of lead exposure and tactile defensiveness in children or animals in spite of the fact that lead exposure is also associated with inattention and emotional dysregulation. OBJECTIVES: In this study we tested whether lead exposure induces tactile defensiveness in rhesus monkeys. METHODS: We tested 61 monkeys from a 3 (no lead, 1-year lead, 2-year lead) x 2 (succimer chelation or not) factorial experiment for tactile defensiveness at 4 years of age. Lead-treated monkeys had been orally administered lead in a daily milk solution from 8 days of life to either 1 or 2 years of age to produce blood lead levels of 35-40 mg/dL. Succimer chelation therapy or placebo was administered at 1 year of age. We measured tactile defensiveness using six repeated trials of each of three textures as a swipe to the cheek and neck. RESULTS: Lead-exposed monkeys showed higher negative responses to repeated tactile stimulation compared with controls. Blood lead during the first 3 months of life was positively correlated with the negative response on the tactile defensiveness test. There was an interaction of lead exposure x succimer chelation x trials, but it is not clear that succimer chelation was beneficial with respect to tactile defensiveness. CONCLUSIONS: This is the first report to implicate lead as a potential cause of tactile defensiveness. Research should examine whether lead exposure is associated with tactile defensiveness in children.

Acute toxicity of meso-2,3-dimercaptosuccinic acid on mice / 中国基层医药

Objective To explore acute toxicity of succimer on mice.Methods Twenty Kunming mice(10 males and 10 females) weighting approximately (21.2?2.3)g were acclimatized for 3 days prior to dosing,then were divided into control group and experiment group with 10 mice in each group according to body weight.Fasted for 12 hours,the mice in experiment group received intragastric administration of 160mg DMSA in deionized water in 24 hours,and the control group received the same volume of deionized water,and then they were observed for 7 days.Blood was collected into heparinized-tubes by removal of eyeball.All mice were sacrificed and brain,heart,liver and kidney were removed and washed with normal saline.The activity or amount of BUN,Scr,AST,ALT,SOD, GSH-PX and MDA were analyzed.Results (1)Given 160rag DMSA in 24 hours,gastrointestinal symptoms were main side effects.During the observation,experiment group lost weight due to the decrease of food-intake ,and some mice had slight hydroabdomen.(2)High dose of DMSA caused a significant inhibition of GSH-PX(P0.05).The hepatic cell was damaged accord- ing to the significant raise of MDA in liver(P0.05),which was related to acute toxicity on liver.Conclusion Succimer could inhibit the antioxidarrt systems and could do damage to liver and kidney.