RESUMEN
BACKGROUND: Vital pulp therapy maintained functionality, vitality, and asymptomatic teeth. Compared to normal root canal treatment, pulpotomy was more helpful for irreversible pulpitis in adult permanent teeth. The research was aimed to assess effectiveness of vital pulp therapy using mineral trioxide aggregate with Apple Vinegar and Ethylene diamine tetra acetic acid (17%) for five minutes in adult carious exposed pulp of permanent teeth. METHODS: Forty patients between 18 and 50 years old with a clinical diagnosis of symptomatic irreversible pulpitis but no periapical radiolucency were then divided randomly into two groups based on the irrigation method; ethylene diamine tetraacetic acid or apple vinegar. If pulpal bleeding could not be managed in less than six minutes, the assigned procedure was abandoned. After mineral trioxide aggregate application as a pulpotomy agent, glass ionomer and composite restoration were placed. Using a visual analogue scale, the pre and post-operative pain were recorded after 2,6,24,48, and 72 h. Success was assessed using radiographic and clinical examination data at three, six, and twelve months. RESULTS: The success rate was discovered to be non-statistically significant in both groups after a year follow-up. Apple vinegar had a lower mean value than ethylene diamine tetra acetic acid at the preoperative baseline pain level, which was significant.Postoperatively, the ethylene diamine tetraacetic acid group reported the greatest mean value after two hours while Apple vinegar group reported the lowest mean values after 48 h (P < 0.05). After 72 h, pain level recorded insignificant difference. CONCLUSION: Apple vinegar yielded a marginally successful outcome but substantially improved pain alleviation. TRIAL REGISTRATION: The trial was registered in Clinical trials.gov with this identifier NCT05970536 on 23/7/2023.
Asunto(s)
Compuestos de Aluminio , Compuestos de Calcio , Quelantes , Combinación de Medicamentos , Óxidos , Pulpitis , Silicatos , Humanos , Adulto , Pulpitis/terapia , Femenino , Masculino , Silicatos/uso terapéutico , Compuestos de Calcio/uso terapéutico , Persona de Mediana Edad , Compuestos de Aluminio/uso terapéutico , Quelantes/uso terapéutico , Adolescente , Adulto Joven , Óxidos/uso terapéutico , Ácido Edético/uso terapéutico , Ácido Acético/uso terapéutico , Pulpotomía/métodos , Resultado del Tratamiento , Cerámica , Dimensión del DolorAsunto(s)
Quelantes , Terapia por Quelación , Ácido Edético , Infarto del Miocardio , Humanos , Quelantes/uso terapéutico , Terapia por Quelación/métodos , Infarto del Miocardio/epidemiología , Infarto del Miocardio/prevención & control , Ácido Edético/administración & dosificación , Infusiones Intravenosas , Diabetes Mellitus/tratamiento farmacológico , Cadmio , Plomo , Prevención Secundaria/métodos , Ensayos Clínicos Controlados Aleatorios como Asunto , Resultado del TratamientoRESUMEN
Essential transition metals have key roles in oxygen transport, neurotransmitter synthesis, nucleic acid repair, cellular structure maintenance and stability, oxidative phosphorylation, and metabolism. The balance between metal deficiency and excess is typically ensured by several extracellular and intracellular mechanisms involved in uptake, distribution, and excretion. However, provoked by either intrinsic or extrinsic factors, excess iron, zinc, copper, or manganese can lead to cellular damage upon chronic or acute exposure, frequently attributed to oxidative stress. Intracellularly, mitochondria are the organelles that require the tightest control concerning reactive oxygen species production, which inevitably leaves them to be one of the most vulnerable targets of metal toxicity. Current therapies to counteract metal overload are focused on chelators, which often cause secondary effects decreasing patients' quality of life. New therapeutic options based on synthetic or natural antioxidants have proven positive effects against metal intoxication. In this review, we briefly address the cellular metabolism of transition metals, consequences of their overload, and current therapies, followed by their potential role in inducing oxidative stress and remedies thereof.
Asunto(s)
Antioxidantes , Estrés Oxidativo , Elementos de Transición , Humanos , Antioxidantes/uso terapéutico , Antioxidantes/metabolismo , Estrés Oxidativo/efectos de los fármacos , Elementos de Transición/metabolismo , Animales , Mitocondrias/metabolismo , Mitocondrias/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Hierro/metabolismo , Metales/metabolismo , Quelantes/uso terapéutico , Quelantes/farmacologíaRESUMEN
OBJECTIVES: Wilson disease (WD) is a rare genetic disease affecting copper metabolism and the biliary tract's copper excretion. Lifelong medication is necessary to prevent liver failure, neurological complications, and death. Although D-penicillamine (DPA), trientine, and zinc are used to treat WD, there is limited research on the long-term outcomes of these drugs, especially in children. This study aimed to evaluate the efficacy and safety of DPA, trientine, and zinc in patients diagnosed with WD during childhood. METHODS: Ninety out of 92 patients were included in the analysis, excluding two patients who underwent liver transplantation without drug treatment due to an acute liver failure diagnosis. Treatment outcomes and reasons for discontinuation of therapy in 148 treatment blocks (37 DPA, 50 trientine, and 61 zinc) were analyzed using Kaplan-Meier analysis. RESULTS: The median age at diagnosis was 8.3 years. There was a statistically significant difference in drug changes due to treatment ineffectiveness among the three drugs: trientine (22/50, 44%), zinc (15/61, 25%), and DPA (2/37, 5%) (all p < 0.05). Regarding drug changes due to adverse effects, the rate was the highest for DPA, followed by zinc and trientine. There were significant differences between DPA and zinc, zinc and trientine (all p < 0.05), but no significant difference was observed between DPA and zinc (p = 0.22). CONCLUSIONS: In pediatric WD, DPA, zinc, and trientine have therapeutic effects in that order. However, DPA and zinc are associated with more adverse effects compared to trientine.
Asunto(s)
Degeneración Hepatolenticular , Penicilamina , Trientina , Zinc , Humanos , Degeneración Hepatolenticular/tratamiento farmacológico , Degeneración Hepatolenticular/metabolismo , Penicilamina/uso terapéutico , Penicilamina/efectos adversos , Trientina/uso terapéutico , Trientina/efectos adversos , Niño , Masculino , Femenino , Zinc/uso terapéutico , Adolescente , Preescolar , Quelantes/uso terapéutico , Resultado del TratamientoRESUMEN
BACKGROUND AND AIMS: Few studies have focused on the outcomes of Wilson's disease (WD) diagnosed before age of 5 years. This study aimed to summarize the clinical features of early diagnosed WD and analyse treatment outcomes and the risk factors associated with treatment failure. METHODS: A total of 139 children confirmed with WD before 5 years were enrolled in this study. Only patients with follow-up over 1 year were analysed with Kaplan-Meier survival analysis. The composite outcomes included death, progression to liver failure or acute hepatitis, development of renal or neurological symptoms and persistent elevation of alanine aminotransferase (ALT). The treatment failure was defined as occurrence of at least one of above outcomes. RESULTS: Among 139 WD patients at diagnosis, two (1.4%) WD patients presented with symptomatic liver disease, whereas 137 (98.6%) were phenotypically asymptomatic, including 135 with elevated ALT and 2 with normal liver function. Median serum ceruloplasmin (Cp) was 3.1 mg/dL, and urinary copper excretion was 87.4 µg/24-h. There were 71 variants identified in the the copper-transporting ATPase beta gene, and 29 were loss of function (LOF). 51 patients with LOF variant were younger at diagnosis and had lower Cp than 88 patients without LOF. Among 93 patients with over 1 year of follow-up, 19 (20.4%) received zinc monotherapy, and 74 (79.6%) received a zinc/D-penicillamine combination therapy. 14 (15.1%) patients underwent treatment failure, and its occurrence was associated with poor compliance (p < .01). CONCLUSIONS: Cp is a reliable biomarker for early diagnosis, and zinc monotherapy is an effective treatment for WD during early childhood. Good treatment compliance is critical to achieve a favourable outcome.
Asunto(s)
Ceruloplasmina , ATPasas Transportadoras de Cobre , Degeneración Hepatolenticular , Penicilamina , Humanos , Degeneración Hepatolenticular/diagnóstico , Degeneración Hepatolenticular/genética , Degeneración Hepatolenticular/tratamiento farmacológico , Degeneración Hepatolenticular/sangre , Degeneración Hepatolenticular/terapia , Femenino , Masculino , Preescolar , Ceruloplasmina/análisis , Ceruloplasmina/metabolismo , ATPasas Transportadoras de Cobre/genética , Penicilamina/uso terapéutico , Pronóstico , Alanina Transaminasa/sangre , Niño , Cobre/sangre , Factores de Riesgo , Insuficiencia del Tratamiento , Diagnóstico Precoz , Progresión de la Enfermedad , Estimación de Kaplan-Meier , Lactante , Quelantes/uso terapéuticoRESUMEN
Scandium (Sc) isotopes have recently attracted significant attention in the search for new radionuclides with potential uses in personalized medicine, especially in the treatment of specific cancer patient categories. In particular, Sc-43 and Sc-44, as positron emitters with a satisfactory half-life (3.9 and 4.0 h, respectively), are ideal for cancer diagnosis via Positron Emission Tomography (PET). On the other hand, Sc-47, as an emitter of beta particles and low gamma radiation, may be used as a therapeutic radionuclide, which also allows Single-Photon Emission Computed Tomography (SPECT) imaging. As these scandium isotopes follow the same biological pathway and chemical reactivity, they appear to fit perfectly into the "theranostic pair" concept. A step-by-step description, initiating from the moment of scandium isotope production and leading up to their preclinical and clinical trial applications, is presented. Recent developments related to the nuclear reactions selected and employed to produce the radionuclides Sc-43, Sc-44, and Sc-47, the chemical processing of these isotopes and the main target recovery methods are also included. Furthermore, the radiolabeling of the leading chelator, 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), and its structural analogues with scandium is also discussed and the advantages and disadvantages of scandium complexation are evaluated. Finally, a review of the preclinical studies and clinical trials involving scandium, as well as future challenges for its clinical uses and applications, are presented.
Asunto(s)
Quelantes , Compuestos Heterocíclicos con 1 Anillo , Medicina Nuclear , Radioisótopos , Radiofármacos , Escandio , Escandio/química , Humanos , Radioisótopos/química , Radioisótopos/uso terapéutico , Quelantes/química , Quelantes/uso terapéutico , Radiofármacos/química , Radiofármacos/uso terapéutico , Compuestos Heterocíclicos con 1 Anillo/química , Medicina Nuclear/métodos , Animales , Tomografía de Emisión de Positrones/métodos , Neoplasias/diagnóstico por imagen , Neoplasias/radioterapia , Tomografía Computarizada de Emisión de Fotón Único/métodosRESUMEN
Numerous physiological processes happening in the human body, including cerebral development and function, require the participation of biometal ions such as iron, copper, and zinc. Their dyshomeostasis may, however, contribute to the onset of Alzheimer's disease (AD) and potentially other neurodegenerative diseases. Chelation of biometal ions is therefore a therapeutic strategy against AD. This review provides a survey of natural and synthetic chelating agents that are or could potentially be used to target the metal hypothesis of AD. Since metal dyshomeostasis is not the only pathological aspect of AD, and the nature of this disorder is very complex and multifactiorial, the most efficient therapeutics should target as many neurotoxic factors as possible. Various coumarin derivatives match this description and apart from being able to chelate metal ions, they exhibit the capacity to inhibit cholinesterases (ChEs) and monoamine oxidase B (MAO-B) while also possessing antioxidant, anti-inflammatory, and numerous other beneficial effects. Compounds based on the coumarin scaffold therefore represent a desirable class of anti-AD therapeutics.
Asunto(s)
Enfermedad de Alzheimer , Quelantes , Cumarinas , Enfermedad de Alzheimer/tratamiento farmacológico , Humanos , Cumarinas/farmacología , Cumarinas/uso terapéutico , Quelantes/farmacología , Quelantes/uso terapéutico , Animales , Inhibidores de la Colinesterasa/farmacología , Metales/químicaRESUMEN
Iron and copper chelation therapy plays a crucial role in treating conditions associated with metal overload, such as hemochromatosis or Wilson's disease. However, conventional chelators face challenges in reaching the core of iron and copper metabolism - the mitochondria. Mitochondria-targeted chelators can specifically target and remove metal ions from mitochondria, showing promise in treating diseases linked to mitochondrial dysfunction, including neurodegenerative diseases and cancer. Additionally, they serve as specific mitochondrial metal sensors. However, designing these new molecules presents its own set of challenges. Depending on the chelator's intended use to prevent or to promote redox cycling of the metals, the chelating moiety must possess different donor atoms and an optimal value of the electrode potential of the chelator-metal complex. Various targeting moieties can be employed for selective delivery into the mitochondria. This review also provides an overview of the current progress in the design of mitochondria-targeted chelators and their biological activity investigation.
Asunto(s)
Quelantes , Cobre , Hierro , Mitocondrias , Cobre/metabolismo , Mitocondrias/metabolismo , Mitocondrias/efectos de los fármacos , Humanos , Hierro/metabolismo , Quelantes/uso terapéutico , Quelantes/metabolismo , Quelantes del Hierro/farmacología , Animales , Terapia por Quelación/métodosRESUMEN
Psoriasis, characterized as a chronic relapsing disease with a protracted course, often drives patients to seek relief through Chinese folk remedies (CFR). Nonetheless, the complex compositions of these remedies frequently result in unintended adverse effects, notably various types of heavy metal poisoning. Our study involved an exhaustive collection and analysis of clinical data from psoriasis patients who developed heavy metal poisoning due to CFR usage, admitted to Beijing Chao-Yang Hospital from January 2011 to October 2023. Our analysis identified 44 cases of mercury poisoning, 17 of lead poisoning, 21 of arsenic poisoning, and 4 instances of mixed heavy metal poisoning. The folk remedies used ranged from fumigation and inhalation to skin application and oral administration. Distinct pathogenic characteristics were observed in each poisoning type. After treatment with metal chelating agents, all patients experienced a reduction in heavy metal levels in their bodies, accompanied by varying degrees of symptom alleviation. This study underscores the vital necessity of opting for formal, medically approved treatments for psoriasis, thereby avoiding the hazardous consequences of unregulated folk remedies that may lead to severe heavy metal poisoning.
Asunto(s)
Intoxicación por Metales Pesados , Medicina Tradicional China , Psoriasis , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto Joven , Quelantes/uso terapéutico , Medicamentos Herbarios Chinos , Medicina Tradicional China/efectos adversos , Metales Pesados , Psoriasis/tratamiento farmacológico , Estudios RetrospectivosRESUMEN
The clinical success of [223Ra]RaCl2 (Xofigo®) for the palliative treatment of bone metastases in patients with prostate cancer has highlighted the therapeutic potential of α-particle emission. Expanding the applicability of radium-223 in Targeted Alpha Therapy of non-osseous tumors is followed up with significant interest, as it holds the potential to unveil novel treatment options in the comprehensive management of cancer. Moreover, the use of barium radionuclides, like barium-131 and -135m, is still unfamiliar in nuclear medicine applications, although they can be considered as radium-223 surrogates for imaging purposes. Enabling these applications requires the establishment of chelators able to form stable complexes with radium and barium radionuclides. Until now, only a limited number of ligands have been suggested and these molecules have been primarily inspired by existing structures known for their ability to complex large metal cations. However, a systematic inspection of chelators specifically tailored to Ra2+ and Ba2+ has yet to be conducted. This work delves into a comprehensive investigation of a series of small organic ligands, aiming to unveil the coordination preferences of both radium-223 and barium-131/135m. Electronic binding energies of both metal cations to each ligand were theoretically computed via Density Functional Theory calculations (COSMO-ZORA-PBE-D3/TZ2P), while thermodynamic stability constants were experimentally determined for Ba2+-ligand complexes by potentiometry, NMR and UV-Vis spectroscopies. The outcomes revealed malonate, 2-hydroxypyridine 1-oxide and picolinate as the most favorable building blocks to design multidentate chelators. These findings serve as foundation guidelines, propelling the development of cutting-edge radium-223- and barium-131/135m-based radiopharmaceuticals for Targeted Alpha Therapy and theranostics of cancer.
Asunto(s)
Radio (Elemento) , Radio (Elemento)/química , Radio (Elemento)/uso terapéutico , Humanos , Radioisótopos/química , Complejos de Coordinación/química , Complejos de Coordinación/uso terapéutico , Bario/química , Partículas alfa/uso terapéutico , Quelantes/química , Quelantes/uso terapéutico , Neoplasias/tratamiento farmacológico , Nanomedicina Teranóstica/métodos , Metales Alcalinotérreos/química , Radiofármacos/química , Radiofármacos/uso terapéuticoRESUMEN
BACKGROUND: Wilson disease (WD) is an autosomal recessive disorder that leads to organ toxicity due to copper overload. Early diagnosis is complicated by the rarity and diversity of manifestations. OBJECTIVE: To describe the diagnostic features and response to treatment in our cohort of WD patients. METHODS: This was a retrospective analysis of 262 WD patients stratified by clinical presentation, complementary exams, ATP7B genotyping, and response to treatment. RESULTS: Symptoms occurred at an average age of 17.4 (7-49) years, and patients were followed up for an average of 9.6 (0-45) years. Patients presented mainly with hepatic (36.3%), neurologic (34.7%), and neuropsychiatric (8.3%) forms. Other presentations were hematologic, renal, or musculoskeletal, and 16.8% of the patients were asymptomatic. Kayser-Fleischer rings occurred in 78.3% of the patients, hypoceruloplasminemia in 98.3%, and elevated cupruria/24h in 73.0%, with an increase after D-penicillamine in 54.0%. Mutations of the ATP7B gene were detected in 84.4% of alleles. Brain magnetic resonance imaging showed abnormalities in the basal ganglia in 77.7% of patients. D-penicillamine was the first choice in 93.6% of the 245 patients, and 21.1% of these patients were switched due to adverse effects. The second-line therapies were zinc and trientine. The therapeutic response did not differ significantly between the drugs (p = 0.2). Nine patients underwent liver transplantation and 82 died. CONCLUSION: Wilson disease is diagnosed at a late stage, and therapeutic options are limited. In people under 40 years of age with compatible manifestations, WD could be considered earlier in the differential diagnosis. There is a need to include ATP7B genotyping and therapeutic alternatives in clinical practice.
ANTECEDENTES: A doença de Wilson (DW) é um distúrbio autossômico recessivo caracterizado por acúmulo de cobre lesivo aos órgãos. O diagnóstico precoce é dificultado pela raridade e diversidade de apresentações. OBJETIVO: Descrever características ao diagnóstico e resposta ao tratamento em uma coorte de DW. MéTODOS: Análise retrospectiva de 262 casos de DW quanto à apresentação clínica, exames complementares, genotipagem e resposta ao tratamento. RESULTADOS: Os sintomas surgiram em uma média aos 17,4 (749) anos, e os pacientes foram acompanhados por uma média de 9,6 (045) anos. Os pacientes apresentaram principalmente formas hepáticas (36,3%), neurológicas (34,7%) e neuropsiquiátricas (8,3%). Outras apresentações foram hematológicas, renais e musculoesqueléticas. Apenas 16,8% eram assintomáticos. Anéis de Kayser-Fleischer ocorreram em 78,3% dos pacientes, hipoceruloplasminemia em 98,3%, e cuprúria elevada/24h em 73,0%, com aumento após D-penicilamina em 54,0%. Mutações do gene ATP7B foram detectadas em 84,4% dos alelos pesquisados. A ressonância magnética cerebral mostrou alterações em gânglios da base em 77,7% dos pacientes. O tratamento com D-penicilamina foi a escolha inicial em 93,6% dos 245 casos e foi trocado em 21,1% devido a efeitos adversos. Terapias de segunda linha foram zinco e trientina. A resposta terapêutica não diferiu significativamente entre os medicamentos (p = 0,2). Nove pacientes receberam transplante hepático e 82 faleceram. CONCLUSãO: O diagnóstico da DW ainda ocorre em estágios tardios, e as opções terapêuticas são limitadas. A DW deve ser considerada precocemente no diagnóstico diferencial de pessoas com menos de 40 anos com manifestações compatíveis. É necessário incorporar na prática clínica a genotipagem do ATP7B e alternativas terapêuticas à penicilamina.
Asunto(s)
ATPasas Transportadoras de Cobre , Degeneración Hepatolenticular , Penicilamina , Humanos , Degeneración Hepatolenticular/genética , Degeneración Hepatolenticular/terapia , Degeneración Hepatolenticular/diagnóstico , Degeneración Hepatolenticular/tratamiento farmacológico , Estudios Retrospectivos , Femenino , Masculino , Adolescente , Niño , Adulto , ATPasas Transportadoras de Cobre/genética , Adulto Joven , Penicilamina/uso terapéutico , Resultado del Tratamiento , Persona de Mediana Edad , Adenosina Trifosfatasas/genética , Mutación , Genotipo , Imagen por Resonancia Magnética , Quelantes/uso terapéutico , Proteínas de Transporte de Catión/genética , CobreRESUMEN
INTRODUCTION: Hyperphosphatemia and hyperparathyroidism are common in end-stage kidney disease and are associated with poor outcomes. In addition to adequate dialysis, medications are usually required for optimum control of serum phosphate and parathyroid hormone (PTH) levels. The use of calcium-based phosphate binders (CBPBs) and active vitamin D is associated with an increase in serum calcium and worsening vascular calcification. To overcome these limitations, non-calcium-based phosphate binders (NCBPBs) and calcimimetics have been developed. However, the coverage for these new medications remains limited in several parts of the world due to the lack of patient-level outcome data and cost. The present study examined the differences in mineral outcomes between two main categories of healthcare programs that provided different coverage for medications used to control mineral and bone disorders (MBD). The Social Security/Universal Coverage (SS/UC) program covered only CBPBs and active vitamin D, whereas the Civil Servant/State Enterprise (CS/SE) program provided coverage of CBPBs, active vitamin D, NCBPBs, and calcimimetics. METHODS: This 10-year retrospective cohort study examined the differences in mineral outcomes between two healthcare programs in maintenance hemodialysis patients. The differences in serum calcium, phosphate, and PTH levels, as well as the aortic arch calcification score, were analyzed according to dialysis vintage by linear mixed-effects regression analyses. The difference in the composite outcome of severe hyperparathyroidism and parathyroidectomy was analyzed by the Cox-proportional hazard regression model. RESULTS: 714 patients were included in the analyses (full cohort). Of these patients, 563 required at least one type of medication to control MBD (MBD medication subgroup). Serum calcium, phosphate, and the proportions of patients with hypercalcemia and hyperphosphatemia were substantially higher in the SS/UC group compared with the CS/SE group after appropriate adjustments for confounders in both the full cohort and the MBD medication subgroup. These findings were confirmed in propensity-score matched analyses. Higher parathyroid hormone levels and a higher rate of the composite endpoint of severe hyperparathyroidism and parathyroidectomy were also observed in the SS/UC group. A more rapid progression of aortic arch calcification was suggested in the SS/UC group, but between-group changes were not significant. CONCLUSION: Patients under the healthcare program that did not cover the use of NCBPBs and calcimimetics showed higher serum calcium and phosphate levels and a more rapid progression of hyperparathyroidism. The difference in the progression of vascular calcification could not be confirmed in the present study.
Asunto(s)
Calcimiméticos , Calcio , Hiperfosfatemia , Fosfatos , Diálisis Renal , Humanos , Masculino , Femenino , Estudios Retrospectivos , Persona de Mediana Edad , Calcimiméticos/uso terapéutico , Hiperfosfatemia/etiología , Hiperfosfatemia/tratamiento farmacológico , Hiperfosfatemia/sangre , Calcio/sangre , Anciano , Fosfatos/sangre , Fallo Renal Crónico/terapia , Fallo Renal Crónico/sangre , Fallo Renal Crónico/complicaciones , Hormona Paratiroidea/sangre , Vitamina D/sangre , Quelantes/uso terapéuticoRESUMEN
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the accumulation of amyloid - ß extracellular plaques and tau interfibrillar tangles, leading to memory loss, cognitive decline, and behavioral changes. With dementia posing a growing global health concern, there is an urgent need for comprehensive strategies to address its challenges. The economic burden of dementia is projected to rise significantly, emphasizing the necessity for collaborative efforts in research and healthcare. In the United States alone, millions are affected by AD, with prevalence increasing with age and even affecting younger individuals. The complexity of AD involves intricate biological processes, including the aggregation of amyloid beta, oxidative stress, and metal ion dysregulation. Metal ions, particularly those from copper, iron, and zinc, play pivotal roles in AD pathology, influencing Aß deposition and tau protein accumulation. Current treatments offer symptomatic relief but do not address the underlying disease mechanisms. This paper explores the potential of various chelating compounds to target metal ions involved in AD pathology. N-acylhydrazones, morpholine, chrysin, quinoline, oxindole, cyclam, catechol-based, and quinazolinone-based derivatives show promising chelation activity and therapeutic effects. Metal chelation therapy offers a targeted approach to AD treatment by addressing the core pathology. By selectively binding to metal ions implicated in disease progression, chelators may minimize side effects associated with broad-spectrum treatments. Additionally, chelators may offer neuroprotective effects beyond metal binding, further enhancing their therapeutic potential. Overall, metal chelation therapy presents a promising strategy in combating AD, with the potential to significantly impact disease progression and improve patient outcomes.
Asunto(s)
Enfermedad de Alzheimer , Quelantes , Cobre , Zinc , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Humanos , Quelantes/uso terapéutico , Quelantes/química , Cobre/química , Cobre/metabolismo , Zinc/uso terapéutico , Zinc/química , Zinc/metabolismo , Hierro/metabolismo , Hierro/química , Animales , Péptidos beta-Amiloides/metabolismo , Péptidos beta-Amiloides/antagonistas & inhibidoresRESUMEN
OBJECTIVES: Long-term D-penicillamine (D-pen) therapy in Wilson disease (WD) has numerous adverse effects which advocates its withdrawal, but with an inherent risk of relapse. This prospective observational study was conducted with the objective of evaluating incidence of relapse following withdrawal of D-pen from combination (D-pen + zinc) therapy in maintenance phase of previously symptomatic hepatic WD. METHODS: Hepatic WD patients <18 years of age and on combination therapy for >2 years with 6 months of biochemical remission were included. Biochemical remission was defined as achievement of (i) aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤1.5 times upper limit of normal (ULN), (ii) serum albumin >3.5 g/dL, international normalized ratio (INR) <1.5 and (iii) 24-h urinary copper excretion (UCE) <500 mcg/day, nonceruloplasmin-bound-copper (NCC) <15 mcg/dL. After D-pen withdrawal, monthly liver function test (LFT) and INR and 3 monthly UCE and NCC were done till 1 year or relapse (elevation of AST/ALT/both >2 times ULN or total bilirubin >2 mg/dL), whichever occurred earlier. RESULTS: Forty-five patients enrolled with median combination therapy duration of 36 months. Sixty percent of them had their index presentation as decompensated cirrhosis. Fourteen patients (31.8%) relapsed (cumulative incidence: 4 at 3 months, 11 at 6 months, and 14 at 12 months after D-pen discontinuation). All relapsers had index presentation as decompensated cirrhosis. On Cox-regression, ALT at D-pen withdrawal was an independent predictor of relapse (hazard ratio [HR]: 1.077, 95% confidence interval [CI]: 1.014-1.145, p = 0.017) with area under the receiver operating characteristic (AUROC) of 0.860. ALT ≥40 U/L predicted risk of relapse with 85.7% sensitivity, 70.9% specificity. CONCLUSION: Incidence of relapse after withdrawal of D-pen from combination therapy is 31.8% in hepatic WD. ALT ≥40 U/L, at the time of D-pen stoppage, predicts future relapse.
Asunto(s)
Quelantes , Quimioterapia Combinada , Degeneración Hepatolenticular , Penicilamina , Recurrencia , Humanos , Degeneración Hepatolenticular/tratamiento farmacológico , Penicilamina/uso terapéutico , Penicilamina/administración & dosificación , Femenino , Masculino , Estudios Prospectivos , Adolescente , Niño , Quelantes/uso terapéutico , Quelantes/administración & dosificación , Alanina Transaminasa/sangre , Aspartato Aminotransferasas/sangre , Zinc/administración & dosificación , Zinc/uso terapéutico , Pruebas de Función Hepática/métodos , Cobre/sangre , Privación de TratamientoRESUMEN
BACKGROUND: Calcium supplements are commonly prescribed to prevent fractures in patients with osteoporosis. Nonetheless, they are generally eschewed in hemodialysis patients because they increase vascular calcification and induce cardiovascular disease. This retrospective cohort study aimed to investigate the effect of calcium-based phosphate binders (CBPB) on bone mineral density (BMD) in hemodialysis patients. METHODS: Outpatients on dialysis who underwent BMD measurement from January to December 2017, whose data on BMD trends and CBPB administration were recorded over the next 4 years, were enrolled. Patients receiving anti-osteoporotic medications were excluded. The association between the presence and duration of CBPB administration and changes in BMD was evaluated. RESULTS: The femoral neck's BMD decreased from 0.836 g/cm2 (0.702-0.952) to 0.764 g/cm2 (0.636-0.896) (P < 0.001) in the non-CBPB group (patients who never received CBPB over 4 years, n = 32). The CBPB group (n = 56) exhibited only a minute decrease from 0.833 g/cm2 (0.736-0.965) to 0.824 g/cm2 (0.706-0.939) (P = 0.004). Multivariate linear regression analysis revealed better BMD maintenance in the CBPB group [ß-coefficient (95% CI): 0.033 (0.001-0.065); P = 0.046] than in the non-CBPB group. Additionally, the prolonged-CBPB administration group showed superior BMD preservation [ß-coefficient (95% CI): 0.038 (0.001-0.076); P = 0.042]. CONCLUSION: CBPB administration may be associated with BMD maintenance.
Asunto(s)
Densidad Ósea , Diálisis Renal , Humanos , Diálisis Renal/efectos adversos , Estudios Retrospectivos , Densidad Ósea/efectos de los fármacos , Femenino , Masculino , Persona de Mediana Edad , Anciano , Cuello Femoral/diagnóstico por imagen , Osteoporosis/prevención & control , Osteoporosis/etiología , Fosfatos , Quelantes/uso terapéuticoRESUMEN
BACKGROUND: The reduction in cardiovascular disease (CVD) events with edetate disodium (EDTA) in the Trial to Assess Chelation Therapy (TACT) suggested that chelation of toxic metals might provide novel opportunities to reduce CVD in patients with diabetes. Lead and cadmium are vasculotoxic metals chelated by EDTA. We present baseline characteristics for participants in TACT2, a randomized, double-masked, placebo-controlled trial designed as a replication of the TACT trial limited to patients with diabetes. METHODS: TACT2 enrolled 1,000 participants with diabetes and prior myocardial infarction, age 50 years or older between September 2016 and December 2020. Among 959 participants with at least one infusion, 933 had blood and/or urine metals measured at the Centers for Diseases Control and Prevention using the same methodology as in the National Health and Nutrition Examination Survey (NHANES). We compared metal levels in TACT2 to a contemporaneous subset of NHANES participants with CVD, diabetes and other inclusion criteria similar to TACT2's participants. RESULTS: At baseline, the median (interquartile range, IQR) age was 67 (60, 72) years, 27% were women, 78% reported white race, mean (SD) BMI was 32.7 (6.6) kg/m2, 4% reported type 1 diabetes, 46.8% were treated with insulin, 22.3% with GLP1-receptor agonists or SGLT-2 inhibitors, 90.2% with aspirin, warfarin or P2Y12 inhibitors, and 86.5% with statins. Blood lead was detectable in all participants; median (IQR) was 9.19 (6.30, 13.9) µg/L. Blood and urine cadmium were detectable in 97% and median (IQR) levels were 0.28 (0.18, 0.43) µg/L and 0.30 (0.18, 0.51) µg/g creatinine, respectively. Metal levels were largely similar to those in the contemporaneous NHANES subset. CONCLUSIONS: TACT2 participants were characterized by high use of medication to treat CVD and diabetes and similar baseline metal levels as in the general US population. TACT2 will determine whether chelation therapy reduces the occurrence of subsequent CVD events in this high-risk population. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov. Identifier: NCT02733185. https://clinicaltrials.gov/study/NCT02733185.
Asunto(s)
Terapia por Quelación , Humanos , Femenino , Masculino , Persona de Mediana Edad , Anciano , Terapia por Quelación/métodos , Método Doble Ciego , Ácido Edético/uso terapéutico , Plomo/sangre , Plomo/orina , Cadmio/orina , Cadmio/sangre , Quelantes/uso terapéutico , Enfermedades Cardiovasculares/prevención & control , Enfermedades Cardiovasculares/sangreRESUMEN
Wilson's disease (WD) is an inherited disorder of copper metabolism in which pathological copper accumulation, mainly in the liver and the brain, leads to hepatic and/or neuropsychiatric signs and symptoms. Chelators and zinc salts can successfully induce negative copper balance in many patients; however, neurological deterioration may still be observed. This phenomenon can be divided into: (1) early 'paradoxical' neurological deterioration, which usually develops in the first 6 months of anti-copper treatment and may be commonly related to drug type, or (2) late neurological deterioration, which mostly occurs after 6 months of treatment and is often related either to non-compliance with treatment, overtreatment resulting in copper deficiency, or adverse drug reactions. Another explanation, especially for early neurological deterioration, is natural WD progression, which can be difficult to differentiate from drug-related deterioration, but usually leads to a worse outcome. There is still no consensus on how to define neurological deterioration in WD using scales or biomarkers, how to distinguish it from the natural disease progression, its risk factors, and optimal management. This narrative review, based on the current literature, aims to provide definitions, prevalence, pathological mechanisms and factors related to neurological deterioration, and also proposes schemes for diagnosis and treatment.
Asunto(s)
Cobre , Progresión de la Enfermedad , Degeneración Hepatolenticular , Degeneración Hepatolenticular/terapia , Degeneración Hepatolenticular/diagnóstico , Degeneración Hepatolenticular/metabolismo , Humanos , Cobre/metabolismo , Quelantes/uso terapéutico , Enfermedades del Sistema Nervioso/etiología , Enfermedades del Sistema Nervioso/diagnóstico , Enfermedades del Sistema Nervioso/terapia , Manejo de la EnfermedadRESUMEN
OBJECTIVE: Hepatocellular carcinoma (HCC) with portal vein thrombosis (PVT) have limited therapeutic options, Re-188 lipiodol transarterial therapy being one of them. We aimed to assess the safety and efficacy of Re-188 lipiodol exclusively in HCC with PVT as well as to compare two chelating agents for the synthesis of Re-188 lipiodol: novel bis-(diethyldithiocarbamato) nitrido (N-DEDC) with existing acetylated 4-hexadecyl 1-2,9,9-tetramethyl-4,7-diaza-1,10-decanethiol [(A)HDD]. METHODS: Patients with radiological diagnosis of HCC with PVT having Eastern Cooperative Oncology Group (ECOG) performance status ≤2 and Child Pugh score (PS) A or B were recruited. Patients received an empirical dose of transarterial Re-188 lipiodol, labelled with (A)HDD or N-DEDC. Radiological response on MRI (modified response evaluation criteria in solid tumors), biochemical response with serum alpha fetoprotein and clinical response with ECOG PS was assessed at three months and survival was estimated at the end of the study. RESULTS: Fifteen therapies were performed in 14 patients with a median age of 62 years (range: 41-70â years). Eight therapies were with Re-188 (A)HDD lipiodol and seven with Re-188 N-DEDC lipiodol. Overall mean injected dose was 2.6â ±â 0.37â GBq. Radiological objective response rate was 31% and disease control rate was 85%. Mean overall survival was 14.21 months and mean progression free survival was 10.23 months. Percentage survival assessed at 3, 6 and 9 months was 93%, 64% and 57%, respectively. Safety parameters, response and survival outcome were comparable for (A)HDD and N-DEDC groups. CONCLUSION: Transarterial Re-188 lipiodol in HCC with PVT is safe and effective in disease control as well as improving survival outcome. Additionally, cost-effective and high-yielding novel agent N-DEDC appears to be a comparable alternative to (A)HDD for the same.
Asunto(s)
Carcinoma Hepatocelular , Quelantes , Aceite Etiodizado , Neoplasias Hepáticas , Vena Porta , Trombosis de la Vena , Humanos , Carcinoma Hepatocelular/complicaciones , Carcinoma Hepatocelular/diagnóstico por imagen , Proyectos Piloto , Neoplasias Hepáticas/complicaciones , Neoplasias Hepáticas/diagnóstico por imagen , Masculino , Femenino , Vena Porta/diagnóstico por imagen , Persona de Mediana Edad , Aceite Etiodizado/uso terapéutico , Anciano , Trombosis de la Vena/diagnóstico por imagen , Trombosis de la Vena/tratamiento farmacológico , Quelantes/uso terapéutico , Quelantes/química , Radioisótopos/uso terapéutico , Adulto , Resultado del TratamientoRESUMEN
Cuproptosis has recently been identified as a novel regulatory mechanism of cell death. It is characterized by the accumulation of copper in mitochondria and its binding to acylated proteins. These characteristics lead to the downregulation of iron-sulfur cluster proteins and protein toxicity stress, ultimately resulting in cell death. Cuproptosis is distinct from other types of cell death, including necrosis, apoptosis, ferroptosis, and pyroptosis. Cu induces oxidative stress damage, protein acylation, and the oligomerization of acylated TCA cycle proteins. These processes lead to the downregulation of iron-sulfur cluster proteins and protein toxicity stress, disrupting cellular Cu homeostasis, and causing cell death. Cuproptosis plays a significant role in the development and progression of various kidney diseases such as acute kidney injury, chronic kidney disease, diabetic nephropathy, kidney transplantation, and kidney stones. On the one hand, inducers of cuproptosis, such as disulfiram (DSF), chloroquinolone, and elesclomol facilitate cuproptosis by promoting cell oxidative stress. In contrast, inhibitors of Cu chelators, such as tetraethylenepentamine and tetrathiomolybdate, relieve these diseases by inhibiting apoptosis. To summarize, cuproptosis plays a significant role in the pathogenesis of kidney disease. This review comprehensively discusses the molecular mechanisms underlying cuproptosis and its significance in kidney diseases.
Asunto(s)
Cobre , Enfermedades Renales , Humanos , Cobre/metabolismo , Cobre/toxicidad , Animales , Enfermedades Renales/metabolismo , Estrés Oxidativo , Quelantes/uso terapéutico , Quelantes/farmacología , Mitocondrias/metabolismo , Mitocondrias/efectos de los fármacosRESUMEN
ABSTRACT: Arsenic compounds are colorless and odorless and toxicity can occur either acutely following ingestion of arsenicals with gastrointestinal disturbances or due to chronic exposure usually presenting with dermatologic lesions and peripheral neuropathy. We report a young couple who presented with signs and symptoms of painful sensorimotor peripheral neuropathy in a typical "stocking and glove" pattern. They had raised urinary arsenic levels with normal blood levels and thus, a diagnosis of chronic arsenic poisoning due to contaminated water intake was made after detecting elevated arsenic levels in their home water supply. Both patients underwent chelation therapy with dimercaprol for 14 days and reported subjective and objective improvement in symptoms with the reduction in urinary arsenic levels at the end of therapy.