RESUMO
We have previously described the role played by toxic-metal burdens in the etiology of neurodegenerative diseases (ND). We herein report an updated evaluation of toxic-metal burdens in human subjects affected or not affected by ND or other chronic diseases. Each subject underwent a chelation test with the chelating agent calcium disodium ethylenediaminetetraacetic acid (CaNA2EDTA or EDTA) to identify the presence of 20 toxic metals in urine samples using inductively coupled plasma mass spectrometry. Our results show the constant presence of toxic metals, such as lead, cadmium, cesium, and aluminum, in all examined subjects but the absence of beryllium and tellurium. Gadolinium was detected in patients undergoing diagnostic magnetic resonance imaging. The presence of toxic metals was always significantly more elevated in ND patients than in healthy controls. Treatment with EDTA chelation therapy removes toxic-metal burdens and improves patient symptoms.
RESUMO
Neurotoxicity can be caused by numerous direct agents, of which toxic metals, organophosphorus pesticides, air pollution, radiation and electromagnetic fields, neurotoxins, chemotherapeutic and anesthetic drugs, and pathogens are the most important. Other indirect causes of neurotoxicity are cytokine and/or reactive oxygen species production and adoptive immunotherapy. The development of neurodegenerative diseases has been associated with neurotoxicity. Which arms are useful to prevent or eliminate neurotoxicity? The chelating agent calcium disodium ethylenediaminetetraacetic acid (EDTA)-previously used to treat cardiovascular diseases-is known to be useful for the treatment of neurodegenerative diseases. This review describes how EDTA functions as a therapeutic agent for these diseases. Some case studies are reported to confirm our findings.
Assuntos
Terapia por Quelação , Ácido Edético/uso terapêutico , Síndromes Neurotóxicas/tratamento farmacológico , Animais , Humanos , Resultado do TratamentoRESUMO
There is a distinct correlation between aluminium (Al) intoxication and neurodegenerative diseases (ND). We demonstrated how patients affected by ND showing Al intoxication benefit from short-term treatment with calcium disodium ethylene diamine tetraacetic acid (EDTA) (chelation therapy). Such therapy further improved through daily treatment with the antioxidant Cellfood. In the present study we examined the efficacy of long-term treatment, using both EDTA and Cellfood. Slow intravenous treatment with the chelating agent EDTA (2 g/10 mL diluted in 500 mL physiological saline administered in 2 h) (chelation test) removed Al, which was detected (using inductively coupled plasma mass spectrometry) in urine samples collected from patients over 12 h. Patients that revealed Al intoxication (expressed in µg per g creatinine) underwent EDTA chelation therapy once a week for ten weeks, then once every two weeks for a further six or twelve months. At the end of treatment (a total of 22 or 34 chelation therapies, respectively), associated with daily assumption of Cellfood, Al levels in the urine samples were analysed. In addition, the following blood parameters were determined: homocysteine, vitamin B12, and folate, as well as the oxidative status e.g. reactive oxygen species (ROS), total antioxidant capacity (TAC), oxidized LDL (oxLDL), and glutathione. Our results showed that Al intoxication reduced significantly following EDTA and Cellfood treatment, and clinical symptoms improved. After treatment, ROS, oxLDL, and homocysteine decreased significantly, whereas vitamin B12, folate and TAC improved significantly. In conclusion, our data show the efficacy of chelation therapy associated with Cellfood in subjects affected by Al intoxication who have developed ND.
Assuntos
Alumínio/intoxicação , Terapia por Quelação/efeitos adversos , Síndromes Neurotóxicas/tratamento farmacológico , Adolescente , Adulto , Idoso , Alumínio/sangue , Alumínio/urina , Aminoácidos/efeitos adversos , Aminoácidos/uso terapêutico , Terapia Enzimática , Enzimas/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Minerais/efeitos adversos , Minerais/uso terapêutico , Síndromes Neurotóxicas/etiologia , Sulfatos/efeitos adversos , Sulfatos/uso terapêuticoRESUMO
The aetiology of neurodegenerative diseases (ND) seems to involve susceptibility genes and environmental factors. Toxic metals are considered major environmental pollutants. Following our study of a case of multiple sclerosis (MS) improvement due to removal of aluminium (Al) and other toxic metals, we have examined the possible relationship between Al intoxication and ND. We used the slow intravenous treatment with the chelating agent EDTA (calcium disodium ethylene diamine tetraacetic acid) (chelation test) to remove Al and detected it in the urine collected from the patients for 12 hours. Patients affected by MS represented 85.6% of total ND. Al was present in 44.8% of cases comprehensive of ND and healthy patients. Al levels were significantly higher in ND patients than in healthy subjects. We here show that treatment of patients affected by Al burden with ten EDTA chelation therapies (EDTA intravenous administration once a week) was able to significantly reduce Al intoxication.
Assuntos
Alumínio/toxicidade , Alumínio/urina , Quelantes/uso terapêutico , Terapia por Quelação/métodos , Esclerose Múltipla/tratamento farmacológico , Doenças Neurodegenerativas/tratamento farmacológico , Adolescente , Adulto , Idoso , Alumínio/isolamento & purificação , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neurotoxinas/isolamento & purificação , Neurotoxinas/toxicidade , Neurotoxinas/urina , Resultado do Tratamento , Adulto JovemRESUMO
OBJECTIVE: This prospective pilot study aimed at evaluating the effects of therapy with antioxidant compounds (Cellfood, and other antioxidants) on patients affected by neurodegenerative diseases (ND), who displayed toxic metal burden and were subjected to chelation treatment with the chelating agent calcium disodium ethylenediaminetetraacetic acid (CaNa2EDTA or EDTA). METHODS: Two groups of subjects were studied: (a) 39 patients affected by ND and (b) 11 subjects unaffected by ND (controls). The following blood parameters were analyzed before and after three months' treatment with chelation+Cellfood or chelation+other antioxidants: oxidative status (reactive oxygen species, ROS; total antioxidant capacity, TAC; oxidized LDL, oxLDL; glutathione), homocysteine, vitamin B12, and folate. RESULTS: After 3-months' chelation+Cellfood administration oxLDL decreased, ROS levels were significantly lower, and TAC and glutathione levels were significantly higher than after chelation+other antioxidants treatment, both in ND patients and in controls. Moreover, homocysteine metabolism had also improved in both groups. CONCLUSIONS: Chelation+Cellfood treatment was more efficient than chelation+other antioxidants improving oxidative status and homocysteine metabolism significantly in ND patients and controls. Although limited to a small number of cases, this study showed how helpful antioxidant treatment with Cellfood was in improving the subjects' metabolic conditions.
Assuntos
Aminoácidos/farmacologia , Antioxidantes/análise , Quelantes/uso terapêutico , Enzimas/farmacologia , Minerais/farmacologia , Doenças Neurodegenerativas , Sulfatos/farmacologia , Aminoácidos/administração & dosagem , Antioxidantes/metabolismo , Colesterol/sangue , Enzimas/administração & dosagem , Glutationa/sangue , Humanos , Lipoproteínas/sangue , Minerais/administração & dosagem , Doenças Neurodegenerativas/sangue , Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neurodegenerativas/metabolismo , Projetos Piloto , Estudos Prospectivos , Espécies Reativas de Oxigênio/sangue , Sulfatos/administração & dosagemRESUMO
Multiple sclerosis (MS) is a chronic progressive disease of the central nervous system (CNS) provoking disability and neurological symptoms. The exact causes of SM are unknown, even if it is characterized by focal inflammatory lesions in CNS accompanied by autoimmune reaction against myelin. Indeed, many drugs able to modulate the immune response of patients have been used to treat MS. More recently, toxic metals have been proposed as possible causes of neurodegenerative diseases. The objective of this study is to investigate in vivo the impact of heavy metal intoxication in MS progression. We studied the case of a patient affected by MS, who has been unsuccessfully treated for some years with current therapies. We examined his levels of toxic heavy metals in the urine, following intravenous "challenge" with the chelating agent calcium disodium ethylene diamine tetraacetic acid (EDTA).The patient displayed elevated levels of aluminium, lead and mercury in the urine. Indeed, he was subjected to treatment with EDTA twice a month. Under treatment, the patient revealed in time improved symptoms suggestive of MS remission. The clinical data correlated with the reduction of heavy metal levels in the urine to normal range values. Our case report suggests that levels of toxic metals can be tested in patients affected by neurodegenerative diseases as MS.
Assuntos
Quelantes/uso terapêutico , Metais Pesados/metabolismo , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/metabolismo , Adulto , Ácido Edético , Humanos , Masculino , Adulto JovemRESUMO
BACKGROUND: Ozonated autohemotherapy (OA) has been previously successfully used in the treatment of patients affected by peripheral occlusive arterial disease. OA consists of an intrafemoral reinfusion of autologous blood previously exposed to a mixture of oxygen/ozone (O2/O3). This study analyzes the effects of OA in protecting rat kidney from ischemia and ischemia/reperfusion damage. METHODS: We performed OA 30 min before the induction of 60 min renal ischemia or at the induction of 60 min postischemic reperfusion in rats subjected to unilateral nephrectomy. In addition, to evidence the possible protection induced by O2/O3 on endothelial functions, the present study analyzes the in vitro effects of O2/O3 on oxygen consumption by human umbilical vein endothelial cells (HUVEC). RESULTS: 1) OA preserves rat kidney functions and architecture, as demonstrated by the improved levels of serum creatinine and blood urea nitrogen and by histology; 2) such protection does not correlate with the increase of plasmatic nitric oxide, but is compatible with a focal renal increase of renal ßNADPH-diaphorase; 3) treatment of HUVEC with O2/O3 significantly increases both the rate of oxygen consumption and the mitochondrial activity assessed by confocal microscopy. CONCLUSION: The preservation of the mitochondrial activity of endothelium could in vivo limit the endothelial dysfunction provoked by the Isc or Isc/R processes.
Assuntos
Transfusão de Sangue Autóloga/métodos , Rim/irrigação sanguínea , Rim/fisiopatologia , Nefrectomia/efeitos adversos , Ozônio/administração & dosagem , Traumatismo por Reperfusão/prevenção & controle , Traumatismo por Reperfusão/fisiopatologia , Animais , Infusões Intra-Arteriais , Rim/efeitos dos fármacos , Masculino , Ratos , Ratos Wistar , Traumatismo por Reperfusão/etiologia , Resultado do TratamentoRESUMO
BACKGROUND: Micronutrient inadequate intake is responsible of pathological deficiencies and there is a need of assessing the effectiveness of metal supplementation, frequently proposed to rebalance poor diets. Manganese (Mn) is present in many enzymatic intracellular systems crucial for the regulation of cell metabolism, and is contained in commercially available metal supplements. METHODS: We compared the effects of two different commercial Mn forms, gluconate (MnGluc) and oxyprolinate (MnOxP). For this purpose we used the polarized Caco-2 cells cultured on transwell filters, an established in vitro model of intestinal epithelium. Since micronutrient deficiency may accelerate mitochondrial efficiency, the mitochondrial response of these cells, in the presence of MnGluc and MnOxP, by microscopy methods and by ATP luminescence assay was used. RESULTS: In the presence of both MnOxP and MnGluc a sustained mitochondrial activity was shown by mitoTraker labeling (indicative of mitochondrial respiration), but ATP intracellular content remained comparable to untreated cells only in the presence of MnOxP. In addition MnOxP transiently up-regulated the antioxidant enzyme Mn superoxide dismutase more efficiently than MnGluc. Both metal treatments preserved NADH and ßNADPH diaphorase oxidative activity, avoided mitochondrial dysfunction, as assessed by the absence of a sustained phosphoERK activation, and were able to maintain cell viability. CONCLUSIONS: Collectively, our data indicate that MnOxP and MnGluc, and primarily the former, produce a moderate and safe modification of Caco-2 cell metabolism, by activating positive enzymatic mechanisms, thus could contribute to long-term maintenance of cell homeostasis.
Assuntos
Gluconatos/farmacocinética , Manganês/farmacocinética , Disponibilidade Biológica , Células CACO-2 , Dieta , Humanos , Mucosa Intestinal/citologia , Micronutrientes/deficiência , Microscopia Confocal , Mitocôndrias/metabolismoRESUMO
Toxic metals are involved in the pathogenesis of some neurodegenerative and vascular diseases and are known to impair the immune system functions. We report here the case of a patient affected by heavy metal intoxication, who had developed an autoimmune disease. There was evidence of aluminium, cadmium and lead intoxication in a 63-year old Italian woman affected by rheumatoid arthritis (RA). We treated the patient with calcium disodium edetate (EDTA) once a week for a year in order to remove traces of heavy metal intoxication. Oxidative status profile was carried out at the beginning and after 6 months' EDTA chelation. At the end of the treatment, the patient did not show any signs of metal intoxication, RA symptoms and oxidative status improved.
Assuntos
Artrite Reumatoide/induzido quimicamente , Artrite Reumatoide/tratamento farmacológico , Quelantes/uso terapêutico , Terapia por Quelação/métodos , Ácido Edético/uso terapêutico , Metais Pesados/toxicidade , Artrite Reumatoide/patologia , Quelantes/química , Gerenciamento Clínico , Ácido Edético/química , Feminino , Humanos , Metais Pesados/química , Metais Pesados/urina , Pessoa de Meia-Idade , Estresse OxidativoRESUMO
INTRODUCTION: A great deal of data regarding the toxicology of mercury has been recently reported. Although the most common human exposures to mercury are currently mercury vapour from amalgam tooth fillings, methylmercury from seafood and ethylmercury as a preservative in vaccines, in the past mercury compounds have been used in the treatment of syphilis. CASE PRESENTATION: Mercury intoxication was found in a 67 year-old Italian man affected by neurological symptoms of apparently unknown origin. The patient developed syphilis forty years ago and then underwent therapy with mercurials to treat his chronic bacterial infection. We treated the patient with disodium edetate chelation therapy. Six months after the beginning of the therapy, the patient's neurological symptoms began to decrease, and were completely cured after two years of therapy. CONCLUSION: This case supports the use of chelation therapy with disodium edetate to remove damages caused by mercury intoxication.
RESUMO
OBJECTIVE: To examine the rationale of the combined use of a new expiratory device in association with a previously assessed inspiratory device in improving 3 indicators of the respiratory muscle strength, for example, maximal inspiratory pressure (MIP), maximal expiratory pressure (MEP), and dyspnea grade. DESIGN: Randomized trial. SETTING: Home-based pulmonary rehabilitation. PARTICIPANTS: Adults (N=32; mean age, 68y). MAIN OUTCOME MEASURE: We instructed 32 patients with mild to very severe COPD to use the devices, and randomized them in a 1:1 ratio: they were assigned to the sham training control group (16 patients who trained at a load not able to improve MIP and MEP) or to the training group (16 patients). The patients trained at home twice daily for 15 minutes, 7 days a week, for 12 months. MIP and MEP as well as dyspnea perception were evaluated at 1, 6, and 12 months from the beginning of the training. The impact of additional work of breathing was measured at baseline and after the use of the expiratory device. RESULTS: The patients who performed the respiratory training showed significant and progressive improvements of MIP (81+/-4 at 12 months vs 57+/-7 as basal values expressed in cm H2O; P<.05) and MEP (97+/-2 at 12 months vs 62+/-4 as basal values; P<.05) at the end of the training. In addition, they showed a significant reduction of dyspnea perception (1.18+/-0.29 vs 2.93+/-0.32 as basal values; P<.05) at the end of the training. CONCLUSIONS: This study suggests that home exercise with the combined use of our expiratory and inspiratory devices leads to a significant improvement of respiratory muscle function in patients with mild to very severe COPD.
Assuntos
Exercícios Respiratórios , Expiração , Inalação , Doença Pulmonar Obstrutiva Crônica/reabilitação , Músculos Respiratórios/fisiopatologia , Idoso , Equipamentos e Provisões , Feminino , Humanos , Masculino , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Testes de Função RespiratóriaRESUMO
BACKGROUND: Chelation therapy with sodium edetate (EDTA) improved renal function and slowed the progression of renal insufficiency in patients subjected to lead intoxication. This study was performed to identify the underlying mechanism of the ability of EDTA treatment to protect kidneys from damage. METHODS: The effects of EDTA administration were studied in a rat model of acute renal failure induced by 60 minutes ischemia followed or not by 60 minutes reperfusion. Renal ischemic damage was evaluated by histological studies and by functional studies, namely serum creatinine and blood urea nitrogen levels. Treatment with EDTA was performed 30 minutes before the induction of ischemia. Polymorphonuclear cell (PMN) adhesion capability, plasmatic nitric oxide (NO) levels and endothelial NO synthase (eNOS) renal expression were studied as well as the EDTA protection from the TNFalpha-induced vascular leakage in the kidneys. Data was compared by two-way analysis of variance followed by a post hoc test. RESULTS: EDTA administration resulted in the preservation of both functional and histological parameters of rat kidneys. PMN obtained from peripheral blood of EDTA-treated ischemized rats, displayed a significant reduction in the expression of the adhesion molecule Mac-1 with respect to controls. NO was significantly increased by EDTA administration and eNOS expression was higher and more diffuse in kidneys of rats treated with EDTA than in the controls. Finally, EDTA administration was able to prevent in vivo the TNFalpha-induced vascular leakage in the kidneys. CONCLUSION: This data provides evidence that EDTA treatment is able to protect rat kidneys from ischemic damage possibly through the stimulation of NO production.
Assuntos
Quelantes/farmacologia , Ácido Edético/farmacologia , Isquemia/prevenção & controle , Rim/irrigação sanguínea , Rim/efeitos dos fármacos , Injúria Renal Aguda/tratamento farmacológico , Injúria Renal Aguda/fisiopatologia , Injúria Renal Aguda/prevenção & controle , Animais , Nitrogênio da Ureia Sanguínea , Permeabilidade Capilar/efeitos dos fármacos , Permeabilidade Capilar/fisiologia , Adesão Celular/fisiologia , Quelantes/uso terapêutico , Creatinina/sangue , Modelos Animais de Doenças , Progressão da Doença , Ácido Edético/uso terapêutico , Hemodinâmica/efeitos dos fármacos , Hemodinâmica/fisiologia , Isquemia/tratamento farmacológico , Isquemia/fisiopatologia , Rim/química , Rim/patologia , Antígeno de Macrófago 1/análise , Masculino , Neutrófilos/química , Neutrófilos/patologia , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo III/análise , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/fisiopatologia , Traumatismo por Reperfusão/prevenção & controle , Fator de Necrose Tumoral alfa/farmacologiaRESUMO
BACKGROUND: We previously showed that local use of periodate oxidized ATP (oATP, a selective inhibitor of P2X7 receptors for ATP) in rat paw treated with Freund's adjuvant induced a significant reduction of hyperalgesia Herein we investigate the role of oATP, in the rat paws inflamed by carrageenan, which mimics acute inflammation in humans. RESULTS: Local, oral or intravenous administration of a single dose of oATP significantly reduced thermal hyperalgesia in hind paws of rats for 24 hours, and such effect was greater than that induced by diclofenac or indomethacin. Following oATP treatment, the expression of the pro-inflammatory chemokines interferon-gamma-inducible protein-10 (IP-10), mon ocyte chemoattractant protein-1 (MCP-1) and interleukin-8 (IL-8) within the inflamed tissues markedly decreased on vessels and infiltrated cells. In parallel, the immunohistochemical findings showed an impairment, with respect to the untreated rats, in P2X7 expression, mainly on nerves and vessels close to the site of inflammation. Finally, oATP treatment significantly reduced the presence of infiltrating inflammatory macrophages in the paw tissue. CONCLUSION: Taken together these results clearly show that oATP reduces carrageenan-induced inflammation in rats.
Assuntos
Trifosfato de Adenosina/análogos & derivados , Analgésicos não Narcóticos/uso terapêutico , Anti-Inflamatórios não Esteroides/uso terapêutico , Quimiocinas/biossíntese , Hiperalgesia/tratamento farmacológico , Trifosfato de Adenosina/administração & dosagem , Trifosfato de Adenosina/farmacologia , Trifosfato de Adenosina/fisiologia , Trifosfato de Adenosina/uso terapêutico , Administração Cutânea , Administração Oral , Analgésicos não Narcóticos/administração & dosagem , Analgésicos não Narcóticos/farmacologia , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/farmacologia , Carragenina/toxicidade , Quimiocina CCL2/biossíntese , Quimiocina CCL2/genética , Quimiocina CXCL10 , Quimiocinas/genética , Quimiocinas CXC/biossíntese , Quimiocinas CXC/genética , Diclofenaco/administração & dosagem , Diclofenaco/uso terapêutico , Modelos Animais de Doenças , Membro Posterior , Temperatura Alta , Hiperalgesia/induzido quimicamente , Hiperalgesia/etiologia , Indometacina/administração & dosagem , Indometacina/uso terapêutico , Injeções Intravenosas , Interleucina-8/biossíntese , Interleucina-8/genética , Macrófagos/efeitos dos fármacos , Masculino , Antagonistas do Receptor Purinérgico P2 , Ratos , Ratos Wistar , Receptores Purinérgicos P2/biossíntese , Receptores Purinérgicos P2/genética , Receptores Purinérgicos P2X7 , Método Simples-CegoRESUMO
OBJECTIVE: Oxidized ATP (oATP) is a selective inhibitor of the P2Z/P2X7 ATP receptor for extracellular ATP, which contributes to the antinociceptive effect. This study sought to determine the mechanism by which local administration of oATP is able to relieve inflammatory pain in arthritic rat paws. METHODS: Arthritis was induced in Wistar rats by injections of Freund's complete adjuvant into one hind paw. Nociceptive thresholds were measured before and after local injection of oATP into the inflamed paws. The influence on pain transmission due to the presence of recruited inflammatory cells at the site of inflammation was determined by inhibiting the initial phase of their migration (by intravenous treatment with fucoidin, which blocks the adhesion molecules of the selectin family). ATP intraplantar content was determined in the different experimental conditions. Histologic features of the hind paws were evaluated by using the anti-P2X7 receptor polyclonal antibody. RESULTS: Intraplantar administration of oATP into inflamed paws significantly relieved inflammatory pain. The antinociceptive effect of oATP was independent of the immune-cell recruitment. ATP levels in inflamed tissues were significantly reduced by oATP treatment. A variable presence of P2X7 receptors on cutaneous sensory nerves with respect to the different treatments was observed. Following oATP treatment, there was a reduction in P2X7 expression in the endings of peripheral nerves, as well as in endothelial cells. CONCLUSION: Oxidized ATP inhibits inflammatory pain in arthritic rats by inhibition of the P2X7 receptor for ATP, which is localized on nerve terminals.
Assuntos
Trifosfato de Adenosina/análogos & derivados , Trifosfato de Adenosina/uso terapêutico , Artrite/tratamento farmacológico , Artrite/fisiopatologia , Dor/fisiopatologia , Antagonistas do Receptor Purinérgico P2 , Trifosfato de Adenosina/administração & dosagem , Trifosfato de Adenosina/metabolismo , Administração Tópica , Analgésicos/uso terapêutico , Animais , Artrite/metabolismo , Artrite/patologia , Edema/tratamento farmacológico , Pé , Membro Posterior , Sistema Imunitário/fisiopatologia , Imuno-Histoquímica , Masculino , Cuidados Paliativos , Ratos , Ratos Wistar , Receptores Purinérgicos P2X7 , Tela Subcutânea/metabolismoRESUMO
The neurotransmitter adenosine triphosphate (ATP) is released from sensory nerve endings during inflammation and acts at the level of P2X receptors. We used the irreversible inhibitor of P2z/P2X7 receptor, designated oxidized ATP (oATP), to test its possible antinociceptive activity in arthritic rats. We induced unilateral inflammation of the rat hind paw by local injection of Freund's complete adjuvant. Administration of the adjuvant resulted in a significant reduction of paw pressure threshold (PPT). Injection of oATP into inflamed paws significantly increased, in a dose-dependent manner, PPT values to levels comparable with or higher than those evaluated in control uninflamed paws. The data indicate that the P2z/P2X7 receptor system exerts a role in nociception and that oATP, by inhibiting such a receptor, reduces the nociceptive signal in the course of peripheral inflammation.