Chelation Therapy Associated with Antioxidant Supplementation Can Decrease Oxidative Stress and Inflammation in Multiple Sclerosis: Preliminary Results.

An imbalance of oxy-inflammation status has been involved in axonal damage and demyelination in multiple sclerosis (MS). The aim of this study was to investigate the efficacy of an antioxidant treatment (calcium disodium ethylenediaminetetracetic acid-EDTA) chelation therapy associated with a micronutrient complex in MS patients. A total of 20 MS patients and 20 healthy subjects, enrolled as a control group (CTR), were recruited. We measured the plasma ROS production and total antioxidant capacity (TAC) by a direct assessment using Electron Paramagnetic Resonance; activities of the antioxidant system (thiols' redox status and enzymes); and the urinary presence of biomarkers of oxidative stress by immunoenzymatic assays. We also evaluated the levels of inflammation by plasmatic cytokines (TNFα, IL-1ß, and IL-6) and assessed the sICAM levels, as well as the nitric oxide (NO) catabolism and transthyretin (TTR) concentration. Comparing CTR and MS, in the latter ROS production, oxidative damage, inflammatory biomarkers, and NO metabolite concentrations results were significantly higher, while TAC was significantly lower. Treatment in MS induced significant (p < 0.05) down-regulating of pro-inflammatory sICAM1, TNF-α, IL6, as well as biomarkers of lipid peroxidation and DNA damage production. The protective effect exhibited may occur by decreasing ROS production and increasing antioxidant capacity, turning into a more reduced thiols' status.

Neuron Protection by EDTA May Explain the Successful Outcomes of Toxic Metal Chelation Therapy in Neurodegenerative Diseases.

Many mechanisms have been related to the etiopathogenesis of neurodegenerative diseases (NDs) such as multiple sclerosis, amyotrophic lateral sclerosis, Parkinson's disease, and Alzheimer's disease. In this context, the detrimental role of environmental agents has also been highlighted. Studies focused on the role of toxic metals in the pathogenesis of ND demonstrate the efficacy of treatment with the chelating agent calcium disodium ethylenediaminetetraacetic acid (EDTA) in eliminating toxic metal burden in all ND patients, improving their symptoms. Lead, cadmium, aluminum, nickel, and mercury were the most important toxic metals detected in these patients. Here, I provide an updated review on the damage to neurons promoted by toxic metals and on the impact of EDTA chelation therapy in ND patients, along with the clinical description of a representative case.

EDTA Chelation Therapy in the Treatment of Neurodegenerative Diseases: An Update.

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.

EDTA Chelation Therapy for the Treatment of Neurotoxicity.

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.

Defibrotide in the treatment of hepatic veno-occlusive disease.

Hepatic veno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome (SOS), represents the most frequent complication in patients in early phase following hematopoietic stem-cell transplantation (HSCT). In its severe form, VOD/SOS can be associated with multiorgan failure and with a mortality rate >80% by day +100. Defibrotide (DF) (a mixture of 90% single-stranded phosphodiester oligonucleotides and 10% double-stranded phosphodiester oligonucleotides derived from controlled depolarization of porcine intestinal mucosal DNA) has been proposed for the treatment of SOS due to its ability to restore thrombo-fibrinolytic balance and protect endothelial cells. The present review highlights why the mechanisms of action of DF allow its successful use in the prevention and treatment of SOS following HSCT.

Rationale for the Successful Management of EDTA Chelation Therapy in Human Burden by Toxic Metals.

Exposure to environmental and occupational toxicants is responsible for adverse effects on human health. Chelation therapy is the only procedure able to remove toxic metals from human organs and tissue, aiming to treat damage related to acute and/or chronic intoxication. The present review focuses on the most recent evidence of the successful use of the chelating agent ethylenediaminetetraacetic acid (EDTA). Assessment of toxic-metal presence in humans, as well as the rationale of EDTA therapy in cardiovascular and neurodegenerative diseases, is reported.

Efficacy of chelation therapy to remove aluminium intoxication.

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.

Aluminium involvement in neurotoxicity.

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.

Improvement of oxidative and metabolic parameters by cellfood administration in patients affected by neurodegenerative diseases on chelation treatment.

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.

A case of multiple sclerosis improvement following removal of heavy metal intoxication: lessons learnt from Matteo's case.

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.

Ozonated autohemotherapy: protection of kidneys from ischemia in rats subjected to unilateral nephrectomy.

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.

Mn bioavailability by polarized Caco-2 cells: comparison between Mn gluconate and Mn oxyprolinate.

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.

Metal chelation therapy in rheumathoid arthritis: a case report. Successful management of rheumathoid arthritis by metal chelation therapy.

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.

Purinoceptors in inflammation: potential as anti-inflammatory therapeutic targets.

Purinergic receptors or purinoceptors are expressed in many mammalian cells and are activated by extracellular purines (adenine, purine nucleotides and nucleosides). Both adenosine (P1) and nucleotide/nucleoside (P2, grouped in P2X and P2Y subtypes) receptors exert important role in the inflammatory processes. The significative up-regulation of many purinoceptors located on the immune cells (neutrophils, eosinophils, monocytes, macrophages, mast cells and lymphocytes) in the course of inflammatory diseases supports the interpretation of their functions. New insights into the involvement of purinoceptors also in the neuro-inflammatory diseases (e.g. conditions of chronic inflammation associated with neurodegenerative diseases) are proposed. The identification of antagonists of purinergic receptors potentially useful to control inflammatory pathways represents the object of many studies reported in the recent literature. Aim of this review is to recapitulate the most recent data and experimental findings that highlight the critical, double edge, effect of these receptors in inflammation, making consistent the possibility to target them to control and regulate inflammation.

The usefulness of chelation therapy for the remission of symptoms caused by previous treatment with mercury-containing pharmaceuticals: a case report.

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.

Rationale of the combined use of inspiratory and expiratory devices in improving maximal inspiratory pressure and maximal expiratory pressure of patients with chronic obstructive pulmonary disease.

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.

Unexpected perinatal loss versus Sids-a common neuropathologic entity.

OBJECTIVE: To evaluate the involvement of alterations of the central autonomic nervous system, particularly of the brainstem and cerebellum, in a wide set of victims of sudden and unexplained perinatal and infant death. MATERIAL AND METHODS: The study population consisted of 63 stillbirths, 28 neonatal deaths and 140 suspected SIDS. The victims were subjected to in-depth anatomopathological examination following appropriate guidelines. The protocol included, in particular, the histological evaluation on serial sections of the cardiorespiratory autonomic nervous system. RESULTS: A diagnosis of "unexplained death" was established for 217 of the 231 victims (59 stillbirths, 28 newborns and 130 SIDS). In a very high percentage of these deaths (84%) we observed one or more anomalies of the nuclei and/or structures of the brainstem and cerebellum related to vital functions. CONCLUSION: Unexpected perinatal loss should not be regarded as a separate entity from SIDS, given the common neuropathological substrates.

Cracked mercury dental amalgam as a possible cause of fever of unknown origin: a case report.

INTRODUCTION: Sudden fever of unknown origin is quite a common emergency and may lead to hospitalization. A rise in body temperature can be caused by infectious diseases and by other types of medical condition. This case report is of a woman who had fever at night for several days and other clinical signs which were likely related to cracked dental mercury amalgam. CASE PRESENTATION: A healthy women developed fever many days after had cracked a mercury dental amalgam filling. Blood tests evidenced increased erythrocyte sedimentation rate, anemia and elevated white cell count; symptoms were headache and palpitations. Blood tests and symptoms normalized within three weeks of removal of the dental amalgam. CONCLUSION: This case highlights the possible link between mercury vapor exposure from cracked dental amalgam and early activation of the immune system leading to fever of unknown origin.

The vasostatin-I fragment of chromogranin A inhibits VEGF-induced endothelial cell proliferation and migration.

UNLABELLED: A growing body of evidence suggests that chromogranin A (CgA), a secretory protein released by many neuroendocrine cells and frequently used as a diagnostic and prognostic serum marker for a range of neuroendocrine tumors, is a precursor of several bioactive fragments. This work was undertaken to assess whether the N-terminal fragment CgA(1-76) (called vasostatin I) can inhibit the proangiogenic activity of vascular endothelial growth factor (VEGF), a factor involved in tumor growth. The effect of recombinant human vasostatin I (VS-1) on VEGF-induced human umbilical endothelial cells (HUVEC) signaling, proliferation, migration, and organization has been investigated. We have found that VS-1 (3 microg/ml; 330 nM) can inhibit VEGF-induced ERK phosphorylation, as well as cell migration, proliferation, morphogenesis, and invasion of collagen gels in various in vitro assays. In addition, VS-1 could inhibit the formation of capillary-like structures in Matrigel plugs in a rat model. VS-1 could also inhibit basal ERK phosphorylation and motility of HUVEC, leading to a more quiescent state in the absence of VEGF, without inducing apoptotic or necrotic effects. CONCLUSION: These findings suggest that vasostatin I may play a novel role as a regulator of endothelial cell function and homeostasis.