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BACKGROUND: Obsessive-compulsive disorder (OCD) is often challenging to treat and resistant to psychological interventions and prescribed medications. The adjunctive use of nutraceuticals with potential neuromodulatory effects on underpinning pathways such as the glutamatergic and serotonergic systems is one novel approach. OBJECTIVE: To assess the effectiveness and safety of a purpose-formulated combination of nutraceuticals in treating OCD: N-acetyl cysteine, L-theanine, zinc, magnesium, pyridoxal-5' phosphate, and selenium. METHODS: A 20-week open label proof-of-concept study was undertaken involving 28 participants with treatment-resistant DSM-5-diagnosed OCD, during 2017 to 2020. The primary outcome measure was the Yale-Brown Obsessive-Compulsive Scale (YBOCS), administered every 4 weeks. RESULTS: An intention-to-treat analysis revealed an estimated mean reduction across time (baseline to week-20) on the YBOCS total score of -7.13 (95% confidence interval = -9.24, -5.01), with a mean reduction of -1.21 points per post-baseline visit (P ≤ .001). At 20-weeks, 23% of the participants were considered "responders" (YBOCS ≥35% reduction and "very much" or "much improved" on the Clinical Global Impression-Improvement scale). Statistically significant improvements were also revealed on all secondary outcomes (eg, mood, anxiety, and quality of life). Notably, treatment response on OCD outcome scales (eg, YBOCS) was greatest in those with lower baseline symptom levels, while response was limited in those with relatively more severe OCD. CONCLUSIONS: While this pilot study lacks placebo-control, the significant time effect in this treatment-resistant OCD population is encouraging and suggests potential utility especially for those with lower symptom levels. Our findings need to be confirmed or refuted via a follow-up placebo-controlled study.

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Vanadium compounds can exert anticancer effects, partly due to inhibition of tyrosine phosphatases. Here, we report the effect of N,N'-ethylenebis (pyridoxylideneiminato) vanadium (IV) complex (Pyr2 enV(IV)), that induced 93% and 57% of cell mortality in A375 (human melanoma) and A549 (human lung carcinoma) cells, respectively; the mortality was <24% in other cancer cell lines and in human normal epidermal keratinocytes, lung cells and peripheral blood mononuclear cells. The mechanism of Pyr2 enV(IV) effect relied on apoptosis induction; this was triggered by ROS increase, followed by mitochondrial membrane depolarization. Indeed, the addition of N-acetyl cysteine to cell cultures abated Pyr2 enV(IV)-induced apoptosis. These results disclose the pro-apoptotic activity of Pyr2 enV(IV) and its mechanism, relying on intracellular ROS increase.

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The risk of cardiotoxicity is the main drawback of anthracycline antibiotics. However, these drugs remain among the most effective and frequently used anti cancer drugs. In this study we aimed to assess the cardioprotective effects of aroylhydrazone iron (FE) chelators: pyridoxal isonicotinoyl hydrazone (PIH) and its two analogs: salicyladehyde isonicotinoyl hydrazone (SIH) and pyridoxal o-chlorbenzoyl hydrazone (o-108). In rabbits, chronic treatment with daunorubicin (DAU) (3 mg/kg weekly for 10 weeks) induced mortality (33%) as well as left ventricular (LV) dysfunction. Co-administrations of PIH (25 mg/kg, i.p.), SIH hydrochloride [1 mg/kg, iv] as well as o-108 (10 mg/kg, i.p.), fully prevented premature deaths and most of the DAU-induced functional impairments were significantly suppressed. However, when 2- to 2.5-fold higher doses of the chelators were used, they led to rather paradoxical and mostly negative results regarding both cardioprotection and overall mortality.

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Aminoguanidine inhibits the formation of advanced glycation end-products, and has been extensively examined in animals. However, administration of aminoguanidine decreases the hepatic content of pyridoxal phosphate. In order to avoid this problem, we developed an aminoguanidine pyridoxal Schiff base adduct and examined its efficacy in vitro as well as in a model of diabetic nephropathy. Mice with streptozotocin-induced diabetes were treated with aminoguanidine or aminoguanidine pyridoxal adduct for 9 weeks. An in vitro study was also performed to assess the antioxidant activity of aminoguanidine and its pyridoxal adduct. Neither drug altered glycemic control. Aminoguanidine pyridoxal adduct significantly improved urinary albumin excretion by 78.1 % compared with the diabetic control, and also had a better preventive effect on the progression of renal pathology than aminoguanidine did. Inhibition of glycation by both drugs was similar, but the antioxidant activity of the pyridoxal adduct was far superior. These findings suggest that aminoguanidine pyridoxal adduct may be superior to aminoguanidine, as it not only prevents vitamin B6 deficiency but is also better at controlling diabetic nephropathy, as this adduct inhibits oxidation as well as glycation.

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The success of DFO at markedly inhibiting the growth of aggressive tumors such as neuroblastoma and leukemia justifies interest in the development of chelators as anti-neoplastic agents. This is emphasized by the fact that DFO has suboptimal properties, namely poor membrane permeability and a very short serum half-life. More recently, the thiosemicarbazone chelator, Triapine, has entered a phase I clinical trial again confirming the potential of these compounds. Further studies examining the effects of chelators on neoplastic cells will not only be valuable in terms of identifing novel anti-cancer agents, but will also provide new information on the role of Fe in cell cycle control.

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Previously, in monkeys undergoing 20 min whole brain ischemia we demonstrated that the activated calpain-induced lysosomal disruption with the resultant leakage of cathepsins B and L, causes neuronal death in the cornu Ammonis (CA) 1 sector on day 5. Selective cathepsin inhibitors significantly protected ischemic CA1 neurons from delayed necrosis. Recently, pyridoxal phosphate (PLP) and pyridoxal (hydrochloride) (PL) were demonstrated to inhibit cathepsins B and L in vitro, because the active aldehyde at position 4 of the pyridine ring has an affinity for the active site -SH of cysteine residues of cathepsins. Here, we studied whether PLP and PL can, in vivo, protect monkey CA1 neurons from ischemic insult. In monkeys undergoing 20 min whole brain ischemia, 15 mg/kg body weight/day of drugs were intravenously injected for 10 days before and after the ischemic insult. Histological analysis of the surviving CA1 neurons was done using the hippocampus resected on day 5 after ischemia. For PLP or PL, approximately 17% (P = 0.0639) or 54% (P < 0.0001) of the total population (100%) of control CA1 neurons were, respectively, saved from the ischemia-induced neuronal death, showing a remarkable contrast to the surviving neurons (approximately 3.9%) in non-treated monkeys. These data suggested that PL (perhaps PLP intracellularly) is useful as a novel neuroprotectant in primates.

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Cancer cells have a high requirement for iron (Fe) as it plays a crucial role in a variety of metabolic processes including energy production and DNA synthesis. Studies in vitro and in vivo have demonstrated that the Fe chelator in current clinical use, desferrioxamine (DFO), can effectively inhibit the growth of some neoplasms, including leukemia and neuroblastoma. Unfortunately, DFO suffers from a number of serious disadvantages, including its high cost, the need for prolonged subcutaneous infusion (12-24 h/day, 5-6 nights/week), and its poor intestinal absorption precluding oral administration. Hence, the development of more effective Fe chelators is necessary. The Fe chelator, pyridoxal isonicotinoyl hydrazone (PIH), was initially identified as a ligand that showed high activity at mobilizing Fe from cells. More recently, a range of PIH analogues have been examined for their anti-proliferative effect, with several classes of these compounds showing high activity at inhibiting tumor growth in vitro. In fact, some of these hydrazones, particularly those derived from 2-hydroxy-1-naphthylaldehyde, showed comparable activity to the cytotoxic drugs cis-platin and bleomycin. In this review the role of Fe in cellular proliferation will be examined followed by a description of the most recent studies using the PIH analogues as effective anti-proliferative agents. Further studies in vivo with these Fe chelators are essential to determine their potential as chemotherapeutic agents.

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At present, the only iron (Fe) chelator in clinical use for the treatment of Fe overload disease is the tris-hydroxamate deferoxamine (DFO). However, DFO suffers from a number of disadvantages, including the need for subcutaneous infusion (12 to 24 hours a day, 5 or 6 times per week), its poor intestinal absorption, and high cost. Therefore, there is an urgent need for an efficient, economical, and orally effective Fe chelator. Pyridoxal isonicotinoyl hydrazone (PIH) is a tridentate Fe-chelating agent that shows high Fe chelation efficacy both in vitro in cell culture models and also in vivo in rats and mice. In addition, this chelator is relatively nontoxic, economical to synthesize, and orally effective, and it shows high selectivity and affinity for Fe. However, over the last 10 years the development of PIH and its analogs has largely been ignored because of justifiable interest in other ligands such as 1,2-dimethyl-3-hydroxypyrid-4-one (L1). Unfortunately, recent clinical trials have shown that significant complications occur with L1 therapy, and it is controversial whether this chelator is effective at reducing hepatic Fe levels in patients. Because of the current lack of a clinically useful Fe chelator to replace DFO, PIH and its analogs appear to be potential candidate compounds that warrant further investigation. In this review we will discuss the studies that have been performed to characterize these chelators at the chemical and biologic levels as effective agents for treating Fe overload. The evidence from the literature suggests that these ligands deserve further careful investigation as potential orally effective Fe chelators.

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The newborn retina is particularly sensitive and frequently subjected to peroxidative stresses that result in visual sequelae. We compared two iron chelators, deferoxamine and a newer compound, pyridoxal isonicotinoyl hydrazone (PIH), in protecting the retina of newborn pigs (1-3 d old) from asphyxia-reoxygenation insults. Animals were treated IV with either saline, deferoxamine 15.2 mumol/kg (10 mg/kg) or PIH 34.8 mumol/kg (10 mg/kg); n = 10 in each treatment group. Scotopic and photopic electroretinograms (ERG) were recorded before and 40 min after drug treatment as well as 45 min following a 5-min period of asphyxia by interrupting ventilation. In separate animals the indices of peroxidation, malondialdehyde (MDA: TBARS) and hydroperoxides, were measured in retina at the same times. In saline-treated animals, there was a marked increase in MDA and hydroperoxide concentrations in the retina following the asphyxia-reoxygenation period. This was associated with a decrease in the a- (photoreceptor generated) and b-wave (generated by Müller and bipolar cells) amplitudes measured under photopic (cone-mediated response) and scotopic (rod-mediated response) conditions, and an increase in their implicit times. PIH and deferoxamine prevented the postasphyxial increase in MDA and hydroperoxides. However, only PIH prevented the postasphyxial changes in a- and b-wave amplitudes and implicit times, whereas deferoxamine markedly altered the preasphyxial ERG and provided only partial postasphyxial protection simply to the retinal outer segment. Our findings indicate that the iron chelator PIH effectively inhibits peroxidation and retinal electrophysiological alterations secondary to asphyxia-reoxygenation-induced oxidative stresses to newborn animals, whereas deferoxamine adversely affects retinal function; hence, PIH may be a preferred alternative to deferoxamine.

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We have demonstrated, using confocal laser scanning microscopy, that pyridoxal treatment of B16C3 murine melanoma cells inhibits triamcinolone acetonide induced translocation of the glucocorticoid receptor to the nucleus of intact cells. In addition to inhibiting glucocorticoid receptor nuclear translocation, pyridoxal kills B16C3 murine melanoma cells and WM983A human melanoma cells in culture. Cortexolone, a glucocorticoid antagonist, also kills cells in culture. This mechanism, however, appears to initiate in the glucocorticoid receptor signal transducing cascade at a point prior to the impact of pyridoxal treatment alone. The glucocorticoid antagonist RU486 has no detrimental effect on melanoma cell viability, however, in combination with pyridoxal, RU486 extends cell viability. Since pyridoxal kills melanoma cells in culture, a pilot study was carried out examining the efficacy of topical application of a pyridoxal cream to inhibit the growth and/or cause regression of (B16C3) xenograft melanoma tumors in an immunocompetent (Hairless Rhino-J3) and an immunocompromised (Crl: nu/nu (CD1)BR) murine animal model. The results of the study with immunocompetent animals are encouraging. While tumors are brought under control by pyridoxal treatment, further work is needed to determine the most efficacious treatment regimen and to establish formal concentrations for pyridoxal in topical ointments. Trials using immunocompromised animals indicated that although some qualitative differences may be detected between the control and experimental animals, tumor growth in these animals is so aggressive that multiple applications or higher concentrations of pyridoxal may be needed to obtain useful data.

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In the course of three experiments it was established that all the toxic effects of a lethal dose of Albizia versicolor pods (greater than 4.5 g/kg) in guinea-pigs could be countered by concurrent subcutaneous injection of pyridoxine (10 mg/kg). This treatment was also successful once severe symptoms had set in. Pyridoxal, on the other hand, was found to be ineffective as a therapeutic agent. The fact that pyridoxal does not counter the action of the toxin indicates an atypical site of action by the toxin as regards the normal pathways which require vitamin B6 as a co-factor.

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Formation constants for the calcium(II), magnesium(II) and zinc(II) complexes of the orally effective iron chelator, pyridoxal isonicotinoyl hydrazone (PIH) and three analogues, pyridoxal benzoyl hydrazone (PBH), pyridoxal p-methoxybenzoyl hydrazone (PpMBH) and pyridoxal m-fluorobenzoyl hydrazone (PmFBH) have been determined by potentiometry at 25 degrees C and I = 0.1 M [KNO3]. The four ligands bind calcium(II) weakly and magnesium(II) only slightly more strongly, as a 1:1 complex which is formed at pH greater than 8. The chelation of zinc(II) for all the ligands studied was greater than that for calcium(II) and magnesium(II), with complexation generally becoming significant at about pH 5. Thus, chelation of zinc(II) but not calcium(II) or magnesium(II) at physiological pH, 7.4 may be expected. Calculated values of the concentration of uncomplexed metal ion indicate that the selectivity of these ligands towards Fe(III) is comparable to that of the clinically used chelator desferrioxamine.

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Fifteen compounds reported to be inhibitors of gelation or sickling were studied by standard methods. These tests included (1) the determination of the solubility of deoxyhemoglobin S or Csat, (2) evaluation of sickling in whole SS blood at various pO2s, (3) measurement of the oxygen affinity of hemoglobin and blood, and (4) examination of red cell indices and morphology. Among the 4 noncovalent agents tested, butylurea was the most potent inhibitor of gelation and sickling in vitro; however, relatively high concentrations were required compared to the covalent agents. In the latter group, bis-(3,5 dibromosalicyl)-fumarate, nitrogen mustard, and dimethyladipimidate were especially effective inhibitors of gelation and/or sickling. All of these compounds require further development before they can be considered for clinical use.

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Iron chelation therapy for patients maintained on a regular transfusion regime is at present best carried out by means of daily infusions of desferrioxamine (Hussain et al 1977; Pippard et al 1978) but this is onerous for the patient and has social and economic disadvantages. Many recent attempts to provide more effective drugs for iron chelation have been summarized by Jacobs (1979) and increasing attention is now being paid to the possibility of oral iron chelation therapy. Hoy et al (1979) showed that when isonicotinic acid hydrazide (INH) and pyridoxal are mixed in equimolar amounts a hydrazone is formed which chelates iron, and oral administration of this compound to rats results in an eightfold increase in faecal iron excretion. It is effective on repeated administration (Cikrt et al 1980), the main route of iron excretion being through the bile. Long term studies in the rat have not been successful in reducing the iron load of test animals and this appears to be related both to their high dietary iron content and instability of the hydrazone. Its effective shelf life at room temperature is no longer than one month and this is a considerable disadvantage from a therapeutic point of view. Pyridoxal is known to form a Schiff base with many amino acids and its reactivity has led us to examine complexes of pyridoxal with a number of substances in an attempt to find an alternative iron chelator of greater stability than the INH complex and of comparable effectiveness on oral administration. The screening procedures used were the effects on Chang cell iron metabolism (White et al 1976) and on iron excretion in the rat (Hoy et al 1979).

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The animal assay of potential new iron-chelating agents is at present dependent on cumbersome and imprecise iron balance studies in hypertransfused rodents. We report the development of a radioisotope assay in intact rats based on the transient labeling by ferritin 59Fe of the main source of chelatable iron within hepatocytes. The isotope was maximally available to chelators during the first 6 hr after its injection, nearly all the excretion being in the bile. The bile 59Fe/total iron ratio was independent of both the chelator and its dose. However, in iron-loaded rats, the ratio was reduced, and the isotope excretion was a less sensitive measure of intrahepatic chelation. In the proposed assay, test chelators were given to normal rats 2 hr after an intravenous injection of 59Fe-ferritin. Four hours later, the radioiron in the liver and in the gut gave a sensitive measure of the mobilization of hepatic iron to the bile. In addition, chemical iron determinations identified a small alternative source of urinary chelate with agents known to promote urine excretion in man. The assay gave a rapid and precise screen for chelators given by parenteral and oral routes.

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To test the antisickling activity of pyridoxal, we compared the oxygen affinity and the percent sickling at low PO2 of untreated erythrocytes with values for cells from the same blood sample incubated with pyridoxal, glyceraldehyde, or pyridoxine. Pyridoxal increased oxygen affinity much more than glyceraldehyde. 20 mM pyridoxal and glyceraldehyde had equivalent antisickling activity. At PO2 levels above 20 mm Hg, both agents reduced sickling to less than 2%. In samples examined by electron microscopy, pyridoxal reduced the percent sickled cells and the percent cells that contain hemoglobin S fibers by the same amount (from 74 to 3%). Pyridoxine had no effect on oxygen affinity or sockling. Pyridoxal reacts with intracellular hemoglobin to increase oxygen affinity, which inhibits hemoglobin S polymerization and sickling.

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5'-Deoxypyridoxal, which reacts specifically with the terminal amino groups of the alpha chains of hemoglobin, increases the oxygen affinity of hemoglobin solutions as well as of dilute suspensions of normal and sickle red cells and whole blood. As a result, the proportion of deoxyhemoglobin (which is responsible for sickling) is decreased at venous oxygen tensions and this is reflected by a sharply reduced sickle cell count in this range of oxygen pressures.

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