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Background: Tenofovir disoproxil fumarate (TDF, Viread ® ) had been used as a standard treatment option of chronic hepatitis B (CHB). This clinical trial was conducted to evaluate the efficacy and safety of DA-2802 (tenofovir disoproxil orotate) compared to TDF., Methods: The present study was a double blind randomized controlled trial. Patients with CHB were recruited from 25 hospitals in Korea and given DA-2802 at a dose of 319 mg once daily or Viread ® at a dose of 300 mg once daily for 48 weeks from March 2017 to January 2019. Change in hepatitis B virus (HBV) DNA level at week 48 after dosing compared to baseline was the primary efficacy endpoint. Secondary efficacy endpoints were proportions of subjects with undetectable HBV DNA, those with normal alanine aminotransferase (ALT) levels, and those with loss of hepatitis B envelop antigen (HBeAg), those with loss of hepatitis B surface antigen (HBsAg). Adverse events (AEs) were also investigated., Results: A total of 122 patients (DA-2802 group: n = 61, Viread ® group: n = 61) were used as full analysis set for efficacy analysis. Mean age, proportion of males, laboratory results and virologic characteristics were not different between the two groups. The change in HBV DNA level at week 48 from baseline was -5.13 ± 1.40 in the DA-2802 group and -4.97 ± 1.40 log 10 copies/mL in the Viread ® group. The analysis of primary endpoint using the nonparametric analysis of covariance showed statistically significant results ( P < 0.001), which confirmed non-inferiority of DA-2802 to Viread ® by a prespecified noninferiority margin of 1. The proportion of undetectable HBV DNA was 78.7% in the DA-2802 group and 75.4% in the Viread ® group ( P = 0.698). The proportion of subjects who had normal ALT levels was 75.4% in the DA-2802 group and 73.3% in the Viread ® group ( P = 0.795). The proportion of those with HBeAg loss was 8.1% in the DA-2802 group and 10.8% in the Viread ® group ( P = 1.000). No subject showed HBsAg loss. The frequency of AEs during treatment was similar between the two groups. Most AEs were mild to moderate in severity., Conclusion: DA-2802 is considered an effective and safe treatment for patients with CHB., Trial Registration: ClinicalTrials.gov Identifier: NCT02967939., Competing Interests: The authors have no potential conflicts of interest to disclose., (© 2022 The Korean Academy of Medical Sciences.)

Objective: To assess the efficacy and safety of Aβ-targeting agents for mild to moderate Alzheimer's disease., Methods: The MEDLINE, Embase, Cochrane Central Register of Controlled Trials, PsycINFO, ClinicalTrials.gov and the WHO's International Clinical Trials Registry Platform search portal were searched from their inception to April 2020. We generated pooled estimates using random effects meta-analyses., Results: Nineteen randomised controlled trials, of which 17 had a low risk of bias, included 12 903 participants. The meta-analysis showed no difference in the cognitive subscale of Alzheimer's Disease Assessment Scale (ADAS-Cog) between anti-Aβ drugs and placebo (mean difference (MD): 0.20, 95% CI -0.40 to 0.81; I 2 =99.8%; minimal important difference 3.1-3.8 points, moderate-certainty evidence). For ADAS-Cog, results suggested that one drug that increases Aβ clearance may differ in effect (MD: -0.96, 95% CI -0.99 to -0.92) from drugs that reduce Aβ production (MD: 0.78, 95% CI 0.25 to 1.32) (interaction p<0.000001); this difference also existed in the outcome of MMSE and CDR-SOB. Compared with placebo, anti-Aβ drug-related adverse events were as follows: anxiety, depression, diarrhoea, fatigue, rash, syncope and vomit., Discussion: From current evidence, anti-Aβ interventions are unlikely to have an important impact on slowing cognitive or functional decline. Although the subgroup analysis suggested possible benefits from Aβ clearance drugs, the analysis has limited credibility, and a benefit from drugs that increase clearance, if real, is very small., Trial Registration Number: PROSPERO registration number CRD42019126272., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Epidemiological outburst of type 2 diabetes is of great global concern. T2D starts with Insulin Resistance (IR) which arises largely due to environmental factors and to a lesser extent due to genetic factor. IR gradually develops into T2D and encompasses a wide array of conditions including Impaired Glucose Tolerance (IGT), hyperinsulinemia, Impaired Fasting Glucose (IFG), and Impaired Insulin Release (IIR). Initiation of IR increases the risk of Cardiovascular Diseases (CVD). Therefore, early diagnosis and management of IR and its related outcomes (hyperinsulinemia, hyperglycemia, and dyslipidemia) should be the prime focus of intervention therapies. Present research aimed to evaluate the synergistic combination of Magnesium orotate (MOD), Menaquinone- 7 (MK-7), and Cholecalciferol (CHOL) for the management of these therapeutic targets in the Streptozotocin-Nicotinamide-induced T2D Wistar rat model. Synergistic combination was found to be superior over its individual components in management of hyperglycemia, impaired insulin secretion, Homeostatic Model Assessment of Insulin Resistance (HOMA-IR), and dyslipidemia (p < 0.01 or p < 0.05). Its effect was found to be equivalent or better than reference drugs (p < 0.01 or p < 0.05). Histopathological analysis depicted that combination treatment was able to regenerate and preserve pancreatic β-cell mass in diabetic rats. In conclusion, combination studied in present research can be evaluated further under clinical settings for management of IR and its related outcomes.

Background: Orotic acid (OA) has been intensively utilized to induce fatty liver in rats. Although the capacity of OA to cause steatosis is species-specific, previous in vitro studies indicate that humans could also be susceptible to OA-induced fatty liver. The aim of the present study was to re-elucidate the potential of OA exposure to modulate the cellular mechanisms involved in both non-alcoholic fatty liver disease pathogenesis and cellular protection from lipid accumulation. In addition, alterations in detailed fatty acid (FA) profiles of cells and culture media were analyzed to assess the significance of lipid metabolism in these phenomena., Methods: In our experiments, human hepatocellular carcinoma HepG2 cells were exposed to OA. Bacterial endotoxin, lipopolysaccharide (LPS), was used to mimic hepatic inflammation. The lipogenic and inflammatory effects of OA and/or LPS on cells were assessed by labeling cellular lipids with Nile red stain and by performing image quantifications. The expression levels of key enzymes involved in de novo lipogenesis (DNL) and of inflammatory markers related to the disease development were studied by qRT-PCR. FA profiles of cells and culture media were determined from total lipids with gas chromatography-mass spectrometry., Results: Our data indicate that although OA possibly promotes the first stage of DNL, it does not cause a definite lipogenic transformation in HepG2 cells. Reduced proportions of 16:0, increased stearoyl-Coenzyme A desaturase 1 mRNA expression and relatively high proportions of 16:1n-7 suggest that active delta9-desaturation may limit lipogenesis and the accumulation of toxic 16:0. Inflammatory signaling could be reduced by the increased production of long-chain n-3 polyunsaturated FA (PUFA) and the active incorporation of certain FA, including 18:1n-9, into cells. In addition, increased proportions of 20:4n-6 and 22:6n-3, total PUFA and dimethyl acetal 18:0 suggest that OA exposure may cause increased secretion of lipoproteins and extracellular vesicles., Conclusions: The present data suggest that, apart from the transcription-level events reported by previous studies, modifications of FA metabolism may also be involved in the prevention of OA-mediated steatosis. Increased delta9-desaturation and secretion of lipoproteins and extracellular vesicles could offer potential mechanisms for further studies to unravel how OA-treated cells alleviate lipidosis.

Objective The objective of this study was to evaluate dental sensitivity using visual analogue scale, a Computerized Visual Analogue Scale (CoVAS) and a neurosensory analyzer (TSA II) during at-home bleaching with 10% carbamide peroxide, with and without potassium oxalate. Materials and Methods Power Bleaching 10% containing potassium oxalate was used on one maxillary hemi-arch of the 25 volunteers, and Opalescence 10% was used on the opposite hemi-arch. Bleaching agents were used daily for 3 weeks. Analysis was performed before treatment, 24 hours later, 7, 14, and 21 days after the start of the treatment, and 7 days after its conclusion. The spontaneous tooth sensitivity was evaluated using the visual analogue scale and the sensitivity caused by a continuous 0°C stimulus was analyzed using CoVAS. The cold sensation threshold was also analyzed using the TSA II. The temperatures obtained were statistically analyzed using ANOVA and Tukey's test (α=5%). Results The data obtained with the other methods were also analyzed. 24 hours, 7 and 14 days before the beginning of the treatment, over 20% of the teeth presented spontaneous sensitivity, the normal condition was restored after the end of the treatment. Regarding the cold sensation temperatures, both products sensitized the teeth (p<0.05) and no differences were detected between the products in each period (p>0.05). In addition, when they were compared using CoVAS, Power Bleaching caused the highest levels of sensitivity in all study periods, with the exception of the 14th day of treatment. Conclusion We concluded that the bleaching treatment sensitized the teeth and the product with potassium oxalate was not able to modulate tooth sensitivity.

Orotate (OA) is well-known as a precursor in biosynthesis of pyrimidines; in mammals it is released from the mitochondrial dihydroorotate dehydrogenase (DHODH) for conversion to UMP by the cytoplasmic UMP synthase enzyme. OA is also a normal part of the diet, being found in milk and dairy products, and it is converted to uridine for use in the pyrimidine salvage pathway predominantly in liver, kidney and erythrocytes. Early research into nutrition identified orotate as "vitamin B13," and its use as a complex with organic cations or metal ions was promulgated in body-building, and in assisting therapies of metabolic syndromes. It has recently been established that the amelioration of gout by dairy products arises from the competition of orotate and urate at the hURAT1 transporter. The orotic aciduria that arises in children with defective UMP synthase can be rescued by oral uridine therapy, since UMP is the end-product and also a feedback inhibitor of the de novo pathway. In contrast, Miller (dysmorphology) syndrome is connected with defects in DHODH, and hence in the supply of OA, and cannot be helped by uridine. Other models of dysmorphisms are connected with enzymes early in the pyrimidine de novo pathway. We conclude that the OA molecule is itself required for the regulation of genes that are important in the development of cells, tissues and organisms.

Aim: To make a meta-analysis of clinical trials of magnerot (magnesium orotate) used in cardiac patients., Subjects and Methods: The meta-analysis covered the data of 19 randomized trials including a total of 603 patients treated with magnerot (a case group) and 587 receiving placebo (a control group). The patients' mean age was 36 ± 19 years. On the average, the patients took magnerot 1878 ± 823 mg/day for 4.2 ± 29 months., Results: Associations between the intake of magnerot and the risk of 50 pathological conditions were analyzed. Significant associations were established between the drug's administration and the reduced risk of conditions, such as hypomagnesemia (relative risk (RR) = 0.06; 95% confidence intervals (C): 0.04 to 0.09; p = 2 · 10(-46)), exercise intolerance (RR = 0.41; 95% CI: 0.27 to 0.62; p = 0.0004), dysautonomia (RR = 0.08; 95% CI: 0.04 to 0.14; p = 2 · 10(-21)), morning headache (RR = 0.16; 95% CI: 0.09 to 0.29; p = 1.5-10(-6)), tension headache (RR = 0.16; 95% Cl: 0.09 to 0.27; p = 5 · 10(-10)), dizziness (RR = 0.28; 95% CI: 0.15 to 0.50; p = 0.0004), first-degree mitral valve prolapse (MVP) (RR = 0.05; 95% CI: 0.03 to 0.09; p = 1.2 · 10(-25)), grade 1 regurgitation (RR = 0.29; 95 CI: 0.14 to 0.60; p = 0.0075), supraventricular (RR = 0.30; 95% CI: 0.21 to 0.44; p = 1 · 10(-8)) and ventricular (RR = 0.48; 95% CI: 0.30 to 0.76; p = 0.019) premature contraction, paroxysmal supraventricular tachycardia (RR = 0.28; 95% CI: 0.15 to 0.50; p = 0.0002), and hypertension (RR = 0.32; 95% CI: 0.17 to 0.58; p = 0.0027)., Conclusion: The use of magnesium orotate is promising not only in treating MVP and compensating for hypomagnesemia, but also in preventing and treating cardiac arrhythmias, regulating blood pressure, and improving the function of the autonomic nervous system.

Orotic acid and its salts chronically administered have been shown to significantly improve cardiac function in pathological settings associated with ischemia-reperfusion (I/R) injury. The aim of our study was to investigate the effect of magnesium orotate (Mg-Or) administration at the onset of post-ischemic reperfusion on myocardial function and infarct size (IS). Ex-vivo experiments performed on isolated perfused rat hearts were used to compare Mg-Or administration with a control group (buffer treated), ischemic post-conditioning, orotic acid treatment, and MgCl2 treatment. Mg-Or administration was also investigated in an in-vivo model of regional I/R performed in rats undergoing reversible coronary ligation. The effect of Mg-Or on mitochondrial permeability transition pore (mPTP) opening after I/R was investigated in vitro to gain mechanistic insights. Both ex-vivo and in-vivo experiments showed a beneficial effect from Mg-Or administration at the onset of reperfusion on myocardial function and IS. In-vitro assays showed that Mg-Or significantly delayed mPTP opening after I/R. Our data suggest that Mg-Or administered at the very onset of reperfusion may preserve myocardial function and reduce IS. This beneficial effect may be related to a significant reduction of mPTP opening, a usual trigger of cardiac cell death following I/R.

There were analyzed the results of treatment of 574 children, suf fering anatomic anomalies of a large bowel, in whom a chronic constipation was revealed. In 61 patients the ileoceocal valve (IV) insufficiency was noted. To all the patients together with complex conservative treatment there was prescribed a preparation, containing magnesium orotat, for restoration of the IV insufficiency. In 56 (91.8%) patients conservative treatment was effective and in 5--surgical intervention was conducted as a consequence of ineffective conservative treatment. Negative correlation dependence was established between a patient age and results of treatment.

There were analyzed the results of treatment of 112 patients, suffering postoperative abdominal hernia, in whom the anterior abdominal wall alloplasty was performed as well as postoperative pathogenetically substantiated complex therapy, taking into account the presence of a connective tissue dysplasia syndrome (CTDS) and the early and late postoperative complications prophylaxis. The peculiarities of postoperative period course and late follow-up results were studied up. Phenotypic features of CTDS were revealed in 53 (47.3%) patients, immunohistochemical features of a connective tissue dysplasia (a failed collagen type I and III ratio, manifested by increase of a collagen type III fibers quantity in 3 or more times) were revealed in 78 (69.6%) patients, in whom the processes of a collagen and its supermolecular formations synthesis were stimulated, using a magnesium orotate (Magnerot), which was prescribed in 1 g dose twice a day during 4 - 6 weeks. Application of composite nets, owing big pores, in a complex with a postoperative pathogenetically substantiated therapy conduction have positively influenced the disease course and the late follow-up results achieved.

The Bcr/Abl kinase has been targeted for the treatment of chronic myelogenous leukaemia (CML) by imatinib mesylate. While imatinib has been extremely effective for chronic phase CML, blast crisis CML are often resistant. New therapeutic options are therefore needed for this fatal disease. Although more common in solid tumors, increased microvessel density was also reported in chronic myelogenous leukaemia and was associated with a significant increase of angiogenic factors, suggesting that vascularity in hematologic malignancies is a controlled process and may play a role in the leukaemogenic process thus representing an alternative therapeutic target. Carboxyamidotriazole-orotate (CTO) is the orotate salt form of carboxyamidotriazole (CAI), an orally bioavailable signal transduction inhibitor that in vitro has been shown to possess antileukaemic activities. CTO, which has a reduced toxicity, increased oral bioavailability and stronger efficacy when compared to the parental compound, was tested in this study for its ability to affect imatinib-resistant CML tumor growth in a xenograft model. The active cross talk between endothelial cells and leukemic cells in the bone marrow involving exosomes plays an important role in modulating the process of neovascularization in CML. We have thus investigated the effects of CTO on exosome-stimulated angiogenesis. Our results indicate that CTO may be effective in targeting both cancer cell growth and the tumor microenvironment, thus suggesting a potential therapeutic utility for CTO in leukaemia patients.

To test the hypothesis that co-delivery of synergistic drug combinations in the same liposome provides a better anti-tumor effect than the drugs administered in separate liposomes, fluoroorotic acid (FOA) alone and in combination with irinotecan (IRN) were encapsulated in liposomes and evaluated for their anti-tumor activity in the C26 colon carcinoma mouse model. A new chaotropic loading strategy was devised wherein FOA was dissolved in 7 M urea to increase its solubility. This enabled the passive loading of FOA into liposomes at a high concentration. IRN was remote loaded into liposomes that contained the ammonium salt of the multi-valent 1,2,3,4-butanetetracarboxylic acid with a greater than 90% efficiency and at a drug to lipid ratio of 0.2:1. When the two molecules were loaded into the same liposome, FOA was used to remote load IRN. Modulation of the drug/lipid ratio, temperature, and loading time allowed for consistent co-encapsulation of FOA+IRN at various molar ratios. The anti-tumor activity of L-FOA, L-IRN, L-FOA-IRN (5:1), and the L-FOA+L-IRN mixture (5:1) were examined in the C26 mouse model. The maximum tolerated dose of L-FOA was 10 mg/kg given weekly as compared to 100 mg/kg of the non-encapsulated FOA. Delivering two drugs in the same liposome provided a statistically better anti-tumor effect than delivering the drugs in separate liposomes at the same drug ratio. However, the synergistic activity of the 5:1 ratio of free drugs measured on C26 cells in vitro was not observed in the C26 tumor mouse model. These findings point out the challenges to the design of synergistic treatment protocols based upon results from in vitro cytotoxicity studies. L-FOA at 10 mg/kg as a single agent provided the best anti-tumor efficacy which supports previous suggestions that L-FOA has useful properties as a liposome dependent drug., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Resistance to antimalarial antifolates necessitates a search for new antimetabolites targeting other enzymes of the folate metabolic pathway. In this study, 5-fluoroorotate (FOA), reported to be an inhibitor of thymidylate synthase, was assayed against Plasmodium berghei NK 65 in mice, with(out) an oral uridine supplement. FOA (2.5 and 5.0 mg/kg bw.) was tested alone, or in a double and triple combination with a fixed oral dose of 1.25 and 2.5 mg/kg of pyrimethamine (PYR); 1.0 and 2.0 mg/kg of dapsone (DAP); 1.0 and 2.0 mg/kg of artesunate (ART). FOA achieved high suppression which ranged from 95.7% to aparasitaemic, activity that was dose-dependent. At the highest dosages used, FOA-PYR and FOA-DAP-ART combinations were synergistic with 100% cure rate, while FOA-PYR-ART was antagonistic. Drugs in a synergistic combination may exert less resistance selection pressure, thus FOA-PYR and FOA-DAP-ART warrant further evaluation with an ultimate object of possible clinical use against drug-resistant malaria.

Hypertension is a common problem in elderly patients, which usually requires chronic therapy under various physiological conditions including low gastric acidity (hypo- or anacidity). This study investigated a new salt type of amlodipine (CAS 88150-42-9) on blood pressure and hypertension-related complications in stroke-prone spontaneously hypertensive rats (SHR-SP). Amlodipine orotate was prepared by reacting orotic acid and amlodipine to increase the dissolution rate at higher gastric pH conditions. Twelve-week-old SHR-SP were randomly divided into five groups to receive either amlodipine orotate or amlodipine besylate (CAS 111470-99-6) at the doses of 3 and 10 mg/kg/day orally for four weeks. The age-matched normotensive Wistar Kyoto rats (WKY) served as the normal positive control group. The systolic blood pressure was reduced in the amlodipine treated SHR-SP in a dose-dependent manner with a similar potency irrespective of the salt type. Both amlodipines also reduced the left ventricular hypertrophy at high doses and concentration-dependently inhibited the Ca2+ induced contraction with a similar potency. Furthermore, semi-quantitative analysis of a cerebral injury revealed that the two salts of amlodipine reduced the stroke-re-lated lesions to a similar degree. These results suggest that the amlodipine orotate is effective in terms of its effects on hypertension, cardiac hypertrophy and stroke-related cerebral damage in SHR-SP.

According to results of clinical and instrumental investigation magnesium orotate (50 mg/day during first week and 25 mg/day thereafter) was found to be effective therapy of children with syndrome of cardiac connective tissue dysplasia (mainly with mitral valve prolapse and anomalous chordae tendineae).

Magnesium orotate dihydrate (MO) has the sum formula C10H6MgN4O8 x 2H2O and a MG of 370.52. The salt is poorly soluble in water and hence does not bind gastric acid nor does it exhibit noteworthy laxative effects upon oral administration in contrast to easily dissociable Mg salts. As a source of magnesium (Mg), MO is indicated for the oral treatment of extracellular Mg deficiency. Orotic acid (OA), the second active ingredient of MO, is a key intermediate in the biosynthetic pathway of pyrimidines and is shown to improve the energy status of injured myocardium by stimulating, a.o., the synthesis of glycogen and ATP. Myocardial energy-rich phosphate levels are decreased during hypoxic conditions; subsequently, intracellular Mg is depleted and lost via the urine. Since binding sites for Mg (ATP) are provided by OA it can be classified as "Mg-fixing agent". Accordingly MO is also indicated for the treatment of Mg depletion as convincingly shown in animal experiments and also in coronary heart patients undergoing e.g. aortocoronary bypass surgery.

A randomized, placebo-controlled clinical pilot study was performed in order to examine the effect of magnesium-orotate in male idiopathic infertility. Ten males were treated daily for 90 consecutive days with 3000 mg magnesium-orotate (Magnerot) tablets (Group M). As a control, ten other males were treated in the same way with placebo (Group P). Conventional microscopic sperm characteristics (sperm concentration, motility ratio, total number of motile sperm cells, normal morphology ratio), plus total and ionized magnesium levels in seminal plasma and blood serum were evaluated both prior to treatment and on day 90, at the conclusion of the study. No significant changes in sperm characteristics, blood ionized or total Mg, or ejaculate total Mg levels were detected. However, ejaculate ionized Mg levels increased in Group M from 0.18 +/- 0.05 to 0.30 +/- 0.05 (mmol/l; mean +/- SD, p < 0.05). Within the observation period of 3 months, one pregnancy occurred in the partner of a male from Group M. In conclusion, magnesium-orotate treatment at a dose of 3000 mg/day leads neither to a significant improvement of sperm variables nor does it increase the pregnancy rates of female partners of treated males as compared to those of controls. Thus, magnesium-orotate treatment was not shown to be effective therapy for idiopathic male infertility.

Volatile sulphur compounds (VSC) produced in the oral cavity, are a major cause of oral malodour. Zinc (Zn) ions inhibit VSC formation. The objective of this study was to examine whether Zn salts with low stability constants were more suitable as sources of Zn in lozenges than salts with high stability constants. The former provide free Zn ions upon dissolution in water, whereas the latter provide almost no free Zn. Identical lozenges containing Zn-acetate and -gluconate, which have low stability constants, and Zn citrate and amino acid-chelated Zn, which have extremely high stability constants, were tested. All the lozenges contained 0.9% w/w Zn. Ten volunteers sucked the lozenges until dissolved, and oral VSC were measured by gas chromatography. Zn-acetate, -gluconate and -chelate had an impressive anti-VSC effect even 3 h after the lozenges were taken. Zn citrate had significantly less effect than the other lozenges except Zn acetate after 2 and 3 h. It was concluded that the anti-VSC effect was not related to the stability constants of the Zn compounds tested. Alternative ligands. with stronger affinity for Zn than the ligands in the lozenges, must be present in the oral cavity to explain these results. It is suggested that the sulphide ion may serve this function.

The paper reviews clinical and experimental studies into the mechanisms of action of orotic acid (OA). OA has been shown to take an active participation in metabolic processes in the body. As a pyrimidine precursor, it plays a key role in the biosynthesis of nucleic acids and protein, regulates water-salt exchange, by increasing diuresis and reducing the volume of extracellular fluid. OA is also a cellular fixative of magnesium by producing pronounced antiarrhythmic, vasodulator, and cardioprotective effects. OA has ascertained to stimulate erythro- and leukopoiesis. The involvement of OA in metabolic processes explains its cardio- and neuroprotective effects. By enhancing the resistance of myocytes to ischemia, OA favourably affects the clinical course of myocardial infarction and on manifestations of heart failure. OA has been noted to have an angioprotective action and to play an important role in the energy provision of the hypertrophic myocardium, by increasing its contractility. The ability to enhance the functional reserves of the heart adapted to higher exercises accounts for its use in sportive medicine. When there are emergency emotional and vestibular stimuli, OA drugs show an antistressor actions and are effective in treating patients with borderline nervous and mental disorders. Whether OA can be used to treat gastrointestinal diseases is to be clarified.

The paper presents a complex psychophysiological analysis of the effect of a combined administration of pantogam and potassium orotate (kalii orotas) on the dynamics of cognitive function in patients with neurotic disorders. The investigation was conducted in an 8-stage consecutive cycle and employed computer-aided diagnostic system. It was established that the combined use of pantogam and potassium orotate produces a positive effect upon the dynamics of restoration of the attention and memory mechanisms in neurotic patients.

Efficiency of some drugs in the treatment of periodontitis in combination with corrective treatment of thyroid function was evaluated in 70 patients with hypo- and hyperthyrosis with different initial level of nonspecific resistance. The therapeutic complex including drugs commonly used in the treatment of periodontitis and irrigation of the periodontium with lithium chloride and chlorohexidine solutions was highly effective in patients with thyroid dysfunction and relatively favorable status of nonspecific resistance of the organism. In patients with hypo- and hyperthyrosis with poor nonspecific resistance the best effect in the treatment of periodontitis was attained with potassium orotate as an immunomodulator and lithium chloride.

There are some experimental and clinical results regarding blood vessel protective properties of magnesium orotate (CAS 27067-77-2) till now. The goal of the present investigation was to verify the therapeutical efficacy of magnesium orotate vs. its singular components in cholesterol fed rabbits. Besides, the blood-lipid concentrations (LDL as risk factor for atherosclerosis and HDL as negative risk factor) were analyzed in relation to pathomorphological changes in the aortic blood vessel wall. The results of our experiments in New Zealand rabbits support the assumption that orotic acid and especially magnesium orotate influence the lipid level and/or the LDL/HDL-quotient in a favorable way and that they decrease the interaction between monocytes/macrophages and the endothelium of the blood vessels. Consequently, the plaque formation will be decreased in a clinically relevant manner.

Aim: To assess efficiency of magnerot, magnesium orotate, in patients with idiopathic mitral prolapse (IMP)., Material and Methods: 84 patients with IMP were randomized to the study group (43 patients) and control group (41 patients). Patients of the study group received magnerot tablets (Germany) containing 500 mg of magnesium orotate (daily dose 3000 mg) for 6 months. The examination performed before the treatment and 6 months after it included: modified clinical and phenotypic records, echocardiography, 24-h ECG and AP monitoring, spectral analysis of cardiac rhythm variability, evaluation of quality of life according to Visual Analog Scale and Disability Scale and of treatment results according to Clinical Global Impression scales, measurements of magnesium in the hair by plasmic nuclear emission spectrometry, histological and histochemical skin tests., Results: IMP patients appeared to suffer from magnesium deficiency which is responsible for many symptoms in mitral prolapse. 6-month therapy with magnerot completely or partially reduced the symptoms in more than half the patients. Positive changes were registered primarily in clinicofunctional manifestations. Morphological changes in the skin correlating with the disease severity alleviated., Conclusion: Good objective and subjective response to magnerot 6-month therapy (3000 mg/day) is demonstrated.

The benefit of the treatment with magnesium orotate (magnerot) was assessed in a randomised, single blind and placebo controlled study. Respecting the inclusion criteria were selected 32 patients with ischemia chronic failure in early postoperative period after CABG. The main improvements induced by magnesium orotate are the increase in exercise capacity (distance ambulated during 6 minutes walk test and ergospirometric parameters) and the reduction of ventricular premature beats. The treatment was well tolerated and the adverse reactions were not significant. The study strongly suggests the benefit of magnesium orotate added to classical antiischemic therapy in the complex management of coronary patients after CABG.

In a pilot study at 14 patients with coronary heart disease (CHD) and left-ventricular dysfunction (left ventricular enddiastolic volume [LVEDV] > or = 100 ml), who actively participated in an ambulatory cardiac sports group, left ventricular endsystolic volume (LVESV), LVEDV and duration of exercise were analyzed by echocardiographic and ergometric tests. An initial workup was followed by a 4 week double blind treatment phase, in which magnesium orotate 3 x 1 g or placebo was given additionally to medication taken prior to the study. At the end of this phase a concluding workup was performed. Magnesium orotate decreased significantly (p = 0.016) LVESV, increased significantly (p = 0.035) EF, decreased in tendency (p = 0.054) LVEDV and increased significantly (p = 0.011) exercise duration. The study gives references to favourable effects of oral magnesium orotate to left ventricular function and exercise tolerance in patients with CHD.

The article addresses the issue of comparative efficacy of those drug preparations having hepatoprotective action (hepatofalk, ursofalk, lipin, lavalon) by parameters characterizing lipid peroxidation (LPO). The above drug preparations enhance resistance of brush membranes, lower LPO processes. It was hepatofalk and lipin that had the most pronounced positive effect on LPO processes in patients with chronic toxic and postviral hepatitis.

We studied the effects of orotic acid, a precursor of pyrimidine nucleotide, on delayed neuronal death of hippocampal CA1 neurones induced by global cerebral ischaemia in Mongolian gerbils. Neuronal damage was significantly reduced in animals treated with orotic acid 2 h before ischaemia at doses of 100, 200 or 300 mg kg-1, i.p. A dose of 300 mg kg-1 given 24 h after ischaemia also suppressed CA1 neuronal damage, but had no effect when given at 48 or 72 h. These results demonstrate a protective effect of orotic acid on ischaemic neuronal damage with a wide therapeutic time window.

Background: We have previously shown that infarction impairs recovery of global function after subsequent cardioplegic arrest and that therapy with orotic acid improves recovery. The aim of this study was to measure the effect of infarction on regional and global left ventricular function and to determine whether orotic acid exerts a beneficial effect exclusive of the effects of cardioplegia., Methods: Acute myocardial infarction was produced in dogs. They then received either orotic acid or placebo (control) orally (n = 12 per group). Fractional radial shortening and systolic wall thickening were measured by two-dimensional echocardiography before and 1 and 3 days after infarction with and without beta-adrenergic blockade, and in 6 dogs up to 9 days after infarction. Global function was measured under anesthesia 4 days after infarction., Results: In control animals, fractional radial shortening in the infarct decreased from 20.6% +/- 5.1% before infarction to 3.0% +/- 2.2% at day 1 and to 1.9% at day 3 (p < 0.01). In the border zone radial shortening declined from 21.9% +/- 3.7% to 11.0% +/- 2.3% at day 1 and 9.3% +/- 2.8% at day 3 (p < 0.05). In the noninfarcted myocardium radial shortening also declined from 27.1% +/- 1.9% before infarction to 18.3% +/- 2.3% on day 1 (p < 0.05) and to 16.0% +/- 2.8% on day 3 after infarction (p < 0.05) with recovery to preinfarct levels by 9 days after infarction. These findings were confirmed by measurements of systolic thickening. Before infarction beta-receptor blockade decreased fractional shortening in all regions of the left ventricle, but this effect was absent on day 3 after infarction, implying that the myocardium had become less responsive to beta-adrenergic stimulation. Measurements of global function 4 days after infarction showed marked depression of stroke work. There was no effect of orotic acid treatment on regional or global function., Conclusions: Myocardial infarction causes reversible depression of resting function and beta-adrenergic responsiveness in the remote and border zone areas, which is not prevented by metabolic therapy with orotic acid. This finding may explain the adverse response of the infarcted heart to cardioplegic arrest.

Heart and blood vessel diseases are one of the leading causes of death, so their prevention and therapy are very important. In the present study the effects of magnesium chloride, magnesium orotate and orotic acid were tested. New Zealand rabbits were fed with enriched (2%) cholesterol diet during 112 days; starting with day 56 all rabbits were treated with MgCl2, Mg-orotate or orotic acid (orally). Aortas, coronaries, renal and femoral arteries were removed and evaluated by morphological and morphometric methods. Atherosclerotic alterations in each vessel could be influenced moderately by Mg-chloride, quite well by orotic acid and excellently by Mg-orotate. From these results one can conclude that orotic acid and Mg-orotate have a beneficial effect in the prevention and therapy of heart and vessels diseases.

Nicergoline (NE)--a cerebral vasodilator with nicotinic acid esterified in its molecule--and Antagonic-Stress (AS) composition--a neurometabolic nootropic, also containing nicotinic acid but with fast and prolonged release--were evaluated in senile dementia of Alzheimer's type (SDAT), mild to moderate intensity (DSM-IV Options Book, 1991 and ICD-10, 1990 criteria). A double-blind, randomized, comparative, and parallel clinical trial was performed on 62 old people divided into 2 groups and exclusively treated with NE or AS. Psychogeriatric evaluations (Sandoz Clinical Assessment-Geriatric scale, Self-Assessment Scale-Geriatric and their subscales) and psychometric tests (digit symbol of WAIS, Wechsler Memory Scale, and Wechsler Adult Intelligence Scale-WAIS) were made before and after 3 months of treatment. Prolonged and large dose treatments with NE and AS significantly decreased the psychogeriatric scores, diminished the deterioration index, and improved cognitive performances (ANOVA). Therapeutical effects of AS were significantly higher than those of NE (ANCOVA). The better actions of AS in senile dementia and for improving cognitive function and behavior are discussed in connection with its multiple neurometabolic composition, the synergism of components, the antiischemic action of its antioxidants, its anti-free radical complementary action (deceleration of the aging rate, brain and erythrocyte lipofuscinolysis, complex antioxidative and scavenger formula), the multivitamin and multimineral supplementation and, finally, with the superiority of multitherapy vs. monotherapy.

Malarial parasites, in contrast to mammalian cells, utilize orotic acid more efficiently than uracil or uridine. Recently, chloroquine-susceptible and chloroquine-resistant clones of Plasmodium falciparum were shown to be inhibited by 5-fluoroorotate, with a 50% inhibitory concentration of 6 nM in vitro. Mammalian cells were far less sensitive to 5-fluoroorotate, particularly in the presence of uridine. In this report, the antimalarial activity of 5-fluoroorotate was tested in vivo. Initially, levels of 5-fluoroorotate in plasma were determined in Swiss mice injected intraperitoneally with radioactive 5-fluoroorotate. On the basis of the pharmacokinetics profile, mice infected with Plasmodium yoelii were treated with 5-fluoroorotate at a dose of 0.2 or 5 mg/kg (body weight) every 4 h for 3 days. At the nontoxic dose of 0.2 mg/kg, the reduction in parasitemia was followed by a temporary resurgence of parasitemia. This second wave of parasitemia cleared without additional 5-fluoroorotate treatment. To radically eliminate P. yoelii from mice and avoid the second wave of parasitemia, a higher dose of 5 mg of 5-fluoroorotate per kg had to be used. In the absence of uridine, repeated doses of 5 mg/kg were toxic to mice, as judged by weight loss, diarrhea, decreased numbers of leukocytes, and increased mortality. However, in the presence of uridine, repeated doses of 5 mg/kg could be used for antimalarial chemotherapy without obvious toxicity. Mice cured with 5-fluoroorotate and uridine were immune to subsequent challenge with a potentially lethal inoculum of P. yoelii.

As a result of the experimental investigation of the liver damaged with CCL4, its essential structural changes have been revealed. They resemble those specific for a chronic toxic hepatitis. Administration of potassium orothate (100 mg/kg) increases proliferative activity of hepatocytes without any essential influence on intracellular regeneration. Under conditions of a delayed differentiation and lack of resorption of an abundantly outgrowing connective tissue, this results in a more profound pathological process in the liver. Benzonal administration (50 mg/kg) facilitates structural normalization of the chronically damaged liver, owing to activation of both cellular and intracellular regeneration.

Enzyme activities in the circulating lymphocytes permit to judge the character of the regenerative process in the lung, and the severity of the patient's condition; it helps in estimating the prognosis and in evaluating the efficacy of the applied therapy. Potassium orotate and Riboxin intensify the regenerative process in the lung undergoing a compensatory-hypertrophic rearrangement, and enhance the functional activity of circulating lymphocytes as participants of the regenerative process and stimulate the oxidation-reduction processes in lymphocytes.

Four compounds, prednisolone, sodium phenobarbitone, azathioprine and orotic acid, were tested for their ability to inhibit galactosamine induced hepatitis in the rat. Prednisolone offered total protection at doses of 100 mg/kg and above; sodium phenobarbitone and orotic acid modified the response to galactosamine and azathioprine was without effect.

The efficacy of potassium orotate (200 mg/kg), hyperbaric oxygenation (3 at. abs, totally six 50-minute sessions) and their combinations was studied in experiments on 150 rabbits. According to polarography, analysis of the level of nucleic acids and pathomorphological changes, the best effect can be achieved by combined use of potassium orotate and hyperbaric oxygenation. However, even under these circumstances the cardiac activity is not completely recovered on day 14 after the treatment is commenced.

A study was made of the radioprotective and therapeutic effect of potassium orotate on rats subjected to whole-body gamma-irradiated with doses of 11, 9 and 4 Gy. The preparation exerted a radioprotective action when administered intraperitoneally 60 min before irradiation as was estimated with a reference to the survival rate and leukocyte level in the peripheral blood. Fron the analysis of the peripheral blood consumption it was inferred that potassium orotate weakened the radiation damage and enhanced the recovery processes during the postirradiation period.