[Experimental evidence of magnesium salts for treatment of calcium oxalate nephrolithiasis in an animal model based on sodium oxalate and a cyclooxygenase 2 selective inhibitor].

The purpose of present study was to investigate influence of magnesium (Mg) salts (Mg L-aspartate, Mg chloride) and their combinations with pyridoxine on development of calcium-oxalate nephrolithiasis induced by sodium oxalate (3% diet weight) and celecoxib (100 mg per kg of bodyweight) according to B.C. Jeong et al. (Urol. Res. 2005; 33(6): 453-459). On 14th day of diet urinary oxalate level and crystalluria were significantly increased, creatinine clearance tended to be lower as compared to control group. Mg L-aspartate, Mg chloride and their combinations with pyridoxine, MagneB6 (Mg lactate in combination with pyridoxine) and Mg sulfate were given by intragastric intubation from 15th till 28th days of diet (50 mg Mg per kg body weight). On 28th day urinary oxalate level in rats treated with Mg salts was lower by in average 45%, creatinine clearance was increased by 19%, Ca/Mg ratio decreased by 1.5-2 times in comparison with animals fed with diet alone. Light microscopic examination of kidney sections have revealed decreased inclusion volume fraction of renal calcification in rats treated with Mg salts as to compare with untreated rats receiving sodium oxalate and celecoxib (0.3-1.0% vs. 4%). So, Mg salts prevented development of calcium-oxalate nephrolithiasis in hyperoxaluric rats. Morphological and laboratory tests showed Mg aspartate and magne B6 were more effective Mg-containing substances in comparison with other studied salts.

[The effectiveness of certain magnesium salts in nephrolithiasis caused by the use of sodium oxalate and celecoxib].

The study was aimed to evaluation the effect of different magnesium salts and their combinations with pyridoxine on a course of calcium-oxalate nephrolithiasis, which was modeled by adding the sodium oxalate (3% of weight of the diet) and selective cyclooxygenase-2 inhibitor celecoxib at a dose 100 mg/kg body weight to a diet for 4 weeks. Starting from the 2nd week of the experiment, the animals had received one of the following compounds: magnesium L-aspartate, magnesium chloride, and their combination with vitamin B6; magnesium sulfate and Magne B6 (magnesium lactate and vitamin B6) as comparators. 28 days after the start of the experiment, disorders progressed in the group receiving only celecoxib and oxalate-rich diet: the urine level of oxalate increased by 171% (p < 0,0001), crystalluria had increased (up to 105 crystals in 10 microml of urinary sediment, p < 0,0001), creatinine clearance decreased by 29%, compared to control (p = 0,087). Increasing calcium/magnesium and oxalate/creatinine ratios in urine by 16 and 189%, respectively, was observed. In the renal parenchyma of animals treated with sodium oxalate and celebrex, calcifications with a volume fraction of 4% were identified, whereas these changes were absent in intact animals. According to the degree of correction ofhyperoxaluria and elimination of calcium oxalate crystals, investigated salts showed similar efficacy, with the exception of magnesium sulfate, which less contributed the compensation of abnormalities in kidney and urinary. According to the data of morphological study, the volume fraction of calcifications was lowest in the groups receiving magnesium L-aspartate and Magne B6.

[Structure and physiological role of NHE1 and pharmacological regulation of its activity].

This article summarizes results of preclinical and clinical trials concerning the effects of NHE1 inhibitors and prospects for their clinical application. NHE1 has been identified as the most abundant isoform of Na+/H+ exchanger in the heart of mammals. NHE1 regulates pH homeostasis, cell proliferation, migration, adhesion, and apoptosis. Ischemic activation of the NHE1 in myocardium results in intracellular calcium overload, which aggravates ischemic/reperfusion injury. In accordance with results of preclinical experimental studies, selective inhibition of the sarcolemmal NHE1 can delay progression of injury during ischemia, thereby reducing myocardial necrosis and improving recovery of ventricular function upon reperfusion. Inhibitors of NHE1, which can provide beneficial effect in the clinical treatment of these conditions, are currently under preclinical and clinical tests. At present, there are 481 NHE inhibitors known according to the Thomson Reuters Integrity database.

[Correction of isoproterenol-induced myocardial injury with magnesium salts in magnesium-deficient rats].

The effect of Mg L-asparaginate (Mg-L-Asp), Mg chloride (MgCl2) and Mg sulfate (MgSO4) on the severity of isoproterenol-induced myocardial injury in Mg-deficient rats has been evaluated. To induce Mg deficiency, twenty-eight rats were placed on a low Mg diet (Mg content < 15 mg/kg) and demineralized water for 10 weeks. Twelve control rats were fed a basal control diet (Mg content = 500 mg/kg) and water (with Mg content 20 mg/l) for equal duration. On day 49 of low Mg diet, Mg-deficient rats were randomly divided into four groups: 1) group that continued to receive low Mg diet; 2) low Mg diet plus oral MgSO4; 3) low Mg diet plus oral Mg-L-Asp and 4) low Mg diet plus oral MgCl2 (50 mg of Mg per kg of body weight). Isoproterenol was injected subcutaneously (30 mg/kg BW, twice, at an interval of 24 hours) on the day 70 of the study, when plasma and erythrocyte Mg level in rats fed a low Mg diet were significantly decreased by 47% and 45% compared to intact animals. Twenty-four hours after second injection of isoproterenol, tests for activities of creatine kinase (CK), lactate dehydrogenase (LDH) and aspartate aminotransferase (AST) were run and histopathological study was carried out. Administration of isoproterenol to rats resulted in significantly elevated plasma CK, LDH and AST, however analyses in Mg deficient group demonstrated more dramatically increased activity of CK and AST compared to control rats (3,06 and 4,67 fold in Mg-deficient group vs. 1,91 and 3,92 fold in intact group). Increased leakage of cardiac injury markers was concomitant to increased volume of fuchsinophilic cardiomyocytes (54.2 +/- 1.7% in Mg-deficient group and 38.9 +/- 1.9% in intact group, p < 0.05). However, pretreatment with of MgCl2, MgSO4 and Mg-L-Asp during 21 days favorably decreased sensitivity of myocardium to isoproterenol-induced ischemic injury. All evaluated salts significantly decreased myocyte marker enzymes as well as protected myocardium against isoproterenol-induced histopathological perturbations.

[Functional reserves of the heart under conditions of alimentary magnesium deficit].

Aim of the study was to assess functional reserves of myocardium in animals with deficit of magnesium during stress tests. Magnesium deficit was modeled by 10 week long magnesium deficient diet. After 54% lowering of magnesium level in erythrocytes we registered left ventricular pressure, myocardial contraction and relaxation rates, heart rate, systolic and diastolic arterial pressure, intensity of structures functioning. Than we subjected hearts of these animals to volume load, graded stimulation of cardiac adrenoreceptors, maximal isometric load by clamping ascending aorta. In animals with magnesium deficit we noted smaller increases of left ventricular pressure, myocardial contraction and relaxation rates under conditions of all functional tests, and of systolic arterial pressure during loading with volume and adrenaline. Lowering of myocardial reactivity under conditions of volume and adrenaline loading as well as isometric work load could constitute a basis of genesis of heart failure in magnesium deficit.

[Effects of magnesium salts on the course of experimental calcium-oxalate urolithiasis].

Experimental urolithiasis was induced in 80 white non-inbred male rats by adding 0.75% ethylene glycol and 2% ammonium chloride to drinking water by Fan et al. After significant differences in crystalluria, oxaluria and urine pH were achieved in hyperoxaluric rats vs controls one, hyperoxaluric rats were given magnesium (Mg) salts Mg chloride, Mg L-aspartate either alone or in combination with pyridoxine hydrochloride (B6) in comparison with Mg sulfate and magne B6 (mg lactate in combination with B6) in a dose of 50 mg of elementary Mg per 1 kg of body weight. All the rats were fed with Mg-adequate diet containing 0.84 g of Mg oxide (0.5 g of elementary Mg per kg of diet). Calcium-oxalate urolithiasis has developed in rats taking ethylene glycol and ammonium chloride for 28 days. An urinary oxalates levels increased threefold, oxalate/creatinine--fourfold. Calcium oxalate crystals were detected in the urine of rats drinking solution of ethylene glycol and ammonium chloride, pH decreased by 20%, fractional excretion (FE) of Mg increased by 60%, FE of phosphate--by 58.2%, FE of calcium--by 95.8%, creatinine clearance lowered by 39.2% in comparison with intact group. Magnesium salts administration resulted in reduction of urine oxalates, crystalluria, phosphate excretion, Ca/Mg and oxalate/creatinine ratios, increased urine pH and creatinine clearance. Mg L-aspartate in combination with vitamin B6 appeared the most effective salt and significantly more effective than magnesium sulfate.

Correction of furosemide-induced magnesium deficiency with different stereoisomers of organic magnesium salts: a comparative study.

We compared the efficiency of different stereoisomers of organic magnesium salts (Mg DL-, Mg D-, and Mg L-aspartate and Mg L- and Mg DL-glutamate) after oral administration under conditions of furosemide-induced magnesium deficiency. The time to complete compensation of erythrocyte magnesium level was 5 days for Mg L-aspartate, 10 and 8 days for Mg L-glutamate and Mg D-aspartate, respectively, and 11 days for Mg DL-aspartate and Mg DL-glutamate. These findings attest to better bioavailability of Mg complex with L-stereoisomer of aspartate in comparison with DL and D-stereoisomers and stereoisomers of Mg glutamate.

[Pharmacological correction of pain sensitivity threshold in magnesium deficiency].

The purpose of this study was to compare effect of: Mg L-aspartate and MgCl2 alone and in combination with pyridoxine (B6) on hyperalgesia in rats fed with Mg-deficient diet. To induce hypomagnesemia, two hundred rats were placed on a Mg-deficient diet (MP Biomedicals Inc., OH) and demineralized water. To evaluate pain sensitivity, motor and vocalization threshold in response to a mechanical stimulus (Randall-Selitto paw pressure test) and tail withdrawal, simple and brief vocalization threshold in response to an electrical stimulation (algesimetry by electrical stimulation of the tail through intracutaneous needles) were assessed. In our study Mg deficiency results in reduced vocalization threshold by 42% in response to a mechanical stimulus. Thresholds of motor tail response, simple vocalization and brief vocalization after discharge in response to an electrical stimulation were decreased by 32.5%, 20.5% and 23.8%. Oral magnesium salts led to normalization of thresholds of pain sensitivity with a return to pre-deficient levels. Magnesium salts in combinations with pyridoxine tended to be significantly more effective in Randall-Selitto paw pressure test as compared with salts without pyridoxine. The effect of studied salts was comparable with those observed in Magne B6 treatment and significantly higher than in magnesium sulfate treatment.

[Comparative study of magnesium salts bioavailability in rats fed a magnesium-deficient diet].

The purpose of this study was to compare efficiency of compensation of alimentary Mg deficiency after administration of 12 organic and 8 inorganic magnesium salts and to evaluate the ability of vitamin B6 to accelerate their effect. Two hundred eighty rats were placed on a Mg-deficient diet (Mg content (15 mg/kg) and demineralized water for 7 weeks. Twelve control rats were fed a basal diet (Mg content 500 mg/kg). Starting from day 49 of the Mg-deficient diet, the rats were given magnesium salts (50 mg magnesium and 5 mg pyridoxine per kg): Mg chloride, Mg sulphate, Mg oxide, M nitrate, Mg thiosulphate, Mg hydrophosphate, Mg carbonate, Mg trisilicate, Mg (L-, D- and DL-) aspartate, Mg (L- and DL-) pyroglutamate, Mg succinate, Mg glycinate, Mg orotate, Mg taurate, Mg lactate or their combination with vitamin B6 (5 mg/kg b.w.). Erythrocyte and plasma Mg levels were measured by spectrophotometry following the colour reaction between Mg and titanium yellow. Mg L-aspartate compensated for magnesium deficit more effectively and faster than all other salts. Mg chloride showed the highest efficiency among inorganic magnesium salts. Both Mg chloride and Mg L-aspartate in combination with vitamin B6 caused statistically significant compensation of magnesium deficit.

[Effects of mangesium salts and their combinations with vitamin B6 on oxalates crystalluria in rats fed with pyridoxine-deficient diet].

We studied the effects of oral magnesium (Mg) salts either alone or in combination with pyridoxine hydrochloride in rats on pyridoxine-deficient diet. Fifty-four male rats were randomized into two groups and were fed either a standard diet or a pyridoxine-deficient diet for 3 weeks. A significant rise of the EGOT index ( > 1.5), oxaluria (from 74.8 +/- 5.2 to 117.9 +/- 12.3 mcM/l, p = 0.035), and crystalluria in rats fed with pyridoxine deficient diet were revealed. Oral Mg chloride, Mg L-aspartate either alone or in combination with pyridoxine in comparison with magnesium sulfate, magne B6 (Mg lactate with pyridoxine) and pyridoxine alone were administered (50 mg of magnesium and/or 5 mg of pyridoxine per kg body weight). Magnesium salts in combination with pyridoxine lowered an oxalate level and crystalluria whereas magnesium salts alone reduced only crystalluria. Antilithis effects of Mg L-aspartate and Mg chloride in combination with pyridoxine were comparable with those observed in magne B6 or pyridoxine treatment and were significantly higher than in magnesium sulfate treatment.

Features of central neurotransmission in animals in conditions of dietary magnesium deficiency and after its correction.

Magnesium is important in the regulation of neurotransmitter metabolism and the modulation of receptor function in the CNS, including neurotransmitters and receptors involved in the pathogenesis of many mental disorders. The aim of the present work was to perform a pharmacological evaluation of the central mechanisms of action of magnesium salts in the clofelin, phenamine, arecoline, nicotine, apomorphine, and 5-hydroxytryptophan tests in conditions of dietary magnesium deficiency. After reaching the magnesium deficiency state, animals were given oral (via tube) magnesium L-asparaginate and magnesium chloride lone and in combination with vitamin B(6), as well as the reference agent Magne B6. Our assessments of phenamine stereotypy in magnesium-deficient animals showed reductions in the latent period by an average of 14.89% and a significant increase in the duration of phenamine stereotypy by an average of 19.44% (from 268.23 +/- 8.17 to 320.36 +/- 19.90 min) as compared with intact rats. Studies of hyperkinesia induced by 5-hydroxytryptophan showed a two-fold reduction in its extent in the magnesium-deficient group (p

[Depression-like and anxiety-related behaviour of rats fed with magnesium-deficient diet].

The aims of this study were to estimate of psychomotor activity, emotional status and magnesium (Mg) content in blood of rats fed with Mg-deficient diet for 49 days; and to find out whether the combination of vitamin B6 with Mg will reveal antidepressant- and anxiolytic-like activity and reduce the length of the treatment needed to recover rats from Mg-deficient condition. To induce hypomagnesemia, seventy-nine rats were placed on a Mg-deficient diet (Mg content < or = 15 mg/kg) and demineralized water for 7 weeks. Eight control rats were fed a basal control diet. On the forty-ninth day of Mg-deficient diet, rats were treated one of the six supplementations: Mg L-aspartate alone and in combination with pyridoxine, MgCl2 x 6H2O alone and in combination with pyridoxine, Magne B6 (Mg lactate with pyridoxine) and Mg sulfate (50 mg Mg and 5 mg vitamin B6 per kg). In our study Mg-deficiency was associated with depleted intraerythrocytic (0.748 +/- 0.036 vs. 1.83 +/- 0.026 mmol/l, p < 0.001) and plasma (0.567 +/- 0.029 vs. 1.20 +/- 0.030 mmol/l, p < 0.001) Mg level compared to control rats. It was shown Mg deficiency resulted in depression-like and anxiety-related behavior in rats. Open field test result in rats including locomotor activity (number of crossed squares) and vertical activity (number of standing on hind paws), number of visiting in central squares were decreased significantly. In the elevated plus maze test, the number of visiting open arms (by 63.6%) and residence time (by 78.5%) of rats were significantly less as compared with the control group. In the forced swimming test, time immobile was significantly increased (by 70.2%) and time of swimming was decreased (by 15%) compared to control. Mg salts alone and in combination with vitamin B6 administered to Mg-deficient rats increased the Mg level in plasma and erythrocytes. Furthermore, this increase was in relation to vitamin B6 given to the animal. It was established, that the application of Mg L-aspartate and MgCl2 x 6H2O in combinations with pyridoxine led to correction of behavioural disturbances of Mg-deficient animals. Antidepressant- and anxiolytic-like activity of studied salts was comparable with those observed in Magne B6 treatment and significantly higher than in Mg sulfate treatment.

[The characterization of central neuromediation in rats fed with magnesium-deprived diet before and after magnesium replenishment].

Magnesium (Mg) has been proposed to take part in biochemical dysregulation contributing to psychiatric disorders. The aims of this study was to estimate acute behavioural responses to clonidine (0.1 mg/kg i.p.), d-amphetamine (5 mg/kg, i.p), arecoline (15 mg/kg i.p), nicotine (6 mg/kg i.p.), apomorphine (1.5 mg/kg i.p.) and L-5-hydroxytryptophan (300 mg/kg i.p.) in rats fed with Mg-deprivated diet for 49 days and then treated with organic and inorganic Mg salts (50 mg Mg per kg) ether alone or in combination with pyridoxine (5 mg vitamin B6 per kg). In our study Mg-deficient rats were more sensitive to d-amphetamine-induced motor stereotypes compared with control rats; time of onset of the stereotypies insignificantly decreased by 14.89% and duration of the stereotypies significantly increased by 19.44% (320.36 +/- 19.90 vs. 268.23 +/- 8.17 minutes; p = 0.043). Mg deficiency did not modulate sensitivity to nicotine-induced seizure. The time between nicotine injection and emergence of clonic seizure (seizure latency) in the controls and Mg-deficient rats were 0.80 +/- 0.26 and 0.96 +/- 0.21 minutes respectively. Duration of the seizures in the controls and Mg-deficient rats were 64.93 +/- 7.20 and 79.32 +/- 8.13 minutes. In our study, Mg deficiency did not affect on clonidine- and apomorphine-induced hypothermia. Clonidine produced similar decreases in rectal temperature in controls and Mg-deficient group. In experiments using apomorphine, values of hypothermia were similar to those observed with clonidine. Mg deficiency antagonized 5-hydroxytryptophan-induced head-twitch response. The number of head twitches produced by 5-hydroxytryptophan was significantly (p = 0.49) decreased: twofold in magnesium-deficient rats (1.23 +/- 0.44 per minute) as compared with controls (2.42 +/- 0.52 per minute). Arecoline-induced tremor was comparably less expressed in Mg-deficient rats than in controls. The time between arecoline injection and time of onset of the tremor in the controls and Mg-deficient rats were 92.75 +/- 19.35 and 245.17 +/- 121.86 seconds respectively (p < or = 0.035). Duration of the tremors in the controls and Mg-deficient rats were 1175.58 +/- 127.87 and 703.83 +/- 89.33 seconds (p = 0.015). Magnesium salts (Mg chloride, Mg L-aspartate alone and in combination with B6) were administered through gastric tube during twenty days up to complete compensation oferythrocyte and plasma Mg levels in all experimental groups. In our study administration of Mg salts resulted in normalization of acute behavioural responses in Mg-deficient rats to d-amphetamine, arecoline, and L-5-hydroxytryptophan. Behavioural responses in rats treated with both Mg chloride and Mg L-aspartate in combinations with B6 were comparable with those observed in MagneB6 treatment.

[Effect of some organic and inorganic magnesium salts on lipoprotein state in rats fed with magnesium-deficient diet].

Low serum magnesium (Mg) concentrations have been reported in patients with atherosclerosis. From the other hand numerous clinical reports suggest the beneficial effects of Mg adjuvant therapy for the treatment of atherosclerosis. The purpose of this present study was to compare the effect of Mg L-aspartate and Mg chloride alone and in combinations with pyridoxine, Mg sulfate and Magne B6 (Mg lactate with pyridoxine) on lipid profile in rats fed with Mg deficient diet. To induce hypomagnesemia, fifty-three rats were placed on a Mg-deficient diet (ICN Biomedicals Inc. Aurora, OH) and demineralized water for 7 weeks. Seven control rats were fed a basal control diet (Mg content = 500 mg/kg) and water (with Mg content 20 mg/l) for equal duration. On the forty-ninth day of Mg-deficient diet, rats were treated one of the six supplementations: Mg chloride, Mg L-aspartate alone and in combinations with pyridoxine, Mg sulphate and Magne B6 (50 mg Mg and 5 mg vitamin B6 per kg). In our study Mg deficiency resulted in increase of triglyceride (by 35.2 %p < 0.0001), LDL (more than fourfold p < 0.0001), total cholesterol (by 38.7% p < 0.0001), apolipoprotein B (by 74.1%, p = 0.0006) levels and decrease in concentration of HDL (by 28.7% p < 0.0001). The non-HDL cholesterol/HDL cholesterol ratio was more than threefold increased (p < 0.0001). Oral magnesium salts led to normalization of lipid state with a return to pre-deficient levels. Magnesium salts in combinations with pyridoxine tended to be significantly more effective as compared with salts without pyridoxine. The hypolipidemic effect of studied salts was comparable with those observed in Magne B6 treatment and significantly higher than in magnesium sulfate treatment.

[The role of alimentary magnesium deficiency in development of nephrolithiasis and its correction with magnesium salts in rats].

Aims of our work were to appraise the quantity and nature of renal calcifications and mineral metabolism in the magnesium-deficient rats; and to find out whether the combination of pyridoxine with Mg L-aspartate or Mg chloride will reduce the length of the treatment needed to recover rats from magnesium deficient condition and urolithiasis state. To induce hypomagnesemia, fifty rats were placed on a magnesium-deficient diet (magnesium content < or = 15 mg/kg) and demineralized water for 10 weeks. On the forty-ninth day of magnesium-deficient diet, rats were treated one of the six supplementations: MgCl2, Mg-L-Asp or their combinations with pyridoxine hydrochloride, magnesium sulfate, magne B6.

Arrhythmogenic threshold of the myocardium under conditions of magnesium deficiency.

We studied the arrhythmogenic threshold of the myocardium after injection of CaCl2 to magnesium-deficient rats receiving Mg2+ L-aspartate, MgCl2, their combination with vitamin B6, and reference preparations Magne B6 and MgSO4 until complete compensation of magnesium level in the plasma and erythrocytes. Magnesium-deficient diet and deionized water were used for inducing alimentary Mg2+ deficiency and modeling pathological changes in rats. After reducing Mg2+ level to 0.7 mmol/liter in the plasma and to 1.5 mmol/liter in erythrocytes, Mg L-aspartate, MgCl2, their combination with vitamin B6, as well as Mg2+ deficiency led to a decrease in the dose of CaCl2 provoking heart rhythm disturbances in 50% animals and shortening of animal life span. Administration of the test magnesium salts increased the arrhythmogenic threshold; Mg2+ salts were comparable by their efficiency with Magne B6 and were far superior to MgSO4.

[Study of anti-inflammatory activity of some organic and inorganic magnesium salts in rats fed with magnesium-deficient diet].

The purpose of the present research was comparative study of anti-inflammatory action of some Mg salts in rats fed with Mg-deficient diet. It was shown in our study that administration of Mg L-aspartate with pyridoxine leads to higher compensation of Mg deficiency in rats with diet-induced Mg depletion as compared with other Mg supplementations. According to the Mg deficiency correction rate Mg salts may be ranged in the following order: Mg L-aspartate with pyridoxine > or = Mg chloride with pyridoxine > or = Mg lactate with pyridoxine > or = Mg L-aspartate > Mg chloride > Mg orotate. In our study administration of Mg salts resulted in decreased number of blood leukocytes, reduced peripheral vasodilation visible in the external ear, decreased spleen weight, and as consequences in reduced inflammatory and immunological response. According to correction rate of the inflammatory response Mg salts may be ranged in the following order: Mg orotate > or = Mg chloride > or = Mg chloride with pyridoxine > or = Mg L-aspartate > or = MgL-aspartate with pyridoxine > or = Mg lactate with pyridoxine.

Effect of magnesium chloride and magnesium L-aspartate on seizure threshold in rats under conditions of dietary magnesium deficiency.

We studied the effect of Mg-L-aspartate, MgCL2, and their combinations with vitamin B6, magneB6, and MgSO4 on seizure threshold in rats with dietary Mg2+ deficiency. Mg2+ deficiency was followed by a decrease in the threshold dose of corazol (from 79.20 to 49.48 mg/kg), shortening of the latency of the first jerk (by 33.6%, p=0.012), and reduction of the time to the first episode of clonic seizures (by 32.6%, p=0.011). Seizure threshold and latencies of the first jerk and first episode of clonic seizures increased over 3 weeks after peroral administration of Mg2+ salts. The combination of Mg2+ salts and pyridoxine was most effective in this respect.