Hypermagnesemia disturbances in rats, NO-related: pentadecapeptide BPC 157 abrogates, L-NAME and L-arginine worsen.

AIM: Stable gastric pentadecapeptide BPC 157, administered before a high-dose magnesium injection in rats, might be a useful peptide therapy against magnesium toxicity and the magnesium-induced effect on cell depolarization. Moreover, this might be an NO-system-related effect. Previously, BPC 157 counteracts paralysis, arrhythmias and hyperkalaemia, extreme muscle weakness; parasympathetic and neuromuscular blockade; injured muscle healing and interacts with the NOS-blocker and NOS-substrate effects. MAIN METHODS: Assessment included magnesium sulfate (560 mg/kg intraperitoneally)-induced muscle weakness, muscle and brain lesions, hypermagnesemia, hyperkalaemia, increased serum enzyme values assessed in rats during and at the end of a 30-min period and medication (given intraperitoneally/kg at 15 min before magnesium) [BPC 157 (10 µg, 10 ng), L-NAME (5 mg), L-arginine (100 mg), alone and/or together]. In HEK293 cells, the increasing magnesium concentration from 1 to 5 mM could depolarize the cells at 1.75 ± 0.44 mV. KEY FINDINGS: L-NAME + magnesium-rats and L-arginine + magnesium-rats exhibited worsened severe muscle weakness and lesions, brain lesions, hypermagnesemia and serum enzymes values, with emerging hyperkalaemia. However, L-NAME + L-arginine + magnesium-rats exhibited all control values and normokalaemia. BPC 157 abrogated hypermagnesemia and counteracted all of the magnesium-induced disturbances (including those aggravated by L-NAME or L-arginine). Thus, cell depolarization due to increasing magnesium concentration was inhibited in the presence of BPC 157 (1 µM) in vitro. SIGNIFICANCE: BPC 157 likely counteracts the initial event leading to hypermagnesemia and the life-threatening actions after a magnesium overdose. In contrast, a worsened clinical course, higher hypermagnesemia, and emerging hyperkalaemia might cause both L-NAME and L-arginine to affect the same events adversely. These events were also opposed by BPC 157.

Magnesium sulfate induced toxicity in vitro in AGS gastric adenocarcinoma cells and in vivo in mouse gastric mucosa.

Magnesium sulfate is widely used as a food additive and as an orally administered medication. The aim of this study was to evaluate the possible cytotoxicity of magnesium sulfate on AGS human gastric adenocarcinoma cells and gastric mucosa in mice. A trypan blue exclusion assay was used to determine the reduction in viability of AGS cells exposed to magnesium sulfate, and then effects on cell proliferation were quantified. The role of magnesium sulfate-mediated pro-inflammatory cytokine production in AGS cells was also investigated. mRNA expression for IL-1ß, IL-6, IL-8, and TNF-α was determined by RT-PCR, and secretion of these cytokines was measured by ELISA. Immunohistochemical evaluation of IL-1ß, IL-6, and TNF-α expression was conducted in mouse gastric mucosa. Addition of 3 to 50 mM magnesium sulfate to AGS cells inhibited both cell proliferation and cell viability in a dose-dependent manner. Magnesium sulfate had little effect on production of IL-1ß or IL-6 but significantly inhibited production of IL-8. The animal model demonstrated that magnesium sulfate induced production of IL-1ß, IL-6, and TNF-α. These preliminary data suggest that magnesium sulfate had a direct effect on the stomach and initiates cytotoxicity in moderate concentrations and time periods by inhibiting viability and proliferation of AGS cells and by regulating expression and/or release of pro-inflammatory cytokines.

TRPA1, NMDA receptors and nitric oxide mediate mechanical hyperalgesia induced by local injection of magnesium sulfate into the rat hind paw.

Previous studies have shown that while magnesium, an antagonist of the glutamate subtype of N-methyl-D-aspartate receptors, possesses analgesic properties, it can induce writhing in rodents. The aim of this study was to determine the effect and mechanism of action of local (intraplantar) administration of magnesium sulfate (MS) on the paw withdrawal threshold (PWT) to mechanical stimuli. The PWT was evaluated by the electronic von Frey test in male Wistar rats. Tested drugs were either co-administered intraplantarly (i.pl.) with MS or given into the contralateral paw to exclude systemic effects. MS at doses of 0.5, 1.5, 3 and 6.2 mg/paw (i.pl.) induced a statistically significant (as compared to 0.9% NaCl) and dose-dependent mechanical hyperalgesia. Only isotonic MS (250 mmol/l or 6.2% or 6.2 mg/paw) induced mechanical hyperalgesia that lasted at least six hours. Isotonic MS-induced mechanical hyperalgesia was reduced in a dose-dependent manner by co-injection of camphor, a non-selective TRPA1 antagonist (0.3, 1 and 2.5 µg/paw), MK-801, a NMDA receptor antagonist (0.001, 0.025 and 0.1 µg/paw), L-NAME, a non-selective nitric oxide (NO) synthase inhibitor (20, 50 and 100 µg/paw), ARL 17477, a selective neuronal NOS inhibitor (5.7 and 17 µg/paw), SMT, a selective inducible NOS inhibitor (1 and 2.78 µg/paw), and methylene blue, a guanylate cyclase inhibitor (5, 20 and 125 µg/paw). Drugs injected into the contralateral hind paw did not produce significant effects. These results suggest that an i.pl. injection of MS produces local peripheral mechanical hyperalgesia via activation of peripheral TRPA1 and NMDA receptors and peripheral production of NO.

Protective effect of Dalbergia sissoo Roxb. ex DC. (family: Fabaceae) leaves against experimentally induced diarrhoea and peristalsis in mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Dalbergia sissoo Roxb. ex DC. (family: Fabaceae; Indian Rosewood), is used in India, especially in rural communities by traditional medicine practitioners to treat diarrhoea. However, scientific evidence does not exist in any literature to substantiate the claim of therapeutic success of the plant species in diarrhoea. AIM: To study the protective effect of ethanol extract from D. sissoo Roxb. ex DC. leaves (EDSL) against experimentally induced diarrhoea and peristalsis in mice. MATERIALS AND METHODS: Castor oil-induced diarrhoea and magnesium sulphate (MgSO4)-induced diarrhoea tests were used to assess the antidiarrhoeal activity of D. sissoo. Gastrointestinal tract transit of charcoal meal test and barium sulphate milk was used to assess the peristalsis activity of the extract, while the acute toxicity study and determination of total phenolics and total flavonoids were carried out using well-established protocols and methods. RESULTS: The EDSL significantly reduced faecal output in castor oil-induced and MgSO4-induced diarrhoea and also significantly reduced the number of diarrhoeal episodes. D. sissoo significantly delayed the onset of diarrhoea induced by both castor oil and MgSO4 and comparable to loperamide, a standard antidiarrhoeal drug. Both D. sissoo and atropine sulphate significantly reduced the peristalsis activity of charcoal meal and barium sulphate milk in mice. The preliminary phytochemical analysis of EDSL revealed the presence of carbohydrates, phenolics, glycosides, and flavonoids. The median lethal dose of EDSL was greater than 2000 mg/kg (orally (p.o.)). CONCLUSION: The data obtained indicate that the EDSL has antidiarrhoeal and antiperistalsis activities and thus supports its traditional use. The data also show that the plant material given p.o. may be safe and/or non-toxic in mice.

Neurotoxic effects of intrathecal magnesium sulphate.

BACKGROUND AND OBJECTIVES: To assess the potential neurotoxic effects at the ultrastructural level of magnesium sulfate administered intrathecally as a single or multi-dose. METHODS: Our study was conducted with 24 Sprague-Dawley rats that weighed 250-300 g. After a 4-hour fast, the rats were given 10 mg.kg(-1) xylazine chloride intraperitoneal and then randomly allocated into three groups. Group I (n = 8) received 0.9% normal saline, Group II (n = 8) was given one intrathecal injection of 0.02 mL of 15% magnesium sulphate, and Group III (n = 8) was given 0.02 mL of 15% magnesium sulphate once a day for seven days. The injections were given within 0.40x50 mm from the lumbar area. After seven days, the animals were sacrificed under anesthesia with an aortic injection of 10% formaldehyde and their tissues were fixed. The medulla spinalis was then examined and histopathologically evaluated under an electron microscope. The Kruskal-Wallis test was used for statistical evaluation. A value of p < .05 was considered to be statistically significant. RESULTS: Significant neurodegeneration was detected in rats given single or repeated magnesium sulphate injections compared to the control group. The histopathological evaluation score of this group was also high. CONCLUSIONS: Based on electron microscopic examination, we found that intrathecal magnesium sulphate administration induced neurodegeneration.

Aquatic toxicity of magnesium sulfate, and the influence of calcium, in very low ionic concentration water.

The toxicity of magnesium sulfate (MgSO(4)), and the influence of calcium (Ca), were assessed in very soft freshwater (natural Magela Creek water [NMCW]) using six freshwater species (Chlorella sp., Lemna aequinoctialis, Amerianna cumingi, Moinodaphnia macleayi, Hydra viridissima, and Mogurnda mogurnda). The study involved five stages: toxicity of MgSO(4) in NMCW, determination of the toxic ion, influence of Ca on Mg toxicity, toxicity of MgSO(4) at an Mg:Ca mass ratio of 9:1, and derivation of water quality guideline values for Mg. The toxicity of MgSO(4) was higher than previously reported, with chronic median inhibition concentration (IC50)/acute median lethal concentration (LC50) values ranging from 4 to 1,215 mg/L, as Mg. Experiments exposing the 3 most sensitive species (L. aequinoctialis, H. viridissima, and A. cumingi) to Na(2)SO(4) and MgCl(2) confirmed that Mg was the toxic ion. Additionally, Ca was shown to have an ameliorative effect on Mg toxicity. For L. aequinoctialis and H. viridissima, Mg toxicity at the IC50 concentration was eliminated at Mg:Ca (mass) ratios of < or =10:1 and < or =9:1, respectively. For A. cumingi, a 10 to 30% effect persisted at the IC50 concentration at Mg:Ca ratios <9:1. The toxicity of MgSO(4) in NMCW at a constant Mg:Ca ratio of 9:1 was lower than at background Ca, with chronic IC50/acute LC50 values from 96 to 4,054 mg/L, as Mg. Water quality guideline values for Mg (to protect 99% of species) at Mg:Ca mass ratios of >9:1 and < or =9:1 were 0.8 and 2.5 mg/L, respectively. Magnesium can be toxic at concentrations approaching natural background levels, but toxicity is dependent on Ca concentrations, with exposure in very low ionic concentration, Ca-deficient waters posing the greatest risk to aquatic life.

Increased expression of glucose transporter 3 in gerbil brains following magnesium sulfate treatment and focal cerebral ischemic injury.

Glucose is the primary energy substrate for neurons. Glucose transporter 3 (Glut3) localizes at the neuronal cellular membrane, which transports glucose from the extracelluar space into neurons. Ischemia results in an increased energy demand that is associated with profound changes in brain energy metabolism. Magnesium sulfate (MgSO(4)) ameliorates ischemia-induced neuronal death in the rat and gerbil model. We investigated the effects of MgSO(4) administration on the expression of Glut3 in cortex and hippocampus of gerbils during ischemia. The focal cerebral ischemia was produced by unilateral occlusion of the right common carotid artery and right middle cerebral artery. Following ischemia, Glut3 expression increased significantly versus non-ischemic (contra-lateral) cortex and hippocampus. MgSO(4) treatment significantly increased the level of Glut3 expression in the non-ischemic and ischemic cortex and hippocampus. We found that the MgSO(4)-induced increase in Glut3 expression was not reversed by administration of U0126, a MEK kinase inhibitor. These results suggest that other factors may function to modulate the MgSO(4)-induced Glut3 response. In all, our data showed that MgSO(4) increases the expression of Glut3 in the cortex and hippocampus of gerbil brains both in non-ischemia and ischemia status. However, the MEK signaling pathway might not be involved in MgSO(4)-induced Glut3 expression following focal ischemia.

Lipid peroxidation in the kidney of rats treated with V and/or Mg in drinking water.

Spontaneous and stimulated lipid peroxidation (LPO) after vanadate and magnesium treatment was studied in kidney supernatants obtained from outbred 5-month-old, albino male Wistar rats. The 2-month-old animals daily received: group I (control), deionized water to drink; group II, water solution of sodium metavanadate, NaVO(3) (SMV, 0.125 mg V ml(-1)); group III, water solution of magnesium sulfate, MgSO(4) (MS, 0.06 mg Mg ml(-1)); and group IV, water solution of SMV-MS at the same concentrations as in groups II and III for V and Mg, respectively, over a 12-week period. FeSO(4), NaVO(3) and MgSO(4) were selected as agents that may modify LPO process in in vitro conditions. Spontaneous malondialdehyde (MDA) levels in kidney supernatants increased significantly in the rats in groups II and IV, compared with groups I and III; and they were also significantly higher in all the groups of rats compared with the liver supernatants. The total antioxidant status (TAS) in groups II and IV tended to be higher too. Vanadium concentration in the kidney of the rats in groups II and IV increased, whereas the kidney Mg content in groups II, III and IV decreased, compared with levels in the liver. As the two-way ANOVA indicated, the changes in the basal MDA level, TAS and Mg concentration in the liver of rats at combined V and Mg application only resulted from independent action of V. As far as the in vitro results are concerned, in the supernatants obtained from the rats in groups II and IV, a significant increase in MDA level was demonstrated in the presence of 30 microm of exogenous FeSO(4) as well as 30, 100, 200 and 400 microm NaVO(3) and 100, 200, 400, 600, 800 and 1000 microm MgSO(4), compared with groups I and III. The 600, 800 and 1000 microm of exogenous MgSO(4) also significantly elevated MDA production in the supernatants obtained from the rats in group III, compared with spontaneously formed MDA in the same supernatants. The three-way ANOVA showed that the changes in LPO induced by in vitro treatment of kidney supernatants with exogenous Fe or V or Mg (600, 800 and 1000 microm) were a consequence of independent action of those metals and they also resulted from the interactions between exogenous Fe (Fe(exog)) and endogenous V (V(end)) and between V(end) and exogenous V (V(exog)). In conclusion, V (as NaVO(3)) consumed by the rats with drinking water at a dose of 12.9 mg V kg(-1) b.w. per 24 h for 12 weeks increased the basal LPO and markedly enhanced TAS in the renal tissue. Its pro-oxidant potential was also found in in vitro conditions. The Mg dose (6 mg Mg kg(-1) b.w. per 24 h) ingested by the rats together with V (12.7 mg V kg(-1) b.w. per 24 h) neither reduced nor intensified the spontaneous LPO, compared with V-only intoxicated animals; however, the stimulating effect of Mg on LPO was revealed in in vitro conditions.

Anti-diarrhoeal and ulcer-protective effects of violacein isolated from Chromobacterium violaceum in Wistar rats.

Violacein was isolated from Chromobacterium violaceum, a soil Gram-negative bacterium collected from the forest water body soil sample from Kolli Hills of Tamil Nadu, India. In the present study the anti-diarrhoeal and ulcer-protective properties of violacein were investigated in Wistar rats using castor oil, magnesium sulphate and ethanol. The intestinal transit in rats was significantly (P < 0.001) reduced and gastric emptying was delayed; 40 mg/kg of violacein elicited a greater anti-motility activity than 0.1 mg/kg of atropine. Violacein exhibited ulcer-protective properties against ethanol-induced ulceration in rats with maximal anti-ulcer activity at 40 mg/kg. Violacein also exerted significant anti-enteropooling effects, causing a dose-related inhibitory effect on castor oil-induced enteropooling in rats. A profound anti-diarrhoeal activity was observed when violacein was tested in diarrhoeic rats. The frequencies of defaecation as well as the wetness of the faecal droppings were significantly reduced. Furthermore, violacein (40 mg/kg) produced 87.84% inhibition of castor oil-induced diarrhoea in rats. The results suggested that violacein can be used for the treatment of diarrhoeal and ulcer-related diseases.

High dose magnesium sulfate exposure induces apoptotic cell death in the developing neonatal mouse brain.

BACKGROUND: Magnesium sulfate (MgSO4) is often used as a treatment for pre-eclampsia/eclampsia and preterm labor, resulting in the exposure of a significant number of neonates to this drug despite a lack of evidence suggesting that it is safe, or effective as a tocolytic. While there is evidence that MgSO4 may be neuroprotective in perinatal brain injury, recent reviews have suggested that the effects are dependent upon dose, and that higher doses may actually increase neonatal morbidity and mortality. There is a lack of evidence investigating the neurotoxic effects of neonatal magnesium (Mg) exposure on the developing brain, specifically in terms of neurodevelopmental apoptosis, a cell-killing phenomenon known to be potentiated by other drugs with mechanisms of action at Mg-binding sites (i.e. NMDA receptor antagonists such as MK-801, ketamine, and PCP). OBJECTIVE: To investigate the effects of Mg exposure on the neonatal mouse brain at different postnatal ages to determine whether MgSO4 treatment causes significant cell death in the developing mouse brain. METHODS: C57Bl/6 mice were treated with four doses of MgSO4 (250 mg/kg) on postnatal days 3 (P3), 7 (P7) or 14 (P14). Caspase-3 immunohistochemistry, cupric silver staining, and electron microscopy techniques were used to examine Mg-treated brains for neurotoxic effects. RESULTS: Qualitative evaluation using cupric silver staining revealed widespread damage throughout the brain in P7 animals. Results of electron microscopy confirmed that the cell death process was apoptotic in nature. Quantitative evaluation of damage to the cortex, caudate-putamen, hippocampus, thalamus, and cerebellum showed that Mg treatment caused significant brain damage in animals treated on P3 and P7, but not P14. CONCLUSIONS: Administration of high doses of Mg may be detrimental to the fetal brain, particularly if exposure occurs during critical periods of neurodevelopment.

Synergistic effects of iron and aluminum on stress-related gene expression in primary human neural cells.

Disturbances in metal-ion transport, homeostasis, overload and metal ion-mediated catalysis are implicated in neurodegenerative conditions such as Alzheimer's disease (AD). The mechanisms of metal-ion induced disruption of genetic function, termed genotoxicity, are not well understood. In these experiments we examined the effects of non-apoptotic concentrations of magnesium-, iron- and aluminum-sulfate on gene expression patterns in untransformed human neural (HN) cells in primary culture using high density DNA array profiling and Western immunoassay. Two week old HN cells were exposed to low micromolar magnesium, iron, or aluminum for 7 days, representing trace metal exposure over one-third of their lifespan. While total RNA yield and abundance were not significantly altered, both iron and aluminum were found to induce HSP27, COX-2, betaAPP and DAXX gene expression. Similarly up-regulated gene expression for these stress-sensing, pro-inflammatory and pro-apoptotic elements have been observed in AD brain. The combination of iron and aluminum together was found to be particularly effective in up-regulating these genes, and was preceded by the evolution of reactive oxygen intermediates as measured by 2',7'-dichlorofluorescein diacetate assay. These data indicate that physiologically relevant amounts of iron and aluminum are capable of inducing Fenton chemistry-triggered gene expression programs that may support downstream pathogenic responses and brain cell dysfunction.

Evaluation of anti-diarrhoeal activity in seed extracts of Mangifera indica.

Mangifera indica is commonly grown in many parts of the world. Its seeds have been used for anti-diarrhoeal activity in Indian traditional medicine. This study evaluates the potential anti-diarrhoeal activity of methanolic (MMI) and aqueous (AMI) extracts of seeds of M. indica in experimental diarrhoea, induced by castor oil and magnesium sulphate in mice. Both MMI and AMI were given orally in the dose of 250 mg/kg, showed significant anti-diarrhoeal activity comparable with that of the standard drug loperamide. However, only MMI significantly reduced intestinal transit in charcoal meal test as compared with atropine sulphate (5 mg/kg; im). The in vitro antimicrobial activity of MMI and AMI showed variable results. While, AMI significantly inhibited growth of Streptococcus aureus and Proteus vulgaris, both MMI and AMI did not show any significant effect on growth of E. coli and Klebsiella. The results illustrate that the extracts of M. indica have significant anti-diarrhoeal activity and part of the activity of MMI may be attributed to its effect on intestinal transit.

Intravenous infusion of magnesium sulfate and regional redistribution of fetal blood flow during maternal hemorrhage in late-gestation gravid ewes.

OBJECTIVES: Even though magnesium sulfate is commonly prescribed for women with preeclampsia as prophylaxis against seizure and for women with preterm labor as a tocolytic agent there is limited information about its effects on the fetus. It is of particular concern that women with preeclampsia or in premature labor are at high risk for abruptio placentae with consequent compromise of fetal oxygenation. Magnesium sulfate is a vasodilator and thus may exert cardiovascular effects on the fetus. The goal of this study was to evaluate the effects of magnesium sulfate on fetal organ blood flow, especially regional cerebral blood flow, during the stressful condition of maternal hemorrhage. STUDY DESIGN: Studies were performed with 11 long-term instrumented pregnant ewes and their fetuses at 121 to 128 days' gestation (term, 147 days' gestation). Animals were randomly allocated to either the experimental (n = 5) or the control (n = 6) group. After a 60-minute baseline period, experimental fetuses received intravenous magnesium sulfate diluted in 0.9% sodium chloride (0.3 g loading dose, then 0.3 g/h at a rate of 3 mL/h) and control fetuses were infused with an equivalent volume of intravenous 0.9% sodium chloride. After 60 minutes of this infusion-only period, the infusions were continued and ewes were intermittently bled 4 times at a rate of 5 mL/kg for 10 minutes with 5 minutes between hemorrhages. The total blood lost at the end of the hemorrhage-plus-infusion hour was 20 mL/kg. The infusions were continued and the sheep were observed for 1 hour after this period (posthemorrhage period). At the end of baseline, infusion-only, and hemorrhage-plus-infusion periods, fetal and maternal blood pressures and blood gas values were measured and fetal organ blood flows were determined through a fluorescent microsphere technique. Repeated-measures analysis of variance and Wilcoxon tests were used to determine the significance of changes in hemodynamic, blood gas, and organ blood flow parameters between different time points within each group. Comparisons between groups were made with rank sum tests (Mann-Whitney tests). RESULTS: There were no significant differences between groups or within groups for baseline and infusion-only measurements in any measured hemodynamic or hematologic factor. Mean maternal blood pressure decreased significantly (P <.05) after hemorrhage, with similar median decrements in both control and experimental groups of 41 mm Hg (interquartile range, 24-57 mm Hg) and 41 mm Hg (interquartile range, 12-43 mm Hg), respectively. There were no significant differences between groups in fetal blood gas values or hemodynamic parameters. Fetal arterial PO(2) decreased significantly after hemorrhage plus infusion, with similar mean (+/-SEM) decreases in control and experimental groups of 5.9 +/- 1.4 mm Hg and 4.5 +/- 1.5 mm Hg, respectively. Fetal pH also decreased significantly in both groups. After hemorrhage plus infusion there were significant increases in fetal regional cerebral and myocardial blood flows in both groups. Adrenal blood flow increased significantly from baseline (214%, 183%-294%) in the control group after hemorrhage plus infusion but not in the experimental group. No other difference in organ blood flow between control and experimental groups was observed. Significant regional variations in cerebral blood flow were not observed in either group at any time. CONCLUSIONS: In these initially healthy, late-gestation fetal lambs magnesium sulfate exposure did not impair cardiac output redistribution, nor did it cause fetal death in response to maternal hemorrhage.

[A single dose toxicity study of magnesium sulfate in rats and dogs].

A single dose toxicity study of magnesium sulfate by intravenous administration was conducted in rats and dogs. The results are summarized in the following. Magnesium sulfate was administered once at dose levels of 90, 130, 200, 300 and 450 mg/kg to Crj:CD(SD) rats at 6 weeks of age. Deaths occurred in the 200 mg/kg and above groups in both sexes. The LD50 values were 206 mg/kg for males and 174 mg/kg for females. In the surviving animals, in the 130 mg/kg and above groups, tonic convulsions, abnormal gait and tachypnea were seen. However, these signs disappeared gradually and all animals returned to a normal state by 15 min after dosing. There were no treatment-related changes in the body weight or gross pathology. Magnesium sulfate was infused for 6 hr at dose levels of 75, 300 and 1200 mg/kg (12.5, 50 and 200 mg/kg/hr) to female beagle dogs at 6 months of age. No deaths were observed in any of the dose groups and it was considered that the lethal dose level would be higher than 1200 mg/kg(200 mg/kg/hr). In the 1200 mg/kg group, vomiting, decreased spontaneous movement, staggering gait, prone position and flush of the conjunctiva and ear auricles were seen. However, these signs disappeared gradually and animals returned to a normal state by 1 hr after dosing. There were no treatment-related changes in the body weight, food consumption or gross pathology.

[A study for effects on pre- and postnatal development, including maternal function in rats treated subcutaneously with magnesium sulfate].

Magnesium sulfate, at dose levels of 250, 500 and 1000 mg/kg, was administered subcutaneously three times daily to Crj:CD(SD) female rats from day 15 through day 20 of gestation. The effects of the compound on dams and F1 animals were examined. In the dams, decreased food consumption was observed in the 500 and 1000 mg/kg groups. Hypolocomotion, pronation, bradypnea and decreased body weight gain were observed in the 1000 mg/kg group. But there were no effects on the delivery or lactation conditions and necropsy from administration of the test article. In the F1 animals, low body weight, delays in differentiation (eruption of lower incisor, opening of eyelid) and reversible change in ribs (wavy rib) were observed in the 1000 mg/kg group. But there were no effects from administration of the test article in viability, functional examinations, behavior tests or reproductive ability. Based on the above results, under the conditions of this study, it was concluded that the non-toxic dose levels for general toxicological effects on dams was 3 x 250 mg/kg/day, for reproductive ability of dams was 3 x 1000 mg/kg/day, and for development of F1 animals was 3 x 500 mg/kg/day.

[A 2-week toxicity study of magnesium sulfate administered by 24-hr intravenous infusion in beagle dogs followed by 2-week recovery period].

A 2-week toxicity study of magnesium sulfate administered by a 24-hr intravenous infusion at the dosage levels of 0, 12.5, 50, 100 and 200 mg/kg/hr in female beagle dogs was conducted, with 2-week follow-up observation after drug withdrawal. One of 2 animals in the 200 mg/kg/hr group died approx. 32 hr after the start of infusion. At the same time, the remaining 1 animal of the same group was sacrificed in a moribund state. Changes attributable to the treatment of magnesium sulfate were decreased food consumption and body weight gain, anemia, mild prolongation of conduction time in electrocardiogram and tubular basophilia in the kidneys in the animals treated with 100 mg/kg/hr. Furthermore, decreased calcium level was recorded in the animals treated with 50 mg/kg/hr or more. However, these changes disappeared after drug withdrawal, and reversibility was suggested. Judging from the mode of occurrence, since the change in calcium level observed in the group treated with 50 mg/kg/hr was slight, it was considered to be toxicologically insignificant. In conclusion, the nontoxic dosage level of magnesium sulfate was judged to be 50 mg/kg/hr under the condition of the present study.