Evaluation of the acute oral toxicity class of tricentric chromium(III) propionate complex in rat

Chromium(III) is an essential element for carbohydrate and lipid metabolism, and various chemical forms of this element are widely used in dietary supplements. Of particular interest is [Cr₃O(O₂CCH₂CH₃)₆(H₂O)₃]⁺ cation (CrProp), that has been proposed as an alternative source of Cr. However, its safety has not been studied completely. In this study, we evaluated the acute toxicity class of CrProp in Wistar rats applying the OECD 423 procedure. Male and female Wistar rats (n = 12, 6 ♀ and 6 ♂) were given by gavage either a single dose of CrProp 2000 mg kg⁻¹ body mass or equivalent volumes of distilled water, and fed Labofeed B diet, and observed carefully for 14 days, than sacrificed to collect samples for biochemical and histologic examination. No death cases were detected, no major abnormalities in animal behaviour, body mass gains, gross organ histology, and blood morphology, and biochemistry were observed, except some changes of liver mass and the activity of ALT in female rats. The results demonstrate that LD₅₀ of CrProp is greater than 2000 mg kg⁻¹ when administrated orally to rat, thus this compound appears to be belong the fifth category in the GHS system or the fourth class (“unclassified”) in the EU classification system.     

Chromium(III) propionate complex supplementation improves carbohydrate metabolism in insulin-resistance rat model

The purpose of this study was to evaluate the antidiabetic potential and safety of the chromium(III) propionate complex (CrProp) in insulin resistance induced by a high-fructose diet in rats. The experiment was carried out on 32 nine-week old male Wistar rats divided into 4 groups of 8 rats each. Animals were fed at libitum: the control diet (AIN-93M), and high-fructose diets (HF) containing various levels of Cr(III) given as CrProp (1 mg Cr kg⁻¹ diet (HF) and supplemented with 10 mg Cr kg⁻¹ diet (HFCr10), or 50 mg Cr kg⁻¹ diet (HFCr50), equal to approx. 0.1, 1 and 5 mg kg⁻¹ body mass per day) for 8 weeks.     

Evaluation of anti-diabetic potential of chromium(III) propionate complex in high-fat diet fed and STZ injected rats

The aim of this study was to examine the anti-diabetic potential of the chromium(III) propionate complex (CrProp) in a diabetic rat model. Male Wistar rats (n = 28, 8-week old) were divided into 4 groups (with 7 rats each) and fed at libitum: the control diet (AIN-93M), and high-fat diets with or without supplementary CrProp (10 and 50 mg Cr kg⁻¹ diet; 1 and 5 mg kg⁻¹ body mass per day) for 5 weeks, and subsequently injected with STZ to induce diabetes. Rats were further fed the same diets for another week until the end of the experiment. Blood indices and the contents of minerals (Fe, Zn, Cu and Cr) in rat tissues were determined by atomic absorption spectrometry. Supplementary CrProp did not affect blood glucose level, but significantly improved insulin sensitivity (HOMA-IR index) and reduced serum levels of triacylglycerols, total and LDL cholesterols. Both supplementary dosages of CrProp (10 and 50 mg Cr kg⁻¹ diet) normalized the increased liver Fe content, reduced hepatic and renal Cu levels and elevated renal Cr contents in diabetic rats. In conclusion, CrProp has a significant anti-diabetic (insulin-sensitizing and hypolipidemic) potential; thus it might be a candidate for a therapeutic agent in diabetes.     

Genotoxicity assessment of chromium(III) propionate complex in the rat model using the comet assay

The aim of the study was to assess genotoxicity of a chromium(III) propionate complex in rat’s peripheral blood lymphocytes by the comet assay. The study was carried out on 18 12-weeks old female Wistar rats that were divided into three equal groups (six animals each): control (0), control-Cr(VI) and Cr(III)-tested rat fed ad libitum a basal diet and the diet supplemented either with 10 mg Cr(VI)/kg diet (given as K₂Cr₂O₇, equivalent of 1 mg/kg body mass/day) or 1000 mg Cr(III)/kg diet (given as [Cr₃O(O₂CCH₂CH₃)6(H₂O)₃]NO₃), equivalent of 100 mg Cr/kg body mass/day) for 4 weeks. High doses of supplementary Cr(III) were found to not affect body mass gain, feeding efficiency ratio and internal organ masses. Treatment of rats with the Cr(III) propionate complex, in contrast to Cr(VI), did not affect significantly the comet assay results in lymphocytes, which suggests that the compound does not exert genotoxic effects in rats.     

Disposition of intratracheally administered chromium(III) and chromium(VI) in rabbits

Intratracheal instillation of ⁵¹CrCl₃ in anaesthetized rabbits resulted in partial absorption. In blood, the absorbed material was entirely confined to the plasma compartment. Only trace amounts were deposited in liver and kidney. By contrast, after similar application of Na₂⁵¹CrO₄ the bulk of blood radioactivity was present in erythrocytes. Substantial deposition occurred in liver and kidneys. It is concluded that Cr(VI) may enter the body unreduced via the lung and is partly deposited in cells over a prolonged period of time.     

Chromium(III) complexes of D-glucosaminic acid and their effect on decreasing blood sugar in vivo

Two chromium(III) complexes of glucosaminic acid were synthesized by neutralization and exchange reaction. The formation of 1 : 1 and 2 : 3 (Cr : glucosaminate) complexes was confirmed by elemental analyses and spectroscopic studies. The effect of the complexes on decreasing blood sugar was investigated on type-2 diabetes model rats induced by tetraoxypyrimidine. The results indicated that the effect on decreasing blood sugar was comparable to that of picolinate chromium complex (Cr(pic)(3)) currently used world wide.     

铬(Ⅲ)配合物治疗高脂蛋白血症95例

本文报道用铬(Ⅲ)配合物治疗各型高脂蛋白血症95例的临床疗效。采用自身单盲前后对照观察,先服安慰剂1.5mo,继服本药5mg bid 1.5mo。血清总胆固醇增高者42例,治疗后平均下降0.7mmol/1,总有效率65％。甘油三酯增高者89例,平均下降1.4 mmol/1,总有效率74％。治疗后各项血脂水平改变与服安慰剂后相比有非常显著性差异(P<0.01)。治前同时血糖增高者,亦有明显下降,平均下降0.74 mmol/1。血液流变学指标亦有不同程度的改善。治疗中未发现有毒副反应。本药为一种治疗脂质及糖代谢紊乱的有效药物,值得进一步研究。     

Safety and toxicological evaluation of a novel chromium(III) dinicocysteinate complex

Chromium(III) is an essential trace element required for normal protein, fat and carbohydrate metabolism. It also helps in energy production and increasing lean body mass. Chromium(III) dinicocysteinate (CDNC) is a unique form of bioavailable chromium(III). This study was focused on determining the broad spectrum safety of CDNC. Acute oral, acute dermal, primary dermal and eye irritation studies, Ames’ bacterial reverse mutation assay, mammalian erythrocyte micronucleus test, and a 90-day dose-dependent oral toxicity study were conducted. Acute oral and dermal LD₅₀ of CDNC was found to be greater than 2000?mg/kg in Sprague-Dawley rats. A primary skin irritation study in New Zealand Albino rabbits demonstrated CDNC as slightly irritating. An eye irritation study exhibited that CDNC is moderately irritating. Ames’ bacterial reverse mutation assay and mammalian erythrocyte micronucleus test demonstrated CDNC as non-mutagenic. A dose-dependent 90-day oral toxicity study demonstrated no significant toxicity of CDNC. Body weight, food and water consumption, selected organ weights (expressed as percentages of body or brain weights), ocular health, hematology, blood chemistry, and histopathology showed no abnormal changes. Clinical and histopathological evaluation of CDNC identified a dose level of 5.7?mg/kg/day as the no observed adverse effect level (NOAEL). Overall, these results demonstrate the broad spectrum safety of CDNC.     

Speciation of Cr(III) and Cr(VI) in geological and water samples by ytterbium(III) hydroxide coprecipitation system and atomic absorption spectrometry

A novel coprecipitation method with ytterbium(III) hydroxide has been established for speciation of Cr(III) and Cr(VI) in geological and water samples. At pH 10, while Cr(III) was quantitatively recovered, Cr(VI) was recovered under 10% levels. Total chromium was determined reducing of Cr(VI) to Cr(III) in acidic media with KI reagent. The concentration of Cr(VI) was calculated by the concentration difference between the total chromium and Cr(III). For the quantitative recovery of Cr(III), parameters such as pH, amount of ytterbium, centrifugation time and speed, matrix effect, KI amount, and sample volume were investigated. The preconcentration factor was 30. The limit of detection was obtained as 1.1 μg/L for Cr(III). The accuracy was checked by analyte addition and analyses of standard reference materials (TMDA-54.4 Certified Reference Water, NIST 2710 Montana Soil). Method has been successfully applied to the chromium speciation for industrial waste water of leather factories located in Bor-Nigde, and also for mine and soil samples.     

Low level chromium (VI) inhalation effects on alveolar macrophages and immune functions in Wistar rats

In inhalation chambers, 5-week-old male Wistar rats of the strain TNO-W-74 were continuously exposed to submicron aerosols of sodium dichromate in concentrations from 25 (low level) to 200 g/m³ Cr (high level). Subacute exposure (28 days) to 25 and 50 g/m³ Cr resulted in activated alveolar macrophages with stimulated phagocytic activities, and significantly elevated antibody responses to injected SRBC's. After subchronic (90 days) low level exposure there was a more pronounced effect on activation of the alveolar macrophages, with increased phagocytic activities. However, at high Cr (VI) exposure level (200 g/m³), inhibited phagocytic function of the alveolar macrophages was seen. In rats which were exposed to this chromium aerosol concentration for 42 days, the lung clearance of inert iron oxide was reduced significantly. The humoral immune system was still stimulated at subchronic low chromium aerosol concentrations of 100 g/m³, but significantly depressed at 200 g/m³ Cr. These results show that respiratory defence and immunologic functions were stimulated or inhibited depending on dose and time of chromium (VI) inhalation.This paper was presented in part at the International Seminar on the Immunological System as a Target for Toxic Damage, November 6–9, 1984, Luxembourg     

孕妇甲状腺功能亢进应用丙基硫氧嘧啶对妊娠结局及甲状腺功能的影响分析

目的研究孕妇甲状腺功能亢进应用PTU（丙基硫氧嘧啶）对妊娠结局及甲状腺功能产生的影响。方法回顾分析2008年11月至2012年11月治疗的50例甲亢孕妇临床资料,依据治疗方式将其分为2组,每组25例,研究组应用PTU治疗,对照组未用PTU治疗。对两组孕妇甲状腺功能、妊娠结局、临床并发症发生率进行比较。结果研究组孕妇甲状腺指标、妊娠结局、产妇临床并发症发生率与对照组比较,均呈明显差异（P〈0.01）。研究组胎儿情况与对照组比较,不具统计学差异（P〉0.05）。结论孕妇甲状腺功能亢进应用PTU,不仅能够对孕期的甲状腺功能给予较好的控制,并能改善孕妇的妊娠结局,对新生儿的畸形率也不产生影响,效果显著,应予推广。     

An application of Ag(III) complex chemiluminescence system for the determination of enoxacin in capsule and biological fluid

Ag(III) complex chemiluminescence (CL) system was applied for the determination of enoxacin (ENX). The CL conditions of [Ag(HIO(6))(2)](5-)-H(2)SO(4)-ENX systems without any luminescence reagent were investigated and optimized. Under the optimized conditions, the CL intensity was proportional to the concentration of ENX in the range from 6.6 × 10(-5) to 3.3 × 10(-3) g/L. The limit of detection (s/n = 3) was 2.0 × 10(-5) g/L. The recovery of ENX from the spiked pharmaceutical preparations was in the range of 82.9-108% with a relative standard deviation of 1.9-3.0%. For spiked serum and urine samples the recovery of ENX was in the range of 83.7-110% with a relative standard deviation of 1.1-2.8%. The proposed method was applied successfully to the determination of the drug in capsule, serum and urine samples.     

Fast uptake kinetics in vitro of 51Cr (VI) by red blood cells of man and rat

Fast transport kinetics of ⁵¹Cr (VI) into red blood cells (RBCs) in vitro were studied. No significant species differences were found between RBCs of man and rat. The uptake of ⁵¹Cr (VI) by RBCs in whole blood was composed of two different first order processes of different velocities (apparent t_1/2 of 22.7 s and 10.4 min for man and 6.9 s and 10.1 min for rat, respectively). However, even after longer time periods a fixed portion of approximately 15% of the administered dose remained in the plasma and did not penetrate into RBCs Over the entire concentration range studied (10 M–50 mM), the fast initial uptake followed Michaelis-Menten kinetics. The maximal capacity of this Cr(VI) transport into RBCs of man and rat was 3.1×10⁸ CrO₄ ^2– ions × cell^–1 × min^–1 and 2.5×10⁸ CrO₄ ^–2 ions × cell^–1 × min^–1, respectively. It is likely that Cr(VI) is transported into RBCs via a physiological anion carrier (band-3-protein).     

Cadmium and zinc concentrations in fetal and maternal rat tissues after parenteral administration of cadmium during pregnancy

Cadmium (Cd) and zinc (Zn) concentrations were determined by solid sampling atomic absorption spectrometry (AAS) in rat maternal and fetal tissues after exposure to cadmium. Cadmium was administered subcutaneously as CdCl₂ in saline daily during pregnancy. Two experiments were performed. In expt. I we investigated the tissue concentration at day 19 (gestational age) after administration of several doses: 0, 1.1, 2.2, 4.4, and 8.8 mol Cd/kg/ day. In expt. II the course of the Cd and Zn concentrations during pregnancy was investigated by collecting samples at days 14, 16, 18 and 20, after daily injections of 4.4 mol Cd/kg. Cadmium concentrations in blood, maternal liver, placenta and fetal liver increased with dose and duration of exposure. Cadmium was heavily accumulated in the liver and transferred to the fetus only in small amounts. The zinc concentration in the maternal liver was positively correlated with the cadmium concentration. In the placenta the zinc concentration was not affected. Zinc in fetal liver was decreased from day 18 onward. Despite relatively high cadmium levels and decreased zinc levels in the fetus, we observed no adverse effects on various reproduction parameters, such as birth weights and obvious malformations.These investigations were financially supported by the Netherlands Technology Foundation (STW)     

Cytotoxic activity of Gd(III)- and Dy(III)-complexes

The complexes of gadolinium(III) and dysprosium(III) were synthesized by reaction of the respective inorganic salts with 3,5-pyrazoledicarboxylic acid in amounts equal to metal to ligand molar ratio of 1 : 2. The structures of the final complexes were determined by means of spectral and elemental analyses. To help further the binding mode elucidation in the new Gd(III)- and Dy(III)-complexes of H(3)pdc, detailed vibrational analysis was performed on the basis of comparison of experimental vibrational spectra of the ligand and its Ln(III)-complexes using data theoretically predicted by us earlier, as well as data from the literature about related compounds. Significant differences in the IR and Raman spectra of the complexes were observed as compared to the spectra of the ligand. The ligand and the complexes were tested for their cytotoxic activities on the chronic myeloid leukemia-derived K-562, overexpressing the BCR-ABL fusion protein and the non-Hodgkin lymphoma-derived DOHH-2, characterized by a re-expression of the anti-apoptotic protein bcl-2 cell lines. The results obtained indicate that the tested compounds exerted a considerable cytotoxic activity upon the evaluated cell lines in a concentration-dependent manner, which enabled the construction of dose-response curves and the calculation of the corresponding IC(50) values. The inorganic salts exerted a very weak cytotoxic effect on these cells. This is in contrast to the lanthanide complexes, which exhibited potent cytotoxic activity, even more than the activity of cisplatin towards K-562 and DOHH-2 cell lines.     

Investigation of penbutolol—iron(III) complex and its spectrophotometric determination in tablets

It has been established that penbutolol reacts with iron(III) chloride in the presence of ammonium thiocyanate to form a pink complex (2:1) that is soluble in chloroform with a maximum absorbance at 478 nm. By application of the methods of Sommer and Job involving non-equimolar solutions, the conditional stability constant (log k′) of the complex at the optimum pH of 1.5±0.02 and an ionic strength of (μ) 0.14 M, was found to be 5.769. The molar absorptivity at 478 nm was 136 l mol⁻¹ cm⁻¹ at pH 1.5±0.02. The validity of Beer's law has been tested in the concentration range 3–18 × 10⁻⁴ M; the relative standard deviation (n = 8) was 1.52–3.21%. The proposed method was found to be suitable for the accurate, simple and rapid analysis of penbutolol in the bulk drug and in tablets.     

Effects of maternal exposure to di(2-ethylhexyl)phthalate (DEHP) during pregnancy on susceptibility to neonatal asthma

Di(2-ethylhexyl) phthalate (DEHP) is used as a plasticizer and is widely dispersed in the environment. In this study, we investigated the effects of maternal exposure to DEHP during pregnancy on neonatal asthma susceptibility using a murine model of asthma induced by ovalbumin (OVA). Pregnant BALB/c mice received DEHP from gestation day 13 to lactation day 21. Their offspring were sensitized on postnatal days (PNDs) 9 and 15 by intraperitoneal injection of 0.5 μg OVA with 200 μg aluminum hydroxide. On PNDs 22, 23 and 24, live pups received an airway challenge of OVA for 30 min. Offspring from pregnant mice that received DEHP showed reductions in inflammatory cell count, interleukin (IL)-4, IL-13, and eotaxin in their bronchoalveolar lavage fluid and in total immunoglobulin E and OVA-specific IgE in their plasma compared with offspring from pregnant mice that did not receive DEHP treatment. These results were consistent with histological analysis and immunoblotting. Maternal exposure to DEHP reduces airway inflammation and mucus production in offspring, with a decrease in inducible nitric oxide synthase (iNOS) in the lung tissue. This study suggests that maternal exposure to DEHP during pregnancy reduces asthmatic responses induced by OVA challenge in offspring. These effects were considered to be closely related to the suppression of Th2 immune responses and iNOS expression.     

A novel chemiluminescence quenching method for determination of sulfonamides in pharmaceutical and biological fluid based on luminol-Ag(III) complex reaction in alkaline solution

A novel chemiluminescence (CL) quenching method for the determination of sulfonamides is proposed. The CL reaction between Ag(III) complex [Ag(HIO₆)₂]^5? and luminol in alkaline solution was investigated. The quenching effect of sulfonamides on CL emission of [Ag(HIO₆)₂]^5?–luminol system was found. Quenching degree of CL emission was proportional to sulfonamide concentration. The effects of the reaction conditions on CL emission and quenching were examined. Under optimal conditions, the detection limits (s/n = 3) were 7.2, 17 and 8.3 ng/mL for sulfadiazine, sulfameter, and sulfadimethoxine, respectively. The recoveries of the three drugs were in the range of 91.3–110% with RSDs of 1.9–2.7% for urine samples, and 106–112% with RSDs of 1.6–2.8% for serum samples. The proposed method was used for the determination of sulfadiazine at clinically relevant concentrations in real urine and serum samples with satisfactory results. Copyright © 2011 John Wiley & Sons, Ltd.     

Spectrophotometric determination of alendronate in pharmaceutical formulations via complex formation with Fe(III) ions

The formation of the complex between alendronate, non-chromophoric bisphosphonate drug important for the treatment of a variety of bone diseases, and iron(III) chloride in perchloric acid solution was studied. The stoichiometric ratio of alendronate to Fe(III) ions in the chromophoric complex was determined to be 1:1. The conditional stability constant was log K′_ave=4.50 (SD=0.15), indicating that the Fe(III)–alendronate complex is a complex of medium stability. The optimum conditions for this reaction were ascertained and a spectrophotometric method was developed for the determination of alendronate in the concentration range 8.1–162.5 μg ml⁻¹, the detection limit being 2 μg ml⁻¹. The method was validated for the direct determination of alendronate in tablet dosage formulations.     

New lanthanum (III) complex--synthesis, characterization, and cytotoxic activity

The complex of lanthanum (III) was synthesized reacting the respective inorganic salt with 5-aminoorotic acid in amounts equal to the metal:ligand molar ratio of 1:3. The complex was prepared by adding an aqueous solution of lanthanum (III) nitrate to an aqueous solution of the ligand, subsequently raising the pH of the mixture gradually to approx. 5.0 through addition of a dilute solution of sodium hydroxide. The structure of the final complex was determined by means of spectral data (IR, Raman,( 1)H-NMR) and elemental analysis. Significant differences in the IR spectrum of the complex were observed as compared to the spectrum of the ligand. A comparative analysis of the Raman spectrum of the complex with that of the free 5-aminoorotic acid allowed a straightforward assignment of the vibrations of the ligand groups involved in coordination. The ligand and the complex were tested for the cytotoxic activities on the chronic myeloid leukemia derived K-562, overexpressing the BCR-ABL fusion protein and the non-Hodgkin lymphoma derived DOHH-2, characterized by a re-expression of the anti-apoptotic protein bcl-2 cell lines. The results obtained indicate that the tested compounds exerted a considerable cytotoxic activity upon the evaluated cell lines in a concentration-dependent matter, which enabled the construction of dose-response curves and the calculation of the corresponding IC(50 )values. The inorganic salt exerted a very weak cytotoxic effect on these cells, which is in contrast to the lanthanum (III) complex.