A 91-d repeated dose oral toxicity study of PureSorb-Q(TM)40 in rats

As part of a series of non-clinical studies to evaluate the safety of PureSorb-Q(TM)40 (Water-soluble type CoQ(10) powder, CoQ(10) content is 40 w/w%; hereinafter referred to as P40), male and female rats were treated orally by gavage with P40 once a day for 91 d, and its repeated dose toxicity was assessed. Control animals were treated with a 0.5 w/v% solution of methylcellulose, the vehicle for P40. Each test group consisted of 6 animals of each sex. No adverse effects of P40 were noted in general signs, body weight, food consumption, ophthalmological examination, urinalysis, hematological examination, blood chemical analysis, necropsy, organ weights, or histopathological examination in animals of either sex. From these results, the no observed adverse effect level of P40 was estimated at 2,000 mg/kg in both sexes of rats under the conditions of the present study, and P40 was confirmed to be a food material whose safety is high.     

Comparison of uptake between PureSorb-Q40 and regular hydrophobic coenzyme Q10 in rats and humans after single oral intake

Coenzyme Q10 (CoQ10) is a lipid-soluble antioxidant and essential component of the mitochondrial electron transfer system in the body, and is in wide use as a functional food material and cosmetic raw material. However, as CoQ10 is extremely lipid-soluble, absorption by the body is not easy. In general, people use soft-gel capsules in which CoQ10 is suspended in oil, and take these capsules with food. PureSorb-Q40 (P40) was developed to improve CoQ10 processability and absorption when taken without food, and the present study compared the effects of food on absorption between P40 and conventional lipid-soluble CoQ10 in rats and humans. The results of a rat study showed higher uptake when P40 was administered in the fasting state or with food compared to lipid-soluble CoQ10. The results of a human study showed that uptake was favorable when P40 was administered in the fasting state, and even when administered postprandially, a significant difference was noted in uptake rate up to 6 h after intake and uptake volume up to 8 h after intake when compared to lipid-soluble CoQ10. These results show that any CoQ10 product using P40 can be quickly and reliably absorbed by the body regardless of dosage form or intake time.     

Oral toxicity of indium in rats: single and 28-day repeated administration studies

Indium is widely used in the electronics industry to make semiconductors, liquid-crystal panels, and plasma display panels, and its production is increasing. However, it is necessary to handle it more cautiously than before, because the pulmonary toxicity of inhaled indium has been identified. The present study aimed to characterize the potential toxic effects of indium through oral administration and observation for fourteen days following a single dose of 0 or 2,000 mg/kg (acute oral toxicity study), and repeated oral administration for 28 days at dose levels of 0, 40, 200, or 1,000 mg/kg daily (28-day repeated oral dose toxicity study) to male and female Crj:CD (SD) IGS rats (SPF). No deaths and no abnormalities in clinical signs, body weights, and necropsy findings were observed for any of the animals in the acute oral toxicity study. Furthermore, no changes related to indium were also observed in the dose groups up to 1,000 mg/kg of the 28-day repeated oral dose toxicity study. From the results described above, the lethal dose 50% (LD(50)) of indium is greater than 2,000 mg/kg under these study conditions, and the no-observed-adverse-effect-level (NOAEL) is considered to be 1,000 mg/kg for males and females under these conditions.     

Effects of oral coenzyme Q10 supplementation on sodium nitrite-induced lipid peroxidation in rats.

Studies were carried out to examine the anti-oxidative effect(s) of oral coenzyme Q10 supplementation (10 mg/kg b.w./day) in rats treated per os with either sodium nitrite (10 mg/kg b.w./day) or saline (control) for 14 days. Results showed that sodium nitrite increases thiobarbituric-acid reactive substances (TBARS in rat small intestinal mucosa and liver, and the agent did not have any effect(s) on the total anti-oxidant status (TAS) and lipid peroxidation of rat blood. Pretreatment of nitrite-poisoned rats with coenzyme Q10 mitigated TBARS and increased TAS in animal blood. Coenzyme Q10 has been found to be a promising anti-oxidant agent in sodium nitrite-induced lipid peroxidation.     

Blood concentration of coenzyme Q(10) increases in rats when esterified forms are administered

Coenzyme Q levels decrease during aging in most tissues and in the target organs of a number of diseases. The uptake of this lipid into the blood and other tissues was investigated in 6-wk-old male Sprague-Dawley rats after 3 wk of dietary supplementation. In addition to the natural form of coenzyme Q(10), acetylated and succinylated forms were also administered. Coenzyme Q(10) was taken up into the blood, but uptake was significantly greater in rats given the succinylated ( approximately 40%), and particularly, the acetylated forms ( approximately 70%). All three forms increased significantly the total coenzyme Q concentration in both the liver ( approximately 100%) and spleen ( approximately 130%). Coenzyme Q(10) and its esterified forms were not taken up into kidney, heart, muscle or brain. Intraportal and intraperitoneal administration of succinylated coenzyme Q(10) gave results similar to those obtained in the dietary experiments. Uptake of the dietary coenzyme Q(10) into the liver and spleen did not down-regulate the endogenous synthesis, i.e., the amounts of isolated coenzyme Q(9) did not change in these tissues. Thus, esterification of coenzyme Q increases the uptake of dietary lipid into the blood; however, the derivatization does not contribute to the elevation of coenzyme Q levels in various organs.     

Comparative study between single dose 600 microg and repeated dose of oral misoprostol for treatment of incomplete abortion

OBJECTIVE: To evaluate and compare the effectiveness and side effects of two regimens of oral misoprostol, single dose (600 microg) and repeated dose (1200 microg), in the treatment of incomplete abortion. METHODS: A prospective randomized controlled trial was conducted. One-hundred women who had incomplete abortion (gestational age < 20 weeks) and consented to randomization by computer-generated randomization model prior to treatment. A single oral 600-microg dose or repeated oral dose after 4 h (total 1200 microg) was given to the randomized women. RESULTS: The overall incidence of complete abortion was 86.9%. This incidence was not statistically different between the single-dose and repeated-dose groups (81.6% vs. 92%, p > 0.05). However, there was a significantly decreased incidence of diarrhea (18.4% vs. 40%, p < 0.05) with the use of single-dose treatment. Overall rate of acceptability and tolerable side effects were 88.9% and 97.9%, respectively. These rates were similar in both groups (87.8% vs. 90% and 98% vs. 98%, p > 0.05). CONCLUSIONS: Oral misoprostol may be a practical alternative in the management of incomplete abortion. Oral misoprostol is acceptable and tolerable to women. Single-dose regimen is as effective as repeated-dose regimen, with a reduction in the incidence of diarrhea.     

A 90-day repeated dose oral toxicity study of magnesium chloride in F344 rats

In order to examine the toxicity of magnesium chloride hexahydrate, four groups of 10 male and 10 female F344 rats received the compound by dietary supplementation at 2.5, 0.5, 0.1 or 0% for 90 days. No treatment-related death was observed during the study. Transient soft stool and sustained increase in water consumption were observed both in males and females of the 2.5% group and slight reduction in body weight gain was noted in the high-dose males. There were no toxic changes in food consumption, organ weights, hematology and biochemistry, and histopathological examinations in any treated-groups. Based on these results, the no-observed-adverse-effect-level was estimated to be 0.5%, and 2.5% is considered to be appropriate as highest dose for a 2-year carcinogenicity study.     

Increase of bioavailability of coenzyme Q(10) and vitamin E

Commercial coenzyme Q(10) (CoQ(10)) and alpha-tocopherol (vitamin E) formulations often show poor intestinal absorption. Delivery of CoQ(10) and vitamin E was enhanced when used with a new formulation, NanoSolve (Lipoid GmbH, Ludwigshafen, Germany), as shown by an open, comparative monocenter, crossover study of 24 volunteers. Plasma CoQ(10) and vitamin E were determined from predose until +14 hours. To compare bioavailability, corrected maximum concentration, time to reach maximum concentration, and area under the curve from 0 to 14 hours were assessed. The NanoSolve test formulation contained 100 mg of CoQ(10) and 120 mg of vitamin E. The pure substances in hard gelatin capsules served as the reference. Although identical amounts of CoQ(10) and vitamin E were administered, absolutely higher serum concentrations of the active ingredients were achieved by the NanoSolve formulation than by the pure materials in gelatin capsules. The bioavailability of CoQ(10) increased fivefold after administration of the NanoSolve formulation, and the bioavailability of vitamin E was enhanced 10-fold both compared to the pure substances.     

Potential role of ubiquinone (coenzyme Q10) in pediatric cardiomyopathy

Pediatric cardiomyopathy (PCM) represents a group of rare and heterogeneous disorders that often results in death. While there is a large body of literature on adult cardiomyopathy, all of the information is not necessarily relevant to children with PCM. About 40% of children who present with symptomatic cardiomyopathy are reported to receive a heart transplant or die within the first two years of life. In spite of some of the advances in the management of PCM, the data shows that the time to transplantation or death has not improved during the past 35 years. Coenzyme Q10 is a vitamin-like nutrient that has a fundamental role in mitochondrial function, especially as it relates to the production of energy (ATP) and also as an antioxidant. Based upon the biochemical rationale and a large body of data on patients with adult cardiomyopathy, heart failure, and mitochondrial diseases with heart involvement, a role for coenzyme Q10 therapy in PCM patients is indicated, and preliminary results are promising. Additional studies on the potential usefulness of coenzyme Q10 supplementation as an adjunct to conventional therapy in PCM, particularly in children with dilated cardiomyopathy, are therefore warranted.     

Oral toxicity of bismuth in rat: single and 28-day repeated administration studies

The consumption and production of bismuth are increasing, however there is very little information about the direct toxic effect of bismuth. The present study aimed to characterize the potential toxic effects of bismuth through oral administration and observation for fourteen days following single dose of 0 and 2,000 mg/kg (acute oral toxicity study), and repeated oral administration for twenty-eight days at dose levels of 0, 40, 200, and 1,000 mg/kg daily (28-d repeated oral dose toxicity study) to male and female Crj:CD (SD) IGS rats (SPF). We found no deaths and no abnormalities in clinical signs, body weights, and necropsy findings for any of the animals in the acute oral toxicity study and no changes attributable to bismuth in either males or females in the dose group up to 1,000 mg/kg of the 28-d repeated-dose toxicity study. Therefore, we determined that the lethal dose with a 50% mortality rate (LD50) is greater than 2,000 mg/kg and the no-observed-adverse-effect level (NOAEL) of bismuth is 1,000 mg/kg in both sexes. We conclude that the adverse toxic effects of bismuth as a simple metal substance are low compared to lead toxicity under the conditions tested in our studies.     

A 90-day repeated dose toxicity study of madder color in F344 rats: a preliminary study for chronic toxicity and carcinogenicity studies

A 90-day toxicity study of madder color was performed in F344 rats by feeding the pellet diet containing 0, 0.6, 1.2, 2.5 and 5.0% of test substance to clarify its toxic potential and to determine the dose levels for the following chronic toxicity/carcinogenicity studies. Body weight gain and food consumption were dose-dependently decreased at 1.2% or more in males and at 2.5% or more in females throughout the experimental period. All animals were survived until the end of experiment and subjected to autopsy. Hematologically, the following parameters were fluctuated in relation to the treatment: decreases in the red blood cells, hemoglobin, and hematocrit in females at 2.5% or more; increase of platelets in males at 2.5% or more, and in females at 5%; increase in white blood cells in males at 5%. Serum protein parameters were also affected by the treatment in males at 1.2% or more and in females at all doses. Increase in the serum calcium level was observed in males at 2.5% or more and in females at 5%. Serum inorganic phosphorus level was also increased in males at 1.2% or more and in females at 2.5% or more. At autopsy, both absolute and relative kidney weights of females increased dose-dependently at 0.6% or more. Relative liver weight in females also increased at 1.2% or more. Histopathologically, microvesicular vacuolar degeneration of proximal tubules was observed in the kidney of both sexes (males at 1.2% or more; females at 0.6% or more). In addition, mononuclear cell infiltration (both sexes) and hyaline casts and tubular regeneration (male) appeared in the kidney at 5%. In the female liver, focal liver cell necrosis associated with mononuclear cell infiltration was evident at 5%. The results demonstrate the toxic effects of madder color on the liver (in females at 5%) and kidney (in males at 1.2% or more; in females at 0.6% or more) of F344 rats when treated orally for 90 days. In addition, toxicities in hematopoietic system and/or bone would probably be appeared when rats are treated with 1.2% or more of madder color for long-term over 90 days. NOAEL was determined to be 0.6% in males, but could not be determined in females under the condition of this study. Based on the results of this study, the dose levels for subsequent chronic toxicity and carcinogenicity studies were determined to be 0.2, 1.0 and 5.0%, and 2.5 and 5.0%, respectively.     

六苄基六氮杂异伍兹烷大鼠28天重复剂量经口毒性

将40只成年SPF级SD大鼠按体重随机分为4组,分别给予淀粉溶液及250 mg/kg、500 mg/kg和1000 mg/kg的六苄基六氮杂异伍兹烷(HBIW)混悬液,连续给药28 d,进行重复剂量经口毒性试验。结果实验组和对照组大鼠在观察期内均未出现中毒症状和死亡,四组间二氧化碳(CO2)、平均血小板体积(MPV)、血小板分布宽度(PDW)、凝血酶原时间(PT)和国际标准化比值(INR)差异均有统计学意义,且实验组均高于对照组。组织病理学检查未发现明显改变。提示HBIW对大鼠凝血系统可能有损害作用。     

Comparison of the relative bioavailability of different coenzyme Q10 formulations with a novel solubilizate (Solu Q10)

The relative bioavailability of coenzyme Q10 (CoQ10) is markedly influenced by its delivery systems. The aim of this study was to compare four standard CoQ10 supplements available on the market with a novel solubilizate formulation of CoQ10 (Solu Q10). Pharmacokinetic parameters were assessed in 54 healthy volunteers after single and multiple intakes of 60 mg CoQ10 over a time period of 14 days. Solubilizates showed earlier flooding compared with oily dispersions and crystalline CoQ10, resulting in significantly elevated area under the curve between 0 and 4 h (P<0.01 solubilizates versus crystalline). The difference in the pharmacokinetic parameters of maximum plasma concentration, time to reach the peak plasma concentration and area under the curve between 0 and 12 h was not statistically significant between formulations. Long-term supplementation resulted in significantly higher plasma levels (P<0.01) for all formulations, with Solu Q10 performing best. Intracellular CoQ10 levels measured in buccal mucosa cells were increased (P<0.05) in response to supplementation when starting within the physiological range. In summary, solubilizates were clearly superior to oily dispersions and crystalline CoQ10 in their overall bioavailability, with the best absorption characteristics seen for the novel Solu Q10 solubilizate.     

辅酶Q10与营养素联合使用对大鼠体内抗氧化状态的影响

目的研究辅酶Q10(CoQ10,CQ)以及CoQ10与混合类胡萝卜素(番茄红素和叶黄素,LL)、锌硒(ZS)联合使用对大鼠抗氧化状态的影响。方法以AIN-76配方为基础制备大鼠饲料,并添加4%猪油,将大鼠按体重随机分为6组:对照组、CQ组[CQ 10mg/(kg·d)]、CQ+ZS组[CQ 10mg/(kg·d),Zn 1mg/(kg·d),Se 4μg/(kg·d)]、CQ+LL组[CQ 10mg/(kg·d),叶黄素1mg/(kg·d),番茄红素2mg/(kg·d)]、CQ+ZS+LL组[CQ 10mg/(kg·d),Zn 1mg/(kg·d),Se 4μg/(kg·d),叶黄素1mg/(kg·d),番茄红素2mg/(kg·d)]以及VE组[VE 2mg/(kg·d)]。8周后处死大鼠,测定各项抗氧化指标。结果CoQ10单独补充组血浆SOD、TOAC及肝SOD、GPX水平显著高于对照组,与其他物质联合补充能更进一步提高大鼠血浆和肝匀浆抗氧化酶活性,降低脂质过氧化和淋巴细胞自发性氧化损伤水平。结论CoQ10可以提高大鼠抗氧化能力,降低氧化损伤,与其他抗氧化物质联合补充的效果要强于单独补充。     

辅酶Q10对大鼠脑缺血再灌注所致氧化损伤及炎性反应的拮抗作用

目的 研究辅酶Q10对脑缺血再灌注所致氧化损伤及炎性反应的拮抗作用,并初步探讨其机制.方法 选择清洁级成年健康雄性Wistar大鼠40只,体重180～220 g,按体重随机分为对照组、假手术组、模型组(MCAO组)和辅酶Q10处理组(CoQ10组),每组10只.MCAO组和CoQ10组采用改良线栓法建立大鼠脑缺血再灌注模型(缺血2h,再灌注24h).CoQ10组造模前给予辅酶Q1010 mg/(kg·d)腹腔注射,其他组给予生理盐水10 ml/(kg·d)腹腔注射,连续1周.进行大鼠神经功能障碍评分并计算脑梗死面积,测定脑组织中超氧化物歧化酶(SOD)活力和丙二醛(MDA)含量以及血浆中C反应蛋白(CRP)、肿瘤坏死因子-α(TNF-α)含量.结果 与对照组比较,MCAO组和CoQ10组大鼠均出现神经行为学评分升高、脑梗死面积增大、脑组织SOD活力下降、MDA含量升高(P＜0.01),假手术组、MCAO组和CoQ1o组的CRP、TNF-α含量均升高(P＜0.01);与假手术组比较,MCAO组和CoQ10组神经行为学评分和脑梗死面积均升高(P＜0.01),脑组织SOD活力下降而MDA含量升高(P＜0.01),CRP、TNF-α含量均升高(P＜0.01);与MCAO组比较,CoQ10组的神经功能评分和脑梗死面积减小(P＜0.01),MDA含量下降而SOD活力升高(P＜0.01),CRP、TNF-α含量均下降(P＜0.01).结论 辅酶Q10对大鼠局灶性脑缺血再灌注损伤具有保护作用,其作用机制可能与清除自由基、抑制脂质过氧化以及减少炎性介质释放、抑制炎性反应有关.     

Redox levels of intravenously administered [14C]coenzyme Q10 and coenzyme Q10-reducing activity in subcellular fractions of guinea pig liver

The blood level of [14C]coenzyme Q10 and the redox levels of [14C]coenzyme Q10 in the liver and heart were measured after intravenous injection of [14C]coenzyme Q10 solubilized in multilamellar liposomes into guinea pigs. The blood level of radioactivity declined biexponentially with half-lives of 11.5 min and 15.6 h in the first and second phases, respectively. The levels of reduced [14C]coenzyme Q10 in the liver and heart reached 55.8 and 46.4%, respectively, of the labeled compound in the tissues at 30 min after the injection. Coenzyme Q10-reducing activity in cytosol, microsomes and mitochondria was also investigated. This activity was found in all the fractions. The total activity was the highest in the liver cytosol. Moreover, the results of experiments using a purified enzyme suggested that one of the coenzyme Q10-reducing enzymes was NAD(P)H: quinone oxidoreductase [EC 1.6.99.2, DT-diaphorase]. These results are discussed in relation to the protective effect of reduced coenzyme Q10 against lipid peroxidation in membranes.     

Acute administration of red yeast rice (Monascus purpureus) depletes tissue coenzyme Q(10) levels in ICR mice

In this study, we attempted to evaluate the effect of administration of a high quantity of red yeast rice on coenzyme Q10 (CoQ10) synthesis in the tissues of ICR mice. Eighty-eight adult male ICR mice were housed and divided into control and experimental groups for red yeast rice treatment. Animals were gavaged with a low (1 g/kg body weight) or a high dose (5 g/kg body weight, approximately five times the typical recommended human dose) of red yeast rice dissolved in soyabean oil. After gavagement, animals of the control group were immediately killed; mice of the experimental groups (eight for each subgroup) were killed at different time intervals of 0.5, 1, 1.5, 4 and 24 h. The liver, heart and kidney were taken for analysis of monacolin K (liver only) and CoQ10 analysis. Liver and heart CoQ10 levels declined dramatically in both groups administered red yeast rice, especially in the high-dose group, within 30 min. After 24 h, the levels of hepatic and cardiac CoQ10 were still reduced. A similar trend was also observed in the heart, but the inhibitory effect began after 90 min. The higher dose of red yeast rice presented a greater suppressive effect than did the lower dose on tissue CoQ10 levels. In conclusion, acute red yeast rice gavage suppressed hepatic and cardiac CoQ10 levels in rodents; furthermore, the inhibitory effect was responsive to the doses administered.