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Biomedical subjects

A Bär

Publications and source records attributed to A Bär.

At least 19 recordsLinked to original sources
PubMed1996

Disposition of 14C-erythritol in germfree and conventional rats.

The metabolism and disposition of U-14C-erythritol was examined in four groups of three male and three female, nonfasted rats each. The rats of groups A and D were germfree; the rats of groups B and C were kept under conventional conditions. The rats of group B received an erythritol-supplemented diet for 3 weeks prior to the experiment (adapted rats). The rats of groups A, C, and D were kept on an ordinary diet which was sterile for groups A and D (not adapted rats). On the day of the experiment, each rat was dosed with U-14C-erythritol by gavage (5 microCi/kg body wt; sp act 50 microCi/g erythritol). The radiochemical purity of the erythritol was 96.43% for groups A-C. Group D, which was attached to the study after evaluation of the results of groups A-C, received a more purified erythritol with a radiochemical purity of 99.46% because the data of group A pointed to a possible interference by a 14C-labeled impurity in the commercial 14C-erythritol. After dosing, respiratory CO2 and urine were collected from each rat at regular intervals for 24 hr. At termination, feces were also collected. The animals were killed and intestinal contents, organs, tissues, and the remaining carcass processed for determination of 14C-14C was excreted rapidly in the urine of all groups (range of groups A-D: 47.3-60.6% of the administered dose within the first 4 hr). Total 24-hr urinary excretion varied between 67.0% (group B) and 81.4% (group D). HPLC analysis of the urine showed that more than 96% of the eluted radiolabel represented erythritol. Conventional, adapted rats expired more 14CO2 than conventional, unadapted rats [10.9% (B) vs 6.7% (C)]. Germfree rats expired much less 14CO2 [0.8% (A) and 0.3% (D)]. In germfree rats, 14CO2 expiration started shortly after dosing, reaching half of the 24-hr excretion after about 2.5 hr. In conventional rats 14CO2 expiration started with a delay of about 2 hr reaching half the 24-hr excretion after 4-6 hr. The excretion of 14C with feces was similar in all groups (8.3% on average of all rats). Slightly more 14C was retained in the intestinal contents of germfree than conventional rats (1.9 vs 0.5%). The body retention was higher in conventional than in germfree rats (3.4 vs 2.0%). In group D, body retention was lowest (1.6%). The total recovery of 14C was similar in all groups (95.6%, average of all rats). It is concluded that ingested erythritol is efficiently absorbed mainly from the small intestine, is not metabolized to a relevant extent in the body, and is excreted unchanged in the urine. The fraction of erythritol not absorbed is fermented by the gut microflora to intermediate products which are largely absorbed and metabolized. The data support a proposed physiological energy value for erythritol of about 0.5 kcal/g.

Absorption↗
PubMed1996

Subchronic oral toxicity studies with erythritol in mice and rats.

Erythritol is a sugar alcohol (polyol) with potential applications as a low-calorie, bulk sweetener. Ingested erythritol is efficiently absorbed and excreted unchanged via the urine since it is not metabolized systemically by the animal or human body. Erythritol was administered to four groups of 10 male and 10 female Swiss CD-1 mice and four groups of 15 male Wistar Crl:(WI) WU BR rats at dietary levels of 0, 5, 10, or 20% for 90 days. A fifth group of rats received a diet containing 20% erythritol on a time-restricted basis (6 hr/day), and a sixth group received a diet containing 20% mannitol for comparison. There were no treatment-related mortalities in either mice or rats. Soft stools and occasional diarrhea were observed in rats fed diets with 20% erythritol or mannitol but not in mice. Body weights were slightly yet significantly reduced in rats fed 20% erythritol or mannitol and in male mice of the 20% dose group. Erythritol intake in the high-dose group was approximately 12 g/kg body wt in rats and 44 and 45 g/kg body wt in male and female mice, respectively. Hematological and clinicochemical examinations of blood and plasma did not reveal any treatment-related effects. Urine output increased with increasing erythritol dose. In male and female mice of the 20% erythritol group, the creatinine-normalized urinary excretion of protein, K-glutamyltransferase (GGT), and electrolytes (Na+, K+, Ca2+, Pi, citrate) was significantly increased while urinary N-acetylglucosaminidase (NAG) remained unchanged. At the 10% level, significantly increased urinary protein (both sexes) and GGT (males only) excretion were seen. In rats, the creatinine-normalized urinary excretion of GGT, NAG, and some electrolytes (Na+, K+, and Ca2+) was increased in some erythritol groups but a clear dose-response relationship was evident only for calcium. On termination of the study, cecal enlargement was seen in rats of the 10 and 20% dose groups and in mice of the 20% dose group. Increased relative and absolute kidney weights were observed in both sexes of mice in the 20% erythritol group, in male mice of the 5 and 10% groups, and in rats of the 10 and 20% erythritol groups. Histopathological examination did not reveal any treatment-related abnormalities in either mice or rats. In conclusion, the ingestion of erythritol for 90 days at dietary levels of up to 20% did not produce signs of toxicity in mice or rats. In particular, the morphological integrity of the kidneys was not adversely affected by the treatment in either species. The increases in urinary excretion of protein, GGT, NAG, and electrolytes were considered to result from extensive osmotic diuresis and a potential overload of the renal excretory system at the high dose levels employed.

Administration, Oral↗
PubMed1996

Embryotoxicity and teratogenicity study with erythritol in rats.

The embryotoxicity/teratogenicity of erythritol, a low-calorie polyol sugar substitute, was examined in Wistar Crl:(WI) WU BR rats. Erythritol was fed at dietary concentrations of 0, 2.5, 5, and 10% to groups of 32 female rats from Day 0 to 21 of gestation. The treatment was generally well tolerated and no mortality occurred in any group. Weight gain during gestation, food consumption, and food efficiency were similar in all groups except for a significantly reduced weight gain in the 10% erythritol group in Week 2 of gestation. Reproductive performance was not affected by the treatment but the fertility index was generally rather low (69% in both control and high-dose group). Examination of the fetuses for external, visceral, and skeletal alterations did not reveal any fetotoxic, embryotoxic, or teratogenic effects. The slightly lower maternal body weight in the high-dose group was interpreted as a trivial result of the consumption of a low-calorie test substance in high amounts. In conclusion, no adverse effects were observed at erythritol doses of up to about 6.6 g/kg body wt/day, i.e., the highest dose tested.

Abnormalities, Drug-Induced↗
PubMed1996

Two-generation reproduction study of erythritol in rats.

Erythritol was fed at dietary concentrations of 0, 2.5, 5, or 10% to Crl:(WI) WU BR rats of both sexes through two successive generations (F0 and F1). Twenty-four rats of each sex were mated in each group. For each generation one litter was reared until the pups were 21 days old. In the 10% erythritol group, food consumption among F0-males and -females was initially significantly reduced until the animals adapted to the erythritol diet during the first week of the study. Thereafter, food intake was higher than in controls. A consistently increased food intake also was seen in F1-males and-females of this dose group. This effect was considered to result from the caloric dilution of the food by erythritol, which has a low physiological energy value. The lower body weight and weight gain of the F0-animals of the 10% erythritol group were attributed to the initially reduced food consumption and occurrence of transient diarrhea until the animals had adapted to the erythritol intake. In the F1-animals of the 10% erythritol group, which were adapted to the treatment from weaning, the rate of body weight gain did not differ from controls. The F1-males and -females of this dose group did, however, have a reduced body weight from weaning, which was attributed to a reduced energy intake among the corresponding F0-dams during Weeks 2 and 3 of lactation. This effect was not seen in the F2-generation. It is concluded that under the conditions of this experiment, the intake of erythritol had no adverse effect on fertility and reproductive performance of parent rats or on the development of their progeny. Gross necropsy and microscopic examination of the parenteral reproductive organs also did not reveal treatment-related changes.

Animals↗
PubMed1996

Chronic toxicity and carcinogenicity study of erythritol in rats.

The potential toxicity and carcinogenicity of erythritol, a low-calorie sugar substitute, were examined in Wistar Crl:(WI) WU BR rats. Groups of 50 rats of each sex consumed diets with 0, 2, 5, or 10% erythritol, or 10% mannitol, for a period of 104-107 weeks. To each of these main groups, two satellite groups of 20 males each were attached for interim kills after 52 and 78 weeks of treatment. At start of the study, the rats were 5-6 weeks old. The average intakes of erythritol in the 2, 5, and 10% groups were 0.9, 2.2, and 4.6 g/kg body wt/day for males and 1.0, 2.6, and 5.4 g/kg body wt/day for females, respectively. Mannitol intakes were 4.4 and 5.2 g/kg body wt/day in males and females, respectively. All treatments were well tolerated without diarrhea or other side effects. Body weights were significantly below control levels during most of the study in males of the 5% erythritol group and in males and females of the 10% erythritol and 10% mannitol groups. Survival of the animals was not adversely affected by the treatments. Hematological and clinicochemical examinations did not reveal noticeable changes which could be attributed to treatment. Analysis of urine samples collected during five 48-hr periods, from rats of the satellite groups in Weeks 26, 42, 50, and 78 and from rats of the main groups in Week 102, showed that about 60% of ingested erythritol was excreted unchanged. The urine volumes increased with increasing dietary erythritol levels. In line with previous observations on other polyols, erythritol and mannitol ingestion led to an increased excretion of urinary calcium and citrate. The urinary excretions of sodium, potassium, phosphate, N-acetylglucosaminidase (NAG), gamma-glutamyltransferase (GGT), low-molecular-weight protein (LMP), and total protein (TP) were slightly elevated in the 10% erythritol group. Increased GGT and NAG excretions also were seen occasionally at the 5% dose. Significantly increased relative cecum weights were seen in rats of either sex in the 10% mannitol and, somewhat less pronounced, 10% erythritol groups. Some cecal enlargement also was seen in the 5% erythritol group. The relative weight of the kidneys was highest in the 10% erythritol group, the difference from controls reaching statistical significance at interim kills (males) and termination (females). Except for more frequent pelvic nephrocalcinosis in female rats of all erythritol dose groups, the histopathological examinations did not reveal any nonneoplastic, preneoplastic, or neoplastic changes that could be attributed to the ingestion of erythritol. In male and female rats of the 10% mannitol group, pelvic nephrocalcinosis, which in females was associated occasionally with pelvic hyperplasia, was the only remarkable finding. The incidence and progression of nephrosis, which is commonly seen in aging rats of this strain, were not influenced by the treatments. In the absence of morphological alterations in the kidneys or other signs of nephrotoxicity, the increased excretions of NAG, GGT, LMP, and TP are regarded as innocuous, functional sequelae of the renal elimination of erythritol. In conclusion, the toxicological profile of erythritol in rats resembles that of other polyols in several respects. Except for nephrocalcinosis, which is commonly seen in polyol-fed rats, no other treatment-related, morphological changes were observed in the kidneys. Evidence for a tumor-inducing or tumor-promoting effect of erythritol was not seen.

Acetylglucosaminidase↗
PubMed1996

Tolerance to subchronic, high-dose ingestion of erythritol in human volunteers.

Erythritol is a sugar alcohol (polyol) which is absorbed from the small intestine in substantial amounts, not metabolized in the human body, and therefore excreted in the urine. Erythritol holds promise as a low-calorie sugar substitute. Human tolerance to repeated oral doses of erythritol was examined in a double-blind, two-way crossover study in 12 healthy, male volunteers. The participants consumed erythritol and, for comparison, sucrose for a duration of 7 days each. The daily dose of the test compounds ingested was 0.3 g/kg on Day 1, 0.6 g/kg on Day 2, and 1.0 g/kg on subsequent days. The daily dose was consumed under supervision in five portions, i.e., with the three main meals, a midmorning snack, and during the afternoon. The test compounds were incorporated into yoghurt, cookies, soft drinks, and chocolate. On each treatment day, body weight and blood pressure were measured and the participants were interviewed about side effects and their perception of stool and urine production. During the last 96 hr of each treatment period, urine was collected at 3-hr intervals during the day and for a 9-hr interval overnight for analysis of erythritol and different urinary parameters. On Days 3 to 7 of each treatment period, the participants were institutionalized. Body weights and blood pressure remained stable during the entire study. Signs of gastrointestinal intolerance were not seen and stool frequency and appearance were not different between the two treatments. The intake of liquids, which were provided ad libitum, was generally rather high (32.8 g/kg body wt/day on average) but not different between erythritol and sucrose consumption. Urine output also was high during both treatment periods. About 78% of ingested erythritol was excreted in the urine which led to a higher urinary osmolality but did not influence the 24-hr output of creatinine, citrate, urea, or electrolytes (Na+, K+, Cl-, Pi). The excretion of calcium was slightly higher during the erythritol test period but in absolute terms this increase was small. The urinary excretions of albumin, beta 2-microglobulin, and N-acetyl-glucosaminidase were slightly elevated during the erythritol test period but they were still well within the physiological range. None of the observed urinary changes became more pronounced with increasing duration of the erythritol treatment. In conclusion, the results of the present study demonstrate that the repeated ingestion of erythritol at daily doses of 1 g/kg body wt was well tolerated by humans.

Administration, Oral↗
PubMed1995

Metabolic disposition in rats of regular and enzymatically depolymerized sodium carboxymethylcellulose.

Partially enzyme-hydrolysed sodium carboxymethylcellulose (CMC-ENZ), which holds promise as a new, functional food ingredient, is obtained from sodium carboxymethylcellulose (CMC) by enzymatic hydrolysis with a cellulase preparation from Trichoderma longibrachiatum. In the safety evaluation of CMC-ENZ, a comparative disposition study on 14C-labelled CMC and CMC-ENZ was conducted in conventionally kept rats. The 14C label was in the two C atoms of the carboxymethyl group. Two groups of four male and four female rats each were fed diets with 5% unlabelled CMC or CMC-ENZ for a 2-wk adaptation period. A single oral dose of 14C-CMC or 14C-CMC-ENZ solution was then given by gavage (500 mg/kg body weight). Respiratory CO2, urine and faeces were collected at regular intervals, and after 120 hr organs, tissues and the carcass were sampled as well. For both experimental groups, total mean recovery of 14C was 98%, about 95% of the label being excreted with the faeces, 2% or less in the urine, 1% or less with CO2 and a small fraction being retained in the body (CMC, 0.58%; CMC-ENZ, 0.75%). Tissue retention of 14C was highest in the liver of rats of both experimental groups. Only about 49 and 65% of the faecal 14C was extracted with water in the 14C-CMC and 14C-CMC-ENZ dosed rats, respectively. Gel permeation chromatography (GPC) of the dosing solutions and the faecal extracts revealed that CMC is depolymerized during intestinal passage whereas CMC-ENZ is excreted nearly unchanged. Consequently, the molecular weight distribution of the 14C-CMC and 14C-CMC-ENZ faecal excretion products was similar. It is concluded that there is no toxicologically relevant difference between the disposition of CMC and CMC-ENZ.

Administration, Oral↗
PubMed1995

Subchronic oral toxicity study with regular and enzymatically depolymerized sodium carboxymethylcellulose in rats.

Enzymatically depolymerized sodium carboxymethylcellulose (CMC-ENZ) is a new functional food ingredient which has a lower molecular weight and viscosity than regular sodium carboxymethylcellulose (CMC). Both compounds are known not to be absorbed to a significant extent, and the human safety of CMC as a thickening agent and stabilizer in food is well established. In the present study, the subchronic oral toxicity of CMC-ENZ was examined and compared with that of CMC in Wistar rats. Seven groups of 20 rats/sex were fed diets with 0 (controls), 2.5, 5 and 10% CMC and 2.5, 5 and 10% CMC-ENZ for a 3-month period. There was only one death that was unrelated to the treatment. Water intake, urine production and urinary sodium excretion increased with increasing doses of CMC and CMC-ENZ due to their sodium content of about 7-8%. The treatment-related occurrence of diarrhoea and caecal enlargement in the mid- and high-dose groups, a slight increase of plasma alkaline phosphatase, and increased urinary calcium and citrate excretions were considered to be generic effects that typically are observed in rodent studies with low digestible carbohydrates. The increased occurrence of nephrocalcinosis and hyperplasia of the urothelial epithelium in some of the treated groups was interpreted as an indirect consequence of a more alkaline urine coupled with an increased calcium excretion. As the frequency and severity of all these changes did not differ between corresponding CMC and CMC-ENZ dose groups, it is concluded that the two products have a similar toxicological profile.

Administration, Oral↗
PubMed1992

Intake of intense sweeteners in Germany.

The dietary intake of aspartame, cyclamate, and saccharin was evaluated in Germany (FRG) in 1988/89. In the first part of the study the sweetener intake was evaluated in a representative sample of the population. Complete 24-h records of the amount and type of all foods and drinks consumed were obtained from 2,291 individuals. The total daily intake was calculated for each person from the sweetener content of each product and was expressed in mg/kg body weight (bw). 35.9% of the participants ingested one or more sweeteners on the examination day. Cyclamate and saccharin were the prominent sweeteners because aspartame was at that time permitted only under special regulatory exemption, and products containing acesulfame were not yet available. For users of intense sweeteners the mean intakes of aspartame, cyclamate, and saccharin were 0.15, 2.62, and 0.250 mg/kg bw/day, respectively. At the 90th percentile of intake, i.e., for the heavy consumer, the ingestion of cyclamate and saccharin was about 2.5 times higher. Persons who adhered to a diet (diabetes, weight control) did not ingest sweeteners in substantially higher amounts. Tabletop sweeteners and beverages were the most important sources of sweeteners, and they contributed more than 80% of the total intake. Consumption of sweeteners in excess of the Acceptable Daily Intake (ADI) was rarely observed (saccharin: one person, cyclamate: 16 persons). In the second part of the study, the sweetener intake was further evaluated during a 7-day period in those subjects who in the 1-day study ingested any of the sweeteners in excess of 75% of the ADI. Complete 7-day food records were available from 40 out of the 41 subjects who fulfilled this criterium. In this selected subgroup in which 19 subjects were less than 19 years old, the mean daily intakes of aspartame, cyclamate, and saccharin were 0.13, 4.53, and 0.42 mg/kg body weight (bw), respectively. These levels correspond to 0.33, 41 and 17% of the corresponding ADI values. No subject exceeded the ADI of aspartame or saccharin on any day of the study. For cyclamate, the mean daily intake over the 7-day period exceeded the ADI in 4 subjects. The results indicate that at the time of the study the then valid German sweetener regulation protected the consumer adequately, and that the sweetener intake was in 99.8% of all examined persons within recommended limits.

Adolescent↗
PubMed1989

Chronic stimulation-induced changes of myosin light chains at the mRNA and protein levels in rat fast-twitch muscle.

Transitions in the expression of the myosin light chains (LC) were investigated in fast-twitch muscles of the rat during chronic (10 h/day), low-frequency (10 Hz) stimulation. Changes were followed at the mRNA level by Northern blot analysis and in vitro translation, as well as at the protein level by electrophoresis under denaturing and nondenaturing conditions. In vivo synthesis of the light chains was assessed by measuring the incorporation of intramuscularly injected [35S]methionine. Chronic stimulation induced a transition in the isomyosin pattern with an increase of FM3, a concomitant decrease in FM1 and, after longer stimulation periods, the appearance of low concentrations of the slow isomyosin. These changes were accompanied by an elevated LC1f/LC3f ratio and increases in the amounts of both the LC1sb and, to a lesser degree, LC2s proteins. Alterations in the amounts of specific mRNAs were the same whether determined by Northern blot analysis or by in vitro translation of total RNA preparations from the same muscles. Generally, the changes in the relative concentrations of fast and slow light-chain proteins agreed with the changes detected at the mRNA level and the alterations in protein synthesis detected with the use of an in vivo labeling assay. An exception was the elevated tissue content of LC2s where no changes were detectable in the concentration of its mRNA as determined by in vitro translation or in vivo synthesis. The increase in LC2s protein may, therefore, have been due to reduced degradation. In addition, the decrease in LC3f was more pronounced at the protein level than at the mRNA level. This might indicate an increased turnover of LC3f or the existence of additional post-transcriptional regulations of LC3f expression.

Animals↗
PubMed1989

Altered expression of myosin light-chain isoforms in chronically stimulated fast-twitch muscle of the rat.

Fast-twitch tibialis anterior muscle of the rat was chronically stimulated for periods of 18 days, 28 days and 56 days. Changes in the myosin light-chain (LC) pattern consisted in an increase in LC1f, concomitant with a decrease in LC3f. In contrast to previous findings in chronically stimulated fast-twitch tibialis anterior muscle of the rabbit, no substantial increases occurred in the slow myosin light-chain isoforms. In vivo labeling using [35S]methionine incorporation revealed differences in relative turnover between the fast myosin light chains. The relative turnover of the fast myosin light chains appeared to increase in normal muscle in the order LC2f less than LC1f less than LC3f. As judged from [35S]methionine incorporation, the changes in light-chain tissue content mainly resulted from altered synthesis rates. However, in the case of LC3f the decrease in protein content could not only be explained by a reduced synthesis, but, additionally, appeared to be due to enhanced degradation. Parvalbumin, which was included in the present study, was also found to decrease in the stimulated muscle. However, its decrease appeared to result primarily from reduced synthesis.

Animals↗
PubMed1988

Three fast myosin heavy chains in adult rat skeletal muscle.

A new fast myosin heavy chain isoform was electrophoretically detected in adult rat skeletal muscles. It was present at high levels in diaphragm and, therefore, designated as MHCIId. Appreciable amounts of MHCIId were detected in tongue musculature, the extraocular muscles, and in the deep red portions of various fast muscles. Its concentration in fast-twitch muscle was greatly increased by chronic stimulation.

Animals↗