Riboflavin laurate nanosuspensions as an intramuscular injection for long-term riboflavin supplementation.

The aim of this study was to prepare riboflavin laurate (RFL) nanosuspensions as an intramuscular injection for long-term riboflavin supplementation. Stable RFL nanosuspensions were obtained by injecting RFL/poloxamer solution in N,N-dimethyl formamide into a trehalose solution. Long soft nanostructures initially appeared and then tube-like rigid nanostructures were obtained after removal of solvents according to the transmission electron microscopic images. The nanosuspensions had narrow size distribution and the mean size was about 300 nm. Molecular self-assembly of RFL may drive the formation of nanostructures. RFL formed a monolayer at the air/water interface and poloxamer 188 could insert into the monolayer. The nanosuspensions were intramuscularly injected into rats to provide long-term riboflavin supplementation for more than 30 days in light of body weight, food intake, and urinary riboflavin. The nanosuspensions were also used to resist the riboflavin deficiency induced by methotrexate chemotherapy. RFL nanosuspensions are a promising nanomedicine for long-term riboflavin supplementation.

Methazid-induced vitamin B2 deficiency in rats and its prevention.

It has been estimated that ten-day rectal administration of metazid in the form of suppositories (20 mg per 100 g of body mass) gives rise to vitamin B2 deficiency both in rats with initial vitamin B2 insufficiency and in those adequately supplied. This is confirmed by a decrease in the vitamin B2 content both in the liver and in the blood plasma. Development and use of suppositories containing combined preparation of metazid and riboflavin (in the dose of 100 micrograms per a rat according to the daily recommended allowance) completely prevent metazid-induced vitamin B2 deficiency.

[Metazid-inducible vitamin B2 deficiency in rats and its prevention]. / Metazidindutsiruemaia nedostatochnost' vitamina B2 u krys i ee predotvrashchenie.

Rectal administration of metaside (20 mg per 100 g body weight) as suppositories for 10 days was found to cause vitamin B2 deficiency both in rats on low-vitamin B2 diet and in those on balanced diet. This appeared as decreased vitamin B2 levels in the liver and plasma. The design and application of suppositories containing the mixed preparation of metaside and riboflavin drug (in a dose of 100 micrograms per rat, which corresponds to the recommended daily requirement) completely prevents vitamin B2 deficiency.

Riboflavin deficiency caused by treatment with adriamycin.

The present study was undertaken to determine whether administration of adriamycin causes the depletion of riboflavin content. Rats received intraperitoneal injections of adriamycin (4 mg per kg body weight) for 6 consecutive days. Urinary riboflavin excretion began to increase after 2 days of treatment with adriamycin. Erythrocyte FAD levels decreased gradually and plasma lipid peroxide contents increased markedly at the 6th day. The activity coefficient of erythrocyte glutathione reductase showed a significant increase before the decrease of flavin content and the elevation of lipid peroxide level. Therefore, the value of this coefficient obtained from erythrocyte appears to be a reliable index of riboflavin deficiency, particularly during the early stage.

[Distribution and replenishing of riboflavin in albino mice with acute alcoholic intoxication]. / Raspredelenie i obnovliaemost' riboflavina v organizme belykh myshei v usloviiakh ostroi alkogol'noi intoksikatsii.

It is shown that acute alcohol intoxication in the tissues of white mice accelerates riboflavin metabolism. In this case arrival of the exogenous vitamin with accompanying depletion of its endogenous resources is observed to intensify.

Analysis of the syndrome of congenital malformations induced in genetically defined mice by acute riboflavin deficiency.

The role of genetics in the expression of a complex syndrome of teratologically induced congenital malformations was examined by the use of three inbred strains and 15 related crosses of mice. The syndrome, which included various limb, brain, orofacial, gastrointestinal, and miscellaneous malformations, was induced by an intense riboflavin deficiency produced by feeding the antagonist galactoflavin during midgestation. Analyses of the data showed that, although all three strains shared the major and most other features of the syndrome, there occurred in its manifestation vast quantitative and qualitative differences among them, in which they were resembled by their related crosses such as to constitute strain-specific malformation patterns. The results can be regarded as typifying an animal counterpart of human situations, the three strains representing in toto the mouse family, each strain individually exhibiting the variety that occurs between siblings in expressing a single syndrome.

New approaches to the possible prevention of side effects of chemotherapy by nutrition.

In an effort to develop new methods for preventing side effects of chemotherapy, the authors initiated studies to determine whether Adriamycin (doxorubicin) inhibits the metabolism of riboflavin (vitamin B2). Adriamycin has been shown to form a 1:1 stoichiometric complex with riboflavin, as well as to compete for binding to tissue proteins. Adult rats treated with Adriamycin in clinically relevant doses were compared to control animals in ability to convert riboflavin into flavin adenine dinucleotide (FAD), the active flavin coenzyme derivative, in heart, skeletal muscle, liver, and kidney. Rats treated with Adriamycin exhibited diminished formation of carbon 14 (14C)FAD in skeletal muscle to nearly 50% that of controls, and in heart to about 70% to 80% of controls. Under these conditions, (14C)FAD formation in liver and kidney was largely unaffected by Adriamycin. In preliminary studies, riboflavin-deficient animals treated with Adriamycin had accelerated mortality rates compared to those of food restricted controls treated with similar doses of Adriamycin. The data as a whole suggest a potential mechanism for Adriamycin-induced cardiac and skeletal myopathy, i.e., inhibition of synthesis of FAD, a flavin coenzyme which is involved in electron transport, lipid metabolism, and energy generation. These findings in an animal model raise the possibility that defects of riboflavin nutriture, either dietary or drug-induced, may be a determinant of Adriamycin toxicity. Further studies are required to explore the potential for preventing side effects due to Adriamycin by administration of this vitamin.

Development of riboflavin deficiency in alcohol-fed hamsters.

Riboflavin deficiency may be induced by dietary restriction or by drugs. High incidence of rifoflavin deficiency in alcoholics might be due to diet, to the toxic effect of alcohol, or to an interaction of these variables. Aims of this study were to investigate the effects of alcohol on the riboflavin status of Syrian hamsters fed three different levels of riboflavin in a liquid diet. Male Syrian outbred hamsters of 5 weeks of age, acclimated to liquid diets, were randomly assigned to groups that received alcohol-containing diets (AR0, AR1, AR2) or nonalcohol-containing diets (OR0, OR1, OR2) where R1 = 0.5 microgram riboflavin/kcal added and R2 = 1.5 microgram riboflavin added/kcal. No alcohol groups were pair-fed to the alcohol groups. Riboflavin status was monitored by repeated erythrocyte glutathione reductase assays. Animals were sacrificed at 13 weeks of age and liver flavins were determined. Riboflavin depletion occurred during the first 2 weeks of the study and this was followed by a 4-week period of relative improvementin riboflavin status. Thereafter riboflavin depletion continued in all groups but most severely in the alcohol group as measured by erythrocyte glutathione reductase assays. Total liver flavins were lowest in the alcohol-fed, riboflavin-restricted group, indicating that chronic alcohol feeding can induce riboflavin deficiency when intake of the vitamin is marginal.

Effect of diet on vitamin deficiencies in retarded individuals receiving drugs.

A population of mentally retarded and physically disabled individuals on long-term therapy with anticonvulsant drugs had a high prevalence of folic acid and riboflavin deficiency, 20% and 17%, respectively, as they entered an institution devoted to their care. Their previous diet was probably nutritionally marginal, as it was cooked and prepared to baby food consistency, and milk was rarely given. They were fed in the recumbent position, resulting in frequent vomiting. In this institution, a carefully planned dietary regimen that was adequate in essential nutrients was fed by trained personnel. Drug therapy was continued. After a year no signs of folic acid or riboflavin deficiency were evident. We conclude that these weak vitamin antagonists may precipitate deficiencies on marginally adequate diets. A good dietary regimen prevented the appearance of these vitamin deficiencies.

Vitamin status in patients on chronic anticonvulsant therapy.

Vitamin levels in blood were estimated in 146 epileptics, aged 20-40 years. Compared to healthy subjects, no higher risk rates of a vitamin deficiency were found in epileptics for vitamins B1, B12, A, C, E and beta-carotene. alpha EGR was elevated only in epileptic females, alpha EGOT in epileptic males, indicating a higher risk of a vitamin B2 and B6 deficiency in these groups. Markedly reduced levels of folate, 25-hydroxy-cholecalciferol, and biotin were found in the epileptics; folate and biotin levels showed a significant negative correlation with the total amount and the average daily dose of anticonvulsants administered.

Drugs and vitamin deficiency.

During the past 10 to 20 years it has become increasingly clear that a certain number of drugs may lead to increased vitamin requirements. However, it is unusual for symptomatic avitaminosis to develop, and then only when circumstances are present which in themselves increase the risk of vitamin deficiency. Therapeutic doses of drugs will interfere with the vitamin status only to a restricted degree, provided they are administered for brief periods and to patients receiving a normal supply of vitamins. Most cases of vitamin deficiency have in fact been described in connection with drugs usually taken for a longer period of time by patients who were already in negative vitamin balance as a result of disease or marginal supply of the necessary vitamins. This review describes some of the more important articles covering this topic.

Riboflavin nutriture of oral contraceptive users.

A Cross-Sectional and Follow-UP study of young women taking oral contraceptive agents (OCA) revealed no significant adverse effect of OCA Bon riboflavin nutriture. Three of 33 women in the Cross-Sectional study had biochemical evidence of deficiency, while only 1 of the 12 women in the Follow-Up study developed biochemical deficiency after a period of 3 months. The biochemical riboflavin status showed no relationship with the duration of OCA use. Dietary riboflavin intake was adequate in the majority of the subjects and revealed no correlation with activity coefficient of erythrocyte glutathione reductase activity.

PIP: A cross-sectional and follow-up study was conducted to determine the biochemical effects of oral contraceptives (OCs) on the vitamin B2 nutriture of 65 young healthy women ( 18 years old). The subjects were divided into: 1) control group (N = 20 women, 18-23 years of age who had never taken OCs); 2) the cross-sectional study group (N=33 women, 18-28 years of age who had been on OCs for at least 3 months); and 3) follow-up study group comprising of 12 women (18-23 years) who had never used OCs and who were studied before the initiation of OC use and after 3-6 months of OC use. Food intake data for 3 days were recorded by the subjects using the weighed inventory method. Blood samples (10 ml) were collected in heparinized tubes after an overnight fast. Erythrocyte glutathione reductase activity (EFR) with and without addition of flavine adenine dinucleotide (FAD) in vitro was estimated using the method of Nichoalds. 3 of 33 women in the cross-sectional group manifested biochemical deficiency of riboflavin while in the follow-up group, only 1 developed biochemical deficiency after 3 months. Biochemical riboflavin status did not correlate with OC use. Most of the subjects had adequate riboflavin intake. No correlation was observed between riboflavin intake and activity coefficient of EGR. In developing countries it is possible that the combined effects of poor dietary riboflavin nutrition and OCs contribute to the further deterioration of dietary riboflavin nutrition. Further research should be done to determine why some women are prone to riboflavin deficiency and others are not.

Riboflavin deficiency in women taking oral contraceptive agents.

The effect of oral contraceptive agents (OCA) on riboflavin nutritional status of women of child-bearing age in a low socioeconomic population was studied. For a control group, 100 women in the same age and socioeconomic group using alternate forms of contraception were selected. Riboflavin deficiency was determined by measuring erythrocyte glutathione reductase activity, a reliable index of the deficiency. None of the women was on vitamin supplements or had clinical conditions effecting dietary intake or utilization. Eleven of 100 women in the control group had biochemical evidence of deficiency. This compared to 24 of 56 OCA users who were deficient. The frequency of deficiency increased among those on OCA for longer periods of time. Thirteen of 17 OCA users for 3 years or more, compared to 11 of 39 users under 3 years were deficient. There were no discernable dietary differences between the groups. These studies demonstrate that riboflavin deficiency is a problem of women in the lower socioeconomic level in the child-bearing age. The use of OCA aggravates the prevalence of deficiency.

Effects of galactoflavin-induced riboflavin deficiency upon rat hepatic cell ultrastructure.

The primary cytoplasmic effect of galactoflavin-induced riboflavin deficiency upon rat liver cells involved focal sites of degradation which were manifested by the formation of membranous whorls. The nuclear effect of riboflavin deficiency concerned fluctuations in the total number of perichromatin granules per nucleus. These granules increased in number during the deficiency reaching a peak at three weeks. Nucleoli appeared compact with no evidence for segregation of nucleolar components. The possible correlation between increased synthesis of perichromatin granules and altered protein synthesis is discussed.

Effects of riboflavin deficiency on the ultrastructure of rat sciatic nerve fibers.

Ultrastructural studies indicate that riboflavin deficiency induced by either dietary restrictions alone or with the addition of the antagonist galactoflavin severely affects the structural integrity of myelin lamellae. The degenerative process induced by riboflavin deficiency is time dependent. Nonmyelinated nerve fibers are not affected ultrastructurally by the deficiency. Cellular organelles of both myelinated and nonmyelinated nerve fibers remain intact and presumably functional.

Preventive effect of riboflavin and ATP on the teratogenic effects of the phenothiazine derivative T-82.

To examine the hypothesis that the teratogenic effects of the phenothiazine derivative T-82 are due to its causing a riboflavin deficiency day 11 or 12 pregnant CB Wistar rats were each given 2,000 mg/kg T-82 po plus 100 mg/kg riboflavin ip, 12.4 mg/kg ATP ip, or both. The rates of fetal mortality and external malformations were significantly decreased in all supplementation experiments. The frequencies of cleft palate, micrognathia, and micromelia were unchanged but those of ectopic testis and hydrops fetalis were significantly increased in the group treated with T-82 and ATP on day 12.