betadex and Weight-Gain

A series of studies were conducted to assess Polysorbate 80 (PS80), Propylene Glycol (PG), and Hydroxypropyl-β-Cyclodextrin (HPβCD), when compared with Hydroxypropyl Methylcellulose (MC) in developmental and reproductive toxicology (DART) studies.. In the rat fertility study, 20 mg/kg MC, 10 mg/kg PS80, 1,000 mg/kg PG, 500 mg/kg HPβCD or 1,000 mg/kg HPβCD were administered orally before/during mating, and on gestation Day (GD) 0-7, followed by an assessment of embryonic development on GD 14. In the rat and rabbit teratology studies, the doses of MC, PS80, PG, and HPβCD were the same as those in the fertility study. In these teratology studies, pregnant females were dosed during the period of organogenesis, followed by an assessment of fetal external, visceral, and skeletal development.. In the rat fertility and rat teratology studies, PS80, PG, and HPβCD did not exhibit toxicity, when compared with MC. Similarly, in the rabbit teratology study, there was no PS80 or PG-related toxicity, when compared with MC. However, individual rabbits in the 500 and 1,000 mg/kg HPβCD groups exhibited maternal toxicity, which included stool findings, decreased food consumption, and body weight gain. Furthermore, one rabbit each in the 500 and 1,000 mg/kg HPβCD groups exhibited evidence of abortion, which was considered secondary to maternal toxicity.. Although HPβCD was not well tolerated in rabbits at doses of 500 and 1,000 mg/kg, PS80 and PG were comparable to MC and should be considered for use in developmental and reproductive toxicology studies.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; Abnormalities, Drug-Induced; Animals; beta-Cyclodextrins; Dose-Response Relationship, Drug; Eating; Embryo, Mammalian; Female; Hypromellose Derivatives; Methylcellulose; Pharmaceutical Vehicles; Polysorbates; Pregnancy; Propylene Glycol; Rabbits; Rats; Reproduction; Toxicity Tests; Weight Gain

Recombinant human growth hormone (rhGH) therapy for short stature must be administered as a daily injection because of its poor bioavailability and short half-life. In the present study, a sustained-release formulation of rhGH (SR-rhGH), DA-3003, was prepared using double emulsion solvent evaporation with poly(D,L-lactide-co-glycolide) (PLGA), zinc oxide and hydroxypropyl-beta-cyclodextrin (HPCD) as the release modulator, stabilizer, and aggregation-prevention agent, respectively. After a single administration of DA-3003, the elevated concentration of rhGH in plasma was sustained for 14 days in rats and 28 days in monkeys. The plasma concentration of insulin-like growth factor-1 (IGF-I) and insulin-like growth factor binding protein-3 (IGFBP-3), which are pharmacodynamic markers of rhGH administration, increased and remained elevated for approximately 28 days in monkeys. Monkeys administered DA-3003 did not develop antibodies to hGH, indicating safety of the SR-rhGH formulation comparable to that observed with daily rhGH injections (Growtropin II). There were no significant differences in efficacy between Growtropin II (daily dose of 5 microg/animal for 14 days) and DA-3003 (weekly dose of 35 microg/animal for 14 days with a dosing interval of a week) in hypophysectomized rats, as assessed by changes in body weight and the width of the tibial growth plate. These results show that a sustained-release rhGH formulation, DA-3003, has the potential to be used safely and efficaciously in a weekly dosing regimen.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; Animals; Antibody Formation; beta-Cyclodextrins; Delayed-Action Preparations; Human Growth Hormone; Humans; Macaca mulatta; Male; Microscopy, Electron, Scanning; Microspheres; Polyglactin 910; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Weight Gain; Zinc Oxide

Beta-cyclodextrin is a compound that forms inclusion complexes with a variety of molecules, specially bile acids and sterols. This study examines the effects of beta-cyclodextrin on cholesterol and bile acid metabolism in hypercholesterolaemic rats. Male Wistar rats were divided into 4 groups that received during 7 weeks: control diet, 2% cholesterol diet (A), A+2.5% beta-cyclodextrin (B) and A+5% beta-cyclodextrin (C). The cholesterol-rich diet induced hepatomegaly and fatty liver and significantly reduced cholesterol, bile acid and phospholipid secretion. Addition of beta-cyclodextrin normalised biliary lipid secretion. Moreover, when compared to A, beta-cyclodextrin significantly lowered plasma phospholipid concentration (B: -21%; C: -29%) and the liver free/total cholesterol molar ratio (B: -40%; C: -38%), increased bile acid faecal output (B: +17%; C: +62%) and enhanced cholesterol 7alpha-hydroxylase activity (B:+50%; C : +100%)and mRNA levels (B: + 14%; C: +29%). 5% beta-cyclodextrin also reduced plasma triglycerides concentration (-38%). However, ALT and AST activities were significantly increased (B: +140% and +280%; C: +72% and +135%) and there was a high incidence of cell necrosis with portal inflammatory cell infiltration. Addition of beta-cyclodextrin to a cholesterol-rich diet results in a triglyceride-lowering action, enhancement of bile acid synthesis and excretion, and normalization of biliary lipid secretion, but produces a marked hepatotoxic effect.

Topics: Alanine Transaminase; Animals; Anticholesteremic Agents; Aspartate Aminotransferases; beta-Cyclodextrins; Bile; Bile Acids and Salts; Cholesterol; Cholesterol 7-alpha-Hydroxylase; Cholesterol, Dietary; Cyclodextrins; Diet; Eating; Feces; Hypercholesterolemia; Liver; Male; Rats; Rats, Wistar; Weight Gain

Following the unexpected activity of the excipient beta-cyclodextrin against experimental infection by Cryptosporidium parvum in suckling mice, its efficacy in the prevention and treatment of natural infections in lambs was evaluated under field conditions. Fifty-three crossbred neonatal lambs were randomly selected for the study. Treatment consisted of oral administration of an aqueous suspension of beta-cyclodextrin at a dose of 500 mg/kg of body weight. To test prophylactic efficacy, the suspension was administered at 1, 2 and 3 days of age. To evaluate therapeutic efficacy, the suspension was administered on each of the 3 days following onset of diarrhoea. Infection was monitored by daily examination of faecal samples, from birth to 30 days. The criteria studied in evaluating efficacy were: oocyst shedding, the presence of diarrhoea, and weight gain at 15 and 30 days. In the group that received prophylactic treatment with beta-cyclodextrin, there were no mortalities and, compared with control lambs, there was a decrease in the number of animals infected, a longer prepatent period and notable reduction in the patent period and the duration of diarrhoea. Therapeutic treatment also reduced the patent period and the severity of diarrhoea. beta-cyclodextrin was well tolerated by all of the treated animals.

Topics: Animals; Animals, Newborn; beta-Cyclodextrins; Cryptosporidiosis; Cryptosporidium parvum; Cyclodextrins; Diarrhea; Feces; Female; Male; Parasite Egg Count; Sheep; Sheep Diseases; Spain; Statistics, Nonparametric; Weight Gain

The effect of dietary cyclodextrins on liver and serum lipids and cecal organic acid production was investigated. Male Wistar rats were fed a basal diet and a diet containing 5% of alpha-, beta-, or gamma-cyclodextrin. The body weight gain in rats fed the alpha-cyclodextrin diet was not significantly different from rats fed the other three kinds of diets. The feeding of dietary alpha-cyclodextrin increased total lipid and phospholipids in the liver. Beta-cyclodextrin significantly lowered serum total cholesterol and phospholipid levels compared with the basal diet et al. A decrease in serum triacylglycerol levels was also observed in beta-cyclodextrin-fed rats. Dietary alpha-cyclodextrin significantly increased the weight of cecal tissues and contents, and an approximate fourfold increase in acetate, propionate, and total organic acids was noted, indicating the fermentibility of beta-cyclodextrin compared with the basal diet. It seems likely that the suppression of serum cholesterol levels by alpha- and beta-cyclodextrins might be due to the increasing acetate and propionate productions in the cecum. cecal organic acid, cyclodextrin, serum cholesterol, rats

Topics: Acetates; alpha-Cyclodextrins; Animals; beta-Cyclodextrins; Blood Glucose; Butyrates; Cecum; Cholesterol; Cyclodextrins; Fermentation; gamma-Cyclodextrins; Lipid Metabolism; Lipids; Liver; Male; Propionates; Rats; Rats, Wistar; Succinic Acid; Triglycerides; Weight Gain