Amoxicillin chewable tablets intended for pediatric use: formulation development, stability evaluation and taste assessment.

To cover the unpleasant taste of amoxicillin (250 mg), maize starch (baby food) and milk chocolate were co-formulated. The raw materials and the final formulations were characterized by means of Dynamic Light Scattering (DLS), Differential Scanning Calorimetry (DSC) and Fourier-Transform Infrared (FT-IR) spectroscopy. To evaluate the taste masking two different groups of volunteers were used, according to the Ethical Research Committee of the Aristotle University of Thessaloniki. The optimization of excipients' content in the tablet was determined by experimental design methodology (crossed D-optimal). Due to the matrix complexity, amoxicillin was extracted using liquid extraction and analyzed isocratically by HPLC. The developed chromatographic method was validated (%Recovery 98.7-101.3, %RSD = 1.3, LOD and LOQ 0.15 and 0.45 µg mL-1 respectively) according to the International Conference on Harmonization (ICH) guidelines. The physicochemical properties of the tablets were also examined demonstrating satisfactory quality characteristics (diameter: 15 mm, thickness: 6 mm, hardness <98 Newton, loss of mass <1.0%, disintegration time ∼25min). Additionally, dissolution (%Recovery >90) and in vitro digestion tests (%Recovery >95) were carried out. Stability experiments indicated that amoxicillin is stable in the prepared formulations for at least one year (%Recovery <91).

Chronic Effect of Aspartame on Ionic Homeostasis and Monoamine Neurotransmitters in the Rat Brain.

Aspartame is one of the most widely used artificial sweeteners globally. Data concerning acute neurotoxicity of aspartame is controversial, and knowledge on its chronic effect is limited. In the current study, we investigated the chronic effects of aspartame on ionic homeostasis and regional monoamine neurotransmitter concentrations in the brain. Our results showed that aspartame at high dose caused a disturbance in ionic homeostasis and induced apoptosis in the brain. We also investigated the effects of aspartame on brain regional monoamine synthesis, and the results revealed that there was a significant decrease of dopamine in corpus striatum and cerebral cortex and of serotonin in corpus striatum. Moreover, aspartame treatment significantly alters the tyrosine hydroxylase activity and amino acids levels in the brain. Our data suggest that chronic use of aspartame may affect electrolyte homeostasis and monoamine neurotransmitter synthesis dose dependently, and this might have a possible effect on cognitive functions.

Nutrition and eating behavior in patients with chronic pain receiving long-term opioid therapy.

OBJECTIVE: To assess eating behavior and nutrient intake in a group of patients who were diagnosed with chronic pain and received long-term opioid analgesic therapy. DESIGN: A descriptive, exploratory study with a convenience sample. SETTING: An outpatient pain rehabilitation center. PARTICIPANTS: Patients diagnosed with chronic pain who received long-term opioid analgesic therapy (N = 50). MAIN OUTCOME MEASUREMENTS: Body mass index, the Food Frequency Questionnaire developed by the Nutrition Assessment Shared Resource of Fred Hutchinson Cancer Research Center, and the Eating Behavior Inventory. RESULTS: Of 50 participants, 14 (28%) and 22 (44%) were found to be overweight and obese, respectively. Mean (±SD) daily caloric intake (kcal) was 2008.5 ± 926.0 among men and 1694.8 ± 672.4 among women. Daily mean (±SD) consumption of fruit and vegetable servings, calculated with the summation method, was found to be 1.8 ± 1.1 and 1.9 ± 1.5, respectively. Our patient sample showed the following mean (±SD) daily intake of the following substances: added sugars (g), 74.4 ± 43.0; fiber (g), 17.3 ± 7.5; cholesterol (mg), 266.5 ± 234; saturated fat (g), 25.8 ± 16.8; omega-3 fatty acids (g), 1.6 ± 0.99; trans-fatty acids (g), 2.7 ± 1.7; sodium (mg), 2868.5 ± 1388.1; caffeine (mg), 199.9 ± 160.8; alcohol (g), 1.6 ± 0.5; vitamin D (IU), 244 ± 208; and calcium (mg), 1111.7 ± 672.1. The mean (±SD) score as calculated by the Eating Behavior Inventory was 74.9 ± 9.1. CONCLUSIONS: Obesity, deficient nutrient intake, and poor eating behavior were highly prevalent in our sample of patients with chronic pain who underwent long-term opioid therapy. Larger prospective studies are necessary to assess the eating behavior of patients with chronic pain who are treated with or without opioid analgesics.

Dietary aspartyl-phenylalanine-1-methyl ester delays osteoarthritis and prevents associated bone loss in STR/ORT mice.

OBJECTIVE: STR/ORT mice provide a well-known model for murine idiopathic OA, with histological joint lesions resembling those of human OA. This model was used to investigate protective effects of the dipeptide aspartyl-phenylalanine-1-methyl ester (Asp-Phe-OMe or aspartame) via the oral route vs a regular diet. METHODS: STR/ORT mice were housed individually and fed diets with or without Asp-Phe-OMe (4 mg/kg), after weaning at the age of 3 weeks, until 15 months of age (average of 20 animals per group). The study groups were kept blinded to the investigators, who measured food consumption and body weight and performed gait mobility tests. Radiographic scans were also performed at regular time intervals to evaluate differential radiographic anomalies associated with progress of OA in response to oral Asp-Phe-OMe therapy. RESULTS: The Asp-Phe-OMe-fed animals presented a pattern of significantly delayed disease onset. In addition, their muscle and bone mass were highly preserved, even at later time points after OA was established. Moreover, control animals presented a higher variability in gait motility in comparison with the Asp-Phe-OMe-fed animals, suggesting a protective effect from movement limitations associated with advanced OA. CONCLUSION: Asp-Phe-OMe, given orally, delays OA in the spontaneous STR/ORT model, improves bone cortical density and muscle mass, and may contribute to a better quality of life for these diseased animals.

Avaliação do efeito do aspartame em ratas tratadas durante a prenhez e o reflexo do tratamento em seus fetos / The evaluation of aspartame administration in rats treated during pregnancy and its effect in their fetuses

JUSTIFICATIVA E OBJETIVOS: O objetivo deste estudo foi avaliar o efeito do aspartame em ratas tratadas durante a prenhez e o reflexo do tratamento em seus fetos. MÉTODO: Foram estudadas 33 ratas (11 em cada grupo) da espécie Rattus norvegicus albinus Wistar, com peso médio de 200 g divididas em três grupos distintos: G1 (controle - água), G2 (aspartame - 25 mg/kg/dia) e G3 (aspartame - 50 mg/kg/dia), cujo tratamento ocorreu a partir do 8º ao 12º dia de prenhez. Realizaram-se as determinações séricas de glicose, triglicerídeos, colesterol total e colesterol HDL dos animais. Para as análises estatísticas utilizou-se a Análise de Variância, seguidas pela comparação múltipla, por meio do teste de Tukey (p < 0,05). RESULTADOS: As ratas tratadas do G3 apresentaram as maiores taxas de glicose, colesterol total e HDL. Com relação aos dados morfométricos, o G2 apresentou maior média nas medidas do cordão umbilical e do peso da placenta, com diferença estatisticamente significante apenas no peso da placenta. O G2 apresentou maior média no peso corpóreo e no peso do encéfalo, com diferença estatística, entre todos os grupos, para as duas medidas. Os fetos das ratas tratadas com aspartame (25 e 50 mg/kg/dia) apresentaram resultado estatisticamente significante de malformações em comparação com o G1. CONCLUSÃO: O uso de aspartame pela gestante deve ser restrito a menos que a quantidade diária máxima recomendada.

BACKGROUND AND OBJECTIVES: The aim of this study was to evaluate the effect of aspartame in rats treated during pregnancy and its consequences on their fetuses. METHOD: We studied 33 rats (11 in each group) of the species Rattus norvegicus Wistar albinos, weighing an average of 200 g that were divided into three groups: G1 (control - water), G2 (aspartame 25 mg/kg/day), and G3 (aspartame 50 mg/kg/day), whose treatment occurred from the 8th to the 12th day of pregnancy. The levels of serum glucose, triglycerides, total cholesterol and HDL cholesterol of the animals were determined. For statistical analysis we used Variance Analysis followed by multiple comparisons using the Tukey test (p < 0.05).RESULTS: The rats treated with G3 showed the highest rates of glucose, total cholesterol and HDL. Regarding the morphometric data, the rats treated with G2 had higher average in measurements of the umbilical cord and placental weight. There was statistically significance only in placental weight. The group of fetuses of rats treated with G2 had higher average in body and brain weights, with statistical difference between all groups for both measures. The fetuses of rats treated with aspartame (25 and 50 mg/kg/day) showed a statistically significant result of malformations compared with the control group. CONCLUSION: The use of aspartame for pregnant women should be restricted to less than the maximum recommended daily dosage

Adverse rearing experiences enhance responding to both aversive and rewarding stimuli in juvenile rhesus monkeys.

BACKGROUND: While adverse rearing is thought to alter threat responding, the effects on appetitive behavior remains minimally explored. This study examines the effects that early life emotional adversity has on response to both threatening and appetitive stimuli in juvenile rhesus monkeys. METHODS: Twenty-four, 2-year-old monkeys with differential rearing histories were tested for fear-potentiated startle responding and consumption of an artificially sweetened solution. RESULTS: Relative to monkeys reared under typical conditions, monkeys removed from their mothers at birth and reared with peers demonstrated both increases in reward responding, as evidenced by greater consumption of a palatable solution in a free choice test, and increased threat responding, as evidenced by enhanced fear-potentiated startle responding. CONCLUSIONS: Findings suggest that early rearing impacts juvenile manifestations of both appetitive and aversive emotional systems. Results are discussed in the context of development, anxiety, depression, and substance abuse.

Genotoxicity testing of low-calorie sweeteners: aspartame, acesulfame-K, and saccharin.

Low-calorie sweeteners are chemicals that offer the sweetness of sugar without the calories. Consumers are increasingly concerned about the quality and safety of many products present in the diet, in particular, the use of low-calorie sweeteners, flavorings, colorings, preservatives, and dietary supplements. In the present study, we evaluated the mutagenicity of the three low-calorie sweeteners in the Ames/Salmonella/microsome test and their genotoxic potential by comet assay in the bone marrow cells of mice. Swiss albino mice, Mus musculus, were orally administered with different concentrations of aspartame (ASP; 7, 14, 28, and 35 mg/kg body weight), acesulfame-K (ASK; 150, 300, and 600 mg/kg body weight), and saccharin (50, 100, and 200 mg/kg body weight) individually. Concurrently negative and positive control sets were maintained. The animals were sacrificed and the bone marrow cells were processed for comet assay. The standard plate-incorporation assay was carried with the three sweeteners in Salmonella typhimurium TA 97a and TA 100 strains both in the absence and presence of the S9 mix. The comet parameters of DNA were increased in the bone marrow cells due to the sweetener-induced DNA strand breaks, as revealed by increased comet-tail extent and percent DNA in the tail. ASK and saccharin were found to induce greater DNA damage than ASP. However, none could act as a potential mutagen in the Ames/Salmonella /microsome test. These findings are important, since they represent a potential health risk associated with the exposure to these agents.

The effect of aspartame metabolites on the suckling rat frontal cortex acetylcholinesterase. An in vitro study.

UNLABELLED: Aspartame (ASP) consumption is suggested to be implicated with muscarinic dysfunction. The aim of this work was to evaluate the effect of ASP and its metabolites on acetylcholinesterase (AChE) activity in rat frontal cortex and pure enzyme. Rat frontal cortex homogenate or pure enzyme AChE (eel E. Electricus) were incubated with ASP and each of ASP components, phenylalanine (Phe), aspartic acid (asp), and methanol (MeOH) for 1 h at 37 degrees C. AChE was measured spectrophotometrically. The results showed that incubation of rat tissue or pure enzyme with the sum of ASP metabolites, as reported to be found in the CSF after 150 or 200 mg/kg ASP consumption, inhibited frontal cortex and pure AChE about -11% to -29% (p<0.001). Asp, Phe or MeOH concentrations related to their CSF levels after ingestion of abuse or toxic ASP doses, when separately incubated with frontal cortex or pure AChE, resulted in a significant decrease of the enzyme activities. IN CONCLUSION: ASP compounds may directly and/or indirectly act on the frontal cortex AChE. High or toxic doses of the sweetener remarkably decreased the enzyme activity. If this in vitro finding comes into human reality, it may be suggested that cholinergic symptoms are related to the consumption of the above ASP doses.

Long-term dietary compensation for added sugar: effects of supplementary sucrose drinks over a 4-week period.

The long-term physiological effects of refined carbohydrates on appetite and mood remain unclear. Reported effects when subjects are not blind may be due to expectations and have rarely been studied for more than 24 h. The present study compared the effects of supplementary soft drinks added to the diet over 4 weeks on dietary intake, mood and BMI in normal-weight women (n 133). Subjects were categorised as 'watchers' or 'non-watchers' of what they ate then received sucrose or artificially sweetened drinks (4 x 250 ml per d). Expectancies were varied by labelling drinks 'sugar' or 'diet' in a counter-balanced design. Sucrose supplements provided 1800 kJ per d and sweetener supplements provided 67 kJ per d. Food intake was measured with a 7 d diary and mood with ten single Likert scales. By 4 weeks, sucrose supplements significantly reduced total carbohydrate intake (F(1,129) = 53.81; P<0.001), fat (F(2,250) = 33.33; P<0.001) and protein intake (F(2,250) = 28.04; P<0-001) compared with sweetener supplements. Mean daily energy intake increased by just under 1000 kJ compared with baseline (t (67 df) = 3.82; P< 0.001) and was associated with a non-significant trend for those receiving sucrose to gain weight. There were no effects on appetite or mood. Neither dietary restraint status as measured by the Dutch Eating Behaviour Questionnaire nor the expectancy procedure had effects. Expectancies influenced mood only during baseline week. It is concluded that sucrose satiates, rather than stimulates, appetite or negative mood in normal-weight subjects.

Functional magnetic resonance imaging of human hypothalamic responses to sweet taste and calories.

BACKGROUND: Evidence exists that beverages do not trigger appropriate anticipatory physiologic responses, such as cephalic phase insulin release. Therefore, it is of interest to elucidate the food properties necessary for triggering adaptive responses. Previously, we found a prolonged dose-dependent decrease in the hypothalamic functional magnetic resonance imaging signal after ingestion of a glucose solution. OBJECTIVES: The aims of the present study were to measure the effects of sweet taste and energy content on the hypothalamic response to glucose ingestion and to measure the concomitant changes in blood glucose and insulin concentrations. DESIGN: Five healthy, normal-weight men participated in a randomized crossover design trial. The subjects were scanned 4 times for 37 min on separate days with functional magnetic resonance imaging. After 7 min, they ingested 1 of the following 4 stimuli (300 mL of each): water (control), a glucose solution, an aspartame (sweet taste) solution, or a maltodextrin (nonsweet carbohydrate) solution. RESULTS: Glucose ingestion resulted in a prolonged and significant signal decrease in the upper hypothalamus (P < 0.05). Water, aspartame, and maltodextrin had no such effect. Glucose and maltodextrin ingestions resulted in similar increases in blood glucose and insulin concentrations. However, only glucose triggered an early rise in insulin concentrations. Aspartame did not trigger any insulin response. CONCLUSIONS: Our findings suggest that both sweet taste and energy content are required for a hypothalamic response. The combination of sweet taste and energy content could be crucial in triggering adaptive responses to sweetened beverages.

Aspartame: review of safety.

Over 20 years have elapsed since aspartame was approved by regulatory agencies as a sweetener and flavor enhancer. The safety of aspartame and its metabolic constituents was established through extensive toxicology studies in laboratory animals, using much greater doses than people could possibly consume. Its safety was further confirmed through studies in several human subpopulations, including healthy infants, children, adolescents, and adults; obese individuals; diabetics; lactating women; and individuals heterozygous (PKUH) for the genetic disease phenylketonuria (PKU) who have a decreased ability to metabolize the essential amino acid, phenylalanine. Several scientific issues continued to be raised after approval, largely as a concern for theoretical toxicity from its metabolic components--the amino acids, aspartate and phenylalanine, and methanol--even though dietary exposure to these components is much greater than from aspartame. Nonetheless, additional research, including evaluations of possible associations between aspartame and headaches, seizures, behavior, cognition, and mood as well as allergic-type reactions and use by potentially sensitive subpopulations, has continued after approval. These findings are reviewed here. The safety testing of aspartame has gone well beyond that required to evaluate the safety of a food additive. When all the research on aspartame, including evaluations in both the premarketing and postmarketing periods, is examined as a whole, it is clear that aspartame is safe, and there are no unresolved questions regarding its safety under conditions of intended use.

Pulmonary peptide delivery: effect of taste-masking excipients on leuprolide suspension metered-dose inhalers.

The purpose of this study was to evaluate the effect of taste-masking excipients on in vitro and in vivo performance of a leuprolide metered-dose inhaler (MDI) suspension formulation. Taste-masking excipients (aspartame and menthol) were added to a leuprolide suspension MDI formulation. The leuprolide MDI formulation with the taste-masking excipients was characterized in terms of milling time, particle size distribution, dose delivery and uniformity, and drug absorption in dogs. The data were compared with a formula that did not contain taste-masking excipients. It was found that the longer milling time for the leuprolide suspension with the taste-masking excipients was required to obtain a similar particle size distribution compared with the formula without taste-masking excipients using a fluid energy mill. Although measurable differences in mass median aerodynamic diameter (MMAD) and geometric standard deviation (GSD) were not observed between the two formulations, the percent of particles < or = 5 microns and the actuator retention for the formula with the taste-masking excipients were significantly different from the formula without taste-masking excipients using the Marple-Miller cascade impactor. Taste-masking excipients did not show a significant effect on valve delivery and through-can dose uniformity. However, the mean ex-actuator dose was 150.4 mg for the formula with the taste-masking excipients and 162.2 mg for the reference formula, respectively, indicating a significant difference. In tracheostomized dogs, both formulations showed comparable pharmacokinetic parameters including Cmax, Tmax, AUC0-12 and bioavailability (F%), indicating that the taste-masking excipients do not have an effect on lung absorption of leuprolide acetate. Therefore, inclusion of taste-masking excipients in the leuprolide MDI suspension formulation showed a significant impact on drug micronization, exactuator dose, and particle deposition pattern. Mechanistically, the unfavorable performance of leuprolide MDI in the presence of taste-masking excipients could be due to modification of the properties of the suspension itself and alteration of propellant evaporation following actuation.

Safety of long-term large doses of aspartame.

Safety of long-term administration of 75 mg/kg of aspartame per day was evaluated with the use of a randomized, double-blind, placebo-controlled, parallel-group design in 108 male and female volunteers aged 18 to 62 years. Subjects received either aspartame or placebo in capsule form three times daily for 24 weeks. No persistent changes over time were noted in either group in vital signs; body weight; results of standard laboratory tests; fasting blood levels of aspartame's constituent amino acids (aspartic acid and phenylalanine), other amino acids, and methanol; or blood formate levels and 24-hour urinary excretion of formate. There also were no statistically significant differences between groups in the number of subjects experiencing symptoms or in the number of symptoms per subject. These results further document the safety of the long-term consumption of aspartame at doses equivalent to the amount of aspartame in approximately 10 L of beverage per day.

Aspartame and its constituent amino acids: effects on prolactin, cortisol, growth hormone, insulin, and glucose in normal humans.

Because large doses of phenylalanine stimulate prolactin secretion in man, we studied the acute effects of oral doses of aspartame (0.534 g, equivalent to the amount of aspartame in approximately 1 L beverage), aspartic acid (0.242 g), and phenylalanine (0.3 and 1.0 g) on serum prolactin and other hormones in normal humans. Prolactin was not stimulated by any of the aspartame meals, aspartic acid, or 0.3 g phenylalanine; a small rise in serum prolactin, similar to that produced by a high-protein mixed meal, followed ingestion of 1.0 g phenylalanine. Serum growth hormone showed no statistically significant changes in response to any of the experimental meals whereas cortisol and insulin fell slightly and glucose rose slightly during each of the meals. We conclude that these doses of aspartame do not alter secretion of prolactin, cortisol, growth hormone, or insulin in normal individuals.

Aspartame and the rat brain monoaminergic system.

A high dose of aspartame (APM) was administered to rats to study possible effects on brain monoaminergic systems. APM and its metabolite phenylalanine (Phe) were given orally at doses of 1000 and 500 mg/kg, respectively. Significant increases were seen in brain Phe and tyrosine (Tyr) levels. Two different approaches were used to study monoaminergic systems: whole tissue measurements by HPLC-ED and in vivo voltammetry in freely moving rats. Dopamine, serotonin and their metabolites were taken as indexes of neuronal activity. In spite of the high dose used, no modification was found in monoamines or their metabolites in striatum, hippocampus and nucleus accumbens.