Aspartame and Phenylketonuria: an analysis of the daily phenylalanine intake of aspartame-containing drugs marketed in France.

BACKGROUND: Phenylketonuria (PKU) is a rare genetic metabolic disorder in which especially high phenylalanine (Phe) concentrations cause brain dysfunction. If untreated, this brain dysfunction results in severe microcephaly, intellectual disability, and behavioral problems. Dietary restriction of Phe is the mainstay of PKU treatment, with long-term successful outcomes. Aspartame, an artificial sweetener sometimes added into medications, is metabolized in the gut into Phe. Then, patients suffering from PKU on a Phe-restricted diet should avoid consumption of aspartame. The aim of our study was to evaluate the number of drugs containing aspartame and/or Phe as an excipient, and to quantify their corresponding Phe intake. METHODS: The list of drugs marketed in France containing aspartame and/or Phe was established using a national medication database called "Theriaque". For each drug, the corresponding daily Phe intake was calculated according to age and weight and was distributed into 3 categories: high (> 40 mg/d), medium (10 to 40 mg/d) and low (< 10 mg/d) Phe intake. RESULTS: The number of drugs containing Phe or its precursor aspartame remained very limited (n = 401). Among the aspartame containing drugs, Phe intakes were significant (medium or high) for only half of them whereas there were negligible for the others. Furthermore, these medications with a significant Phe intake were limited to few pharmaceutical classes (mainly antiinfectives agents, analgesics, and drugs for nervous system), and within these classes the drugs were limited to a small number of molecules, including principally amoxicillin, amoxicillin + clavulanic acid and paracetamol/ acetaminophen. DISCUSSION: In situations requiring the use of these molecules, we propose as an alternative, the use of an aspartame-free form of these molecules or a form with a low Phe intake. If it is not possible, we propose as second-line the use of another antibiotics or analgesics. Finally, we have to remember the benefits-risk balance to use medications containing significant Phe intake in PKU patients. Indeed, it may be better to use a Phe containing medication in the absence of an aspartame-free form of this drug rather than to leave a person with PKU without treatment.

Noncaloric Sweeteners in Children: A Controversial Theme.

Noncaloric sweeteners (NCS) are food additives used to provide sweetness without adding calories. Their consumption has become more widespread around the world in all age groups, including children. The aim of this study is to show the state of the art about the intake of noncaloric sweeteners in children, as well as their benefits and consumption risk. Scientific searchers were used (PUBMED, Scopus, and Scielo) to analyze articles that included keywords (noncaloric sweeteners/saccharin/cyclamate/acesulfame potassium/aspartame/sucralose/stevia/children) in English, Spanish, and Portuguese. Authors conclude that it is imperative that health professionals judiciously and individually evaluate the overall benefits and risks of NCS use in consumers before recommending their use. Different subgroups of the population incorporate products containing NCS in their diet with different objectives, which should be considered when recommending a diet plan for the consumer. In childhood, in earlier age groups, this type of additives should be used as a dietary alternative when other forms of prevention in obesity are not sufficient.

Aspartame: Should Individuals with Type II Diabetes be Taking it?

BACKGROUND: Individuals with Type II Diabetes (T2D) have to manage blood glucose levels to sustain health and longevity. Artificial sweeteners (including aspartame) are suggested sugar alternatives for these individuals. The safety of aspartame in particular, has long been the centre of debate. Although it is such a controversial product, many clinicians recommend its use to T2D patients, during a controlled diet and as part of an intervention strategy. Aspartame is 200 times sweeter than sugar and has a negligible effect on blood glucose levels, and it is suggested for use so that T2D can control carbohydrate intake and blood glucose levels. However, research suggests that aspartame intake may lead to an increased risk of weight gain rather than weight loss, and cause impaired blood glucose tolerance in T2D. OBJECTIVE: This review consolidates knowledge gained from studies that link aspartame consumption to the various mechanisms associated with T2D. METHOD: We review literature that provides evidence that raise concerns that aspartame may exacerbate T2D and add to the global burden of disease. RESULT: Aspartame may act as a chemical stressor by increasing cortisol levels, and may induce systemic oxidative stress by producing excess free radicals, and it may also alter gut microbial activity and interfere with the N-methyl D-aspartate (NMDA) receptor, resulting in insulin deficiency or resistance. CONCLUSION: Aspartame and its metabolites are safe for T2D is still debatable due to a lack of consistent data. More research is required that provides evidence and raise concerns that aspartame may exacerbate prevalence of pathological physiology in the already stressed physiology of T2D.

Polyaspartamide-doxorubicin conjugate as potential prodrug for anticancer therapy.

PURPOSE: To synthesize a new polymeric prodrug based on α,ß-poly(N-2-hydroxyethyl)(2-aminoethylcarbamate)-d,l-aspartamide copolymer bearing amine groups in the side chain (PHEA-EDA), covalently linked to the anticancer drug doxorubicin and to test its potential application in anticancer therapy. METHODS: The drug was previously derivatized with a biocompatible and hydrophilic linker, leading to a doxorubicin derivative highly reactive with amino groups of PHEA-EDA. The PHEA-EDA-DOXO prodrug was characterized in terms of chemical stability. The pharmacokinetics, biodistribution and cytotoxicity of the product was investigated in vitro and in vivo on human breast cancer MCF-7 and T47D cell lines and NOD-SCID mice bearing a MCF-7 human breast carcinoma xenograft. Data collected were compared to those obtained using free doxorubicin. RESULTS: The final polymeric product is water soluble and easily hydrolysable in vivo, due to the presence of ester and amide bonds along the spacer between the drug and the polymeric backbone. In vitro tests showed a retarded cytotoxic effect on tumor cells, whereas a significant improvement of the in vivo antitumor activity of PHEA-EDA-DOXO and a survival advantage of the treated NOD-SCID mice was evidenced, compared to that of free doxorubicin. CONCLUSIONS: The features of the PHEA-EDA-DOXO provide a potential protection of the drug from the plasmatic enzymatic degradation and clearance, an improvement of the blood pharmacokinetic parameters and a suitable body biodistribution. The data collected support the promising rationale of the proposed macromolecular prodrug PHEA-EDA-DOXO for further potential development and application in the treatment of solid cancer diseases.

Aspartame Administration and Insulin Treatment Altered Brain Levels of CYP2E1 and CYP3A2 in Streptozotocin-Induced Diabetic Rats.

This study demonstrates that aspartame consumption and insulin treatment in a juvenile diabetic rat model leads to increase in cytochrome P450 (CYP) 2E1 and CYP3A2 isozymes in brain. Diabetes mellitus was induced in postweaned 21-day-old Wistar male rat by streptozotocin. Animals were randomly assigned to one of the following groups: untreated control, diabetic (D), D-insulin, D-aspartame, or the D-insulin + aspartame-treated group. Brain and liver tissue samples were used to analyze the activity of CYP2E1 and CYP3A2 and protein levels. Our results indicate that combined treatment with insulin and aspartame in juvenile diabetic rats significantly induced CYP2E1 in the cerebrum and cerebellum without modifying it in the liver, while CYP3A2 protein activity increased both in the brain and in the liver. The induction of CYP2E1 in the brain could have important in situ toxicological effects, given that this CYP isoform is capable of bioactivating various toxic substances. Additionally, CYP3A2 induction in the liver and brain could be considered a decisive factor in the variation of drug response and toxicity.

Evaluation and comparison of antinociceptive activity of aspartame with sucrose.

BACKGROUND: Artificial sweeteners are low-calorie substances used to sweeten a wide variety of foods. At present they are used increasingly not only by diabetics, but also by the general public as a mean of controlling the weight. This study was carried out to evaluate and compare antinociceptive activity of the artificial sweeteners, aspartame and sucrose and to study the mechanisms involved in this analgesic activity. METHODS: Forty eight white albino Wistar rats were divided into two groups of 24 rats each. Group 1 received sucrose and group 2 received aspartame solution ad libitum for 14 days as their only source of liquid. On 14(th) day, both groups of rats were divided into 3 subgroups having 8 rats each. Group Ia and IIa served as control. Group Ib and IIb were given naloxone and Ic and IIc received ketanserin, the opioid and serotonergic receptor antagonists, respectively. RESULTS: Tail withdrawal latencies (tail flick analgesiometer) and paw licking/jumping latencies (Eddy's hot plate method) were increased significantly in both aspartame and sucrose group. The analgesia produced by aspartame was comparable with sucrose. The opioid receptor antagonist naloxone and the 5-HT(2A/2C) serotonergic receptor antagonist ketanserin partly reversed the antinociceptive effect of these sweeteners. CONCLUSIONS: Thus, the artificial sweetening agent aspartame showed antinociceptive activity like sucrose in rats. Reduction in antinociceptive activity of aspartame and sucrose by opioid and serotoninergic antagonists demonstrate the involvement of both opioid and serotonergic system.

Migraine MLT-down: an unusual presentation of migraine in patients with aspartame-triggered headaches.

Aspartame, an artificial sweetener added to many foods and beverages, may trigger headaches in susceptible individuals. We report two patients with aspartame-triggered attacks in whom the use of an aspartame-containing acute medication (Maxalt-MLT) worsened an ongoing attack of migraine.

Aspartame effect in sickle cell anemia.

OBJECTIVE: To examine the in vitro and in vivo attributes of aspartame and to determine its efficacy for treating sickle cell anemia. RATIONALE: Aspartame (l-aspartyl-l-phenylalanine methyl ester) binds with 2 human Bence Jones proteins. The proteins (Mcg and Sea) showed phenylalanine penetrating into hydrophobic binding sites. This aspartame property suggested a potential to interfere with sickle hemoglobin fibril formation. METHODS: For the in vitro studies, blood from 20 subjects monitored for sickle cell anemia was collected in heparinized tubes. Specimens were divided in thirds and aspartame was added to 2 tubes to yield a 1 mg/mL or 2 mg/mL concentration. Sickled cells that were present after a drop from each aliquot was added to a fresh 2% metabisulfite solution were counted 3 times. For the in vivo studies, 23 subjects from the Sickle Cell Clinic (University of Oklahoma Health Sciences Center, Oklahoma City, Okla) consented to participate in a randomized single-dose administration of 1.5, 3.0, or 6 mg/kg aspartame. Heparinized blood was obtained at 0, 30, 60, 120, 240, 480, and 1440 minutes after aspartame administration. Specimens were counted in a blinded manner by means of the technique used for the in vitro method, but a photomicrograph of 1 field from each triplicate count was made. The pictures were marked and were computer counted. RESULTS: For the in vitro studies, sickled cells decreased from 28% to < 14% when 1 mg/mL aspartame was added and decreased further with 2 mg/mL. For the in vivo studies, a decreased number of sickled cells in homozygous blood (HbSS) were observed after oral administration of aspartame. Sickling was inhibited by 6 mg/kg aspartame for at least 6 hours in 15 subjects with HbSS anemia. CONCLUSIONS: Further evaluations of the efficacy of aspartame for sickle crisis and crisis prevention appears to be warranted.

Interference of rheumatoid factor activity by aspartame, a dipeptide methyl ester.

Circulating autoimmune complexes of IgM rheumatoid factors (RF) bound to the Fc portions of normal, polyclonal IgG antibodies are frequently present in humans with rheumatoid arthritis (RA). The sweet tasting methyl ester of L-Asp-L-Phe (aspartame or APM) was found to relieve pain and improve joint mobility in subjects with osteo- and mixed osteo/rheumatoid arthritis [Edmundson, A. B. and Manion, C. V. (1998). Clin. Pharmac. Ther. 63, 580-593]. These clinical observations prompted the testing of the inhibition by APM of the binding interactions of human IgM RFs with IgG Fc regions. The propensity of APM to inhibit IgM RF binding was assessed by competitive enzyme immunoassays with solid-phase human IgG. Ten RA serum samples and three purified monoclonal cryoglobulins, all of which had RF activity, were tested in this system. We found that the presence of APM significantly reduced the binding of IgM RFs. The inhibitory propensity of APM with monoclonal RF cryoglobulins was increased by the addition of CaCl(2) to the binding buffer. Similar inhibition of the binding of RA derived RFs to IgG was observed for Asp-Phe and its amidated derivative, indicating that the methyl ester is not required for APM's interaction with IgM antibodies. A human (Mez) IgM known to bind octameric peptides derived from the Fc portion of a human IgG(1) antibody was tested for binding of dipeptides by the Pepscan method of combinatorial chemistry. The relative binding constants of Asp-Phe and Phe-Asp were ranked among the highest values for 400 possible combinations of the 20 most common amino acids. Possible blocking interactions of APM were explored by computer-assisted docking studies with the model of a complex of an RF Fab with the Fc of a human IgG(4) antibody. Modeling of ternary immune complexes revealed a few key residues, which could act as molecular recognition sites for APM. A structural hypothesis is presented to explain the observed interference with RF reactivity by APM. Extrapolations of the current results suggest that APM may inhibit the binding of IgG in a substantial proportion of IgM RFs. Interference of RF reactivity, especially in RA patients, may alleviate the pain and immobility resulting from chronic inflammation of the joints.

Interference of rheumatoid factor activity by aspartame, a dipeptide methyl ester.

Circulating autoimmune complexes of IgM rheumatoid factors (RF) bound to the Fc portions of normal, polyclonal IgG antibodies are frequently present in humans with rheumatoid arthritis (RA). The sweet tasting methyl ester of L-Asp-L-Phe (aspartame or APM) was found to relieve pain and improve joint mobility in subjects with osteo- and mixed osteo/rheumatoid arthritis [Edmundson, A. B. and Manion, C. V. (1998). Clin. Pharmac. Ther. 63, 580-593]. These clinical observations prompted the testing of the inhibition by APM of the binding interactions of human IgM RFs with IgG Fc regions. The propensity of APM to inhibit IgM RF binding was assessed by competitive enzyme immunoassays with solid-phase human IgG. Ten RA serum samples and three purified monoclonal cryoglobulins, all of which had RF activity, were tested in this system. We found that the presence of APM significantly reduced the binding of IgM RFs. The inhibitory propensity of APM with monoclonal RF cryoglobulins was increased by the addition of CaCl(2) to the binding buffer. Similar inhibition of the binding of RA derived RFs to IgG was observed for Asp-Phe and its amidated derivative, indicating that the methyl ester is not required for APM's interaction with IgM antibodies. A human (Mez) IgM known to bind octameric peptides derived from the Fc portion of a human IgG(1) antibody was tested for binding of dipeptides by the Pepscan method of combinatorial chemistry. The relative binding constants of Asp-Phe and Phe-Asp were ranked among the highest values for 400 possible combinations of the 20 most common amino acids. Possible blocking interactions of APM were explored by computer-assisted docking studies with the model of a complex of an RF Fab with the Fc of a human IgG(4) antibody. Modeling of ternary immune complexes revealed a few key residues, which could act as molecular recognition sites for APM. A structural hypothesis is presented to explain the observed interference with RF reactivity by APM. Extrapolations of the current results suggest that APM may inhibit the binding of IgG in a substantial proportion of IgM RFs. Interference of RF reactivity, especially in RA patients, may alleviate the pain and immobility resulting from chronic inflammation of the joints.

The effect of chewing sugar-free gum after meals on clinical caries incidence.

To determine the effect of chewing sugar-free gum on caries incidence, the authors conducted a randomized clinical study. A total of 1,402 children in Puerto Rico, in grades 5 through 7 at baseline, completed the study. They were randomized by classroom into a control group or chewing gum group; those in the gum group were instructed to chew sugar-free gum for 20 minutes after each of three meals a day. Clinical and radiographic evaluations were performed at baseline and after two and three years. The results show that all subjects and high-risk subjects, respectively, in the gum group developed 7.9 percent and 11.0 percent fewer decayed, missing or filled surfaces than subjects in the control group. Based on these findings, the authors concluded that chewing sorbitol-based sugar-free gum after eating significantly reduces the incidence of dental caries.

Treatment of osteoarthritis with aspartame.

OBJECTIVE: The binding of sweet-tasting compounds in a human (Mcg) Bence-Jones dimer has been characterized by x-ray crystallography. Aspartame binding in this immunoglobulin fragment is remarkable. Unexpected pain relief noted by A.B.E., a crystallographer with diagnosed osteoarthritis, suggested that the accommodation of aspartame in the active site of the dimer may represent surrogate binding by other proteins, with analgesia as the outcome. METHODS: X-ray analysis of the complex of aspartame and the Bence-Jones dimer was conducted with crystalline Mcg protein and pure aspartame. A single-blind (n = 1) study to confirm analgesia was completed by administration of aspartame to A.B.E. A controlled double-blind trial was performed in patients with x-ray-documented osteoarthritis. Pain and performance changes were evaluated with use of two doses of placebo and two doses of aspartame. Effects on bleeding time were then evaluated by determination of template bleeding times in 34 normal volunteers. Finally, antipyretic effects were studied in Sprague-Dawley rats given intramuscular turpentine injections. RESULTS: Aspartame binding in the Bence-Jones dimer was verified by x-ray crystallography. Improvements in performance and pain relief were observed in A.B.E. at p < 0.001. Decreased pain and improved performance were also observed in patients with osteoarthritis (p < 0.001). Mild antihemostatic responses were observed in bleeding times after aspartame treatment. Modified template bleeding times increased at p < 0.01. Aspartame blocked the turpentine-mediated febrile responses in the treated rats (p < 0.01). CONCLUSIONS: L-Aspartyl-L-phenylalanine methyl ester is biologically active and appears to relieve pain, induce mild antithrombotic effects in humans, and decrease fever in animals.

Cariostatic effect of aspartame in rats.

This study examined the effects of aspartame (APM) on caries and the Streptococcus sobrinus population. Six groups of rats (20 in each group) colonized with S. sobrinus were fed varying amounts of sucrose (SU) and APM in their diets as follows: 1-0.15% APM, 2-0.30% APM, 3-30% SU, 4-30% SU + 0.15% APM, 5-50% SU and 6-50% + 0.15% APM. Ten from each group were sacrificed at 6 weeks and 10 at 12 weeks. S. sobrinus populations at both intervals were negligible in groups 1 and 2 and had no differences between groups 3, 4, 5 and 6. No caries were found in groups 1 and 2 Animals fed SU plus APM had significantly lower caries than animals fed the same amounts of SU (p = 0.001-0.0002). We conclude that APM is noncariogenic and anticariogenic.

Adverse reactions to aspartame: double-blind challenge in patients from a vulnerable population.

This study was designed to ascertain whether individuals with mood disorders are particularly vulnerable to adverse effects of aspartame. Although the protocol required the recruitment of 40 patients with unipolar depression and a similar number of individuals without a psychiatric history, the project was halted by the Institutional Review Board after a total of 13 individuals had completed the study because of the severity of reactions within the group of patients with a history of depression. In a crossover design, subjects received aspartame 30 mg/kg/day or placebo for 7 days. Despite the small n, there was a significant difference between aspartame and placebo in number and severity of symptoms for patients with a history of depression, whereas for individuals without such a history there was not. We conclude that individuals with mood disorders are particularly sensitive to this artificial sweetener and its use in this population should be discouraged.

Efficacy of sweeteners and sugar substitutes in caries prevention.

The caries-preventive efficacy of sweeteners and sugar substitutes is not clearly established on an epidemiological scale. A review of cariogenicity assessments in vitro and in vivo as well as of human clinical caries trials, however, clearly demonstrates that the replacement of sugar by such products has a caries-preventive effect. The clinical relevance of some bacteriostatic and/or cariostatic properties ascribed to saccharin, aspartame, and xylitol remains to be corroborated.

Aspartame and dental caries in the rat.

Aspartame (NutraSweet--The NutraSweet Co., Deerfield, IL) an artificial intense sweetener, was tested for its cariogenicity alone and in the presence of sucrose. Sprague-Dawley rat pups (Charles River Laboratories, Bloomington, MA) inoculated with Streptococcus mutans were fed basal diet 2000 with one of the following added: 50% sucrose; 30% sucrose; 30% sucrose + 0.15% aspartame; 0.30% aspartame; 0.15% aspartame and no addition. The animals were sacrificed after eight weeks. Caries was evaluated using Keyes' technique. It was found that the addition of 0.15% aspartame to 30% sucrose diet significantly reduced caries in comparison to rats fed only 30% sucrose diet. In animals fed aspartame only, there was no caries. The S. mutans counts were high in the animals receiving sucrose diets with and without aspartame. The animals receiving only aspartame had very low S. mutans counts.