Aspartame—True or False? Narrative Review of Safety Analysis of General Use in Products

Aspartame is a sweetener introduced to replace the commonly used sucrose. It was discovered by James M. Schlatter in 1965. Being 180–200 times sweeter than sucrose, its intake was expected to reduce obesity rates in developing countries and help those struggling with diabetes. It is mainly used as a sweetener for soft drinks, confectionery, and medicines. Despite its widespread use, its safety remains controversial. This narrative review investigates the existing literature on the use of aspartame and its possible effects on the human body to refine current knowledge. Taking to account that aspartame is a widely used artificial sweetener, it seems appropriate to continue research on safety. Studies mentioned in this article have produced very interesting results overall, the current review highlights the social problem of providing visible and detailed information about the presence of aspartame in products. The studies involving the impact of aspartame on obesity, diabetes mellitus, children and fetus, autism, neurodegeneration, phenylketonuria, allergies and skin problems, its cancer properties and its genotoxicity were analyzed. Further research should be conducted to ensure clear information about the impact of aspartame on health.     

Cisplatin-induced reductions in renal functional reserve uncovered by unilateral nephrectomy: an experimental study in the pig

Summary Groups of mature Large White female pigs, approximately 10 months of age, received single intravenous infusions of 1.5, 2 or 2.5 mg/kg body weight (equivalent to90, 120 and 150 mg/m²) cisplatin. Glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were measured before and at 4 weeks after cisplatin infusion by renography using [^{99 m}Tc]-DTPA (diethylenetriamminepentaacetic acid and iodohippurate sodium I 131, respectively. The left kidney of each cisplatin-treated animal plus that of four age-matched control pigs was then removed surgically,and GRF and ERPF were measured in the remaining kidney at 4 weekly intervals for up to 24 weeks after unilateral nephrectomy (UN). The pigs treated with cisplatin exhibited no consistent change in either GFR or ERPF at 4 weeks after treatment. A histological evaluation of kidneys from animals treated with 2mg/kg cisplatin that had been removed at UN revealed both tubular and glomerular lesions. The latter consisted of cell proliferation on the parietal surface of the urinary space; damage to the S₁ portion of the proximal convolution was also noted. Following UN there was a pronounced dose-dependent reduction in the functional status of the remaining kidney such that the increase in GRF and ERPF in pigs initially receiving 2.5 mg/kg cisplatin was <50% of that seen in age-matched UN controls. Moreover, the glomerular lesions observed at 4 weeks after cisplatin infusion had apparently progressed to glomerular hyalinisation by 24 weeks after UN. Thus, prior treatment with cisplatin may cause a permanent reduction in renal functional reserve that may be clinically silent until exposure to an additional nephrotoxic insult.This study was supported by the Cancer Research Campaign     

Breast cancer angiogenesis — new approaches to therapy via antiangiogenesis,hypoxic activated drugs,and vascular targeting

Summary Several groups have shown that quantitation of tumor angiogenesis by counting blood vessels in primary breast cancer gives an independent assessment of prognosis. Poor prognosis is associated with high blood vessel counts. We have shown that the rate of cell division in endothelial cells is much higher in breast tumours than in normal breast. Breast cancer cell lines and primary human breast tumours express a wide range of vascular growth factors, including VEGF, placenta growth factor, pleiotrophin, TGF1, acidic and basic FGF, and platelet-derived endothelial cell growth factor. Inhibiting angiogenesis by blocking vascular growth factors would be difficult with highly specific agents, but drugs with a broader spectrum of antagonism may be effective. We have developed several suramin analogues which are less toxic than suraminin vivo but more potent in inhibiting angiogenesis, and these have been developed for Phase I. A combination of anti-angiogenesis agents with drugs activated by hypoxia may also be useful, because anti-angiogenesis alone may not kill cells, whereas activation of hypoxic drugs could synergize.New endpoints may be necessary because inhibition of new blood vessel formation may not cause tumour regression. Thus, the endpoint of stable disease and biochemical assessment of inhibition of angiogenesis may be much more important in therapeutic studies and for drug development in the future. The prognostic importance of angiogenesis suggests that this should be a major new therapeutic target.Presented at the symposium "New Approaches in the Therapy of Breast Cancer", Georgetown University Medical Center, Washington DC, October 1994, generously supported by an education grant from Bristol-Myers Squibb.     

A study on prostaglandin F2α in photodermatoses

Summary Prostaglandin F₂ (PGF₂) as a possible mediator was studied. Its plasma content was determined by radioimmunoassay. Changes in the DNA synthesis were followed by autoradiography. In active polymorphous light eruption (PLE) and porphyria cutanea tarda (PCT) a remarkable increase (over 300 pg/ml) in plasma content occurred, especially in cases involving large skin areas. Values returned to normal in remission. PGF₂ administered i.d., significantly increased the DNA synthesis of the epidermal cells 48 h after injection similar to the effect of three minimal erythema dosis UV-irradiation. This was more pronounced in PLE patients than in controls. These findings suggest some role of PGF₂ in producing the inflammatory and perhaps proliferative components of the skin symptoms in PLE. PGF₂ — in parallel to literary data concerning PGE — seems to be a mediator of UV-induced changes in DNA synthesis of the epidermal cells. Offprint requests to: Irene Horkay, MD (address see above)     

Reduced cardiotoxicity of doxorubicin given in the form ofN-(2-hydroxypropyl) methacrylamide conjugates: an experimental study in the rat

Summary A rat model was used to evaluate the general acute toxicity and the late cardiotoxicity of 4 mg/kg doxorubicin (DOX) given either as free drug or in the form of threeN-(2-hydroxypropyl)methacrylamide (HPMA) copolymer conjugates. In these HPMA copolymers, DOX was covalently bound via peptide linkages that were either non-biodegradable (Gly-Gly) or degradable by lysosomal proteinases (Gly-Phe-Leu-Gly). In addition, one biodegradable conjugate containing galactosamine was used; this residue was targeted to the liver. Over the first 3 weeks after the i.v. administration of free and polymer-bound DOX, all animals showed a transient reduction in body weight. However, the maximal reduction in body weight seen in animals that received polymer-bound DOX (4 mg/kg) was significantly lower than that observed in those that received free DOX (4 mg/kg) or a mixture of the unmodified parent HPMA copolymer and free DOX (4 mg/kg;P<0.01). Throughout the study (20 weeks), deaths related to cardiotoxicity were observed only in animals that received either free DOX or the mixture of HPMA copolymer and free DOX; in these cases, histological investigations revealed marked changes in the heart that were consistent with DOX-induced cardiotoxicity. Sequential measurements of cardiac output in surviving animals that received either free DOX or the mixture of HPMA copolymer and free DOX showed a reduction of 30% in function beginning at the 4th week after drug administration. The heart rate in these animals was 12% lower than that measured in age-matched control rats (P<0.05). Animals that were given the HPMA copolymer conjugates containing DOX exhibited no significant change in cardiac output throughout the study (P<0.05). In addition, no significant histological change was observed in the hearts of animals that received DOX in the form of HPMA copolymer conjugates and were killed at the end of the study. However, these animals had shown a significant increase in heart rate beginning at 8 weeks after drug administration (P<0.01). This study demonstrates that covalent binding of DOX to HPMA copolymer conjugates via both stable and biodegradable peptidyl linkages considerably reduces both the general acute toxicity and the late cardiotoxicity of DOX in the rat and could offer the potential for improving the therapeutic index in the clinical application of DOX.     

Detection of migrated allogeneic oligodendrocytes throughout the central nervous system of the galactocerebrosidase-deficient twitcher mouse

Summary Galactocerebrosidase-deficient oligodendrocytes of twitcher (twi/twi) mice degenerate prematurely. Transplantation of normal bone marrow cells has been shown to alleviate symptoms and to prolong survival time. However, characteristic ataxia (twitching) is not cured. In an attempt to improve further the condition of twitcher mice, allogeneic foetal liver cells were transplanted as a source of normal haemopoietic stem cells and supplemented with intracerebral transplantation of foetal brain cells. A reliable method was developed to detect donor-type cells in brain tissue. Bacteriophage . transgenic foetal mice were used as donors of both foetal liver and brain cells. Integrated copies of . DNA in donor cells were detected byin situ hybridization with biotinylated probes, which were then stained using streptavidin alkaline phosphatase. This technique was combined with immunohistochemistry to distinguish donor-type oligodendrocytes from macrophages. Immunoperoxidase staining with an antiserum to carbonic anhydrase-II produced dark perikarya of oligodendrocytes. The results demonstrated that local foetal brain cell grafts resulted in a wide dissemination of donor-type oligodendrocytes throughout the twitcher brain. The addition of a foetal brain cell graft to haemopoietic cell transplantation resulted in significantly prolonged survival of twitcher mice.     

Effects of aminoguanidine on pre- and post-irradiation regional cerebral blood flow,systemic blood pressure and plasma histamine levels in the primate

Exposure to ionizing radiation causes hypotension, cerebral ischemia and release of histamine (HA). To investigate the relationship among these three responses, rhesus monkeys (Macaca mulatta) received aminoguanidine (AG) (1 mg/kg), then were given either 50 Gy whole-body irradiation or sham-irradiation. Monkeys receiving AG had lower mean arterial blood pressure (MABP) than saline-treated controls. Compared to controls, rCBF was lower in irradiated monkeys but pre-treatment with AG did not influence this effect. Among untreated, irradiated monkeys, HA levels were increased only at two minutes post-irradiation, but among AG-treated, irradiated monkeys, HA levels were higher at all times postirradiation. Radiation-induced release of HA may be associated with radiation-induced hypotension and reduced rCBF, but failure of AG to alter rCBF suggests that released HA may not be the sole mediator of these effects. Because elevations in plasma HA are probably due to HA derived from degranulation of mast cells, release of other bioactive substances from mast cells may also influence these cardiovascular effects. Surprisingly, in sham-irradiated monkeys, AG alone had a slight but significant hypotensive effect.Supported by the Armed Forces Radiobiology Research Institute, Defense Nuclear Agency, under work unit 00105. Views presented in this paper are those of the authors; no endorsement by the Defense Nuclear Agency has been given or should be inferred. Research was conducted according to the principles enunciated in the Guide for the Care and Use of Laboratory Animals prepared by the Institute of Laboratory Animal Resources, National Research Council.     

Effect of heat on dsb repair in G1- and S-phase studied in the human HeLa S3 cell line

PURPOSE: The aim of this study was to investigate the relation between double-strand breaks and thermal radiosensitization in dependence on cell-cycle position. MATERIALS AND METHODS: The experiments were performed with the human tumour cell line HeLa S3. Cells synchronized in G1- and S-phase were exposed to X-rays alone or in combination with prior heating at 44 degrees C for 20 min. Cell kill was determined by means of colony forming assay, double-strand breaks (dsb) using constant-field gel electrophoresis and apoptotic cell death was scored using the fraction of detached cells. RESULTS: In both cell-cycle phases heating at 44 degrees C for 20 min prior to irradiation resulted in an increased cellular radiosensitivity, whereby the thermal enhancement ratio (TER) was significantly higher in S- than in G1-phase cells with TER=2.1 and 1.2, respectively. Prior heating at 44 degrees C did not affect the number of radiation-induced dsb but was found to modify their repair as measured for a X-ray dose of 40 Gy. In both cell cycle phases dsb repair kinetics measured after irradiation alone could be described by a fast and a slow component with the majority of dsb being repaired with fast kinetics. Prior heating at 44 degrees C was found to have only a minor effect on these half-times but mainly to affect the number of slowly rejoined dsb. In G1-phase cells the number of slowly rejoined dsb measured 300 min after irradiation was enhanced by a factor of 1.8 and in S-phase cells even by a factor of 3.2. Fraction of apoptotically dying cells was low after X-irradiation alone but was clearly enhanced after combined treatment, which was especially pronounced for S-phase cells. CONCLUSIONS: The pronounced thermal radiosensitization found for S-phase cells was attributed to the heat-mediated increase in the number of slowly rejoined dsb and partly also to the enhanced fraction of apoptotically dying cells when compared to G1-phase cells.