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Three cases of human bladder cancer following high dose cyclamate ingestion.

Vesical implantation and oral feeding studies in animals raised sufficient suspicion of the carcinogenic propensity of cyclamates to result in their withdrawal from sale throughout the world. The structural similarity to known carcinogens, an effect on human chromosomes in tissue culture and a high carcinogenic potential when combined with non-injurious co-carcinogens gave further support to this ban. On the other hand, numerous epidemiological studies failed to support any statistical relationship between cyclamate ingestion and vesical carcinoma in man. Three patients are described in whom vesical carcinoma developed after a prolonged period of ingestion of an unusually high amount of cyclamate sweetener. Moreover, the severity of the disease appeared to be proportional to the dose ingested. Although this is not a conclusive indictment of the role of cyclamates we believe that patients with bladder cancer should be questioned about intake of cyclamates either directly or in diet soft drinks.

Aged

[Sweetness potency of saccharin and cyclamate in hot drinks].

The sweetness potency of sweeteners depends on temperature. At 50 degrees C the 2.4-fold concentration of saccharin and the 1.3-fold of cyclamate respectively is needed to produce the same sweetness (as related to sucrose) as in solutions at 20 degrees C. As well as in water the sweetening power decreases in chinese tea with increasing temperature. Only in case of cyclamate solutions of high sweetness this effect is diminished. In the mathematical description of the relation between stimulus and perception the decrease of the relative sweetness observed can be expressed by a comformable decrease of the concentration coefficient. The effect of temperature on the perception of sweetness can be explained by the Arrhenius' conception. The critical increments are 23 kJ/mol for saccharin and 8 kJ/mol for both cyclamate and fructose.

Cyclamates

[Studies of the interractions of cyclamate with phenprocomon (author's transl)].

The effect of cyclamate on the anticoagulant activity of phenprocoumon was investigated in rats after single oral doses of phenprocoumon, cyclamate, or phenprocoumon/cyclamate. By means of high pressure liquid chromatrography [HPLC] the change of the concentration of phenprocoumon per unit time in sera was determined. The anticoagulant acitivity of phenprocoumon was determined by the extension of the prothromin-time (Quick-test). It was found that cyclamate gives rise to an elevated of phenprocoumon in the blood, and a reduction of the anticoagulanting potency.

4-Hydroxycoumarins

Protective effects of cholestyramine in rats fed a low-fiber diet containing toxic doses of sodium cyclamate or amaranth.

Immature male rats were fed a purified, low-fiber diet containing massive doses of sodium cyclamate or amaranth (FD and C Red No. 2). Sodium cyclamate when incorporated at a 5% level in the purified, low-fiber diet resulted in toxic manifestations which were counteracted by the concurrent administration of the anion exchange resin cholestyramine at a 2 1/2% level in the diet. Other anion exchange resins were also active in this regard. Cholestyramine at a 2 1/2% level of supplementation was also active in counteracting the toxic effects induced by amaranth when the latter was incorporated at a 5% level in the purified, low-fiber diet.

Amaranth Dye

[Subchronic toxicologic studies using cyclamate-Na in dogs].

2 male and 2 female beagle dogs were fed cyclamate-Na in daily doses of 0 (control), 150, 500, 1500 mg/kg of body weight with the diet. Liquid feces occurred only after feeding 1500 mg/kg/day during the first few days of the experiment. Haematological, clotting and clinical chemistry parameters were unchanged in the groups up to the level of 1500 mg/kg/day. No effects were noted in carbohydrate and fat metabolism, nor in ECG or blood pressure. Gross pathology and histopathology did not reveal any change in any dose group. Daily fed doses of cyclamate-Na up to 1500 mg/kg body weight were well tolerated for three month in the dog.

Animals

Saccharin, cyclamate, and human bladder cancer. No evidence of an association.

An epidemiologic study designed to elucidate the possible roles of the artificial sweeteners saccharin and cyclamate in human urinary bladder cancer was recently completed. The previous intake of each of these substances among 519 patients with histopathologically confirmed bladder cancer and an equal number of matching controls in metropolitan Baltimore did not differ significantly in frequency, quantity, or duration. These normal findings persisted after simultaneous adjustment for the effects of smoking, occupation, age, diabetes mellitus, and a number of other potentially confounding factors. They are substantiated by the failure of the relative risk of bladder cancer to increase with increasing exposure to artificial sweeteners. It is concluded that neither saccharin nor cyclamate is likely to be carcinogenic in man, at least at the moderate dietary ingestion levels reported by the patient sample.

Cyclamates

Correlation of chemical structure and taste in the cyclamate series and the steric nature of the chemoreceptor site.

The requirements of compounds in the cyclamate series for sweet taste stimulation are: synclinal conformation between NH and SO in the aminosulphonate group, length less than 0.7 nm of the group on the nitrogen, and hydrophobic character of the latter group. A hypothetical receptor site for these compounds should have a spatial barrier at a distance of about 0.7 nm from the nitrogen interaction point with the receptor site, and a hydrophobic interaction area between the nitrogen interaction point and the barrier.

Chemical Phenomena

[The reaction of cyclohexylsulphamic acid (Cyclamate) with nitrous acid in aqueous HCl-solution, isolated human gastric juice and urine (author's transl)].

The pH dependence of the formation and decomposition of the N-nitroso derivative, which is produced by the reaction of cyclohexylsulphamic acid with nitrous acid, was investigated by means of continuous photometric measurement of the changes in absorbance. Reaction at pH 2.45 resulted in an optimal yield of the N-nitroso derivative. The half-life of the decomposition reaction (the reactants cyclohexylsulphamic acid/sodium nitrite being in a molar ratio of 1:1.11) at pH 2.61 was 13.6 min. The N-nitroso derivative showed a relatively high stability at pH 4.5. The reaction in isolated human gastric juice and urine showed the same pH dependency as in aqueous HCl solution.

Cyclamates