The cardiovascular actions of cyclohexylamine, and its formation from cyclamate in humans
The cardiovascular actions of cyclohexylamine, and its formation from cyclamate in humans
Cyclamate (CHS), a non-nutritive sweetener, is metabolised following chronic administration, to Cyclohexylamine (CHA). Over 70% of the population metabolise less than 0.1% of the daily dose while 3-4% metabolise over 20% (see Renwick, 1986). CHA is an indirectly acting sympathomimetic amine and therefore represents a potential toxicant to a minority of individuals. A minimum plasma CHA concentration of around 0.7 μg/ml was required to increase significantly the mean arterial blood pressure following a single oral dose of CHA in human volunteers (Eichelbaum et al., 1974). The cardiovascular effects (CV) of CHA were more pronounced during the rapid increase in plasma concentrations following a single oral dose than during the subsequent elimination phase. The incidence and extent of CHS metabolism in 194 diabetics receiving 1g CHS per day for 7 days was similar to previous published studies. There were no changes in CV parameters even in the highest converters who had plasma concentrations of CHA> 0.7μg/ml. The formation of CHA took several days to reach steady-state so that the rate of increase in plasma concentrations of CHA did not resemble those reported after a single oral dose of CHA and no pressor effect would be produced. The extent of rapid fluctuations in plasma CHA concentrations and CV effects was assessed by an investigation in 20 patients from the first study. Patients received 2g CHS per day for 14 days after which blood samples and CV measurements were taken every 30min for one dose interval(8h). During the dose interval there were no significant short-term fluctuations in plasma CHA concentration. However, in several patients gradual increases or decreases in plasma concentration, over the dose-interval, were found which were comparable to the known day-to-day fluctuations in cyclamate metabolism. Since there was no evidence of any short-term fluctuations in plasma CHA concentration it was concluded that no transient pressor effects would be expected during chronic CHS intake and that the CV assessment in the initial study would have been representative of individuals during steady-state metabolism. The studies described in this thesis have shown that CHA-related CV effects are unlikely to occur during chronic CHS intake. This may be explained in relation to the kinetics of its slow formation during which tachyphylaxis develops, without neuronal noradrenaline depletion, and the absence during steady-statemetabolism of any significant transient fluctuations in plasma CHA concentrations.
University of Southampton
Buss, Neil Edward
d7680e32-a79e-483d-a107-37713afd2e40
1991
Buss, Neil Edward
d7680e32-a79e-483d-a107-37713afd2e40
Buss, Neil Edward
(1991)
The cardiovascular actions of cyclohexylamine, and its formation from cyclamate in humans.
University of Southampton, Doctoral Thesis.
Record type:
Thesis
(Doctoral)
Abstract
Cyclamate (CHS), a non-nutritive sweetener, is metabolised following chronic administration, to Cyclohexylamine (CHA). Over 70% of the population metabolise less than 0.1% of the daily dose while 3-4% metabolise over 20% (see Renwick, 1986). CHA is an indirectly acting sympathomimetic amine and therefore represents a potential toxicant to a minority of individuals. A minimum plasma CHA concentration of around 0.7 μg/ml was required to increase significantly the mean arterial blood pressure following a single oral dose of CHA in human volunteers (Eichelbaum et al., 1974). The cardiovascular effects (CV) of CHA were more pronounced during the rapid increase in plasma concentrations following a single oral dose than during the subsequent elimination phase. The incidence and extent of CHS metabolism in 194 diabetics receiving 1g CHS per day for 7 days was similar to previous published studies. There were no changes in CV parameters even in the highest converters who had plasma concentrations of CHA> 0.7μg/ml. The formation of CHA took several days to reach steady-state so that the rate of increase in plasma concentrations of CHA did not resemble those reported after a single oral dose of CHA and no pressor effect would be produced. The extent of rapid fluctuations in plasma CHA concentrations and CV effects was assessed by an investigation in 20 patients from the first study. Patients received 2g CHS per day for 14 days after which blood samples and CV measurements were taken every 30min for one dose interval(8h). During the dose interval there were no significant short-term fluctuations in plasma CHA concentration. However, in several patients gradual increases or decreases in plasma concentration, over the dose-interval, were found which were comparable to the known day-to-day fluctuations in cyclamate metabolism. Since there was no evidence of any short-term fluctuations in plasma CHA concentration it was concluded that no transient pressor effects would be expected during chronic CHS intake and that the CV assessment in the initial study would have been representative of individuals during steady-state metabolism. The studies described in this thesis have shown that CHA-related CV effects are unlikely to occur during chronic CHS intake. This may be explained in relation to the kinetics of its slow formation during which tachyphylaxis develops, without neuronal noradrenaline depletion, and the absence during steady-statemetabolism of any significant transient fluctuations in plasma CHA concentrations.
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Published date: 1991
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Local EPrints ID: 460577
URI: http://eprints.soton.ac.uk/id/eprint/460577
PURE UUID: dcb100e2-3bf5-450a-b748-12a93c44cdaa
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Date deposited: 04 Jul 2022 18:24
Last modified: 23 Jul 2022 00:58
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Author:
Neil Edward Buss
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