Journal of Toxicology and Environmental Health
ISSN: 0098-4108 (Print) (Online) Journal homepage: http://www.tandfonline.com/loi/uteh19
Use of aspartame in phenylketonuric heterozygous adults Richard Koch , Kenneth N. F. Shaw , Malcolm Williamson & Margaret Haber To cite this article: Richard Koch , Kenneth N. F. Shaw , Malcolm Williamson & Margaret Haber (1976) Use of aspartame in phenylketonuric heterozygous adults, Journal of Toxicology and Environmental Health, 2:2, 453-457, DOI: 10.1080/15287397609529446 To link to this article: http://dx.doi.org/10.1080/15287397609529446
Published online: 20 Oct 2009.
Submit your article to this journal
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Citing articles: 9 View citing articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=uteh20 Download by: [NSTL]
Date: 28 September 2015, At: 02:56
SWEETENER REVIEW
USE OF ASPARTAME IN PHENYLKETONURIC HETEROZYGOUS ADULTS Richard Koch, Kenneth N. F. Shaw, Malcolm Williamson, Margaret Haber
Downloaded by [NSTL] at 02:56 28 September 2015
Child Development & Medical Genetics Divisions, Childrens Hospital of Los Angeles, and Department of Pediatrics, University of Southern California School of Medicine, Los Angeles, California
Aspartame, a new artificial sweetener, was administered to 45 obligate phenylketonuric adults for 28 wk. This new sweetening agent was well tolerated, and no untoward medical or biochemical changes were noted.
INTRODUCTION The purpose of this study was to evaluate the use of aspartame (L-aspartylphenylalanine methyl ester) in heterozygotes for phenylketonuria (PKU). In PKU elevated serum phenylalanine levels greater than 20 mg are associated with the development of mental retardation; moderately elevated levels (5-20 mg) may be associated with perceptual difficulties and learning disorders. Because aspartame contains phenylalanine, it is important to show that individuals with the heterozygous state of PKU do not show accumulation of phenylalanine in their body tissues. Because aspartame is an artificial sweetener, it can be assumed that individuals will consume varying amounts of phenylalanine from this source in addition to that normally consumed in the average American diet. Although no data have been published on the phenylalanine content of the normal diet, it has been estimated that the maximum amount of phenylalanine that the average person might consume as aspartame would range from 0.34 to 2 or 3 g/day. From all sources a normal adult may consume as much as 4-5 g phenylalanine/day. In this study PKU heterozygotes were defined as parents of known PKU patients under the care of the investigators. PKU is an autosomally inherited recessive disease. Thus, by definition, parents must be either heterozygotes (carriers) or homozygotes. Each parent in the study was carefully screened by appropriate blood and urine tests to rule out the This paper was presented at the American College of Nutrition First Annual Interim Meeting, Scientific Review of a New Sweetener, supported by a grant-in-aid from G. D. Searle & Co. Requests for reprints should be sent to Richard Koch, Childrens Hospital of Los Angeles, P.O. Box 54700, Los Angeles, California 90054.
453 Journal of Toxicology and Environmental Health, 2:453-457,1976 Copyright © 1976 by Hemisphere Publishing Corporation
454
R. KOCHETAL.
latter possibility. Parents of 83 PKU children were contacted for support of and participation in the proposed study; 45 individuals agreed to participate.
Downloaded by [NSTL] at 02:56 28 September 2015
METHODS
Administrating Test Substance A double-blind study design was utilized. Participants were divided according to sex and assigned random study numbers. Identical capsules of either aspartame or placebo were supplied by G. D. Searle and Co. The containers were numbered to correspond with the randomly assigned study number of the participants and were labeled to indicate each study week. Table 1 describes the schedule of capsule intake and the daily intake of aspartame and phenylalanine consumed by ingestion of the capsules containing aspartame. The study was divided into two phases. During the first 7 wk (phase A), aspartame was increased at weekly intervals from 3 to 37 capsules per day. For the next 21 wk (phase B), six capsules per day were ingested. Monitoring Participants
Before taking the capsules, each participant received a medical and ophthalmologic examination to determine general health status. During each week of the study period, blood pressures and weights were obtained. Medication intake was recorded, and participants' observations and complaints were noted and reviewed weekly. A daily diary of food intake was recorded by the participants and reviewed weekly by the consulting nutritionist. At the completion of the study, the medical and opthalmologic examinations were repeated with special emphasis on any health changes occurring during the study period.
TABLE 1. Capsule Intake Schedule by Study Week Phase A 1
2
Phase B
4
5
4
5
7
9
2
3
6
7-27
Number of capsules taken with each meal (three times per day)
1
2
Amount of aspartame per capsule (g)
0.2
0.2
0.2
0.3
0.3
0.3
0.3
Total amount aspartame per day (g)
0.6
1.2
2.4
4.5
6.3
8.1
1.8
Total daily phenylalanine from aspartame (g)
0.34 0.67 1.35 2.53 3.54 4.55
1.01
TABLE 2. Laboratory Studies Undertaken before and during Phase A, by Study Week Study week
1
Downloaded by [NSTL] at 02:56 28 September 2015
Screening period
6
Hematology 0
CBC PTT Protein time Urinalysis including phenistix
X
in in
Th
M
M
Th
Th
M
X
X
X
X
X
X
X
X
6 Th
Th
M
X X
X
7 M
X X
X
X
1 / / / / / /
\ \
/ /
/
u
v1 /
1 5 •"
k \ \ // \I
3 S
\
/
\
/
\l
/
X
\
/
X
\/
X
X
Urine chromatographyc
X
70
\ /
\
Glucose: 0, 3 0 , 6 0 min Insulin: 0, 30, 60 min
/
\
/ \ / \ / \ / \ / \ / \ / \
Glucose tolerance 6
(urine gonadotropin)
1
y A
Bilirubin D/l SGOT
Pregnancy test
I
\ /
BUN T4
Alkaline phosphatase Uric acid Creatinine Cholesterol (total) Cholesterol (esters) Triglycerides
M
5
X
X
\ \ \ \ \ \ \
Chemistry •U
Th
4
3
X
Serum phenylalanine (8 a.m.)° Tyrosine (12 n o o n )
M Tu
2
. ...
\
X
"Performed fasting; nothing by mouth after midnight. ^Performed after fasting for 4 hr following a breakfast consisting of 3 oz orange juice, one slice buttered toast, one egg (fried, scrambled, or soft boi(ed), one cup coffee or hot tea sweetened with one teaspoonful of cane sugar and up to 6 oz water. No cream or substitute allowed. 'Postprandial.
TABLE 3. Laboratory Studies Performed during Phase B, by Study Week Study week
M
or T
or T
Serum phenylalanine (8 a.m.)"
X
Tyrosine(12 noon)*
X
Hematology
9
11
13
15
17
19
21
23
25
27
28
M
M
or T
or T
M or
M or
M or
M or
M or
M or
M or
M or
X
X
X
X
X X
X
X
X
X X
X
X
X
X
0
CBC PTT
/
Chemistry
BUN T4 Bilirubin O/l SGOT Alkaline phosphatase Uric acid Creatinine Cholesterol (total) Cholesterol (esters) Triglycerides
/ /
wv
\
I /
v
/
I
A / \ / / / / / f
Glucose tolerance* Glucose: 0, 30, 60 min Insulin: 0, 30, 60 min
X
/
\
/ /
A / M /1 / / \ / \ /
\
X
\
/ /
I / \ / \ /
/
\
\
/
/
X
\
\ /
X
ft
a £
h
j\
I\ I \ I \
\/
O •o
\ \ i
i / /
/\
x,
•a
yy
I
/
f\
/
\
v
A \ //\I
/
1
/
I
i/
Urine chromatography^ Pregnancy test (urine gonadotropin)
/ / / / /
\ /
Protein time Urina lysis including phenistix
4*
X
X
tud
Downloaded by [NSTL] at 02:56 28 September 2015
8 M
/
X
\
X X XX
"Performed fasting; nothing by mouth after midnight. ^Performed after fasting for 4 hr following a breakfast consisting of 3 oz orange juice, one slice buttered toast, one egg (fried, scrambled, or soft boiled), one cup coffee or hot tea sweetened with one teaspoonful of cane sugar and up to 6 oz water. No cream or substitute allowed. c Postprandial.
ASPARTAME IN PKU HETEROZYGOTES
457
Extensive laboratory studies were performed before and during phase A (Table 2). Table 3 outlines the tests performed during phase B and at the termination of the study to assist in assessment of the medical status of all participants. Any abnormal findings were repeated to establish accuracy. In addition to routine laboratory studies, urines were analyzed spectrophotometrically for phenylpyruvic acid and by two-dimensional paper chromatography for phenylalanine and its metabolites o-hydroxyphenylacetic acid and phenylacetylglutamine.
Downloaded by [NSTL] at 02:56 28 September 2015
RESULTS Of the 45 PKU heterozygotes who agreed to participate in phase A, 20 were male and 25 were females. Age ranged from 28 to 50 yr, averaging 35. All were in apparent good health. The initial physical examinations revealed two persons (one male and one female) who were overweight and thus excluded. Initial laboratory results for one female suggested hypothyroidism. Clinically, however, she was not sluggish, did not exhibit dry hair or skin, and was not constipated; therefore, she was continued in the study. Total participants numbered 43 in phase A and 41 in phase B. Eye examinations, including slit lamp studies, were performed. All results were normal, and no significant ophthalmologic changes were observed during the entire study. During the second week, one woman developed an acute dental abscess that was treated with antibiotics and dental extraction. No changes occurred in her laboratory studies. Two women, one in late menopause and the other age 36, developed vaginal spotting and were referred to an obstetrician for further evaluation. In both cases the spotting subsided spontaneously. Table 2 and 3 indicate the various laboratory tests and timing employed during the study. No significant changes in the serum phenylalanine, tyrosine, or urinary metabolite levels were noted. All follow-up medical examinations throughout the study were also unchanged from initial evaluations. CONCLUSIONS No significant medical or biochemical changes were noted during the 28-wk study in PKU heterozygotes receiving aspartame. Serum phenylalanine and tyrosine levels remained within normal limits throughout the study period. This new sweetening agent was well tolerated.
ISSN: 0098-4108 (Print) (Online) Journal homepage: http://www.tandfonline.com/loi/uteh19
Use of aspartame in phenylketonuric heterozygous adults Richard Koch , Kenneth N. F. Shaw , Malcolm Williamson & Margaret Haber To cite this article: Richard Koch , Kenneth N. F. Shaw , Malcolm Williamson & Margaret Haber (1976) Use of aspartame in phenylketonuric heterozygous adults, Journal of Toxicology and Environmental Health, 2:2, 453-457, DOI: 10.1080/15287397609529446 To link to this article: http://dx.doi.org/10.1080/15287397609529446
Published online: 20 Oct 2009.
Submit your article to this journal
Article views: 4
View related articles
Citing articles: 9 View citing articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=uteh20 Download by: [NSTL]
Date: 28 September 2015, At: 02:56
SWEETENER REVIEW
USE OF ASPARTAME IN PHENYLKETONURIC HETEROZYGOUS ADULTS Richard Koch, Kenneth N. F. Shaw, Malcolm Williamson, Margaret Haber
Downloaded by [NSTL] at 02:56 28 September 2015
Child Development & Medical Genetics Divisions, Childrens Hospital of Los Angeles, and Department of Pediatrics, University of Southern California School of Medicine, Los Angeles, California
Aspartame, a new artificial sweetener, was administered to 45 obligate phenylketonuric adults for 28 wk. This new sweetening agent was well tolerated, and no untoward medical or biochemical changes were noted.
INTRODUCTION The purpose of this study was to evaluate the use of aspartame (L-aspartylphenylalanine methyl ester) in heterozygotes for phenylketonuria (PKU). In PKU elevated serum phenylalanine levels greater than 20 mg are associated with the development of mental retardation; moderately elevated levels (5-20 mg) may be associated with perceptual difficulties and learning disorders. Because aspartame contains phenylalanine, it is important to show that individuals with the heterozygous state of PKU do not show accumulation of phenylalanine in their body tissues. Because aspartame is an artificial sweetener, it can be assumed that individuals will consume varying amounts of phenylalanine from this source in addition to that normally consumed in the average American diet. Although no data have been published on the phenylalanine content of the normal diet, it has been estimated that the maximum amount of phenylalanine that the average person might consume as aspartame would range from 0.34 to 2 or 3 g/day. From all sources a normal adult may consume as much as 4-5 g phenylalanine/day. In this study PKU heterozygotes were defined as parents of known PKU patients under the care of the investigators. PKU is an autosomally inherited recessive disease. Thus, by definition, parents must be either heterozygotes (carriers) or homozygotes. Each parent in the study was carefully screened by appropriate blood and urine tests to rule out the This paper was presented at the American College of Nutrition First Annual Interim Meeting, Scientific Review of a New Sweetener, supported by a grant-in-aid from G. D. Searle & Co. Requests for reprints should be sent to Richard Koch, Childrens Hospital of Los Angeles, P.O. Box 54700, Los Angeles, California 90054.
453 Journal of Toxicology and Environmental Health, 2:453-457,1976 Copyright © 1976 by Hemisphere Publishing Corporation
454
R. KOCHETAL.
latter possibility. Parents of 83 PKU children were contacted for support of and participation in the proposed study; 45 individuals agreed to participate.
Downloaded by [NSTL] at 02:56 28 September 2015
METHODS
Administrating Test Substance A double-blind study design was utilized. Participants were divided according to sex and assigned random study numbers. Identical capsules of either aspartame or placebo were supplied by G. D. Searle and Co. The containers were numbered to correspond with the randomly assigned study number of the participants and were labeled to indicate each study week. Table 1 describes the schedule of capsule intake and the daily intake of aspartame and phenylalanine consumed by ingestion of the capsules containing aspartame. The study was divided into two phases. During the first 7 wk (phase A), aspartame was increased at weekly intervals from 3 to 37 capsules per day. For the next 21 wk (phase B), six capsules per day were ingested. Monitoring Participants
Before taking the capsules, each participant received a medical and ophthalmologic examination to determine general health status. During each week of the study period, blood pressures and weights were obtained. Medication intake was recorded, and participants' observations and complaints were noted and reviewed weekly. A daily diary of food intake was recorded by the participants and reviewed weekly by the consulting nutritionist. At the completion of the study, the medical and opthalmologic examinations were repeated with special emphasis on any health changes occurring during the study period.
TABLE 1. Capsule Intake Schedule by Study Week Phase A 1
2
Phase B
4
5
4
5
7
9
2
3
6
7-27
Number of capsules taken with each meal (three times per day)
1
2
Amount of aspartame per capsule (g)
0.2
0.2
0.2
0.3
0.3
0.3
0.3
Total amount aspartame per day (g)
0.6
1.2
2.4
4.5
6.3
8.1
1.8
Total daily phenylalanine from aspartame (g)
0.34 0.67 1.35 2.53 3.54 4.55
1.01
TABLE 2. Laboratory Studies Undertaken before and during Phase A, by Study Week Study week
1
Downloaded by [NSTL] at 02:56 28 September 2015
Screening period
6
Hematology 0
CBC PTT Protein time Urinalysis including phenistix
X
in in
Th
M
M
Th
Th
M
X
X
X
X
X
X
X
X
6 Th
Th
M
X X
X
7 M
X X
X
X
1 / / / / / /
\ \
/ /
/
u
v1 /
1 5 •"
k \ \ // \I
3 S
\
/
\
/
\l
/
X
\
/
X
\/
X
X
Urine chromatographyc
X
70
\ /
\
Glucose: 0, 3 0 , 6 0 min Insulin: 0, 30, 60 min
/
\
/ \ / \ / \ / \ / \ / \ / \
Glucose tolerance 6
(urine gonadotropin)
1
y A
Bilirubin D/l SGOT
Pregnancy test
I
\ /
BUN T4
Alkaline phosphatase Uric acid Creatinine Cholesterol (total) Cholesterol (esters) Triglycerides
M
5
X
X
\ \ \ \ \ \ \
Chemistry •U
Th
4
3
X
Serum phenylalanine (8 a.m.)° Tyrosine (12 n o o n )
M Tu
2
. ...
\
X
"Performed fasting; nothing by mouth after midnight. ^Performed after fasting for 4 hr following a breakfast consisting of 3 oz orange juice, one slice buttered toast, one egg (fried, scrambled, or soft boi(ed), one cup coffee or hot tea sweetened with one teaspoonful of cane sugar and up to 6 oz water. No cream or substitute allowed. 'Postprandial.
TABLE 3. Laboratory Studies Performed during Phase B, by Study Week Study week
M
or T
or T
Serum phenylalanine (8 a.m.)"
X
Tyrosine(12 noon)*
X
Hematology
9
11
13
15
17
19
21
23
25
27
28
M
M
or T
or T
M or
M or
M or
M or
M or
M or
M or
M or
X
X
X
X
X X
X
X
X
X X
X
X
X
X
0
CBC PTT
/
Chemistry
BUN T4 Bilirubin O/l SGOT Alkaline phosphatase Uric acid Creatinine Cholesterol (total) Cholesterol (esters) Triglycerides
/ /
wv
\
I /
v
/
I
A / \ / / / / / f
Glucose tolerance* Glucose: 0, 30, 60 min Insulin: 0, 30, 60 min
X
/
\
/ /
A / M /1 / / \ / \ /
\
X
\
/ /
I / \ / \ /
/
\
\
/
/
X
\
\ /
X
ft
a £
h
j\
I\ I \ I \
\/
O •o
\ \ i
i / /
/\
x,
•a
yy
I
/
f\
/
\
v
A \ //\I
/
1
/
I
i/
Urine chromatography^ Pregnancy test (urine gonadotropin)
/ / / / /
\ /
Protein time Urina lysis including phenistix
4*
X
X
tud
Downloaded by [NSTL] at 02:56 28 September 2015
8 M
/
X
\
X X XX
"Performed fasting; nothing by mouth after midnight. ^Performed after fasting for 4 hr following a breakfast consisting of 3 oz orange juice, one slice buttered toast, one egg (fried, scrambled, or soft boiled), one cup coffee or hot tea sweetened with one teaspoonful of cane sugar and up to 6 oz water. No cream or substitute allowed. c Postprandial.
ASPARTAME IN PKU HETEROZYGOTES
457
Extensive laboratory studies were performed before and during phase A (Table 2). Table 3 outlines the tests performed during phase B and at the termination of the study to assist in assessment of the medical status of all participants. Any abnormal findings were repeated to establish accuracy. In addition to routine laboratory studies, urines were analyzed spectrophotometrically for phenylpyruvic acid and by two-dimensional paper chromatography for phenylalanine and its metabolites o-hydroxyphenylacetic acid and phenylacetylglutamine.
Downloaded by [NSTL] at 02:56 28 September 2015
RESULTS Of the 45 PKU heterozygotes who agreed to participate in phase A, 20 were male and 25 were females. Age ranged from 28 to 50 yr, averaging 35. All were in apparent good health. The initial physical examinations revealed two persons (one male and one female) who were overweight and thus excluded. Initial laboratory results for one female suggested hypothyroidism. Clinically, however, she was not sluggish, did not exhibit dry hair or skin, and was not constipated; therefore, she was continued in the study. Total participants numbered 43 in phase A and 41 in phase B. Eye examinations, including slit lamp studies, were performed. All results were normal, and no significant ophthalmologic changes were observed during the entire study. During the second week, one woman developed an acute dental abscess that was treated with antibiotics and dental extraction. No changes occurred in her laboratory studies. Two women, one in late menopause and the other age 36, developed vaginal spotting and were referred to an obstetrician for further evaluation. In both cases the spotting subsided spontaneously. Table 2 and 3 indicate the various laboratory tests and timing employed during the study. No significant changes in the serum phenylalanine, tyrosine, or urinary metabolite levels were noted. All follow-up medical examinations throughout the study were also unchanged from initial evaluations. CONCLUSIONS No significant medical or biochemical changes were noted during the 28-wk study in PKU heterozygotes receiving aspartame. Serum phenylalanine and tyrosine levels remained within normal limits throughout the study period. This new sweetening agent was well tolerated.
