Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Reexamination Certificate
1999-04-26
2001-05-01
Lee, Howard C. (Department: 1623)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
C514S892000, C536S001110
Reexamination Certificate
active
06225452
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention relates to the use of tagatose in increasing fertility in mammals, in promoting healthy fetal development in mammals, in increasing the probability for delivering live fetuses in mammals and in controlling food intake during pregnancy of a mammal.
U.S. Pat. No. 4,786,722 discloses edible formulations and methods for preparation of edible formulations in which D-tagatose is used as a low-calorie carbohydrate sweetener and bulking agent. In this patent, D-tagatose is described as useful in foodstuffs and other edible formulations for people whose metabolizable carbohydrate intake must be restricted because of conditions such as diabetes mellitus or obesity.
Safety tests performed on tagatose in its development as a low-calorie sweetener included developmental toxicity studies in rats. Rats are accepted by the US FDA as good models for humans in studying safety and efficacy of food additives and drugs. Newly impregnated rats were placed on various doses of tagatose in their daily diet. Female rats were housed with males nightly in a one-to-one ratio, and each morning inspections for vaginal plugs were made, and in their absence, vaginal smears were taken and tested for sperm. Those females which had been mated were selected for monitoring of fetal development and assigned to tagatose dose groups in a manner so as to provide an equal distribution of mated females among groups and also to equalize the Day
0
gestation mean body weights among the groups. There were 24 mated females in each group. On Days 6-15 of gestation three of the groups received respective total doses of 4,000, 12,000 and 20,000 mg/kg body wt/day administered via gastric intubation in two equally divided doses separated by a four-hour interval. Each dose was administered in 30 ml/kg body weight of distilled, deionized water. Control animals received distilled, deionized water at a comparable volume and frequency. For a period of 20 days following mating, the rats were observed and measurements taken daily. Upon the 20
th
day, the rats were killed and a wide variety of physical, toxicological, and fetal developmental parameters was determined for treatment effects. No adverse effects in the dams or fetuses were found. However, I noted unpredictable, novel and beneficial effects with respect to fertility and fetal development.
Table 1 presents the reproductive performance of the test and control groups of rats. It is seen that the numbers of females impregnated was 83.3% for the rats receiving no tagatose, and 100%, 91.3% and 100%, respectively for the rats receiving 4,000, 12,000 and 20,000 mg/kg body wt/day. Since each of the rats was selected after mating, with, therefore, equal chance of becoming pregnant, it is evident that the administration of tagatose on the 6
th
through 15
th
days after mating resulted in greater numbers of pregnancies.
TABLE 1
Reproductive Performance of Female Crl:CD (SD) BR Rats Fed D-Tagatose from Days 6 to 15 of Gestation
Dose levels of D-Tagatose (in mg/kg/day)
0
4,000
12,000
20,000
Number of females placed with males
24
23
a
23
a
24
Number of females pregnant (%)
b
20 (83.3%)
23 (100%)
21 (91.3%)
24 (100%)
Fertility index
83.3
100
91.3
100
Number of females bearing viable fetuses
20
23
21
24
Number of
corpora lutea
c
17.8 ± 3.0
17.7 ± 2.8
17.7 ± 2.9
17.4 ± 2.8
Number of implantation sites
c
15.3 ± 3.2
16.5 ± 2.3
15.9 ± 2.9
15.3 ± 2.9
Preimplantation loss
c,d
0.129 ± 0.183
0.053 ± 0.113
0.094 ± 0.151
0.107 ± 0.162
Number of resorptions
c
1.0 ± 1.2
1.1 ± 0.9
0.5 ± 0.9
0.8 ± 0.8
Postimplantation loss
c,e
0.059 ± 0.071
0.068 ± 0.051
0.043 ± 0.087
0.047 ± 0.049
Number of litters with resorptions(%)
b
12 (60.0%)
18 (78.3%)
6 (28.6%)
13 (54.2%)
Total number of viable fetuses
287
354
322
350
Number of males fetuses
c
6.9 ± 2.0
7.4 ± 2.3
7.8 ± 2.3
7.5 ± 2.3
Number of female fetuses
c
7.5 ± 2.5
8.0 ± 2.2
7.5 ± 2.2
7.1 ± 2.3
Number of dead fetuses
0
0
0
0
Body weight (g) of viable fetuses
c
3.47 ± 0.28
3.56 ± 0.21
3.75 ± 0.32**
3.57 ± 0.24
Male fetuses
c
3.58 ± 0.27
3.64 ± 0.22
3.84 ± 0.33*
3.68 ± 0.27
Female fetuses
c
3.37 ± 0.27
3.49 ± 0.20
3.65 ± 0.35**
3.49 ± 0.19
a
Excludes data from one female that delivered prior to Day 20. On the basis of the weight of the delivered pups, pregnancy appeared to be greater than Day 20 gestation.
b
N (%), total number affected (percentage of total number evaluated).
c
Values are means ± SD.
d
Preimplantation loss = (
corpora lutea
-implants)/(
corpora lutea
).
e
Postimplantation loss = (resorptions/implantations).
*Difference from control statistically significant (P ≦ 0.05).
**Difference from control statistically significant (P ≦ 0.01).
Table 1 also shows that, of the impregnated rats, each in those groups receiving tagatose produced greater numbers of live fetuses than those not given tagatose. Thus tagatose not only increased the numbers of pregnancies, but also was responsible for greater numbers of fetuses maintained alive up to the date of sacrifice. Total numbers of live fetuses were 354, 322 and 350 for the groups receiving 4,000, 12,000 and 20,000 mg/kg body wt/day, respectively, versus 287 live fetuses for the control group. Thus, tagatose administered six through 15 days after mating resulted in a greater number of live fetuses at Day 20 than in rats not receiving tagatose.
It is commonly known that underweight fetuses are subject to increased risks of disease and many forms of growth and developmental problems in utero and after birth. Table 1 shows that the fetuses of each group of rats on tagatose weighed more than the fetuses of the control rats. It is seen that this was true for the total numbers of fetuses as well as for males and females separately. Furthermore, fetuses from rats on tagatose were within the normal weight range for their ages: 3.35-3.86 g for males and 3.19-3.63 g for females.
One of the common problems associated with pregnancy is overeating which can result in excess weight gain with its concomitant health risks to the mother and fetus. As seen in Table 2, during the rats' period on tagatose, Day 6 through Day 15, their total daily food intakes were less than the daily food intakes of rats in the control group. This represents a clear health advantage for both dam and fetus receiving tagatose. That tagatose was responsible is seen by the fact that Table 2 shows that food intakes for the test and control groups were essentially the same from Day 0 to Day 6, when tagatose administration began, and that food intakes for the test rats increased after they were taken off tagatose, beginning Day 16. In this rat study, no consistent weight loss in the dams accompanied the reduction in intakes (except for the period from Day 6 to Day 9 attributed to taxation in the high tagatose dose groups).
TABLE 2
Food Consumption in Female Crl: CD(SD)BR Rats Fed D-Tagatose
during Pretreatment (Days 0 to 6 of Gestation), Treatment (Days 6 to 15
of Gestation), and Posttreatment (Days 16-20 of Gestation)
Dose levels of D-tagatose (in mg/kg/day)
Days of pregnancy
0
4,000
12,000
20,000
Number of dams/
20
23
21
24
group
Food intake (g/kg body wt/day)
a
Days 0-6
104 ± 11
103 ± 7
104 ± 8
107 ± 9
Days 6-9
93 ± 7
84 ± 4
69 ± 7**
51 ± 4**
Days 9-12
93 ± 5
91 ± 5
84 ± 5**
80 ± 7**
Days 12-16
89 ± 4
90 ± 5
83 ± 5**
77 ± 6**
Days 16-20
90 ± 4
94 ± 3
99 ± 5**
102 ± 6**
Food intake (g/animal)
a
Days 0-6
145 ± 17
144 ±
Biospherics Incorporated
Lee Howard C.
Roylance Abrams Berdo & Goodman L.L.P.
White Everett
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