US20010020008A1 - Increased fertility and improved fetal development drug - Google Patents

Increased fertility and improved fetal development drug Download PDF

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Publication number
US20010020008A1
US20010020008A1 US09/727,692 US72769200A US2001020008A1 US 20010020008 A1 US20010020008 A1 US 20010020008A1 US 72769200 A US72769200 A US 72769200A US 2001020008 A1 US2001020008 A1 US 2001020008A1
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Prior art keywords
tagatose
mammal
day
taken
efficacious amount
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US09/727,692
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Gilbert Levin
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Priority to US10/299,816 priority patent/US20030087834A1/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7004—Monosaccharides having only carbon, hydrogen and oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives

Definitions

  • 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.
  • 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.
  • 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.
  • 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 also shows that, of the impregnated rats, each in those groups receiving tagatose produced greater numbers of live fetuses than those not given tagatose.
  • 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.
  • 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.
  • a method for increasing the fertility of a female mammal especially a human female which comprises administering to said mammal an efficacious amount of tagatose, preferably D-tagatose.
  • a method for promoting healthy fetal development in a pregnant female mammal, especially a pregnant human female which comprises administering to said mammal an efficacious amount of tagatose, preferably D-tagatose, during pregnancy.
  • a method for increasing the birth weight of a fetus in a pregnant female mammal, especially a pregnant human female which comprises administering to said mammal an efficacious amount of tagatose, preferably D-tagatose.
  • a method for reducing excessive food intake of a pregnant female mammal, especially a pregnant human female which comprises administering to said mammal an efficacious amount of tagatose, preferably D-tagatose.
  • the tagatose may be administered to a mammal subject in combination with a food, beverage or taken separately in powder, crystalline or liquid form.
  • a mammal subject in combination with a food, beverage or taken separately in powder, crystalline or liquid form.
  • liquid or solid carriers such as water, starch, alcohol, or other non-toxic substances.
  • the tagatose is administered within the range of 100-2000 mg/kg body weight/day.
  • the tagatose may be administered daily, every other day or at other prescribed frequencies.
  • the tagatose may be D-tagatose, L-tagatose or a mixture thereof.
  • a 70 kg human female with a history of difficulty in conceiving begins taking tagatose twice daily at five g per dose, beginning one month before an attempt to conceive. She finds that her attempt is successful and she is pregnant.
  • a 70 kg human female with a history of spontaneous abortions and stillbirths takes tagatose twice daily at five g per dose, beginning one month before an attempt to conceive. She becomes pregnant, and the pregnancy proceeds to a successful conclusion, delivering a live birth.
  • a 70 kg human female takes precautions against giving birth to a below average weight infant by taking tagatose twice daily at five g per dose, beginning one month before an attempt to conceive. She becomes pregnant and delivers a baby within the normal birth weight range despite a family history of frequent low birth weight babies.
  • a 70 kg human female inclined toward obesity desires a child, but is concerned that pregnancy may increase her food intake causing weight problems as experienced in her past pregnancies. She takes tagatose twice daily at five g per dose, beginning one month before an attempt to conceive. She becomes pregnant, but her average daily diet does not increase, and her weight gain is within the range advised by her physician. She delivers a healthy, normal child.

Abstract

A method for increasing the fertility of a female mammal comprising administering to said female mammal an efficacious amount of tagatose.
A method for promoting healthy fetal development in a pregnant female mammal which comprises administering to said mammal an efficacious amount of tagatose.
A method for increasing the birth weight of a fetus in a pregnant female mammal which comprises administering to said mammal an efficacious amount of tagatose.
A method for reducing excessive food intake of a pregnant female mammal which comprises administering to said mammal an efficacious amount of tagatose.

Description

    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. [0001]
  • 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. [0002]
  • Safety tests performed on tagatose in its development as a low-calorie sweetener included developmental toxicity studies in rats. Rats are accepted by the U.S. 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[0003] 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[0004] th through 15th 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 23a 23a 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 luteac 17.8 ± 3.0 17.7 ± 2.8 17.7 ± 2.9 17.4 ± 2.8
    Number of implantation sitesc 15.3 ± 3.2 16.5 ± 2.3 15.9 ± 2.9 15.3 ± 2.9
    Preimplantation lossc,d 0.129 ± 0.183 0.053 ± 0.113 0.094 ± 0.151 0.107 ± 0.162
    Number of resorptionsc 1.0 ± 1.2 1.1 ± 0.9 0.5 ± 0.9 0.8 ± 0.8
    Postimplantation lossc,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 fetusesc 6.9 ± 2.0 7.4 ± 2.3 7.8 ± 2.3 7.5 ± 2.3
    Number of female fetusesc 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 fetusesc 3.47 ± 0.28 3.56 ± 0.21 3.75 ± 0.32** 3.57 ± 0.24
    Male fetusesc 3.58 ± 0.27 3.64 ± 0.22 3.84 ± 0.33* 3.68 ± 0.27
    Female fetusesc 3.37 ± 0.27 3.49 ± 0.20 3.65 ± 0.35** 3.49 ± 0.19
  • 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. [0005]
  • 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. [0006]
  • 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 laxation in the high tagatose dose groups). [0007]
    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)
    Days of
    pregnancy Dose levels of D-tagatose (in mg/kg/day)
    Number of 0 4,000 12,000 20,000
    dams/group 20 23 21 24
    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 ± 14**
    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 ± 11 148 ± 8   149 ± 14 
    Days 6-9 77 ± 8 70 ± 5 58 ± 6**  43 ± 12**
    Days 9-12 80 ± 6 78 ± 7 73 ± 6** 67 ± 7**
    Days 12-16 109 ± 8  112 ± 9  105 ± 9**   94 ± 10**
    Days 16-20 121 ± 9  129 ± 10  137 ± 9**  138 ± 11**
    • SUMMARY OF THE INVENTION
  • In accordance with one aspect of this invention, there is provided a method for increasing the fertility of a female mammal, especially a human female which comprises administering to said mammal an efficacious amount of tagatose, preferably D-tagatose. [0008]
  • In accordance with another aspect of this invention, there is provided a method for promoting healthy fetal development in a pregnant female mammal, especially a pregnant human female, which comprises administering to said mammal an efficacious amount of tagatose, preferably D-tagatose, during pregnancy. [0009]
  • According to another aspect of this invention, there is provided a method for increasing the birth weight of a fetus in a pregnant female mammal, especially a pregnant human female, which comprises administering to said mammal an efficacious amount of tagatose, preferably D-tagatose. [0010]
  • According to another aspect of this invention, there is provided a method for reducing excessive food intake of a pregnant female mammal, especially a pregnant human female, which comprises administering to said mammal an efficacious amount of tagatose, preferably D-tagatose. [0011]
    • DETAILED DESCRIPTION OF THE INVENTION
  • The tagatose may be administered to a mammal subject in combination with a food, beverage or taken separately in powder, crystalline or liquid form. As diluent, if needed, one may use liquid or solid carriers, such as water, starch, alcohol, or other non-toxic substances. Preferably, the tagatose is administered within the range of 100-2000 mg/kg body weight/day. The tagatose may be administered daily, every other day or at other prescribed frequencies. The tagatose may be D-tagatose, L-tagatose or a mixture thereof. [0012]
    • EXAMPLE 1 Increased Fertility
  • A 70 kg human female with a history of difficulty in conceiving begins taking tagatose twice daily at five g per dose, beginning one month before an attempt to conceive. She finds that her attempt is successful and she is pregnant. [0013]
    • EXAMPLE 2 Increased Probability Of Live Birth
  • A 70 kg human female with a history of spontaneous abortions and stillbirths takes tagatose twice daily at five g per dose, beginning one month before an attempt to conceive. She becomes pregnant, and the pregnancy proceeds to a successful conclusion, delivering a live birth. [0014]
    • EXAMPLE 3
  • Increased Birth Weight [0015]
  • A 70 kg human female takes precautions against giving birth to a below average weight infant by taking tagatose twice daily at five g per dose, beginning one month before an attempt to conceive. She becomes pregnant and delivers a baby within the normal birth weight range despite a family history of frequent low birth weight babies. [0016]
    • EXAMPLE 4 Reduced Food Intake
  • A 70 kg human female inclined toward obesity desires a child, but is concerned that pregnancy may increase her food intake causing weight problems as experienced in her past pregnancies. She takes tagatose twice daily at five g per dose, beginning one month before an attempt to conceive. She becomes pregnant, but her average daily diet does not increase, and her weight gain is within the range advised by her physician. She delivers a healthy, normal child. [0017]

Claims (24)

What is claimed is:
1. A method for increasing the fertility of a female mammal comprising administering to said female mammal an efficacious amount of tagatose.
2. The method of
claim 1
 wherein the mammal is a human.
3. The method of
claim 1
 wherein from 100-2000 mg/kg body weight/day is administered to said mammal.
4. The method of
claim 1
 wherein the prescribed dose is taken every day.
5. The method of
claim 1
 wherein the prescribed dose is taken every other day.
6. The method of
claim 1
 wherein said tagatose is D-tagatose, L-tagatose or a mixture thereof.
7. A method for promoting healthy fetal development in a pregnant female mammal which comprises administering to said mammal an efficacious amount of tagatose.
8. The method of
claim 7
 wherein the mammal is a human.
9. The method of
claim 7
 wherein from 100-2000 mg/kg body weight/day is administered to said mammal.
10. The method of
claim 7
 wherein the prescribed dose is taken every day.
11. The method of
claim 7
 wherein the prescribed dose is taken every other day.
12. The method of
claim 1
 wherein said tagatose is D-tagatose, L-tagatose or a mixture thereof.
13. A method for increasing the birth weight of a fetus in a pregnant female mammal which comprises administering to said mammal an efficacious amount of tagatose.
14. The method of
claim 13
 wherein the mammal is a human.
15. The method of
claim 13
 wherein from 100-2000 mg/kg body weight/day is administered to said mammal.
16. The method of
claim 13
 wherein the prescribed dose is taken every day.
17. The method of
claim 13
 wherein the prescribed dose is taken every other day.
18. The method of
claim 13
 wherein said tagatose is D-tagatose, L-tagatose or a mixture thereof.
19. A method for reducing excessive food intake of a pregnant female mammal which comprises administering to said mammal an efficacious amount of tagatose.
20. The method of
claim 19
 wherein the mammal is a human.
21. The method of
claim 19
 wherein from 100-2000 mg/kg body weight/day is administered to said mammal.
22. The method of
claim 19
 wherein the prescribed dose is taken every day.
23. The method of
claim 19
 wherein the prescribed dose is taken every other day.
24. The method of
claim 19
 wherein said tagatose is D-tagatose, L-tagatose or a mixture thereof.
US09/727,692 1999-04-26 2000-12-04 Increased fertility and improved fetal development drug Abandoned US20010020008A1 (en)

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EP (1) EP1173185A4 (en)
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9060962B2 (en) 2008-11-04 2015-06-23 University Of Kentucky Research Foundation D-tagatose-based compositions and methods for preventing and treating atherosclerosis, metabolic syndrome, and symptoms thereof

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7189351B2 (en) * 2001-10-25 2007-03-13 Spherix Incorporated D-tagatose as an anti-biofilm agent

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4786722A (en) 1986-08-29 1988-11-22 Biospherics Incorporated D-tagatose as a low-calorie carbohydrate sweetener and bulking agent
US5002612A (en) 1989-07-19 1991-03-26 Biospherics Incorporated Process for manufacturing tagatose
CA2077257C (en) 1989-07-19 2002-02-19 James R. Beadle Process for manufacturing tagatose
US5356879A (en) 1992-02-14 1994-10-18 Biospherics, Incorporated D-tagatose as anti-hyperglycemic agent

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9060962B2 (en) 2008-11-04 2015-06-23 University Of Kentucky Research Foundation D-tagatose-based compositions and methods for preventing and treating atherosclerosis, metabolic syndrome, and symptoms thereof

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US6225452B1 (en) 2001-05-01
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WO2000064452A1 (en) 2000-11-02
AU4068500A (en) 2000-11-10
EP1173185A1 (en) 2002-01-23

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