WO1995032725A1 - Angiotensin ii for improving fertilization - Google Patents

Angiotensin ii for improving fertilization Download PDF

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Publication number
WO1995032725A1
WO1995032725A1 PCT/GB1995/001202 GB9501202W WO9532725A1 WO 1995032725 A1 WO1995032725 A1 WO 1995032725A1 GB 9501202 W GB9501202 W GB 9501202W WO 9532725 A1 WO9532725 A1 WO 9532725A1
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Prior art keywords
angiotensin
sperm
fertilization
analogue
samples
Prior art date
Application number
PCT/GB1995/001202
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French (fr)
Inventor
Gavin Paul Vinson
Original Assignee
Queen Mary And Westfield College
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Queen Mary And Westfield College filed Critical Queen Mary And Westfield College
Priority to JP50048796A priority Critical patent/JP2001506225A/en
Priority to DE69535263T priority patent/DE69535263T2/en
Priority to EP95919568A priority patent/EP0760672B1/en
Priority to US08/750,316 priority patent/US6011015A/en
Priority to AU25345/95A priority patent/AU2534595A/en
Publication of WO1995032725A1 publication Critical patent/WO1995032725A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/08—Peptides having 5 to 11 amino acids
    • A61K38/085—Angiotensins
    • 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
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the present invention relates to the use of angiotensin II, or an analogue thereof, for promoting fertilization of mammalian eggs, especially human eggs.
  • it relates to the use of angiotensin II to improve sperm otility.
  • the invention also relates to a method of promoting in vitro fertilization.
  • Angiotensin II is an octapeptide, usually regarded as being produced in the blood, firstly by the action of renin, an enzyme secreted by the kidney, on angiotensinogen, resulting in the formation of the decapeptide precursor, angiotensin I, and secondly the action of a dipeptidase "angiotensin converting enzyme"; this enzyme acts on angiotensin I to form angiotensin II.
  • Angiotensin II undergoes hydrolysis by an aminopeptidase to yield the heptapeptide angiotensin III (angiotensin 1-7) .
  • the hormone angiotensin II forms part of the renin - angiotensin system which helps to control electrolyte balance and blood pressure within the body.
  • Ang II angiotensin II
  • tissues within the body upon which Ang II acts include the adrenal gland, uterus, liver, brain and kidney.
  • angiotensin II it is known to be involved in vaso- constriction, which leads to hypertension. Most treatments for high blood pressure will include blockage of angiotensin function in one way or another. Ang II also stimulates the secretion of aldosterone by the adrenal cortex. Aldosterone is a potent hormone which acts primarily on the kidney to promote sodium retention and thus inter alia, heightens the hypertensive effects of angiotensin acting directly on the vasculature.
  • Ang II is known to act on various sites in the brain, and one of its actions in animals is the regulation of thirst and drinking.
  • Angiotensin also has trophic effects on the vasculature, promoting growth of the muscles in the arterial
  • SUBSTITUTE SHEET (RULE 26 ⁇ wall. It is also thought to be angiogenic, i.e. it causes vascularisation of newly developing tissue.
  • Ang II Ang II receptor
  • AT- ⁇ subtype of the Ang II receptor which is a seven transmembrane domain receptor.
  • This receptor has been cloned and ⁇ equenced from a variety of tissues, and has been found to be a 359 amino acid polypeptide with a predicted molecular weight of around 40kD (Bernstein and Alexander, (1992) , Endocr. Rev. , 13 , 381- 386) .
  • Photo-affinity labelling and crosslinking agents have suggested molecular weights for mature receptor of approximately 65kD and 116 kD, respectively, which may reflect glycosylation of asparagine residues within the extra-cellular domain.
  • angiotensin II increases both the percentage of motile sperm and their linear velocity.
  • angiotensin II or a salt or analogue thereof to promote fertilization of mammalian eggs. Such fertilization may take place in vitro.
  • angiotensin II or a salt or analogue thereof to increase sperm motility.
  • angiotensin II or a salt or analogue thereof, for the manufacture of a medicament for use in promoting fertilization, in particular in vitro fertilization.
  • Analogues of angiotensin II which may be used for increasing sperm motility, and thereby promoting fertilization, include angiotensin II amide, angiotensin III (angiotensin 1-7) and angiotensin IV (angiotensin 3-8) .
  • oocytes approximately 10,000 sperm per oocyte
  • a method of promoting in vitro fertilization of mammalian eggs comprising adding angiotensin II or a salt or analogue thereof to incubation medium containing oocytes and sperm.
  • Angiotensin II, or an analogue thereof may be added either in the washing stages, or during the final incubation with the oocyte. When added to the incubation medium, angiotensin II, or an analogue thereof, is added at a concentration of preferably 1 nmole/1.
  • Percentage motility was estimated on playback of the video tapes by freezing the frame to count all of the sperm within a field and then, in forward mode, by counting immotile sperm, i.e. those which within the period of observation did not move to an adjacent square (100 ⁇ metre) on the Makler Chamber grid. In practice, rigid use of this definition was rarely necessary as sperm were either completely immotile or progressed freely.
  • Percentage motility was estimated in the same way as in Example 1.
  • Example 2 Sperm samples were obtained from the same source as Example 1. One series of samples was kept as controls. To a second series Angiotensin II amide (10 nmole/1 was added. A third series was treated with monoclonal antibody to the AT-,, receptor before angiotensin was added.
  • Example 1 Sperm samples were obtained from the same source as Example 1. One series of samples was kept as controls. A second series was exposed to angiotensin II (1 ⁇ mol/1) for five minutes. A third series was exposed to angiotensin II (1 ⁇ mol/1) for 5 minutes and then DuP-753 (l ⁇ mol/1) was added.
  • the percentage of motile sperm was measured using the same method as was used in Example 1.
  • Example 2 Sperm samples were obtained from the same source as Example 1. One series of samples was kept as controls. To a second series angiotensin II amide (1 nmol/1) was added.
  • Sperm motility was assayed by using a computer system which measures different aspects of sperm motility, namely curvilinear velocity (VCL) and amplitude of lateral head displacement (ALH) .
  • VCL curvilinear velocity
  • AH amplitude of lateral head displacement
  • Figures 5(a) and 5(b) show the percentage of motile sperm in each of two samples, over a 30 minute period in the presence (shaded bars) and absence (clear bars) of angiotensin II amide (1 nmol/1) .
  • Figure 6(a) and 6(b) show the same samples assayed for VCL.
  • Figure 7(a) and 7(b) show the same samples assayed for ALH.
  • Figure 8 compares VCL and ALH in control (unstimulated clear symbols) and angiotensin II (All) stimulated (solid symbols) sperm samples.
  • angiotensin II amide stimulates both VCL and ALH, both parameters that are associated with increased fertility.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Reproductive Health (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Epidemiology (AREA)
  • Endocrinology (AREA)
  • Vascular Medicine (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Immunology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Gynecology & Obstetrics (AREA)
  • Pregnancy & Childbirth (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
  • Peptides Or Proteins (AREA)
  • Soil Working Implements (AREA)

Abstract

The present invention relates to the use of angiotensin II, or an analogue thereof, for promoting the fertilization of mammalian eggs. It also relates to a method of promoting in vitro fertilization of mammalian using angiotensin II.

Description

Angiotensin II For Improving Fertilization
The present invention relates to the use of angiotensin II, or an analogue thereof, for promoting fertilization of mammalian eggs, especially human eggs. In particular, it relates to the use of angiotensin II to improve sperm otility. The invention also relates to a method of promoting in vitro fertilization.
Angiotensin II is an octapeptide, usually regarded as being produced in the blood, firstly by the action of renin, an enzyme secreted by the kidney, on angiotensinogen, resulting in the formation of the decapeptide precursor, angiotensin I, and secondly the action of a dipeptidase "angiotensin converting enzyme"; this enzyme acts on angiotensin I to form angiotensin II. Angiotensin II, in turn, undergoes hydrolysis by an aminopeptidase to yield the heptapeptide angiotensin III (angiotensin 1-7) .
The hormone angiotensin II (Ang II) forms part of the renin - angiotensin system which helps to control electrolyte balance and blood pressure within the body. There are several tissues within the body upon which Ang II acts, they include the adrenal gland, uterus, liver, brain and kidney.
Amongst the several established functions of angiotensin II, it is known to be involved in vaso- constriction, which leads to hypertension. Most treatments for high blood pressure will include blockage of angiotensin function in one way or another. Ang II also stimulates the secretion of aldosterone by the adrenal cortex. Aldosterone is a potent hormone which acts primarily on the kidney to promote sodium retention and thus inter alia, heightens the hypertensive effects of angiotensin acting directly on the vasculature.
Ang II is known to act on various sites in the brain, and one of its actions in animals is the regulation of thirst and drinking.
Angiotensin also has trophic effects on the vasculature, promoting growth of the muscles in the arterial
SUBSTITUTE SHEET (RULE 26} wall. It is also thought to be angiogenic, i.e. it causes vascularisation of newly developing tissue.
Most of the established effects of Ang II have been found to occur via the AT-^ subtype of the Ang II receptor, which is a seven transmembrane domain receptor. This receptor has been cloned and εequenced from a variety of tissues, and has been found to be a 359 amino acid polypeptide with a predicted molecular weight of around 40kD (Bernstein and Alexander, (1992) , Endocr. Rev. , 13 , 381- 386) . Studies using photo-affinity labelling and crosslinking agents have suggested molecular weights for mature receptor of approximately 65kD and 116 kD, respectively, which may reflect glycosylation of asparagine residues within the extra-cellular domain.
From the recent development of a hybridoma cell line, see Barker, S., et al, J. Mol Endocr. , 11, 241-245, (1993), it has been found possible to produce monoclonal antibodies to the AT^subtype of the Ang II receptor. In consequence, such receptors have been found to exist both on maturing rat and human sperm tails, and on free swimming sperm obtained by vaginal lavage from mated rats, and in human ejaculated sperm.
It has now been found that angiotensin II, or an analogue thereof, increases both the percentage of motile sperm and their linear velocity.
This newly discovered property of angiotensin II enables Ang II to be used to promote fertilization, since the capacity of sperm to fertilise ova is closely related to their motility.
According to one aspect of the invention there is provided the use of angiotensin II or a salt or analogue thereof to promote fertilization of mammalian eggs. Such fertilization may take place in vitro.
According to a second aspect of the invention there is provided the use of angiotensin II or a salt or analogue thereof to increase sperm motility.
According to another aspect of the invention there is provided the use of angiotensin II, or a salt or analogue thereof, for the manufacture of a medicament for use in promoting fertilization, in particular in vitro fertilization.
Analogues of angiotensin II which may be used for increasing sperm motility, and thereby promoting fertilization, include angiotensin II amide, angiotensin III (angiotensin 1-7) and angiotensin IV (angiotensin 3-8) .
Standard procedures for in vitro fertilisation are described in "In vitro fertilisation: a treatment for male infertility", Cohen, J. , Edwards, R. et al, 1985, Fertility and Sterility, 44 , 422-432. In general, sperm samples are washed in MEM tissue culture medium, centrifuged at approximately 400g, resuspended and recentrifuged. They are then resuspended in a few drops of MEM and 0.5ml of fresh medium is layered on top. After 30min in the incubator at 37°C, the top 30% of the medium, containing essentially motile sperm, is removed and distributed to oocytes (approximately 10,000 sperm per oocyte) in MEM and left for 24hrs for fertilisation to occur.
According to yet another aspect of the invention there is provided a method of promoting in vitro fertilization of mammalian eggs comprising adding angiotensin II or a salt or analogue thereof to incubation medium containing oocytes and sperm.
Angiotensin II, or an analogue thereof, may be added either in the washing stages, or during the final incubation with the oocyte. When added to the incubation medium, angiotensin II, or an analogue thereof, is added at a concentration of preferably 1 nmole/1.
The invention will be further described with reference to the following examples:- Example 1
Effect of Angiotensin II stimulation on sperm motility
Human sperm samples were obtained from 12 volunteers and patients attending the Newham Hospital assisted fertility clinic. Samples were suspended in modified minimum essential medium with Earle's salts (MEM) and glutamine and viewed in a Makler chamber using an Olympus inverted microscope fitted with an Olympus ARTF-2 video camera. Fields were recorded on video tape and percentage motility evaluated at 1 min and 5 min. After mixing with MEM alone (unstimulated controls) or with MEM containing 1 nmole/litre angiotensin II amide.
Percentage motility was estimated on playback of the video tapes by freezing the frame to count all of the sperm within a field and then, in forward mode, by counting immotile sperm, i.e. those which within the period of observation did not move to an adjacent square (100 μmetre) on the Makler Chamber grid. In practice, rigid use of this definition was rarely necessary as sperm were either completely immotile or progressed freely.
From Figure 1(a) it can be seen that there was no significant difference in percentage motility after 5 minutes in the unstimulated controls. Within the angiotensin II stimulated group, however, percentage motility after 5 minutes was significantly different from percentage motility after 1 minute. Example 2
Effect of AT-^, receptor antagonist on sperm motility
A series of six sperm samples, obtained from the same source as Example 1, were mixed either with unmodified MEM, or MEM containing DuP-753 (1 nmol/1)
Percentage motility was estimated in the same way as in Example 1.
From Figure 2 it is evident that, in the presence of DuP-753, (2-n-butyl-4-chloro-5-hydroxymethyl-l-[ (2 •-(1H- tetrazol-5-yl) biphenyl-4-yl)methyl] imidazole, potassium salt) , percentage motility was significantly decreased relative to the untreated controls. Example 3
Effect of angiotensin II on sperm velocity
Sperm samples were obtained from the same source as Example 1. One series of samples was kept as controls. To a second series Angiotensin II amide (10 nmole/1 was added. A third series was treated with monoclonal antibody to the AT-,, receptor before angiotensin was added.
Velocity was measured by timing forwardly progressive sperm traversing the grid on the Makler Chamber and timing them manually. From Figure 3(a) it can be seen that stimulation with angiotensin II significantly stimulated forward progressive velocity compared with the untreated controls, whilst addition of the monoclonal antibody inhibited the response to angiotensin II.
From Figure 3(b) it can be seen that similar results were obtained for the effect on the percentage of motile sperm. Example 4
Sperm samples were obtained from the same source as Example 1. One series of samples was kept as controls. A second series was exposed to angiotensin II (1 μmol/1) for five minutes. A third series was exposed to angiotensin II (1 μmol/1) for 5 minutes and then DuP-753 (lμmol/1) was added.
The percentage of motile sperm was measured using the same method as was used in Example 1.
From Figure 4 it can be seen that, when compared with the controls, in most samples angiotensin II enhanced the percentage of sperm which were motile after 5 minutes. This enhancement was generally reduced in the samples to which DuP-753 had been added. Example 5
Effect of angiotensin on sperm motility
Sperm samples were obtained from the same source as Example 1. One series of samples was kept as controls. To a second series angiotensin II amide (1 nmol/1) was added.
Sperm motility was assayed by using a computer system which measures different aspects of sperm motility, namely curvilinear velocity (VCL) and amplitude of lateral head displacement (ALH) .
Figures 5(a) and 5(b) show the percentage of motile sperm in each of two samples, over a 30 minute period in the presence (shaded bars) and absence (clear bars) of angiotensin II amide (1 nmol/1) .
Figure 6(a) and 6(b) show the same samples assayed for VCL.
Figure 7(a) and 7(b) show the same samples assayed for ALH. Figure 8 compares VCL and ALH in control (unstimulated clear symbols) and angiotensin II (All) stimulated (solid symbols) sperm samples.
From the figures it is clear that angiotensin II amide stimulates both VCL and ALH, both parameters that are associated with increased fertility.

Claims

1. Use of angiotensin II or a salt or analogue thereof to promote fertilization of mammalian eggs.
2. The use as claimed in claim 1 wherein fertilization takes place in vitro.
3. Use of angiotensin II or a salt or analogue thereof to increase sperm motility.
4. Use of angiotensin II or a salt or analogue thereof for the manufacture of a medicament for use in promoting fertilization.
5. The use as claimed in any one of claims 1 to 4 wherein the analogue of angiotensin is angiotensin II amide, angiotensin III (angiotensin 1-7) or angiotensin IV (angiotensin 3-8) .
6. The use as claimed in claim 2 wherein angiotensin II is used at a concentration of 1 nmol/1.
7. A method of promoting in vitro fertilization of mammalian eggs comprising adding angiotensin II or a salt or analogue thereof to incubation medium containing oocytes and sperm.
8. A method as claimed in claim 7 wherein the angiotensin is added at a concentration of 1 nmol/1.
PCT/GB1995/001202 1994-05-27 1995-05-25 Angiotensin ii for improving fertilization WO1995032725A1 (en)

Priority Applications (5)

Application Number Priority Date Filing Date Title
JP50048796A JP2001506225A (en) 1994-05-27 1995-05-25 Angiotensin to promote fertilization
DE69535263T DE69535263T2 (en) 1994-05-27 1995-05-25 ANGIOTENSIN II FOR IMPROVING FERTILIZATION
EP95919568A EP0760672B1 (en) 1994-05-27 1995-05-25 Angiotensin ii for improving fertilization
US08/750,316 US6011015A (en) 1994-05-27 1995-05-25 Angiotensin II for improving fertilization
AU25345/95A AU2534595A (en) 1994-05-27 1995-05-25 Angiotensin ii for improving fertilization

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9410639A GB9410639D0 (en) 1994-05-27 1994-05-27 Method of improving fertilization
GB9410639.0 1994-05-27

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JP (2) JP2001506225A (en)
AT (1) ATE342062T1 (en)
AU (1) AU2534595A (en)
DE (1) DE69535263T2 (en)
ES (1) ES2277332T3 (en)
GB (1) GB9410639D0 (en)
WO (1) WO1995032725A1 (en)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997047315A1 (en) * 1996-06-11 1997-12-18 Queen Mary And Westfield College Method of stimulating cilia
WO2001013932A2 (en) * 1999-08-26 2001-03-01 King's College London Stimulation of sperm function
WO2004039396A1 (en) * 2002-10-29 2004-05-13 Gen Kondoh Drug containing angiotensin convertase
WO2005051412A3 (en) * 2003-11-20 2005-08-25 Queen Mary & Westfield College Regulation of sperm function
EP3334434A4 (en) * 2015-09-09 2019-03-06 Allergy Research Group, LLC Phospholipid compositions and use thereof to enhance spermatozoa motility and viability

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* Cited by examiner, † Cited by third party
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CA2272865A1 (en) * 1996-11-21 1998-05-28 Promega Corporation Alkyl peptide amides and applications
JP4601880B2 (en) * 2000-10-18 2010-12-22 株式会社クラレ Process for producing ethylene-vinyl acetate copolymer, saponified copolymer obtained by this process, and molded article containing the same
PL1765085T3 (en) 2004-05-17 2015-11-30 Massachusetts Gen Hospital Compositions comprising female germline stem cells and methods of use thereof
US9767341B2 (en) * 2010-12-14 2017-09-19 The Regents Of The University Of California Method and device for holographic opto-fluidic microscopy
MX2013011990A (en) 2011-04-14 2013-11-20 Gen Hospital Corp Compositions and methods for autologous germline mitochondrial energy transfer.
BR112013033797A2 (en) 2011-06-29 2017-02-14 Harvard College composition, isolated cell, isolated mitochondria, methods of preparing an oocyte, in vitro fertilization, improving fertility in an individual, sustaining embryonic development, recovering or increasing ovarian function in an individual, preparing a tissue or cell thereof, and producing an oocyte, oocyte, and bioenergetic agent

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995009186A1 (en) * 1993-09-27 1995-04-06 Queen Mary And Westfield College Type i angiotensin ii receptor specific monoclonal antibodies and hybridomas

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992005784A1 (en) * 1990-10-02 1992-04-16 Warner-Lambert Company 4,5,6,7-tetrahydro-1h-imidazo[4,5-c]pyridine derivatives and analogues as angiotensin ii receptor antagonists

Patent Citations (1)

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Publication number Priority date Publication date Assignee Title
WO1995009186A1 (en) * 1993-09-27 1995-04-06 Queen Mary And Westfield College Type i angiotensin ii receptor specific monoclonal antibodies and hybridomas

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
KANEKO S. ET AL: "Effects of Angiotensin on the motility of human sperm", JOURNAL OF PHARMACOBIO-DYNAMICS, vol. 7, no. 2, TOKYO, pages 87 - 93 *
MIZUTANI T. ET AL: "Motility of seminal plasma-free spermatozoa in the presence of several physiological compounds", ANDROLOGIA, vol. 17, no. 2, BERLIN, pages 150 - 156 *
VINSON G.P. ET AL: "Type 1 angiotensin II receptors in rat and human sperm", JOURNAL OF ENDOCRINOLOGY, vol. 144, LONDON, pages 369 - 378 *

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997047315A1 (en) * 1996-06-11 1997-12-18 Queen Mary And Westfield College Method of stimulating cilia
WO2001013932A2 (en) * 1999-08-26 2001-03-01 King's College London Stimulation of sperm function
WO2001013932A3 (en) * 1999-08-26 2001-08-02 King S College London Stimulation of sperm function
WO2004039396A1 (en) * 2002-10-29 2004-05-13 Gen Kondoh Drug containing angiotensin convertase
US7407933B2 (en) 2002-10-29 2008-08-05 Gen Kondoh Drug containing angiotensin convertase
WO2005051412A3 (en) * 2003-11-20 2005-08-25 Queen Mary & Westfield College Regulation of sperm function
EP3334434A4 (en) * 2015-09-09 2019-03-06 Allergy Research Group, LLC Phospholipid compositions and use thereof to enhance spermatozoa motility and viability

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ATE342062T1 (en) 2006-11-15
ES2277332T3 (en) 2007-07-01
JP2001506225A (en) 2001-05-15
US6011015A (en) 2000-01-04
JP2007091753A (en) 2007-04-12
EP0760672B1 (en) 2006-10-11
DE69535263T2 (en) 2007-05-24
GB9410639D0 (en) 1994-07-13
AU2534595A (en) 1995-12-21
DE69535263D1 (en) 2006-11-23
EP0760672A1 (en) 1997-03-12

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