EP0678030A1 - Utilisation de polysaccharides sulfates pour prevenir des maladies sexuellement transmissibles - Google Patents

Utilisation de polysaccharides sulfates pour prevenir des maladies sexuellement transmissibles

Info

Publication number
EP0678030A1
EP0678030A1 EP94909436A EP94909436A EP0678030A1 EP 0678030 A1 EP0678030 A1 EP 0678030A1 EP 94909436 A EP94909436 A EP 94909436A EP 94909436 A EP94909436 A EP 94909436A EP 0678030 A1 EP0678030 A1 EP 0678030A1
Authority
EP
European Patent Office
Prior art keywords
sulfated polysaccharide
composition according
transmission
organism
carrageenan
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP94909436A
Other languages
German (de)
English (en)
Inventor
David M. 432 Maitland Avenue Phillips
Clyde Wayne Bardin
Rachel Pearce-Pratt
Xin Tan
Vanaja Zacharopoulos
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Population Council Inc
Original Assignee
Population Council Inc
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 Population Council Inc filed Critical Population Council Inc
Publication of EP0678030A1 publication Critical patent/EP0678030A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • 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
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0034—Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals

Definitions

  • This invention relates to a method and composition for preventing sexual transmission of sexually transmitted diseases, inter alia, the HIV virus, the causative organism of Acquired Immune Deficiency Syndrome (AIDS) , and also Chlamydia infection.
  • sexually transmitted diseases inter alia, the HIV virus, the causative organism of Acquired Immune Deficiency Syndrome (AIDS) , and also Chlamydia infection.
  • AIDS Acquired Immune Deficiency Syndrome
  • AIDS is a catastrophic disease which leads to a failure of the immune system.
  • the disease can be transmitted via infected blood and blood products, sexually transmitted, and transmitted through the placenta in utero.
  • an HIV infected lymphocyte 1 containing virions V attaches to the surface of an epithelial cell 2 within a cavity 3 such as the vagina, cervix, skin of the penis or penile uretha.
  • the virions shed from the lymphocyte 1 fuse with and enter the epithelial cell 2 which thus becomes infected.
  • Fig. IB Fig. IB
  • the virus then replicates in the epithelial cell 2 while the infected lymphocyte 1 may move on to infect other epithelial cells 2 '. (Fig. 1C) . Finally, the infected epithelial cell 1 sheds virions into the underlying connective tissue 4 where lymphocytes 5 are infected. (Fig. ID) .
  • the Chlamydia organism is an obligate intracellular parasite or "quasi bacteria".
  • the usual mode of human transmission is heterosexual vaginal intercourse, during which the free organism adheres to and then enters first the vaginal and cervical epithelial cells, and then subsequently the epithelial cells of the upper genital tract i.e. the uterus and Fallopian tubes. It often causes 'silent' infection with no apparent signs or symptoms, but it causes scarring of the Fallopian tubes and is one of the main causes of infertility in the human female.
  • sulfated polysaccharides prevent the transmission of the Chlamydia organism.
  • cell-to-cell transmission of HIV and thus the sexual transmission of AIDS, is inhibited by the direct application of sulfated polysaccharides to the epithelium of the vaginal mucosa, cervix or penis.
  • the sexual transmission of Chlamydia infection is inhibited by the direct application of sulfated polysaccharides to the epithelium of the vaginal mucosa, cervix or penis.
  • examples 8 and 11 In vitro studies describing this are set forth in examples 7 and 10.
  • sulfated polymers include, but are not limited to, iota carrageenan and dextran sulfate, kappa carrageenan, lambda carrageenan, heparin mimetics, heparan sulfate, pentosan polysulfate, chondroitin sulfate and fucoidan.
  • the sulfated polysaccharides may be formulated into a cream, suppository, gel or foam composition, and such compositions are an aspect of the invention.
  • Figs. 1A-1D are a schematic representation of cell-to-cell transmission of HIV;
  • Fig. 2 shows a segment of an exemplary sulfated polysaccharide;
  • Fig. 3 shows the results of a blocking study to evaluate inhibition of HIV-1 infectivity
  • Figs. 4-7 show the fluorescence measurements to determine the adhesion blocking ability of various materials.
  • Fig. 8 shows cell adhesion results in a test employing HIV infected lymphocytes.
  • This invention relates to a method of inhibiting sexually transmitted diseases, inter alia, the acquired immune deficiency syndrome and Chlamydia. It is now recognized that AIDS is caused by two lentiviruses:
  • HIV-1 Human Immunodeficiency Virus type 1 (HIV-1) and type 2 (HIV-2) .
  • Other names, including LAV and HTLV-III, have been previously used to identify HIV-1.
  • Chlamydia infection is caused by an obligate intracellular parasite which passes into the epithelial cells of the female genital tract during vaginal intercourse.
  • the invention is based on the observation that HIV is transmitted from infected lymphocytes to epithelial cells which lack the CD4 receptors normally associated with HIV transmission by cell-to-cell transfer, and the discovery that this cell-to-cell transfer can be blocked by sulfated polysaccharides.
  • Sulfated polysaccharides for use in the invention are long chain polymers of sugars linked to sulfates and optionally other functional groups.
  • Fig. 2 shows a segment of an exemplary sulfated polysaccharide. Sugars other than those shown in Fig. 2, other combinations of ⁇ and ⁇ linkages in the polymer and other substitutions can also be employed.
  • sulfated polysaccharides for use in the invention will have a molecular weight of 5000 to 1,000,000, more preferably from 50,000 to 500,000. In addition, from 10 to 100 percent of the available binding sites are sulfated, more preferably from 50 to 100%. This percentage is referred to as the degree of sulfate substitution.
  • Particular sulfated polysaccharides useful in the invention include carrageenans, chondroitin sulfate, dextran sulfate, lentinan sulfate, curdlan sulfate, heparin sulfate, and de-N-sulfated heparin. These materials are all available commercially, e.g., from Sigma Chemical Co. of St. Louis, Missouri. In addition, methods for their isolation or synthesis are published. See, e.g., Bray et al., Bioche . J. .38., 142 (1944); Hatanaka et al., J. Med. Chem. 3_0; 810-814 (1987) .
  • sulfated polysaccharides are topically applied to the vaginal or rectal mucosa in an amount effective to inhibit virus transmission. Specific amounts may depend on interactions with carrier materials, but in general, application of from approximately 1.0-10.0 grams of sulfated polysaccharide per dosage is preferred.
  • the preferred sulfated polysaccharides of the invention are the Carrageenans.
  • Iota carrageenan is the most efficacious of the commercially available sulfated polysaccharides in preventing HIV infection and in blocking Chlamydia infection in vitro and in vivo. Because it is a large linear molecule, iota carrageenan forms a gel. Thus, no additives are needed to thicken a formulation of this polysaccharide. The simplicity of this formulation avoids potential problems which may result from interactions between the active ingredient and other components.
  • the sulfated polysaccharides of the invention are advantageously formulated with a carrier.
  • a carrier may be any one of the numerous creams, gels and foams known for use in vaginal or rectal lubricants or therapeutics.
  • the sulfated polysaccharides will generally be present in an amount ranging from 1% to 10% by weight of the carrier.
  • compositions of the invention may include additional ingredients such as agents which inhibit sperm function (e.g. nonoxynol-9, benzalkonium chloride, chloroquine, and diethyldithiol carbonate) .
  • agents which inhibit sperm function e.g. nonoxynol-9, benzalkonium chloride, chloroquine, and diethyldithiol carbonate
  • the sulfated polysaccharides of the invention can be used in conjunction with mechanical contraceptives including condoms, diaphragms, sponges and intrauterine devices or NORPLANT®.
  • the preservatives that may be used in the formulations include any of the commonly used preservatives.
  • the preferred preservative is benzoyl alcohol. Firstly, it is considered to be safe and is the most common preservative in use in OTC vaginal products in the U.S. Also, potential problems may exist when other preservatives are combined with carrageenan.
  • Example 1 The ability of various sulfated polysaccharides and other materials to block adhesion of lymphocytes to epithelial cells was tested.
  • the agents tested included spermicides and other compounds with properties suggesting that they were as follows: Tergitol (NP-9, Sigma Chemical Co., St. Louis, MO), commonly referred to as nonoxynol-9 (N-9) , is a nonionic surfactant employed as the active ingredient in most vaginal spermicides.
  • Benzalkonium chloride (B- 1383), Sigma Chemical Co., St. Louis, MO) is a cationic surface-active agent also used in vaginal spermicides.
  • Proflavine (3,6-acridinamine, P-4646, Sigma Chemical Co., St.
  • Chloroquine is a quinone analog with antimalarial, antiamebic, and antirheumatic properties which is known for its suppressive effect on the immune system in lupus erythematosus.
  • Polyvinyl pyrrolidone PVP-l, Sigma Chemical Co., St. Louis, MO
  • Diethyldithiocarba ate (C5H10NNaS2) (D- 3506, Sigma Chemical Co., St. Louis, MOS) is a chelating agent with immunomodulating and T-cell specific immunostimulant effects.
  • the tilorone analog which we used (T-8014, Sigma Chemical Co., St. Louis, MO) also has immunomodulatory effects, possibly via induction of interferon production.
  • Glutathione (G-4251, Sigma Chemical Co., St. Louis, MO) is a reducing agent rich in thiol groups.
  • Chlorophyllin (No. 25,828-8, Aldrich Chemical Co., Milwaukee, WI) which is an analog of chlorophyll, is a chelating agent. Chondroitin sulfate A(C-8529, Sigma Chemical Co., St.
  • Dextran sulfate (D-6001, Sigma Chemical Co., St. Louis, MO) is a heparin-like sulfated polysaccharide used as an anticoagulant and is also antihyperlipoproteinemic.
  • BCECF-AM (No. 1170, Molecular Probes, Eugene, OR) a fluorogenic ester readily passes through the cell membrane of viable cells and is nonfluorescent until hydrolysed by intracellular esterases.
  • BCECF-AM was used to label lymphocytes and the fluorescence level was found to be directly proportional to the number of lymphocytes added to an epithelium. This fluorescence was, therefore, used to determine the level of cell adhesion.
  • the ability of compounds which block adhesion of HIV infected lymphocytes to inhibit transmission of HIV to epithelial cells was tested using BeWo trophoblast- derived cells.
  • the cells were maintained on RPMI-1640 medium, supplemented with 10% heat inactivated fetal bovine serum (FBS) .
  • FBS heat inactivated fetal bovine serum
  • the cells were plated into 6-well test plates at 10 5 cells/well and incubated in RPMI-1640 for one day. The cells were then incubated with RPMI/FBS medium alone (control), 0.5 or 5 ⁇ g/ml.
  • soluble CD4 Pharmacia Piscataway, NJ
  • 0.5,5 and 50 ⁇ g/ml. of dextran sulfate Sigma, St. Louis, MO
  • Fig. 3 shows the results of the ELISA tests on the BeWo cells from ten sets of tests. Dextran sulfate blocked infection in a dose-dependent manner. Soluble CD4 was not shown to inhibit infection of the BeWo epithelial cells.
  • Carrageenan I (CI) is a polymeric material having a molecular weight of 140,000-300,000 daltons and contains predominantly kappa carrageenan. It has the lowest sulfate substitution level of the carrageenan family, about one sulfate in each disaccharide repeating unit.
  • Carrageenan II (CII) has the same molecular weight range as Carrageenan I, but contains predominantly iota carrageenan and has the highest sulfate substitution level.
  • CI and CII are both non-cytotoxic at levels ⁇ 10 mg/ml.
  • carrageenans are approved by the U.S. FDA for use in foods.
  • CI, CII, pentosan polysulfate (a sulfated polymer with a molecular weight of 3000-4000 daltons) and mannitol were evaluated for their ability to block adhesion of lymphocytes using the fluorescence assay of Example 1. As shown in Fig. 4, both CI and CII inhibited adhesion at non-toxic concentrations of 2.5 and 5 mg/ml.
  • "Co” in Fig. 4 is the control fluorescence measured for untreated cells; "Bgd” reflects the background fluorescence measurement without addition of fluorogenic lymphocytes.
  • Example 5 The fluorescence-based adhesion assay of Example 1 was repeated for glutathione, dextran sulfate, Carrageenan I and Carrageenan II using HIV-infected lymphocytes. As shown in Fig. 8, all of the materials were effective inhibitors of cell adhesion, with the Carrageenans being effective at lower concentrations.
  • the agents tested are compositions comprising various sulfated polysaccharides including iota carrageenan, kappa carrageenan, lambda carrageenan, dextran sulfate.
  • Benzyl alcohol (Sigma, St. Louis, MO) and 6 ml. 0.1 N HCl are added to 93 ml. distilled water in a 250 ml. beaker.
  • Two grams of iota carrageenan are added slowly over a 30 minute period while the mixture is continuously stirred with a spatula, at room temperature.
  • HlV-infected lymphocytes are contacted with the epithelial cells in an amount effective to cause adhesion to, and transmission of the virus into, the epithelial cells.
  • the same amount of HIV-infected lymphocytes together with the sulfated polysaccharide composition of Example 6 is contacted with a further same amount of epithelial cells.
  • the amount of sulfated polysaccharide used is an amount effective to inhibit cell adhesion and transmission of the virus.
  • Example 1 The fluorescence assay of Example 1 is used to determine the level of cell adhesion. It is found that the sulfated polysaccharide composition prevents adhesion of the HIV-infected lymphocytes to the epithelial cells and transmission of the virus.
  • the ability of various sulfated polysaccharides to block adhesion of the Chlamydia organism to epithelial cells is tested.
  • the human strain of the Chlamydia organism is introduced into the vagina of each of 100 mice in an amount effective to transmit the organism across the vaginal epithelial cells and infect the mice.
  • the same amount of Chlamydia organism together with the sulfated polysaccharide composition described in example 6 is introduced into the vagina of each of another 100 mice.
  • the amount of sulfated polysaccharide used is an amount effective to inhibit transmission of the Chlamydia organism. Specific amounts may depend on interactions with carrier materials. It is found that the sulfated polysaccharide composition prevents transmission of the Chlamydia organism. Histology of the ' reproductive tract is used to determine whether or not the animal is infected.
  • Example 7 The experiment performed in Example 7 is performed in vitro using epithelial cells from the human cervix.
  • the results are similar in that transmission of the Chlamydia organism to the epithelial cells does not occur in the presence of the sulfated polysaccharide composition.
  • Example 9 The agents tested are compositions comprising various sulfated polysaccharides and various contraceptive compositions intended for vaginal administration.
  • 1.0 ml. of Benzyl alcohol (Sigma, St. Louis, Mo) and 10.0 ml. 0.1 N HCl are added to 88 ml. distilled water in a 250 ml. beaker.
  • 1.0 gram of sulfated polystyrene (ORF 13904) is added slowly, with stirring until it is in solution.
  • 2.0 grams of iota carrageenan (Sigma, St. Louis, MO) are added slowly over a 30 minute period while the mixture is continuously stirred with a spatula, at room temperature.
  • Example 6 The experiment performed in Example 6 is performed using the sulfated polysaccharide composition of Example 9. The results are found to be the same.
  • Example 7 The experiment performed in Example 7 is performed using the sulfated polysaccharide composition of Example 9. The results are found to be the same.
  • Example 8 The experiment in Example 8 is performed using the sulfated polysaccharide composition of example 9. The results are found to be the same.
  • Compounds 1, 2, 3 and 4 exhibit spermicidal activity at 0.6, 0.5-1, 1 and 2.5 mg/ml respectively. Remaining compounds non-spermicidal.
  • Non-toxic compounds which inhibit cell-cell adhesion.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Molecular Biology (AREA)
  • Gynecology & Obstetrics (AREA)
  • Reproductive Health (AREA)
  • Urology & Nephrology (AREA)
  • Virology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

On empêche la transmission, de cellule à cellule, du VIH, et donc la transmission sexuelle du sida, par application directe de polysaccharides sulfatés sur l'épithélium des muqueuses vaginales, du col de l'utérus ou du pénis. Les polysaccharides sulfatés comprennent le carraghénane et le dextrane, dont la composition peut se présenter sour forme de crème, de suppositoire, de gel ou de mousse, de telles compositions constituant un aspect de la présente invention.
EP94909436A 1993-01-08 1994-01-06 Utilisation de polysaccharides sulfates pour prevenir des maladies sexuellement transmissibles Withdrawn EP0678030A1 (fr)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US179593A 1993-01-08 1993-01-08
US1795 1993-01-08
US17379093A 1993-12-27 1993-12-27
PCT/US1994/000210 WO1994015624A1 (fr) 1993-01-08 1994-01-06 Utilisation de polysaccharides sulfates pour prevenir des maladies sexuellement transmissibles
US173790 2009-04-29

Publications (1)

Publication Number Publication Date
EP0678030A1 true EP0678030A1 (fr) 1995-10-25

Family

ID=26669479

Family Applications (1)

Application Number Title Priority Date Filing Date
EP94909436A Withdrawn EP0678030A1 (fr) 1993-01-08 1994-01-06 Utilisation de polysaccharides sulfates pour prevenir des maladies sexuellement transmissibles

Country Status (3)

Country Link
EP (1) EP0678030A1 (fr)
JP (1) JPH08506570A (fr)
WO (1) WO1994015624A1 (fr)

Families Citing this family (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5658893A (en) * 1995-03-29 1997-08-19 Abbott Laboratories Method for inhibition of rotavirus infection with carrageenan
CH690814A5 (it) * 1996-11-04 2001-01-31 Applied Pharma Res Composizioni per uso topico contenenti polisaccaridi solfati.
US6310073B1 (en) * 1998-07-28 2001-10-30 Queen's University At Kingston Methods and compositions to treat glycosaminoglycan-associated molecular interactions
EP1609467A1 (fr) * 1998-07-28 2005-12-28 Neurochem (International) Limited Compositions pour le traitement des maladies associées aux interactions moleculaires des glycosaminoglycanes
JP4633233B2 (ja) * 2000-06-29 2011-02-16 生化学工業株式会社 クラミジア感染症処置剤
US20050080045A1 (en) * 2001-12-24 2005-04-14 Alan Chapman Composition comprising dextrinsulfate for the treatment of sexual transmitted diseases (std)
US8367098B2 (en) 2002-04-30 2013-02-05 The Population Council, Inc. Unique combinations of antimicrobial compositions
JP4896745B2 (ja) 2004-02-02 2012-03-14 アンブレツクス・インコーポレイテツド 修飾されたヒトインターフェロンポリペプチドおよびこれらの使用
US20060292102A1 (en) * 2004-12-10 2006-12-28 Roman Stephen B Thixotropic personal lubricant
CN100494222C (zh) * 2006-04-30 2009-06-03 华南理工大学 β-1，4-葡聚糖-6，2，3-硫酸酯的制备方法
CA2688346A1 (fr) 2007-05-23 2008-12-04 Vical Incorporated Compositions et procedes pour ameliorer la reponse immunitaire a des vaccins
CN101784272B (zh) 2007-08-24 2014-03-12 玛丽诺姆德生物技术公司 包含硫酸多糖的抗病毒组合物
WO2014123880A1 (fr) 2013-02-05 2014-08-14 The Population Council, Inc. Anneau intravaginal pour l'administration de combinaisons uniques de compositions antimicrobiennes
CN106163539A (zh) 2014-01-28 2016-11-23 人口委员会股份有限公司 用于预防性传播感染的组合产品

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IT1213323B (it) * 1986-08-07 1989-12-20 Crinos Industria Farmaco Composizione per uso locale ad atti vita' spermicida virulicida ,disinfettante e/o battericida
JPH02178230A (ja) * 1988-12-28 1990-07-11 Ueno Seiyaku Oyo Kenkyusho:Kk 坐剤

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9415624A1 *

Also Published As

Publication number Publication date
WO1994015624A1 (fr) 1994-07-21
JPH08506570A (ja) 1996-07-16

Similar Documents

Publication Publication Date Title
CA2305331C (fr) Methodes pour la reduction de la frequence de transmission d'infections virales et pour la prevention et le traitement d'infections bacteriennes a l'aide d'excipients d'acetophtalate de cellulose ou de phtalate d'hydroxypropyl methylcellulose
WO1994015624A1 (fr) Utilisation de polysaccharides sulfates pour prevenir des maladies sexuellement transmissibles
ES2357474T3 (es) Composiciones y su uso para atrapar e inactivar microbios patógenos y espermatoziodes.
US8552064B2 (en) Suramin and derivatives thereof as topical microbicide and contraceptive
US8367098B2 (en) Unique combinations of antimicrobial compositions
EA011298B1 (ru) Применение бактерицидных пиримидинов для профилактики передачи вич половым путём и фармацевтические композиции на их основе
US20050261240A1 (en) Carrageenan based antimicrobial compositions
JPH10507178A (ja) 抗性行為感染症製剤の使用と組成
JP2004506482A (ja) 非ホルモン性腟内避妊用具
JP5322918B2 (ja) 避妊用組成物
Uckun et al. Prophylactic contraceptives for HIV/AIDS
US20020151521A1 (en) Universal antiviral composition
US8518434B2 (en) Antiseptic spermicidal composition and means for its application
Haineault et al. Thermoreversible gel formulation containing sodium lauryl sulfate as a potential contraceptive device
Low-Beer et al. Dextrin sulfate as a vaginal microbicide: randomized, double-blind, placebo-controlled trial including healthy female volunteers and their male partners
Anderson et al. Contraception by Ushercell™(cellulose sulfate) in formulation: duration of effect and dose effectiveness
Cohen Women: absent term in the AIDS research equation
Mauck et al. An update on vaginal microbicides
Malcolm et al. Vaginal microbicides for the prevention of HIV transmission
AP868A (en) Pharmaceutical compositions for the prevention or treatment of retrovirus infections.
Ladipo et al. A new vaginal antimicrobial contraceptive formulation: phase I clinical pilot studies
Scholand et al. Anti-HIV-1 microbicides-'Chemical condoms' designed to limit the scourge of the HIV-1 pandemic
JPH11503745A (ja) Ｈｉｖ感染症に対する２，４−ジクロロベンジルアルコール及びアミルメタクレゾール
Bassol et al. Comparative trial between two soft jelly capsules containing nonoxynol as spermicidal contraceptives
Carlson Gentle spermicide also inhibits HIV

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 19950623

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB GR IE IT LI LU MC NL PT SE

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION HAS BEEN WITHDRAWN

18W Application withdrawn

Withdrawal date: 19980209