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AU711634B2 - Compositions having antiviral properties and preparation process - Google Patents
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AU711634B2 - Compositions having antiviral properties and preparation process - Google Patents

Compositions having antiviral properties and preparation process Download PDF

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Publication number
AU711634B2
AU711634B2 AU48340/96A AU4834096A AU711634B2 AU 711634 B2 AU711634 B2 AU 711634B2 AU 48340/96 A AU48340/96 A AU 48340/96A AU 4834096 A AU4834096 A AU 4834096A AU 711634 B2 AU711634 B2 AU 711634B2
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Australia
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composition
composition according
extract
coconut
retrovirus
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AU48340/96A
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AU4834096A (en
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Alix-Roland Commin
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18Magnoliophyta (angiosperms)
    • A61K36/185Magnoliopsida (dicotyledons)
    • A61K36/22Anacardiaceae (Sumac family), e.g. smoketree, sumac or poison oak
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18Magnoliophyta (angiosperms)
    • A61K36/185Magnoliopsida (dicotyledons)
    • A61K36/33Cactaceae (Cactus family), e.g. pricklypear or Cereus
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18Magnoliophyta (angiosperms)
    • A61K36/185Magnoliopsida (dicotyledons)
    • A61K36/47Euphorbiaceae (Spurge family), e.g. Ricinus (castorbean)
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18Magnoliophyta (angiosperms)
    • A61K36/88Liliopsida (monocotyledons)
    • A61K36/889Arecaceae, Palmae or Palmaceae (Palm family), e.g. date or coconut palm or palmetto
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18Magnoliophyta (angiosperms)
    • A61K36/88Liliopsida (monocotyledons)
    • A61K36/896Liliaceae (Lily family), e.g. daylily, plantain lily, Hyacinth or narcissus
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18Magnoliophyta (angiosperms)
    • A61K36/88Liliopsida (monocotyledons)
    • A61K36/90Smilacaceae (Catbrier family), e.g. greenbrier or sarsaparilla
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12Antivirals
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12Antivirals
    • A61P31/14Antivirals for RNA viruses
    • A61P31/18Antivirals for RNA viruses for HIV

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  • Health & Medical Sciences (AREA)
  • Natural Medicines & Medicinal Plants (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Alternative & Traditional Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Mycology (AREA)
  • Microbiology (AREA)
  • Medical Informatics (AREA)
  • Botany (AREA)
  • Biotechnology (AREA)
  • Virology (AREA)
  • Communicable Diseases (AREA)
  • General Chemical & Material Sciences (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • AIDS & HIV (AREA)
  • Molecular Biology (AREA)
  • Medicines Containing Plant Substances (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Description

1. 1- .ii-i--lii.. Field of Invention The present invention is directed generally to compositions having antiviral properties and a process of producing anti-retroviral compounds.
Background Art The struggle against diseases due to retroviruses has mobilised many teams throughout the world to investigate this area. A great deal of research has been directed to fighting against the AIDS (Acquired Immune Deficiency Syndrome) epidemic.
It is known that the agent responsible for AIDS is a retrovirus called HIV (Human Immune Deficiency Virus) according to an English abbreviated form.
The antiviral drugs most used come from nucleosides, including "zidovudine", or AZT, which was the first anti-retroviral drug available. Since then, the emergence of tough mutant viruses has led to a search for new treatments.
15 The present inventor has found that compositions including a mixture of acid and natural products are capable of inactivating, to some extent, the infectious power of HIV.
There is clearly a need for providing new efficient antiviral compositions.
20 Disclosure of the Invention The present invention is directed to a composition for treating retroviruses. the composition comprising acetic acid, extracts of coconut powder, mineral salts solution, extracts of plant families Cactacea, liliaceous, Anacardiaceae and Euphorbiaceae.
25 Preferably, the extracts of coconut powder are obtained from the coconut tree fruit. More preferably, the extracts of coconut are the white grated content of the coconut.
Preferably, the mineral salt solution is selected from the group consisting of sodium, potassium, calcium, magnesium phosphates, chlorides, sulfates, carbonates and bicarbonates.
Preferably, the extract of Cactacea family is an extract from the plant Opuntia. More preferably, the Opuntia is Nopal. Most preferably, the Nopal is green Nopal fruit.
Preferably the extracts of liliaceous in the composition include "sarsaparilla". More preferably, the "sarsaparilla" is the lily like "sarsaparilla" root.
Preferably, the extract of the plant family Anacardiaceae is an extract from Mombin. more preferably, the Mombin is the bark of Mombin.
Preferably, the extract of the plant family Eeuphorbiacea is from the castor oil plant. More preferably, the composition includes the seeds of the castor oil plant, and most preferably, the composition includes seeds that have been roasted and powdered.
In one preferred embodiment, the present invention is directed to a composition including acetic acid, grated coconuts, sea water, green Nopal fruits, "sarsaparilla" root. "Mombin" bark, and roasted and powdered seeds of the castor oil plant.
Preferably. these ingredients are used in the composition in the following proportions:acetic acid from 5 to 10 litres, more preferably from 7 to 8 litres; coconut powder (preferably the white grated content); approximately 15 coconuts: mineral salts solution (preferably sodium, potassium, magnesium.
calcium. phosphates, chlorides, sulphates. carbonates and bicarbonates).
More preferably, sea water: from 3 to 5 litres: 4 litres: Nopal and in particular grated fruits of green Nopal: from 10 to 20 fruits accounting for 1 to 2kg and more preferably 15 fruits, accounting roughly for "sarsaparilla" root: from 500g to 1kg and more preferably about 750g "Mombin" bark from 500g to 1.5kg and more preferably about 1kg roasted and ground seeds of castor oil plant: from 500g to 1.5kg and 25 more preferably about 1kg.
The present invention is further directed to a process of producing an antiviral composition comprising macerating coconut in the presence of acetic acid for 24 hours, boiling the mixture, filtering the boiled and macerated coconut/acid mixture to remove particulate matter, and adding to the filtrate mineral salts and extracts of plant families Cactacea. liliaceous. Anacardiaceae and Euphorbiaceae.
It has been found that the composition of the present invention has an inhibitory effect of HIV-1 "reverse transcriptase" activity which is likely to exceed 90% compared to the activity calculated on the pilot cells. Further. a drop in the cythopathogenic effect of HIV-1 on cells contaminated by the virus and treated with the compositions of the invention is achieved.
The absence of toxicity of these compositions has been demonstrated on the mouse by intraperitoneal injection with physiological pH.
In another aspect, the present invention is directed to a pharmaceutical composition including a composition according to the first aspect of the invention together with a pharmaceutical excipient.
The pharmaceutical compositions of the invention are particularly adapted to prevent and treat AIDS. combined with other drugs if necessary.
The pharmaceutical compositions are preferably administered by injection in solutions or isotonic injectable suspensions with regard to the blood plasma. Dosage requirements will vary according to the patients health.
The quantity of active principle (dry extract) for a man may change from 1 to 500mg a day.
The invention will be illustrated hereafter with an example of composition of great efficiency regarding HIV-1 virus and with results of 15 testings in vitro and in vivo.
Examples Example 1 Preparation of a composition according to the invention.
The white dry grated content of 10 coconuts and 7 to 8 litres of white vinegar or acetic acid were macerated for at least 24 hours.
20 The resulting mixture was then filtered and the following ingredients were added to the filtrate.
solution rich in minerals, eg. sea water 4 litres green grated Nopal (about 15 fruits) bark of "Mombin" 1kg 25 roasted and powdered seeds of castor oil plant 1kg The resulting mixture was boiled for about 1 hour and then filtered.
Example 2 Study of inactivation of HIV-1 with the composition of Example 1.
Experimental Protocol Inactivation of the virus.
A suspension of viral particles in a RPMI 1640 culture (HIV-1 III B, "inverse transcriptase" activity 3.8 x 1 0 cpm/ml) is incubated with the composition of Example 1 hereafter called "the composition", at 4 C for 2 minutes, then at room temperature for 1 hour and finally at 37 0 C for 2 hours. Following the incubation, the mixture was diluted with an added of foetal calf serum first warmed up at 56 0 C for 30 minutes, to 1/10th, 1/20th, 1/40th. 1/100th. 1/200th the original concentration in the RPMI 1640 culture diluted.
P_ iI/ iiil 1 i i i_ __f Infection Samples of 5 x 10 5 MT4 cells (human cells of lymphoid origin changed by human T lymphocyte virus (HTLV-1) are suspended in 2501 of various dilutions of virus-composition mixture.
After one hour of absorption at room temperature, the cells were resuspended at 5 minute intervals and centrifuged. The virus that was not absorbed was removed. The cells were washed twice with RPMII and put in suspension again in the RPNMI medium with a 10% foetal calf serum concentrated at a 2 x 10 5 /ml. The contaminated cells were put in culture in "microtitration" plates (Costar 96 pots) split into 200~l/pot.
Every culture was made at least in duplicate. Cultures were diluted in the same volume of medium after 5 days and then after 8 days of infection.
A number of control cultures were contaminated at the same time that the suspension of virus A was made with the RPfMI medium.
15 Incubations and dilutions of the control culture were strictly made under the same conditions as for the virus treated with the composition.
An additional control was made with the virus preincubated with a 0.15iM NaCI solution.
The production of the virus was estimated from a correct proportioning 20 of "inverse transcriptase" activity, associated with viral particles that the cells released in the medium. The "inverse transcriptase" is also called "reverse transcriptase" or RT in its abbreviated form.
The RT test was made from 65)l of medium, according to the protocol described by Moog et al., in Antiviral Research. 24, (1994), 275-288. The 25 results were expressed in cpm/test (see Table 2).
The cellular viability was estimated by the MTT test described by Moog et al., as abovementioned (see Table The colouring intensity was expressed in milli DO.
Experiment A The HIV production was estimated after contamination of the MT4 cells with virus preincubated with the composition. After 5 to 7 days of contamination the RT values were approximately 699 to 1.538 cpm/test, whereas for floating particles of non-contaminated cultures, the RT values were approximately 1.400 to 2.100 cpm/test. Every culture contaminated with the non treated virus produced virus after 5 to 11 days.
I_ ~II_ Experiment B The production of HIV was estimated after contamination of CEM-SS cells with HIV-LAi.
A suspension of virus B (HIV-1 LAi, "reverse transcriptase" activity 3 x 10" cpm/ml) was incubated with the composition. All other stages are described in the experiment made on MT4 cells.
Under these conditions, cultures contaminated with the pilot virus (not incubated with the composition) produced virus measurable by RT, 11 days after contamination.
In the case of cells contaminated with the virus preincubated with the composition, the RT values were similar to those ones estimated on the floating particles of the uncontaminated cultures'(1,707 to 2,564 cpm/test) after 11 days of contamination.
Experiment C 15 The experimental protocol followed was the same as that described in ,Experiment A. The measurements recorded at 5 days and 7 days after the 9 o contamination indicated that detection of virus replication was low when it has been preincubated with the composition (RT of uncontaminated pilot cells 972-12.192 cpm/test).
Experiment D In order to estimate the production of virus more quickly than in 9* Experiment B. a virus concentration 10 times more potent was used.
After 5 to 8 days, the production of virus appeared to be strongly inhibited when the virus was preincubated with the composition.
25 The absence of effect noted when using 0.15M NaC1 solution suggests that the virus inhibition was specific to the composition.
These results suggest that the HIV-1 virus preincubated with the composition of the invention results in the inactivation of the infectious power of the viral particles.
Example 3 Study of the composition effect of the first example on the "reverse transcriptase" activity of HIV-1.
A suspension of the HIV-1 virus was melted to different dilutions of the composition. The "reverse transcriptase" activity (RT) was determined, in association with the viral particles, as described by Moog et al in the above reference.
The measurements were determined from at least two samples.
The results obtained are found in Table 1.
Increased concentrations of the composition inhibit the RT activity to more than Another series of experiments, the results of which are given in Table 2, confirm this information.
The experiments suggest that the compositions inhibit the "reverse transcriptase" activity of HIV-1 when measured in vitro.
It will be appreciated by persons skilled in the art that numerous variations and/or modifications may be made to the invention as shown in the specific embodiments without departing from the spirit or scope of the invention as broadly described. The present embodiments are, therefore, to be considered in all respects as illustrative and not restrictive.
Chart 1 RT activity (cpm/test) FINAL DILUTION OF COMPOSITION/VIRUS THE SOLUTIONS
AVERAGE
1/21.164 973 783 1/6 759 724 (94%) 688 1/8 2.453 2,664.(80%) 2.875 1/54 6.875 6,412 (50%)1 1/162 10.035 9,128 (29%o) 1,486 11.747 12.364 12.981
S
S S *5 *5*5
S.
pa
S
S *5 S
S
S.
*S
S S a
S
*5 S a 14,318 1.764 743AVERAGE PILOT VIRUS 12 .68 7 12 .218 15,036 The figures in brackets indicate the 06 of inhibition of the RT activity 9 Chart 2 RT activity (cpm/test) FINAL DILUTION OF THE SOLUTIONS COMPOSITION/VIRUS1
S
0 S. *5
S
S
S*
C
5 0 *5 4**e *5*S
S
S
.5 *5*S S S
SO
*5 S S
S
55 S. 50 S S S. S
SO
55
S
AVERAGE
1/2 550 666 (100%)- /4 925 724 (100%) 524 1/8 572 507 (100%) 1/6910 854 (100%) 797 13227.045 28,790 (820%) 30.5 1/455.180 63.265 75.351 1/128 108.652 106.163 103,6 73 1/25 6 129 .555 10 7.540 18,548 (24%o) 1 4 1/512 1.024 167.936 156,267 The figures in brackets indicate the of inhibition of the RT activity

Claims (24)

1. A composition for the treatment of a virus or retrovirus, comprising acetic acid; extract of coconut: mineral salts; and extracts from each of the plant families Cactacea, liliaceous, Anacardiaceae and Euphorbiaceae.
2. The composition according to claim 1, wherein extract of coconut is the grated white content of the coconut.
3. The composition according to claim 1 or 2 wherein the mineral salts are selected from the group consisting of sodium, potassium, calcium, magnesium, phosphates, chlorides, sulphates, carbonates and bicarbonates.
4. The composition according to any one of claims 1 to 3, wherein extract :of plant family Cactacea is an extract from the plant Opuntia. 15
5. The composition according to claim 4, wherein Opuntia is a Nopal.
6. The composition according to claim 5, wherein Nopal is a green Nopal fruit.
7. The composition according to any one of claims 1 to 6. wherein the composition further includes an extract from "sarsaparilla". 20
8. The composition according to claim 7, wherein "sarsaparilla" is the lily- like root of "sarsaparilla".
9. The composition according to any one of claims 1 to 8, wherein the extract from the plant family Anacardiaceae is an extract from "Mombin".
10. The composition according to claim 9. wherein "Mombin" is the bark of 25 "Mombin".
11. The composition according to any one of claims 1 to 10, wherein the extract from the plant family Euphorbiaceae is castor oil plant seeds.
12. The composition according to claim 11, wherein the castor oil plant seeds are roasted and powdered.
13. Composition for the treatment of a virus or a retrovirus, wherein the composition comprises acetic acid, grated coconut, sea water, green Nopal fruits, "sarsaparilla" root, "Mombin" bark, powdered and roasted castor oil plant seeds.
14. Composition for the treatment of a virus or a retrovirus. wherein the composition comprises: 5 to 10 litres of acetic acid: grated coconut of 10 coconuts: 3 to 5 litres of mineral salts and sea water; 1 to 2kg of green Nopal fruit; 500g to lkg of "sarsaparilla" root: 500g to 1.5kg of "Monibin" bark; and 500g to 1.5kg of ground and roasted castor oil plant seeds.
The composition according to claim 14 wherein the composition includes 7 to 8 litres of acetic acid.
16. The composition according to any one of claims 14 or 15 wherein the composition includes 4 litres of mineral salts and sea water.
17. The composition according to any one of claims 14 to 16 wherein the composition includes 1.5kg of green Nopal fruit.
18. The composition according to any one of claims 14 to 17 wherein the composition includes 75Og "sarsaparilla" root. 9999'* 15
19. The composition according to any one of claims 14 to 18 wherein the composition includes lkg of "Monibin" bark.
The composition according to any one of claims 14 to 19 wherein the composition includes 1kg of ground and roasted seed of the castor oil plant.
21. A process of producing an antiviral composition comprising: o 20 macerating coconut in the presence of acetic acid for 24 hours to form a S"mixture; boiling the mixture; filtering the boiled and macerated coconut/acid mixture to remove particulate matter, and adding to the filtrate mineral salts and extract from each of plant families SCactacea, liliaceous. Anacardiaceae and Euphorbiaceae
22. Use of the composition as claimed in any one of claims 1 to 20 for the preparation of a medicament for the treatment of a retrovirus.
23. The use according to claim 22 wherein the retrovirus is HIV.
24. A medicament for the treatment of a retrovirus wherein the medicament includes the composition according to any one of claims 1 to 20 together with a pharmaceutical excipient. 12 A method of treating a retrovirus comprising administering to a subject in need of treatment a therapeutically effective amount of the composition as claimed in claim Dated this twentieth day of August 1999 Alix-Roland Commin Patent Attorneys for the Applicant: F B RICE CO 00 0*00
AU48340/96A 1995-03-06 1996-02-13 Compositions having antiviral properties and preparation process Ceased AU711634B2 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
FR9502595 1995-03-06
FR9502595A FR2731354B1 (en) 1995-03-06 1995-03-06 COMPOSITIONS HAVING ANTIVIRAL PROPERTIES AND PROCESS FOR OBTAINING SAME
PCT/FR1996/000230 WO1996027383A1 (en) 1995-03-06 1996-02-13 Compositions having antiviral properties and preparation process

Publications (2)

Publication Number Publication Date
AU4834096A AU4834096A (en) 1996-09-23
AU711634B2 true AU711634B2 (en) 1999-10-21

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AU48340/96A Ceased AU711634B2 (en) 1995-03-06 1996-02-13 Compositions having antiviral properties and preparation process

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EP (1) EP0768887B1 (en)
JP (1) JPH10506124A (en)
AP (1) AP705A (en)
AT (1) ATE201825T1 (en)
AU (1) AU711634B2 (en)
CA (1) CA2189474C (en)
DE (1) DE69613190T2 (en)
DK (1) DK0768887T3 (en)
EA (1) EA000112B1 (en)
ES (1) ES2171653T3 (en)
FR (1) FR2731354B1 (en)
GR (1) GR3036556T3 (en)
OA (1) OA10332A (en)
PT (1) PT768887E (en)
WO (1) WO1996027383A1 (en)

Families Citing this family (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000001398A1 (en) * 1998-07-02 2000-01-13 Nobutho Gladys Makupula Anti-viral plant extract
US6238672B1 (en) 1999-04-23 2001-05-29 E. Excel International Inc. Dietary supplements containing dehydrated cactus fruit juice and ginseng berry juice
MY124001A (en) * 1999-04-23 2006-06-30 E Excel Int Dietary supplements containing dehydrated cactus fruit juice and ginseng berry juice
US6524626B2 (en) 1999-04-23 2003-02-25 E Excel International, Inc. Ginseng berry topical products
US6576286B1 (en) 1999-04-23 2003-06-10 E Excel International Cactus fruit drinks and food products
US6210738B1 (en) 1999-04-23 2001-04-03 E Excel Internatioanal Inc. Freeze-dried ginseng berry tea
FR2926465B1 (en) * 2008-01-17 2016-08-12 Alix Roland Commin ANTI-VIRAL COMPOSITION, IN PARTICULAR AIDS
WO2011010000A1 (en) * 2009-07-22 2011-01-27 Alix Roland Commin Antiviral and retroviral composition, in particular for treating aids

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0825890B2 (en) * 1987-06-18 1996-03-13 呉羽化学工業株式会社 Antiviral agent
FR2662353A1 (en) * 1990-05-22 1991-11-29 Neyroud Andre SOFT BREAD OR LIQUID ANTISEPTIC LIQUID, WHICH KILLS AIDS VIRUSES, PROVIDES BODY HYGIENE AND PROTECTS SKIN.
GB9126393D0 (en) * 1991-12-12 1992-02-12 Skinner Gordon R B Anti microbial activity from extracts of cactus

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WO1996027383A1 (en) 1996-09-12
CA2189474A1 (en) 1996-09-12
DE69613190D1 (en) 2001-07-12
EA199600087A1 (en) 1997-09-30
AP9600872A0 (en) 1996-10-31
OA10332A (en) 1997-10-07
FR2731354B1 (en) 1997-05-09
EP0768887B1 (en) 2001-06-06
GR3036556T3 (en) 2001-12-31
JPH10506124A (en) 1998-06-16
DE69613190T2 (en) 2002-01-31
EA000112B1 (en) 1998-08-27
EP0768887A1 (en) 1997-04-23
DK0768887T3 (en) 2001-09-10
ATE201825T1 (en) 2001-06-15
CA2189474C (en) 2003-07-29
AU4834096A (en) 1996-09-23
ES2171653T3 (en) 2002-09-16
FR2731354A1 (en) 1996-09-13
PT768887E (en) 2001-11-30
AP705A (en) 1998-12-04

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