WO1990014086A1 - Utilisation of acridine derivatives in the treatment of retroviral infections in humans - Google Patents

Utilisation of acridine derivatives in the treatment of retroviral infections in humans Download PDF

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Publication number
WO1990014086A1
WO1990014086A1 PCT/CH1990/000132 CH9000132W WO9014086A1 WO 1990014086 A1 WO1990014086 A1 WO 1990014086A1 CH 9000132 W CH9000132 W CH 9000132W WO 9014086 A1 WO9014086 A1 WO 9014086A1
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Prior art keywords
treatment
acridine
diamino
prophylaxis
intended
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Application number
PCT/CH1990/000132
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French (fr)
Inventor
Georges Mathe
Original Assignee
Debiopharm S.A.
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Publication of WO1990014086A1 publication Critical patent/WO1990014086A1/en

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom

Definitions

  • the subject of the invention is a pharmaceutical composition intended for the treatment or prophylaxis of human retrovirus infections, in particular those with a virus which generates the acquired immunodeficiency syndrome (SIDA / AIDS). It also relates to, as medicaments for the treatment or prophylaxis of such infections, the heterocyclic compounds used in these compositions.
  • SIDA / AIDS acquired immunodeficiency syndrome
  • HIV retrovirus (LAV / HTLV III) seems to be one of the most worrying for civilization today: it is responsible for the acquired immunodeficiency syndrome (SIDA / Engl.: AIDS). It is mainly transmitted by sexual or blood pathway, it affects a growing number of people and its spread is today described as endemic.
  • AZT has the disadvantage of being unstable when heated (it is generally stored at -20 ° C), of producing side effects that are poorly tolerated by individuals weakened by the disease and of being very expensive. AZT is also insoluble in water, which limits the forms of application.
  • the present invention makes it possible to advantageously fill this gap by proposing, as a medicament intended for the treatment or prophylaxis of human retrovirus infections, at least one nitrogen-heterocyclic compound chosen from 3,6-diamino-10-methyl chloride. -acridinium, 3,6-diamino-acridine and 9-amino-acridine.
  • ACD-y Acridine Yellow
  • the compounds used in the context of the present invention all comprise at least one amino group attached to the nitrogen heterocycle; they can be represented as follows: Acriflavine (ACF)
  • the anti-retroviral activity of the compounds mentioned in the context of the present invention has been demonstrated, inter alia, on the leukemigenic virus of Friends (spleen focus forming virus / SFFV-F) during in vivo experiments described below. .
  • acriflavine (ACF) was found to be significantly more effective than AZT at a dose of comparable toxicity, the proflavin (PF) with activity similar to that of AZT.
  • AIDS AIDS
  • the nitrogen heterocyclic compounds proposed by the invention as medicaments have the great advantage of being readily available on the market and of being remarkably stable at room temperature.
  • their toxicity has been the subject of numerous investigations: it is perfectly known and the same goes for possible side effects.
  • Said compounds also have the advantage of being water-soluble, which facilitates their application all the more, by the oral or intravenous route for example.
  • mice from the DBA 2 strain 0.2 ml of a 1% solution of a spleen extract contaminated with the leukemigenic retrovirus from Friends was inoculated into mice from the DBA 2 strain divided into groups of eight. . About 1 hour after this injection, each infected mouse was administered, intraperitoneally, an aqueous solution of the heterocyclic compound chosen, at the doses shown in the table below. A group of 8 infected mice was kept as such as a control sample.
  • a blood plasma sample was taken from the treated and untreated infected mice, and 0.1 ml of this plasma, as is, injected, respectively, after 10% and 1% dilution, into uncontaminated mice from of the DBA2 strain. This injection was done intravenously.
  • the number of viruses received by the latter was determined eight days after this injection, by counting the foci of unit formation in the spleen.
  • the effect of the drug substances used in this experiment was expressed by means of the report between the number of outbreaks counted following injection of plasma from infected infected mice and the number of outbreaks counted following injection of plasma from "control" mice. The values obtained are expressed logarithmically and are reported in the attached figure.
  • PF proflavin

Abstract

A pharmaceutical composition containing, as active ingredient, at least one heterocyclic nitrogenous compound from among 3,6-diamino-10-methyl-acridinium chloride, 3,6-diamino-acridine and 9-amino-acridine, is intended for use in the treatment of retrovirus infections in humans, in particular those due to the acquired immunodeficiency syndrome virus.

Description

UTILISATION DE DERIVES DE L'ACRIDINE DANS LE TRAITEMENT D'INFECTICNS RETROVIRALES CHEZ L'HOMME USE OF ACRIDINE DERIVATIVES IN THE TREATMENT OF RETROVIRAL INFECTIONS IN MEN
L'invention a pour objet une composition pharmaceutique destinée au traitement ou à la prophylaxie des infections humaines à retrovirus, notamment celles à virus générateur du syndrome de l'i munodéficience acquise (SIDA/AIDS). Elle a également pour objet à titre de médicaments pour le traite¬ ment ou la prophylaxie de telles infections, les composés hétérocycliques utilisés dans ces compositions.The subject of the invention is a pharmaceutical composition intended for the treatment or prophylaxis of human retrovirus infections, in particular those with a virus which generates the acquired immunodeficiency syndrome (SIDA / AIDS). It also relates to, as medicaments for the treatment or prophylaxis of such infections, the heterocyclic compounds used in these compositions.
L'un des problèmes majeurs auxquels est aujourd'hui confrontée la médecine est la toute récente apparition des infections humaines à retrovirus. D'une part, les retrovirus eux-mêmes, en particulier les retrovirus humains, sont encore mal connus et leur mode d'action est loin d'être élucidé. D'autre part, la médecine ne dispose pas de produits permet¬ tant de lutter efficacement contre le développement de ces retrovirus dans l'organisme ou contre les conséquences d'un tel développement au sein de l'organisme humain. On est à ce jour réduit à tenter d'enrayer au mieux la propagation de ces retrovirus au sein de la population et à soigner les personnes atteintes à l'aide de médicaments dont les effets secondaires ne sont pas négligeables.One of the major problems facing medicine today is the very recent appearance of human retrovirus infections. On the one hand, the retroviruses themselves, in particular human retroviruses, are still poorly understood and their mode of action is far from being elucidated. On the other hand, medicine does not have products that allow it to effectively fight against the development of these retroviruses in the body or against the consequences of such a development within the human organism. To date, we have been reduced to trying to stop the spread of these retroviruses within the population as much as possible and to treat those affected with drugs whose side effects are not negligible.
Le retrovirus HIV (LAV/HTLV III) semble être, à l'heure actuelle, l'un des plus préoccupants pour le genre humain: il est responsable du syndrome de l'immunodéficience acquise (SIDA/angl. : AIDS) . Se transmettant essentiellement par voie sexuelle ou sanguine, il touche un nombre grandissant de personnes et sa propagation est aujourd'hui qualifiée d'endé¬ mique. Le seul médicament utilisé à l'heure actuelle, avec un succès très relatif, pour ralentir l'évolution du SIDA chez les personnes atteintes, comprend comme principe actif la 3'-azido-3'-deoxythimidine ou AZT (voir p.ex. Demande EP-A-0 196 185) . L'AZT a cependant pour inconvénient d'être instable à la chaleur (il est généralement conservé à -20°C) , de produire des effets secondaires mal supportés par les individus affaiblis par la maladie et d'être fort cher. L'AZT est en outre non soluble dans l'eau, ce qui limite d'autant les formes d'application.The HIV retrovirus (LAV / HTLV III) seems to be one of the most worrying for mankind today: it is responsible for the acquired immunodeficiency syndrome (SIDA / Engl.: AIDS). It is mainly transmitted by sexual or blood pathway, it affects a growing number of people and its spread is today described as endemic. The only drug currently used, with very relative success, to slow the progression of AIDS in people with AIDS, includes the active ingredient 3'-azido-3'-deoxythimidine or AZT (see e.g. Application EP-A-0 196 185). However, AZT has the disadvantage of being unstable when heated (it is generally stored at -20 ° C), of producing side effects that are poorly tolerated by individuals weakened by the disease and of being very expensive. AZT is also insoluble in water, which limits the forms of application.
Tant l'industrie pharmaceutique que la médecine sont à la recherche de médicaments nouveaux permettant de traiter plus efficacement les infections à retrovirus humains tel le SIDA, sans pour autant présenter les désavantages susmen¬ tionnés, en particulier ceux inhérents à l'emploi de l'AZT.Both the pharmaceutical industry and medicine are looking for new drugs which can more effectively treat infections with human retroviruses such as AIDS, without having the above-mentioned disadvantages, in particular those inherent in the use of AZT.
La présente invention permet de combler avantageusement cette lacune en proposant, à titre de médicament destiné au traitement ou à la prophylaxie des infections humaines à retrovirus, au moins un composé heterocyclique azoté -choisi parmi le chlorure de 3,6-diamino-10-méthyl-acridinium, la 3,6-diamino-acridine et la 9-amino-acridine.The present invention makes it possible to advantageously fill this gap by proposing, as a medicament intended for the treatment or prophylaxis of human retrovirus infections, at least one nitrogen-heterocyclic compound chosen from 3,6-diamino-10-methyl chloride. -acridinium, 3,6-diamino-acridine and 9-amino-acridine.
Les composés susmentionnés font partie d'une série plus étendue, communément appelée "acridines" et dont certains dérivés sont connus et utilisés depuis fort longtemps comme agents anti-bactériens tel par exemple le composé de formuleThe above-mentioned compounds are part of a more extensive series, commonly called "acridins" and of which certain derivatives have been known and used for a very long time as anti-bacterial agents such as for example the compound of formula
Figure imgf000004_0001
ou ACD-y (Acridine Yellow) . La découverte des propriétés anti-rétrovirales des dérivés aminés de l'acridine mentionnés ci-dessus est des plus surprenantes car, en l'état actuel de nos connaissances, rien ne permettait de présager une activité de ce type.
Figure imgf000004_0001
or ACD-y (Acridine Yellow). The discovery of the anti-retroviral properties of the amino derivatives of acridine mentioned above is most surprising because, in the current state of our knowledge, there was nothing to predict an activity of this type.
Les composés retenus dans le cadre de la présente invention comportent tous au moins un groupement amino rattaché à l'hétérocycle azoté; ils peuvent être représentés comme suit : Acriflavine (ACF)The compounds used in the context of the present invention all comprise at least one amino group attached to the nitrogen heterocycle; they can be represented as follows: Acriflavine (ACF)
Proflavine (PF)
Figure imgf000005_0001
Proflavin (PF)
Figure imgf000005_0001
A inacrine (AAC)
Figure imgf000005_0002
Inacrine (AAC)
Figure imgf000005_0002
On constate qu'ils ont en commun une structure favorisant par délocaLisation la répartition d'une charge positive pouvant résulter de la protonation ou de la quaternisation de 1'atcme d'azote en position 10, comme dans le cas de l'acriflavine (ACF). Il a en effet été observé que ces composés sont fortement ionisés à pH physiologique, mais rien dans l'art antérieur ne permet de supposer que ces propriétés soient le siège de l'activité anti-rétrovirale mise en évidence.It can be seen that they have in common a structure favoring by delocalization the distribution of a positive charge which may result from the protonation or the quaternization of the nitrogen attack in position 10, as in the case of acriflavine (ACF ). It has in fact been observed that these compounds are strongly ionized at physiological pH, but nothing in the prior art makes it possible to assume that these properties are the seat of the anti-retroviral activity demonstrated.
L'activité anti-rétrovirale des composés cités dans le cadre de la présente invention a été mise en évidence, entre autres, sur le virus leucémigène de Friends (spleen focus forming virus/SFFV-F) lors d'expérimentations in vivo décrites plus loin. Comparées à la 3'-azido-3'-deoxythymidine (AZT) quant à leur effet sur le développement dudit virus, 1'acriflavine (ACF) s'est révélée nettement plus efficace que l'AZT pour une dose de toxicité comparable, la proflavine (PF) présentant une activité similaire à celle de l'AZT. Tout laisse à penser que leur effet anti-rétroviral sur le virus du SIDA (AIDS) soit comparable sinon supérieur à celui de l'AZT. Les composés hétérocycliques azotés proposés par 1'invention au titre de médicament ont le grand avantage d'être aisément accessibles sur le marché et d'être remarqua¬ blement stables à température ambiante. Au vu de leur utilisa¬ tion préalable comme agents anti-bactériens, leur toxicité a fait l'objet de nombreuses investigations : elle est par¬ faitement connue et il en va de même pour les effets secondaires éventuels. Les dits composés ont également l'avantage d'être hydrosolubles, ce qui facilite d'autant leur application, par voie buccale ou intraveineuse par exemple.The anti-retroviral activity of the compounds mentioned in the context of the present invention has been demonstrated, inter alia, on the leukemigenic virus of Friends (spleen focus forming virus / SFFV-F) during in vivo experiments described below. . Compared to 3'-azido-3'-deoxythymidine (AZT) in terms of their effect on the development of said virus, acriflavine (ACF) was found to be significantly more effective than AZT at a dose of comparable toxicity, the proflavin (PF) with activity similar to that of AZT. Everything suggests that their anti-retroviral effect on the AIDS virus (AIDS) is comparable if not greater than that of AZT. The nitrogen heterocyclic compounds proposed by the invention as medicaments have the great advantage of being readily available on the market and of being remarkably stable at room temperature. In view of their prior use as anti-bacterial agents, their toxicity has been the subject of numerous investigations: it is perfectly known and the same goes for possible side effects. Said compounds also have the advantage of being water-soluble, which facilitates their application all the more, by the oral or intravenous route for example.
Au vu de l'énumération ci-dessus et de la connaissance des doses efficaces (ED50 par exemple), l'homme de l'art est en mesure de choisir aisément la formulation la plus adéquate, c'est-à-dire le dosage de l'ingrédient actif, la nature du support ou diluant, la posologie, etc..In view of the above enumeration and knowledge of the effective doses (ED50 for example), those skilled in the art are able to easily choose the most suitable formulation, that is to say the dosage of the active ingredient, the nature of the support or diluent, the dosage, etc.
On décrira ci-après, à titre non limitatif, la mise en évidence in vivo des propriétés anti-rétrovirales des composés hétérocycliques azotés de la présente invention.The in vivo demonstration of the anti-retroviral properties of the heterocyclic nitrogen compounds of the present invention will be described hereinafter without limitation.
ExempleExample
La méthode utilisée est conforme à celle décrite par Georges MATHE et al. dans C.R. Acad. Sci. 259, 4403 (1964).The method used is in accordance with that described by Georges MATHE et al. in C.R. Acad. Sci. 259, 4403 (1964).
A des souris issues de la souche DBA2 réparties par groupes de huit, on a inoculé par voie intraveineuse, au temps t0, 0,2 ml d'une solution à 1% d'un extrait de rate contaminé par le retrovirus leucémigène de Friends. Environ 1 heure après cette injection, on a administré à chaque souris infectée, par voie intrapéritonéale, une solution aqueuse du composé heterocyclique choisi, aux doses figurant dans le tableau ci-après. Un groupe de 8 souris infectées a été gardé tel que, comme échantillon de contrôle.0.2 ml of a 1% solution of a spleen extract contaminated with the leukemigenic retrovirus from Friends was inoculated into mice from the DBA 2 strain divided into groups of eight. . About 1 hour after this injection, each infected mouse was administered, intraperitoneally, an aqueous solution of the heterocyclic compound chosen, at the doses shown in the table below. A group of 8 infected mice was kept as such as a control sample.
Parallèlement, on a administré à un autre groupe de huit souris infectées une suspension huileuse d'AZT, également par voie intrapéritonéale, aux doses figurant dans le tableau ci-après. Les injections de substances médicamenteuses ont été répétées quasiment toutes les 24 heures, selon la séquence suivante : jour zéro - jour 1 - jour 2 - jour 3 - jour 6 - jour 7.At the same time, another group of eight infected mice were administered an oily suspension of AZT, also intraperitoneally, at the doses shown in the table. below. Drug injections were repeated almost every 24 hours, in the following sequence: day zero - day 1 - day 2 - day 3 - day 6 - day 7.
TableauBoard
Composé Dose par injectionCompound Dose by injection
Acriflavine (ACF) * 12,50 g/kgAcriflavine (ACF) * 12.50 g / kg
6,25 mg/kg6.25 mg / kg
Proflavine (PF) 12,50 mg/kgProflavin (PF) 12.50 mg / kg
6,25 mg/kg6.25 mg / kg
3'-Azido-3'-deoxy- 50 mg/kg thy idine (AZT) 25 mg/kg3'-Azido-3'-deoxy- 50 mg / kg thy idine (AZT) 25 mg / kg
12,50 mg/kg12.50 mg / kg
* sous forme de mélange ACF/PF env. 50/30* in the form of ACF / PF mixture approx. 50/30
Au huitième jour, on a effectué un prélèvement de plasma sanguin des souris infectées traitées et non traitées, et injecté 0,1 ml de ce plasma en l'état, respectivement après dilution à 10% et 1%, à des souris non contaminées issues de la souche DBA2. Cette injection s'est effectuée par voie intraveineuse.On the eighth day, a blood plasma sample was taken from the treated and untreated infected mice, and 0.1 ml of this plasma, as is, injected, respectively, after 10% and 1% dilution, into uncontaminated mice from of the DBA2 strain. This injection was done intravenously.
La détermination du nombre de virus reçus par ces dernières a été effectuée huit jours après cette injection, par un comptage des foyers de formation unitaires dans la rate. L'effet des substances médicamenteuses utilisées dans cette expérimentation a été exprimé au moyen du rapport entre le nombre de foyers comptés suite à injection du plasma de souris infectées traitées et le nombre de foyers comptés suite à injection du plasma de souris "contrôle". Les valeurs obtenues sont exprimées logarithmiquement et sont reportées dans la figure ci-jointe.The number of viruses received by the latter was determined eight days after this injection, by counting the foci of unit formation in the spleen. The effect of the drug substances used in this experiment was expressed by means of the report between the number of outbreaks counted following injection of plasma from infected infected mice and the number of outbreaks counted following injection of plasma from "control" mice. The values obtained are expressed logarithmically and are reported in the attached figure.
SFU = "spleen focus units"SFU = "spleen focus units"
On constate ainsi que la proflavine (PF) présente une activité anti-rétrovirale comparable à celle de l'AZT alors que l'acriflavine présente une activité anti-rétrovirale nettement supérieure à celle de l'AZT (min. facteur 10) . It is thus found that proflavin (PF) has an anti-retroviral activity comparable to that of AZT while acriflavine has an anti-retroviral activity significantly greater than that of AZT (min. Factor 10).

Claims

REVENDICATIONS
1. Composition pharmaceutique destinée au traitement ou à la prophylaxie des infections humaines à retrovirus, caractérisée en ce qu'elle contient à titre d'ingrédient pharmacologiquement actif au moins un composé heterocyclique azoté choisi parmi le chlorure de 3,6-diamino-10-méthylacridi- nium, la 3,6-diamino-acridine et la 9-amino-acridine.1. Pharmaceutical composition intended for the treatment or prophylaxis of human retrovirus infections, characterized in that it contains, as pharmacologically active ingredient, at least one heterocyclic nitrogen compound chosen from 3,6-diamino-10- chloride methylacridinium, 3,6-diamino-acridine and 9-amino-acridine.
2. Composition selon la revendication 1 destinée au traitement ou à la prophylaxie de la lymphadenopathie progres¬ sive généralisée.2. Composition according to claim 1 intended for the treatment or prophylaxis of generalized progressive lymphadenopathy.
3. Composition selon la revendication 1 destinée au traitement ou à la prophylaxie des infections à virus lymphotropes des cellules humaines T.3. Composition according to claim 1 intended for the treatment or prophylaxis of lymphotropic virus infections of human T cells.
4. Composition selon la revendication 1 destinée au traitement ou à la prophylaxie des infections à virus généra¬ teurs du syndrome de 1*immunodéficience acquise.4. Composition according to claim 1 intended for the treatment or prophylaxis of infections with virus generators of the syndrome of 1 * acquired immunodeficiency.
5. Composition selon l'une des revendications 1 à 4, caractérisée en ce qu'elle se présente sous une forme apte à une administration orale, intraveineuse ou intrapéritonéale.5. Composition according to one of claims 1 to 4, characterized in that it is in a form suitable for oral, intravenous or intraperitoneal administration.
6. A titre de médicament destiné au traitement et à la prophylaxie des infections humaines à retrovirus, l'un des composés hétérocycliques azotés suivants : le chlorure de 3,6-diamino-10-méthyl-acridinium, la 3,6-diamino-acridine et la 9-amino-acridine. 6. As a medicinal product intended for the treatment and prophylaxis of human retrovirus infections, one of the following heterocyclic nitrogen compounds: 3,6-diamino-10-methyl-acridinium chloride, 3,6-diamino- acridine and 9-amino-acridine.
PCT/CH1990/000132 1989-05-25 1990-05-22 Utilisation of acridine derivatives in the treatment of retroviral infections in humans WO1990014086A1 (en)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0375471A2 (en) * 1988-12-19 1990-06-27 Ste Civile De Recherche Newpharm Use of 1,2,3,4-tetrahydro-acridines in the treatment of AIDS, and compounds
EP0649656A1 (en) * 1993-10-22 1995-04-26 Laboratoire M. Richard Pharmaceutical compositions based on acriflavine useful for the treatment of herpes and zona
FR2711527A1 (en) * 1993-10-22 1995-05-05 Richard Laboratoire M Use of acriflavine as an anti-HIV agent
WO1996007423A1 (en) * 1995-03-23 1996-03-14 Oleg Viktorovich Travkin Immunomodulating medicinal agent

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US3489837A (en) * 1968-07-11 1970-01-13 Leroy J Hyman Synergistic antiseptic composition consisting of 9-aminoacridine hydrochloride and benzethonium chloride
EP0196515A1 (en) * 1985-03-14 1986-10-08 Baxter Travenol Laboratories, Inc. Photodynamic inactivation of virus in therapeutic protein compositions

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Publication number Priority date Publication date Assignee Title
US3489837A (en) * 1968-07-11 1970-01-13 Leroy J Hyman Synergistic antiseptic composition consisting of 9-aminoacridine hydrochloride and benzethonium chloride
EP0196515A1 (en) * 1985-03-14 1986-10-08 Baxter Travenol Laboratories, Inc. Photodynamic inactivation of virus in therapeutic protein compositions

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
Biomed. & Pharmacother., Vol. 43, No. 4, 1989, Elsevier, (Paris, FR), G. MATHE et al.: "Amino Acridines Action on Friend's Retrovirus in Relation to their Molecular Ionization", pages 235-236 *
Chem.-Biol. Interactions, Vol. 8, No. 2, 1988, Elsevier Scientific Publishing Co., (Amsterdam, NL), R. MENEGHINI: "Repair Replication of Opossum Lymphocyte DNA: Effect of Compounds that Bind to DNA", pages 113-126 *
Life Sciences, Vol. 15, No. 1974, Pergamon Press, (US), R. GRAHAM SMITH et al.: "Agents which Inhibit Reverse Transcriptases", pages 1711-1730 *
Mutation Research, Vol. 68, No. 3, 1979, Elsevier/North-Holland Biomedical Press, (Amsterdam, NL), P.E. CROSSEN: "The Effect of Acridine Compounds on Siter-Chromatid Exchange Formation in Cultured Human Lymphocytes", pages 295-299 *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0375471A2 (en) * 1988-12-19 1990-06-27 Ste Civile De Recherche Newpharm Use of 1,2,3,4-tetrahydro-acridines in the treatment of AIDS, and compounds
EP0375471A3 (en) * 1988-12-19 1992-07-08 Ste Civile De Recherche Newpharm Use of 1,2,3,4-tetrahydro-acridines in the treatment of aids, and compounds
EP0649656A1 (en) * 1993-10-22 1995-04-26 Laboratoire M. Richard Pharmaceutical compositions based on acriflavine useful for the treatment of herpes and zona
FR2711526A1 (en) * 1993-10-22 1995-05-05 Richard Laboratoire M Use of Acriflavine as an anti herpes and anti shingles agent.
FR2711527A1 (en) * 1993-10-22 1995-05-05 Richard Laboratoire M Use of acriflavine as an anti-HIV agent
WO1996007423A1 (en) * 1995-03-23 1996-03-14 Oleg Viktorovich Travkin Immunomodulating medicinal agent

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