PT87190B - PROCESS FOR THE PREPARATION OF PHARMACEUTICAL COMPOSITIONS FOR REDUCING THE INDESEJAVIC EFFECTS OF BETA-LACTAMINES - Google Patents
PROCESS FOR THE PREPARATION OF PHARMACEUTICAL COMPOSITIONS FOR REDUCING THE INDESEJAVIC EFFECTS OF BETA-LACTAMINES Download PDFInfo
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Abstract
Description
ção nas na flora intestinal. A invenção refere-se mais particularmenteuma composição contendo bactérias seleccionadas que nãojsão* patogéíticas para o homem.in the intestinal flora. The invention relates more particularly to a composition containing selected bacteria which are not pathogenic for man.
1¾¾ ......È bem conhecido que durante um tratamento -lactaminas de largo espectro, aparecem importantes moditicaçoe^s na flora microbiana normal e mais particularmentte na flora intestinal se utiliza uma β -lactamina substancialmente eliminada pela via biliar.1¾¾ ...... It is well known that during a treatment - broad spectrum lactamines, important modifications appear in the normal microbial flora and more particularly in the intestinal flora using a β-lactamine substantially eliminated by the bile duct.
Estas modificações estão mais particular mente relaccionadas com bactérias estritamente anaeróbicasThese modifications are more particularly related to strictly anaerobic bacteria
CR.CR.
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que constituem a população dominante da flora intestinal e cu ja presença evita geralmente a implantação e desenvolvimento de microorganismos potencialmente patogénicos como por exemplo anterobactérias, pseudomonas, estafilococos, fungos e microorganismos semelhantes. A destruição pelo menos parcial da flora intestinal normalmente dominante pode assim levar ao de^ senvolvimento indesejável de microorganismos infecciosos, que podem ser particularmente perigosos para alguns pacientes.which constitute the dominant population of intestinal flora and whose presence generally avoids the implantation and development of potentially pathogenic microorganisms such as anterobacteria, pseudomonas, staphylococci, fungi and similar microorganisms. The at least partial destruction of the normally dominant intestinal flora can thus lead to the undesirable development of infectious microorganisms, which can be particularly dangerous for some patients.
Foi já proposto administrar simultaneamente várias bactérias ou fungos: contudo, isto foi efectuado apenas para substituir a população microbiana que constitui a flora normalmente existente no intestino e que foi destruída pelo tratamento antibiótico.It has already been proposed to administer several bacteria or fungi simultaneously: however, this was done only to replace the microbial population that constitutes the flora normally existing in the intestine and which has been destroyed by antibiotic treatment.
A presente invenção pretende apresentar novas composições contendo bactérias que se destinam não só à substituição da flora inicial mas também a evitar a destrui, ção da flora intestinal de ocorrência natural.The present invention aims to present new compositions containing bacteria that are intended not only to replace the initial flora but also to prevent the destruction of naturally occurring intestinal flora.
Assim, esta invenção refere-se mais particularmente à preparação de composições terapêuticas de admi nistração oral que contêm bactérias estritamente anaeróbicas, susceptíveis de produzirem -lactamases e reduzirem as acções indesejáveis das -lactaminas na flora intestinal humana, co mo por exemplo :Thus, this invention relates more particularly to the preparation of therapeutic compositions for oral administration which contain strictly anaerobic bacteria, capable of producing β-lactamases and reducing the undesirable actions of β-lactam in the human intestinal flora, such as:
Bacteroides Bacteroides Bacteroides Bacteroides Bacteroides Bacteroides fragilis melaninogenicus intermedius nonfragilis asaccharolyticus biviusBacteroides Bacteroides Bacteroides Bacteroides Bacteroides Bacteroides fragilis melaninogenicus intermedius nonfragilis asaccharolyticus bivius
Bacteroides disiensBacteroides disiens
Bacteroides oralisBacteroides oralis
Bacteroides ruminicolaBacteroides ruminicola
Bacteroides capillosusBacteroides capillosus
Bacteroides uniformisUniform bacteria
Clostridium butyricumClostridium butyricum
Fusobacterium nucleatum (Nord C.E. 1986 Rev. Infect Dis. 8-5 543,548).Fusobacterium nucleatum (Nord C.E. 1986 Rev. Infect Dis. 8-5 543,548).
Estas bactérias estão presentes na flora intestinal de parte da população humana saudável e não apresen tam qualquer toxicidade quando introduzidas no intestino das pessoas que as nao possuem.These bacteria are present in the intestinal flora of part of the healthy human population and do not present any toxicity when introduced into the intestines of people who do not have them.
De acordo com a invenção esta composição terapêutica é administrável oralmente algumas horas antes ou simultaneamente com o tratamento normal por uma^-lactamina. Esta administração pode ser repetida durante o tratamento comAccording to the invention, this therapeutic composition is administrable orally a few hours before or simultaneously with normal treatment with a β-lactamine. This administration can be repeated during treatment with
-lactamina.-lactamine.
Esta composição terapêutica deve ser usa da mais particularmente com um tratamento mo por exemplo :This therapeutic composition should be used more particularly with a hand treatment for example:
lactaminas colactam co
-penicilinas nomeadamente penicilina G e fenoximetilpenicilinas, meticilina e isoxazolilpenicilinas (por exemplo oxacilina e cloxacili na), aminopenicilinas (por exemplo ampicilina e amoxicilina), amidinopenicilinas (por exemplo pivmecilinam), carboxipenicilinas (por exemplo carbenicilina, ticarcilina), metoxicarboxjL penicilinas (por exemplo temocilina), acilureidopenicilinas (por exemplo Mezlocilina, Azlocilina, Piperacilina), acilpeni. cilinas, (por exemplo Apalcilina).-penicillins namely penicillin G and phenoxymethylpenicillins, methicillin and isoxazolylpenicillins (for example oxacillin and cloxacillin), aminopenicillins (for example ampicillin and amoxicillin), amidinopenicillins (for example pivmecylinam, for example, carboxycinyl, carboxyphenyl temocillin), acylureidopenicillins (e.g. Mezlocillin, Azlocillin, Piperacillin), acylpeni. cilinas, (for example Apalcilina).
-cefalosporinas por exemplo cefalotina, cefazolina, cefamandole, cefuroxima, cefotaxima, ceftizoxima, ceftazimidima, ceftriaxona.-cephalosporins for example cephalothin, cefazolin, cefamandole, cefuroxime, cefotaxime, ceftizoxime, ceftazimidime, ceftriaxone.
-monobactamas (com um anel azetidina), por exemplo aztreonam As estirpes bacterianas estritamente ana erobicas utilizadas de acordo com a invenção são, por exemplo, estirpes produtoras dep)-lactamases pertencentes ao género Bacteroides.-monobactams (with an azetidine ring), for example aztreonam The strictly anaerobic bacterial strains used according to the invention are, for example, dep producing strains) -lactamases belonging to the genus Bacteroides.
Para a determinação das estirpes susceptíveis de produzirem β -lactamases, pode utilizar-se o seguin te ensaio in vitro. Neste ensaio, adiciona-se uma solução que supõe conter uma actividade-lactamase a um excesso conhecido de-lactamina e doseia-se a^-lactamina resudual (Rolfe RD e col. J. Infect. Dis. 147, 227, 1983).For the determination of strains capable of producing β-lactamases, the following in vitro assay can be used. In this assay, a solution is added that is supposed to contain a lactamase activity to a known excess of -lactamine and dosed with residual β-lactamine (Rolfe RD et al. J. Infect. Dis. 147, 227, 1983).
Após este ensaio seleccionam-se as estir pes que apresentam uma actividade enzimática de pelo menosAfter this test, strains that have an enzymatic activity of at least
ΓΓ
0,02yzmole de cefaloridina/minuto/mg de proteína.0.02yzmole of cephaloridine / minute / mg of protein.
Podem isolar-se as estirpes que produzem -lactamases de fazes humanas.Strains that produce human-lactamase can be isolated.
As estirpes bacterianas estritamente ana eróbicas e não-patogénicas productoras de-lactamases podem apresentar-se em forma liofilizada a adicionar extemporaneamente a um veículo oralmente absorvível antes da administração. As apresentações alternativas incluem, com veículos adequados se necessário, cápsulas de gelatina, comprimidos ou produtos semelhantes. Para evitar a destruição das bactérias no estômago, as referidas apresentações podem compreender um veículo anti-ácido e/ou um revestimento entérico.Strictly anaerobic and non-pathogenic bacterial strains producing de-lactamases can be presented in lyophilized form to be added extemporaneously to an orally absorbable vehicle prior to administration. Alternative presentations include, with suitable carriers if necessary, gelatin capsules, tablets or similar products. To prevent the destruction of bacteria in the stomach, said presentations may comprise an antacid vehicle and / or an enteric coating.
No homem, as doses de administração por via oral contêm entre cerca de 10 a 10 células bacterianas vivas.In humans, doses of oral administration contain between 10 and 10 live bacterial cells.
A actividade das composiçoes, de acordo com a invenção foi evidenciada em ratos heteroxênicos tratados com ceftriaxona. Previamente, obtiveram-se estirpes da bactérias produtoras de fy -lactamase a partir de amostras de fezes humanas e utilizaram-se as culturas produzidas destas bactéri as para administração. Descreve-se em seguida com maior detalhe esta experimentação :The activity of the compositions, according to the invention, was evidenced in heteroxenic rats treated with ceftriaxone. Previously, strains of fy-lactamase-producing bacteria were obtained from human feces samples and cultures produced from these bacteria were used for administration. This experiment is described in more detail below:
1,- Obtenção de estirpes bacterianas estritamente anaerôbicas productoras de ^-lactamases.1, - Obtaining strictly anaerobic bacterial strains that produce ^ -lactamases.
Isolaram-se fezes de indivíduos saudáveis em condições estritamente anaerôbicas. Em cada indivíduo iden tificaram-se os clones dominantes e mediu-se a actividade ^(-lactamase in vitro das estirpes isoladas.Stool was isolated from healthy individuals in strictly anaerobic conditions. In each individual the dominant clones were identified and the β (- lactamase) activity of the isolated strains was measured in vitro.
Detectaram-se as/¾-lactamases por meio de um ensaio microbiológico semi-quantitativo descrito por Rolfe RD e col. (J. Infect. Dis. 147, 227, 1983). Mede-se a actividade numa escala arbitrária de 0+ a 4+. A actividade máxima de-lactamase é classificada como 4+. As actividades intermédias classificadas como 3+, 2+, 1+ correspondem a uma hidrólise parcial do antibiótico. 0+ é considerado como an sência de actividade^-lactamase. Utilizaram-se neste ensaio o Meio Gelose 5 (Difco ) e a estirpe de controlo B. subtilis ATCC6633./ ¾-lactamases were detected by means of a semi-quantitative microbiological assay described by Rolfe RD et al. (J. Infect. Dis. 147, 227, 1983). Activity is measured on an arbitrary scale from 0+ to 4+. Maximum de-lactamase activity is rated 4+. Intermediate activities classified as 3+, 2+, 1+ correspond to a partial hydrolysis of the antibiotic. 0+ is considered as an absence of β-lactamase activity. Medium Gelose 5 (Difco) and the control strain B. subtilis ATCC6633 were used in this assay.
Incubaram-se as amostras fecais durante 30 minutos a 37QC com uma concentração antibiótica perfeitamente conhecida :Fecal samples were incubated for 30 minutes at 37 ° C with a well-known antibiotic concentration:
Amoxicilina, Amoxicilina + ácido clavulânico, Ticarcilina, Ce fotaxima, Ceftriaxona ou Cefoperazona e doseou-se a actividade antibiótica residual.Amoxicillin, Amoxicillin + clavulanic acid, Ticarcillin, Ce fotaxima, Ceftriaxone or Cefoperazone and the residual antibiotic activity was dosed.
A tabela I seguinte apresenta os resul tados da actividade das estirpes seleccionadas. Os numeros que aparecem são as percentagens de hidrólise dos vários antibióticos de/h -lactamina.Table I below shows the results of the activity of the selected strains. The numbers that appear are the hydrolysis percentages of the various / h-lactam antibiotics.
(*) Os resultados são expressos como percentagem de hidrólise após 30 minutos de incubação a 372C.(*) Results are expressed as percentage of hydrolysis after 30 minutes of incubation at 37 ° C.
o W H H O o cn ϋo W H H O o cn ϋ
ϋ Mϋ M
PERFIS DE SUBSTRATOS/^ -LACTAMASE DE EXTRACTOS DE 10 CLONES DE ANAERÓBICOS ANDOGÉNOSSUBSTRATE PROFILES / ^ -LACTAMASE OF EXTRACTS FROM 10 ANDOGENIC ANAEROBIC CLONES
Foi também determinada _a actividade de β-lactamase de acordo com um método espectrofotométrico (D* Callaghan e col. Antimicrobial Agents Chemotherapy 1, 283, 1972) e os resultados correspondentes são apresentados na tabela II seguinte :Β-lactamase activity was also determined according to a spectrophotometric method (D * Callaghan et al. Antimicrobial Agents Chemotherapy 1, 283, 1972) and the corresponding results are shown in Table II below:
TABELA IITABLE II
ACTIVIDADE β -LACTAMASE DE EXTRACTOS BACTERIANOSΒ-LACTAMASE ACTIVITY OF BACTERIAL EXTRACTS
de cefaloridina/mn/mg de proteína)cephaloridine / mn / mg protein)
Retem-se apenas as estirpes que apresentam uma actividade^ -lactamase 0,02 ^umole de cefaloridina/ /minuto/mg das proteínas bacterianas totais.Only strains that exhibit 0.02 µmol cephaloridin / / minute / mg of total bacterial proteins are retained.
2.- Evidenciação das propriedades das estirpes isoladas de fezes humanas em ratos associados com a flora fecal humana.2.- Evidence of the properties of strains isolated from human feces in rats associated with human fecal flora.
ιι
a) Associação de quatro estirpes anaeróbicas produtorasde β -lactamase e tratamento por ceftriaxona :a) Association of four anaerobic strains producing β-lactamase and treatment with ceftriaxone:
Guardam-se ratos sem germes (axénicos) C3H (Centre de Selection des Animaux de Laboratoires, Orléans, França), num isolador de plástico flexível. Como bebida, eles bebem apenas água esterilizada pelo calor a pH 3. 0 alimento é um produto comercialmente disponível (R03, Villemoisson/Orge, França) esterilizado por irradiação a 4 megarad.C3H (axenic) germ-free mice (Center de Selection des Animaux de Laboratoires, Orléans, France) are stored in a flexible plastic insulator. As a beverage, they drink only water sterilized by heat at pH 3. The food is a commercially available product (R03, Villemoisson / Orge, France) sterilized by irradiation at 4 megarad.
A estes ratos estão associados três estirpes de bacteróides e um de clostridium :These rats are associated with three strains of bacteroids and one of clostridium:
Antes do tratamento por ceftriaxona, não se encontra uma actividadey^)-lactamase (0+) enquanto se pode observar uma implatação de estirpes bacterianas a 1(ίΧθ’ — — 0’3X)ufg/g de fezes. Quando os mesmos ratos recebsn ceftriaxona per os (adicionada a água a uma dose de 2 mg/ml), as contagens totais não são modificadas e não se detecta actividade enzima tica mas o antibiótico não ê detectável nas fezes.Before treatment with ceftriaxone, there is no activity ^ ^ - lactamase (0+) while an implantation of bacterial strains at 1 (ί Χ θ '- - 0' 3X ) ufg / g of feces can be observed. When the same rats receive ceftriaxone per os (water is added at a dose of 2 mg / ml), the total counts are not modified and no enzyme activity is detected but the antibiotic is not detectable in the stool.
b) Acção da introdução de estirpes produtoras àe. β-lactamases de anaeróbios em ratos com uma flora intestinal humana e tratados por ceftriaxona :b) Action for the introduction of strains producing ae. Anaerobic β-lactamases in rats with human intestinal flora and treated with ceftriaxone:
Associaram-se também ratos axénicos a uma flora humana complexa. A preparação da solução alimentar é fei. ta numa câmara anaeróbica a partir de fezes humanas recente mente recolhidas. Moi-se a amostra, dilui-se 100 vezes em meio LCY e coloca-se a preparação no isolador contendo os ratos axé nicos. Para evitar qualquer contacto desta solução bacteriana com oxigénio, utilizam-se tubos hermeticamente fechados para colocar a mesma na câmara anaeróbica. Tal como efectuado anteriormente, os ratos previamente submetidos a jejum hídrico fo ram alimentados por via gástrica e rectal.Axenic rats were also associated with a complex human flora. The preparation of the food solution is done. in an anaerobic chamber from human feces recently collected. The sample is ground, diluted 100 times in LCY medium and the preparation is placed in the isolator containing the axonic rats. To avoid any contact of this bacterial solution with oxygen, hermetically sealed tubes are used to place it in the anaerobic chamber. As previously performed, the rats previously subjected to water fasting were fed gastric and rectally.
i <i <
Repete-se a alimentação após 24 horas. São necessários dez a quinze dias para se obter o equilíbrio intestinal com efeitos de barreira semelhantes aos encontrados no homem.Feeding is repeated after 24 hours. It takes ten to fifteen days to achieve intestinal balance with barrier effects similar to those found in man.
Inoculam-se ratos associados com flora humana intragastricamente com 1 ml de caldo TGY (Tripticase 30 g/1, extracto de fungo 20 g/1, glicose 5 g/1, tioglicolato de sódio 1 g/1, pH = 7,4) contendo 5x10 cfu/ml de 4 estirpes productoras ά&β-lactamase (Cl, C6, E9, V4E3) imediatamente antes da administração oral de Ceftriaxona (2 mg/ml na água de beber). Apresentam-se os resultados obtidos na tabela III.Rats associated with human flora are inoculated intragastrically with 1 ml of TGY broth (Tripticase 30 g / 1, fungus extract 20 g / 1, glucose 5 g / 1, sodium thioglycolate 1 g / 1, pH = 7.4) containing 5x10 cfu / ml of 4 ά & β-lactamase producing strains (Cl, C6, E9, V4E3) immediately before oral administration of Ceftriaxone (2 mg / ml in drinking water). The results obtained are shown in table III.
Durante o tratamento, não se encontra concentração de antibiótico nas fezes. Encontra-se actividadefy-lactamase contra ceftriaxona após 14 dias de tratamento (compreendida entre 1+ e 4+).During treatment, there is no concentration of antibiotics in the stool. Fy-lactamase activity against ceftriaxone is found after 14 days of treatment (between 1+ and 4+).
As enterobactérias susceptíveis à ceftria zona são eliminadas. As contagens de enterococos são equivalen tes às encontradas em controlos não tratados, Mantem-se a resistência a uma colonização por microorganismos exógenos resis tentes ã ceftriaxona (Ent. cloacae IGR67, C. albicans IGR66) em ratos em que se introduziram previamente estirpes bacteróides.Enterobacteria susceptible to the cephatric zone are eliminated. Enterococcal counts are equivalent to those found in untreated controls. Resistance to colonization by exogenous microorganisms resistant to ceftriaxone (Ent. Cloacae IGR67, C. albicans IGR66) is maintained in rats in which bacteroid strains were previously introduced.
As bactérias anaeróbicas estão ainda presentes no grupo que recebeu bacteróides e as contagens totais obtidas em camara anaeróbica não são significativamente modifi cadas pela presença destas bactérias, quando comparadas com os controlos. Os valores de MIC 50 e 90 destas bactérias são respectivamente de 512 e acima de 1024 yig de ceftriaxona por ml.' Os bacilos gram negativos perfazem 84 Ί desta flora e existem também 13 % de bacilos gram positivos esporulados e 3 aL de cocos.Anaerobic bacteria are still present in the group that received bacteroids and the total counts obtained in anaerobic chamber are not significantly modified by the presence of these bacteria, when compared to controls. The MIC 50 and 90 values of these bacteria are 512 and above 1024 yig of ceftriaxone per ml respectively. ' Gram negative bacilli make up 84 Ί of this flora and there are also 13% sporulated gram positive bacilli and 3 to L of coconuts.
método de identificação usando o sistema Api 20A permite a detecção entre estas estirpes de C. cios tridiformis e B. uniformis que apresentam as mesmas caracterís ticas das administradas imediatamente antes do início da Ceftriaxona.identification method using the Api 20A system allows the detection between these strains of C. cios tridiformis and B. uniformis that have the same characteristics as those administered immediately before the start of Ceftriaxone.
**
TABELA IIITABLE III
EFEITO DOS ANAERÓBIOS PRODUCTORES DE p -LACTAMASE NO IMPACTE ECOLÓGICO DA CEFTRIAXONA (2 mg/ml NA AÓUA DE BEBER) EM RATOS ASSOCIADOSEFFECT OF ANAEROBIC PRODUCERS OF p -LACTAMASE ON THE ECOLOGICAL IMPACT OF CEFTRIAXONE (2 mg / ml IN DRINKING WATER) IN ASSOCIATED RATS
COM FLORA HUMANAWITH HUMAN FLORA
k >*k> *
Média + SEM ufc/g de fezes (10 g) em 6 tomadasAverage + SEM cfu / g of feces (10 g) in 6 takes
Resultados sublinhados : diferenças significativas p ?0,5 * Valores extremos s = número de ratos ensaiados n = número de amostras fecais estudadasUnderlined results: significant differences p? 0.5 * Extreme values s = number of rats tested n = number of fecal samples studied
Em terapia humana, a administração é de cerca de 10 a cerca de 10 bactérias por dia de tratamento antibiótico sob a forma de cápsulas de gelatina gastrorresis tentes com revestimento entérico (cada cápsula de gelatina contem 5x10 bacteroides).In human therapy, administration is about 10 to about 10 bacteria per day of antibiotic treatment in the form of enteric coated gastroresis gelatin capsules (each gelatin capsule contains 5x10 bacteroids).
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FR8705110A FR2613624B1 (en) | 1987-04-10 | 1987-04-10 | ORAL ADMINISTRATIVE PHARMACEUTICAL COMPOSITION FOR REDUCING THE EFFECTS OF B-LACTAMINES |
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PT87190A PT87190A (en) | 1988-05-01 |
PT87190B true PT87190B (en) | 1992-08-31 |
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JP (1) | JPH01503537A (en) |
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FR (1) | FR2613624B1 (en) |
OA (1) | OA09023A (en) |
PT (1) | PT87190B (en) |
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FI920206A0 (en) * | 1992-01-17 | 1992-01-17 | Pekka Untamo Heino | MEDICINSK ANVAENDNING, MEDICINSKT FOERFARANDE OCH PREPARAT. |
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PT3650033T (en) | 2015-06-15 | 2022-05-25 | 4D Pharma Res Ltd | Compositions comprising bacterial strains |
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GB201520497D0 (en) | 2015-11-20 | 2016-01-06 | 4D Pharma Res Ltd | Compositions comprising bacterial strains |
MA41013A (en) | 2015-11-20 | 2017-08-30 | 4D Pharma Res Ltd | COMPOSITIONS CONTAINING BACTERIAL STRAINS |
GB201612191D0 (en) | 2016-07-13 | 2016-08-24 | 4D Pharma Plc | Compositions comprising bacterial strains |
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TW201821093A (en) | 2016-07-13 | 2018-06-16 | 英商4D製藥有限公司 | Compositions comprising bacterial strains |
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MA48939B1 (en) | 2017-05-22 | 2021-06-30 | 4D Pharma Res Ltd | Compositions comprising bacterial strains |
WO2018215782A1 (en) | 2017-05-24 | 2018-11-29 | 4D Pharma Research Limited | Compositions comprising bacterial strain |
HUE053488T2 (en) | 2017-06-14 | 2021-06-28 | 4D Pharma Res Ltd | Compositions comprising bacterial strains |
LT3638271T (en) | 2017-06-14 | 2021-01-11 | 4D Pharma Research Limited | Compositions comprising bacterial strains |
MD3600364T2 (en) | 2017-06-14 | 2020-12-31 | 4D Pharma Res Ltd | Compositions comprising a bacterial strain of the genus Megasphaera and uses thereof |
-
1987
- 1987-04-10 FR FR8705110A patent/FR2613624B1/en not_active Expired - Fee Related
-
1988
- 1988-04-07 ZA ZA882426A patent/ZA882426B/en unknown
- 1988-04-08 JP JP63503346A patent/JPH01503537A/en active Pending
- 1988-04-08 AU AU15786/88A patent/AU604117B2/en not_active Ceased
- 1988-04-08 PT PT87190A patent/PT87190B/en not_active IP Right Cessation
- 1988-04-08 EP EP88903277A patent/EP0309532A1/en not_active Withdrawn
- 1988-04-08 WO PCT/FR1988/000172 patent/WO1988007865A1/en not_active Application Discontinuation
- 1988-12-09 OA OA59487A patent/OA09023A/en unknown
Also Published As
Publication number | Publication date |
---|---|
PT87190A (en) | 1988-05-01 |
ZA882426B (en) | 1988-09-28 |
AU1578688A (en) | 1988-11-04 |
FR2613624A1 (en) | 1988-10-14 |
JPH01503537A (en) | 1989-11-30 |
AU604117B2 (en) | 1990-12-06 |
EP0309532A1 (en) | 1989-04-05 |
WO1988007865A1 (en) | 1988-10-20 |
FR2613624B1 (en) | 1990-11-23 |
OA09023A (en) | 1991-03-31 |
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