GB2292884A - Rifamycin & bismuth salts for treating bacterial infections - Google Patents
Rifamycin & bismuth salts for treating bacterial infections Download PDFInfo
- Publication number
- GB2292884A GB2292884A GB9418345A GB9418345A GB2292884A GB 2292884 A GB2292884 A GB 2292884A GB 9418345 A GB9418345 A GB 9418345A GB 9418345 A GB9418345 A GB 9418345A GB 2292884 A GB2292884 A GB 2292884A
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- United Kingdom
- Prior art keywords
- bismuth
- rifampicin
- rifamycin
- bismuth salt
- antibiotic
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- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
- A61K33/245—Bismuth; Compounds thereof
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Inorganic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Staphylococcal or pseudomonal infections are treated by the separate or simultaneous administration of a bismuth salt (e.g. bismuth subcitrate, subnitrate or subsalicylate) and a rifamycin antibiotic. The compositions are particularly useful in nosocomial wound or urinary tract infections.
Description
ANTIMICROBIAL COMPOSITION
TECHNICAL FIELD OF THE INVENTION
The present invention relates to antimicrobial pharmaceutical compositions and uses thereof for the treatment or prevention of staphylococcus infections. More particularly the invention relates to antimicrobial pharmaceutical compositions containing a bismuth salt and a rifamycin antibiotic agent for the treatment or prevention of staphylococcus infections.
BACKGROUND OF THE INVENTION
Staphylococcus aureus is encountered as a normal inhabitant of human skin and mucous membranes. However, it is responsible for a variety of clinical disorders in man and in animals ranging from pustules to fulminating septicemia.
The rifamycin antibiotic agents, such as rifabutin, rifamide, rifamycin sodium, rifapentine, rifaximin and rifampicin are complex macrocyclic antibiotics based on natural products of Streptomyces mediterranei. They inhibit bacterial RNA synthesis by binding to DNA-dependent RNA polymerase. Rifampicin (chemically 3-4(4-methylpiperazinyliminomethylidene)-rifamycin SV) is an extremely efficient inhibitor of the bacterial enzyme. It inhibits the growth of most gram-positive bacteria, as well as many gram-negative microorganisms and mycobacteria.
Rifamycin antibiotics, especially rifampicin, have been used frequently for therapy of selected staphylococcal infections in animals and humans. In vitro rifampicin is extremely active against staphylococci, the growth is usually inhibited by rifampicin concentrations < 0.03 I,lg/ml. However, mutants resistant to rifampicin can be detected both in vitro and in vivo amongst most of the bacteria usually sensitive to rifampicin. For example S. aureus has a propensity to rapidly acquire resistance to rifampicin after exposure to the agent as monotherapy. The resistance is usually the result of one-step mutation which alters the ss-subunit of RNA-polymerase, reducing its binding affinity for rifampicin.
The rapid development of resistance when rifampicin is used alone is a serious problem and greatly limits the usefulness of rifampicin in the treatment of e.g. S. aureus infections. The successful use of rifampicin in e.g.
serious staphylococcal infections depends on the elimination of resistant variants present in the bacterial population.
To overcome the problem of rapid emergence of resistant bacteria during a treatment with rifampicin alone in S. aureus infections, combinations with other antibiotics are recommended although they do not necessarily inhibit the development of resistant mutants.
Further, of the various antibiotics tested with rifampicin only nafcillin, novobiocin and teicoplanin have been found to suppress the emergence of rifampicin resistance in S.
aureus (Eng et al., J. Antimicrob. Chemother., 1985, 15, pp 201-207 and Dixson et al., Eur. J. Clin. Microbiol., 1985; 4/1, 19-23).
Colloidal bismuth subcitrate and bismuth subsalicylate have been found to be useful in combination with nitroimidazole by preventing the development of acquired nitroimidazole resistance of Helicobacter pylori (Axon,
A.T.R., J. Gastroenterol. Hepatol., 1991, 6/2, 131-137).
In vitro synergistic activity of the combination of bismuth subcitrate and rifampicin against Helicobacter pylori has been demonstrated. (D.L. Van Caekenberghe, J.
Breyssens; Antimicrobial Agents and Chemotherapy, 1987, 31/9: 1429-1430).
There are no reports concerning the effect of bismuth salts on the development of resistance against antibiotics in staphylococci.
DISCLOSURE OF THE INVENTION
The purpose of this invention is to overcome the problem of rapid development of rifampicin resistance in
Staphylococcus by combining a bismuth salt with a rifamycin antibiotic agent. Further the purpose of this invention is to prepare antimicrobial pharmaceutical compositions containing a rifamycin antibiotic and a bismuth salt and thereby to inhibit the development of resistance.
When bismuth subcitrate was combined with rifampicin, it was unexpectedly found that the development of resistance against rifampicin was suppressed or totally inhibited among S. aureus whereby the effective doses of these substances could be decreased noticeably.
Thus, the present invention provides an antimicrobial pharmaceutical composition comprising a rifamycin antibiotic agent and a bismuth salt in an amount suppressing the development of rifampicin resistance in
Staphylococcus.
Staphylococcus infections which may be treated are preferably local rather than systemic infections and include e.g. S. aureus, and S. epidermis.
The pharmaceutical compositions according to the invention include for example granulates, tablets, capsules, dragees, powders, ointments, gels, emulsions, suspensions and infusions (solutions) and can be administered for example orally, rectally, topically or by bladder infusion. Both agents are preferably administered concurrently, but the pharmaceutical effect of the present composition will be present if both agents exist concurrently for a certain duration in the body, particularly at the infection site. For example, the second of the two agents to be administered may be administered within the metabolic half life at the infection site of the first agent to be administered. So, the bismuth salt can be administered sequentially, separately or simultaneously with the rifamycin antibiotic.
These two agents can be administered via different routes, for example the rifamycin antibiotic orally and the bismuth salt topically.
The pharmaceutical compositions according to the invention may be formulated and employed in the usual manner. These compositions are particularly well-suited for ophthalmic, otic or topical uses (gels, ointments, powders, sprays and aqueous or oily emulsions and suspensions), but could also find other applications. However, topical use of bismuth salts is preferred. Systemic treatment of infections with bismuth salts is not recommended because of the possibility of serious side effects. Nausea and vomiting as well as darkening of the tongue have been reported. Further, the possibility of bismuth encephalopathy exists after prolonged use (Martindale, The
Extra Pharmacopoeia, ed. by James E.F. Reynolds, 30th ed.
The Pharmaceutical Press, London, 1993, p. 909).
The concentration of a bismuth salt in a pharmaceutical preparation containing also rifamycin should be in the range of 5 - 3000 Ug/ml e.g. 5 to 400 Ug/ml. The effect is not concentration dependent and at low bacterial densities even a relatively low bismuth salt concentration may be sufficient. In topical ointments, powders, gels rinsing solutions, eye and ear drops and wound dressings etc. the weight ratio of a bismuth salt to rifamycin is preferably between 1:0.0003 - 1:50 e.g. 1:0.0003 to 1:20, particularly 1:0.0003 to 1:0.625.
The pharmaceutical compositions containing the active combination may also be used in veterinary medicine.
Further, the compositions according to the present invention are applicable also in the treatment of certain infections caused by either Staphylococcus or Pseudomonas such as hospital infections which in many instances are extremely resistant to antibiotics. The most common hospital infections are the urinary tract and wound infections where the causative agent is often Ps.
aeruginosa or S. aureus. Because of the possibility that these two bacteria are simultaneously present at the infection site, the use of the present combination is especially advantageous for the treatment of this kind of infections / these kinds of infection.
In veterinary clinical praxis a common disease in dogs is otitis externa which is often caused by Ps. aeruginosa or S. aureus. Because of the difficulty of reliable laboratory diagnosis, it is advantageous to treat the infection with the present combination which has a good effect on both types of bacteria.
Examples of bismuth salts which may be used in accordance with the present invention include bismuth subcitrate, bismuth subnitrate and bismuth subsalicylate.
Bismuth subcitrate is preferred.
The following examples are presented to further illustrate the present invention. They should not be interpreted as limiting the scope of the invention in any way.
EXAMPLE 1
Comparison of the number of Staphylococcus resistant to rifampicin recovered after exposure in MH-broth to rifamricin, rifampicin + bismuth subcitrate. bismuth subcitrate and nil.
Twelve strains of S. aureus were used in the experiment. Strain 1 (FRI-1104) was obtained from Food
Research Institute (FRI), Madison, USA and strains 2 - 12 (ATCC-12600, ATCC-8096, ATCC-25923, ATCC-25178, ATCC-8095,
ATCC-27664, ATCC-13565, ATCC-19095, ATCC-14458, ATCC-27154 and ATCC-6538) were obtained from American Type Culture
Collection (ATCC), Maryland, USA. All strains were tested by the broth microdilution method for sensitivity of rifampicin. The minimum inhibitory concentration (MIC) was for all strains < 0.008 pg/ml. The strains were similarly tested for their sensitivity of bismuth subcitrate. The MIC for strain 5 was found to be 800 Sg/ml and for the others the MIC-values were > 3200 pg/ml.
The success rate of developing rifampicin resistance after exposure to rifampicin, rifampicin together with bismuth subcitrate, bismuth subcitrate or nil was performed by suspending S. aureus organisms to a density of about 1-10' cfu/ml in Mueller-Hinton (MH) broth containing 0.1 Ug/ml rifampicin, 0.1 ssg/ml rifampicin together with 400 pg/ml bismuth subcitrate, 400 ssg/ml bismuth subcitrate or no additions, respectively. After incubating 18 h at 370C, an amount of 0,1 ml of each incubation mixture was quantitatively subcultured on plain MH-agar and on MH-agar containing 0.1 or 1 ,ug/ml rifampicin. The number of viable organisms which appeared on the agars after an overnight incubation at 37 "C was determined.
The results are summarized in tables 1 and 2. The first column (rif) in both tables shows the log cfu/ml of the 12 strains of S. aureus resistant to either 0.1 Fg/ml (table 1) or 1 Fg/ml (table 2) rifampicin recovered after exposure to 0.1 wg/ml rifampicin for 18 h over the log cfu/ml of total viable organisms. The second column (rif+bic) shows correspondingly the log cfu/ml of the resistant organisms over the log cfu/ml of the total viable organisms after exposure to 0.1 ,wg/ml rifampicin together with 400 ,ug/ml bismuth subcitrate.
The third column (bic) shows the log cfu/ml of the rifampicin resistant staphylococci over the log cfu/ml of the total viable organisms after exposure to 400 ,ug/ml bismuth subcitrate only. And the fourth column (nil) shows the log cfu/ml of the rifampicin resistant organisms over the log cfu/ml of the total viable organisms after exposure only to MH-broth.
The success rate of development of rifampicin resistance after the various exposures (results given in tables 1 and 2) shows that all the 12
S. aureus strains developed resistance against both 0.1 ,eg/ml and 1 eg/ml rifampicin after 18 h exposure to 0.1 ,wg/ml rifampicin. The fact that the bacteria did not die during the exposure although their MICs of rifampicin were as low as < 0.008 ,eg/ml can be partly explained by the well known inoculum effect (Chapman, R. and Steigbiegel, R., 1975, J. Infect .Dis., 147, 156 - 163). The
MIC-values were obtained with an inoculum of 105 cfu/ml while the initial bacterial density in the exposure studies was about 1010 cfu/ml.When studying the first (rif) and the second (rif+bic) columns in tables 1 and 2 it can be seen that the emergence of rifampicin resistance was suppressed when the bacteria were exposed to both rifampicin and bismuth subcitrate. The exposure of bismuth subcitrate alone did not significantly affect the total number of vialble organisms or have any clear effect on the number of rifampicin resistant organisms. The comparison of the second (rif+bic) and the fourth (nil) columns in the tables shows that among most of the strains (except perhaps strains 11 and 12) the development of new resistant organisms was possibly totally inhibited by bismuth subcitrate.
The mechanism behind the effect of bismuth subcitrate remain obscure.
Rifampicin resistance is primarily caused by alteration in the bacterial RNApolymerase (Wehrli, W., 1983, Rev. Infect. Dis., 5 (suppl.3), 407 - 411).
A change of one amino acid in the subuhit causes resistance. This change is apparently inhibited by bismuth salt.
The effects of bismuth subcitrate were measured by using a maximum bismuth subcitrate concentration of 400 Fg/ml on a bacterial density of about 1010 cfu/ml. Higher concentrations were avoided because they could have generally suppressed the growth of staphylococci. To have an effect on the development of resistance bismuth salt must apparently react with the individual bacteria. The concentration of bismuth salt that is required for the effect seen thus obviously depends also on the number of bacteria in the study medium. Further, even relatively low bismuth subcitrate concentrations can suppress the emergence of resistance among staphylococci if the density of bacteria in the study system is low enough.
Table 1.
Strain Number of rifampicin resistant organisms / total No: number of organisms after exposure to (log cfulml) rif rif+bic bic 1 7.1 / 9.4 4.9 110.3 2.8 /10.3 5.5/ 10.6 2 3.6110.4 1.8 / 9.4 1.2 / 9.3 2.9/10.4 3 5.2 /10.2 2.4 /10.0 2.9 / 9.9 3.8/10.2 4 7.2 /10.5 2.9 /10.3 2.8 /10.3 3.2/10.3 5 5.5 /7.1 1.2 /6.7 1.4 /6.0 2.1/6.5 6 7.2 /10.6 3.2 /10.4 3.0 /10.3 3.4/10.6 7 4.8 /10.3 2.1 /10.0 2.0/9.7 2.8/10.2 8 6.9/10.3 2.4/10.2 2.1/10.1 3.0/10.2 9 6.5 / 10.0 3.4 /9.8 2.1 / 9.5 2.9 19.6 10 3.8/10.4 2.5/9.6 1.9 / 9.6 2.9/10.2 11 7.6 /10.3 5.7 /9.9 2.4 /10.1 2.9/10.3 12 10.4 / 10.4 4.4/10.2 2.5/10.2 3.1/10.5 Table 2.
Strain Number of rifampicin resistant organisms I total No: number of organisms after exposure to (logcki/ml) rit if + bic bic nil 1 7.119.4 4.2 110.3 2.4 /10.3 5.1 110.6 2 3.5 /10.4 1.4 /9.4 1.3 /9.3 2.8 J10.4 3 3.0 /10.2 1.9 /10.0 2.7 /9.9 3.5 /10.2 4 7.2 /10.5 2.4 /10.3 2.4 /10.3 2.7 /10.3 5 5.6 /7.1 1.2 /6.7 2.2 /6.0 2.0 16.5 6 7.0 /10.6 2.8 /10.4 2.4 /10.3 3.1 /10.6 7 4.9 /10.3 1.2 /10.0 1.3/9.7 2.4110.2 8 6.8/ 10.3 2.6 /10.2 1.8 110.1 2.7/102 9 6.4 /10.0 3.4 /9.8 1.0 /9.5 2.3 /9.6 10 2.9 /10.4 2.3 /9.6 1.4 19.6 2.7 /10.2 11 7.6 /10.3 5.8 /9.9 2.3 /10.1 2.7 /10.3 12 3.1 /10.4 ND/10.2 2.3 /10.2 2.6 /10.5 EXAMPLE 2
Concentration dependence
To study the effect of the concentration of bismuth subcitrate on the development of rifampicin resistance in S. aureus strain 4 was suspended and incubated in MH-broth as discribed in example 1. The broth contained either no addition or 0.1 ,ltg/ml rifampicin or 0.1 g/ml rifampicin and 50, 100, 200 or 400 Fg/ml bismuth subcitrate. An amount of 0.1 ml of each incubation mixture was quantitatively subcultured on MH-agar as described in example 1 except that plates containing 0.1 ,gg/ml rifampicin were omitted. The number of viable organisms after an overnight incubation at 37 C was determined.
The comparative effect of 5 different bismuth subcitrate concentrations (0, 50, 100, 200 and 400 Fg/ml ) on the development of rifampicin resistance in S. aureus strain 4 during an overnight incubation with 0.1 ,wg/ml rifampicin in MH-broth is presented in table 3.
The results in table 3 do not show any concentration dependent effect of bismuth subcitrate on the development of resistance to rifampicin on S.
aureus. These results further show that the number of organisms resistant to rifampicin after overnights exposure to 0.1 Wg/ml rifampicin plus 50 - 400 Fg/ml bismuth subcitrate do not significantly differ from the number of resistant organisms recovered after overnights incubation in the plain MH-broth. This suggests that bismuth subcitrate totally inhibited the development of rifampicin resistance due to rifampicin exposure on the studied S. aureus strain.
Table 3.
Exposure Number of rifampicin resistant / total number of organisms (log cfu/ml) Rif 8.6 / 10.6 Rif + 50 lig/ml BiC 2.7 / 10.6 Rif + 1001lg/ml BiC 3.0 10.4 Rif + 200 rg/ml BiC 2.6 / 10.3 Rif + 400 g/ml BiC 2.6 / 10.5 plain MH-broth 2.9 /10.6 EXAMPLE 3
Ointment or gel formulation for the treatment of skin infections or wounds
A topical ointment or gel formulation according to the present invention is prepared by combining rifampicin (0.005 %) and bismuth subcitrate (0.02%) with an appropriate ointment or gel base and with necessary additives.
Claims (11)
1. A product which is an antimicrobial pharmaceutical composition comprising a rifamycin antibiotic and bismuth salt for use in the treatment of
Staphylococcus infections.
2. A product comprising (i) a rifamycin antibiotic and (ii) a bismuth salt as a combined preparation for simultaneous, separate or sequential use in the treatment or prevention of a Staphylococcus infection.
3. A product according to claim 1 or 2 wherein the bismuth salt is bismuth subcitrate, bismuth subsalicylate or bismuth nitrate.
4. A product according to claim 3 wherein the bismuth salt is bismuth subcitrate.
5. A product according to any one of claims 1 to 4 wherein the rifamycin antibiotic is rifampicin.
6. A product according to claim 5 wherein the ratio of bismuth salt to rifamycin antibiotic is from 1:0.0003 1:50.
7. A product according to any one of claims 1 to 6 wherein the bismuth salt is in a form suitable for administration simultaneously with the antibiotic agent.
8. A product according to any one of claims 1 to 6 wherein the bismuth salt is in a form suitable for administration separately from the antibiotic agent.
9. Use of a bismuth salt and a rifamycin antibiotic in the manufacture of a medicament for use in the treatment of a Staphylococcus infection.
10. A method of treatment or prevention of a
Staphylococcus infection comprising administering to a subject an effective amount of a bismuth salt and an effective amount of a rifamycin antibiotic.
11. A pharmaceutical or veterinary formulation comprising as active ingredients a rifamycin antibiotic and a bismuth salt formulated for pharmaceutical or veterinary use respectively.
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9418345A GB2292884A (en) | 1994-09-12 | 1994-09-12 | Rifamycin & bismuth salts for treating bacterial infections |
| AU33884/95A AU3388495A (en) | 1994-09-12 | 1995-09-12 | Antimicrobial composition |
| PCT/FI1995/000493 WO1996008258A1 (en) | 1994-09-12 | 1995-09-12 | Antimicrobial composition |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9418345A GB2292884A (en) | 1994-09-12 | 1994-09-12 | Rifamycin & bismuth salts for treating bacterial infections |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| GB9418345D0 GB9418345D0 (en) | 1994-11-02 |
| GB2292884A true GB2292884A (en) | 1996-03-13 |
Family
ID=10761198
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB9418345A Withdrawn GB2292884A (en) | 1994-09-12 | 1994-09-12 | Rifamycin & bismuth salts for treating bacterial infections |
Country Status (3)
| Country | Link |
|---|---|
| AU (1) | AU3388495A (en) |
| GB (1) | GB2292884A (en) |
| WO (1) | WO1996008258A1 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1057487A1 (en) * | 1998-02-24 | 2000-12-06 | Kaneka Corporation | Antimicrobial compositions with synergistic effect, drugs and remedies for digestive diseases containing the same, process for the production thereof and preparations associated therewith |
| RU2632766C1 (en) * | 2016-07-26 | 2017-10-09 | Общество с ограниченной ответственностью "Медико-инженерный центр + 16" | Antimicrobial tympanic shunt |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1057001A (en) * | 1991-07-13 | 1991-12-18 | 沈阳市红旗制药厂 | The preparation method of anti-enteritis capsule |
| EP0206625B1 (en) * | 1985-06-13 | 1992-09-30 | Barry James Dr. Marshall | Compositions for the treatment of gastrointestinal disorders |
| CN1080529A (en) * | 1992-06-23 | 1994-01-12 | 沈阳市光华兽药厂 | The manufacture method of dysentery medicine (Salibao) |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ATE158301T1 (en) * | 1993-06-28 | 1997-10-15 | Merck & Co Inc | 4-AZA-PREGNAN-5-ALPHA-REDUCTASE ISOZYME 1 INHIBITORS |
-
1994
- 1994-09-12 GB GB9418345A patent/GB2292884A/en not_active Withdrawn
-
1995
- 1995-09-12 WO PCT/FI1995/000493 patent/WO1996008258A1/en active Application Filing
- 1995-09-12 AU AU33884/95A patent/AU3388495A/en not_active Abandoned
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0206625B1 (en) * | 1985-06-13 | 1992-09-30 | Barry James Dr. Marshall | Compositions for the treatment of gastrointestinal disorders |
| CN1057001A (en) * | 1991-07-13 | 1991-12-18 | 沈阳市红旗制药厂 | The preparation method of anti-enteritis capsule |
| CN1080529A (en) * | 1992-06-23 | 1994-01-12 | 沈阳市光华兽药厂 | The manufacture method of dysentery medicine (Salibao) |
Non-Patent Citations (5)
| Title |
|---|
| Antimicrob. Agents Chemother., Vol. 31(9), 1987, pp 1429-30 * |
| CAS ONLINE Abstract Accession No. 117:33698 & CN 1057001 A * |
| CAS ONLINE Abstract Accession No. 121:65580 & CN 1080529 A * |
| DIALOG: File 377 Abstract Accession No. 92-37481 & Clin. Res., Vol. 40, No. 2, 1992, p 428A * |
| Med. Microbiol. Lett., 3(3), 1994, pp 114-119 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1057487A1 (en) * | 1998-02-24 | 2000-12-06 | Kaneka Corporation | Antimicrobial compositions with synergistic effect, drugs and remedies for digestive diseases containing the same, process for the production thereof and preparations associated therewith |
| EP1057487A4 (en) * | 1998-02-24 | 2006-09-20 | Activbiotics Inc | Antimicrobial compositions with synergistic effect, drugs and remedies for digestive diseases containing the same, process for the production thereof and preparations associated therewith |
| RU2632766C1 (en) * | 2016-07-26 | 2017-10-09 | Общество с ограниченной ответственностью "Медико-инженерный центр + 16" | Antimicrobial tympanic shunt |
Also Published As
| Publication number | Publication date |
|---|---|
| GB9418345D0 (en) | 1994-11-02 |
| WO1996008258A1 (en) | 1996-03-21 |
| AU3388495A (en) | 1996-03-29 |
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| Date | Code | Title | Description |
|---|---|---|---|
| WAP | Application withdrawn, taken to be withdrawn or refused ** after publication under section 16(1) |