ZA200302270B - Antibiotic pharmaceutical composition with lysergol as bio-enhancer and method of treatment. - Google Patents
Antibiotic pharmaceutical composition with lysergol as bio-enhancer and method of treatment. Download PDFInfo
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- lysergol
- antibiotics
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- 230000003115 biocidal effect Effects 0.000 title claims description 53
- BIXJFIJYBLJTMK-UHFFFAOYSA-N Lysergol Natural products C1=CC(C2=CC(CO)CN(C2C2)C)=C3C2=CNC3=C1 BIXJFIJYBLJTMK-UHFFFAOYSA-N 0.000 title claims description 45
- BIXJFIJYBLJTMK-MEBBXXQBSA-N lysergol Chemical compound C1=CC(C2=C[C@@H](CO)CN([C@@H]2C2)C)=C3C2=CNC3=C1 BIXJFIJYBLJTMK-MEBBXXQBSA-N 0.000 title claims description 45
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 33
- 238000000034 method Methods 0.000 title claims description 19
- 239000003623 enhancer Substances 0.000 title description 6
- 239000003242 anti bacterial agent Substances 0.000 claims description 49
- 229940088710 antibiotic agent Drugs 0.000 claims description 42
- 150000001875 compounds Chemical class 0.000 claims description 27
- 230000000694 effects Effects 0.000 claims description 19
- 239000000203 mixture Substances 0.000 claims description 16
- 230000002829 reductive effect Effects 0.000 claims description 14
- 241000196324 Embryophyta Species 0.000 claims description 12
- JQXXHWHPUNPDRT-WLSIYKJHSA-N rifampicin Chemical compound O([C@](C1=O)(C)O/C=C/[C@@H]([C@H]([C@@H](OC(C)=O)[C@H](C)[C@H](O)[C@H](C)[C@@H](O)[C@@H](C)\C=C\C=C(C)/C(=O)NC=2C(O)=C3C([O-])=C4C)C)OC)C4=C1C3=C(O)C=2\C=N\N1CC[NH+](C)CC1 JQXXHWHPUNPDRT-WLSIYKJHSA-N 0.000 claims description 8
- 229960001225 rifampicin Drugs 0.000 claims description 8
- 230000002195 synergetic effect Effects 0.000 claims description 8
- 244000063299 Bacillus subtilis Species 0.000 claims description 6
- 241000588724 Escherichia coli Species 0.000 claims description 6
- 241000187480 Mycobacterium smegmatis Species 0.000 claims description 6
- 239000004098 Tetracycline Substances 0.000 claims description 6
- 229960002180 tetracycline Drugs 0.000 claims description 6
- 229930101283 tetracycline Natural products 0.000 claims description 6
- 235000019364 tetracycline Nutrition 0.000 claims description 6
- 150000003522 tetracyclines Chemical class 0.000 claims description 6
- 235000014469 Bacillus subtilis Nutrition 0.000 claims description 5
- 208000035143 Bacterial infection Diseases 0.000 claims description 5
- 241000221760 Claviceps Species 0.000 claims description 5
- 241000111158 Convolvulus nodiflorus Species 0.000 claims description 5
- 241000233866 Fungi Species 0.000 claims description 5
- 241000235527 Rhizopus Species 0.000 claims description 5
- 208000022362 bacterial infectious disease Diseases 0.000 claims description 5
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- 241000207783 Ipomoea Species 0.000 claims description 4
- 235000021506 Ipomoea Nutrition 0.000 claims description 4
- 239000000654 additive Substances 0.000 claims description 4
- AVKUERGKIZMTKX-NJBDSQKTSA-N ampicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=CC=C1 AVKUERGKIZMTKX-NJBDSQKTSA-N 0.000 claims description 4
- 229960000723 ampicillin Drugs 0.000 claims description 4
- 230000000845 anti-microbial effect Effects 0.000 claims description 4
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- 230000002147 killing effect Effects 0.000 description 8
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- 238000003556 assay Methods 0.000 description 6
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- 238000002474 experimental method Methods 0.000 description 5
- 210000001035 gastrointestinal tract Anatomy 0.000 description 5
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Natural products OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 5
- 241000282414 Homo sapiens Species 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- 230000001404 mediated effect Effects 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 3
- 206010059866 Drug resistance Diseases 0.000 description 3
- 241000598138 Ipomoea muricata Species 0.000 description 3
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- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 231100000252 nontoxic Toxicity 0.000 description 3
- 230000003000 nontoxic effect Effects 0.000 description 3
- WVWHRXVVAYXKDE-UHFFFAOYSA-N piperine Natural products O=C(C=CC=Cc1ccc2OCOc2c1)C3CCCCN3 WVWHRXVVAYXKDE-UHFFFAOYSA-N 0.000 description 3
- MXXWOMGUGJBKIW-YPCIICBESA-N piperine Chemical compound C=1C=C2OCOC2=CC=1/C=C/C=C/C(=O)N1CCCCC1 MXXWOMGUGJBKIW-YPCIICBESA-N 0.000 description 3
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- 244000203593 Piper nigrum Species 0.000 description 2
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- SAHHMCVYMGARBT-UHFFFAOYSA-N Isochanoclavine I Natural products C1=CC(C(C(NC)C2)C=C(C)CO)=C3C2=CNC3=C1 SAHHMCVYMGARBT-UHFFFAOYSA-N 0.000 description 1
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Description
ANTIBIOTIC PHARMACEUTICAL COMPOSITION WITH LYSERGOL AS BIO-
ENHANCER AND METHOD OF TREATMENT
*
, 5 The invention relates to a synergistic antibiotic pharmaceutical composition with lysergol as bioactive enhancer and bioavailability facilitator for broad-spectrum antibiotics. The present invention has direct implication in reducing the dosage of antibiotics while increasing the efficiency of absorption of nutritional elements. The present invention also * provides a method of treatment for bacterial infections.
The consumption of antibiotics and drugs by man is increasing at an alarming rate. Out of the total drugs and chemicals, 20%-50% of that use is unnecessary depending on the class of antibiotic. In addition, indiscriminate use of antibiotics promotes antibiotic resistance leading to multiple drug resistance and makes it difficult to control the diseases. Really speaking, the infected individuals consume much more amount of antibiotics in the given dosage that is actually required to control a given population of parasite in the body. This may be due to (i) reduced absorption in the gut membrane when taken orally (it) restrictive uptake by the target microbe or (iii) operation of efflux pump leading to indiscriminate extrusion of the antibiotics or therapeutic molecules. So the major amount of the drugs we apply are wasted and only a minor percentage is being targeted to the infective microbes.
In addition, the unutilized drug / antibiotic amount remains as a load in the body and environment acting as a selection pressure facilitating emergence of drug resistance in parasites and their predominance, ultimately leading to failure of antibiotics against resistant infections. This also is responsible for side effects, illness and reduction in life expectancy. One of the ways, which has been feasible to reduce drug dosage, has been synergism between two therapeutic agents. However, if both have the antibiotic property, still the problem of continued selection pressure on microbes is likely to continue. So, we thought of searching only those molecules, which by them are not microbicidal but when present with a drug or active molecule, enhance its activity and availability (bioenhancers).
This way these molecules by their presence will not exert any selection pressure for mutants to emerge resistant against them and on the other hand could reduce the dosage of antibiotics or drugs so that their ill effects are minimized and the resistance development process will be substantially delayed ultimately leading to enhanced life-span of the novel and existing antibiotics. Such drug / molecule facilitators should have novel properties like non-toxic to human, animal or plants, should be effective at a very low concentration in a combination, should be easy to formulate and most importantly enhance uptake/absorption and activity of the drug molecules. This can lead in developing judicious and strategic concentrations of antibiotics with specific bioenhancers to improve availability of the drug right up to the target for effectively controlling the infectious organisms. The present invention was the result of planned experiments to provide a plant compound 'Lysergol' with novel properties for improving activity and bioavailability of antibiotics, drugs and other molecules in different formulations. The bioavailability enhancement of antibiotic effect is relevant to human, plant as well as animal health and thus the compositions and methods of the invention are also intended to be used in agriculture and veterinary practice.
Use of ayurvedic preparation "trikatu" dates back to the period between the seventh century B.C. and the sixth century A.D, which is a Sanskrit, word meaning three acrids. It refers to a combination of black pepper (Piper nigrum Linn.), long pepper (Piper longum
Linn.) and ginger (Zingiber officinale Rosc.). It is believed that the use of "trikatu", and its constituents individually as well as collectively, enhances the bioavailability of a number of drugs. In specific studies carried out on animals as well as human volunteers, it was noted that the active component responsible for the increase in bioavailability of various drugs was piperine (United States Patent 5,616,593 and 5,972,382). Till today thus, the known bio-availability enhancer documented is piperine and a series of inventions related to this compound have been described in the following prior arts. Though the compound piperine has been reported to be enhancing the bioavailability of drugs, nutrients and vitamins, still a proper formulation for the combination is yet to come to the market.
The present invention is to obtain a molecule with bioenhancing action of higher potency.
Thus a large numbers of the available extracts and known compounds are screened in the laboratory, particularly those by themselves possessing no antibacterial property. After extensive experimentation, it has been found that a plant compound lysergol enhanced the killing activities of different antibiotics on bacteria. The compound is isolated from genera of lower fungi: Claviceps, Penicillium and Rhizopus. From higher plants like Rivea corymbosa, Ipomoea violacea and Ipomoea muricata the compound is also isolated and well-defined isolation protocols are already available. The seeds of Ipomoea muricata are commonly known as ‘Kaladana’ in trade and are being used as purgative in Pakistan and
India. The seeds are a good source of clavine alkaloids. The seeds are reported to contain 0.49% of total alkaloid, out of which lysergol constitutes 53% and chanoclavine 37%.
Lysergol is used as hypotensive, psychotrophic, analgesic, immunostimulant, analeptic and
AMENDED SHEET
} uterus and intestine stimulating drug. Also, the compound is available commercially (Sigma Chemicals, USA).
The compound lysergol is chemically known as 9,10-Didehydro-6-methylergoline-8-0- methanol. Ergotamine and all compounds either structurally and/or pharmacologically similar to it like lysergol are SHT agonist vasoactive agents (United States Patent 6,077,539) that means ensure normal blood flow in blood vessels in a therapeutically effective amount.
This compound also is reportedly psychoactive causing nausea, which may be experienced during first hour. This compound also has hallucination and anti-tension properties.
Great emphasis now is being laid towards quality assurance of crude drugs from plants sources widely used in the Indian system of medicine. The scientific study of traditional medicines, derivation of drugs through bioprospection and systematic conservation, domestication and cultivation of the concerned medicinal plants has assumed great importance in the present day context when more and more people prefer safe and effective medicines at affordable price for curing their ailments. The present invention enlarges the scope and use of the natural plant compound lysergol in therapeutical applications.
A need exists to provide a non-toxic bioenhancer lysergol to be used in an antibiotic pharmaceutical composition.
Another need exists to provide a synergistic antibiotic pharmaceutical composition for the treatment of bacterial infections.
Yet another need exists to provide an antibiotic pharmaceutical composition having reduced concentration of antibiotic compounds.
A further need exists to provide an antibiotic pharmaceutical composition to prevent antibiotic drug resistance.
SUMMARY OF THE IVNENTION
The invention provides a synergistic pharmaceutical composition with lysergol as bio- enhancer of antibiotic action on the target. The molecule of invention helps in the absorption of antibiotics across the cell membrane in animal cells for action against gram positive and negative bacteria. The present invention also provides a method of treatment for bacterial infections.
Accordingly, the present invention provides a synergistic antibiotic pharmaceutical composition having enhanced bioactivity, said composition comprising:
(a) an antibiotic compound 0.2-20 pg/ml; (b) an effective amount lysergol 2-10pg/ml; and (c) optionally pharmaceutically acceptable additives.
An embodiment of the present invention, wherein the antibiotic is selected from the group consisting of rifampicin, tetracycline and ampicillin. ]
Yet another embodiment of the present invention, wherein the preferable dosage of lysergol is 10pg/ml.
Still another embodiment of the present invention, wherein the enhanced activity of antimicrobial effect is in the range of 2-12 folds.
Yet another embodiment of the present invention, wherein said composition is effective against broad-spectrum microbes both gram positive and negative, selected from the group consisting E.coli, Bacillus subtilis and Mycobacterium smegmatis and other similar microbes.
Further embodiment of the present invention, wherein lysergol is isolated from a genera of lower fungi consisting of Claviceps, Pencillium and Rhizopus and from the plants selected from Rivea corymbosa and ipomoea violace.
Yet another embodiment of the present invention, wherein lysergol enhances the transport of antibiotics across the intestinal gut and cell membrane for better efficacy on the target site.
Still another embodiment of the present invention, wherein the reduced dosage of antibiotics and the enhanced bioactivity of the composition reduces the ill effects of antibiotics.
Yet another embodiment of the present invention, wherein the resistance to antibiotics is substantially reduced due to reduced concentration of antibiotics.
The present invention also provides a method of treating bacterial infection, wherein administering to subject an effective amount of synergistic pharmaceutical composition, said composition comprising: (a) an antibiotic compound; (b) an effective amount lysergol 2-10pug/ml; and ) (c) optionally pharmaceutically acceptable additives.
An embodiment of the present invention, a method wherein the antibiotic is selected from the group consists of rifampicin, tetracycline and ampicillin.
Yet another embodiment of the present invention, a method wherein the preferable dosage of lysergol is [0pg/ml.
Still another embodiment of the present invention, a method wherein the enhanced activity of antimicrobial effect is in the range of 2-12 folds.
Further embodiment of the present invention a method wherein said composition is ' effective against broad-spectrum microbes both gram positive and negative, selected from 5 the group consisting E.coli, Bacillus subtilis and Mycobacterium smegmatis and other similar microbes.
Yet another embodiment of the present invention, a method wherein lysergol is isolated from genera of lower fungi consisting of Claviceps, Pencillium and Rhizopus and from higher plants selected from Rivea corymbosa and ipomoea violace.
Still another embodiment of the present invention, a method wherein lysergol enhances the transport of antibiotics across the intestinal gut and cell membrane for better efficacy on the target site.
Further embodiment of the present invention, a method wherein the reduced dosage of antibiotics and the enhanced bioactivity of the composition reduces the ill effects of antibiotics.
Still another embodiment of the present invention, a method wherein the resistance to antibiotics is substantially reduced due to reduced concentration of antibiotics.
Yet another embodiment of the present invention, a method wherein the subject is selected from mammals and humans.
The invention is further explained in the form of following embodiments. 1. Assay for bio-enhancement of anti-infective agents (a) The minimum inhibitory concentration (MIC) of antibiotic is determined against Escherichia coli (ATCC 10536), Bacillus subtilis (ATCC 6051) and
Mycobacterium smegmatis (ATCC 14468) in broth and disc diffusion assay. (b) The antibiotics at concentrations 1/4, 1/3, 1/2 and equal to MIC are added alone and in combination with the test compound at varying concentrations on disc and in broth to evaluate the comparative inhibition. (c) These combinations showing significant advantage or higher activity than ' antibiotic alone in terms of enhanced inhibition of bacterial growth (large inhibition zone in disc diffusion and effectivity of lower concentration in broth assay) are picked up for future testing. (d) In broth assay the activity is quantified by counting number of viable cells in a given treatment and converted in fold enhancement by combination compared to antibiotic / drug alone in the killing percentage of cells.
(e) The pretreatment assay followed to determine whether the compound is required along with antibiotic to enhance its activity or even its withdrawal after treatment or prior to antibiotic treatment would benefit. For this, the cells are treated with compound for 4 to 8 hours and then washed free of it by ) centrifugation and washing in sterile water. This is followed by treatment with antibiotic as in steps b to d.
Process for the isolation of lysergol.
The seeds of Ipomoea muricata are powdered and defatted with hexane and then extracted with methyl alcohol. The alcoholic extract is dried and extracted with 5-10% Hcl solution.
The acidic extract is then converted to basified upto pH 9.0 and extracted with chloroform and butanol successively. The crude alkaloid obtained in chloroform and butanol extract is further purified by column chromatography to yield lysergol in maximum yield upto 0.2%.
Bioactivity is experimented with the killing activities of different antibiotics against the bacteria singly and in combination with the test compound Lysergol following the method described above. These experiments are being described in the following examples. When the bacteria are grown in presence of the compound as such no significant killing is observed. In all the experiments the Lysergol concentration is kept at 10 pg/ml, unless it is specifically mentioned.
The invention is further explained in the form of examples. However, these examples should not be considered as limiting the scope of the invention.
Example 1
Lysergol mediated enhancement in the killing action of antibiotics against Gram negative bacterium Escherichia coli.
Table 1:
Antibiotics Concentration | Survival fraction of | Survival fraction of | *Fold pg/ml viable cells upon | viable cells upon | enhancement treatment with | treatment with | in antibiotic antibiotic alone antibiotic + lysergol | activity combination ’ *It is calculated as = Survival fraction of viable cells upon treatment with antibiotic and lysergol in combination / Survival fraction of viable cells upon treatment with antibiotic alone
\
Example 2.
Lysergol mediated enhancement in the killing action of antibiotics against Gram positive bacterium Bacillus subtilis. ) Table 2:
Antibiotics Concentration | Survival fraction | Survival fraction of | *Fold pg/ml of viable cells | viable cells upon | enhancement in upon treatment | treatment with | antibiotic with antibiotic | antibiotic + lysergol | activity alone combination *It is calculated as = Survival fraction of viable cells upon treatment with antibiotic and lysergol in combination / Survival fraction of viable cells upon treatment with antibiotic . alone
Example 3
Lysergol mediated enhancement in the killing action of antibiotics against bacterium
Mycobacterium smegmatis
Table 3:
Antibiotics Concentration | Survival fraction of | Survival fraction of | *Fold ug/ml viable cells upon | viable cells upon | enhancement treatment with | treatment with | in antibiotic antibiotic alone antibiotic + lysergol | activity combination
Rifampicin 0.2 0.45-0.54 0.09-0.10 4.5-6.0 *1t is calculated as = Survival fraction of viable cells upon treatment with antibiotic and lysergol in combination / Survival fraction of viable cells upon treatment with antibiotic alone ’ From the above experiments it is deduced that the potency of the antibiotic is increased ) against both Gram positive and negative bacteria when applied along with the compound lysergol.
Example 4
Lysergol mediated enhancement in the killing action of antibiotic against bacteria in disc diffusion assays.
AMENDED SHEET
Table 4:
Content of left arm Absorbency at 340 nm (for rifampicin) and 223 nm (for
Oh 2h Increase in | Fold increase ll cl A i 0 Cc CE
In other observations the compound lysergol enhances the transport of antibiotics e.g.
Rifampicin, Tetracycline across the gut as well as artificial membrane. We performed the experiments in U-shaped tubes with joint in between, where the freshly isolated gut membrane is fixed. In control tube only antibiotic solution (4ml @ 1mg/ml solution) is poured in the left arm where as in the right arm only water is poured. In the other tube in addition to the antibiotic solution lysergol (4pg @ lpg/ml) is added. Then changes in absorbency in the right arm of both the tubes are noted at 340nm (for rifampicin) and 223nm (for tetracycline). The enhancement in transport is approximately 2.96 to 8.53 folds. This in-turn has immense importance for absorption of the drugs, pharmaceuticals, nutraceutical and other related compounds and ions by the cells.
ADVANTAGES
1. The main advantage of the present invention is the reduction of antibiotic dosage by means of synergistic composition. 2. Reduction in antibiotic dosage resulting in prevention of antibiotic drug resistance. 3. Incorporation of bioactive enhancer in the antibiotic composition, which non-toxic to animals and humans. "Comprises/comprising" when used in this specification is taken to specify the presence of stated features, integers, step or components but does not preclude the presence or addition of one or more other features, integers, steps or components or groups thereof.
Claims (22)
1. A synergistic antibiotic pharmaceutical composition having enhanced bioactivity in subjects, said composition comprising: (a) an antibiotic compound; (b) an effective amount lysergol 1 -10pug/ml; and (c) optionally pharmaceutically acceptable additives.
2. A pharmaceutical composition according to claim 1, wherein the antibiotic is selected from the group consisting of rifampicin, tetracycline and ampicillin.
3. A pharmaceutical composition according to claim 1, wherein the dosage of lysergol is 10pg/ml.
4. A pharmaceutical composition according to claim 1, wherein the enhanced activity of antimicrobial effect is in the range of 2-12 folds over antibiotic compounds used singly.
5. A pharmaceutical composition according to claim 1, wherein said composition is effective against broad-spectrum microbes both gram positive and negative, selected from the group consisting E.coli, Bacillus subtilis and Mycobacterium smegmatis and other similar microbes.
6. A pharmaceutical composition according to claim 1, wherein lysergol is isolated from genera of lower fungi consisting of Claviceps, Pencillium and Rhizopus and from the plants selected from Rivea corymbosa and ipomoea violace.
7. A pharmaceutical composition according to claim 1, wherein lysergol enhances the transport of antibiotics across the intestinal gut and cell membrane for better efficacy on the target site.
8. A pharmaceutical composition according to claiml, wherein the reduced dosage of antibiotics and the enhanced bicactivity of the composition reduces the ill effects of antibiotics.
9. A pharmaceutical composition according to claim 1, wherein the resistance to antibiotics is substantially reduced due to reduced concentration of antibiotics.
10. A pharmaceutical composition according to claim 1, wherein the subject is selected from mammals and humans.
11. A synergistic pharmaceutical composition comprising: (a) an antibiotic compound, (b) an effective amount lysergol 2-10pug/ml; and
AMENDED SHEET g ® 10 . (c) optionally pharmaceutically acceptable additives, for use in the treatment of bacterial infection by a method which comprises administering to the subject an effective amount of the pharmaceutical composition.
12. A pharmaceutical composition according to claim 11, wherein the antibiotic is selected from the group consisting of rifampicin, tetracycline and ampicillin.
13. A pharmaceutical composition according to claim 11, wherein the preferable dosage of lysergol is 10ug/ml.
14. A pharmaceutical composition according to claim 11, wherein the enhanced activity of antimicrobial effect is in the range of 2-12 folds.
15. A pharmaceutical composition according to claim 11, wherein said composition is effective against broad-spectrum microbes both gram positive and negative, selected from the group consisting E.coli, Bacillus subtilis and Mycobacterium smegmatis and other similar microbes.
16. A pharmaceutical composition according to claim 11, wherein lysergol is isolated from genera of lower fungi consisting of Claviceps, Pencillium and Rhizopus and from higher plants selected from Rivea corymbosa and ipomoea violace.
17. A pharmaceutical composition according to claim 11, wherein lysergol enhances the transport of antibiotics across the intestinal gut and cell membrane for better efficacy on the target site.
18. A pharmaceutical composition according to claiml1, wherein the reduced dosage of antibiotics and the enhanced bioactivity of the composition reduces the ill effects of antibiotics.
19. A pharmaceutical composition according to claim 11, wherein the resistance to antibiotics is substantially reduced due to reduced concentration of antibiotics.
20. A pharmaceutical composition according to claim 11, wherein the subject is selected from mammals and humans.
21. A pharmaceutical composition according to the invention, substantially as hereinbefore described and exemplified.
22. A pharmaceutical composition including any new and inventive integer or combination of integers, substantially as herein described.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ZA200302270A ZA200302270B (en) | 2003-03-24 | 2003-03-24 | Antibiotic pharmaceutical composition with lysergol as bio-enhancer and method of treatment. |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ZA200302270A ZA200302270B (en) | 2003-03-24 | 2003-03-24 | Antibiotic pharmaceutical composition with lysergol as bio-enhancer and method of treatment. |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ZA200302270B true ZA200302270B (en) | 2004-09-29 |
Family
ID=34080998
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ZA200302270A ZA200302270B (en) | 2003-03-24 | 2003-03-24 | Antibiotic pharmaceutical composition with lysergol as bio-enhancer and method of treatment. |
Country Status (1)
| Country | Link |
|---|---|
| ZA (1) | ZA200302270B (en) |
-
2003
- 2003-03-24 ZA ZA200302270A patent/ZA200302270B/en unknown
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