WO2016189545A1 - Composés provenant de vitex nigundo pour améliorer une activité antibiotique et surmonter la résistance aux médicaments - Google Patents

Composés provenant de vitex nigundo pour améliorer une activité antibiotique et surmonter la résistance aux médicaments Download PDF

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Publication number
WO2016189545A1
WO2016189545A1 PCT/IN2016/000129 IN2016000129W WO2016189545A1 WO 2016189545 A1 WO2016189545 A1 WO 2016189545A1 IN 2016000129 W IN2016000129 W IN 2016000129W WO 2016189545 A1 WO2016189545 A1 WO 2016189545A1
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Prior art keywords
extract
antibiotics
leaves
vitex
nigundo
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PCT/IN2016/000129
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English (en)
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WO2016189545A4 (fr
Inventor
Kamal DEV
Anuradha SOURIRAJAN
Sonika Gupta
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Shoolini University Of Biotechnology And Management Sciences
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Publication of WO2016189545A1 publication Critical patent/WO2016189545A1/fr
Publication of WO2016189545A4 publication Critical patent/WO2016189545A4/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/85—Verbenaceae (Verbena family)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the field of invention pertains to natural extracts for enhancing the bioactivity of antibiotic compositions (natural and synthetic). More specifically, it pertains to extracts from the leaves of Vitex nigundo which when added to antibiotic compositions greatly enhance the activity of such antibiotics, making them effective at lower concentrations and also helping to overcome drug resistance.
  • Antibiotics are antimicrobial compounds which are active against bacteria and are often used in medical treatment of bacterial infections. They may either kill (bacteriocidal) or inhibit the growth of bacteria (bacteriostatic) and are classified based on their mechanism of action, chemical structure or spectrum of activity. Further categorization is based on their target specificity. "Narrow-spectrum" antibacterial antibiotics target specific types of bacteria, such as Gram-negative or Gram-positive bacteria, whereas broad-spectrum antibiotics affect a wide range of bacteria and may be derived from natural sources e.g. onion, ginger, garlic, lemon etc. or synthesized in the laboratory e.g. ciprofloxacin. Some of the antibiotics can also be derived from bacteria and fungi via fermentation.
  • Natural antibiotics These are plant extracts and natural product compositions e.g. powdered mixtures of herbs used in ayurvedic system of medicine or defined botanical extracts which have natural antibiotic activity e.g. extracts from Lemon (C. limori) , Ginger (Zingiber officinale) , Cinnamon (Cinnamomum verum) , Cumin (Cuminum cyminum), Cayenne Pepper (Capsicum annuum) and Onions (Allium cepa) all have natural antibiotic activity. Natural antibiotics have the advantage of being 'body friendly' and may have lesser side-effects or harmful effects. 3. Synthetic antibiotics: These are compounds which are synthesized in the laboratory and have well defined structure and activity.
  • Synthetic antibiotics e.g. amoxicillin, penicillin etc. are very popular and are used in large quantities. They offer the advantage of well-defined industrial level production but suffer from the limitations of undesirable side-effects e.g. killing of intestinal or gut micro flora and upsetting of the stomach.
  • Active Pharmaceutical Ingredients Any substance or combination of substances used in a finished pharmaceutical product (FPP), intended to furnish pharmacological activity or to otherwise have direct effect in the diagnosis, cure, mitigation, treatment or prevention of disease, or to have direct effect in restoring, correcting or modifying physiological functions in human beings. (Reference: WHO: Working document QAS/11.426/Rev. l, July 2011)
  • Excipients are the ingredients/compounds in a pharmaceutical composition that are not biologically active but are added along with the active ingredient to provide some additional benefits in making the formulation e.g. as sticking agents or bulking agents or taste masking agents in case of bitter formulations etc. They may also confer a therapeutic enhancement of the active ingredient by facilitating drug absorption or solubility or activity.
  • Phytocompounds are chemical compounds that occur naturally in plants (phyto means "plant” in Greek). Phytochemicals may have biological significance for example carotenoids or flavonoids but are not established as essential nutrients.
  • Drug resistance is the reduction in effectiveness of a drug such as an antimicrobial in curing a disease or condition. Some bacteria are naturally resistant to certain antibiotics while others can acquire resistance through mutations in some of their genes when they are exposed to an antibiotic. This resistance- natural or acquired can spread to other bacterial species since bacteria can easily exchange genetic material from one to another, even if they are from different species.
  • MDR Multiple drug resistance
  • Antibiotic resistance is one of the major threats in the treatment of infectious diseases. Antibiotics have transformed health care since they were introduced in the 1940s and have been widely used to fight bacterial infections. However, some infectious organisms have developed resistance to these antibiotics which makes them less effective. One issue stated in the WHO report is that there are very few antibiotics discovered and developed since 1985 to replace those becoming ineffective.
  • Combinations or mixtures of antibiotics can at times be more effective than individual antibiotics but they suffer from limitations of development of multidrug resistance (MDR) in bacteria and toxic side effects in patients.
  • MDR multidrug resistance
  • Extracts of Salvadora persica have been reported to enhance the inhibitory effect of tetracycline and penicillin against Staphylococcus aureus. It was found that addition of phytocompounds to the antibiotic was much more effective and caused more inhibition than antibiotics alone (Ahmed Z, S.S. Khan, M. Khan, A. Tanveer and Z.A. Lone (2009) Synergistic effect of Salvadora persica extracts, tetracycline and penicillin against Staphylococcus aureus. African Journal of Basic and Applied Sciences, 2: 25-29).
  • the present invention discloses an alcoholic extract from the leaves of Vitex nigundo which when added to antibiotics, not only increases their activity but also helps to overcome antibiotic resistance in bacteria.
  • the extract has distinctive analytical fingerprints as given in Fig. 1 and Fig. 2 and the marker compounds in the extract are vitexin and quercetin as confirmed by use of reference standards of vitexin and quercetin. Analysis of analytical fingerprints indicates that some of the phytocompounds present in the extract are derivatives of vitexin and quercetin.
  • the extract potentiates the action of existing antibiotic compositions e.g. synthetic antibiotic compositions such as Ciprofloxacin, etc. and also natural or ayurvedic compositions e.g. oil based compositions for burns and wounds, against drug resistant S. aureus and E. coli.
  • existing antibiotic compositions e.g. synthetic antibiotic compositions such as Ciprofloxacin, etc. and also natural or ayurvedic compositions e.g. oil based compositions for burns and wounds, against drug resistant S. aureus and E. coli.
  • composition and method of the present invention permit a reduction in the antibiotic dose while providing a desired therapeutic effect, thus reducing adverse side effects.
  • US20120121696 Discloses various It does not discloses any terpenes. Instead it terpenes as excipients to enhance the discloses ethanolic extracts of Vitex nigundo solubility of Clofazinine and to enhance the bio-activity of existing Digoxin. antibiotics (natural or synthetic).
  • US20070258996 It discloses Discloses ethanolic extracts of Vitex nigundo antimicrobial composition having to enhance the bio-activity of existing potentiating agents (carbohydrates, antibiotics (natural or synthetic). No peptides, terpenes, peptides, alkaloids) as an carbohydrates, terpenes or alkaloids as in active ingredient against E.coli. prior art are disclosed.
  • WO 2004093876 A2 Berberine and Present invention does not disclose Berberine an antimicrobial or antibiotic are used but phytocompounds of Vitex nigundo which to treat mammals including humans enhance efficacy of antibiotics (natural or against microbial infections. synthetic).
  • EP 2624702 A2 Discloses use of a Polyphenol compound or daptomycin is not polyphenol plant extract (code named disclosed. Rather, present invention discloses as 220D-F2) in combination with the use of phytocompounds obtained as ethanolic extracts from Vitex nigundo to enhance the antibiotic activity of existing Daptomycin (antibiotic) to inhibit the antibiotic compositions e.g. Ciprofloxacin or growth of bio-films. natural compositions e.g. ayurvedic oils or powders for treatment of bacterial infections.
  • WO 2005110404 A2 Anthocyanin- Does not disclose any anthocyanin compound rich extract (ARE) obtained from at all or its use for enhancing activity of antichoke berry plant in combination cancer drugs. Discloses alcoholic extracts with hemotherapeutic agent 5FU from leaves of Vitex nigundo for enhancing drug is used for the treatment of the efficacy of antibiotics (natural or cancer. synthetic) against bacterial infections.
  • ARE anthocyanin compound rich extract
  • WO 2013042140 A2 It discloses the Does not disclose the use of any synthetic or synergistic activity of chemical artificial compound at all. Rather it discloses compound (EDTA) with antibiotic use of phytocompounds obtained as ethanolic compounds for the treatment of extracts from leaves of Vitex nigundoio multi drug resistant bacteria. enhance the antibiotic activity of existing synthetic antibiotic compositions e.g.
  • Ciprofloxacin amoxyclav and also natural compositions e.g. ayurvedic.
  • IN485 KOL 2011A Discloses an Does not disclose specific anti-malarial anti-malarial herbal composition herbal composition rather it discloses use of comprising therapeutically effective phytocompounds obtained as ethanolic amounts of plant extracts ofPaederia extracts from leaves of Vitex nigundoio scandens, Embilica officinalis, enhance the antibiotic activity of existing Gmelina arborea, Wattak ka synthetic antibiotic compositions e.g. Oolubilis, Clerodendrum inerme and Ciprofloxacin, amoxyclav and also natural Vitex nigundo. compositions e.g. ayurvedic. 8.
  • IN-1153/DEL/2009 Discloses a The present invention does not disclose vitex formulation to treat rheumatic nigundo extract as surfactant and also not disorders and related infections that specifically for the treatment of rheumatic include a co-surfactant extracted disorders in combination with the ingredients from several herbs one of which is as mentioned in prior art patent.
  • none of the prior art anticipates or discloses the present invention consisting of an alcoholic extract from the leaves of Vitex nigundo which when added to antibiotic, not only increases their activity but also helps to overcome antibiotic resistance in bacteria.
  • the extract has distinctive analytical fingerprints as given in Fig. 1 and Fig. 2 and the marker compounds in the extract are vitexin and quercetin. Data analysis of the fingerprints indicates that some of the phytocompounds present in the extract are derivatives of vitexin and quercetin.
  • One more object is to disclose extracts having analytical fingerprints as disclosed in Fig. 1 and Fig. 2 and in which the marker compounds are vitexin and quercetin.
  • Still another object is to disclose that quercetin or its derivatives can be used as antibiotic activity enhancers.
  • a further object is to provide scientific evidence regarding bioactivity enhancing action of the extracts on existing antibiotic compositions (natural or synthetic).
  • Yet another object of the invention to disclose an improved composition of antibiotics in which side-effects are reduced owing to reduction in dosage, without affecting bioactivity.
  • a still further object is to disclose a broad spectrum anti-microbial composition effective against MDR (multiple drug resistant) bacteria, owing to use of bioactivity enhancing extracts in the composition
  • the present invention discloses an alcoholic extract from the leaves of Vitex nigundo which when added to antibiotics, not only increases their activity but also helps to overcome antibiotic resistance in bacteria.
  • the extract has distinctive analytical fingerprints as given in Fig. 1 and Fig. 2 and the marker compounds in the extract are vitexin and quercetin. Analysis of the fingerprints
  • the process for preparation of the extract involves taking fresh leaves, washing and sterilizing them and then drying at 37 degree Celsius. The dried leaves are then powdered and extracted with ethanol. Significant enhancement of activity of the synthetic antibiotics, such as ciprofloxacin and amoxyclav was observed against S. aureus, E. coli, S. typhi and P. aeruginosa,
  • the present invention discloses alcoholic extract from the leaves of Vitex nigundo for increasing the efficacy of already available synthetic as well as natural antibiotics e.g. Ciprofloxacin, amoxyclav and also some ayurvedic compositions for treatment of skin infections, burns and 180 wounds e.g. Jatyadi oil.
  • the extract contains several phytocompounds as evident from peaks in Fig. 1 and Fig. 2.
  • the marker compounds identified in the extract are vitexin and quercetin. Analysis of the fingerprints indicates that some of the phytocompounds present in the extract are derivatives of vitexin and quercetin.
  • Method of extraction involves the steps of sample collection, sterilization and extraction as explained below:
  • Sterilization is carried out by washing the leaves with 1.0% sodium hypochlorite for 5 minutes followed by 3-4 washes with sterile distilled water and dried at 37°C.
  • Extraction and Purification is carried out by powdering the dried leaves and extracting with organic solvent such as ethyl alcohol for three times followed by purification on silica gel column to obtain the final extract of invention.
  • Sample collection the fresh plant sample (leaves) of Vitex nigundo were taken and washed under running tap water followed by distilled water.
  • the ethanolic extract from 500 g leaves of Vitex nigundo was fractionated by silica column chromatography and tested for antimicrobial and synergistic activity.
  • Four fractions of Vitex nigundo named as Ml , M2, ME1, and ME2 showed antimicrobial as well as synergistic effect when combined with ciprofloxacin against 5". aureus (Table 2).
  • Table 2 Antibiotic enhancing activity of purified alcoholic extract fractions
  • Ml, M2, ME1, and ME2 fractions were subjected to GC-MS analysis. Quercetin and vitexin were used as standards. The ion peak of vitexin and quercetin was detected at 431.3 and 312.2, respectively. Similar to quercetin, Ml, M2, and ME1 showed a quercetin ion peak at 312.2, suggesting the presence of quercetin in these fractions (indicated by solid arrows). In contrast, ME2 fractions showed ion peaks different from vitexin and quercetin. The ion peak at 337.8 detected in ME2 fraction corresponds to quercetin dihydrate (338.2).
  • the novelty of the present invention lies in disclosing novel compounds extracted from the leaves of Vitex nigundo, which not only significantly enhanced the activity of existing antibiotics (natural or synthetic) but also help to overcome drug resistance.
  • the antibiotic enhancers of present invention have not been disclosed in the prior art.
  • the technical advancement of knowledge lies in disclosing specific phytocompounds present in alcoholic extracts of leaves of Vitex nigundo, which when added to existing antibiotic compositions (natural or synthetic) not only help to enhance the activity of such antibiotics but also make the antibiotics effective against drug resistant bacteria i.e. help overcome drug resistance.
  • the extracts contains several phytocompounds as evident from peaks in Fig. 1 and Fig. 2.
  • the marker compounds identified in the extract are vitexin and quercetin. Analysis of the fingerprints indicates that some of the phytocompounds present in the extract are derivatives of vitexin and quercetin.
  • the treatment of bacterial infections using antibiotics represents a billion dollar industry worldwide.
  • the phytocompounds of present invention thus have considerable industrial importance in not only enhancing the efficacy of existing antibiotics but also overcoming drug resistance towards existing antibiotics, thus rendering those antibiotics also effective, which had become redundant.

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  • Health & Medical Sciences (AREA)
  • Natural Medicines & Medicinal Plants (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Alternative & Traditional Medicine (AREA)
  • Biotechnology (AREA)
  • Botany (AREA)
  • Medical Informatics (AREA)
  • Medicinal Chemistry (AREA)
  • Microbiology (AREA)
  • Mycology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines Containing Plant Substances (AREA)

Abstract

La présente invention concerne un extrait alcoolique provenant de feuilles de Vitex nigundo qui, lorsqu'il est ajouté à des antibiotiques, accroît non seulement leur activité, mais aide également à surmonter la résistance aux antibiotiques dans des bactéries. L'extrait possède des empreintes digitales d'analyse distinctives telles qu'indiquées sur la Figure 1 et la Figure 2, et les composés marqueurs dans l'extrait sont la vitexine et la quercétine. Une partie des phytocomposés présents dans l'extrait sont des dérivés de la vitexine et de la quercétine. La préparation de l'extrait selon l'invention consiste à prendre des feuilles fraîches, à les laver et les stériliser, à les sécher à 37 °C, puis à les réduire en poudre, et à réaliser l'extraction avec de l'alcool et la purification sur une colonne de gel de silice. Une amélioration significative de l'activité des antibiotiques synthétiques, tels que la ciprofloxacine et l'amoxiclav, a été observée contre les bactéries de type S. aureus, E. coli, S. typhi et P. aeruginosa, lorsque l'extrait selon la présente invention a été utilisé conjointement avec les antibiotiques.
PCT/IN2016/000129 2015-05-23 2016-05-23 Composés provenant de vitex nigundo pour améliorer une activité antibiotique et surmonter la résistance aux médicaments WO2016189545A1 (fr)

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IN1464/DEL/2015 2015-05-23

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114031084A (zh) * 2021-11-08 2022-02-11 华东理工大学 硼类化合物修饰的硅胶材料、制备方法及应用
CN115137676A (zh) * 2021-03-30 2022-10-04 海南师范大学 一种鸡屎藤提取物及其在制备牙膏中的应用

Citations (1)

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Patent Citations (1)

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Publication number Priority date Publication date Assignee Title
US3833472A (en) * 1971-10-03 1974-09-03 Hisamitsu Pharmaceutical Co Process for isolating oleandrin from nerium odorum

Non-Patent Citations (3)

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Title
JTC JUNIOR ET AL.: "Phytochemical Analysis and Modulation of Antibiotic Activity by Luehea paniculata Mart. & Zucc. (Malvaceae) in Multiresistant Clinical Isolates of Candida Spp", BIOMED RESEARCH INTERNATIONAL;, vol. 2015, pages 1 - 11, XP055331859 *
MM MAMUN ET AL.: "Antibacterial Activity of Vitex negundo L. against a Multidrug Resistant Pathogenic Bacterium", EUROPEAN JOURNAL OF MEDICINAL PLANTS;, vol. 8, no. 2, 24 April 2015 (2015-04-24), pages 97 - 106, XP055331861 *
MU AMIN ET AL.: "Antibiotic additive and synergistic action of rutin, morin and quercetin against methicillin resistant Staphylococcus aureus", BMC COMPLEMENTARY AND ALTERNATIVE MEDICINE;, vol. 15, no. 59, 12 March 2015 (2015-03-12), pages 1 - 12, XP021219392 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115137676A (zh) * 2021-03-30 2022-10-04 海南师范大学 一种鸡屎藤提取物及其在制备牙膏中的应用
CN115137676B (zh) * 2021-03-30 2024-03-26 海南师范大学 一种鸡屎藤提取物及其在制备牙膏中的应用
CN114031084A (zh) * 2021-11-08 2022-02-11 华东理工大学 硼类化合物修饰的硅胶材料、制备方法及应用
CN114031084B (zh) * 2021-11-08 2023-10-27 华东理工大学 硼类化合物修饰的硅胶材料、制备方法及应用

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