WO2011001208A1 - Utilisation d'un extrait d'hélichrysum, pour le traitement du vih/sida - Google Patents

Utilisation d'un extrait d'hélichrysum, pour le traitement du vih/sida Download PDF

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Publication number
WO2011001208A1
WO2011001208A1 PCT/IB2009/052807 IB2009052807W WO2011001208A1 WO 2011001208 A1 WO2011001208 A1 WO 2011001208A1 IB 2009052807 W IB2009052807 W IB 2009052807W WO 2011001208 A1 WO2011001208 A1 WO 2011001208A1
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acid
hiv
caffeoylquinic
compounds
caffeoylquinic acid
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PCT/IB2009/052807
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English (en)
Inventor
Nial Mark Harding
Nivan Moodley
Paolo Meoni
Vinesh Jaichand Maharaj
Schalk-Willem Van Rooyen
Marina Van Der Merwe
Jacobus Johannes Marion Meyer
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Csir
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Publication of WO2011001208A1 publication Critical patent/WO2011001208A1/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)
    • A61K36/28—Asteraceae or Compositae (Aster or Sunflower family), e.g. chamomile, feverfew, yarrow or echinacea
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV

Definitions

  • THIS INVENTION relates to the treatment of persons infected with the human immunodeficiency virus (HIV) or who have subsequently developed acquired immunodeficiency syndrome (AIDS).
  • HIV human immunodeficiency virus
  • AIDS acquired immunodeficiency syndrome
  • the virus mainly infects CD4+ helper T cells (cells bearing the CD4 receptor protein on their surface membrane) as well as macrophages and dendritic cells of the human immune system 3 . Infection with the virus leads to reduced levels of CD4+ T cells. Most HIV-infected people eventually develop AIDS and die, especially if the infection is left untreated 4 .
  • the problem with infection with the virus is that the infection gradually depletes the immune system to such a degree that, at the end (often after several years), cell-mediated immunity is lost and the body becomes susceptible to a variety of opportunistic infections that would normally not occur in a healthy functioning body 3 . Patients suffer from severe diarrhoea and wasting of body tissues and usually succumb to pneumonia.
  • the clinical latency period a specific period of infection, called the clinical latency period, patients suffer from few or no symptoms, but the gradual demise of the immune system nevertheless takes place during this period and symptoms start appearing towards the end of the period when AIDS has been established. This period may last from two weeks to 20 years 3 .
  • Nucleoside reverse transcriptase inhibitors are drugs which target the reverse transcriptase enzyme of the HIV and aim to interrupt the virus's ability to copy itself during the early stages of infection. These drugs can help reduce the amount of virus particles in the body, while helping to increase the CD4+ T cell count.
  • Nucleoside analogue medications for HIV include AZT (Azidothymidine), ddC (zalcitabine), ddl (dideoxyinosine), d4T (stavudine) and Abacavir (ziagen) among others 5 .
  • Non- nucleoside reverse transcriptase inhibitors are drugs which also slow down the replication process during the early stages of HIV infection. This group includes Delavridine (Rescriptor), Nevirapine (Viramune) and Efravirenz (Sustiva) 5 .
  • Protease inhibitors are drugs which are intended to interrupt the reproduction of the virus by targeting the protease enzyme of the virus, which is responsible for hydrolysing viral polyproteins into functional protein products that are essential for viral assembly and subsequent activity, but at a later stage of the HIV life cycle. Some of the drugs that fall into this group include Ritonavir (Norvir), Saquinivir (Invirase), and Amprenivir (Agenerase) 5 .
  • Fusion/entry inhibitors are drugs which work by stopping the virus from entering CD4+ T cells thereby preventing the joining of the virus with the cell membranes. This type of treatment should be used in conjunction with another form of treatment 5 .
  • This group currently only has one drug (Fuzeon) approved for use.
  • lntegrase inhibitors are drugs which act on the integrase enzyme of the HIV and prevent viral genomic particles from being embedded in the host cell DNA, thereby halting the production of new viral particles.
  • This group also has only one drug, raltegravir, which has been approved for use.
  • the most common side-effects of the current HIV treatments include nausea, fatigue and diarrhoea.
  • the NRTI's cause a decrease in red and white blood cells, possibly an inflamed pancreas and nerve damage.
  • the NNRTI's have fewer side-effects and these may include rashes and liver toxicity as well as central nervous system side effects such as imbalance, difficulty in concentrating and vivid dreams. But for the most part, these drugs are very well tolerated.
  • the protease inhibitors may cause nausea, diarrhoea and various gastrointestinal problems and may also interact with other drugs causing an allergic reaction.
  • the fusion inhibitor Fuzeon may cause an allergic reaction as well as pneumonia, low blood pressure, vomiting, fever or chills, rashes and difficulty in breathing 5 .
  • side-effects can include easy bruising or bleeding, jaundice (yellowing of the skin or eyes), muscle weakness with fever and dark colored urine, or less urination than usual or not at all 6 .
  • Oxidative stress may contribute to several aspects of the HIV disease pathogenesis, including viral replication, inflammatory response, decreased immune cell proliferation, increased loss of immune function, apoptosis, chronic weight loss and increased sensitivity to certain toxic drugs 9 .
  • the present invention offers a solution to these problems.
  • the invention provides a single product which has multiple actions thereby acting at various stages of the viral cycle resulting in a more effective treatment and reducing the chances of resistance.
  • the invention results in direct antiviral action during clinical latency, it has action as an entry inhibitor of the virus, it has a good antioxidant action and a high natural carbohydrate, fibre and protein content; the invention therefore also provides nutrition to the HIV-infected patient.
  • Extracts and compounds of plants of the genus Helichrysum have anti-HIV activity and can be used in the management or treatment of HIV/AIDS.
  • Plants of this genus belong to the Asteraceae family and the genus includes Helichrysum psilolepis (vernacular name kooigoed).
  • H. psilolepis is distributed along the south-eastern to mid-eastern parts of South Africa particularly in the Eastern Cape, KwaZulu-Natal, Orange Free State and parts of Mpumalanga.
  • the plant extract in spray-dried form has been found to contain various isomers of mono- and di-caffeoylquinic acids. These include (1) 3-caffeoylquinic acid (3-chlorogenic acid), (2) 5-caffeoylquinic acid (5-chlorogenic acid), (3) 1 ,3-di-O-caffeoyl quinic acid, (4) 1 ,5-di-O-caffeoylquinic acid, (5) 1 -methoxy-oxalyl-3,5-di-0-caffeoylquinic acid and (6) the glycosylated flavonoid, kaempferol-3-glucuronic acid.
  • the di- caffeoylquinic acids have been shown in various research studies to be specific inhibitors of HIV-1 integrase, an enzyme that is crucial to the survival of the virus by being responsible for the integration of the viral genome into the host DNA to enable further viral replication and spread 13 14 15 .
  • Kaempferol has been shown to be an inhibitor of the HIV-1 protease enzyme 16 .
  • an extract of a plant of the genus Helichrysum including at least three compounds selected from 3-caffeoylquinic acid (3-chlorogenic acid), 5-caffeoylquinic acid (5-chlorogenic acid), 1 ,3-di-O-caffeoyl quinic acid, 1 ,5-di-O-caffeoylquinic acid, 1 - methoxy-oxalyl-3,5-di-0-caffeoylquinic acid and kaempferol-3-glucuronic acid in the preparation of a medicament for one or both of the management and treatment of HIV/AIDS.
  • 3-caffeoylquinic acid 3-chlorogenic acid
  • 5-caffeoylquinic acid 5-chlorogenic acid
  • 1 ,3-di-O-caffeoyl quinic acid 1 ,5-di-O-caffeoylquinic acid
  • the 'one or both of the management and treatment of HIV/AIDS' may be by a mode of action selected from one or more of inhibiting reverse transcriptase enzymes, inhibiting protease enzymes, inhibiting integrase enzymes, reducing oxidative stress and inhibiting viral entry.
  • the extract and the at least three compounds thus have multiple viral enzymatic targets.
  • the extract may include four, five or six of the compounds.
  • the extract may include four of the compounds.
  • the compounds may be 1 ,3-di-O- caffeoylquinic acid, 1 ,5-di-O-caffeoylquinic acid, 1 -methoxy-oxalyl-3,5-di-0- caffeoylquinic acid and kaempferol-3-glucuronic acid.
  • the compounds may be present in a ratio of about 1 :1 :1 :1 and preferably in a ratio of about 1 :1 ,2:1 ,3:1 ,2 respectively.
  • the extracts may be aqueous extracts.
  • the extracts may be prepared from the aerial parts of the plant. For example, oven-dried plant material may be ground and the ground material may be extracted with boiling water in a steam-jacketed vessel for about an hour. The resulting mixture may then be filtered to separate the extracted plant material, or pulp, from the filtrate. The filtrate (or tea) produced in this way may then be spray-dried to produce a solid powdered extract. The spray-dried extract may then include each of the compounds (1 ) to (6) described above.
  • an extract of a plant of the genus Helichrysum in the preparation of a medicament for one or both of the management and treatment of HIV/AIDS by one or more of inhibiting reverse transcriptase enzymes, inhibiting protease enzymes, inhibiting integrase enzymes, reducing oxidative stress, and inhibiting viral entry.
  • the plant may be a plant of the species H. psilolepis.
  • the extract may include at least one compound selected from 3- caffeoylquinic acid (3-chlorogenic acid), 5-caffeoylquinic acid (5-chlorogenic acid), 1 ,3- di-O-caffeoyl quinic acid, 1 ,5-di-O-caffeoylquinic acid, 1 -methoxy-oxalyl-3,5-di-0- caffeoylquinic acid and kaempferol-3-glucuronic acid.
  • a third aspect of the invention there is provided the use of at least three compounds selected from 3-caffeoylquinic acid (3-chlorogenic acid), 5- caffeoylquinic acid (5-chlorogenic acid), 1 ,3-di-O-caffeoyl quinic acid, 1 ,5-di-O- caffeoylquinic acid, 1 -methoxy-oxalyl-3,5-di-0-caffeoylquinic acid and kaempferol-3- glucuronic acid in the preparation of a medicament for one or both of the management and treatment of HIV/AIDS.
  • the one or both of the mangement and treatement of HIV/AIDS may be by a mode of action selected from one or more of inhibiting reverse transcriptase enzymes, inhibiting protease enzymes, inhibiting integrase enzymes, reducing oxidative stress and inhibiting viral entry.
  • the use may be of four, five or six of the compounds.
  • the compounds may be 1 ,3-di-O-caffeoylquinic acid, 1 ,5-di-O- caffeoylquinic acid, 1 -methoxy-oxalyl-3,5-di-0-caffeoylquinic acid and kaempferol-3- glucuronic acid.
  • These compounds may be used in the ratio of about 1 :1 :1 :1 respectively and preferably in the ratio of about 1 :1 ,2:1 ,3:1 ,2 respectively.
  • the invention thus provides the use of an extract of a plant of the genus Helichrysum, the extract including at least four compounds selected from the compounds 3-caffeoylquinic acid (3-chlorogenic acid), 5-caffeoylquinic acid (5- chlorogenic acid), 1 ,3-di-O-caffeoyl quinic acid, 1 ,5-di-O-caffeoylquinic acid, 1 -methoxy- oxalyl-3,5-di-0-caffeoylquinic acid and kaempferol-3-glucuronic acid in the preparation of a medicament for one or more of the management and treatment of HIV/AIDS.
  • 3-caffeoylquinic acid 3-chlorogenic acid
  • 5-caffeoylquinic acid 5- chlorogenic acid
  • 1 ,3-di-O-caffeoyl quinic acid 1 ,5-di-O-caffeoylquinic acid
  • a pharmaceutical composition comprising at least three compounds selected from 3- caffeoylquinic acid (3-chlorogenic acid), 5-caffeoylquinic acid (5-chlorogenic acid), 1 ,3- di-O-caffeoyl quinic acid, 1 ,5-di-O-caffeoylquinic acid, 1 -methoxy-oxalyl-3,5-di-0- caffeoylquinic acid and kaempferol-3-glucuronic acid.
  • the pharmaceutical composition may include four of the compounds.
  • the compounds may be 1 ,3-di-O-caffeoylquinic acid, 1 ,5-di-O-caffeoylquinic acid, 1-methoxy-oxalyl-3,5-di-0-caffeoylquinic acid and kaempferol-3-glucuronic acid.
  • the four compounds may be present in a ratio of about 1:1 :1:1 respectively. Preferably the ratio will be about 1:1 ,2:1 ,3:1,2 respectively.
  • Figure 1 shows the chemical profile of the spray-dried powder of the invention, including HPLC (diode array) and MS (ES+ and ES-) traces;
  • Figure 2 shows the percentage virus control as a function of concentration in the inhibition of HIV-1 93
  • Figures 3 and 4 show the percentage virus control as a function of time of drug addition (hr Pl refers to hours post infection) for the effect of H. psilolepis extract (BP29- 001 ) time of addition on HIV-1 replication; and
  • Figure 5 shows the percentage virus control as a function of concentration for the inhibition of CCR5-tropic HIV-1 attachment by spray dried extract of H. psilolepis labelled BP29-001 ;
  • H. psilolepis plant material was collected and oven dried at 30 0 C for 24-48 hours until dry.
  • the dried material was ground in a suitable grinder with a sieve size of 5 mm and the ground material (2.39kg) was extracted with 58.551 of boiling water in a steam jacketed vessel for 1 hour.
  • the resulting mixture was filtered to remove plant material, or pulp, to produce an extract.
  • the extract was spray-dried to produce 0.224kg of spray-dried powder.
  • the nutritional analysis of the spray-dried powder is set out in Table 1 .
  • HPLC MS chemical profiling of the spray-dried powder was carried out by HPLC-MS.
  • the main goal was to develop a chemical fingerprint that could be used for the analysis of samples produced during manufacturing to show batch-to-batch reproducibility and which could be used for the development of a specification for the product.
  • Chemical profiling also identified the four active compounds in the plant extract. Identification of the compounds was done by mass analysis and comparison of the fragmentation patterns of the compounds in question with published MS data on the six isomers of the dicaffeoylquinic acids 17 and with published data for kaempferol in the Dictionary of Natural Products.
  • the HPLC profile is shown in Figure 1 and chemical analysis results are shown in table 2.
  • Table 2 Table 2
  • Anti-HIV assay data for the spray dried extract is shown in Figure 2 and Table 3.
  • the description of the assays involves the use of human peripheral blood mononuclear cells (PBMCs) infected with the HIV.
  • Fresh human PBMCs, seronegative for HIV and HBV, were isolated from screened donors (Interstate Blood Bank, Inc. Memphis, TN). Cells were pelleted/washed 2-3 times by low speed centrifugation and re-suspension in PBS to remove contaminating platelets.
  • the Leukophoresed blood was then diluted 1 :1 with Dulbecco's Phosphate Buffered Saline (DPBS) and layered over 14 mL of Lymphocyte Separation Medium in a 50 mL centrifuge tube and then centrifuged for 30 minutes. Banded PBMCs were gently aspirated from the resulting interface and subsequently washed 2X with PBS by low speed centrifugation.
  • DPBS Dulbecco's Phosphate Buffered Saline
  • cells were enumerated by trypan blue exclusion and re-suspended at 1 x 10 7 cells/ml in RPMI 1640 supplemented with 15 % Fetal Bovine Serum (FBS), and 2 mM L-glutamine, 4 ⁇ g/ml Phytohemagglutinin. The cells were allowed to incubate for 48-72 hours at 37°C.
  • FBS Fetal Bovine Serum
  • PBMCs were centrifuged and resuspended in RPMI 1640 with 15% FBS, 2 mM L-glutamine, 100 U/ml penicillin, 100 ⁇ g/ml streptomycin, 10 ⁇ g/ml gentamycin, and 20 U/ml recombinant human IL-2 (R&D Systems, Inc). IL-2 is included in the culture medium to maintain the cell division initiated by the PHA mitogenic stimulation. PBMCs were maintained in this medium at a concentration of 1 -2 x 10 6 cells/mL with biweekly medium changes until used in the assay protocol. Cells were kept in culture for a maximum of two weeks before being deemed too old for use in assays and discarded. Monocytes were depleted from the culture as the result of adherence to the tissue culture flask.
  • PHA-P stimulated cells from at least two normal donors were pooled (mixed together), diluted in fresh medium to a final concentration of 1 x 10 6 cells/mL, and plated in the interior wells of a 96 well round bottom microplate at 50 ⁇ l/well (5 x 10 4 cells/well). Pooling (mixing) of mononuclear cells from more than one donor is used to minimize the variability observed between individual donors, which results from quantitative and qualitative differences in HIV infection and overall response to the PHA and IL-2 of primary lymphocyte populations. Each plate contains virus/cell control wells (cells plus virus), experimental wells (drug plus cells plus virus) and compound control wells (drug plus media without cells, necessary for MTS monitoring of cytotoxicity).
  • test drug dilutions were prepared at a 2X concentration in microtiter tubes and 100 ⁇ l of each concentration was placed in appropriate wells using the standard format. 50 ⁇ l of a predetermined dilution of virus stock was placed in each test well (final MOI ⁇ 0.1 ). The PBMC cultures were maintained for seven days following infection at 37 ⁇ , 5% CO 2 . After this period, cell-free supernatant samples were collected for analysis of reverse transcriptase activity. Following removal of supernatant samples, compound cytotoxicity was measured by addition of MTS to the plates for determination of cell viability. Wells were also examined microscopically and any abnormalities were noted.
  • RT reverse transcriptase
  • Poly rA:oligo dT template:primer (Pharmacia) was prepared as a stock solution by combining 150 ⁇ l poly rA (20 mg/ml) with 0.5 ml oligo dT (20 units/ml) and 5.35 ml sterile dH 2 O followed by aliquoting (1.0 ml) and storage at -20 ⁇ O.
  • the RT reaction buffer was prepared fresh on a daily basis and consisted of 125 ⁇ l 1 .0 M EGTA, 125 ⁇ l dH 2 O, 125 ⁇ l 20% Triton X100, 50 ⁇ l 1.0 M Tris (pH 7.4), 50 ⁇ l 1 .0 M DTT, and 40 ⁇ l 1.0 M MgCI 2 .
  • the final reaction mixture was prepared by combining 1 part 3 H-TTP, 4 parts ClI-I 2 O, 2.5 parts poly rA:oligo dT stock and 2.5 parts reaction buffer. Ten microliters of this reaction mixture was placed in a round bottom microtiter plate and 15 ⁇ L of virus containing supernatant was added and mixed. The plate was incubated at 37 ⁇ for 60 minutes.
  • reaction volume was spotted onto DE81 filter-mats (Wallac), washed 5 times for 5 minutes each in a 5% sodium phosphate buffer or 2X SSC (Life Technologies). Next they were washed 2 times for 1 minute each in distilled water, 2 times for 1 minute each in 70% ethanol, and then dried. Incorporated radioactivity (counts per minute, CPM) was quantified using standard liquid scintillation techniques.
  • assay plates were stained with the soluble tetrazolium-based dye MTS (CellTiter 96 Reagent, Promega) to determine cell viability and quantify compound toxicity.
  • MTS CellTiter 96 Reagent, Promega
  • the mitochondrial enzymes of metabolically active cells metabolize MTS to yield a soluble formazan product. This allows the rapid quantitative analysis of cell viability and compound cytotoxicity.
  • the MTS is a stable solution that does not require preparation before use.
  • 20 ⁇ l of MTS reagent was added per well.
  • the microtiter plates were then incubated 4-6 hrs at 37°C. The incubation intervals were chosen based on empirically determined times for optimal dye reduction.
  • Adhesive plate sealers were used in place of the lids, the sealed plate was inverted several times to mix the soluble formazan product and the plate was read spectrophotometrically at 490/650 nm with a Molecular Devices Vmax or SpectraMaxPlus plate reader.
  • the spray-dried extract of H. psilolepis was further tested in an HIV-1 time of addition assay (TOA) along with five positive control antiretroviral compounds (T-20, AZT, nevirapine, raltegravir and nelfinavir) representing five different classes of anti-HIV-1 drugs.
  • TOA HIV-1 time of addition assay
  • T-20 When added at later time points when the entry/fusion events in the viral replication cycle had already been completed, T-20 was expected to no longer be effective. The same trend was observed for BP29-001 (Figure 3), exhibiting an HIV-1 inhibition pattern similar to that of T-20, showing that it also acts as an entry/fusion inhibitor. Table 4
  • T20 - T20 (pentafuside), a synthetic peptide derived from the HIV-1 gp41 protein, is a selective and potent inhibitor of HIV-1 fusion.
  • AZT - Azidothymidine AZT - Azidothymidine
  • NRTI nucleoside reverse transcriptase inhibitor
  • NVP - Nevirapine a non nucleoside reverse transcriptase inhibitor (NNRTI).
  • NFV - Nelfinavir an HIV-1 protease inhibitor.
  • the attachment assay was designed to detect compounds that block cell-free virus attachment to MAGI-CCR5 cells. Twenty-four hours prior to initiation of the assay, the cells were trypsinised, counted and plated in 96-well plates. Compound in medium was placed on the cells, and incubated for 15 min at 37 Q C. Ten (10) TCID 50 Of the Ba-L strain of HIV-1 was then added to the wells and the incubation continued for 3 h. At the end of the incubation, the wells were washed with DPBS (containing Mg 2+ and Ca 2+ ), followed by addition of fresh medium and the culture was continued for 40 to 48 h at 37 Q C.
  • DPBS containing Mg 2+ and Ca 2+
  • ⁇ -galactosidase enzyme expression was determined by chemiluminescence.
  • Compound toxicity was determined using MTS dye reduction on duplicate plates that were handled identically to the HIV-1 infected plates with the exception that the virus was replaced with media.
  • TAK 779 is positive control
  • the spray dried extract was tested for its anti oxidant properties in the DPPH assay and compared to green tea extract.
  • the results are shown in Table 6
  • the antioxidant assay is performed using DPPH (1 ,1 -diphenyl-2-picryl-hydrazyl) as a free radical molecule and testing the effect of various antioxidants on solutions containing the reagent.
  • the assay is done in a 96-well plate with varying concentrations of the test compounds added to the wells containing a set amount of DPPH. Solutions containing the DPPH have a deep violet colour.
  • the percentage radical scavenging activity of the test antioxidants is then determined by measuring the optical density of the remaining DPPH in solution and expressing the value as a percentage of the control DPPH absorbance reading and subtracting the value from 100% expressed by the following equation:
  • psilolepis performed in a 96-well plate with DPPH as free radical.
  • Radical scavenging activity 100% - [Ex - Blank]/C - Blank x 100%]
  • HIV Integrase The HIV Integrase. Molecular Pharmacology. 50: 846-855.

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Abstract

L'invention porte sur l'utilisation d'un extrait d'une plante du genre hélichrysum, l'extrait comprenant au moins trois composés choisis parmi l'acide 3-cafféoylquinique (acide 3-chlorogénique), l'acide 5-cafféoylquinique (acide 5-chlorogénique), l'acide 1,3-di-O-cafféoylquinique, l'acide 1,5-di-O-cafféoylquinique, l'acide 1-méthoxy-oxalyl-3,5-di-O-cafféoylquinique et l'acide kaempférol-3-glucuronique dans la préparation d'un médicament pour l'un ou les deux parmi la gestion et le traitement du VIH/SIDA.
PCT/IB2009/052807 2009-06-29 2009-06-29 Utilisation d'un extrait d'hélichrysum, pour le traitement du vih/sida WO2011001208A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2830198A1 (fr) * 2001-09-28 2003-04-04 Jean Pierre Willem Compositions pharmaceutiques comprenant des huiles essentielles et leurs utilisations
US7306816B1 (en) * 2004-03-29 2007-12-11 St James Melanie Shane Medicinal plant compositions of matter and method of preparation

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2830198A1 (fr) * 2001-09-28 2003-04-04 Jean Pierre Willem Compositions pharmaceutiques comprenant des huiles essentielles et leurs utilisations
US7306816B1 (en) * 2004-03-29 2007-12-11 St James Melanie Shane Medicinal plant compositions of matter and method of preparation

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
APPENDINO G ET AL: "Arzanol, an Anti-inflammatory and Anti-HIV-1 Phloroglucinol a-Pyrone from Helichrysum italicum ssp. microphyllum", JOURNAL OF NATURAL PRODUCTS, AMERICAN CHEMICAL SOCIETY, US, vol. 70, no. 4, 1 January 2007 (2007-01-01), pages 608 - 612, XP003018877, ISSN: 0163-3864 *
FATHY MOHAMED SOLIMAN, AFAF HASSAN SHEHATA, AMAL EL-SAYED KHALEEL, SHAHIRA MOHAMED EZZAT: "A new y-pyrone, sterols and triterpenes from Helichrysum bracteatum, Gazania nivea and Dimorphotheca ecklonis", PHARMACOGNOSY MAGAZINE 2007 IN, vol. 3, no. 12, 2007, pages 213 - 218, XP001539684, ISSN: 0973-1296 *
LOURENS A C U ET AL: "South African Helichrysum species: A review of the traditional uses, biological activity and phytochemistry", JOURNAL OF ETHNOPHARMACOLOGY, ELSEVIER SCIENTIFIC PUBLISHERS LTD, IE, vol. 119, no. 3, 28 October 2008 (2008-10-28), pages 630 - 652, XP009125555, ISSN: 0378-8741, [retrieved on 20080619] *
SOLIMAN F M ET AL: "Caffeoyl derivatives and flavonoids from three compositae species", PHARMACOGNOSY MAGAZINE, PHCOG.NET, IN, vol. 4, no. 13, 1 January 2008 (2008-01-01), pages 1 - 11, XP001539321, ISSN: 0973-1296 *

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