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WO2008058938A2 - Millepertuis et dérivés de millepertuis constituant des potentialisateurs d'analgésique - Google Patents

Millepertuis et dérivés de millepertuis constituant des potentialisateurs d'analgésique Download PDF

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Publication number
WO2008058938A2
WO2008058938A2 PCT/EP2007/062222 EP2007062222W WO2008058938A2 WO 2008058938 A2 WO2008058938 A2 WO 2008058938A2 EP 2007062222 W EP2007062222 W EP 2007062222W WO 2008058938 A2 WO2008058938 A2 WO 2008058938A2
Authority
WO
WIPO (PCT)
Prior art keywords
morphine
hypericum
analgesic
hypericin
pain
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/EP2007/062222
Other languages
English (en)
Other versions
WO2008058938A3 (fr
Inventor
Enrica Bianchi
Nicoletta Galeotti
Carla Ghelardini
Massimo Guarna
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Universita degli Studi di Siena
Original Assignee
Universita degli Studi di Siena
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Universita degli Studi di Siena filed Critical Universita degli Studi di Siena
Publication of WO2008058938A2 publication Critical patent/WO2008058938A2/fr
Publication of WO2008058938A3 publication Critical patent/WO2008058938A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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)
    • A61K36/38—Clusiaceae, Hypericaceae or Guttiferae (Hypericum or Mangosteen family), e.g. common St. Johnswort
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • Morphine is an analgesic or hyperalgesic agent depending on the administered dosage. Even if the paradoxical effect of morphine is known for a long time, the molecular pathway of the hyperalgesic effect was only recently identified in murine animal model [Galeotti 2006, Fig. I].
  • Hypericum is a genus of about 400 species of flowering plants in the family Clusiaceae, formerly often treated separately in their own family the Hypericaceae. The genus has a nearly world- wide distribution, missing only from tropical lowlands, deserts and arctic region. Hypericum extracts comprise naphtodiantronic derivatives such as hypericin, pseudohypericin and isohypericin [Greeson 2002].
  • Hypericin results to be a powerful inhibitor of protein kinase C (PKC) by interacting with a domain regulating the enzyme [Takahashi 1989].
  • PKC protein kinase C
  • hypericum also known as "St. John's wort”
  • humour changing effect which appears after 2/3 weeks of regular administration at appropriated doses (generally 300 mg/die).
  • Hypericum is active also in anxious-depressive forms and, in combination with Valeriana, it has an effect similar to that of a tricyclic anti-depressant drug.
  • Other morphine effects concern stomach and intestine muscles. Secretions and digestive processes are considerably reduced by morphine and intestinal muscle relaxation causes constipation. Furthermore, an increase in the contractile force of urethras and bladder is observed. These effects can be considered dose-dependent. In clinical practice, it is considered that the maximum tolerated dose by the patient should reflect the equilibrium between the quality of "pain relief obtained and the importance of side effects.
  • morphine has been associated with several compounds, however they do not result to potentiate morphine effect and to reduce its side effects. In high intensity pains, morphine can be associated with paracetamol and/or ketoralac.
  • hypericum or derivatives thereof as, for example, hypericin potentiates morphine action. This effect allows to reduce morphine dosages to be administered while maintaining at least the same level of analgesia.
  • “Strong” opiates such as morphine
  • morphine are widely utilized for treating chronic from moderate to severe pain according to WHO indications. Such indications have been extended and adapted for the treatment of postoperative acute pain.
  • the use of morphine has passed from end-of-life drug to elective drug in the treatment of moderate/serious pain. Therefore, the morphine/hypericin or morphine/hypericum combination is potentially of great use. Since the substances combined (morphine and hypericum or derivatives thereof) are available on the pharmaceutical market, the production of the combined preparation does not require investments to study and validate the single active principles.
  • hypericum extract and one of the components thereof, hypericin are shown to be ideal substances to potentiate morphine-induced analgesia. These substances induce the potentiation of morphine-induced analgesia by inhibiting the hyperalgesic pathway, since both block PKC ⁇ action, one of the enzymes involved in the hyperalgesic pathway.
  • the hypericum/hypericin dosages necessary to potentiate morphine- induced analgesia in an animal model are largely below the dosages used to induce the anti-depressant effect of such substances.
  • Morphine/hypericum and morphine/hypericin combinations change the value of the cost/benefit ratio by greatly reducing the cost (side effects) while increasing the benefits (analgesia).
  • hypericum and hypericin are non-synthetic substances.
  • the administration in pain therapy of a substance which is commonly defined as "natural” can facilitate approval of the patient who is sometimes unwilling to take medicaments considered as "drugs" in the common meaning. Therefore, it is an object of the present invention the use of hypericum or at least one derivative thereof for the preparation of a medicament potentiating the effect of an opiate analgesic.
  • the derivative of hypericum is hypericin.
  • the opiate analgesic is morphine.
  • composition comprising a pharmaceutically acceptable and active amount of an opiate analgesic and of hypericum or at least one derivative thereof, either in separated or joined formulations.
  • the pharmaceutically acceptable and active amount of the opiate analgesic is lower than the amount of the opiate analgesic needed to obtain the same analgesic effect when administered alone.
  • the opiate analgesic is morphine. Still preferably the derivative of hypericum is hypericin.
  • pain comprises both acute and chronic pain.
  • the pain comprises oncological pain.
  • Figure 1 Molecular pathway of morphine-induced analgesia and hyperalgesia.
  • Figure 2 Effect of the hypericum/morphine combination on thermal analgesia.
  • Figure 4 Effect of hypericin/morphine combination on thermal analgesia after morphine chronic treatment.
  • the reported values were obtained from at least 15 mice.
  • Morphine HCl (nor-NBI), hypericum (INDENA), hypericin (Sigma).
  • the substances were dissolved in saline solution (NaCl 0.9%) immediately before use.
  • mice were placed into a steel container thermally set at a temperature of 52.5 ⁇ 0.1 0 C (KW Mechanical Workshop, Siena, Italy).
  • the reaction times (licking latency of the front or rear leg) was evaluated immediately before the administration of morphine or saline and after 15, 30 and 45 min. Each experiment was carried out in blind.
  • the mice, which in the pre-test had a licking latency lower than 12 sec. and higher than 18, were discarded. All experiments were carried out at the same hour of the day (9h00-13h00).
  • the mice were assigned to the respective groups randomly. At the end of the experiments, mice were anesthetized, brains were extracted and cut to verify the trace of the intracerebro ventricular injection. Only the data obtained from mice wherein the trace was placed within the ventricles were taken into consideration.
  • mice model of acute thermal pain show that the treatment with hypericum extract combined to the administration of analgesic doses of morphine induces a potentiation of the analgesic response ( Figures 2-4).
  • hypericum potentiating effect is dose-dependent, even if the administration of hypericum alone does not modify the hyperalgesic threshold.
  • hypericin also potentiates morphine analgesic effect. This could be explained by its profile as a PKC inhibitor. Indeed, it was recently demonstrated, that the
  • PKC ⁇ isoform of PKC is one of the mediators of morphine anti-analgesic pathway
  • the present invention demonstrates that the administration of morphine at analgesic doses in animals treated with hypericin at sub-convulsant doses, induces both the potentiation and the prolongation of analgesia ( Figures 3-4).
  • the present invention demonstrates that hypericum and hypericin are ideal substances to inhibit the hyperalgesic pathway activated by morphine, through blocking PKC ⁇ .
  • the hypericum or hypericin doses necessary to potentiate the morphine-induced analgesia are largely below the doses used to induce the anti-depressant effect of such substances, therefore excluding a possible side effect.
  • the combined treatment morphine/hypericum or morphine/hypericin changes the value of the cost/benefit ratio by greatly decreasing the cost (side effects), while increasing the benefits (analgesia).
  • hypericum and its derivatives are not synthetic but naturals, therefore their use in combination with morphine for pain therapy may be more attractive and better accepted for patients.
  • the assay evaluates the reproducibility in humans of the potentiation of morphine-induce analgesia by morphine/hypericin or morphine/hypericum combination, as already shown in murine model.
  • the potentiation is tested in groups of healthy volunteers, each one made of at least 12 subjects. Each volunteer receives morphine at the analgesic doses reported in the protocols according to different administration routes; after a washout period, the subject receives morphine combined to hypericum or hypericin. Initially, the doses of hypericum are in the range of 600-1800mg/die p.o., starting from the lowest dose until reaching the maximum possible analgesic effect.
  • the hypericin or hypericum dose is obtained by interspecies upscaling from the dose used in mice.
  • the optimum administration route is determined by means of separate experiments. Cancer patients Cancer patients were also treated with a combination of hypericum extract and morphine. The combination results efficient against oncological pain.

Landscapes

  • Health & Medical Sciences (AREA)
  • Natural Medicines & Medicinal Plants (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Medical Informatics (AREA)
  • Rheumatology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pain & Pain Management (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Biotechnology (AREA)
  • Organic Chemistry (AREA)
  • Botany (AREA)
  • Alternative & Traditional Medicine (AREA)
  • Microbiology (AREA)
  • Mycology (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne l'utilisation de millepertuis ou d'au moins un dérivé de millepertuis pour préparer un médicament potentialisant l'effet d'un analgésique opiacé, de préférence la morphine. L'invention concerne également une composition pharmaceutique comprenant une dose pharmaceutiquement acceptable et active d'un analgésique opiacé et de millepertuis ou d'au moins un dérivé de millepertuis, dans des formulations séparées ou communes.
PCT/EP2007/062222 2006-11-13 2007-11-12 Millepertuis et dérivés de millepertuis constituant des potentialisateurs d'analgésique Ceased WO2008058938A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IT000616A ITRM20060616A1 (it) 2006-11-13 2006-11-13 Iperico e suoi derivati come potenziante analgesico
ITRM2006A000616 2006-11-13

Publications (2)

Publication Number Publication Date
WO2008058938A2 true WO2008058938A2 (fr) 2008-05-22
WO2008058938A3 WO2008058938A3 (fr) 2008-07-24

Family

ID=39386106

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2007/062222 Ceased WO2008058938A2 (fr) 2006-11-13 2007-11-12 Millepertuis et dérivés de millepertuis constituant des potentialisateurs d'analgésique

Country Status (2)

Country Link
IT (1) ITRM20060616A1 (fr)
WO (1) WO2008058938A2 (fr)

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7674482B2 (en) * 2002-08-27 2010-03-09 Targeted Medical Pharma Inc. Method and compositions for potentiating pharmaceuticals with amino acid based medical foods

Also Published As

Publication number Publication date
WO2008058938A3 (fr) 2008-07-24
ITRM20060616A1 (it) 2008-05-14

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