WO2004112819A1 - Compositions et methodes de traitement au moyen d'extraits de plantes - Google Patents

Compositions et methodes de traitement au moyen d'extraits de plantes Download PDF

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WO2004112819A1
WO2004112819A1 PCT/US2004/018794 US2004018794W WO2004112819A1 WO 2004112819 A1 WO2004112819 A1 WO 2004112819A1 US 2004018794 W US2004018794 W US 2004018794W WO 2004112819 A1 WO2004112819 A1 WO 2004112819A1
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disease
composition
administration
feverfew
parthenolide
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PCT/US2004/018794
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Stephen C. Roberts M.D.
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Gelstat Corporation
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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
    • 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

Definitions

  • the present invention relates to compositions and methods of treatment. It more particularly relates to a means of benefiting an animal by the effective administration of compositions comprised of a sesquiterpene lactone, or a plant extract from a plant that is a source of sesquiterpene lactone.
  • the present invention more particularly relates to a practical and advantageous means of treating various specific and types of maladies and conditions, especially those known or thought to involve the NF-kB pathway, its components, modulators, products and effects.
  • NF-kB Nuclear Factor-kB pathway
  • NF-kB pathway is a very important regulatory pathway, that it is present in nearly all mammalian cells, and that its regulation or dysregulation can and often does have a significant impact on the health and well being of the organism. Therefore effective, previously unknown compositions and methods of potentially modifying the activity of this regulatory pathway are of great value and tremendous usefulness, especially when such compositions and methods are economical, convenient, and might be employed in such a manner as to be relatively free from serious side effects.
  • NF-kB regulates gene expression, especially of those genes coding for inflammation and immune response. To date there are more than 150 genes found to be regulated by NF-kB (Pahl, 1999). The components of the NF- kB pathway are intimately involved in many important signaling pathways. NF-kB is a family of transcription factors that was originally identified in B cells (in 1986) but was then found to be ubiquitously expressed and also phylogenetically conserved down to Drosophila. Under basal conditions, NF-kB is sequestered within the cytoplasm by the Ik
  • IkB is phosphorylated by the IkB Kinase Complex (IKK). Phosphorylation of two Ser residues on IkB triggers its ubiquination and rapid degradation, thereby releasing NF-kB for translocation into the nucleus and subsequent stimulation of gene expression.
  • the IKK Complex is composed of two catalytic subunits, IKKA, IKKB and a third, non-catalytic subunit, IKKC (also known as NEMO). IKKA is important in early embryonic development of the skin and skeletal system. IKKB and NEMO are indispensable for cytokine signaling.
  • NF-kB tumor necrosis factor-a
  • IL-1 interleukin-1
  • NF-kB family members include RelA (p65), RelB, c-Rel, NF-kB 1 (p50), and NF-kB2 (p52), the latter two being synthesized from the inactive precursor molecules p 105 and p 100 respectively.
  • ⁇ F-kB is rapidly activated in response to a variety of inflammatory and other stimuli that lead to degradation of IkB.
  • Fig. 1 is a schematic representation of ⁇ F-kB activation via the IKKB subunit of the IKK Complex.
  • IKKB an active catalytic subunit of the IKK Complex
  • IKKB is of central importance in regulating ⁇ F-kB, especially its activation, and the resulting transcription of genes, especially those related to inflammation.
  • activation of ⁇ F-kB via IKKB appears to be a conserved mechanism across species and is a convergence point of many upstream signaling pathways (including cytokines and other agents which ultimately up-regulate ⁇ F-kB expression, all or nearly all acting via IKKB.)
  • the IKKB subunit regulates (by regulating ⁇ F-kB) much of the immunologic and inflammatory response in cells and in humans generally.
  • IKKB can be 'turned on' and thus stimulate (result in) NF-kB activation in response to stimuli as diverse as fluid sheer stress in arteries, heat, cold, mechanical trauma, hypoxia, antibodies, exposure to radiation, microorganisms (viral, bacterial, fungal) and various biologic mediators such as complement and cytokines.
  • stimuli as diverse as fluid sheer stress in arteries, heat, cold, mechanical trauma, hypoxia, antibodies, exposure to radiation, microorganisms (viral, bacterial, fungal) and various biologic mediators such as complement and cytokines.
  • Interleukins Interleukins, growth factors, IL-1, TNF-er, lymphotoxin, LFN-7, phorbol esters, mitogens lectins, PDGF, VEGF
  • ⁇ SF indicates colony-stimulating factor
  • GM granulocyte/macrophage
  • RANTES regulated upon activation normal T lymphocyte expressed and secreted
  • MGSA melanoma growth-stimulating activity
  • MAd mucosal addressin
  • XIAP X- linked inhibitor of apoptosis
  • IRF interferon regulatory factor
  • SOD superoxide dismutase
  • PTX pertussis toxin.
  • NF-kB pathway was discovered in 1986 and soon thereafter came to be recognized as a key component in the immune response as well as certain other biologic processes.
  • the scope of knowledge relating to NF-kB and its role is expanding rapidly. It is at present believed to be involved in numerous disease states and may be central to many, including without limitation: those of chronic inflammation (e.g. arthritis, atherosclerosis, arteriosclerosis, inflammatory bowel disease, multiple sclerosis, etc.); those of acute, intermittent inflammation (e.g. migraine, asthma, etc.); those wherein auto-immune processes figure prominently (e.g. lupus, fibromyalgia, autoimmune myocarditis, etc.); those of dysfunctional immune response (e.g.
  • cancer cancer, AIDS, etc.
  • infectious agents and parasites e.g. Hepatitis B&C, H. pylori infection, malaria, tuberculosis, etc.
  • those associated with endocrine function e.g. diabetes, pancreatitis, etc.
  • those associated with degenerative processes e.g. aging, Alzheimer's, Parkinson's, etc.
  • those genetically mediated e.g. muscular dystrophy, etc.
  • various forms of trauma e.g. heat shock, post-perfusion injury, restenosis after angioplasty, etc.
  • the present invention provides a method of treating a disease associated with prolonged or excessive activation of NF-kB, comprising administering a composition comprising at least one plant extract from a plant that is a source of sesquiterpene lactone, or a composition comprising a sesquiterpene lactone in an effective amount to a patient in need thereof.
  • the plant extract is extracted from feverfew, and the sesquiterpene lactone is parthenolide.
  • feverfew is understood to include the herb as well as any portion or preparation thereof, including without limitation various extracts thereof.
  • the present invention more particularly relates to a practical and advantageous means of treating various specific and types of maladies and conditions, especially those known or thought to involve the NF-kB pathway, its components, modulators, products and effects. It has been found that various maladies and conditions, especially maladies and conditions known to be associated with the activation of NF-kB, may be treated by the appropriate administration of an effective amount of a composition comprised of sesquiterpene lactones, more preferably parthenolide and yet more preferably feverfew. Said effective amount is often found to be a surprisingly small amount.
  • compositions comprising sesquiterpene lactones have been previously employed, most particularly the naturally occurring herb feverfew
  • the use of the specific doses and administration routes previously employed has proven to be generally ineffective. Namely, oral administration by means of ingesting tablets, pills and the like is ineffective.
  • the administration of the surprisingly small amount of the composition comprised of sesquiterpene lactones, more preferably parthenolide and yet more preferably feverfew is most effective, and surprisingly is remarkably more effective, when administered by alternate routes as disclosed herein, namely, administration which bypasses the gastrointestinal tract. Parenteral, topical or topical mucosal administration has been found to be required to achieve the most efficacious treatment.
  • an amount of one or more of the compositions disclosed hereby is considered to be effective to treat the disease if the disease either is observed to have a reduced likelihood of occurrence or a reduced rate of symptom or exacerbation occurrence or a reduced rate of increase in severity or to reduce in severity upon treatment as described herein.
  • an amount of one or more of the compositions disclosed hereby is considered to be effective in treatment of migraine, MS, asthma, or similar maladies characterized by episodes of symptoms or exacerbations if the rate of occurrence of such episodes is reduced.
  • FIG. 2 is a schematic representation of NF-kB inhibition by aspirin and parthenolide.
  • FIG. 3 is a schematic representation of basic signaling pathways leading to activation of NF-kB.
  • MMP9 cancer, arthritis
  • c-Myc cancer
  • 5'deiodinase euthyroid sick syndrome
  • HIV LTR AIDS
  • Bcl-xL cancer
  • C-IAP2 cancer
  • iNOS septic shock, migraine
  • COX-2 inflammation generally, colorectal cancer
  • NF-kB A peculiarity of NF-kB is that it may be induced very rapidly and (with few non-pathological exceptions) is only transiently activated, which makes it well suited for the expression of many immune and "stress"-response genes, because these often need to be up-regulated only on demand and then only for a relatively brief period of time before being turned off (down-regulated.)
  • NF-kB A peculiarity of NF-kB is that it may be induced very rapidly and (with few non-pathological exceptions) is only transiently activated, which makes it well suited for the expression of many immune and "stress"-response genes, because these often need to be up-regulated only on demand and then only for a relatively brief period of time before being turned off (down-regulated.)
  • Prolonged activation of NF-kB is, for example, a hallmark of many chronic inflammatory, vascular and autoimmune diseases. It is also noted in and associated with many other pathological conditions. That is, based on evidence accumulated to date, the transient activation of NF-kB appears as though it is often protective or beneficial while its chronic activation appears as though it is often harmful or pathological.
  • NF-kB Of the many products regulated by NF-kB, either in whole or in part, (all or any one of which may be of importance or particular importance in respect of a specific effect, circumstance, condition or ailment), iNOS (inducible nitric oxide synthase) and COX-2 (cyclooxygenase-2) have received a great deal of recent attention.
  • iNOS inducible nitric oxide synthase
  • COX-2 cyclooxygenase-2
  • NF-kB and the activation thereof is thought to play a pivotal role in iNOS (inducible nitric oxide synthase) induction and also in the transcription of many acute phase proteins, including cytokines, adhesion molecules, and antioxidant enzymes, among others It is informative to look at the theoretical relationship between NF-kB activation and iNOS. Under basal (non-inflammation) conditions, NF-kB is sequestered within the cytoplasm by the IkB inhibitory proteins. Phosphorylation of two Ser residues on IkB, mediated by IKKB of the IKK
  • iNOS NF-kappaB enhancer elements regulate cytokine induction of the human inducible nitric oxide synthase gene. JBiol Chem 1998; 273: 15148-15156.) iNOS is believed to be associated with many aspects of inflammation generally, and is believed to be closely associated with certain diseases in particular (migraine, post- cerebral infarct injury, septic shock, etc.).
  • iNOS synthesis can be triggered by and result from cellular exposure to a variety of stimuli, such as bacterial lipopolysaccharide (LPS), cytokines (e.g., tumor necrosis factor- [TNF-], IL-1, and IL-6), and interferon- (IFN-), as well as by oxidative stress.
  • LPS bacterial lipopolysaccharide
  • cytokines e.g., tumor necrosis factor- [TNF-], IL-1, and IL-6
  • IFN- interferon-
  • Reuter and colleagues recently demonstrated that brief exposure to GTN (known to induce migraine in susceptible individuals) increased iNOS expression in rat meninges and generated NO within resident macrophages 6 hours after drug administration (Reuter, U., Chiarugi A., Bolay H., et. al.
  • parthenolide (a sesquiterpene lactone component of the medicinal herb feverfew) has been shown to suppress iNOS and interleukin expression, presumably by blocking NF-kB activity and related transcriptional events.
  • NF-kB NF-kB pathway
  • NF-kB pathway should each be understood to include the pathway, its components, modulators, products and effects.
  • mediators known to be of central importance and shown to be effected or regulated by NF-kB include, without limitation, interleukins and growth factors, cytokine and cell adhesion receptors, apoptosis related mediators, immunomodulatory mediators and others, including iNOS, COX-2, IL-6 and TNF.
  • Figure 2 With few exceptions, neither the herb feverfew, which naturally contains parthenolide as the most abundant sesquiterpene lactone, nor parthenolide itself, nor feverfew extract has been used to prevent or treat conditions associated with NF-kB, including iNOS. In those few cases where historical use of specific doses and administration routes is known (e.g.
  • the treatment has always been prophylactic, never acute, and of questionable value in its supposed prophylactic role.
  • the present invention may provide an effective, novel means of selectively inhibiting iNOS expression by means of its effect on the components, modulators, products and effects of the NF-kB pathway, especially the inhibition thereof.
  • COX-2 is of particular interest and importance, especially considering the relatively recent arrival, popularity and commercial success of selective COX-2 inhibiting NSAIDs (non-steroidal anti-inflammatory drugs). Inflammatory diseases affect more than fifty million Americans. As a result of basic research in molecular and cellular immunology over the last ten to fifteen years, approaches to diagnosing, treating and preventing these immunologically-based diseases has been dramatically altered.
  • NSAIDs non-steroidal anti-inflammatory drugs
  • COX-2 inducible form of the cyclooxygenase enzyme.
  • Constitutive cyclooxygenase (COX) first purified in 1976 and cloned in 1988, functions in the synthesis of prostaglandins (PGs) from arachidonic acid (AA). Three years after its purification, an inducible enzyme with COX activity was identified and given the name COX-2, while constitutive COX was termed COX- 1.
  • COX-2 has made possible the design of drugs that reduce inflammation without removing the protective PGs in the stomach and kidney made by COX-1.
  • These selective COX-2 inhibitors may not only be anti-inflammatory, but may also act in ways that are ultimately beneficial in the prevention and treatment of colon cancer and Alzheimer's disease.
  • COX-2 gene expression is under the control of pro-inflammatory cytokines and growth factors.
  • COX-2 functions in both inflammation and control of cell growth.
  • COX-2 is inducible in many tissues, it is present constitutively in the brain and spinal cord, where it may function in nerve transmission for pain and fever.
  • the two isoforms of COX are nearly identical in structure but have important differences in substrate and inhibitor selectivity and in their intracellular locations.
  • Protective PGs, which preserve the integrity of the stomach lining and maintain normal renal function in a compromised kidney, are synthesized by COX- 1.
  • PGs synthesized by COX-2 in immune cells are central to the inflammatory process.
  • the present invention may provide an effective, novel and advantageous means of selectively inhibiting COX-2 expression, especially by means of its effect on the components, modulators, products and effects of the NF-kB pathway, especially the inhibition thereof.
  • upregulation of COX-2 expression and PG production are commonly found in many cancer cells such as colorectal cancer and a number of COX-2 inhibitors (selective or non-selective) such as nonsteroidal anti-inflammatory drugs (NSAIDs) are able to selectively induce apoptotic cell death in cancer cells (Sano et al., 1995; Shiff et al., 1995; Kutchera et al., 1996;
  • COX-2 inhibitors selective or non-selective
  • NSAIDs nonsteroidal anti-inflammatory drugs
  • COX-2 is involved not only in the onset of inflammation, but also with mitogenic responses (Dubois et al., 1998; Williams et al., 1999). Most probably, COX-2 promotes cell proliferation and inhibits apoptosis in cancer cells through a dual-mechanism: (i) enhanced synthesis of PGs, which favor the growth of malignant cells by increasing cell proliferation (Sheng et al., 1997; 1998), and (ii) reduced level of arachidonic acid, which has recently been found to promote apoptosis in cancer cells (Chan et al., 1998; Cao et al., 2000).
  • Aspirin is known to be a very weak inhibitor of NF-kB, but nonetheless has been noted to exert an anti-carcinogenic effect. Without wishing to be bound or limited by the present theory, the surprising efficacy and substantial benefit of the invention disclosed herein may result from or be largely attributable to its being a much more potent and better inhibitor of NF-kB.
  • parthenolide is capable of inhibiting DNA synthesis and cell proliferation in a number of different types of cancer cells, but the mechanism of action is not known (Woynarowski and Konopa, 1981; Hall et al., 1988; Ross et al., 1999).
  • parthenolide is capable of increasing the sensitivity of human breast cancer cells to paclitaxel, a chemotherapeutical drug (Patel et al., 2000).
  • paclitaxel a chemotherapeutical drug
  • neither the herb feverfew, nor parthenolide or other sesquiterpene lactone has been effectively used to prevent or treat cancer.
  • the present invention provides an effective, novel means of preventing and treating cancer, either as a sole agent or in combination with generally known chemotherapeutic agents.
  • Aspirin treatment also resulted in approximately a 20% reduction in basal rates of hepatic glucose production and approximately a 20% improvement in insulin-stimulated peripheral glucose uptake.
  • type 2 diabetes may be successfully treated by inhibition of the NF-kB pathway, in this case by administration of aspirin at high doses. More specifically, by blocking the IKKB component of the IKK Complex, clinical improvement may be substantial.
  • aspirin is regarded as but a weak inhibitor of NF-kB. The potential value of a more potent such inhibitor might be substantial, especially one found to be economical, convenient, and relatively free from serious side effects.
  • NF-kB activation affects and is involved in many diverse processes and many diverse conditions and diseases, not all of which are presently known, but even the number known being so extensive as to preclude exhaustive discussion or entire inclusion herein. Nonetheless, while not wishing to be bound or limited by any particular theory, the present invention relates to each such diverse disease and condition and provides a novel means for the treatment or prevention of any and each each such diverse disease and/or condition.
  • parthenolide a sesquiterpene lactone and the purported active ingredient in feverfew
  • Parthenolide was shown to bind to and inactivate the IKK Complex by specifically binding with and inactivating its beta subunit, IKKB. This binding to and inactivation of IKKB prevents the activation (up regulation) of NF-kB (Kwok BH, Koh B, Ndubuisi MI, et al. Tlie anti-inflammatory natural product parthenolide from the medicinal herb feverfew directly binds to and inhibits IB kinase.
  • parthenolide has been shown to reduce the DNA binding activity of NF-kB even when administered after IKKB activation. It is believed parthenolide and perhaps other sesquiterpene lactones may also inhibit NF-kB- driven transcription by alkylating p65, thereby preventing its transactivation through the inhibition of binding (figure 3).
  • parthenolide may act by mechanisms independent of NF-kB, including cell membrane destruction as well as by other, even entirely unknown mechanisms. Note that the above actions were reported to have been observed in vitro.
  • NF-AT transcription factor nuclear factor of activated T-cells
  • This transcription factor is also shown to be blocked (inactivated) by a sesquiterpene lactone present in Arnica montana (Klaas, CA Studies on the anti- inflammatory activity of phytopharmaceuticals prepared from Arnica flowers. Planta Med. 2002 May;68(5):385-91.) Since many sesquiterpene lactones studied thus far have been shown to exert similar effects, it is likely that parthenolide acts like the sesquiterpene lactone of Arnica in regard to the inactivation of NF-AT.
  • parthenolide has been shown to inhibit NF-kB activation in vitro, and thus represents a potential means to achieve NF-kB inhibition, and thus affect some or all of the disease states and conditions in which the NF-kB pathway plays a role.
  • NF-kB inhibition may be an effective treatment or even a "cure,” while in others merely a mitigation or limitation of symptoms or the provision of a specific beneficial effect other than a "cure".
  • a composition comprising a sesquiterpene lactone, or more specifically parthenolide, or yet more specifically of feverfew, may possibly be used in combination with other therapies to augment said other therapies and the beneficial effects thereof.
  • Such augmentation use might be employed with another NF-kB inhibitor (e.g. aspirin, steroids) or by augmentation of the effects of a drug or therapy seemingly unrelated to inhibition of NF-kB (e.g.
  • Some other common sesquiterpene lactones are artemisinin, encelin, leucanthin B, enhydrin, melapodin A, tenulin, confertiflorin, bilobalide, burrodin, psilostachyin A, costunolide, strigol, helenalin, 5-.alpha.-hydroxy- dehydrocosruslactone, chlorochrymorin, chrysandiol, chrysartemin A, chrysartemin B, cinerenin, curcolone, cynaropicrin, dehydrocostus lactone, dehydroleucodin, dehydrozaluzanin C, deoxylatucin, eremanthine, eupaformonin, eupaformosanin, eupatolide, furanodienone, heterogorgiolide, lactucin, magnolialide, michelenolide, repin, spir
  • glucocorticoids have been shown to block NF-kb activation, albeit different mechanisms are proposed in respect of different cell types.
  • Glucocorticoids have been reported to directly bind to the RelA and NF-kB 1 subunits of NF-kB, thereby preventing DNA binding and transactivation.
  • Another mechanism involves the induction of IkB at the transcriptional level (more inhibitor thus preventing the activation of NF-kB by keeping a greater percentage sequestered in the cytoplasm).
  • Aspirin and other NSAIDS have been reported to inhibit NF-kB activation.
  • salicylates e.g. aspirin, sodium salicylate
  • Ik2 binding to Ik2
  • RSk2 decreased activity of IKKB
  • Direct inhibition of NF-kB has been demonstrated with sulfasalazine, a sulfa medicine, which is especially used to prevent and treat inflammatory bowel disease (for example ulcerative colitis) and rheumatoid arthritis in patients who have not been helped by or who cannot tolerate other medicines for rheumatoid arthritis.
  • NF-kB neurotrophic factor-kB
  • Other known inhibiters of NF-kB include many natural and synthetic antioxidants (e.g. vitamins A, C & E, polyphenols of green tea, etc.), immunosuppressants, and natural plant compounds, suggesting that the ability to inhibit NF-kB at least partially accounts for their purported mild therapeutic effects (e.g. reducing incidence rates of cancer and atherosclerosis with prolonged usage).
  • trans-resveratol found in red wine
  • Atorvastatin a synthetic 3-hydroxy-3-methylglutaryl- coenzyme A reductase inhibitor that lowers plasma cholesterol levels by inhibiting endogenous cholesterol synthesis, has been shown to prevent activation of NF-kB in SMCs (smooth muscle cells) by interfering with IKKB.
  • SMCs smooth muscle cells
  • IKKB interfering with IKKB.
  • NF-kB inhibitors are proposed to act at several different points in the signaling pathway, including by means of scavenging of oxygen radicals, inhibition of the IKK Complex, inhibition of (subsets of) the proteasome, binding to the transcription factor, interference with transactivation, and interference with the degradation of IkB as well ashy the induction of IkB.
  • Many of the presently known inhibitors e.g., antioxidants
  • Others are associated with severe and limiting side effects, as is generally the case for what might be the single potent inhibitor
  • the present invention is of great benefit as potentially offering a novel means by which one might effectively inhibit NF-kB activity without incurring the severe side effects sometimes encountered with other such inhibitors, especially in that the compositions and methods revealed hereby are practical, relatively inexpensive and clinically effective in the treatment of various diverse ailments and conditions.
  • parthenolide has been shown in vitro to bind to and inactivate
  • crude chloroform extracts of fresh feverfew leaves produced dose-dependent inhibition of the generation of thromboxane B2 and leukotriene B4 by ionophore-and chemoattractant-stimulated rat peritoneal leukocytes and human polymorphonuclear leukocytes.
  • Commercially available powdered leaves also produced dose-dependent inhibition of the generation of thromboxane B2 (TXB2) and leukotriene B4 (LTB4) by ionophore- and chemoattractant-stimulated rat peritoneal leukocytes and human polymorphonuclear leukocytes.
  • IC50 values were in the range 5-50 micrograms/mL, and inhibition of TXB2 and LTB4 occurred in parallel.
  • Sumner, et al concluded that feverfew contains a complex mixture of sesquiterpene lactone and non-sesquiterpene lactone inhibitors of eicosanoid synthesis, and that these biochemical actions may be relevant to the claimed therapeutic actions of the herb.
  • Williams noted feverfew's 6-hydroxyflavonols as inhibitors of cyclo-oxygenase and 5-lipoxygenase (Williams, CA, The flavonoids ofTanacetumparthenium and T. vulgar e and their anti-inflammatory properties Phytochemistry 1999
  • parthenolide may suppress Interleukin-4 (IL-4) expression at the mRNA and protein levels in a dose dependent manner (Li- Weber M.
  • IL-4 Interleukin-4
  • IL-4 is a key cytokine that influences the development of T-helper 2 cells and plays an important role in the pathogenesis of allergic diseases. While not wishing to be bound or limited by any particular theory, it may be that certain of the various findings result from or are closely associated with the action of parthenolide and other sesquiterpene lactones, or even other co-occurring pharmacologically active compounds, as inhibitors of the NF-kB pathway. There may also be effects, either by the sesquiterpene lactones or the other pharmacologically active agents, which, though acting by means of a different mechanism, are synergistic with, or augment these NF-kB effects.
  • active components of feverfew may act by mechanisms significant but as yet unknown.
  • Numerous publications suggest that the active components of feverfew are sesquiterpene lactones, parthenolide being the most abundant. Nonetheless, parthenolide is almost certainly not the sole pharmacologically active constituent of feverfew (Brown et al Pharmacological activity of feverfew (Tanacetum parthenium (L.) Schultz-Bip.): assessment by inhibition of human polymorphonuclear leukocyte chemiluminescence in-vitro. J Pharm Pharmacol. 1997 May;49(5):558-61.)
  • Feverfew and its constituents are generally regarded as being useful only as in vitro research tools and items of investigational curiosity. With but only several isolated exceptions, they not been employed for the treatment of conditions presently believed to involve the NF-kB pathway.
  • One possible exception is the prophylactic (preventative) treatment of migraine headaches using specific doses and administration routes.
  • Established medicine has in fact rejected this prior known use of feverfew in migraine prophylaxis using specific doses and administration routes as being an ineffective means of migraine prophylaxis, or has at best adopted a neutral and skeptical stance in regard to its application.
  • Neglect by medicine and science of feverfew, parthenolide and sesquiterpene lactones for the clinical treatment and/or prevention of various ailments and conditions is not due to lack of knowledge concerning the many proposed in vitro activities of feverfew and parthenolide (or other sesquiterpene lactones), but rather stems from what are believed to be practical considerations concerning what are believed to be limitations or obstructions to its effective in vivo use and practical clinical application.
  • Parthenolide as feverfew, is believed to be only a weak inhibitor of NF-kB and thus of no greater clinical utility than other supposed weak inhibitors such as naturally occurring antioxidants like vitamins C and E, it not being thought possible to employ these in vivo in an effective and practical manner, namely in clinical medicine, specifically in the effective treatment or prevention of pathology, especially in the acute treatment thereof.
  • feverfew or its constituents including parthenolide, or other sesquiterpene lactones, are anything other than very weak inhibitors of NF-kB, or that effective application to the in vivo treatment of various diseases and conditions is possible, and in fact may be achieved by a practical, convenient, economical and effective means that is also clinically advantageous when employed in the treatment of human pathology, especially the acute treatment thereof.
  • the present invention therefore discloses and constitutes a novel and exceptionally useful tool in clinical medicine which is surprisingly effective in the treatment of many diverse maladies and conditions.
  • parthenolide and/or feverfew required to be employed in the laboratory setting to evidence the in vitro effects noted (for example, the use of relatively high concentrations as often employed and the use of relatively long incubation times as often employed, these often in combination) has lead investigators to conclude that parthenolide and/or sesquiterpene lactones and/or feverfew cannot be practically employed in the treatment of various diverse maladies and conditions because such concentrations and/or times of exposure could not practically be achieved in a living organism, especially not in a general setting.
  • the present invention provides an easy, practical and inexpensive means to apply an effective dose in an effective way and thus reveals both the possible and practical application of feverfew and/or its constituents, including parthenolide and other sesquiterpene lactones for use in the treatment of diseases and conditions as described herein.
  • Parthenolide is viewed as an investigational tool, and is employed (as are any other number of known NF-kB suppressors) in vitro in laboratory settings, especially for use in further elaborating the mechanism and role of NF-kB through its in vitro blockade thereof (at relatively high doses and under specific conditions, which specific conditions generally include the exposure of the cells or other system under study to parthenolide at a relatively high concentration and for an extended period of time).
  • Aspirin is but one 'traditional' product which is believed to exert at least some small portion of its effect, at least at high dosages, through the inhibition of NF-kB (believed most likely to act, at least in part, via the same general site of action as that proposed for parthenolide; Fig. 2).
  • Aspirin, as noted, may exert effects by means of its effect on the NF-kB pathway, such as a long-term reduction in the risk of developing certain cancers and perhaps provides its noted cardio-protective effect in the same manner (e.g. reduction in heart attack risk).
  • the dose having been noted to be generally required to achieve a clinically significant acute effect by means of NF-kB suppression is believed to be on the order of 7-9 grams of aspirin per day, somewhat more than 20 standard 325 mg tablets per day.
  • Aspirin use even at 'normal' doses is already associated with significant side effects.
  • the administration of such high doses is very inconvenient, and more importantly would be expected to result in substantial stomach upset as well as additional, more serious side effects.
  • Such a large dose may be genuinely dangerous with regard to short-term toxicity as well as long-term sequelae (e.g. stomach ulcers, kidney failure).
  • Parthenolide as a biological agent is not entirely unique, as it is but one example of a large class of "sesquiterpene lactones" (albeit parthenolide is probably the best known and most studied of this class). It appears that all or many sesquiterpene lactones may exhibit similar effects through their common ⁇ - methylene ⁇ -lactone moiety. Thus other sesquiterpene lactones, though not having been in every case so thoroughly investigated as parthenolide, are often found to behave in a similar manner in vitro. Generally, other sesquiterpene lactones have been shown to exhibit an identical or a very similar mechanism of action as parthenolide.
  • a sesquiterpene lactone from the Korean traditional medicinal herb Carpesium divaricatum has recently been shown, in vitro, to inhibit NF-kB activation (Kim EJ, Suppression by a sesquiterpene lactone from Carpesium divaricatum of inducible nitric oxide synthase by inhibiting nuclear factor-kappaB activation Biochem Pharmacol 2001 Apr 1;61(7):903-10)
  • the sesquiterpene lactones may nonetheless vary somewhat in their actions and effects, especially in relation to specific medical conditions.
  • helenalin and bis (helenalinyl) malonate sesquiterpene lactones shown to be cytotoxic against the growth of P-388 lymphocytic leukemia cells in culture
  • helenalin and bis (helenalinyl) malonate sesquiterpene lactones shown to be cytotoxic against the growth of P-388 lymphocytic leukemia cells in culture
  • helenalin and bis (helenalinyl) malonate sesquiterpene lactones shown to be cytotoxic against the growth of P-388 lymphocytic leukemia cells in culture
  • epoxide moiety Haall et al Inhibition of nucleic acid synthesis in P-388 lymphocytic leukemia cells in culture by sesquiterpene lactones. Anticancer Res.
  • sesquiterpene lactones often act in similar ways and may exert their respective effects by the same general mechanism as has been proposed for parthenolide.
  • all or nearly all sesquiterpene lactones might potentially be in vitro inhibitors ofNF-kB.
  • One important activity proposed to be in part regulated by NF-kB relates to apoptotic cell death (Barkett and Gilmore, 1999). Although there is present uncertainty whether NF-kB promotes or inhibits apoptosis, this appears to depend on the specific cell type under study and perhaps the nature of stimuli otherwise influencing apoptosis.
  • NF-kB activated NF-kB
  • Cancer cells might normally be eliminated by the body's own defense system, but the activation of NF-kB seems, at least in part, to account for their continued survival. Indeed, NF-kB activation in cancer cells may confer not only protection against the body's natural defenses, but also protection against what might otherwise be effective therapeutic interventions.
  • NF-kB activation is increased markedly in certain cancers after exposure to anti-cancer radiation treatments of ionizing radiation (Jung et al NF-kappa B signaling pathway as a target for human tumor radiosensitization. Semin Radiat Oncol.
  • NF-kB activation can be an adaptive response of cells to short term stress, in which case it may be either beneficial or detrimental to the organism.
  • Increased NF-kB activation found in association with (and purportedly resulting from) both radiation therapy and chemotherapy for neoplastic disorders is clearly disadvantageous. In this case, (cancer) cell survival is obviously not what is desired.
  • sesquiterpene lactone (of the several reported to have been investigated) employed in combination with these therapies, the anti-cancer effect appears to be consistent, further supporting the idea that sesquiterpene lactones, as a class, most often exhibit similar effects. These similar effects are most likely due to a similar mechanism of action.
  • Sesquiterpene lactones in general especially those containing an . alpha. -methylene-.gamma.- lactone group, have been shown to possess activity against tumor growth and general inflammation. Hall discloses that sesquiterpene lactones possess activity against general inflammatory reactions (Hall I. et al., "Anti-Inflammatory Activity of Sesquiterpene Lactones and Related Compounds," J. Pharm. Sci., vol. 68, pp. 537-542 (1979)).
  • Sesquiterpene lactones include (without limitation) (+)-Isovelleral; (+)-Isovelleral isomer 2; (+)-Juvabione; (+)-T-Cadinol; (- )-Isovelleral; (1)10-Aristolen-2-one; (5-Hydroxymethyl-5,8a-dimethyl-2-methylene- decahydro-naphthalen-1 -ylmethoxy)-(2-oxo-tetrahydro-furan-3-yl)-acetic acid; (5- Hydroxymethyl-5 , 8 a-dimethyl-2-methylene-decahydro-naphthalen- 1 -ylmethoxy)- (2-oxo-tetrahydro-furan-3-yl)-acetic
  • Acetylcedren; Acoradiene also known as Acoradin
  • Alloaromadendrene Allolaurinterol
  • Allospathulenol alpha- and beta-Santalol
  • alpha-Arteether alpha- Bisabolol; alpha-Bisabolol oxide (A-form)
  • alpha-Cadinol alpha-Eudesmol; alpha- Guaiene; Aplysistatin; ar-5-Hydroxyturmerone; ar-Turmerone
  • Aromadendral also known as Aromadendrene
  • Aromadendrane- 7beta,l lbeta-diol Aromadendren
  • Debneyol Debromolaurinterol; delta-Cadinene; delta-Cadinol; Deoxyelephantopin; Dermatolactone; Deferral; Dihydrolinderazulene; Dihydromicanolide; Dihydrothujopsene; Drimane-7,9(ll)-diene; Elemol; Encelin; Epicubenol; Epiglobulol; Epipolygodial; Eupatolide; Exomerulidal; Exovelleral A; Exovelleral B; Farinosin; Farnesal; Farnesol; Farnesyl acetate; Famesyl methyl ether;
  • Vellerdiol Vellerol; Vetiverol; Vetiveryl acetate; Viridiflorol; Vulgarin;
  • Fig. 3 shows basic signaling pathways leading to activation of NF-kB.
  • soluble mediators e.g., inflammatory cytokines
  • TRAFs that activate members of the MAP3 (NIK, MEKK1) and other kinases.
  • the latter further activate IKK that phosphorylates IkB on amino-terminal serine residues, leading to its proteasome-mediated degradation.
  • IKK phosphorylates IkB on amino-terminal serine residues, leading to its proteasome-mediated degradation.
  • NF-kB is liberated from its cytoplasmic complex and translocates to the nucleus.
  • NF-kB has been specifically shown to be of importance in
  • Incontinentia pigmenti (Courtois & Israel A, 2000); Asthma (Pahl & Szelenyi,
  • HTLV-1 Acute T-cell leukemia
  • EBV Burkitts Lymphoma
  • MBV Burkitts Lymphoma
  • Multiple myeloma Berenson et al. 2001 Diffuse large B-cell lymphoma Davis et al., 2001; Shaffer et al., 2002
  • BCR-ABL Reuther et al. 1999 DBL/DBS Whitehead et al., 1999
  • Parenteral routes are contemplated hereby, though for most applications the treatment is most preferably administered mucosally or transdermally.
  • Parenteral administration includes intravenous, intraarterial, intraperitoneal, subcutaneous, intramuscular, intrathecal, transepithelial (for example in the form of a slow-release subcutaneous implant), nasally, infrapulmonary, transdermal (for example, by means of an external patch or application as described further herein), and all mucosal and transmucosal modes of administration such as sublingual mucosal, buccal mucosal, oral mucosal, nasal mucosal, pulmonary mucosal, vaginal mucosal and rectal mucosal.
  • Parenteral administration may also be by oral or nasal inhalation with the intention of delivering to any combination of oral mucosa, nasal mucosa, any of the branches of the airways (especially pulmonary mucosa), and any of the portions of the digestive tract, where various portions of the digestive tract benefit from local and, as it were, topical administration, versus serving as a route to systemic administration.
  • Formulations for mucosal delivery may be employed for primarily local action at the mucosal site of administration, as well as for systemic delivery thereby, or any combination thereof;
  • Topical mucosal application includes application to the mucosal areas of the rectum, vagina, eye, nose, mouth and both the gastrointestinal tract and respiratory tract generally.
  • topical (e.g. dermal) application primarily for local action and non-systemic delivery is also contemplated hereby.
  • topical (e.g. dermal) application primarily for local action and non-systemic delivery is also contemplated hereby.
  • at least a portion of the administered dosage composition is preferably retained in contact or approximation with the mucosal membrane or topical surface for a time sufficient to allow additional or sufficient absorption by those mucosal tissues or topical surfaces.
  • Parenteral administration may be by discrete dosing or by continuous infusion or administration by any means over a selected period of time.
  • Suitable pharmaceutically acceptable carriers and diluents known in the art may therefore be combined in the preparation of suitable dosage forms comprised of one or more sesquiterpene lactones (including especially parthenolide), preferably comprised of feverfew, or derivatives of one or more sesquiterpene lactones and/or feverfew.
  • a particularly preferred embodiment of the present invention utilizes a feverfew extract comprising a composition extracted from the feverfew plant that contains one or more of the various constituents initially isolatable from the feverfew plant and degradation products thereof.
  • a local route of administration is one in which the primary objective is to deliver actives to the tissue with which the composition comes in direct contact and the immediately adjacent tissues, not withstanding the fact that some minority amount of actives may at any particular time generally be absorbed and distributed systemically.
  • the location to be affected by such local administration includes the tissue with which the composition comes in direct contact and the immediately adjacent tissues.
  • a composition comprised of sesquiterpene lactones, more preferably parthenolide and yet more preferably feverfew is effective, and often extremely effective, in treating or preventing maladies, especially maladies associated with NF-kB, when administered by any means which results in delivery of actives to the bloodstream without substantial reliance on ingestion and subsequent absorption through the gastrointestinal tract, specifically the gastrointestinal tract distal to the pharynx
  • distal gastrointestinal tract typically and previously employed. It further has been found that often a surprisingly small amount of that a composition comprised of sesquiterpene lactones, more preferably parthenolide and yet more preferably feverfew is effective when administered in this manner. The most preferable such means is, generally, through mucosal absorption or transdermal absorption.
  • compositions comprised of sesquiterpene lactones, including parthenolide and feverfew, have at times been administered in specific doses and by specific administration routes, in the few select instances in which they have been administered at all with respect to any of the ailments described herein (e.g. migraine).
  • the present invention provides an effective, practical, convenient means of treating or preventing maladies by the administration of compositions comprising relatively small doses of sesquiterpene lactones, more preferably parthenolide and yet more preferably feverfew.
  • compositions comprised of surprisingly small amounts of sesquiterpene lactones can be employed as effective treatments for a variety of conditions when administered so as to avoid substantial reliance on typical and previously employed ingestion and subsequent absorption through the distal gastrointestinal tract, the most preferably means of such avoidance being by use of mucosal or transdermal administration, most preferably said compositions being comprised of feverfew, an extract of feverfew being generally preferred. This has been neither known nor taught, either in general or with regard to specific ailments and conditions called out herein.
  • compositions comprising one or more sesquiterpene lactones, including parthenolide, and especially feverfew, which are suggested by the scientific literature to have been observed in vitro, previously known only in theory and by way of speculation, but not available for practical, clinical application in the treatment of ailments and conditions, and not useful in the treatment of an animal, particularly a mammal and most particularly a human, become by means of the present invention a clinical and practical reality which may be of great use and tremendous value to a great many individuals in the treatment or prevention of many diverse ailments.
  • compositions comprised of sesquiterpene lactones, preferably parthenolide and most preferably feverfew, are made available in a useful, convenient, generally inexpensive and effective form for treatment of patients, who may thus benefit very substantially in regard to any number of diseases and conditions, especially those wherein NF-kB is known to or does play a role. That the invention is useful and of great benefit will be readily appreciated. That it has been heretofore unknown and has not previously been employed as specified herein for the treatment and prevention of ailments is readily apparent.
  • the present invention provides in one aspect a method of treating or preventing maladies comprising administering parenterally, especially and preferably mucosally and/or transdermally, a composition comprising one or more sesquiterpene lactones, especially parthenolide, to a patient in need thereof, especially in one or more doses in a total (cumulative) amount of less than about 200 mg, and preferably from about 0.025 mg. to about 100 mg. in a two hour period.
  • a "dose" is a predetermined aliquot of composition having a predetermined amount of active ingredient contained therein. Multiple doses may be administered to a patient at about the same time, with each aliquot being administered considered a separate dose.
  • administration may be continuous by any appropriate means of achieving same (slow release salts, transdermal patch, etc.).
  • a plurality of doses of sesquiterpene lactone are administered to a mucus membrane over a 24 hour period, preferably the total amount of sesquiterpene lactone being about 0.025 mg. to about 500 mg.
  • the individual doses of sesquiterpene lactone each do not exceed about 100 mg. except possibly in the case of transdermal administration, where the dose is adjusted to provide delivery at the preferred rate as set forth herein according to the specific transdennal delivery system employed.
  • the sesquiterpene lactone may be administered in one to six doses in a 24 hour period.
  • a multiplicity of both doses and routes may be employed so as to maintain a low but still therapeutic blood level of the active constituents ("Actives" or "Active”).
  • Actives refers to one or more active constituents derived from a source of sesquiterpene lactones.
  • a preferred example of actives includes the active constituents derived from feverfew, especially sesquiterpene lactones and especially parthenolide and the compositions comprised thereof.
  • an immediate sublingual dose may be applied to a patient in need thereof, followed or preceded in a short amount of time (e.g., within approximately two hours) or immediately or nearly immediately by the administration of a transdermal dose.
  • the sublingual (in this example) dose is absorbed rapidly and quickly establishes a therapeutic blood level, while the transdermal (in this example) administration delivers Actives to a therapeutic concentration in a less immediate but more prolonged and sustained manner.
  • Other combinations of fast acting but unsustained administration combined with more sustained administration of Actives are possible as alternate embodiments of the present invention.
  • maladies and/or their associated symptoms are treated by administering a composition comprising feverfew, especially feverfew extract, parenterally, preferably to a mucous membrane or transdermally, to a patient in need thereof, preferably in a total administered amount of from about 2.0 mg. to about 1000 mg. of feverfew extract in a two hour period.
  • a plurality of doses of feverfew extract are administered parenterally, preferably to a mucus membrane or transdennally, over a 24 hour period, the total amount of feverfew extract preferably not exceeding about 5000 mg.
  • the individual doses of feverfew extract each does not exceed about 1000 mg.
  • the feverfew extract is administered parenterally, most preferably to a mucous membrane or transdermally, in one to six doses in a 24 hour period, preferably either mucosally or transdermally.
  • the efficacy of the composition is enhanced, especially when administered via the oral or nasal mucosal route, when the composition is of an acidic pH, preferably at a pH of from about 2.5 to about 6.0. It has additionally been found that the efficacy of the composition is enhanced, especially for oral or nasal mucosal application, when the composition, if a liquid, has a viscosity greater than water, and more preferably when said composition has a viscosity greater than about 100 cP. Liquid compositions having higher viscosity have been found to enable the patient to better establish and maintain contact of the composition with the mucosal membrane, including the nasal or oral mucosa and most particularly the sublingual area.
  • the carrier liquid includes a mucosal permeation enhancer.
  • the treatment may also be used daily or occasionally as a prophylactic treatment, or as needed as a prophylactic treatment, or for the maintenance of health.
  • compositions are provided in a unit dose applicator for oral mucosal or nasal mucosal administration, preferably sublingual administration. More particularly, a unit dose applicator and composition for oral mucosal administration to patients is provided comprising a dispenser for dispensing liquids having a reservoir and a delivery spout. The dispenser has a liquid capacity of about 0.1 to about 10 mis. This dispenser is provided with a liquid composition disposed therein.
  • the composition comprises a sesquiterpene lactone, preferably parthenolide, in an amount not exceeding about 100 mg.
  • the liquid composition in the unit dose dispenser comprises feverfew, preferably feverfew extract, in an amount not exceeding about 1000 mg.
  • the dosage may be administered in any convenient and appropriate form for mucosal or transdermal administration, or any form appropriate for the parenteral route of administration employed, or any form appropriate for the local administration thereof.
  • An active sesquiterpene lactone may be administered to a patient by any suitable means.
  • Pharmaceutically acceptable carrier preparations for parenteral administration include sterile, aqueous or non-aqueous solutions, suspensions, and emulsions.
  • non-aqueous solvents examples include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate.
  • Aqueous carriers include water, alcoholic/aqueous solutions, emulsions or suspensions, including saline and buffered media.
  • Parenteral vehicles include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's, or fixed oils.
  • the Active therapeutic ingredient may be mixed with excipients that are pharmaceutically acceptable and are compatible with the Active ingredient. Suitable excipients include water, saline, dextrose, glycerol and ethanol, or combinations thereof.
  • Intravenous vehicles include fluid and nutrient replenishers, electrolyte replenishers, such as those based on Ringer's dextrose, and the like. Preservatives and other additives may also be present such as, for example, antimicrobials, anti-oxidants, chelating agents, inert gases, and the like. Such compositions may be readily prepared by the routineer in the field, by consulting with established formularies and substituting the indicated active ingredients as taught herein.
  • compositions for injection may be provided in the form of an ampule, each containing a unit dose amount, or in the form of a container containing multiple doses.
  • compositions for treatment of and by application to the eye may be provided in a dropper bottle or similar which is suitable to the intended purpose.
  • compositions for use by application to the nasal mucosa may be provided in a nasal spray squeeze bottle, etc.
  • Active sesquiterpene lactone may be formulated into therapeutic compositions as pharmaceutically acceptable salts.
  • These salts include the acid addition salts formed with inorganic acids such as, for example, hydrochloric or phosphoric acid, or organic acids such as acetic, oxalic, or tartaric acid, and the like. Salts also include those formed from inorganic bases such as, for example, sodium, potassium, arnmonium, calcium or ferric hydroxides, and organic bases such as isopropylamine, trimethylamine, histidine, procaine and the like.
  • Controlled delivery may be achieved by admixing the Active with appropriate macromolecules, for example, polyesters, polyamino acids, polyvinyl pyrrolidone, ethylenevinylacetate, methylcellulose, carboxymethylcellulose, prolamine sulfate, or lactide/glycolide copolymers.
  • the rate of release of the Active may be controlled by altering the concentration of the macromolecule.
  • Another method for controlling the duration of action comprises incorporating the Active into particles of a polymeric substance such as a polyester, peptide, hydrogel, polylactide/glycolide copolymer, or ethylenevinylacetate copolymers.
  • an Active may be encapsulated in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for example, by the use of hydroxymethylcellulose or gelatin-microcapsules or poly(methylmethacrylate) microcapsules, respectively, or in a colloid drug delivery system.
  • Colloidal dispersion systems include macromolecule complexes, nanocapsules, microspheres, beads, and lipid-based systems including oil-in-water emulsions, micelles, mixed micelles, and liposomes.
  • compositions are also provided, wherein the composition comprises a sesquiterpene lactone, preferably parthenolide, in an amount of from about 0.01 mg/ml to about 100 mg/ml, and more preferably from about 0.01 mg/ml to about 10 mg/ml. and yet more preferably in an amount from 0.01 mg/ml to about 5 mg/ml.
  • the composition comprises feverfew, preferably feverfew extract, in an amount of from about 1 mg/ml to about 500 mg/ml.
  • Alternative vehicles appropriate for administration, especially mucosal and transdermal administration are also contemplated. Such compositions may be readily prepared by the routineer in the field, by consulting with established formularies and substituting the indicated active ingredients as taught herein.
  • systemic administration of a composition comprised of a relatively small amount of sesquiterpene lactone, and more preferably, parthenolide, and yet more preferably feverfew, to mucosal membranes, transdermally, or by an alternate, appropriate parenteral route, either alone or in combination with other treatments, provides excellent treatment for various maladies and conditions, including at times the prevention thereof.
  • local, non- systemic administration of Actives is also contemplated hereby as an alternate embodiment of the present invention.
  • the ability to effectively treat maladies using such low yet rapidly effective doses of Active ingredient (Actives) provides substantial benefits, including not only effective relief from maladies, but also the drastic reduction in side effects which might otherwise be associated with said Active ingredient or alternative treatments.
  • sesquiterpene lactones may be administered via the G.I. tract in a manner effective to provide either acute benefit or prophylactic benefit for the diseases described herein.
  • one or more Actives, especially sesquiterpene lactones are administered at a higher dose to account for the amount of Actives destroyed or eliminated by first-pass metabolism. In this embodiment, the amount of G.I.
  • administration dose is determined such that the amount of Actives that are actually delivered to the affected cells of the patient is sufficient to suppress the activity of NF-kB or otherwise be effective. For example, in certain embodiments it may be determined that 95% of Actives are destroyed by first-pass metabolism. In this example, a tablet that contains 20x the amount of Actives is administered to achieve the desired treatment result.
  • This approach of administration is particularly practical in the present invention, in light of the relatively inexpensive nature of the Actives.
  • This aspect of the present invention is particularly desirable where long term administration of Actives, especially sesquiterpene lactone is contemplated for prophylactic treatment due to the convenience and low cost for the patient.
  • a specifically preferred example of such a treatment course is the use of feverfew in a daily administered tablet, which would in one particular example be taken for years as prophylaxis for Alzheimer's disease by patients in the early stages of the disease or who have been identified as having a high risk of developing this disease.
  • Prophylactic treatment by administration of a high dose to account for the amount of Active that is destroyed or eliminated by first-pass metabolism is specifically contemplated for each disease listed herein.
  • Enhancement of the oral G.I. efficacy is contemplated by selection of oral administration formats or content to increase the amount of Active that is delivered after first pass metabolism.
  • enhancements include providing a protective coating, modification of tablet dissolution rates, addition of stabilizers or other such chemical components that counteract the destructive activity of the G.I. tract, or other such measures as may be appropriate to enhance administration of sesquiterpene lactones.
  • Actives especially sesquiterpene lactones may be administered in combination with other active ingredients for treatment of the same or a different malady.
  • Such combination of active ingredients may be desirable for treatment of acute diseases, and is contemplated to be particularly advantageous for long term administration of prophylactic treatments.
  • sesquiterpene lactones may be combined in administration forms with another agent to be taken daily (such as a cholesterol lowering drug), so that the patient need only administer one medication/dose vs. multiple medications and doses.
  • One substantial advantage of the present invention is its safety. But one example of which is the lack of mutagenicity of the Actives. Thirty migraine patients who had taken the leaves, tablets or capsules of feverfew daily for more than 11 consecutive months were compared to 30 feverfew non-user migraine patients who had been individually age- and sex-matched. The frequency of chromosomal aberrations and sister chromatid exchanges (SCE) were determined from lymphocyte cultures established from blood samples taken over a period of several months. Matched pairs were sampled on the same date for two-thirds of the cases, and the greatest difference in sampling time of the remainder was 20 days.
  • SCE sister chromatid exchanges
  • post-feverfew syndrome reported to occur in up to 10% of migraine patients who abruptly stop taking feverfew after a long history of daily use.
  • Another advantage of the present invention is the likely avoidance of such side effects, as the use of feverfew as envisioned hereby is generally not daily, and even when employed daily will generally be in an amount substantially less than those orally ingested amounts reported to have caused these side effects. While most side effects are mild, it is nonetheless advantageous to avoid or reduce their occurrence to the greatest extent possible while still employing an effective dose.
  • NSAIDs non-steroidal anti-inflammatory drugs
  • Glucocorticoids are believed to be more effective inhibitors of NF-kB.
  • Glucocorticoid associated side effects may be serious and can include osteoporosis, susceptibility to bruising, infections, diabetes, cataracts, glaucoma, high blood pressure and weight gain.
  • An additional side effect that may be caused by treatment with glucocorticoids is osteonecrosis, which involves serious damage to the bones. Osteonecrosis may begin to develop even after the short-term use of glucocorticoids to treat rheumatoid arthritis.
  • the alternate inhibitor of NF-kB disclosed hereby including that it may have a substantially more advantageous side effect profile.
  • the invention is particularly beneficial to those patients concerned about using large amounts of medication for treatment of ailments.
  • the low total administered amount of Actives and relatively small amount of total composition that may be applied to the mucosal membranes, transdermally, or otherwise in one aspect of the present invention may additionally be of particular benefit to those treating ailments.
  • the present invention provides substantial benefits to patients, not least of which may be the cost savings associated with a decreased reliance on expensive pharmaceuticals.
  • the present invention often provides rapid relief of symptoms. Depending on the condition treated or the use for which it is employed, beneficial effects of the treatment may be felt within minutes of administration. Alternate existing treatments may be effective for some patients, but not for others, necessitating a lengthy and sometimes costly search by each person for the treatment that will be effective for that particular individual. Surprisingly, the present invention is for many ailments effective for a large percentage of people who try this treatment. Thus, the present invention provides additional substantial benefit to the practitioner or individual who may discover conveniently and without delay those for whom this treatment is effective, searching amongst other alternatives only in those cases where this medication proves insufficiently effective.
  • a particularly preferred embodiment of the present invention comprises administration of feverfew, most preferably feverfew extract. More specifically, a preferred method of treating maladies comprises administering a liquid composition comprising feverfew extract via a mucous membrane, most preferably sublingually, to a patient in need thereof.
  • Feverfew extract is derived from the feverfew plant (Tanaecetum parthenium), which is also known, for example, as Chrysanthemum parthenium, Chrisanthemum parthenium, Pyrethrum parthenium, Tanacete parthenii herba or folium, Matricaria parthenoides, Matricaria parthenium, Leucanthemum parthenium, Matricaria parthenium, Spanish pellitory, Featherfew, Featherfoil, feather-fully, and by a number of common names, various of which are used throughout the world (Midsummer daisy, Bachelor's buttons, Altamisa, nosebleed, flirtwort, ague plant, devil daisy, feddygen fenyw (Welsh), maid's weed, Missouri snakeroot, mutterkaut (German), prairie-dock, vetter-voo, wild chamomile, grande camomille (French), Santa Maria (Spain),
  • the extract of the feverfew plant generally contains parthenolide, and may additionally contain other components such as Polyynes, Flavonoids and Volatile oils including camphor, bomeol and others, each of which may contribute to the therapeutic effect of the preparation disclosed herein. Feverfew also naturally contains relatively large quantities of sesquiterpene lactones, primarily parthenolide.
  • feverfew extracts and feverfew itself, is known to contain many components, including the following non-ubiquitous chemicals: 1- Beta-hydroxyarbusculin, 10-Epicanin, 8-Beta-reynosin, Apigenin-7-glucuronide, Apigenin-7-glucoside, Chrysanthernolide, Chrysanthemonin, Chrysartemin-A, Chrysartemin-B, Cosmosiin, L-Borneol, L-camphor, Mangoliolide, Reynosin, Santamarin, chrysanthernolide, chrysanthemomin, chrysarten-A, chrsyart-c, chrysoeriol-7-glucuronide, cobalt, cosmosiin, epoxyartemorin, luteolin-7-glucoside, luteolin-7-glucuronide, Tanaparthin, Tanaparthin-1 -alpha, 4-alpha
  • compositions comprising the extract of feverfew are generally preferred for use in the present invention as compared to compositions comprising a highly purified parthenolide or other sesquiterpene lactone that has been isolated from the additional components naturally occurring in feverfew extract.
  • compositions comprising a highly purified parthenolide or other sesquiterpene lactone that has been isolated from the additional components naturally occurring in feverfew extract.
  • feverfew preparations including fresh feverfew, dried feverfew, feverfew powder, and dried leaf bits in solution, among a number of other such possible preparations.
  • Preferred embodiments of the present invention use feverfew extract that has been standardized to initially contain a predetermined standardized parthenolide concentration of preferably not less than about 1.0%, and more preferably 4.0% and higher.
  • the source of sesquiterpene lactone, especially parthenolide, in compositions of the present invention is preferably feverfew as discussed above, it may alternatively be obtained from any number of other plant species.
  • plant species include especially other members of the Compositae family, which include especially the many species of chrysanthemums, daisies, marigolds, chamomile, yarrow and aster.
  • Parthenolide and other sesquiterpene lactones can also be obtained from tansy and a very large number of other woody and herbaceous plants.
  • sesquiterpene lactones, including parthenolide may be made by any appropriate synthetic route.
  • composition to be used in the present invention may optionally comprise additional active ingredients.
  • active ingredients may also be provided as a treatment of maladies or may provide other physical benefits, provided that the treatment benefit of sesquiterpene lactones such as parthenolide and/or the feverfew extract is not adversely affected.
  • additional amounts of already present sesquiterpene lactones or additional sesquiterpene lactones are incorporated in the compositions of the present invention.
  • Preferred such sesquiterpene lactones include especially those which are known to be contained in (naturally occur in) feverfew, such as 3-Beta-hydroxyparthenolide, seco- tanaparthenolide A, canin, artecanin, chrysanthemonin, chrysartemin A and B, santamarin and balchanin, as well as those occurring in other plant species such as encelin, leucanthin B, enhydrin, melampodin A, tenulin, confertiflorin, burrodin, psilostachyin A, costunolide, guaianolide, cinerenin, artemisinin, aristolactone, lactarorufin A, bilobalide, helenalin, furandiol.
  • 3-Beta-hydroxyparthenolide such as 3-Beta-hydroxyparthenolide, seco- tanaparthenolide A, canin, artecanin,
  • Sesquiterpene lactones in addition to parthenolide may be isolated from plants such as dandelion, burdock, butterburr, mugwort and sunflower plants, among very many others.
  • Compositions to be used in the present invention may optionally additionally comprise other naturally occurring components and extracts, including those identified in the Homeopathic Pharmacopoeia of the United States (HPUS).
  • Preferred additional components include the extracts of bay leaf and/or ginger and/or green tea, and/or turmeric or the isolated components thereof.
  • a particularly preferred isolated component of green tea is L-theanine and a particularly preferred isolated component of turmeric is cucumin.
  • compositions of the present invention contain substantially no active ingredients other than those that are extractable from herbal sources.
  • the compositions contain substantially no active ingredients other than those that are extractable from feverfew, bay leaf, ginger, turmeric and green tea sources.
  • the compositions contain substantially no active ingredients other than those that are extractable from feverfew, ginger and turmeric.
  • the compositions contain substantially no active ingredients other than those that are extractable from feverfew and ginger, or from feverfew alone.
  • Such compositions additionally may comprise non-pharmacologically active ingredients, such as thickeners, carrier liquids and flavorants.
  • compositions may additionally contain one or more members selected from the group consisting of antioxidants, vitamins, minerals, proteins, fats, carbohydrates, glucosamine, chondrotin sulfate and aminosugars. It has surprisingly been discovered that the use of only active ingredients that are extracted from herbs provide particular benefit to the user in being both effective and also providing natural healing conditions particularly suited to the well being of patients. Such compositions contain parthenolide in the amounts as discussed earlier, and preferably contain less than about 500 mg of any given natural active ingredient per dose.
  • compositions as described herein are formulated using a carrier appropriate for administration to the topical region or mucosal membrane employed, the most preferable mucosal membrane being the sublingual region of the mouth, when such administration is employed these are selected from the group consisting of jelly, creme, gel, solid, semi-solid, rapidly dissolving tablet or pill, liquid, droplet, aerosol, powder, microsome, liposome, emulsion, sol-gel, foam, gum (e.g. chewing gum), sustained release, degradable polymer, impregnated film, impregnated fiber, impregnated patch, coated film, coated fiber, coated patch, flexible solid, semisolid carrier, polymeric matrix, suspended microspheres, and thermoreversible gel.
  • the carrier liquid preferably is selected from water, alcohol, oils (such as synthetic mono or digylcerides), fat, polyethylene glycols, glycerin, propylene glycol, and mixtures thereof. Most preferably the carrier comprises water.
  • Thickening agents are preferably incorporated in liquid compositions of the present invention.
  • the thickening agent When employed mucosally, the thickening agent preferably assists in retention of the liquid composition on or in close proximity with the surface of the mucosal region for a time sufficient to allow absorption of the active ingredients by the patient.
  • Thickening agents are particularly desirable in sublingual and nasal applications, as a more viscous agent is more easily retained in the proper area. In the case of sublingual administration, a more viscous agent further reduces the user's involuntary impulse to swallow, in this case perhaps prematurely.
  • the thickening agent may assist in providing sublingual liquid retention or nasal mucosal retention for a time appropriate for proper absorption of the active ingredient by the patient, and also thereby may improve the clinical efficacy of the composition.
  • Any appropriate thickening agent may be used in the composition of the present invention.
  • Preferred such thickening agents include agar, alginate, carrageenan, carboxymethylcellulose, cellulose, chitosan, com starch, Danish agar, dextrin, furcelleran, galactomannans, gelatin, gellan gum, guar gum, gum acacia, gum arabic, gum ghatti, gum tragacanth, hydroxypropyl methylcellulose, karaya gum, methylcellulose, polyvinyl alcohol, carboxyvinyl polymer, polyvinylpyrrolidone, hyaluronic acid and salts thereof, modified starches, mucilage, pectin, potato starch, rice starch, starch, tara gum, vegetable starch, wheat starch, and xanthan gum and combinations thereof.
  • compositions of the present invention when employed in liquid form for sublingual administration have a viscosity that is from about 100 cP (somewhat lower than the viscosity of Olive Oil) to about 50,000 (i.e. the viscosity of molasses), and more preferably from about 500 cP (the viscosity of SAE #10 motor oil) to about 5000 cP (approximately the viscosity of Com Syrup), all measured at 25 °C.
  • compositions as described herein may further comprise suitable adjuvants, such as preservatives (for example, sodium benzoate, sorbic acid and esters of p-hydroxybenzoic acid), stabilizers, antibacterial agents (such as benzyl alcohol or methyl paraben), antioxidants (such as ascorbic acid or sodium bisulfite), chelating agents (such as ethylenediaminetetraacetic acid), buffers (such as acetates, citrates or phosphates), agents for the adjustment of tonicity (such as sodium chloride or dextrose), dyes, colorants, thickening agents, flavorants, sweetening agents, and suspending agents.
  • preservatives for example, sodium benzoate, sorbic acid and esters of p-hydroxybenzoic acid
  • stabilizers such as sodium benzoate, sorbic acid and esters of p-hydroxybenzoic acid
  • antibacterial agents such as benzyl alcohol or methyl paraben
  • antioxidants such as ascorbic acid or
  • the compositions of the present invention are provided in combination with a mucosal permeation enhancer appropriate for enhancing the mucosal absorption of the composition employed.
  • a mucosal permeation enhancer appropriate for enhancing the mucosal absorption of the composition employed.
  • Such permeation enhancer is particularly desirable for applications to nasal mucosal tissue, and is most desirable for applications to oral mucosal tissue, such as buccal and sublingual tissue.
  • Permeation enhancers additionally may be particularly desirable for use in applications to nasal mucosal tissue. Mucosal permeation enhancers may in such cases increase the absorption of Actives and thereby may improve the clinical efficacy of the composition.
  • Preferred mucosal permeation enhancers include azone, sodium glycholate, sodium cholate, sodium tauracholate, sodium taurocholate plus EDTA, deoxycholate, sodium lauryl sulfate, lauric acid, ethanol, lysophosphatidyl choline, polysorbate 80, cyclodextrin, cetylpyridinium chloride, cetyltrimethylammonium bromide, benzalkonium chloride, sodium salicylate, sodium EDTA, aprotinin, dextran sulfate, linoleic acid, labrafil, transcutol, urea, methoxysalicylate, POE 23 lauryl ether, various surfactants and other mucosal permeation enhancers and combinations thereof.
  • the mucosal permeation enhancer comprises sodium lauryl sulfate.
  • the compositions of the present invention are provided at a pH of from about 2.0 to about 6.5, more preferably at a pH of from about 2.5 to about 6.0, and more preferably at a pH of from about 3 to about 5.
  • Various pH adjusters may be used to adjust the pH of the composition to the desired level. Examples of suitable pH adjusters include hydrochloric acid, citric acid, phosphoric acid, acetic acid, tartaric acid, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogen carbonate, boric acid, sodium borate, and the like.
  • the pH of the composition is adjusted to be acidic using ascorbic acid.
  • the composition is buffered by a pharmaceutically acceptable buffer.
  • buffering agents include borate buffers, citrate buffers, phosphate buffers, tartarate buffers, acetate buffers, carbonate buffers, and amino acid salts, etc.
  • the buffer is sodium citrate.
  • Such compositions may be readily prepared by the routineer in the field, by consulting with established formularies and substituting the indicated active ingredients as taught herein.
  • compositions as described herein may be administered using any appropriate technique, such as by use of a medicine dropper, syringe, vial, or the like.
  • the composition is administered using a unit dose applicator that is a dispenser having a reservoir and a delivery spout and having a liquid capacity of about 0.1 to about 10 mis.
  • the unit dose applicator is provided as a dispenser having parthenolide in an amount not exceeding about 100 mg, or other limited quantities as discussed above.
  • the unit dose applicator is provided as a dispenser having feverfew extract in an amount not exceeding about 1000 mg, or other limited quantities as discussed above.
  • a particularly preferred dispenser is the MicroDoseTM dispenser commercially available from Unicep Packaging, Inc., Sandpoint, ID.
  • the dispenser may be an ampule designed to mate with a plunger of a syringe to facilitate controlled delivery of the composition, such as described in U.S. Patent No. 6,328,715.
  • This invention also includes a method of treating inflammatory disorders and related conditions of the skin by applying a topical composition comprising an effective amount of an extract of feverfew to a patient.
  • Biologically active agents to be employed in topical compositions may include, but are not limited to, flavanoid/flavone compounds which include but are not limited to tanetin, 3,7,3'-trimethoxyquercetagetin, apigenin and its derivatives.
  • flavanoid/flavone compounds When flavanoid/flavone compounds are present, they are present at a concentration of between about 0.001% to about 0.5% preferably, between about 0.005% and 0.2% based on the weight of the topical composition.
  • Additional biologically active agents for use in topical applications include but are not limited to sunscreens, anti-wrinkling/antiaging agents, antifungal agents, antibiotic agents, anti-acne and antipsoriatic agents, depigmentating agents, where such agents may be utilized so long as they are physically and chemically compatible with the other components of the topical composition.
  • the compositions of this invention when employed topically may include additional skin actives. Actives can be but not limited to vitamin compounds.
  • Skin lightening agents kojic acid, ascorbic acid and derivatives such as ascorbyl pamiltate, and the like
  • anti-oxidant agents such as tocopherol and esters
  • metal chelators, retinoids and derivatives moisturizing agents, hydroxy acids such as salicylic acid, sun screen such as octyl methoxycinnamate, oxybenzone, avobenzone, and the like, sun blocks such as titanium oxide and zinc oxide, and skin protectants.
  • sun blocks such as titanium oxide and zinc oxide
  • skin protectants Mixtures of above skin actives may be used.
  • Sunscreens which may be used in the compositions of this invention intended for topical use and may include but are not limited to organic or inorganic sunscreens, such as, octylmethoxycinnamate and other cinnamate compounds, titanium dioxide, zinc oxide and the like.
  • Anti-wrinkling/anti-aging agents used in the compositions of this invention intended for topical use may include but are not limited to retinoids (for example, retinoic acid, retinol, retinal, retinyl acetate, and retinyl palmitate) alpha hydroxy acids, galactose sugars (for example, melibiose and lactose), antioxidants, including but not limited to water soluble antioxidants such as sulfhydryl compounds and their derivatives (for example, sodium metabisulfite and N-acetyl-cysteine, acetyl- cysteine), lipoic acid and dihydrolipoic acid, resveratrol, lactoferin, ascorbic acid and ascorbic acid derivatives (for example ascorbyl palmitate and ascorbyl polypeptide).
  • retinoids for example, retinoic acid, retinol, retinal, retinyl acetate, and retinyl palm
  • Oil soluble antioxidants suitable for use in the compositions of this invention include, but are not limited to tocopherols (for example, tocopheryl acetate, . alpha. -tocopherol), tocotrienols and ubiquinone.
  • Natural extracts containing antioxidants suitable for use in the compositions of this invention include, but not limited to extracts containing flavonoids, phenolic compounds, flavones, flavanones, isoflavonoids, mono, di- and tri-terpenes, sterols and their derivatives. Examples of such natural extracts include grape seed, green tea, pine bark and propolis extracts and legume extracts and the like.
  • Antifungal agents used in the compositions of this invention intended for topical use include but are not limited to miconazole, econazole, ketoconazole, itraconazole, fluconazole, bifoconazole, terconazole, butoconazole, tioconazole, oxiconazole, sulconazole, saperconazole, clotrimazole, undecylenic acid, haloprogin, butenafine, tolnaftate, nystatin, ciclopirox olamine, terbinafine, amorolfine, naftifine, elubiol, griseofulvin, and their pharmaceutically acceptable salts.
  • Antibiotic (or antiseptic agents) used in the compositions of this invention intended for topical use include but are not limited to mupirocin, neomycin sulfate, bacitracin, polymyxin B, 1-ofloxacin, tetracyclines (chlortetracycline hydrochloride, oxytetracycline hydrochloride and tetrachcycline hydrochoride), clindamycin phosphate, gentamicin sulfate, benzalkonium chloride, benzethonium chloride, hexylresorcinol, methylbenzethonium chloride, phenol, quaternary ammonium compounds, triclocarbon, triclosan, tea tree oil, benzoyl peroxide and their pharmaceutically acceptable salts.
  • Acne ingredients used in the compositions of this invention intended for topical use include but are not limited to agents that normalize epidermal differentiation (e.g. retinoids), keratolytic agents (e.g. salicylic acid and alpha hydroxy acids), benzoyl peroxide, antibiotics and compounds or plant extracts that regulate sebum.
  • agents that normalize epidermal differentiation e.g. retinoids
  • keratolytic agents e.g. salicylic acid and alpha hydroxy acids
  • benzoyl peroxide e.g. salicylic acid and alpha hydroxy acids
  • Antipsoriatic agents used in the compositions of this invention intended for topical use include but are not limited to corticosteroids (e.g., betamethasone dipropionate, betamethasone valerate, clobetasol propionate, diflorasone diacetate, halobetasol propionate, amcinonide, desoximetasone, fluocinonide, fluocinolone acetonide, halcinonide, triamcinolone acetate, hydrocortisone, hydrocortisone valerate, hydrocortisone butyrate, aclometasone dipropionte, flurandrenolide, mometasone furoate, methylprednisolone acetate), Vitamin D and its analogues (e.g. calcipotriene), retinoids (e.g. Tazarotene) and anthraline.
  • corticosteroids e.g., betamethasone
  • Cosmetic agents which may be used in the compositions of this invention when intended for topical use may include, but are not limited to those agents which prevent potential skin irritation, such as emollients, vitamins and antioxidants (e.g., vitamin E) and herbal extracts (e.g., aloe vera). Further, the cosmetic agents may include humectants, antioxidants/preservatives, plant extracts, flavors, fragrances, surface active agents, and the like.
  • humectants include glycerol, sorbitol, propylene glycol, ethylene glycol, 1,3 -butylene glycol, polypropylene glycol, xylitol, maltitol, lactitol, oat protein, allantoin, acetamine MEA, hyaluronic acid and the like. They may be used either singly or in combination.
  • Cosmetic agents may also include substances which mask the symptoms of inflammatory disorders and related conditions; such substances include but are not limited to pigments, dyes, and other additives (e.g., silica, talk, zinc oxide, titanium oxide, clay powders).
  • the pharmaceutical excipients include but are not limited to pH modifying agents such as pH-modifying agents, organic solvents (e.g., propylene glycol, glycerol, etc.), cetyl alcohol, kaolin, talc, zinc oxide, titanium oxide, cornstarch, sodium gluconate, oils (e.g., mineral oil), ceteareth-20, ceteth-2, surfactants and emulsifiers, thickener (or binders), perfume, antioxidants, preservatives, and water.
  • pH modifying agents such as pH-modifying agents, organic solvents (e.g., propylene glycol, glycerol, etc.), cetyl alcohol, kaolin, talc, zinc oxide, titanium oxide, cornstarch, sodium glucon
  • Binders or thickeners may be used in the compositions of this invention to provide substantivity and physical stability to the compositions.
  • Binders or thickeners suitable for use in the compositions of this invention include cellulose derivatives such as alkali metal salts of carboxymethylcellulose, methyl cellulose, hydroxyethyl cellulose and sodium carboxymethylhydroxyethyl cellulose, alkali metal alginates such as sodium alginate, propylene glycol alginate, gums such as carrageenan, xanthan gum, tragacanth gum, caraya gum and gum arabic, and synthetic binders such as polyvinyl alcohol, polysodium acrylate and polyvinyl pyrrolidone. Thickeners such as natural gums and synthetic polymers, as well as coloring agents and fragrances also are commonly included in such compositions.
  • preservatives which may be used in the compositions of this invention intended for topical use include, but are not limited to, salicylic acid, chlorhexidine hydrochloride, phenoxyethanol, sodium benzoate, methyl para- hydroxybenzoate, ethyl para-hydroxybenzoate, propyl para-hydroxybenzoate, butyl parahydroxybenzoate and the like.
  • flavors and fragrances which may be used in the compositions of this invention intended for topical use include menthol, anethole, carvone, eugenol, limonene, ocimene, n-decylalcohol, citronellol, a-terpineol, methyl salicylate, methyl acetate, citranellyl acetate, cineole, linalool, ethyl linalool, vanillin, thymol, spearmint oil, peppermint oil, lemon oil, orange oil, sage oil, rosemary oil, cinnamon oil, pimento oil, cinnamon leaf oil, perilla oil, wintergreen oil, clove oil, eucalyptus oil and the like.
  • compositions of the present invention may be prepared in a number of forms for topical application to a patient.
  • the composition may be applied in a gel, cream, ointment, shampoo, scalp conditioner, liquid, spray liquid, paint-/brush-on preparation, aerosol, powder or adhesive bandage.
  • the composition may be impregnated on bandages, hydrocolloid dressing, treatment patch or on cloth wipe products, such as baby wipes or facial wipes.
  • the compositions of this invention when intended for topical use may be in the form of emulsions, such as creams, lotions and the like.
  • Such compositions may have more than one phase and may include surface active agents which enable multiphase emulsions to be manufactured.
  • Examples of surface active agents which may be used in the compositions of this invention intended for topical use include sodium alkyl sufates, e.g., sodium lauryl sulfate and sodium myristyl sulfate, sodium N-acyl sarcosinates, e.g., sodium N-lauroyl sarcosinate and sodium N-myristoyl sarcosinate, sodium dodecylbenzenesulfonate, sodium hydrogenated coconut fatty acid monoglyceride sulfate, sodium lauryl sulfoacetate and N-acyl glutamates, e.g., N-palmitoyl glutamate, N-methylacyltaurin sodium salt, N-methylacylalanine sodium salt, sodium a-olefin sulfonate and sodium dioctylsulfosuccinate; N-alkylaminoglycerols, e.g., N-lauryldia
  • a dermatologically acceptable carrier is an important ingredient of the present invention when intended for topical use.
  • a suitable carrier is adequate for topical use. It is not only compatible with the active ingredients described herein, but will not introduce any toxicity and safety issues.
  • An effective and safe carrier varies from about 50% to about 99% by weight of the compositions of this invention and more preferably from about 75% to about 99% of the compositions.
  • compositions of this invention intended for topical use is often controlled or affected by the type of inflammatory disorder or related condition which is being treated. For example, if the compositions of this invention were used to treat a skin inflammation associated with athlete's foot, jock itch or diaper rash, talc would be a preferred pharmaceutical excipient and an antifungal agent would be preferred biological agent. If the compositions of this invention were to be used to treat eczema of the scalp, emulsifiers and oils would be preferred pharmaceutical excipients.
  • the condition of contact dermatitis may be treated by applying a topical composition comprising a sesquiterpene lactone, preferably parthenolide and most preferably feverfew extract.
  • Transdermal administration is also contemplated.
  • convenient systems for administration of sesquiterpene lactones, and as another embodiment parthenolide, and as another embodiment, feverfew extract are provided wherein compositions are provided as a transdermal patch for transdermal administration.
  • US Patent No. 5,503,843 to Santus discloses a transdermal patch for the delivery of a specific Compound to the skin of a patient.
  • the patch comprises a backing layer, a drug depot comprising the compound and a permeation enhancer composition.
  • US Patent No. 5,837,289 to Grasela, et al. discloses a composition and procedures for its formation and administration to provide a convenient, efficacious and simple transdermal administration of medications from a topically applied cream.
  • the composition incorporates at least two separate penetration enhancers which function synergistically to provide for rapid but controllable transport of the medication from the cream into the skin.
  • US Patent No. 6,410,062 to Callaghan, et al. describes a method of treating and preventing inflammatory disorders and related conditions by applying a topical composition comprising an effective amount of an extract of feverfew, where the extract is substantially free of ⁇ -unsaturated ⁇ -lactone, and particularly substantially free of parthenolide.
  • transdermal in this patent is described in a very specific manner that does not contemplate topical application of a composition or a patch, stating that the composition may be "administered transdermally, for example in the form of a slow-release subcutaneous implant.” See column 6, line 26.
  • Transdermal delivery of sesquiterpene lactones offers a means of circumventing the problems of overdosing and underdosing that may sometimes be associated with conventional delivery methods.
  • the transdermal delivery of parthenolide or other Actives as disclosed herein can be designed so that the rate of delivery of the parthenolide or other actives as disclosed herein closely follows the rate of the clearance of the particular active(s) from the environment, thus keeping constant or near constant levels of said active(s) in the blood, and reducing waste of active(s) and overdosing problems.
  • pharmaceutically acceptable refers to a substance which does not interfere with the effectiveness or the biological activity of the active ingredients and which is not toxic to the host or patient.
  • patient refers to a mammal that is being treated. Preferably the patient is a human.
  • an initial dose may be provided by means of, for example, sublingual administration of parthenolide, which provides an immediate and rapid rise in blood levels of the desired composition.
  • Transdermal delivery as presently described may then be employed in combination with the rapid sublingual delivery mechanism, thereby maintaining blood levels of the active agents in the therapeutic range.
  • the amount of time required for onset of absorption of a representative active e.g.
  • nitro glycerin when an active ingredient is delivered via a sublingual administration route is very short (about 2 minutes), while the time required for onset of absorption when the active is delivered via transdermal delivery is much longer (about 11 minutes).
  • the amount of time required to achieve peak plasma concentration when a representative active ingredient (e.g. nitro glycerin) is delivered via a sublingual administration route is also very short (about 5 minutes), while the time required to achieve peak plasma concentration when the active is delivered via transdermal delivery is much longer, generally about 90 minutes, though as another advantage of transdermal dosing, the time required to achieve peak plasma concentration via transdermal dosing can be modified based on the specifics of the transdermal system employed.
  • a particularly preferred embodiment of the present invention is a combination of mucosal, preferably sublingual, and transdermal administration as taught herein, so that one may achieve rapid active ingredient levels that are then sustained over many hours.
  • the transdermal delivery system may be designed to deliver actives, especially a sesquiterpene lactone, at the indicated rate for an extended period.
  • actives especially a sesquiterpene lactone
  • the transdermal delivery system will administer actives at the indicated rates for periods of 24 hours, or from about 1 to about 3 days, or about 3 to about 7 days, or from about 1 week to about 4 weeks. Longer rates of delivery of actives are also contemplated.
  • the extended controlled dose delivery of these as described herein provide particular benefit to the user in prophylactic uses, or where the ailment to be treated is one of long and continuous duration (e.g. arthritis, migraine associated with a menstrual period).
  • transdermal delivery also provides a comfortable, convenient and non-invasive method of administering Actives, especially sesquiterpene lactones, especially parthenolide.
  • Actives especially sesquiterpene lactones, especially parthenolide.
  • Gastrointestinal irritation and other side-effects associated with oral ingestion of actives, including parthenolide or other sesquiterpene lactones may be reduced or eliminated, and patient anxiety regarding invasive delivery methods, such as needles, is also eliminated.
  • transdermal administration avoids the "first pass effect," which often results when a medication is administered orally and thus has to pass through various organs, including the stomach and then, once in the bloodstream, the liver, before reaching the affected area of the body.
  • organs can absorb or chemically alter significant quantities of the passing medication, thus sometimes making effective administration of actives by this route impossible, or requiring that large excess quantities of the medication be administered initially to insure that an effective quantity of the medication will ultimately reach the affected area of the body.
  • compositions are provided in the form of a lotion cream or other spreadable or moldable material.
  • actives including parthenolide may be effectively topically administered by application of the cream to many bodily areas where a patch either will not fit or cannot be shaped to conform to the skin contours.
  • Such compositions may be readily prepared by the routineer in the field, by consulting with established formularies and substituting the indicated active ingredients as taught herein.
  • an appropriate cream composition may be formulated by forming an organogel from lecithin and isopropyl palmitate, as disclosed in U.S. Patent No. 5,837,289. Suitable gel structures thus may be formed and used as the base for a cream composition.
  • Parthenolide is preferably solubilized with a solvent, such as water, alcohol or other appropriate solvent, and mixed into the matrix to formulate an appropriate composition for application to the dermis of a patient, for transdermal systemic delivery of parthenolide to the patient.
  • a solvent such as water, alcohol or other appropriate solvent
  • Additional components such as cosmetic agents, binders, thickeners, preservatives and fragrances may be present in the topically applied cream or other moldable or spreadable material when intended for transdermal systemic delivery.
  • Cosmetic agents which may be used in the compositions of this invention when intended for transdermal systemic delivery may include, but are not limited to those agents which prevent potential skin irritation, such as emollients, vitamins and antioxidants (e.g., vitamin E) and herbal extracts (e.g., aloe vera).
  • the cosmetic agents may include humectants, antioxidants/preservatives, plant extracts, surface active agents, and the like.
  • humectants include glycerol, sorbitol, propylene glycol, ethylene glycol, 1,3 -butylene glycol, polypropylene glycol, xylitol, maltitol, lactitol, oat protein, allantoin, acetamine MEA, hyaluronic acid and the like. They may be used either singly or in combination.
  • Binders or thickeners may be used in the compositions of this invention to provide substantivity and physical stability to the compositions.
  • Binders or thickeners suitable for use in the compositions of this invention include cellulose derivatives such as alkali metal salts of carboxymethylcellulose, methyl cellulose, hydroxyethyl cellulose and sodium carboxymethylhydroxyethyl cellulose, alkali metal alginates such as sodium alginate, propylene glycol alginate, gums such as carrageenan, xanthan gum, tragacanth gum, caraya gum and gum arabic, and synthetic binders such as polyvinyl alcohol, polysodium acrylate and polyvinyl pyrrolidone.
  • Thickeners such as natural gums and synthetic polymers, as well as coloring agents and fragrances also are commonly included in such compositions.
  • preservatives which may be used in the compositions of this invention include, but are not limited to, salicylic acid, chlorhexidine hydrochloride, phenoxyethanol, sodium benzoate, methyl para-hydroxybenzoate, ethyl para- hydroxybenzoate, propyl para-hydroxybenzoate, butyl parahydroxybenzoate and the like.
  • fragrances which may be used in the compositions of this invention include menthol, anethole, carvone, eugenol, limonene, ocimene, n- decylalcohol, cifronellol, a-terpineol, methyl salicylate, methyl acetate, citronellyl acetate, cineole, linalool, ethyl linalool, vanillin, thymol, spearmint oil, peppermint oil, lemon oil, orange oil, sage oil, rosemary oil, cinnamon oil, pimento oil, cinnamon leaf oil, perilla oil, wintergreen oil, clove oil, eucalyptus oil and the like.
  • compositions of the present invention may be prepared in a number of forms for topical application to a patient.
  • the composition may be applied in a gel, cream, ointment, shampoo, scalp conditioners, liquid, spray liquid, paint-/brush-on preparation or aerosol.
  • the composition may be impregnated on a bandages, hydrocolloid dressing, treatment patch or on cloth wipe products, such as baby wipes or facial wipes.
  • compositions of this invention may be in the form of emulsions, such as creams, lotions and the like. Such compositions may have more than one phase and may include surface active agents which enable multiphase emulsions to be manufactured.
  • a cover sheet may be applied over the applied cream or spreadable material containing parthenolide, and further the cover sheet may be secured with an adhesive sheet or strip to protect against undesired exposure of the applied cream to the elements.
  • transdermal application of Actives is carried out by use of a transdermal composite, commonly referred to as a "patch."
  • the transdermal composite is a preconstructed composite capable of adhering to the dermis of a patient, having an effective amount of Actives that can be delivered from the transdermal composite, and a protective overlay material that substantially prevents undesired loss of Actives to the air or to surfaces that may contact the outer portion of the transdermal composite.
  • transdermal refers to systemic delivery, that is, delivery of Actives to regions in addition to the topical area of application and immediately surrounding tissues.
  • the transdermal composite may be provided in a number of configurations, as described herein and as may be readily carried out by the routineer in the drug delivery art.
  • the transdermal patch for the delivery of Active is a simple adhesive patch.
  • the patch comprises an impermeable backing layer, a release liner, and an Active/adhesive containing matrix.
  • the impermeable backing layer defines the top of the delivery device, i.e., the side furthest away from the skin when the device is in use.
  • the backing forms an occlusive layer that prevents the loss of Active and/or enhancers to the environment and protects the patch from contamination from the environment.
  • the backing layer may be opaque so as to protect the Active from light.
  • the backing layer can be made from standard commercially available films for medical use, such as those supplied by 3M Corporation, St.
  • Suitable materials which can be used to form the backing layer include films or sheets of polyolefin, polyester, polyurethane, polyvinyl alcohol, polyvinylidene, polyamide, ethylene- vinylacetate copolymer, ethylene-ethylacrylate copolymer, and the like, metal- apor deposited films or sheets thereof, rubber sheets or films, expanded synthetic resin sheets or films, unwoven fabrics, fabrics, knitted fabrics, paper, and foils. These materials can be used individually or as laminates. These films can be pigmented or metalized.
  • the patch may include a peel strip or release liner to cover the surface of the pressure-sensitive adhesive during storage, and prevent evaporative loss of the Active or enhancer(s).
  • the release liner may be formed with dimples for decreasing contacting surface with the adhesive layer, and it may also be formed with a pull-tab for making it easier for removing it from the device.
  • the peel strip may be made from any impermeable film, such as is specified for the backing layer. Additionally it may be made from metal foil, MylarTM film, polyethylene terephthalate, or any material normally used for this purpose in the art that is compatible with the Active and the chosen adhesive.
  • suitable compositions for the release liner include siliconized polyester, poly (1,1- dihydroperfluoroctylmethacrylate), fumed silica in silicone rubber, end-capped siliconized polyethylene terephthalate, polytefrafluoroethylene, cellophane, a film of polyvinyl chloride having titanium dioxide dispersed therein, and the like.
  • the Active source layer is comprised of the Active and an adhesive, the layer attaching directly to the skin of the patient after the peel strip or release liner is removed.
  • the Active source layer also comprises one or more enhancers.
  • the selection of the adhesive is important to the proper functioning of the transdermal delivery device. This is particularly true if a plasticizer-type enhancer is placed in the adhesive layer. Specifically, the adhesive layer must retain its functioning properties in the presence of the plasticizer-type and solvent-type enhancers, as well as upon exposure to the Active.
  • the adhesive may comprise matrix regions interspersed throughout the adhesive, wherein the matrix regions comprise Active. These matrix regions act as small reservoirs from which Active is released.
  • An alternative embodiment of the transdermal patch of the invention is a matrix patch.
  • a matrix patch comprises an impermeable backing layer, a release liner, a matrix layer comprising a matrix in which Active is dispersed, and a peripheral adhesive layer.
  • the matrix may be a polymer matrix, or a gel or cream in which the Active resides.
  • the patch may also include an optional porous membrane layer.
  • the patch may have an adhesive layer that is co-extensive with the skin facing surface of the patch.
  • the matrix layer comprises the Active, and one or more enhancers dispersed in a polymeric matrix.
  • the matrix layer may also comprise additional components such as diluents, stabilizers, vehicles, biocides, antioxidants, anti-irritants and the like.
  • a preferred embodiment of the matrix patch is a matrix patch with a peripheral adhesive annular ring and an Active source having a hydrogel matrix or a foam matrix.
  • a further embodiment of the invention is the reservoir type patch which allows a higher loading level of active material, and usually, a higher loading level of enhancer.
  • a patch is comprised of an impermeable backing layer which is sealed at its periphery to an inert membrane, thereby defining between these two layers an Active source.
  • An adhesive layer is affixed to the skin facing side of the patch.
  • the patch also comprises a release liner.
  • the Active source contains the Active, and optionally one or more enhancers or gelling components.
  • a membrane separates the Active reservoir from the adhesive layer.
  • the membrane is a non-rate controlling membrane.
  • a non-rate controlling membrane is one in which the rate of permeation of the enhancer(s) and Active through the membrane is greater than their permeation rate through the skin or any other portion of the device (typically two to five times greater or more).
  • a non-rate controlling membrane is extremely permeable to the enhancer(s) and the Active contained in the reservoir.
  • the membrane may be a rate-controlling membrane.
  • a rate-controlling membrane is one in which the rate of permeation of the enhancer(s) and the Active through the membrane is less than or equal to their permeation rate through the skin or any other portion of the device. Rate-controlling membranes are described, for example, in U.S. Pat. Nos. 4,460,372 and 4,379,454.
  • the membrane may comprise a microporous or porous material. Microporous membranes have a distinct pore structure with pores ranging in diameter from approximately 0.08 to 0.5 microns, preferably from about 0.1 and 0.4 microns, and more preferably from about 0.2 and 0.4 microns. Examples of suitable microporous membranes include polyethylene and polypropylene films, nylon, and nitrocellulose film.
  • the membrane and the backing layer are sealed at their peripheral edges to form the Active reservoir.
  • This seal should be substantially fluid-tight to prevent Active leakage from the reservoir through the seal between the backing layer and the membrane.
  • peripheral edges refer to the areas that are sealed together to define the Active reservoir. Therefore, extraneous membrane and backing layer material may extend outwardly from the Active reservoir and peripheral edge.
  • the Active reservoir contains a solution, suspension, or gel of the Active and the permeation enhancers, as well as diluents, such as water, and vehicles or other additives.
  • the Active can be dispersed in the solution, suspension, or gel in either a dissolved or undissolved state.
  • a gelling agent may be incorporated into the reservoir or matrix to increase the viscosity and rheological characteristics of the Active and enhancers.
  • the gelling agent comprises a pharmaceutically-acceptable material that is capable of increasing viscosity of the reservoir solution.
  • the Active delivery devices described herein will employ cellulosic materials as the gelling agent.
  • suitable cellulosic materials include cellulose, cellulose derivatives, alkylcellulose, hydroxy- (lower alkyl) cellulose derivatives where the alkyl group contains one to six carbons, carboxyalkylcellulose and the like.
  • Other gelling agents include PVP, CMC, Klucel, alginates, kaolinate, bentonite, or montmorillonite, other clay fillers, stearates, silicon dioxide particles, carboxy polymethylene, ethylene maleic anhydride, polyacrylamide, and poly (methyl vinyl ether maleic anhydride.)
  • the reservoir or matrix layer also may include diluents, stabilizers, vehicles, biocides, antioxidants, anti-irritants and the like.
  • diluents For example, water is frequently utilized as a diluent in the reservoir type patches. Typically water will be present in the reservoir in an amount not greater than about 50 wt %, based on the reservoir fill solution; preferably, not greater than 40 wt %.
  • Other diluents which will frequently find use in the Active delivery devices described herein include glycerine and propylene glycol .
  • a pressure-sensitive adhesive layer is affixed to the membrane opposite to the backing layer.
  • the adhesive layer should interact minimally with the Active.
  • the adhesive may comprise Active for additional delivery of Active to the user.
  • the adhesive should adhere firmly to the membrane, but removably to the release liner.
  • the device should stick securely to the wearer for extended periods, yet be removed at the desired time with minimum discomfort.
  • the device should not give rise to undue skin irritation, allergic reactions or other dermatological problems. These properties must be maintained from the time of patch manufacture, throughout storage, and up to and throughout the time of application.
  • An alternative embodiment of the reservoir patch has a peripheral adhesive, wherein the area of the adhesive layer is not co-extensive with the active releasing area of the patch, but rather forms an annular ring around the active releasing area of the patch.
  • the delivery of the Active thus is not primarily through the adhesive layer of the patch, although some lateral diffusion may occur within the patch, resulting in delivery of active substance through the adhesive at the periphery of the patch.
  • the shape of the peripheral adhesive region will vary with the shape of the patch, but will generally comprise the outer perimeter of the patch, in order that an adequate adhesive seal is maintained between the skin and the patch to prevent the patch from falling off.
  • the percentage of the patch that comprises the peripheral adhesive portion depends on the type of adhesive, the type of backing layer, the length of time the patch will be worn, and the weight and loading of Active in the patch. Such determinations will be apparent to the skilled artisan.
  • the patches Prior to use, the patches typically are stored in laminate foil pouches, both to prevent contamination and to avoid Active and/or enhancer(s) loss.
  • laminate foil pouches are standard in the industry, and therefore may be selected by the routineer in this art.
  • the patch may be assembled by any of the techniques known in the art for producing transdermal patches.
  • the patches may be of various shapes, but the round shape is preferred as it contains no comers and thus is less easily detached from the skin.
  • a chemical permeation enhancer may be desired.
  • the term “enhancer” is meant to encompass any enhancer or combination of enhancers that increases the flux of a substance across a mammalian stratum comeum.
  • permeation enhancers There are numerous possible permeation enhancers that can be used and they are typically categorized into two groups, solvent-type enhancers and plasticizing-type enhancers.
  • Plasticizer-type enhancers refers to fatty acids, fatty acid esters, fatty alcohols and similar hydrophobic compounds that are capable of increasing the permeability of Actives to the stratum corneum. Without limiting the scope of the present invention, the following is proposed as the mechanism of action of the plasticizer-type enhancers. It is believed that the function of the plasticizer-type enhancers is to migrate into the upper stratum corneum layers of the skin and disrupt the lipids which occupy the extracellular spaces of the stratum comeum. The stratum comeum layer, although only 25-50 microns thick, is the principal barrier to transdermal permeation. The plasticizer-type enhancers that migrate into the skin serve to increase the mobility and diffusion of the Active into the skin.
  • Plasticizer-type enhancers generally will have a molecular weight of greater than 150 but less than 1000.
  • the plasticizer-type enhancers should also be relatively water insoluble or they will leach into the subcutaneous tissue layers below the stratum comeum.
  • plasticizer-type enhancers with water solubility of less than 0.5 wt % are preferred, and more preferably 0.2 wt % or less.
  • a preferred group of plasticizer-type enhancers includes lower alkyl and alkoxy esters of pharmaceutically acceptable fatty acids, fatty acid esters, fatty alcohols, and similar hydrophobic compounds.
  • lower alkyl and lower alkoxy refers to alkyl and alkoxy groups having up to and including 7 carbon atoms and preferably, up to and including 4 carbon atoms.
  • alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, tertiary butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl and heptyl.
  • alkoxy groups include the oxides corresponding to the above alkyl groups.
  • Suitable fatty acid esters include saturated or unsaturated fatty acid esters, including isopropyl myristate, isopropyl palmitate, and the methyl and ethyl esters of oleic and lauric acid.
  • Suitable fatty alcohols include stearyl alcohol and oleyl alcohol.
  • suitable fatty acids include saturated and unsaturated fatty acids, including oleic acid, lauric acid, myristic acid, palmitic acid, stearic acid, linoleic acid, and palmitoleic acid.
  • plasticizer-type enhancers such as diethyl hexyl phthalate, octyldocecyl myristate, isostearyl isostearate, caprylic/capric triglycerides including polyethylene glycol esters of caprylic/capric acids, propylene glycol laurate (Lauroglycol), Miglyol (propylene glycol diester caproic, caprylic, capric, lauric acid), Lexol PG-865 (propylene glycol diester decanoic, octanoic acid), propylene glycol myristate (mirpyl), com oil polyethylene glycol-6 esters (Labrafil M2124CS), polyethylene glycol-8 caprylic capric glycerides (Labrasol), caprylic/capric triglycerides (Labrafac Lipophile WL 1349), caprylic/capric triglyceride polyethylene glycol esters of caprylic/capric
  • a preferred plasticizer-type enhancer for use with the mesylate salt of Rec 15/2739 include caprylic/capric acids triglyceride PEG-4 esters, available as Labrafac Hydro WL 1219, (Gattefosse, Westwood, N.J.) which contains a mixture of saturated polygly colyzed glycerides consisting of glycerides and polyethylene glycol esters of caprylic and capric acids.
  • the plasticizer-type enhancers may be used alone or in combination.
  • a particularly preferred enhancer combination including the caprylic/capric triglycerides for use with the mesylate salt of Rec 15/2739 is an enhancer vehicle consisting essentially of ethanol: caprylic/capric triglycerides polyethylene glycol-4 ester:propylene glycohisopropyl myristate in a 1:1:1:1 ratio.
  • solvent-type enhancer generally refers to relatively hydrophilic compounds having molecular weights of less than about 200 that are capable of increasing the permeability of Actives to the stratum comeum. Solvent- type enhancers typically exhibit solubility parameters between about 10 and 24, and preferably between about 10 and 18.
  • Solvent-type enhancers are often better enhancers because they generally provide higher flux rates for a given permeant than plasticizer-type enhancers.
  • the solvent type enhancers will comprise a pharmaceutically-acceptable lower alkyl alcohol, aryl alcohol, or polyol, for example, ethanol, propanol, butanol, benzyl alcohol, glycerin, or propylene glycol.
  • the solvent-type enhancer is a 2-pyrrolidone or alkyl derivative thereof, such as N-methyl-2-pyrrolidone, 3-hydroxy-N-methyl-2- pyrrolidone, and pyroglutamic acid esters.
  • ethylene glycol ethers include, but are not limited to, ethylene glycol monoalkyl ethers, such as ethylene glycol monomethyl ether (also known as methyl cellosolve), ethylene glycol dialkyl ethers, such as ethylene glycol dimethyl ether (also known as dimethyl cellosolve), and ethylene glycol monoalkyl ether esters, such as ethylene glycol monoethyl ether acetate (also known as cellosolve acetate).
  • ethylene glycol monoalkyl ethers such as ethylene glycol monomethyl ether (also known as methyl cellosolve)
  • ethylene glycol dialkyl ethers such as ethylene glycol dimethyl ether (also known as dimethyl cellosolve)
  • ethylene glycol monoalkyl ether esters such as ethylene glycol monoethyl ether acetate (also known as cellosolve acetate).
  • polyethylene glycol ethers include, but are not limited to, diethylene glycol monoalkyl ethers, such as diethylene glycol monobutyl ether (also known as butyl ethyl Cellosolve or butyl carbitol), diethylene glycol dialkyl ethers; and diethylene glycol monoalkyl ether esters, such as diethylene glycol monoethyl ether acetate (also known as Carbitol acetate), and transcutol (diethylene glycol monoethyl ether).
  • diethylene glycol monoalkyl ethers such as diethylene glycol monobutyl ether (also known as butyl ethyl Cellosolve or butyl carbitol), diethylene glycol dialkyl ethers
  • diethylene glycol monoalkyl ether esters such as diethylene glycol monoethyl ether acetate (also known as Carbitol acetate), and transcutol (diethylene glycol monoethyl
  • solvent type enhancers are also relatively hydrophilic, generally being greater than 2 wt % soluble in water, and are preferably greater than 10 wt % soluble in water. Most preferred solvent type enhancers are completely water miscible. One of skill in the art would appreciate that the solvent type enhancers may be used alone or in combination.
  • the percentage by weight of the Active in the solution, hydrogel or matrix may be varied according to the desired loading of the finished patch.
  • sublingual administration may be achieved by use of solid or semisolid formulations suitable for application under the tongue, such as dissolving tablets and powders.
  • solid or semisolid formulations that may be retained in the mouth and that will effectively deliver total administered amounts as described herein to the mucosal membranes of the mouth, including the sublingual regions and buccal regions, may be used.
  • solid or semisolid formulations include chewable tablets, chewing gum, lozenges, pastes (including formulation as or in combination with a toothpaste), gels, gelatinous wafers and the like.
  • Toothpaste is a particularly preferred vehicle for administration of the present compositions, because it provides the desired administration through exposure of the mucus membranes of the mouth to the active ingredient, and because it is a medium that is routinely used by the person in need of treatment every day. Incorporation of the Active in toothpaste provides exceptional convenience for administration of active to be administered on a daily basis over a long period of time.
  • Vehicles suitable for rectal or vaginal administration such as suppositories, liquids and gels, are also contemplated.
  • Vehicles suitable for administration to nasal tissues such as liquids, gels, semisolids, and solids, are also contemplated.
  • Vehicles suitable for administration to lung tissues such as aerosols, powders, liquids, gels, semisolids, and solids, are also contemplated. Formulation of these various delivery vehicles with the components and total administered amounts as described herein may be readily carried out by the routineer in the drug delivery art.
  • a person in need of treatment administers the composition as described herein mucosally or transdermally in an amount as described above.
  • the composition is administered as a plurality of applications in order to maximize effective uptake of the active ingredient by the patient, for example, for those whose malady or condition may require more composition than can be conveniently administered in one application for its effective or entire relief.
  • the composition when administered as a liquid to the sublingual area (as but one example) is administered as a first sublingual application which first application is held in place under the tongue for a predetermined time, preferably about 30 seconds, or more preferably about 60 seconds or more, after which the composition is swallowed.
  • a predetermined time preferably about 30 seconds, or more preferably about 60 seconds or more
  • the composition is circulated or "swished" around the mouth by the patient prior to swallowing.
  • this apparently minor addition to the procedure noticeably increases the effect of the composition in the treatment.
  • a second composition is then applied and held under the tongue for a predetermined time, preferably about 30 seconds, or more preferably about 60 seconds or more, after which the second composition also is swallowed.
  • composition is circulated or "swished" around the mouth by the patient prior to swallowing.
  • advantageousness of maintaining some prolonged contact with the mucosal membrane or dermal area is considered.
  • This divided dosage administration technique of course may be utilized in the alternative modes of administration to mucosal membranes as described herein.
  • a bottle designed so as to dispense only a certain, measured dose may be used.
  • the composition may be provided in a conventional bottle with instructions to measure a dose, with or without a dedicated appliance for so doing (e.g. cup, syringe).
  • a dedicated appliance for so doing e.g. cup, syringe.
  • Alternative delivery vessels that do not deliver premeasured quantities of liquid lack the advantages of convenience and higher probability of administration of the correct amount of the composition, but may be more economical than delivery of the composition using a unit dose system.
  • the invention has particularly been described in the preferred administration mode of sublingual and transdermal administration.
  • any appropriate mucosal administration route such as buccal, nasal, rectal, vaginal, or by inhalation may be used for effective administration of the compositions as described herein.
  • any parenteral administration may be employed.
  • any topical may be employed as a means of non-systemic administration.
  • the animal may be a member selected from the group consisting of humans, non-human primates, such as dogs, cats, birds, horses, ruminants, other warm blooded animals or other animals.
  • the invention is directed primarily to the treatment of human beings. Administration can be by any method available to the skilled artisan, for example, by oral, topical, transdermal, transmucosal, or any parenteral route.
  • compositions and methods of the present invention provide a surprising efficacy in the treatment of various conditions, optionally using a surprisingly small amount of the composition required to exhibit such efficacy. Additionally a surprisingly rapid time course of relief often is witnessed, and surprising benefits resulting from the use of certain routes of administration are observed as disclosed herein.
  • the effectiveness of the present invention in moderating or eliminating activation of the pro-inflammatory pathways which play a crucial role in the pathogenesis of migraine is believed to be primarily by means of parthenolide mediated IKKB inhibition, subsequent NF-kB down-regulation and resultant iNOS suppression.
  • IKKB inhibition and subsequent NF-kB down-regulation is supported by numerous observations of other effects (as partly related above) when using the composition.
  • the role of iNOS in migraine remains more speculative, but is a presently emerging theory with substantial scientific support, as discussed below.
  • the other, anecdotal effects are consistent with general inhibition of NF-kB and cannot be readily accounted for except by this mechanism.
  • Nitric oxide formed in many cells and tissues by three different isoforms of NO synthase (NOS)
  • NOS NO synthase
  • GTN glyceryl trinitrate
  • an NO prodrug stimulates neuropeptide release from trigeminal fibers innervating feline cerebral blood vessels, augmenting vasodilation, which is closely associated with migraine pain in some theories of migraine pathogenesis (Wei EP, Moskowitz MA, Boccalini P, Kontos HA.
  • Calcitonin gene-related peptide mediates nitroglycerin and sodium nitroprusside-induced vasodilation in feline cerebral arterioles. Circ Res 1992; 70: 1313-1319.)
  • NO is generated within cerebral blood vessels by activation of 5-hydroxytryptamine (5-HT) 2B receptors, and receptor blockers are given to patients to suppress attacks prophylactically.
  • 5-hydroxytryptamine 5-hydroxytryptamine
  • NF-kB The transcription factor nuclear factor-kappaB (NF-kB) plays a pivotal role in iNOS induction and controls transcription of acute phase proteins, including cytokines, adhesion molecules, and antioxidant enzymes, among others.
  • cytokines including cytokines, adhesion molecules, and antioxidant enzymes, among others.
  • NF-kB is ubiquitously expressed and consists of homo- and heterodimers (e.g., p65-p50) of Rel family proteins. Under basal conditions, NF-kB is sequestered within the cytoplasm by the IkB family of inhibitory proteins.
  • NF-kB Phosphorylation of two Ser residues on IkB triggers its ubiquination and rapid degradation, thereby releasing NF-kB to initiate iNOS gene expression after translocation to the nucleus.
  • Recent data also implicate NF-kB in human iNOS gene expression (Taylor BS, de Vera ME, Ganster RW, et al. Multiple NF-kappaB enhancer elements regulate cytokine induction of the human inducible nitric oxide synthase gene.
  • iNOS can be synthesized by a variety of stimuli, such as bacterial lipopolysaccharide (LPS), cytokines (e.g., tumor necrosis factor- [TNF-], IL-1, and IL-6), and interferon- (IFN-), as well as by oxidative stress.
  • LPS bacterial lipopolysaccharide
  • cytokines e.g., tumor necrosis factor- [TNF-], IL-1, and IL-6
  • IFN- interferon-
  • Parthenolide an abundant sesquiterpene lactone found in the medical herb feverfew (Tanacetum parthenium), has been used historically by specific doses and administration routes in the treatment of migraine.
  • Panacetum parthenium has been used historically by specific doses and administration routes in the treatment of migraine.
  • Parthenolide reportedly inhibits the activity of IKK or the p65 binding activity of NF-kB. Parthenolide can also inhibit NF-kB-driven transcription by alkylating p65, thereby preventing its transactivation. In fact, parthenolide reduced the DNA binding activity of NF-kB even when administered after IKK activation and IkB degradation. Parthenolide's ability to block IkB degradation demonstrates at least one potential inhibitory mechanism within rodent meninges.
  • GTN infusion causes a prototypical induction of migraine headache in susceptible humans, and the cellular and molecular features of this response in rodents resemble what has been found in other experimental migraine models, i.e., delayed plasma protein extravasation, mast cell degranulation, and cytokine release.
  • GTN increases electrophysiologically recorded neuronal responses to facial cutaneous stimuli within the trigeminal nucleus caudalis and increases early immediate gene response within this nucleus, although the relation of these events to the occurrence of delayed headache requires further examination.
  • the anti-inflammatory agents parthenolide and aspirin reduce the frequency and intensity of migraine attacks. It is worth noting that aspirin, probably the most widely used drug for the treatment of headache, also blocks IKK activity in addition to cyclooxygenase activity. (Yin MJ, Yamamoto Y, Gaynor RB.
  • the anti-inflammatory agents aspirin and salicylate inhibit the activity of I(kappa)B kinase-beta. Nature 1998; 396: 77-80.
  • drugs such as parthenolide that selectively inhibit NF-kB activation appear to protect from experimental gastric ulcer.
  • NF-kB is the target of diverse pathological and inflammatory stimuli, such as oxidative stress, cytokines, and bacterial and viral products, its activation may provide the substrate within resident meningeal macrophages that contributes to local inflammation and headaches in response to exogenous agents in susceptible individuals. Conversely, NF-kB and the activation thereof is not associated exclusively with disease or a pathological state.
  • NF-kB function is an essential component of general cellular regulation, homeostasis and effective immune functioning (Baldwin, A The Transcription Factor NF-kB and Human Disease, The Journal of Clinical Investigation, Jan. 2001, 107: pp. 3-6.)
  • higher doses of parthenolide might be associated with an 'overdose', this observation perhaps accounting in part for prior belief that parthenolide treatment might not be a practical method of treatment.
  • the present invention solves this problem by demonstrating the surprisingly small amounts of parthenolide required when administered as provided for herein. Whereas the goal is to reduce NF-kB activation where it's overactivation may have led to a pathological state, such as dysregulated inflammation (e.g.
  • NF-kB is truly an acute phase responder, perhaps capable of being turned off as quickly as it is turned on, and that it may in fact be turned on and exert its effects in a much shorter time course than has previously been known or taught.
  • sesquiterpene lactones especially parthenolide
  • compositions comprising sesquiterpene lactones, especially feverfew in the dosages, by the delivery routes and according to the treatment regimens disclosed herein has not been previously taught for relief of pain and inflammation generally.
  • the present invention serves much like a typical over-the-counter analgesic and anti-inflammatory (e.g. like aspirin) with an equal diversity of preparations and applications.
  • the present invention may be employed for relief of pain and inflammation either singly (pain or inflammation) or jointly (both pain and inflammation).
  • NF-kB is intimately involved with many aspects of inflammation. It is also closely linked to many aspects of pain generation and sensation.
  • a topical cream might preferably be employed in the treatment of pain and inflammation limited to one specific area of the body, or sublingual administration might be employed to deliver relief systemically.
  • Autoimmune Disease a topical cream might preferably be employed in the treatment of pain and inflammation limited to one specific area of the body, or sublingual administration might be employed to deliver relief systemically.
  • Autoimmune disease includes, without limitation: Alopecia Areata, Lupus, Anklosing Spondylitis, Meniere's Disease, Antiphospholipid Syndrome, Mixed Connective Tissue Disease, Autoimmune Addison's Disease, Multiple Sclerosis, Autoimmune Hemolytic Anemia, Myasthenia Gravis, Autoimmune Hepatitis, Pemphigus Vulgaris, Behcet's Disease, Pernicious Anemia, Bullous Pemphigoid, Polyarteritis Nodosa, Cardiomyopathy, Polychondritis, Celiac Sprue-Dermatitis, Polyglancular Syndromes, Chronic Fatigue Syndrome (CFIDS), Polymyalgia Rheumatica, Chronic Inflammation leading to Demyelinating conditions, Polymyositis and Dermatomyositis, Chronic Inflammation leading to Polyneuropathy, Primary Agammaglobulinemia, Churg-Strauss Syndrome, Primary Biliary Cirrhosis, Cicatri
  • sesquite ⁇ ene lactones especially parthenolide
  • compositions comprising sesquite ⁇ ene lactones, especially feverfew in the dosages, by the delivery routes and according to the treatment regimens discussed herein has not previously been taught for relief of autoimmune disease.
  • NF-kB is intimately associated with many various aspects of inflammation and immunity.
  • Autoimmune diseases are those wherein a substantial component of the disease process is believed to be related to or caused by the body's own natural defense system attacking the tissues of the body.
  • This 'overactivation' of the immune system can be lessened by the use of compositions comprised of sesquite ⁇ ene lactones, as described herein, to decrease the activation of certain aspects of the immune system which may be critical in certain autoimmune diseases, or to decrease immune reactivity generally and thus reduce disease or symptom severity.
  • the preferred route and means of administration of the invention will vary according the condition treated. For example, eyedrops might preferably be employed in the treatment of the ocular symptoms of Sjogren's Syndrome, while sublingual administration might be employed to deliver relief for the systemic manifestations of that same disease.
  • Arthritis might preferably be employed in the treatment of the ocular symptoms of Sjogren's Syndrome, while sublingual administration might be employed to deliver relief for the systemic manifestations of
  • sesquite ⁇ ene lactones especially parthenolide
  • compositions comprising sesquite ⁇ ene lactones, especially feverfew in the dosages, by the delivery routes and according to the treatment regimens discussed herein has not previously been taught for relief of arthritis.
  • Both osteoarthritis and rheumatoid arthritis are diseases associated with chronic inflammation.
  • Other various forms of arthritis may also be treated by the present invention.
  • the present invention provides a means whereby to treat chronic inflammation such as in the case of arthritis.
  • Gastric Maladies Gastric maladies include gastritis, peptic ulcers, duodenal ulcers, acid reflux,
  • sesquite ⁇ ene lactones especially parthenolide
  • compositions comprising sesquite ⁇ ene lactones, especially feverfew in the dosages, by the delivery routes and according to the treatment regimens discussed herein has not previously been taught for relief of gastric maladies.
  • the anti-inflammatory agents aspirin and salicylate inhibit the activity of I(kappa)B kinase-beta. Nature 1998; 396: 77-80.) However, unlike aspirin, which causes gastrointestinal side effects, d gs such as parthenolide that selectively inhibit NF-kB activation appear to protect from experimental gastric ulcer. (Toumier H, Schinella G, de Balsa EM, et al. Effect of the chloroform extract of Tanacetum vulgare and one of its active principles, parthenolide, on experimental gastric ulcer in rats. J Pharm Pharmacol 1999; 51: 215-219.) Diabetes, Types I and II
  • sesquite ⁇ ene lactones especially parthenolide
  • compositions comprising sesquite ⁇ ene lactones, especially feverfew in the dosages, by the delivery routes and according to the treatment regimens discussed herein has not previously been taught for prevention and relief of diabetes.
  • inhibition of Nf-kB by means of high dose aspirin administration has been shown to be potentially beneficial in the treatment of Type II diabetes.
  • Type I diabetes often evolves from Type II, therefore an effective treatment of Type II might delay or eliminate the onset of Type I in certain instances.
  • the invention disclosed herein may be used to treat Type II diabetes, another of its many novel applications.
  • NF-kB activation is associated with these sequelae, sometimes manifesting as an inflammatory component thereof.
  • Sequelae which may be treated or prevented include diabetic retinopathy, peripheral neuropathy and peripheral vascular disease. Cystic Fibrosis
  • Cystic Fibrosis affects approximately 30,000 people in the United States.
  • lung inflammation (as but one manifestation of the disease) leads to severe tissue destruction and ultimately organ failure.
  • the transcription factor nuclear NF-kB regulates expression of many pro-inflammatory mediators believed crucial in the pathogenesis of CF.
  • Recent evidence suggests that the manifestation of CF in the lungs is primarily an inflammatory disorder resulting from dysregulation of NF-kB (Blackwell T. Editorial Focus: Dysregulated NF-kB activation in cystic fibrosis: evidence for a primary inflammatory disorder.
  • sesquite ⁇ ene lactones especially parthenolide
  • compositions comprising sesquite ⁇ ene lactones, especially feverfew in the dosages, by the delivery routes and according to the treatment regimens discussed herein has not previously been taught for prevention and relief of CF.
  • the preferred route and means of administration of the invention will vary according the desired effect. For example, an aerosolized mist might be effectively employed for inhalation into the lungs and the treatment thereof locally, or sublingual administration might be employed to deliver relief systemically .
  • Demyelinating Disease includes Multiple Sclerosis (the most common member of this group), Guillain-Barre Syndrome, Encephalomyelitis & Neuritis, Acute disseminated encephalomyelitis (postinfectious encephalomyelitis), HTLV- associated myelopathy, X-adrenoleukodystrophy, Adrenolekodystrophy,
  • These are generally acquired inflammatory diseases that attack the myelin sheath. At times some may also be classified as autoimmune disease.
  • NF-kB activation is central to many inflammatory processes.
  • Nitric oxide (NO) has been implicated in the etiopathology of central nervous system (CNS) diseases such as multiple sclerosis (MS).
  • parthenolide Inhibition of NO synthesis has recently been proposed to be a possible mechanism of action of relevance in the treatment of multiple sclerosis and migraine, parthenolide was found to be an inhibitor of iNOS/NO synthesis, suggesting that parthenolide might have a potential in the treatment of CNS diseases, especially where NO is part of the pathophysiology (Fiebich BL. Inhibition of LPS-induced p42/44 MAP kinase activation and iNOS/NO synthesis by parthenolide in rat primary microglial cells. J Neuroimmunol.
  • Neurodegenerative Disorders Neurodegenerative diseases include Parkinson's disease, Alzheimers and
  • AIDS Dementia among others. An estimated 4.5 million Americans have Alzheimer's disease and 1.2 million have Parkinson's. NF-kB is known to play a central role in neuronal cell survival, it's excess activation thought to be an important aspect of each disease.
  • the use of sesquite ⁇ ene lactones, especially parthenolide, and compositions comprising sesquite ⁇ ene lactones, especially feverfew, in the dosages, by the delivery routes and according to the treatment regimens discussed herein has not previously been taught for prevention and relief of neurodegenerative disorders. Hvpercholesterolemia and Hyperlipidemia High Cholesterol is a substantial problem in the United states and many other developed countries. The primary untoward manifestation of each being damage to vasculature.
  • Hypercholesterolemia a pro-oxidant condition, activates NF-kB and is associated with coronary endothelial dysfunction. It may be that inhibition of NF-kB results in an actual decrease in cholesterol and triglycerides, as in studies referenced prior with inhibition of NF-kB by high dose aspirin. Alternately, inhibition of NF-kB may simply attenuate the harmful effects of high cholesterol, as has been demonstrated in a recent study of hypercholesterolemic pigs (Rodriguez- Porcel M. Chronic antioxidant supplementation attenuates nuclear factor-kappa B activation and preserves endothelial function in hypercholesterolemic pigs. Cardiovasc Res.
  • sesquite ⁇ ene lactones especially parthenolide
  • compositions comprising sesquite ⁇ ene lactones, especially feverfew in the dosages, by the delivery routes and according to the treatment regimens discussed herein has not previously been taught for prevention and relief of hypercholesterolemia and hyperlipidemia and the sequelae thereof.
  • conditions or diseases include, without limitation: pain; fever; inflammation; malaria; chagas disease;
  • Glucocorticoid resistance Glucocorticoid resistance
  • heavy metal poisoning e.g., rheumatoid arthritis
  • allergies e.g., suppression of inflammation in chronic inflammatory diseases such as asthma, rheumatoid arthritis, inflammatory bowel disease (IBD) and autoimmune diseases; any autoimmune disease, including: Alopecia Areata, Lupus, Anklosing Spondylitis, Meniere's Disease, Antiphospholipid Syndrome, Mixed Connective Tissue Disease,
  • rheumatic diseases such as spondyloarthropathies like Ankylosing spondylitis, Juvenile ankylosing spondylitis, Late onset spondyloarthropathy, Psoriatic arthritis, Reiter's syndrome/reactive arthropathy, Enteropathic spondylitis and Undifferentiated spondyloarthropathy; Rheumatoid arthritis; Osteoarthritis; Aseptic arthritis; inflammatory bowel disease such as
  • sesquite ⁇ ene lactones and compositions comprising sesquite ⁇ ene lactones, especially feverfew in the amounts and by the delivery- routes, mechanisms and regimens described herein to treat or prevent any disease or condition associated with the NF-kB pathway in an animal, in combination with other therapies and/or prescription dmgs and/or nonprescription dmgs to treat any condition associated with the NF-kB pathway in an animal.
  • NSAIDS As but several examples of other such therapies: NSAIDS; Acetaminophin; Celecoxib (COX-2 inhibitor; NSAID); other COX-2 inhibitors; Anti-malarial dmgs; Lactacystin, a proteasome inhibitor; Glucocorticoids; Diethyldithiocarbamate (Ditiocarb, DDTC) for heavy metal poisoning; Cetirizine (HI antihistamine); ionizing radiation as employed in the treatment of cancer and other proliferative disorders; cancer chemotherapeutic drugs; analgesics; drags intended for the treatment of type 2 diabetes; angiotensin converting enzyme inhibitors (ACE inhibitors); and any other drag or therapy against any disease or condition associated with the NF-kB pathway in an animal or in which the effect of the other drag or therapy can be enhanced or improved by the supression of NF-kB activation.
  • COX-2 inhibitor As but several examples of other such therapies: NSAIDS; Acetaminophin;
  • a particularly preferred embodiment of the present invention is the near simultaneous use of both a long acting and a short acting method of administering the composition, as discussed herein, primarily consisting of the administration of a dose sublingually or by other mucous membrane with the near simultaneous or appropriately timed administration of a transdermal dose.
  • the result intended to be achieved and achieved thereby is both rapid onset of action and also the maintenance of a therapeutic concentration over time.
  • Other means of achieving the same effect through the combination of various formats and compositions are envisioned, whereby a long therapeutic blood concentration is obtained along with a rapid rise in blood concentration to an effective amount is achieved.
  • a sesquite ⁇ ene lactone especially parthenolide, preferably as feverfew
  • Said toothpaste may also comprise other known beneficial agents including, without limitation, trans-resveratrol (lyophilized red wine) or other antioxidants such as vitamins C and E.
  • the toothpaste may be an existing formulation, or a specifically prepared formulation as may be created by the routines in the formulary art by reference to known fonnulations, modifying the same as taught herein.
  • a sesquite ⁇ ene lactone especially parthenolide, preferably as feverfew
  • food or beverage which is commonly ingested, the intention being to achieve contact with the mucosal areas of the mouth such that mucosal abso ⁇ tion was sufficient to result in the effective dosing of Actives by way of repeated contact with numerous bites and during mastication if a solid food or repeated swallows and residue liquid if a liquid food.
  • a sesquite ⁇ ene lactone especially parthenolide, preferably as feverfew
  • a sesquite ⁇ ene lactone is employed as a supplement meant to aid particularly athletes and others who, as a result of vigorous exercise or exertion, suffer substantial wear and tear to their muscles and wish to accelerate the healing thereof, thus lessening recovery time and increasing subsequent performance, especially performance which is required or opted for prior to that time at which they would otherwise be fully recovered.
  • a particularly useful form of the present invention for such pu ⁇ oses might be a chewing gum or similar presentation.
  • a method of treating a disease associated with prolonged or excessive activation of NF-kB comprising first a) identifying a disease associated with prolonged or excessive activation of NF-kB.
  • the location of administration of a composition in a patient in need of treatment for the disease identified in step is then determined, and the amount of plant extract from a plant that is a source of sesquite ⁇ ene lactone that is effective to inhibit NF-kB at the desired location of administration determined in step b) to a degree sufficient to treat the disease determined in step a) is also determined.
  • This method may be carried out for compositions comprising sesquite ⁇ ene lactones as described herein as well. This method may be carried out specifically for all diseases and all modes of administration discussed herein.

Abstract

Méthodes de traitement d'une maladie associée à une activation prolongée ou excessive de NF-kB, consistant à administrer une composition comprenant au moins un extrait de plante fournissant un lactone de sesquiterpène en dose efficace à un patient ayant besoin d'un tel traitement. Dans un mode de réalisation préférée, l'extrait de plante provient de la grande camomille et le lactone de sesquiterpène est un parthénolide. Dans un mode de réalisation préféré, la composition est administrée par une voie en dérivation de la voie gastro-intestinale. Dans un autre mode préféré de réalisation, la quantité de principe actif dans la composition administrée est étonnamment faible.
PCT/US2004/018794 2003-06-13 2004-06-14 Compositions et methodes de traitement au moyen d'extraits de plantes WO2004112819A1 (fr)

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US60/478,316 2003-06-13
US49997903P 2003-09-02 2003-09-02
US60/499,979 2003-09-02

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EP1627632A1 (fr) * 2003-05-19 2006-02-22 Takara Bio Inc. Agent therapeutique
WO2008010335A1 (fr) * 2006-07-21 2008-01-24 Mmt Co., Ltd. Extrait végétal ayant un effet préventif sur l'arthrite
WO2012104845A1 (fr) * 2011-02-06 2012-08-09 Ben Gurion University Of The Negev Research And Development Authority Compositions comportant du bêta-caryophyllène et leurs procédés d'utilisation
KR101378433B1 (ko) 2012-11-05 2014-03-27 초당약품공업 주식회사 세스퀴터핀 락톤계 위장 질환 치료용 의약 조성물
KR101378431B1 (ko) * 2012-11-05 2014-03-27 초당약품공업 주식회사 세스퀴터핀 락톤계 위장 질환 치료용 의약 조성물
EP2852382A1 (fr) * 2012-05-22 2015-04-01 King Abdullah University Of Science And Technology Combinaison comprenant du parthenolide pour le traitement de la maladie d'alzheimer et d'autres troubles neurodégénératifs
CN106074484A (zh) * 2012-04-28 2016-11-09 张国营 茶氨酸在制备具有预防和治疗癌症疾病的产品中的应用
US20170143660A1 (en) * 2012-09-11 2017-05-25 Olatec Therapeutics Llc Methods for treating inflammation and pain
CN110787159A (zh) * 2019-09-05 2020-02-14 金乡县人民医院 一种倍半萜类化合物在制备治疗胃肠间质瘤药物中的用途
CN112891330A (zh) * 2021-03-15 2021-06-04 云南民族大学 斯巴醇在制备抗偏头痛药物中的应用
WO2021220273A1 (fr) * 2020-04-28 2021-11-04 ZALTZMAN, Zahava Compositions pharmaceutiques pour le soulagement de symptômes de la covid-19 et procédés de production et d'utilisation de celles-ci
CN114903878A (zh) * 2022-04-22 2022-08-16 广州医科大学 倍半萜类化合物在抑制trpa1通道的活性中的应用
CN115768417A (zh) * 2020-06-02 2023-03-07 一丸自然美健有限公司 肌肉萎缩抑制剂

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WO2001045699A1 (fr) * 1999-12-23 2001-06-28 Advanced Research And Technology Institute, Inc. Utilisation du parthenolide pour inhiber le cancer
WO2002009698A1 (fr) * 2000-08-01 2002-02-07 Ashni Naturaceuticals, Inc. Compositions ayant une action inhibitrice synergique de l'expression et/ou de l'activite de la cyclooxygenase-2

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WO2001045699A1 (fr) * 1999-12-23 2001-06-28 Advanced Research And Technology Institute, Inc. Utilisation du parthenolide pour inhiber le cancer
WO2002009698A1 (fr) * 2000-08-01 2002-02-07 Ashni Naturaceuticals, Inc. Compositions ayant une action inhibitrice synergique de l'expression et/ou de l'activite de la cyclooxygenase-2

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1627632A4 (fr) * 2003-05-19 2009-01-07 Takara Bio Inc Agent therapeutique
EP1627632A1 (fr) * 2003-05-19 2006-02-22 Takara Bio Inc. Agent therapeutique
WO2008010335A1 (fr) * 2006-07-21 2008-01-24 Mmt Co., Ltd. Extrait végétal ayant un effet préventif sur l'arthrite
WO2012104845A1 (fr) * 2011-02-06 2012-08-09 Ben Gurion University Of The Negev Research And Development Authority Compositions comportant du bêta-caryophyllène et leurs procédés d'utilisation
CN106074484A (zh) * 2012-04-28 2016-11-09 张国营 茶氨酸在制备具有预防和治疗癌症疾病的产品中的应用
EP2852382A1 (fr) * 2012-05-22 2015-04-01 King Abdullah University Of Science And Technology Combinaison comprenant du parthenolide pour le traitement de la maladie d'alzheimer et d'autres troubles neurodégénératifs
US9763909B2 (en) * 2012-09-11 2017-09-19 Olatec Therapeutics Llc Methods for treating inflammation and pain
US20170143660A1 (en) * 2012-09-11 2017-05-25 Olatec Therapeutics Llc Methods for treating inflammation and pain
KR101378433B1 (ko) 2012-11-05 2014-03-27 초당약품공업 주식회사 세스퀴터핀 락톤계 위장 질환 치료용 의약 조성물
WO2014069800A1 (fr) * 2012-11-05 2014-05-08 초당약품공업 주식회사 Composition pharmaceutique à base de lactone sesquiterpénique pour le traitement de maladies gastro-intestinales
WO2014069801A1 (fr) * 2012-11-05 2014-05-08 초당약품공업 주식회사 Composition pharmaceutique à base de lactone sesquiterpène pour le traitement de maladies gastro-intestinales
KR101378431B1 (ko) * 2012-11-05 2014-03-27 초당약품공업 주식회사 세스퀴터핀 락톤계 위장 질환 치료용 의약 조성물
CN110787159A (zh) * 2019-09-05 2020-02-14 金乡县人民医院 一种倍半萜类化合物在制备治疗胃肠间质瘤药物中的用途
WO2021220273A1 (fr) * 2020-04-28 2021-11-04 ZALTZMAN, Zahava Compositions pharmaceutiques pour le soulagement de symptômes de la covid-19 et procédés de production et d'utilisation de celles-ci
CN115768417A (zh) * 2020-06-02 2023-03-07 一丸自然美健有限公司 肌肉萎缩抑制剂
CN112891330A (zh) * 2021-03-15 2021-06-04 云南民族大学 斯巴醇在制备抗偏头痛药物中的应用
CN114903878A (zh) * 2022-04-22 2022-08-16 广州医科大学 倍半萜类化合物在抑制trpa1通道的活性中的应用
CN114903878B (zh) * 2022-04-22 2023-09-22 广州医科大学 倍半萜类化合物在抑制trpa1通道的活性中的应用

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