EP4100034A1 - Compositions comprising extracts of aplinia and other plants for improving joint health and treating arthritis - Google Patents
Compositions comprising extracts of aplinia and other plants for improving joint health and treating arthritisInfo
- Publication number
- EP4100034A1 EP4100034A1 EP21708882.2A EP21708882A EP4100034A1 EP 4100034 A1 EP4100034 A1 EP 4100034A1 EP 21708882 A EP21708882 A EP 21708882A EP 4100034 A1 EP4100034 A1 EP 4100034A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- alpinia
- extract
- cartilage
- joint
- magnolia
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
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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)
- A61K36/67—Piperaceae (Pepper family), e.g. Jamaican pepper or kava
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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)
- A61K36/88—Liliopsida (monocotyledons)
- A61K36/906—Zingiberaceae (Ginger family)
- A61K36/9062—Alpinia, e.g. red ginger or galangal
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
Definitions
- Osteoarthritis is a multifactorial disease that affects the entire joint structure and is characterized by cartilage destruction and loss, degeneration of soft tissues, localized bone hypertrophy including subchondral thickening and osteophyte formation, varying degrees of synovitis, and thickening of the joint capsule (Loeser, 2013).
- osteoarthritis is no longer considered as a “wear and tear” degenerative disease anticipated to happen as a consequence of aging or no longer considered to be a “noninflammatory” form of arthritis.
- imaging technology such as MRI
- synovial membrane inflammation has been shown to be correlated with high prevalence to the severity and progression of OA and was believed to be the primary cause of pain (Pickering et al ., 2005; Roemer et al ., 2011).
- Articular cartilage is an avascular, non-innervated tissue composed of a dense extracellular matrix (ECM) with a sparse distribution of highly specialized cells called chondrocytes. Chondrocytes originate from mesenchymal stem cells and constitute about 2% of the total volume of articular cartilage (Alford and Cole, 2005).
- ECM extracellular matrix
- Chondrocytes are metabolically active cells that play a pivotal role in the development, maintenance, and repair of the ECM which is mainly composed of type II collagen and aggrecan.
- Collagen is the most abundant structural macromolecule in ECM where type II collagen represents 90% - 95% of the collagen in the tissue and forms fibers intertwined with proteoglycan aggregates.
- Proteoglycans are heavily glycosylated protein monomers representing the second-largest group of macromolecules in the ECM and account for up to 10% - 15%.
- Proteoglycans consist of a protein core with one or more linear glycosaminoglycan (GAG) chain covalently attached. These structures provide the visco-elasticity property and resistance to compression forces to the articular cartilage.
- GAG linear glycosaminoglycan
- ECM extracellular matrix
- Pro-inflammatory cytokines such as TNF- a, IL-Ib, and IL-6 are known to play important roles in cartilage matrix degradation in articular cartilage through a cascade of catabolic events that lead to stimulation of aggrecanase and matrix metalloproteinase (MMP) secretion (Kapoor el al ., 2011).
- MMP matrix metalloproteinase
- these collective catabolic mediators decrease the response and sensitivity of chondrocytes to the surrounding anabolic signals, further shifting the balance more towards catabolic cartilage degradation than anabolic rebuilding and renewal of ECM and cartilage.
- natural compositions with the capacity of reversing the direction from catabolic to anabolic processes could act as disease-modifying agents and have beneficial effects, such as modifying, slowing down, or reversing the progression of arthritis.
- glucosamine sulfate and chondroitin sulfate were recommended by the Osteoarthritis Research Society International (OARSI) as possible structural modifying agents in hip and knee OA (Jordan et al., 2003; Zhang el al., 2007).
- OARSI Osteoarthritis Research Society International
- the recently published OARSI guidelines downgraded these agents to “uncertain” as a symptom reliever or “not appropriate” as a disease-modifying agent when used for all OA patients.
- oral, and transdermal opioid painkillers were graded as “uncertain” for managing OA (Zhang etal., 2008, 2010).
- RA Rheumatoid arthritis
- RA is a chronic, inflammatory, autoimmune disease that primarily affects the joints (Smolen et al ., 2018).
- RA is a systemic disease and a variety of immunological events occur outside the joint at mucosal surfaces and primary lymphoid tissues, the synovium is a central player.
- the disease is characterized by infiltration of the synovial membrane of joints with cellular and humoral immunity cells such as T cells, B cells, and monocytes. This process is preceded by neovascularization (activation of endothelial cells leading to growth of new blood vessels) which is considered as a hallmark of RA synovitis.
- synovial fibroblast-like and macrophage-like cells in the synovial membrane leads to a hyperplastic synovial lining layer.
- This expanded synovial membrane often termed “pannus,” invades the periarticular bone at the cartilage-bone junction and leads to bony erosions and cartilage degradation.
- cytokine networks integrate pro-inflammatory and tissue damaging cellular activities in synovitis.
- Proinflammatory cytokines primarily TNF-a, and IL-6, are known to induce molecules such as receptor activator of nuclear factor KB ligand (RANKL), prostaglandins (PGE2), matrix metalloproteinases (MMP-13, MMP-3, MMP-9, MMP-1) and aggrecanases in RA.
- RNKL nuclear factor KB ligand
- PGE2 prostaglandins
- MMP-13, MMP-3, MMP-9, MMP-1 matrix metalloproteinases
- aggrecanases RA.
- TNF-a, and IL-6 also stimulate generation of osteoclasts within the synovial membrane and promote bone damage.
- compositions disclosed in this disclosure produced comparable outcomes to methotrexate in symptomatic relief, and reduction of key inflammatory cytokines (TNF-a and IL6) and matrix degrading enzymes (MMP- 13 and MMP-3) when tested in collagen-induced arthritis (CIA).
- TNF-a and IL6 key inflammatory cytokines
- MMP- 13 and MMP-3 matrix degrading enzymes
- CIA collagen-induced arthritis
- the proprietary compositions consisting of, but not limited to, individual Alpinia, Pepper, Magnolia and Kochia extracts, and/or at various combinations of 2 to 3 of those extracts with examples of, but not limited to Alpinia:Pepper (AP) and Alpinia:Magnolia:Kochia (AMK), resulted in unexpected faster and improved cartilage repairing activity with synergy as reflected in the animal weight bearing data and histopathological observation of the cartilage repairing parameters in diseased animal models.
- AP Alpinia:Pepper
- AMK Alpinia:Magnolia:Kochia
- the levels of cartilage synthesis markers such as type IIA procollagen amino terminal propeptide (PIIANP) and the growth factor TGF-bI, were found significantly higher in rats treated with individual extracts of Alpinia, Pepper, Magnolia and Kochia and also by those compositions of AMK and AP when compared to vehicle-treated disease models. These compositions have also shown significant cartilage protection activity in the collagen-induced rat arthritis model and anti-pain and anti-inflammatory activity in the carrageenan-induced rat paw edema model. The merits of combining these extracts to yield, but not limited to, AP or AMK composition were also evaluated using the Colby's equation (Colby, 1967) and unexpected synergy was found for combined compositions.
- PIIANP type IIA procollagen amino terminal propeptide
- TGF-bI growth factor-bI
- Enteral and parenteral routs of drug administration are among the commonly used methods of drug delivery for patients suffering from musculoskeletal pain.
- the commonly prescribed or over the counter anti-pain medications such as selective and non-selective non steroidal anti-inflammatory drugs are known to cause gastrointestinal, cardiovascular, and renal side effects (Harirforoosh el al ., 2013). Older patients who actually often experience chronic pain are at greater risk of side effects from these routes of intervention (Stanos and Galluzzi). These adverse events could be averted by employing NTHEs by a topical application route.
- pain could be nociceptive, inflammatory, or neuropathic. It has been hypothesized that these medicinal plants could cause suppression in pain sensitivity by directly interfering with the peripheral primary afferent sensory neurons at the receptor level or indirectly by acting through the many pathways of pain transduction, transmission, modulation, and perception. Bradykinin and prostaglandins are among the classic inflammation mediators known to cause pain sensitivity in inflammation.
- Medicinal plant extracts and their bioactives from Alpinia, Magnolia, Kochia and Piper /Pepper are disclosed herein in combination or alone in regulating homeostasis of chondrocytes, extracellular matrix, articular cartilage, and phenotype of arthritis that lead to enhanced anabolic functions of chondrocytes, increased renewal/rebuilding/regeneration of extracellular matrix and articular cartilage, and improved phenotype of osteoarthritis and rheumatoid arthritis.
- the methods of use of the disclosed individual extracts of Alpinia, Pepper, Magnolia and Kochia and/or at various combinations of 2 to 3 of those extracts with examples, but not limited to Alpinia: Piper /Pepper (AP) and Alpinia Magnolia: Kochia (AMK) include, but are not limited to, maintaining cartilage homeostasis, extracellular matrix integrity, and joint cartilage; minimizing cartilage degradation, protecting joint space from narrowing, and promoting healthy joints by protecting cartilage integrity; balancing anabolic and catabolic processes, diminishing the actions of enzymes and proinflammatory cytokines that affect joint health, improving joint movement and/or function, alleviating joint pain, alleviating joint stiffness, improving joint range of motion and/or flexibility, promoting mobility, managing and/or treating osteoarthritis and/or rheumatoid arthritis, preventing osteoarthritis and/or rheumatoid arthritis, or reversing the progression of osteoarthritis and/or rheumatoid arthritis or
- composition for joint health comprises a combination of an Alpinia extract enriched for one or more phenylpropanoids; a Magnolia extract enriched for one or more bisphenolic lignans; and a Kochia extract enriched for one or more triterpenoid saponins.
- composition for joint health comprises a combination of an Alpinia extract enriched for one or more phenylpropanoids; and a Piper extract enriched for one or more alkaloids.
- composition for joint health comprises an Alpinia extract enriched for one or more phenylpropanoids.
- Figure 1 shows individual extracts of Alpinia, Piper/Pepper, Magnolia and Kochia and/or at various combinations of 2 to 3 of those extracts with examples, but not limited to Alpinia:Piper/Pepper (AP) and Alpinia:Magnolia:Kochia (AMK), reverses OA progression by inducing cartilage homeostasis.
- AP Alpinia:Piper/Pepper
- AMK Alpinia:Magnolia:Kochia
- Figure 2 shows a HPLC chromatogram of Alpinia ethanol extract at 254 nm.
- Figure 3 shows images of a drill site of OCD rats after 6 weeks of treatment showing significant differences in healing progress from different oral treatment groups.
- Figure 4 shows Safranin O stain of the subchondral bone of OCD rats at the drill site. The black circle indicates the drill site for representative animal histopathology slides.
- Figure 5 shows histopathology images (HE a-d and Safranin O e-f) from ankle joint of CIA induced rats treated with AMK and MTX.
- FIG 6 shows HE and Safranin O staining histology for CIA rats treated with AP
- Osteoarthritis is a multifactorial disease primarily noted by cartilage degradation that causes significant morbidity, joint pain, stiffness, and limited mobility.
- Present-day management of OA is inadequate due to the lack of principal therapies proven to be effective in hindering disease progression wherein a symptomatic therapy-focused approach, such as the use of nonsteroidal anti-inflammatory drugs, masks the actual etiology leading to irreversible cartilage depletion and joint structural damage.
- novel natural extracts and compositions designated as examples of, but not limited to, Alpinia, Piper/Pepper, Magnolia and Kochia extracts and at various combinations which resulted in unexpected faster and improved cartilage renewal and repairing activity with synergy.
- composition for joint health comprises a combination of an Alpinia extract enriched for one or more phenylpropanoids; a Magnolia extract enriched for one or more bisphenolic lignans; and a Kochia extract enriched for one or more triterpenoid saponins.
- Contemplated compositions are developed such that the Alpinia extract, or Magnolia extract or Kochia extract in the composition are in a range of 1% - 98% by weight of each extract with the optimized weight ratio of Alpinia Magnolia: Kochia (AMK) at 2:4:3 (22.2%:44.4%:33.3%) or 4:3:3 (40%:30%:30%) or 5:4:4 (38.4%:30.8%:30.8%).
- AK optimized weight ratio of Alpinia Magnolia: Kochia
- composition for joint health comprises a combination of an Alpinia extract enriched for one or more phenylpropanoids; and a Piper extract enriched for one or more alkaloids.
- a composition for joint health is disclosed that comprises an Alpinia extract enriched for one or more phenylpropanoids.
- chondrocytes respond to a variety of stimuli, including growth factors, they have limited potential for replication, a factor that contributes to the limited intrinsic healing capacity of cartilage in response to injury.
- Chondrocytes regulate cartilage homeostasis by maintaining a delicate balance between anabolic (regenerative) and catabolic (degradative) activities. These cells represent only 1-2% of the total matrix volume. They are avascular and unable to divide in adulthood, causing a very limited ability for cartilage self-repair and low turnover rate. They usually acquire their nutrition and oxygen primarily through diffusion from the synovial fluid and subchondral bone. Chondrocytes maintain the homeostasis of articular cartilage matrix by modulating the balance between the synthesis and degradation of various articular components.
- Chondrocytes can maintain the integrity of extracellular matrix (ECM) by synthesis of macromolecules such as type II collagen and aggrecans and they can also produce proteins involved in the degradation of ECM such as MMPs and aggrecanases.
- ECM extracellular matrix
- chondrocytes are very responsive and sensitive to changes to their micro-environment, natural extracts and compositions that stimulate the chondrocytes directly or indirectly to produce matrix-forming components and inhibit the secretion of proinflammatory cytokines and matrix degrading enzymes could change the homeostasis of the ECM and the phenotype of arthritis.
- mesenchymal stem cell (MSC) condensation and subsequent chondrocyte differentiation are the initial steps in cartilage formation. These processes are driven by several growth and transcription factors at different stages of cartilage development. Among these factors, SOX9, a key transcription factor for chondrogenesis, is involved in the condensation phase of MSCs, stimulating the expression of cartilage-specific markers and inhibiting terminal differentiation of chondrocytes. Similarly, the TGF-b family of genes is widely expressed in chondrocytes and is a constituent class of growth factors involved in the process of chondrogenesis. Of all the factors expressed during the early stages of chondrogenesis, TGF-bI is one of the most important factors that induces the differentiation of MSCs into chondrocytes.
- MSC mesenchymal stem cell
- This factor also stimulates the proliferation of chondrocytes, increases the production of ECM, and it inhibits endochondral ossification.
- mature chondrocytes will produce cartilage matrix rich in proteoglycan and type II collagen fibers encoded by ACAN and COL2A1 genes, respectively.
- external factors that upregulate the expression of the transcription or growth factors help induce the anabolic process of cartilage development to maintain the surplus of ECM.
- cartilage collagen synthesis markers such as type IIA procollagen amino terminal propeptide (PIIANP) (Examples 40, 48, 56 and 58) and the growth factor TGF-bI (example 31), were found significantly higher in rats treated with individual extracts of Alpinia, Pepper, Magnolia and Kochia and/or at various combinations of 2 to 3 of those extracts with examples, but not limited to Alpinia:Piper/Pepper (AP) and Alpinia:Magnolia:Kochia (AMK) when compared to vehicle-treated disease animals.
- AP Alpinia:Piper/Pepper
- AMK Alpinia:Magnolia:Kochia
- the model utilizes stimulation of the bone marrow in the repairing process by taking advantage of the body’s own healing potential.
- This technique enhances the chondral resurfacing by providing a suitable environment for new tissue formation.
- the exposed weight-bearing surface of the femur subchondral bone plate was drilled with a precision drill bit until fat droplets and blood came out of the microfractured hole in the knee. This provided an optimal environment for the body’s own mesenchymal stem cells from the bone marrow to differentiate into appropriate articular cartilage-like cells that in turn produced the extracellular matrix which eventually matured into stable repaired tissue.
- the cartilage repair activity of individual extracts of Alpinia, Pepper, Magnolia and Kochia and/or at various combinations of 2 to 3 of those extracts with examples, but not limited to Alpinia:Piper/Pepper (AP) and Alpinia:Magnolia:Kochia (AMK) were evaluated using this model administered orally at different dosages and time periods, such as 200 mg/kg/day for 8 weeks.
- AP Alpinia:Piper/Pepper
- AMK Alpinia:Magnolia:Kochia
- OCD animals exhibited limping on the affected legs which showed progressive improvement through the course of the study for all the groups. These changes in the open field observation of the use of their affected legs were also reflected in the incapacitance measurements. There was gradual improvement in the weight-bearing measurements that was significantly improved for rats treated with Alpinia:Piper/Pepper (AP) and Alpinia:Magnolia:Kochia (AMK) compositions. After 6 weeks of daily oral treatment, rats treated with AMK and AP compositions showed 59.9% and 51.5% improvement, respectively, in the use of their affected legs to carry their body weight. This was an indication of reduced pain in the surgically drilled knee.
- AP Alpinia:Piper/Pepper
- AMK Alpinia:Magnolia:Kochia
- Articular cartilage matrix synthesis transcription factor, SOX9, and growth factor TGF-bI were also found up regulated in IL-1 -stimulated human chondrocytes treated with those individual extracts of Alpinia, Pepper, Magnolia and Kochia and also those examples, but not limited to, AP and AMK compositions. These findings show that individual extracts of Alpinia, Pepper, Magnolia, and Kochia and also compositions of these plant extracts, not limited to AMK and AP, promote cartilage regeneration by increasing the levels of master regulators of cartilage synthesis, TGF-bI and SOX9, leading to the increase of cartilage components, ACAN, COL2A1, and PILANP.
- the extracts decreased the expression and activity of MMP13, MMP3, ADAMTS4, and MMP9, enzymes that are responsible for the majority of direct cartilage breakdown.
- the net result of these activities is maintenance of remaining cartilage and initiation of cartilage synthesis to restore integrity to the architecture of the joint.
- Figure 1 shows individual extracts of Alpinia, Piper/Pepper, Magnolia and Kochia and/or at various combinations of 2 to 3 of those extracts with examples, but not limited to Alpinia:Piper/Pepper (AP) and Alpinia:Magnolia:Kochia (AMK), reverses OA progression by inducing cartilage homeostasis.
- AP Alpinia:Piper/Pepper
- AMK Alpinia:Magnolia:Kochia
- NTHE drugs had been formulated at 5% Ibuprofen or 1% Diclofenac, as NTHE controls in the current evaluation.
- Two over the counter (OTC) actives were also obtained to make 0.5% Capsaicin or 5% Menthol as OTC positive control.
- OTC pain relief products such as BENGAY®, have also been utilized as controls.
- Pain is a multifactorial phenomenon triggered by multiple mechanisms.
- Application of these test materials could be involved in, but not limited to, the initial activation and subsequent desensitization of peripheral nerve fibers, competitive inhibition or activation of transient receptor potentials such as TRPV1 and/or TRPA1, modulations of cannabinoid receptors (CB1 and CB2 receptors), antagonization and /or blocking of TRPV1 and TRPA1, an initial increase in release of substance-P followed by a depletion, inhibition of bradykinin activity, and inhibition of peripheral synthesis of inflammatory mediators, such as prostaglandin, bradykinin and cytokines.
- the current topical anti-pain data depicted in this subject matter in association with the carrageenan, the MIA, the CIA and OCD model data, could expand the use of individual extracts of Alpinia, Piper/Pepper, Magnolia, and Kochia and also compositions of these plant extracts, not limited to Alpinia:Piper/Pepper (AP) and Alpinia:Magnolia:Kochia (AMK), by combining these plant materials in a specific ratio for enhanced pain relief activity.
- AP Alpinia:Piper/Pepper
- AMK Alpinia:Magnolia:Kochia
- any concentration range, percentage range, ratio range, or integer range is to be understood to include the value of any integer within the recited range and, when appropriate, fractions thereof (such as one tenth and one hundredth of an integer), unless otherwise indicated.
- any number range recited herein relating to any physical feature, such as polymer subunits, size, or thickness are to be understood to include any integer within the recited range, unless otherwise indicated.
- prodrug is also meant to include any covalently bonded carriers, which release the active compound of this disclosure in vivo when such prodrug is administered to a mammalian subject.
- Prodrugs of a compound of this disclosure may be prepared by modifying functional groups present in the compound of this disclosure in such a way that the modifications are cleaved, either in routine manipulation or in vivo , to the parent compound of this disclosure.
- Prodrugs include compounds of this disclosure wherein a hydroxy, amino or mercapto group is bonded to any group that, when the prodrug of the compound of this disclosure is administered to a mammalian subject, cleaves to form a free hydroxy, free amino or free mercapto group, respectively.
- prodrugs include acetate, formate and benzoate derivatives of alcohol or amide derivatives of amine functional groups in the compounds of this disclosure and the like.
- joint health are meant to indicate improving the health of one or multiple “joints” of hand, elbow joints, wrist joints, axillary articulations, sternoclavicular joints, vertebral articulations, temporomandibular joints, sacroiliac joints, hip joints, knee joints and articulation of foot.
- Solid compound and “stable structure” are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
- Biomarker(s)” or “marker(s)” component(s) or compound(s) are meant to indicate one or multiple indigenous chemical component(s) or compound(s) in the disclosed plant(s), plant extract(s), or combined composition(s) with 2-3 plant extracts that are utilized for controlling the quality, consistence, integrity, stability, and/or biological functions of the invented composition(s).
- “Mammal” includes humans and both domestic animals, such as companion animals, laboratory animals or household pets (e.g ., cats, dogs, swine, cattle, sheep, goats, horses, rabbits), and non-domestic animals, such as wildlife or the like.
- domestic animals such as companion animals, laboratory animals or household pets (e.g ., cats, dogs, swine, cattle, sheep, goats, horses, rabbits), and non-domestic animals, such as wildlife or the like.
- Optional or “optionally” means that the subsequently described element, component, event or circumstances may or may not occur, and that the description includes instances where the element, component, event or circumstance occur and instances in which they do not.
- optionally substituted aryl means that the aryl radical may or may not be substituted and that the description includes both substituted aryl radicals and aryl radicals having no substitution.
- “Pharmaceutically or nutraceutically acceptable carrier, diluent or excipient” includes any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier which has been approved by the United States Food and Drug Administration as being acceptable for use in humans or domestic animals.
- “Pharmaceutically or nutraceutically acceptable salt” includes both acid and base addition salts.
- “Pharmaceutically or nutraceutically acceptable acid addition salt” refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, camphoric acid, camphor- 10- sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1, 2-disulfonic acid,
- “Pharmaceutically or nutraceutically acceptable base addition salt” refers to those salts which retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. Salts derived from inorganic bases include the sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. In certain embodiments, the inorganic salts are ammonium, sodium, potassium, calcium, or magnesium salts.
- Salts derived from organic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, deanol, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, procaine, hydrabamine, choline, betaine, benethamine, benzathine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purines, piperazine, piperidine, L -ethyl pi peri dine, polyamine resins and the like.
- Particularly useful organic bases are isopropylamine, dieth
- solvate refers to an aggregate that comprises one or more molecules of a compound of this disclosure with one or more molecules of solvent.
- the solvent may be water, in which case the solvate may be a hydrate.
- the solvent may be an organic solvent.
- the compounds of the present disclosure may exist as a hydrate, including a monohydrate, dihydrate, hemihydrate, sesquihydrate, trihydrate, tetrahydrate and the like, as well as the corresponding solvated forms.
- the compound of this disclosure may be true solvates, while in other cases, the compound of this disclosure may merely retain adventitious water or be a mixture of water plus some adventitious solvent.
- a “pharmaceutical composition” or “nutraceutical composition” refers to a formulation of a compound of this disclosure and a medium generally accepted in the art for the delivery of the biologically active compound to mammals, e.g ., humans.
- a pharmaceutical composition of the present disclosure may be formulated or used as a standalone composition, or as a component in a prescription drug, an over the counter (OTC) medicine, a botanical drug, an herbal medicine, a natural medicine, a homeopathic agent, or any other form of health care product reviewed and approved by a government agency.
- OTC over the counter
- nutraceutical compositions of the present disclosure may be formulated or used as a standalone composition, or as a nutritional or bioactive component in food, a functional food, a beverage, a bar, a food flavor, a medical food, a dietary supplement, or an herbal product.
- a medium generally accepted in the art includes all pharmaceutically or nutraceutically acceptable carriers, diluents or excipients therefor.
- enriched for refers to a plant extract or other preparation having at least a two-fold up to about a 1000-fold increase of one or more active compounds as compared to the amount of one or more active compounds found in the weight of the plant material or other source before extraction or other preparation.
- the weight of the plant material or other source before extraction or other preparation may be dry weight, wet weight, or a combination thereof.
- major active ingredient or “major active component” refers to one or more active compounds found in a plant extract or other preparation or enriched for in a plant extract or other preparation, which is capable of at least one biological activity.
- a major active ingredient of an enriched extract will be the one or more active compounds that were enriched in that extract.
- one or more major active components will impart, directly or indirectly, most (i.e., greater than 50%, or 20% or 10%) of one or more measurable biological activities or effects as compared to other extract components.
- a major active ingredient may be a minor component by weight percentage of an extract (e.g, less than 50%, 25%, or 10% or 5% or 1% of the components contained in an extract) but still provide most of the desired biological activity.
- Any composition of this disclosure containing a major active ingredient may also contain minor active ingredients that may or may not contribute to the pharmaceutical or nutraceutical activity of the enriched composition, but not to the level of major active components, and minor active components alone may not be effective in the absence of a major active ingredient.
- Effective amount refers to that amount of a compound or composition of this disclosure which, when administered to a mammal, such as a human, is sufficient to effect treatment, including any one or more of: (1) maintaining articular cartilage homeostasis; (2) balancing chondrocytes catabolic and anabolic process; (3) treating or preventing loss of cartilage in a mammal; (4) promoting joint health; (5) suppressing loss of cartilage in a mammal; (6) increasing joint flexibility in a mammal; (7) treating or preventing joint pain in a mammal; (8) modifying inflammation of a joint in a mammal; and (9) increasing joint range of motion, (10) managing and/or treating osteoarthritis and/or rheumatoid arthritis, preventing osteoarthritis and/or rheumatoid arthritis, or reversing the progression of osteoarthritis and/or rheumatoid arthritis in a mammal.
- the amount of a compound, an extract or a composition of this disclosure that constitutes a “therapeutically effective amount” will vary depending on the bioactive compound, or the biomarker for the condition being treated and its severity, the manner of administration, the duration of treatment, or the age of the subject to be treated, but can be determined routinely by one of ordinary skill in the art having regard to his own knowledge and to this disclosure.
- “effective amount” or “therapeutically effective amount” may be demonstrated as the quantity over the body weight of a mammal (i.e., 0.005 mg/kg, 0.01 mg/kg, or 0.1 mg/kg, or 1 mg/kg, or 10 mg/kg, or 50 mg/kg, or 100 mg/kg, or 200 mg/kg, or 500 mg/kg).
- the human equivalent daily dosage can be extrapolated from the “effective amount” or “therapeutically effective amount” in an animal study by utilization of FDA guideline in consideration the difference of total body areas and body weights of animals and human.
- Dietary supplements as used herein are a product that improves, promotes, increases, manages, controls, maintains, optimizes, modifies, reduces, inhibits, or prevents a particular condition associated with a natural state or biological process, or a structural and functional integrity, a homeostasis of a biological function or a phenotypic condition (i.e., are not used to diagnose, treat, mitigate, cure, or prevent disease).
- dietary supplements may be used to maintain joint cartilage, minimize cartilage degradation, promote health joints by protecting cartilage integrity, diminish the action of enzymes that affect joint health, improve joint movement and/or function, alleviate joint pain, alleviate joint stiffness, improve joint range of motion and/or flexibility, promote mobility, balance anabolic and catabolic homeostasis and/or the like.
- dietary supplements are a special category of food, functional food, medical food and are not a drug.
- Treating” or “treatment” as used herein refers to the treatment of the disease or condition of interest in a mammal, such as a human, having the disease or condition of interest, and includes: (i) preventing the disease or condition from occurring in a mammal, in particular, when such mammal is predisposed to the condition but has not yet been diagnosed as having it; (ii) inhibiting the disease or condition, /. e.
- the terms “disease” and “condition” may be used interchangeably or may be different in that the particular malady or condition may not have a known causative agent (so that etiology has not yet been worked out) and it is therefore not yet recognized as a disease but only as an undesirable condition or syndrome, wherein a more or less specific set of symptoms have been identified by clinicians.
- statistical significance refers to a p value of 0.050 or less when calculated using the Students t-test and indicates that it is unlikely that a particular event or result being measured has arisen by chance.
- the compounds of the present disclosure may be administered as a raw chemical or may be formulated as pharmaceutical or nutraceutical compositions.
- Pharmaceutical or nutraceutical compositions of the present disclosure comprise a compound of structures described in this disclosure and a pharmaceutically or nutraceutically acceptable carrier, diluent or excipient.
- the compound of structures described here are present in the composition in an amount which is effective to treat a particular disease or condition of interest - that is, in an amount sufficient promote chondrocyte, or extracellular matrix, or cartilage homeostasis or any of the other associated indications described herein, and generally with acceptable toxicity to a patient.
- compositions of this disclosure can be carried out via any of the accepted modes of administration of agents for serving similar utilities.
- the pharmaceutical or nutraceutical compositions of this disclosure can be prepared by combining a compound of this disclosure with an appropriate pharmaceutically or nutraceutically acceptable carrier, diluent or excipient, and may be formulated into preparations in solid, semi-solid, liquid or gaseous forms, such as tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants, gels, creams, lotions, tinctures, sashay, ready to drink, masks, microspheres, and aerosols.
- Typical routes of administering such pharmaceutical or nutraceutical compositions include oral, topical, transdermal, inhalation, parenteral, sublingual, buccal, rectal, vaginal, or intranasal.
- parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques.
- Pharmaceutical or nutraceutical compositions of this disclosure are formulated so as to allow the active ingredients contained therein to be bioavailable upon administration of the composition to a patient.
- compositions that will be administered to a subject or patient or a mammal take the form of one or more dosage units, where for example, a tablet may be a single dosage unit, and a container of a compound or an extract or a composition of 2-3 plant extracts of this disclosure in aerosol form may hold a plurality of dosage units.
- Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington: The Science and Practice of Pharmacy , 20th Edition (Philadelphia College of Pharmacy and Science, 2000).
- the composition to be administered will, in any event, contain a therapeutically effective amount of a compound of this disclosure, or a pharmaceutically or nutraceutically acceptable salt thereof, for treatment of a disease or condition of interest in accordance with the teachings of this disclosure.
- a pharmaceutical or nutraceutical composition of this disclosure may be in the form of a solid or liquid.
- the carrier(s) are particulate, so that the compositions are, for example, in tablet or in powder form.
- the carrier(s) may be liquid, with the compositions being, for example, oral syrup, injectable liquid or an aerosol, which is useful in, for example, inhalatory administration.
- the pharmaceutical or nutraceutical composition is in either solid cream, suspension and gel forms are included within the forms considered herein as either solid or liquid.
- the pharmaceutical or nutraceutical composition may be formulated into a powder, granule, compressed tablet, pill, capsule, chewing gum, sashay, wafer, bar, or like form.
- a solid composition will typically contain one or more inert diluents or edible carriers.
- binders such as carboxymethylcellulose, ethyl cellulose, cyclodextrin, microcrystalline cellulose, gum tragacanth or gelatin; excipients such as starch, lactose or dextrins, disintegrating agents such as alginic acid, sodium alginate, Primogel, corn starch and the like; lubricants such as magnesium stearate or Sterotex; glidants such as colloidal silicon dioxide; sweetening agents such as sucrose or saccharin; a flavoring agent such as peppermint, methyl salicylate or orange flavoring; and a coloring agent.
- excipients such as starch, lactose or dextrins, disintegrating agents such as alginic acid, sodium alginate, Primogel, corn starch and the like
- lubricants such as magnesium stearate or Sterotex
- glidants such as colloidal silicon dioxide
- sweetening agents such as sucrose or saccharin
- a flavoring agent such
- the pharmaceutical or nutraceutical composition when in the form of a capsule, for example, a gelatin capsule, it may contain, in addition to materials of the above type, a liquid carrier such as polyethylene glycol or oil.
- a liquid carrier such as polyethylene glycol or oil.
- the pharmaceutical or nutraceutical composition may be in the form of a liquid, for example, an elixir, tincture, syrup, solution, emulsion or suspension.
- the liquid may be for oral administration or for delivery by injection, as two examples.
- a useful composition contains, in addition to the present compounds, one or more of a sweetening agent, preservatives, dye/colorant and flavor enhancer.
- a surfactant, preservative, wetting agent, dispersing agent, suspending agent, buffer, stabilizer and isotonic agent may be included.
- the liquid pharmaceutical or nutraceutical compositions of this disclosure may include one or more of the following adjuvants: sterile diluents such as water for injection, saline solution, such as physiological saline, Ringer’s solution, isotonic sodium chloride, fixed oils such as synthetic mono or diglycerides which may serve as the solvent or suspending medium, polyethylene glycols, glycerin, propylene glycol or other solvents; 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 and agents for the adjustment of tonicity such as sodium chloride or dextrose.
- the parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.
- Physiological saline is a
- a liquid pharmaceutical or nutraceutical composition of this disclosure intended for either parenteral or oral administration should contain an amount of a compound of this disclosure such that a suitable dosage will be obtained.
- the pharmaceutical or nutraceutical composition of this disclosure may be intended for topical administration, in which case the carrier may suitably comprise a solution, emulsion, cream, lotion, ointment, or gel base.
- the base for example, may comprise one or more of the following: petrolatum, lanolin, polyethylene glycols, bee wax, mineral oil, diluents such as water and alcohol, and emulsifiers and stabilizers.
- Thickening agents may be present in a pharmaceutical or nutraceutical composition for topical administration.
- the composition may include a transdermal patch or iontophoresis device.
- the pharmaceutical or nutraceutical composition of this disclosure may be intended for rectal administration, in the form, for example, of a suppository, which will melt in the rectum and release the drug.
- the composition for rectal administration may contain an oleaginous base as a suitable nonirritating excipient.
- bases include lanolin, cocoa butter and polyethylene glycol.
- the pharmaceutical or nutraceutical composition of this disclosure may include various materials, which modify the physical form of a solid or liquid dosage unit.
- the composition may include materials that form a coating shell around the active ingredients.
- the materials that form the coating shell are typically inert, and may be selected from, for example, sugar, shellac, and other enteric coating agents.
- the active ingredients may be encased in a gelatin capsule.
- the pharmaceutical or nutraceutical composition of this disclosure in solid or liquid form may include an agent that binds to the compound of this disclosure and thereby assists in the delivery of the compound.
- Suitable agents that may act in this capacity include a monoclonal or polyclonal antibody, a protein or a liposome.
- the pharmaceutical or nutraceutical composition of this disclosure in solid or liquid form may include reducing the size of a particle to, for example, improve bioavailability.
- the size of a powder, granule, particle, microsphere, or the like in a composition, with or without an excipient can be macro (e.g ., visible to the eye or at least 100 pm in size), micro (e.g, may range from about 100 mih to about 100 nm in size), nano ( e.g ., may no more than 100 nm in size), and any size in between or any combination thereof to improve size and bulk density.
- the pharmaceutical or nutraceutical composition of this disclosure may consist of dosage units that can be administered as an aerosol.
- aerosol is used to denote a variety of systems ranging from those of colloidal nature to systems consisting of pressurized packages. Delivery may be by a liquefied or compressed gas or by a suitable pump system that dispenses the active ingredients. Aerosols of compounds of this disclosure may be delivered in single phase, bi-phasic, or tri-phasic systems in order to deliver the active ingredient(s). Delivery of the aerosol includes the necessary container, activators, valves, subcontainers, and the like, which together may form a kit. One skilled in the art, without undue experimentation, may determine the most appropriate aerosol(s).
- compositions of this disclosure may be prepared by methodology well known in the pharmaceutical or nutraceutical art.
- a pharmaceutical or nutraceutical composition intended to be administered by injection can be prepared by combining a compound of this disclosure with sterile, distilled, deionized water so as to form a solution.
- a surfactant may be added to facilitate the formation of a homogeneous solution or suspension.
- Surfactants are compounds that non-covalently interact with the compound of this disclosure so as to facilitate dissolution or homogeneous suspension of the compound in the aqueous delivery system.
- the compounds of this disclosure are administered in a therapeutically effective amount, which will vary depending upon a variety of factors including the activity of the specific compound employed; the metabolic stability and length of action of the compound; the age, body weight, general health, sex, and diet of the patient; the mode and time of administration; the rate of excretion; the drug combination; the severity of the particular disorder or condition; and the subject undergoing therapy.
- Compounds of this disclosure, or pharmaceutically or nutraceutically acceptable derivatives thereof, may also be administered simultaneously with, prior to, or after administration of food, water and one or more other therapeutic agents.
- Such combination therapy includes administration of a single pharmaceutical or nutraceutical dosage formulation which contains a compound or an extract or a composition with 2-3 plant extracts of this disclosure and one or more additional active agents, as well as administration of the compound or an extract or a composition with 2-3 plant extracts of this disclosure and each active agent in its own separate pharmaceutical or nutraceutical dosage formulation.
- a compound or an extract or a composition with 2-3 plant extracts of this disclosure and another active agent can be administered to the patient together in a single oral dosage composition, such as a tablet or capsule, or each agent can be administered in separate oral dosage formulations.
- the compounds of this disclosure and one or more additional active agents can be administered at essentially the same time, i.e., concurrently, or at separately staggered times, /. e. , sequentially; combination therapy is understood to include all these regimens.
- Suitable protecting groups include hydroxy, amino, mercapto and carboxylic acid.
- Suitable protecting groups for hydroxy include trialkylsilyl or diarylalkylsilyl (for example, I- butyldimethylsilyl, /-butyldiphenyl silyl or trimethyl silyl), tetrahydropyranyl, benzyl, and the like.
- Suitable protecting groups for amino, amidino and guanidino include /-butoxycarbonyl, benzyloxycarbonyl, and the like.
- Suitable protecting groups for mercapto include -C(0)-R” (where R” is alkyl, aryl or arylalkyl), / -methoxybenzyl, trityl and the like.
- Suitable protecting groups for carboxylic acid include alkyl, aryl or arylalkyl esters.
- Protecting groups may be added or removed in accordance with standard techniques, which are known to one skilled in the art and as described herein. The use of protecting groups is described in detail in Green, T.W. and P.G.M. Wutz, Protective Groups in Organic Synthesis (1999), 3rd Ed., Wiley.
- the protecting group may also be a polymer resin such as a Wang resin, Rink resin or a 2-chlorotrityl-chloride resin.
- compounds or extracts of the present disclosure can be isolated from plant sources, for example, from those plants included in the Examples and elsewhere throughout the present application. Suitable plant parts for isolation of the compounds include leaves, bark, trunk, trunk bark, stem, stem bark, twigs, tubers, root, rhizome, root bark, bark surface, young shoots, seed, fruit, androecium, gynoecium, calyx, stamen, petal, sepal, carpel (pistil), flower, or any combination thereof.
- the compounds or extracts are isolated from plant sources and synthetically modified to contain any of the recited substituents. In this regard, synthetic modification of the compound isolated from plants can be accomplished using any number of techniques which are known in the art and are well within the knowledge of one of ordinary skill in the art.
- Kochia scoparia also identified as Bassia scoparia, Bassia sieversiana; Kochia alata; Kochia trichophila ; Kochia trichophylla , is a large annual herb growing from seeds with the common names: burning bush, ragweed, summer cypress, kochia and Mexican fireweed.
- the plant is native to Asia but naturalized in many parts of North America as well.
- Kochia scoparia plant contains high levels of protein and is commonly used as forage for livestock. The seeds could be served as food for birds and are also valuable as poultry feed. Kochia seeds are also used as food garnish in Japan called Tonburi or land caviar.
- Kochiae fructus or seeds has been used as folk medicine in Asian countries to treat a variety of diseases, such as skin diseases, diabetes mellitus, rheumatoid arthritis, liver disorders, and jaundice, etc. Recent studies have also reported kochia seeds with antioxidant, anti-inflammatory, antiparasitic, anti-cancer, antidiabetic, hypoglycemic, weight loss, anti-allergic, analgesic properties. Oleanolic acid type triterpenoid saponins were identified as the active components responsible for most of Kochia fructus efficacies.
- Momordin Ic originally isolated from Momordica cochinchinensis, is a principle constituent of Kochiae fructus and is also reported in various natural herbal medicines with antinociceptive and anti-inflammatory activities in hind paw licking and formalin test in mice. Both 70% Kochiae fructus ethanol extracts and Momordin Ic showed inhibitory effects in Carrageenan-induced paw edema model in mice.
- Kochia extract is a contemplated component or constituent that can be utilized as part of a target compound or composition.
- Kochia extract may be obtained from any suitable source, including Kochia scoparia , Bassia scoparia, Bassia angustifolia, Momordica cochinchinensis, Bassia dinteri, Bassia eriophora, Bassia hyssopifolia, Bassia indica, Bassia laniflora, Bassia lasiantha, Bassia littorea, Bassia muricata, Bassia odontoptera, Bassia pilosa, Bassia prostrata, Bassia salsoloides, Bassia stellaris, Bassia tianschanica, Bassia tomentosa, Bassia villosissima or a combination thereof.
- Kochia extract may be enriched for one or more as contemplated herein.
- the Kochia extract comprises about 0.01% to about 99.9% saponins.
- Contemplated saponins isolated from Kochia extract are Bassiasaponin A; Bassiasaponin B; Kochioside A; Kochioside B; Kochioside C; Kochianoside I; Scoparianos A; Scoparianoside B; Scoparianoside C; Momordin Ic; Kochianoside I; Kochianoside II ; Kochianoside III; Kochianoside IV; 2'-0- Glucopyranosylmomordin Ic; 2'-0-Glucopyranosylmomordin lie, etc.
- Alpinia galanga belongs to the ginger family and is used as a spice herb in southeast Asian cuisine with the common names: lengkuas, greater galangal and blue ginger.
- Alpinia galanga as traditionally used to treat various kinds of disease including eczema, bronchitis, otitis internal, gastritis, ulcers and cholera, appetite boosting, tonic effect, etc.
- Many pharmacological activities have been reported for Alpinia galanga , especially as antibacterial, antifungal, antiviral, immunomodulatory, antioxidant, antidiabetic, analgesic and many other pharmacological functions.
- Alpinia galanga The main chemical constituents of Alpinia galanga are reported as flavonoids, such as kaempferol, kaempferide, and volatile components including trans -p-coumaryl diacetate, di-(p- hydroxy-cis-styryl) methane, eugenol acetate, l'-hydroxychavicol acetate, p- hydroxycinnamaldehyde, etc.
- the anti-inflammatory and analgesic activities of the topical application o ⁇ Alpinia galanga methanolic extract were illustrated in the examples 8, 9, 10 and 11.
- the anti-inflammatory and analgesic activity of Alpinia methanol extract was also found in both Carrageenan-induced paw edema model in rats and in formalin test.
- One of major phenylpropanoids, l'-Acetoxychavicol acetate, and Alpinia galanga acetone extract have been reported effective in Incomplete Freund’s Adjuvant (IFA)-induced arthritis model in rats.
- Alpinia extract is a contemplated component or constituent that can be utilized as part of a target compound or composition.
- Alpinia extract may be obtained from any suitable galangal source, including Alpinia galanga, Alpinia officinarum, Boesenbergia rotunda, Kaempferia galanga, Alpinia oxyphylla, Alpinia abundiflora, Alpinia acrostachya, Alpinia caerulea, Alpinia calcarata, Alpinia conchigera, Alpinia globosa, Alpinia javanica, Alpinia melanocarpa, Alpinia mutica, Alpinia nigra, Alpinia nutans, Alpinia petiolate, Alpinia purpurata, Alpinia pyramidata, Alpinia rafflesiana, Alpinia speciosa, Alpinia vittata, Alpinia zerumbe
- Alpinia extract may be enriched for one or more as contemplated herein and as demonstrated in examples 8, 9, 10 and 11.
- Contemplated aromatics isolated from Alpinia extract are extracted with any suitable solvent, including supercritical fluid of CO2, water, methanol, ethanol, alcohol, a water-mixed solvent, organic solvent, such as hexane, ethyl acetate, acetone, butanol; or a combination thereof, or with supercritical fluid, or by water distillation of oil in the rhizomes.
- the Alpinia extract comprises about 0.01% to about 99.9% phenylpropanoid small aromatics.
- Contemplated aromatics isolated from Alpinia extract are l'-Acetoxyeugenol acetate; Coniferyl diacetate; 3-(4-Hydroxyphenyl)-2-propenal; 3-(4- Hydroxyphenyl)-2-propen-l-ol; Methyl cinnamate, FEMA2698; 3-(4-Methoxyphenyl)-2-propen- l-ol; l'-Hydroxychavicol acetate; 4-Acetoxycinnamyl alcohol; 4-Acetoxycinnamyl ethyl ether; G- Ethoxychavicol acetate; l-(3,4-Dihydroxyphenyl)-2-propen-l-ol; (S)-form, 3'-Me ether, 4'-Ac; G- Acetoxychavicol acetate; l-(4-Hydroxyphenyl)-2-propen-l-ol; -form, Di
- Piper nigrum with common name black pepper, is a flowing vine of the family Piperaceae.
- the terms “Piper”, “Pepper”, and “Piper/Pepper” are used interchangeably to refer to embodiments comprising this extract or constituent.
- Black pepper is native to India state in Southeastern India and extensively cultivated in tropical regions, such as Vietnam, India, and Indonesia.
- the ground dried fruit, known as peppercorn has been used for its flavor and as traditional medicine. Black pepper is one of the most commonly used spices in the world.
- Pipeline is the main constituent in black pepper contributing to the hot and pungent flavor.
- Black peppercorns feature as remedies in Ayurveda, Siddha and Unani medicine in South Asia. They are used as an appetizer and to treat digestive system-related problems. Black pepper could be used as a remedy for sore throat to reduce throat inflammation. Externally, it could be applied to reduce hair loss and treat some skin problems. Many pharmacological effects have been reported for black pepper, such as antifungal, antioxidant, digestive boosting, anti-depressant and cognitive effect, analgesic and anti-inflammatory, anticancer, immuno-modulatory, lipid lowering, etc.
- Piper extract is a contemplated component or constituent that can be utilized as part of a target compound or composition.
- Piper extract may be obtained from any suitable source as illustrated in example 5, 6, and 7, including Piper nigrum and many other Piper spp., Periconia sp.
- Piperine The principle active alkaloid compound, Piperine, was extensively studied and reported to act as a central nervous system antidepressant and nerve stimulant, and to have antioxidant, anti- fever, hepatoprotective, pain-relieving, anti-inflammatory, insecticidal and many other effects. Piperine was also reported as a bioavailability enhancer.
- Piper extract may be enriched for one or more as contemplated herein as illustrated in examples 5, 6, and 7.
- Contemplated alkaloids isolated from Piper extract are extracted with any suitable solvent, including supercritical fluid of CO2, water, methanol, ethanol, alcohol, a water- mixed solvent, organic solvent such as ethyl acetate, acetone, butanol or a combination thereof, or with supercritical fluid.
- the Piper extract comprises about 0.01% to about 99.9% piperidine alkaloids.
- Contemplated alkaloids isolated from Piper extract are Piperine; Piperchabamide A; Kaousine; 5-Acetoxy-5,6-dihydro-l-(3-phenylpropanoyl)-2(lH)- pyridinone; 5,6-Dihydro-N-(3,4-dimethoxycinnamoyl)-2(lH)-pyridinone; N-[3-(3,4- Dimethoxyphenyl)propanoyl]-5,6-dihydro-2(lH)-pyridinone; Cenocladamide; 3,4-
- Magnolia officinalis commonly known as “houpu” in Chinese as one of the most popular traditional Chinese medicine plants, with a very wide range of applications. It is a species of Magnolia that is native in China, mainly growing in Sichuan and Hubei provinces. Houpu refers to its thick bark, which can be stripped from the stems, branches, and roots. The traditional indications are to treat wind stroke, cold damage, headache, fight qi and blood impediments. Magnolia bark has been used to treat menstrual cramps, abdominal pain, abdominal bloating and gas, nausea, and indigestion. The bark is also an ingredient in formulas used for treating coughs and asthma. Many of the formulations with Magnolia bark are used in treating lung diseases such as including cough and asthma or intestinal infections and spasms, relieving abdominal swelling of various causes and edema.
- lung diseases such as including cough and asthma or intestinal infections and spasms, relieving abdominal swelling of various causes and edema.
- Bisphenolic lignans are identified as the major active components responsible for the efficacy.
- Magnolol and honokiol as two main polyphenol compounds found in Magnolia bark, have been reported with various pharmacological activities and functions, such as antioxidant, anti-inflammatory, and antitumor (Park 2004).
- the anticancer studies of honokiol have been extended to several different solid tumor types such as breast, prostate, gastric, and ovarian cancer, with potential to enhance current anticancer regimens (Fried 2009).
- Honokiol also reduced inflammation and oxidative stress, providing beneficial effects in neurological protection, and glucose regulation with great potential as therapeutic agents for inflammatory disease.
- magnolol and honokiol have been known to exhibit potent antimicrobial activity against Gram-positive and Gram-negative bacteria as well as fungi such as Propionibacterium sp. and S. aureus showing its potential as antimicrobial agents effective against more infectious and antibiotic resistant microorganisms (Bopaiah 2001; Bang 2000; Syu 2004).
- the content of honokiol and magnolol could be varied from 1-99% in the commercialized Magnolia bark extracts.
- Magnolia extract is a contemplated component or constituent that can be utilized as part of a target compound or composition.
- Magnolia extract may be obtained from any suitable source, including Magnolia officinalis, Magnolia acuminate, Magnolia biondii, Magnolia coco, Magnolia denudate, Magnolia fargesii, Magnolia garrettii, Magnolia grandiflora, Magnolia henryi, Magnolia liliflora, Magnolia kachirachirai, Magnolia Kobus, Magnolia obovata, Magnolia praecocissima, Magnolia pterocarpa, Magnolia pyramidata, Magnolia rostrate, Magnolia salicifolia, Magnolia sieboldii, Magnolia soulangeana, Magnolia stellate, Magnolia virginiana, prod of degradation of birch lignin, Acanthus ebracteatus, Aptosimum spinescens, Aralia bipinnata, Araucaria angustifolia, Araucaria araucana, Artemisia absinthium, Haplophyllum a
- Magnolia extract may be enriched for one or more as contemplated herein.
- Contemplated lignans isolated from Magnolia extract are extracted with any suitable solvent, including supercritical fluid of CO2, water, methanol, ethanol, alcohol, organic solvent such as ethyl acetate, acetone, butanol; a water-mixed solvent or a combination thereof, or with supercritical fluid.
- the Magnolia extract comprises about 0.01% to about 99.9% biphenolic lignans.
- Contemplated lignans isolated from Magnolia extract are magnolol, honokiol, Magnaldehyde D; Magnaldehyde D; 4'-Deoxy, 6'-hydroxy; 6,8-Epoxy-3,3'-ligna-7,8'-dien-4'-ol; 3,3'-Ligna-8,8'-diene-4,6'-diol; 3,3'-Ligna-8,8'-diene-4,4'-diol; 3,3'-Ligna-8,8'-diene-4,6'-diol;7'- Isomer(E-); Magnaldehyde D; 6'-Methoxy, 4'-deoxy; Magnaldehyde A; Magnaldehyde A; 6'- Hydroxy, 4'-deoxy; 6,8-Epoxy-3,3'4igna-7,8'-dien-4'-ol; 9-Hydroxy; 3,3'-Ligna-8,8
- Contemplated compounds, medicinal compositions and compositions may comprise or additionally comprise or consist of at least one active ingredient.
- at least one bioactive ingredient may comprise or consist of plant powder or plant extract or the like.
- compositions comprising mixtures of extracts or compounds may be mixed at a particular ratio by weight. Demonstrated in example 15, an Alpinia extract and a Pepper extract may be blended in a 1 :2 weight ratio, respectively.
- the ratio (by weight) of two extracts or compounds of this disclosure ranges from about 0.5:5 to about 5:0.5. Similar ranges apply when more than two extracts or compounds (e.g., three, four, five) are used.
- ratios include 0.5:1, 0.5:2, 0.5:3, 0.5:4, 0.5:5, 1:1, 1:2, 1:3, 1:4, 1:5, 2:1, 2:2, 2:3, 2:4, 2:5, 3:1, 3:2, 3:3, 3:4, 3:5, 4:1, 4:2, 4:3, 4:4, 4:5, 5:1, 5:2, 5:3, 5:4, 5:5, 1:0.5, 2:0.5, 3:0.5, 4:0.5, or 5:0.5.
- the disclosed individual extracts of Alpinia , and/or Pepper , and/or Magnolia and/or Kochia are blended into a composition with 3 individual extracts in a 1:1:1, 2:1:1, 3:1:1, 4:1:1, 5:1:1, 1:2:1, 1:3:1, 1:4:1, 1:5:1, 1:1:2, 1:1:3, 1:1:4, 1:1:5, 1:2:3, 1:2:4, 1:2:5, 1:2:6, 1:2:6, 1:2:8, 1:2:9 or 1:2:10 etc. weight ratio, respectively.
- the disclosed individual extracts of Alpinia, Pepper, Magnolia and Kochia have been combined into a composition called AMK as an examples but not limited to a blending ratio of 2:4:3 and 5:4:4 as of Alpinia:Magnolia:Kochia as demonstrated in example 14.
- AP Alpinia:Pepper
- AMK Alpinia:Magnolia:Kochia
- compositions with specific blending ratio of individual extracts of Alpinia, or Pepper, or Magnolia or Kochia were selected based on unexpected synergy measured on the in vitro , and/or ex vivo and/or in vivo models due to the diversity of chemical components in each extract and different mechanism of actions from different types of bioactive compounds in each extract, and potential enhancement of ADME of natural compounds in the composition to maximize the biological outputs.
- compositions comprising mixtures of extracts or compounds may be present at certain percentage levels or ratios.
- a composition comprising an Alpinia extract and/or a Kochia extract can include 0.1% to 49.9% or about 2% to about 40% or about 0.5% to about 8% of acetoxychavicol acetate, 0.1% to 49.9% or about 1% to about 10% or about 0.5% to about 3% of Momordin lc, or a combination thereof.
- a composition comprising an Alpinia extract can include from about 0.01% to about 99.9% acetoxychavicol acetate or include at least 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or 80% acetoxychavicol acetate (e.g., G- acetoxychavicol acetate, or p-coumaryl diacetate, or both)
- acetoxychavicol acetate e.g., G- acetoxychavicol acetate, or p-coumaryl diacetate, or both
- composition of this disclosure may be formulated to further comprise a pharmaceutically or nutraceutically acceptable carrier, diluent, or excipient, wherein the pharmaceutical or nutraceutical formulation comprises from about 0.05 weight percent (wt%), or 0.5 weight percent (wt%), or 5%, or 25% to about 95 wt% of active or major active ingredients of an extract mixture.
- the pharmaceutical or nutraceutical formulation comprises from about 0.05 weight percent (wt%) to about 90wt%, about 0.5wt% to about 80wt%, about 0.5wt% to about 75wt%, about 0.5wt% to about 70wt%, about 0.5wt% to about 50wt%, about 1.0wt% to about 40wt%, about 1.0wt% to about 20wt%, about 1.0wt% to about 10wt%, about 3.0wt% to about 9.0wt%, about 5.0 wt% to about 10wt%, about 3.0wt% to about 6wt% of the major active ingredients in an extract mixture, or the like.
- a composition of this disclosure is formulated as a tablet, hard capsule, softgel capsule, powder, or granule.
- contemplated herein are agents of the disclosed compounds. Such products may result from, for example, the oxidation, reduction, hydrolysis, amidation, esterification, and the like of the administered compound, primarily due to enzymatic processes. Accordingly, contemplated compounds are those produced by a process comprising administering a contemplated compound or composition to a mammal for a period of time sufficient to yield a metabolic product thereof.
- Such products are typically identified by administering a radiolabeled or not radiolabeled compound of this disclosure in a detectable dose to an animal, such as rat, mouse, guinea pig, dog, cat, pig, sheep, horse, monkey, or human, allowing sufficient time for metabolism to occur, and then isolating its conversion products from the urine, blood or other biological samples.
- an animal such as rat, mouse, guinea pig, dog, cat, pig, sheep, horse, monkey, or human, allowing sufficient time for metabolism to occur, and then isolating its conversion products from the urine, blood or other biological samples.
- Contemplated compounds, medicinal compositions and compositions may comprise or additionally comprise or consist of at least one pharmaceutically or nutraceutically or cosmetically acceptable carrier, diluent or excipient.
- pharmaceutically or nutraceutically or cosmetically acceptable carrier, diluent or excipient includes any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier which has been approved by the United States Food and Drug Administration as being acceptable for use in humans or domestic animals.
- Contemplated compounds, medicinal compositions and compositions may comprise or additionally comprise or consist of at least one pharmaceutically or nutraceutically or cosmetically acceptable salt.
- pharmaceutically or nutraceutically or cosmetically acceptable salt includes both acid addition and base addition salts.
- bioactives from the disclosed individual extracts of Alpinia, Piper/Pepper, Magnolia and Kochia and/or at various combinations of 2 to 3 of those extracts with examples, but not limited to, Alpinia:Piper/Pepper (AP) and Alpinia:Magnolia:Kochia (AMK), can be optionally combined with other RA and OA management agents, such as non-steroidal anti-inflammatory agents/analgesics, COX-2 inhibiting agents including, but not limited to, acetaminophen, ibuprofen, naproxen, Aspirin, Diclofenac, Indomethacin, Piroxicam, Ketoprofen, Trolamine salicylate; neuropathic pain relief agents such as Lidocaine; biological agents Methotrexate, 11-1 and TNF-a anti-bodies; herbal and/or plant extracts promoting joint health including but not limited to Cannabis sativa (Hemp Oil) oil or CBD/THC, full spectrum Hemp
- inventions of the disclosure relate to methods of use of the disclosed individual extracts of Alpinia, Piper/Pepper, Magnolia and Kochia and/or at various combinations of 2 to 3 of those extracts with examples, but not limited to, Alpinia:Piper/Pepper (AP) and Alpinia:Magnolia:Kochia (AMK), in this disclosure, including, but not limited to maintaining catabolic/anabolic biomarker homeostasis.
- AP Alpinia:Piper/Pepper
- AMK Alpinia:Magnolia:Kochia
- Those catabolic biomarkers are, but not limited to, TNF-a, IL-Ib, IL-6, aggrecanase and matrix metalloproteinase (MMP) such as MMP13, MMP9, MMP3, MMP1, uCTX-II and ADAMTS4; and those anabolic biomarkers are but not limited to SOX 9, TGF-bI, AC AN, COL2A1, and PIIANP.
- MMP matrix metalloproteinase
- inventions of the disclosure relate to methods of use of the disclosed individual extracts of Alpinia, Piper/Pepper, Magnolia and Kochia and/or at various combinations of 2 to 3 of those extracts with examples, but not limited to, Alpinia:Piper/Pepper (AP) and Alpinia:Magnolia:Kochia (AMK), in this disclosure, including, but not limited to maintaining cartilage homeostasis, inducing cartilage synthesis (and hence, anabolic effect) and inhibiting the catabolic process of degradation and broken down, protecting extracellular matrix integrity, and joint cartilage, minimizing cartilage degradation, alleviating cartilage breakdown, and initiating and/or promoting and/or enhancing cartilage synthesis, cartilage renewal and cartilage rebuild, repairing damaged cartilage, maintaining, rebuilding and repairing extra cellular matrix of joint tissue, revitalizing joints structure, maintaining steady blood flow to joints, promoting health joints by protecting cartilage integrity, balancing anabolic and catabolic processes, maintaining synovial fluid for joint lubrication
- inventions of the disclosure relate to methods of use of the disclosed individual extracts of Alpinia, Piper/Pepper, Magnolia and Kochia and/or at various combinations of 2 to 3 of those extracts with examples, but not limited to, Alpinia:Piper/Pepper (AP) and Alpinia:Magnolia:Kochia (AMK), in this disclosure, including, but not limited to improving joint movement and/or physical function, maintaining joint health and mobility into old age, supporting, protecting or promoting joint comfort, alleviating joint pain, reducing joint friction, alleviating joint stiffness, improving joint range of motion and/or flexibility, promoting mobility, reducing inflammation, reducing oxidative stress, reducing and protecting joint wear and tear, managing and/or treating osteoarthritis and/or rheumatoid arthritis, preventing osteoarthritis and/or rheumatoid arthritis, or reversing the progression of osteoarthritis and/or rheumatoid arthritis; Preventing and treating juvenile rheuma
- the dry Kochia scoparia fruits were ground into powder. 20 grams of Kochia scoparia fruit powder were mixed with enough Diatomaceous earth to fill up a lOOmL extraction cell, and extracted with 100% Ethanol (EE), 70% Ethanol/water (70E) or 50% Ethanol/water (50E) by using
- EE Ethanol
- 70E 70% Ethanol/water
- 50E 50% Ethanol/water
- the solution was concentrated with a rotary evaporator at 50°C and high vacuum to produce to a solid extract.
- the target components, such as Momordin lc, in the Kochia extracts were quantified with a Luna Cl 8 reversed-phase column (Phenomenex, 10pm, 250mm x4.6mm) in a Hitachi HPLC system detected at 205 nm wavelength.
- the column was eluted with a binary gradient of 0.1% Trifluoroacetic acid in water (mobile phase A) and acetonitrile (mobile phase B) at 1 ml/min flow rate and 35°C column temperature.
- Reference Standard produced according to Example xx was utilized as the quantification standard. All samples were prepared in MeOH for HPLC analysis with standard in a concentration around 3 mg/ml, and extract samples in a concentration around 10 mg/ml.
- Ethanol extract (EE, 10 g) from fruits of Kochia scoparia was partitioned between organic solvent (100 ml each) and water (150 ml) in the order of Hexane, EtOAC and BuOH to generate Hexane fraction (HE), EtOAC fraction (EA), BuOH fraction (Bu) and water fraction (WA).
- HE Hexane fraction
- EA EtOAC fraction
- BuOH fraction BuOH fraction
- WA water fraction
- the compound Momordin lc was enriched in BuOH fraction (1.7 g), the marker compound was increased from 9.7% in extract to 46.2% in BuOH fraction.
- Kochia scoparia fruit powder (100 g) was refluxed in 500 ml of 0.25 M NaOH water solution for one hour, then centrifuged at 4000 rpm to collect first basic water extract and the extraction was repeated under the same conditions once more.
- the basic water extract solutions were then combined and neutralized to pH 4 with 0.29 M HC1, under which, precipitation in the solution was observed.
- the precipitate was separated from supernatant through centrifugation at 4000 rpm, then washed with 500 mL water to remove any salty substances and centrifuged again to remove supernatant. The water washing was repeated two more times. Then 500 mL of Ethanol was added to the solid, and the EtOH-soluble portion was concentrated and dried under high vacuum to secure 11.8 g solid that contained 14% of Momordin lc.
- Kochia scoparia fruits powder from another collection R00782 (520 g) was divided into two flasks in equal amount, 600 ml of 50% Ethanol/water (50E) added to each flask, refluxed for 1 hour, extract collected through filtration, reflux repeated two more times. All extracts (about 3 liters) were combined, the organic solvent reduced on a rotary-evaporator to the final volume of about 600 mL, and then the volume brought to 2 liters by adding more water. The extract was partitioned with BuOH three times, about 750 mL each time. The BuOH fraction was dried with a rotary evaporator under high vacuum to yield 34 g enriched BuOH fraction. The compound Momordin lc was enriched from 4.2% in 50% ethanol extract (50E) to 24.3% in BuOH fraction.
- Dried Kochia scoparia fruits powder (35 kg) was extracted with 5 to 10-folds volume of 95% ethanol under 90°C for 1 hour, then the decoction was filtered to receive first extract in solution. Added fresh solvent to the biomass and repeated the extraction process 2 more times. Combined extract in solution from three repeats, concentrated and dried under vacuum with temperate between 70-85°C. The production process from 35 kg plant powder to extract powder was repeated three times (3 x 35 kg) to produce three batches of extracts with extraction yielded between 13-15%. The dried extract was ground and blended with 25% maltodextrin, then sieved to pass 80 mess to produce a fine powder extract with final production yield of 18%. The three batches of extract contained 8.4%, 9.1% and 8.6% Momordin lc, respectively.
- Piper nigrum fruit powder (314 g) was divided into two flasks in equal amount, 600 mL organic solvent 50% Methanol in dichloromethane added to each flask, refluxed for 1 hour, extract collected through filtration, reflux repeated two more times under same conditions. All extract solutions were combined, the solvent removed on a rotary-evaporator, and the extract dried under high vacuum to yield 31 g organic extract (OE). This OE extract contained 33.7% Piperine by HPLC.
- the target component, Piperine, in the Piper organic extracts was quantified with a Luna C18 reversed-phase column (Phenomenex, 10pm, 250mm x4.6mm) in a Hitachi HPLC system at 254 nm.
- the column was eluted with a binary gradient of water (mobile phase A) and Methanol
- Dried Piper nigrum fruits (10 kg) were crushed and extracted with 5 to 10-folds volume of 70% Ethanol/water under 80°C for 3 hours, filtered to collect extract, extracted again under the same conditions for 2 hours. Extracts from both extractions were combined, the solvent removed with rotary-evaporator and the sample dried under vacuum to generate 100 g 70% ethanol extract (70E). The extract contained 41.9% Piperine by HPLC analysis.
- Piper nigrum fruits were crushed and extracted with 90% ethanol in water under 80°C. The solution was concentrated under vacuum until the volume was reduced to less than 20% and sat at room temperature for precipitation. The solids were collected and recrystallized in ethanol and water solution. The standardized 15:1 Piper nigrum extract contains no less than 30% Piperine.
- Example 7 Fractionation and Purification of Piperine extract from Piper nigrum The organic extract (10.9 g) of dried Piper nigrum fruits obtained as described in Example
- OE extract 5 was subjected to silica gel column fractionation to pursue GAG releasing inhibition activity.
- the OE extract was divided and loaded separately onto two pre-packed Biotage flash columns (120 g silica, particle size 32-60 pm, 4 cm x 19 cm), and then eluted with Hexane, EtOAc and Methanol (as the mobile phase) at a flow rate of 20 mL/minutes.
- the gradients started with 100% Hexane for 5 minutes, then increased EtOAc from 0% to 100% over the duration of 25 minutes, and held at 100% EtOAc for additional five minutes, then increasing MeOH from 0% to 50% MeOH/EtOAc over next period of 15 minutes, finally changed the elution solution to 100% MeOH and eluted the column for another 16 minutes.
- the total run time was 66 minutes and 88 fractions were generated for each column fractionation.
- the fractions were analyzed by silica gel thin layer chromatography (TLC) and pooled together to generate eight best pools NP1 to NP8.
- TLC silica gel thin layer chromatography
- the GAG releasing inhibition assay confirmed the highest activity was in best pool 4, and it contained 77% of Piperine by HPLC analysis.
- the target component l'-acetoxychavicol acetate in extracts were quantified with a Luna C18 reversed-phase column (Phenomenex, 10pm, 250mm x4.6mm) in a Hitachi HPLC system at
- the column was eluted with a binary gradient of water (mobile phase A) and Acetonitrile (mobile phase B) at 1 ml/min flow rate and 35°C column temperature.
- Reference Standard G- acetoxychavicol acetate purchased from LKT lab contained both l'-acetoxychavicol acetate and p- coumary diacetate peaks with chromatogram purity of 62% and 24%, respectively, was utilized as the quantification standard.
- Figure 2 shows a HPLC chromatogram of Alpinia ethanol extract at 254 nm.
- Alpinia plants were collected from India, China and Thailand from different geological locations and different species. The raw material powders were extracted with EtOH as described above. The yield for EtOH extraction and HPLC quantification of l'-acetoxychavicol acetate (Marker 1) and p-coumary diacetate (Marker 2) are listed in the table below. Table 8: Extraction and HPLC quantification results of Alpinia extract
- Example 9 Isolation and purification of active compounds from extract of Alpinia rhizome Alpinia galangal rhizome dry powder (170 g) was placed in a flask, 600 ml Ethanol was added to reflux for 1 hour, extract collected through filtration, reflux repeated two more times. All extract solutions were combined, the solvent removed on a rotary-evaporator, and the extract dried under high vacuum to yield 27 g Ethanol extract (P05797-EE). This ethanol extract contained 17% l'-acetoxychavicol acetate by HPLC analysis.
- Alpinia extract P05797-EE (12 g) was partitioned between organic solvent (100 ml) and water (150 ml) in the order of Hexane, EtOAc and BuOH to generate Hexane fraction (4.2 g).
- EtOAc fraction 1.2 g
- BuOH fraction 0.6 g
- water fraction 5.1 g
- the GAG release inhibition activity was found in Hexane and EtOAc fractions.
- active fractions Combined both active fractions (5.4 g) and loaded onto a pre-packed Biotage flash columns (120 g silica, particle size 32-60 pm, 4 cm x 19 cm), and then eluted with Hexane, EtOAc and Methanol (as the mobile phase) at a flow rate of 20 mL/minutes.
- the gradients started with 95% Hexane/EtOAc for 5 minutes, then increased EtOAC gradually from 5% to 100% over the duration of 35 minutes, then held at 100% EtOAc for additional 5 minutes, before increasing MeOH from 0-100% over next period of 15 minutes, finally held at 100% MeOH for another 16 minutes.
- the total run time was 66 minutes and 88 fractions were generated.
- the fractions were analyzed by silica gel thin layer chromatography (TLC) and pooled together to generate 11 best pools.
- the best pool NP3 and best pool NP4 contained most of the weight with potent GAG release inhibition activity.
- the silica gel column best pool NP3 (200 mg) was fractionated on a preparative Cl 8 column (21.1 mm x 250 mm) with a linear gradient of 40% Methanol/water to 100% Methanol over 45 minutes at a flow rate of 10 mL/minute to generate 45 fractions, and then combined into 12 best pools based on HPLC profile at 254 nm.
- the best pool RP3 contained the first target compound l'-acetoxychavicol acetate (131.4 mg), and the GAG release inhibition activity (Example 17) was confirmed.
- the silica gel column best pool NP4 (210 mg) was fractionated on a preparative Cl 8 column (21.1 mm x 250 mm) with a linear gradient of 30% acetonitrile/water to 80% acetonitrile over 42 minutes at a flow rate of 10 mL/minute to generate 19 fractions, and then combined into 6 best pools based on HPLC profile at 254 nm.
- the best pool RP3 contained the second target compound p-coumaryl diacetate (4.3 mg), and the GAG activity was confirmed.
- Alpinia galangal powder (45 g) was placed into a 100 ml stainless steel vessel and pressurized with liquid CO2, heated to extraction temperature of 50°C and then pressurized to extraction pressure of 640 bar before beginning the dynamic flow of supercritical CO2.
- the supercritical CO2 containing extract was depressurized into a collection vial. After 75 min, the soluble components extraction was completed and produced 1.23 g extract with yield of 2.96% (WAV) and 56.7% galangal acetate. After the completion of CO2 extraction 5% /WAV Ethanol was added to the supercritical CO2 and the extraction of the same sample was continued at the same conditions of temperature and pressure to produce 0.15 g extract containing 4.7% galangal acetate.
- Example 12 HPLC Quantification of Alpinia extracts from different sources Alpinia extracts were obtained from different geological location and vendors in China and India, then l'-acetoxychavicol acetate was quantified with HPLC method described in Example 8. The HPLC quantification results are shown as table below.
- Dried Magnolia officinalis barks were crushed and extracted with supercritical CO2, followed by concentration and vacuum drying.
- the dried extract was blended with 30% Maltodextrin to produce a powdery of 10: 1 extract.
- the standardized extract contains no less than 50% of total amount of Magnolol and Honokiol combined.
- Ethanol extract of Kochia seeds (R00835-EE, 360 g) was milled into fine powder in a food blender, then Magnolia bark extract powder (L0555, 480 g) was added to the same blender and blended to ensure the powder in uniformity. Afterward, the blended Kochia and Magnolia extract powder was transferred into a deep stainless-steel pan ready to mix with Alpinia extract. The oily Alpinia extract (R00829-EE, 240 g) was weighed out in a beaker, and sonicated in 400 ml MeOH for 1 hour, then the top liquid was transferred into the stainless-steel pan while stirred to mix with Kochia and Alpinia blend.
- AMK composition in a weight ratio of 5:4:4 was prepared by blending all components in powder form as described here. Alpinia extract (L0795, 30 g), Magnolia bark extract (L0789, 24 g) and Kochia seeds extract (L0798A, 24 g) were weighed out separately and placed into a food blender to mix to secure a consistent powder. Based on quantification results of each ingredient and blending ratio, this AMK 5:4:4 composition contained about 3% l'- acetoxychavicol acetate, 18% Magnolol/Honokiol, and 3% Mormodin lc.
- Individual extracts of Alpinia, and/or Pepper, and/or Magnolia and/or Kochia could be combined to a composition with 3 individual extracts at different ratios including 1:1:1, 2:1:1, 3:1:1, 4:1:1, 5:1:1, 1:2:1, 1:3:1, 1:4:1, 1:5:1, 1:1:2, 1:1:3, 1:1:4, 1:1:5, 1:2:3, 1:2:4, 1:2:5, 1:2:6, 1:2:6, 1:2:8, 1:2:9 or 1:2:10 etc. by weight, respectively.
- AP composition was prepared by weighing Alpinia and pepper extracts in 1 : 2 ratio by weight into a vial and added proper solution to sonicate and vortex for homogeneity before each assay.
- the composition contained about 7% l'-acetoxychavicol acetate and 20% Pipeline.
- Example 16 Preparation of extracts from Alpinia, Piper/Pepper, and Magnolia for topical applications Many herbs have been used as anti-inflammation and pain control with application orally or topically as alternative medicine. Their pain relief and anti-inflammatory properties are associated with a broad range of types of bioactive compounds with potential targeting through different mechanisms and pathways.
- analgesics after preparation and topical application which could penetrate the skin and function where they are needed, including alkaloids from Piper nigrum , bisphenolic lignans of Magnolia officinalis and phenylpropanoid Galanga acetate from Alpinia galanga. Those actives represent different types of chemical constituents and could deliver pharmacological effects through different mechanisms.
- Alpinia, Pepper and Magnolia extracts were prepared at a concentration of 50 mg/mL in a combination of DMSO, Propylene glycol, Aloe vera gel (1:2:1) or a combination of DMSO, Propylene glycol and MCT oil (1:1:2) depending on the property and solubility of each material.
- Aloe vera gel served a penetration enhancer to improve the skin penetration during topical administration.
- Example 17 Procedures for testing inhibition of glycosaminoglycan (GAG) release by individual extracts, fractions and compounds of Alpinia, Piper/Pepper, Magnolia, and Kochia plants
- Cartilage tissue is primarily composed of extracellular matrix secreted by chondrocytes.
- the individual components of the tissue include collagen II fibers, hyaluronic acid and proteoglycans, which are composed of a glycosaminoglycan (GAG), such as chondroitin sulfate or keratin sulfate, bonded to a protein core.
- GAG glycosaminoglycan
- Enzymatic breakdown of cartilage tissue leads to free molecules of these components in the extracellular matrix and resorption by the body.
- articular cartilage explant Cultures Articular cartilage from hock joints of rabbits (2.5 kg body weight) was removed immediately after each animal was sacrificed.
- the articular cartilage explants were obtained by following the method described by Sandy et al, 1986. Briefly, after the articular surfaces were exposed surgically under sterile conditions, approximately 200-220 mg articular surfaces per joint were dissected and submerged into complete medium (DMEM, supplemented with heat inactivated 5% FBS; penicillin 100 U/ml; streptomycin 100 pg/ml). They were then rinsed several times with the complete medium and incubated for 2 days at 37°C in a humidified 5% C02/95% air incubator for stabilization.
- DMEM complete medium
- the complete medium was replaced with a basal medium (DMEM, supplemented with heat-inactivated 1% FBS, 10 mM HEPES, and penicillin 100 U/ml streptomycin 100 pg/ml).
- DMEM basal medium
- Approximately 30 mg cartilage pieces (2x3x0.35 mm/piece) were placed in 48-well plates and treated with given concentrations of test agents.
- 5 ng/ml of rhIL-Ia was added to the culture medium and further incubated at 37°C in a humidified 5% C02/95% air incubator.
- the culture medium was collected 24 h later and stored at -80°C until assay.
- Glycosaminoglycan Measurements The amount of sulphated GAGs in the medium at the end of the reaction, reflecting the amount of articular cartilage degradation, was determined through 1,9-dimethy-methylene blue method using commercially available kit (the Blyscan proteoglycan and glycosaminoglycan assay) according to the instructions of the manufacturer. Diclofenac was utilized as a positive control at 300 pg/ml.
- Example 18 Inhibition of glycosaminoglycan (GAG) release by individual extracts of Alpinia, Piper/Pepper, Magnolia, and Kochia plants
- Pepper and Kochia extracts showed roughly the same amount of protection from cartilage degradation, with IC5 0 values of 40.8 pg /mL and 42.1 pg /mL, respectively.
- Alpinia showed the least protective effect, with an IC5 0 value of 71.6 pg /mL. All four of the extracts tested protected cartilage from degradation, as demonstrated by this assay.
- each MMP enzyme was incubated for two hours at 37°C, and the amount of substrate was quantified spectrofluorimetrically. Percent inhibition of each MMP enzyme was calculated for each individual extract as compared to the vehicle control. TEMP -2 was used as a positive control for the inhibition of MMPs.
- Example 20 Inhibition of Matrix Metalloproteinases (MMPs) by individual extracts of Alpinia, Piper/Pepper, Magnolia, and Kochia plants
- MMP enzymes are expressed by chondrocytes in cartilage tissue and play important roles in the degradation of cartilage, as they are catabolic biomarkers for OA disease progression.
- Secretion of MMP- 13 by the chondrocytes takes place after cytokine release and increased inflammatory signaling and leads to degradation of the cartilage through the collagenase activity of the enzyme.
- MMP-9 is a gelatinase enzyme that further breaks down partially digested collagen. (Gepstein et al, 2002). Direct inhibition of either enzyme, but especially MMP- 13 may reduce their activities and lead to a decline in the catabolic pathways responsible for cartilage breakdown.
- Human chondrocytes (ScienCell, catalog# 4650) were thawed and seeded in a T75 Falcon® Tissue Culture Flask (VWR, catalog# BD353136) using Chondrocyte Growth Medium (Sigma, catalog# 411-500). The cells were incubated at 37°C and 5% CC for 24 hours, at which point the media was replaced with fresh, 37°C Chondrocyte Growth Medium. Incubation at 37°C/5% CO2 continued for an additional 48 hours, or until the chondrocytes became -90% confluent. The media was aspirated, and cells were rinsed once with 2-4 mL PBS (VWR, catalog# VWRLOl 19-0500).
- trypsin-EDTA (Sigma, Catalog# T3924-100ML) was added to the flask and left to sit for -3-5 min or until most of the cells were detached. 8 mL of trypsin inhibitor (Sigma, Catalog# T6414-100ML) was added to the flask to bring the total volume to 10 mL. The cell solution was transferred to a 15 mL conical tube and centrifuged for 5 min at 1000 rpm. The supernatant was aspirated, and the chondrocytes were resuspended in 1 mL Chondrocyte Growth Medium.
- 10 ng/mL IL-Ib pretreatment was prepared using IL-Ib (Sigma, Catalog# SRP3083) and ScienCell’ s Basal Chondrocyte Medium. Old media was aspirated and replaced with 500 pL pretreatment solution for the 24-well plates, and 100 pL for the 96-well plates. A few replicates were used as a control and were not pretreated with 10 ng/mL IL-Ib. Instead, fresh Basal Chondrocyte Medium was added to the cells. The cells were incubated for another 24 hours at 37°C/5% CO2.
- Treatments were prepared using plant extract stored at a concentration of 1M or 50 mg/mL in DMSO and ScienCelTs Basal Chondrocyte Medium. 50 pg/mL Piascledine300 and 100 ng/mL BMP -2 protein (Sigma, catalog# SRP6155-10UG) were used as positive controls. All treatments were filtered using VWR’s Vacuum Filtration Unit (VWR, catalog# 10040-460), and brought to an IL-Ib concentration of 10 ng/mL (with the exception of the untreated control). The vehicle treatment consisted only of Basal Chondrocyte Medium and 10 ng/mL IL-Ib. Old media was aspirated from each well and replaced with 500 pL treatment for the 24-well plates, and 100 pL for the 96-well plates. All treatments were applied in triplicate. The cells were incubated at 37°C/5% CO2 for 72 hours.
- RNA extraction procedure was completed according to the manufacturer’s instructions.
- RT-PCR was performed using Superscript IV First-Strand Synthesis System (Life Technologies, catalog# 18091200) according to the manufacturer’s instructions.
- cDNA Quantification and Dilution cDNA was quantified using the Qubit ssDNA Assay Kit (Life Technologies, catalog# Q10212) according to the manufacturer’s instructions. Each cDNA sample was diluted to 2.5 ng/mL with dFLO.
- MM P-13 F AACGCC AGAC AAAT GT GACCC R: TCCGCATCAACCTGCTGAGG
- Each qPCR reaction consisted of 400 nM forward primer, 400 nM reverse primer, 1 ng/pL cDNA, and was brought to a total volume of 24 pL with PowerUpTM SYBRTM Green Master Mix (Applied Biosystems, Catalog# A25742). 10 pL of each reaction was plated in duplicate on a 96- well reaction plate (Applied Biosystems, catalog# 4366932) and run on the Applied Biosystems StepOnePlus Real-Time PCR System according to the following cycling conditions: 50°C/2 minutes; 95°C/2 minutes; 40x [95°C/15 seconds - 60°C/1 minute].
- Magnolia extract resultsed in significant decreased expression of catabolic MMP- 3 and MMP-13, with limited and not significant changes in anabolic gene expression.
- Magnolia extract works to combat cell degradation by interfering with inflated catabolic gene expression in the presence of extracellular IL-Ib.
- Alpinia extract significantly reduced MMP-13 gene expression while significantly up regulating SOX-9, ACAN and COL2A1.
- Enriched Kochia extract significantly upregulated anabolic ACAN, Sox-9, and TORbI gene expression, while having a lesser effect on downregulation of the catabolic markers.
- Pepper extract had a similar effect, causing upregulation of COL2A1, ACAN, SOX-9, and TQRbI, while not significantly affecting catabolic markers.
- the combination of Alpinia:Pepper showed marked synergy of MMP-13 inhibition, while also exhibiting a decrease in ADAMTS4 and maintaining an increase in TORbI.
- Table 14 Fold changes of the expression of anabolic and catabolic genes in human chondrocytes incubated with the extracts of Alpinia, Magnolia and Kochia
- CT values from the qPCR were used to calculate DDOG, which was normalized to the untreated control.
- DDOt values were used to calculate the fold expression change of each gene.
- the values in the table indicate the difference in fold expression change between each treatment and the vehicle control. *P ⁇ 0.05; **P ⁇ 0.005;***P ⁇ 0.0005; 1 Outlier data.
- Magnolia extract can contribute downregulation of catabolic homeostasis
- both Kochia and Pepper extracts can upregulate gene expression of anabolic pathways of chondrocytes
- Alpinia alone and in combination with Pepper extract can demonstrate both activities.
- Example 23 Molecular biological procedures for rat chondrocyte treatment with IL-1 and quantification of TGF-bI gene expression
- Chondrocytes for monolayer cultures were isolated from knee cartilage of young rats and cultured as follows: Sprague Dawley rats, 3 weeks of age, were euthanized and their hind limbs were collected. Knee cartilage was cut from the subchondral bone using a sterile scalpel blade. Cartilage shavings were digested with collagenase in serum-free Dulbecco’s Modified Eagle’s Medium (DMEM). Once digested, the cell suspension was centrifuged to obtain a cell pellet. This pellet was resuspended in DMEM containing 10% FBS and the cells were counted. The cells were then plated on tissue culture plastic at a density of 10,000 cells/cm 2 .
- DMEM Modified Eagle’s Medium
- the isolated chondrocytes were then amplified in monolayer in culture medium (DMEM/FCS-10% supplemented with HEPES (25mM)) until passage 1 and frozen at -80°C. Thawed chondrocytes were used in the experiment described.
- Chondrocytes were seeded at day-1 and cultured in monolayers in 12-well plates for 24 hours. Treatments (including IL-Ib) began at day 0 and were performed over 3 days.
- Treatments were prepared using plant extract stored at a concentration of 100 mg/mL in DMSO and diluted in culture medium. 100 ng/mL BMP -2 protein (RandD Systems, catalog# 355- BM-010) was used as positive control. All treatments were brought to an IL-Ib concentration of 10 ng/mL (with the exception of the untreated control). The vehicle treatment consisted only of chondrocyte medium, 0.1% DMSO and 10 ng/mL IL-Ib. All treatments were applied in triplicate. The cells were incubated at 37°C/5% CO2 for 72 hours.
- B-actin F C C A AC C GT G A A A AG AT G AC C R: ACC AGAGGC AT AC AGGGAC A
- Each qPCR reaction consisted of 5 pL iQTM SYBR Green Supermix (Biorad, ref 1708882), 0.6 pL of forward primer (5 pM), 0.6 pL of reverse primer (5 pM), 1.8 pL H20, and 2 pL cDNA (5 pg/pL).
- Example 24 TGF-bI gene expression in rat chondrocytes treated with the extracts of Alpinia, Pepper, Magnolia and Kochia in an independent trial
- CT values from the qPCR were used to calculate DDOG, which was normalized to the untreated control.
- DDOt values were used to calculate the fold expression change of each gene.
- the values in the table indicate the difference in fold expression change between each treatment and the vehicle control. *P ⁇ 0.05; **P ⁇ 0.005;***P ⁇ 0.0005.
- Magnolia extract can contribute downregulation of catabolic genes in human chondrocytes and upregulation of TGF-bI in rat chondrocytes, while both Alpinia and Kochia extracts can upregulate anabolic gene expression of human chondrocytes while downregulating catabolic genes. Kochia extract also showed upregulation of TGF-bI gene expression in rat chondrocytes, solidifying its role as an anabolic effector in chondrocyte homeostasis.
- Rats were purchased from a USD A approved vendor. Sprague Dawley rats were purchased at the age of 8 weeks and acclimated upon arrival for a week before being assigned randomly to their respective groups. Rats (3/cage) were housed in polypropylene cages and individually identified by numbers on their tails. Each cage was covered with a wire bar lid and filtered top (Allentown, NJ, USA). Individual cages each had a cage card to indicate the project number, test article, dose level, group, and animal numbers for identification. Harlan T7087 soft cob bedding was used and changed at least twice weekly.
- Animals were provided with fresh water and rodent chow diet # T2018 (Harlan Teklad, 370W, Kent, WA, USA) ad libitum and housed in a temperature-controlled room (22.2°C) on a 12 h light-dark cycle. All animal experiments were conducted according to the institutional guidelines congruent with the guide for the care and use of laboratory animals.
- the microfracture technique is one of the few methods utilized to stimulate the bone marrow in the repairing process by taking advantage of the body’s own healing potential. This technique enhances the chondral resurfacing by providing a suitable environment for new tissue formation.
- the exposed weight bearing surface of the femur subchondral bone plate will be drilled with a precision drill bit until fat droplets and blood come out of the microfractured hole into the knee.
- This marrow “super clot” provides an optimal environment for the body’s own marrow cells (mesenchymal stem cells) from the bone marrow to differentiate into appropriate articular cartilage-like cell lines that in turn produce the extracellular matrix which eventually matures into a stable repaired tissue.
- own marrow cells mesenchymal stem cells
- the healing process occurs through a protracted period where post-operative management plays a critical role for a quicker and successful recovery.
- Natural dietary supplements for joint care with anabolic activity could in fact assist a faster recovery by enhancing the body’s cartilage regeneration process.
- Piascledine (avocado/soybean unsaponifiables) is a dietary supplement promoted by the manufacturer as an OA disease modulator with catabolic and anabolic effects demonstrated in preclinical in vitro and in vivo models. It is reported to possess properties known to prevent cartilage degradation by inhibiting the release and activity of matrix metalloproteinases and by increasing tissue inhibitors of these catabolic enzymes. Its cartilage repair activity was also suggested as a result of inhibition of inflammatory cytokines (Christiansen et al., 2015; Goudarzi et ah, 2018)
- a drill bit (1.35 mm) was then used to carefully induce a modified microfracture drill hole using a finger spin on the exposed surface until blood was visible as an indication for the adequate penetration of the bone marrow for all the groups except for the rats in the normal control group, which followed the same surgical procedure without the drilling.
- the joint capsule and the skin were sutured using a 4-0 coated vicryl absorbable suture and the animals were placed back in their cages to recover from anesthesia.
- the incapacitance tester was used to measure the weight bearing for OCD rats treated with Alpinia:Piper/Pepper (AP) and Alpinia:Magnolia:Kochia (AMK) compositions produced in example 14 and 15 against vehicle and positive controls.
- rats shift their body weight to the normal (unaffected) leg to relieve the pain induced by weight to the surgical leg.
- rats were expected to put more weight on the right leg.
- the weight distribution could have changed to reflect the homeostasis of “arthritis” in terms of the speed of healing and the tolerance of pain for each leg.
- Surgery was performed on the left leg of each rat in all the groups. All the rats received drilling on the left leg except the normal control (NC) group which underwent the same surgery procedure without the drilling.
- NC normal control
- Hematoxylin and Eosin (HE) and Safranin O green staining were carried out according to Nationalwide Histology’s protocols. Induction of the model was confirmed by visual observation of a drill hole on the knee ( Figure 3). This was also later confirmed by the histopathology findings showing the normal appearance and scores that were given for the tissue evaluations. Each specimen underwent 3 sections for HE and an additional 3 sections for the Safranin O stain with identical orientation for each block aiming to pass through the drilled hole. It is stated that the more comprehensive quantitative histological scoring system (such as Sellers method) could yield a higher power of discrimination between different degrees of cartilage repair, resulting in enhanced sensitivity and specificity in the pathophysiological condition of articular cartilage repair. As such, we suggested to the pathologist to adapt the Sellers evaluation method for this study and tabulated the data as seen in Tables 18 and 19.
- FIG. 1 shows images of a drill site of OCD rats after 6 weeks of treatment showing significant differences in healing progress from different oral treatment groups.
- the specific regeneration, renewal, rebuilding and regrowth functions are associated with, but not limited to, filling of the defect relative to the surface of normal adj acent cartilage, integrating repair tissue with surrounding articular cartilage, regenerating extra cellular matrix, improving cellular morphology, renewing architecture within the entire defect, regenerating architecture of surface, increasing percentage of new subchondral bone, and enhancing formation of tidemarks.
- Figure 4 shows Safranin O stain of the subchondral bone of OCD rats at the drill site. The black circle indicates the drill site for representative animal histopathology slides. Table 18. Sellers cartilage regeneration parameters from treatment groups
- Table 19 Cartilage Repair Score According to Sellers method of histopathology analysis
- Activated serum was diluted 60-fold and added to a microplate coated with TGF-bI antibody (final dilution factor of serum is 90). After 2 hours at room temperature, TGF-bI in serum was bound to the plate and the plate was thoroughly washed. Enzyme-conjugated TGF-bI antibody was added to the plate and allowed to bind for 2 hours at room temperature. The washing was repeated, and enzyme substrate was added to the plate. After developing for 30 minutes at room temperature, a stop solution was added, and the absorbance was read at 450 nm. The concentration of TGF-bI was calculated based on the absorbance readings of a TGF-bI standard curve.
- TGF-bI as an anabolic regulator of Cartilage synthesis in OCD rats treated with Alpinia:Pepper (AP) and Alpinia:Magnolia:Kochia (AMK) compositions
- AP Alpinia:Pepper
- AMK Alpinia:Magnolia:Kochia
- TGF-bI While the level of TGF-bI is high in healthy cartilage, its expression is low in patients with OA. In experimental animals with arthritis, the injection of TGF- b ⁇ into the knee increased the level of proteoglycan while protecting against cartilage loss in others, suggesting its importance in rebuilding and homeostasis of the extracellular matrix components of the articular cartilage (van Beuningen et al., 1994; Verdi er et al ., 2003; Glansbeek et al., 1998).
- Example 32 Symptom relief function of individual Alpinia, Pepper, Magnolia and Kochia extracts in carrageenan-induced paw edema model
- Carrageenan-induced paw edema in rats was used to evaluate the anti-inflammatory and anti-pain activities of individual Alpinia, Pepper, Magnolia and Kochia extracts.
- Ibuprofen as a positive control was used at 150 mg/kg.
- Paw edema Vehicle 2.51 3.08 2.80 0.19 0.16 0.08 Ibuprofen 1.43 1.59 1.77 0.40 0.30 0.37 43.03 48.38 36.79 Alpinia Galanga 1.69 1.93 2.07 0.11 0.32 0.20 32.67 37.34 26.07 Magnolia officinalis 1.99 2.06 2.59 0.33 0.45 0.60 20.88 33.18 7.50 Kochia Scoparia 2.14 2.64 2.78 0.26 0.23 0.33 14.74 14.16 0.71 Pepper Nigrum 1.70 2.13 2.30 0.23 0.51 0.56 32.27 30.84 17.86 Pain sensitivity
- Example 33 Lead composition-finding study on carrageenan-induced paw edema model
- Carrageenan-induced paw edema model was used to evaluate the anti-inflammatory and anti pain activities of natural compositions that were combinations of individual plant extracts from Alpinia and Magnolia at blending ratios of 1:1 (150:150 mg/kg), 1:2 (100:200 mg/kg), 2:1 (200:100 mg/kg), 1:4 (60:240 mg/kg) and 4:1 (240:60 mg/kg). Rats were administered with the compositions at the same dosage of 300 mg/kg orally. As seen in Table 23 below, significant inhibition in pain and inflammation was observed for all the ratios tested for these medicinal plant combinations. Slightly higher inhibition relative to the other ratios was found when rats were treated with a ratio of 1:2 Alpinia:Magnolia.
- Alpinia and Magnolia combination at 1:2 ratio showed 36.7%, 33.3% and 29.3 % in pain reduction and 37.2%, 34.5% and 29.3% in reduction of inflammation at lh, 3hrs and 5hrs after treatment, respectively, when compared to the vehicle- treated disease model.
- we observed that combining these two medicinal plant extracts at this specific ratio produced higher inhibition of pain and inflammation (in the first hours and at 5hr after treatment) when compared to each individual plant administered at the same dosage (compared to data from example 32 above).
- the composition as example, but not limited to, 1 :2 ratio of Alpinia with Magnolia for more subsequent studies.
- Ibuprofen 150 1 50.51 46.37 37.42 49.50 48.62 37.66
- Example 34 Anti-pain and Anti-inflammatory activities of combinations of Alpinia galanga and Kochia scoparia in the carrageenan-induced paw edema model
- Carrageenan-induced paw edema model was used to evaluate the anti-inflammatory and anti pain activities of Alpinia and Kochia extracts, which were combined at 1:1 (150:150 mg/kg), 1:2 (100:200 mg/kg), 2:1 (200:100 mg/kg), 1:4 (60:240 mg/kg) and 4:1 (240:60 mg/kg) ratios. Rats were administered with the compositions at 300 mg/kg orally in total. As seen in Table 24 below, significant inhibition in pain and inflammation was observed for all the ratios tested for these medicinal plants. A slightly higher inhibition relative to the other ratios was found when rats were tested with a 1:1 Alpinia to Kochia ratio followed by 4:1 Alpinia to Kochia ratio.
- Alpinia and Kochia extract’s combination at 1:1 ratio showed 25.0%, 27.6% and 25.7% in pain reduction and 26.4%, 30.9% and 30.6% in reduction of inflammation at lh, 3hrs and 5hrs after treatment, respectively, when compared to vehicle-treated disease model.
- the Alpinia and Kochia extract combination at 4:1 ratio showed 20.4%, 26.9% and 26.3% in pain reduction and 24.1%, 30.7% and 29.1% in reduction of inflammation at lh, 3hrs and 5hrs after treatment, respectively, when compared to the vehicle-treated disease model.
- Ibuprofen 100 1 50.51 46.37 37.42 50.07 47.40 37.28
- Example 35 Symptom relief effects of composition AMK (Alpinia, Magnolia and Kochia)
- Ibuprofen 150 1 44.4 47.9 30.8 47.3 49.7 37.6
- Example 36 Synergistic activity of Alpinia:Magnolia:Kochia (AMK) composition in reducing pain and inflammation in carrageenan-induced rat paw edema model
- Example 37 AP composition-finding study using the carrageenan-induced paw edema model
- Carrageenan-induced paw edema model was used to evaluate the anti-inflammatory and anti pain activities of Alpinia and Piper/Pepper extracts which were combined at 1:1 (150:150 mg/kg), 1:2 (100:200 mg/kg), 2:1 (200:100 mg/kg), 1:4 (60:240 mg/kg) and 4:1 (240:60 mg/kg) ratios. Rats were administered with the compositions at 300 mg/kg orally in total. As seen in Table 27, below, significant inhibition in pain and inflammation was observed for all the ratios tested for these medicinal plants. Slightly higher inhibition, relative to the other ratios, was found when rats were tested with a 1:2 Alpinia to Piper/Pepper ratio.
- Alpinia and Piper/Pepper extracts combined at a 1:2 ratio showed 42.4%, 44.3% and 34.7% pain reduction and 39.2%, 43.4% and 33.7% reduction of inflammation at lh, 3hrs and 5hrs after treatment, respectively, when compared to vehicle-treated disease model.
- This composition was selected for dose-response and synergy studies.
- Ibuprofen 100 1 48.44 47.46 37.77 45.00 50.31 41.84
- Alpinia to Pepper 300 4 to 1 35.40 37.25 23.73 25.08 29.25 21.77
- Composition AP was selected as the lead composition from previous in vivo experiments due to its inhibition of inflammation and pain at the 1 :2 ratio, when administered orally to rats at 300 mg/kg.
- dose-correlated inhibition of inflammation and pain was observed for the composition.
- the highest anti-inflammatory activities were observed at the 300 mg/kg for the composition followed by the 200 mg/kg and 100 mg/kg.
- Ibuprofen 100 1 50.5 46.1 38.5 51.0 48.0 39.0 Alpinia to Pepper 100 1 to 2 10.7 18.0 13.1 26.2 14.2 11.0 Alpinia to Pepper 200 1 to 2 29.3 33.7 27.8 37.9 27.1 25.1 Alpinia to Pepper 300 1 to 2 44.8 44.4 34.7 42.8 43.5 32.0
- Example 40 Stimulation of cartilage synthesis and inhibition of cartilage degradation by composition Alpinia:Magnolia:Kochia (AMK) in the Collagen-Induced Arthritis (CIA) rat model
- urinary C-telopeptides of type II collagen is a prominent marker for cartilage degradation.
- Urine C-terminal telopeptide of type II collagen has been by far the most studied and frequently referred to and validated biomarker of cartilage degradation that could be used for the purpose of diagnosis, determining the severity of disease or extent of disease progression, prognosis, and monitoring efficacy of treatment (Oesterggaard et al., 2006). In clinical studies, high levels of uCTX-II are a good predictor of increased risk of joint destruction (Garnero et al., 2001).
- Z score number of SDs from the mean of normal control rats.
- Example 41 Collagen-Induced Arthritis model induction and AMK treatment
- Collagen type-II (Lot # 845) from bovine nasal septum and Incomplete Freund’s adjuvant (IF A) (Lot # SLBR0642v) were purchased from Elastin Products Company (Owensville, MI, USA) and Sigma (St. Louise, MO, USA), respectively. All materials were kept at suitable temperatures as recommended by the manufacturer. At the time of preparation, 60 mg of collagen was weighed and added to pre-chilled 15 mL 0.1 M acetic acid in a 60 mL-sized flask with a magnetic stirrer to yield 4 mg/mL concentration (Brand, et ak, 2003; Rosloniec et ak, 2001).
- the mixture was dissolved by gently stirring overnight at 4 °C.
- the dissolved collagen was emulsified with equal volume of IF A (15 mL) to achieve a final concentration of 2 mg/mL collagen.
- Rats sedated with isoflurane were then primed intradermally with 400 pL of the emulsified collagen at the base of their tail at two sites using a 1 mL syringe fitted with a 26 G needle.
- the dissolved mixture was kept in an ice bucket and stirred between groups at the time of injection to preserve uniform consistency.
- rats were inoculated with a booster dose of 2 mg/mL type II collagen emulsified with equal volume of incomplete adjuvant at 100 pL/rat/site.
- Linear trapezoid rule was used to calculate area under the curve (AUC) for days 9-21.
- % Inhibition ⁇ (Mean value of treatment-mean value of CIA+)/(Mean value of control-mean value of CIA) ⁇ *100.
- Example 42 Reduction of Arthritis Severity Index of Rats by composition AMK in the CIA model
- Example 43 Reduction of the ankle diameters of CIA rats by composition AMK, indicating its anti-arthritic activity
- Example 45 Arthritis index, ankle diameter and area under the response curve (AUC) for paw thickness of CIA rats treated with composition Alpinia:Magnolia:Kochia (AMK)
- rats treated with AP showed 64.23%, 55.8% and 51.4% inhibition in paw thickness, ankle diameter and arthritis severity index during the course of the study period when compared to vehicle-treated CIA rats, respectively. These reductions were more than 50% in each parameter and statistically significant for each parameter, indicating the potency of composition AMK in reducing arthritis-associated symptoms.
- Methotrexate- treated rats showed 71.7%, 65.9% and 62.6% reduction in paw thickness, ankle diameter and arthritis severity index, respectively.
- Example 46 Reduction of compression-induced pain in CIA rats by composition Alpinia:Magnolia:Kochia (AMK) indicating its symptom relief activity
- Example 47 Reduction of proinflammatory cytokines and matrix degrading enzymes by composition Alpinia:Magnolia:Kochia (AMK) in CIA rats
- the presence of catabolic cytokines IL-Ib, TNF-a, or IL-6 was measured using Rat IL-Ib, TNF-a, and IL-6 Quantikine ELISA kit from R and D Systems (product#: RLBOO for IL-Ib, RTA00 for TNF-a, and R6000B for IL-6) as follows: diluted serum was added to a microplate coated with polyclonal IL-Ib, TNF-a, or IL-6 antibody and allowed to bind for 2 h at room temperature.
- the microplate was washed thoroughly to remove unbound serum and then a polyclonal enzyme-conjugated IL-Ib, TNF-a, or IL-6 antibody was added and allowed to bind for 2 h at room temperature. Washing was repeated, enzyme substrate was added, and the plate was developed for 30 min at room temperature. After the addition of stop solution, the absorbance was read at 450 nm, multiplied by dilution factor, and the concentration of IL-1 b/TNF-a /IL-6 calculated based on the absorbance readings of an IL- 1 b/TNF-a /IL-6 standard curve.
- MMP-13 Rat Matrix Metallo-Proteinase 13
- Mybiosource product#: MBS702112 for MMP-13
- serum was added to a microplate coated with MMP-13 antibody and allowed to bind for 2 h at 37 °C.
- the samples were removed and then a biotin-conjugated MMP-13 antibody was added and allowed to bind for 1 h at 37 °C.
- the microplate was thoroughly washed, and an avidin-conjugated Horse Radish Peroxidase was added and allowed to bind for 1 h at 37 °C.
- Enzyme substrate was then added, and the plate was developed for 30 min at 37 °C. After the addition of stop solution, the absorbance was read at 450 nm, multiplied by dilution factor, and the concentration of MMP-13 calculated based on the absorbance readings of an MMP-13 standard curve
- AMK-treated rats showed a statistically significant reduction in serum IL-Ib (67.4% inhibition, compared to diseased control), IL-6 (60.2% inhibition, compared to diseased control) and TNF-a (75.5% inhibition, compared to diseased control) levels when compared to vehicle-treated diseased rats (Table 36).
- Methotrexate-treated rats showed reduced serum IL-Ib (71.5% inhibition, compared to diseased control), IL-6 (78.6% inhibition, compared to diseased control) and TNF-a (86.2% inhibition, compared to diseased control) levels when compared to vehicle-treated diseased rats (Table 36).
- This example clearly demonstrated that the natural AMK composition is capable of reducing the catabolic processes of arthritic animals.
- Example 48 Reduced cartilage degradation and increased cartilage regeneration/rebuilding activity of Alpinia:Magnolia:Kochia (AMK) in CIA rats
- the presence of the cartilage degradation biomarker uCTX-II was measured using the Rat CTX-II ELISA kit from Mybiosource (product#: MBS2880519) as follows: diluted urine was added to a microplate coated with CTX-II antibody and allowed to bind for 2 h at 37 °C. A biotin- conjugated antibody against CTX-II was then added and allowed to bind to the CTX-II from the rat urine for 1 h at 37 °C. The microplate was washed thoroughly to remove unbound urine and antibody before an enzyme-conjugated avidin antibody was added to bind to the biotin-conjugated antibody for specific detection. The avidin antibody was allowed to bind for 1 h at 37 °C.
- CTX-II amount was normalized to the amount of Creatinine in the urine using the Creatinine Parameter Assay Kit from R and D Systems (product#: KGE005) as follows: urine was diluted 1 :20, mixed with alkaline picrate (5 parts 0.13% picric acid: 1 part 1 N NaOH) in a microplate and incubated at room temp for 30 min. Absorbance was read at 492 nm and Creatinine amount in urine was calculated based on the absorbance readings of a Creatinine standard curve.
- PIIANP Rat Procollagen Type IIA N-Prop
- Mybiosource product#: MB S9399069
- synovial fluid was added to a microplate coated with PIIANP antibody as well as an HRP-conjugated PIIANP antibody and allowed to bind for one hour at 37°C.
- the microplate was thoroughly washed, and a Chromagen solution was added and allowed to bind for 15 minutes at 37°C. After the addition of stop solution, the absorbance was read at 450 nm and the concentration of PIIANP calculated based on the absorbance readings of a PIIANP standard curve.
- Example 49 Histopathology findings for CIA rats treated with Alpinia:Magnolia:Kochia (AMK),
- the histopathology data was in alignment with the severity score of arthritis.
- vehicle-treated rats showed severe synovitis, marked cartilage degradation, synovial hyperplasia, pannus formation, and bone erosion (Figure 5, Table 38).
- These changes for the vehicle-treated CIA rats in comparison to the normal controls were reflected as 3.3-fold, 3.8-fold, 4.7-fold and 24.2-fold increase in cartilage degradation, GAG loss, bone erosion and inflammation, respectively.
- rats treated with AMK had nearly normal morphology, with minimal alterations in matrix integrity, a smoother articulation cartilage surface, low levels of mononuclear cell infiltration, and synovial hyperplasia, as well as reduced articular bone damage.
- Cartilage protection and hence anti-catabolic activity of composition AMK was found to be 65.1% with a 61.9% maintenance of matrix integrity in comparison to the vehicle-treated CIA rats.
- biomarker data reduced catabolic cytokines IL-Ib, TNF-a and IL-6
- Cartilage destruction (0—6) Cartilage thickness/thinning, irregular surface frayed/fissure loss, degeneration, ulcerative necrosis/fragmentation, severe disorganization/chaotic; Bone damage (0—6): Subchondral bone thickness/volume and density, osteoclastic activity, subchondral bone damage; Inflammation/Cellular infiltration (0—6): Cellular Infiltration/Inflammation and Proliferation, hyper cellular, cluster Zhypocellular; Matrix C A (is loss (0—6): Matrix GAG reduction: radial, interterritorial to pericellular loss of staining, femoral condyle/tibial plateau integrity, and thickness of articular Cartilage. Data expressed as Mean ⁇ SE.
- Figure 5 shows histopathology images (HE a-d and Safranin O e-f) from ankle joint of CIA induced rats treated with AMK and MTX.
- rats are being administered at oral doses of 40, 60, 80 and 120 mg/kg/day of AMK for 5 weeks. These dosages would give a human equivalent dose of 448, 672, 896 and 1344 mg/day for an average 70kg adult. We believe that results from this dose-response study would provide a basis for future human clinical trial dosage determination.
- Example 50 Second Collagen-Induced Arthritis model induction and AP treatment
- Collagen type-II (Lot # 845) from bovine nasal septum and Incomplete Freund’s adjuvant (IF A) (Lot # SLBR0642v) were purchased from Elastin Products Company (Owensville, MI, USA) and Sigma (St. Louise, MO, USA), respectively. All materials were kept at suitable temperatures as recommended by the manufacturer. At the time of preparation, 60 mg of collagen was weighed and added to pre-chilled 15 mL 0.1 M acetic acid in a 60 mL-sized flask with a magnetic stirrer to yield 4 mg/mL concentration (Brand, et ak, 2003; Rosloniec et ak, 2001). The mixture was dissolved by gently stirring overnight at 4°C.
- the dissolved collagen was emulsified with equal volume of IF A (15 mL) to achieve a final concentration of 2 mg/mL collagen.
- Rats sedated with isoflurane were then primed intradermally with 400 pL of the emulsified collagen at the base of their tail at two sites using a 1 mL syringe fitted with a 26 G needle.
- the dissolved mixture was kept in an ice bucket and stirred between groups at the time of injection to preserve uniform consistency.
- rats were inoculated with a booster dose of 2 mg/mL type II collagen emulsified with equal volume of incomplete adjuvant at 100 pL/rat/site.
- Example 51 Reduction of arthritis severity index by composition AP in CIA rats
- Example 52 Reduction of ankle diameter by composition AP in CIA rats
- Example 53 Reduction of paw thickness by composition AP in CIA rats
- rats treated with Methotrexate and AP showed a statistically significant reduction in paw swelling starting from day 12 and maintained this significance for the duration of study (Table 41).
- rats only in the Methotrexate group showed statistically significant 93.8% reduction in paw edema compared to the vehicle-treated CIA group (Table 41).
- Example 54 Arthritis index, ankle diameter and area under the response curve (AUC) for paw thickness of CIA rats treated with composition AP
- Example 56 Catabolic cytokines, matrix degrading enzymes and cartilage synthesis biomarker changes by composition AlpiniarPepper (AP) in CIA rats
- the presence of catabolic cytokines IL-6/TNF-a was measured using the Rat IL-6/TNF-a Quantikine ELISA kit from RandD Systems as follows: undiluted serum was added to a microplate coated with polyclonal IL-6/TNF-a antibody and allowed to bind for 2 hours at room temperature. The microplate was washed thoroughly to remove unbound serum, and then a polyclonal enzyme- conjugated IL-6/TNF-a antibody was added and allowed to bind for 2 hours at room temperature. Washing was repeated, enzyme substrate was added, and the plate was developed for 30 minutes at room temperature.
- MMP-13 Rat Matrix Metalloproteinase 13
- MBS702112 Rat Matrix Metalloproteinase 13
- undiluted serum was added to a microplate coated with MMP-13 antibody and allowed to bind for 2 hours at 37°C.
- the samples were removed, and then a biotin-conjugated MMP-13 antibody was added and allowed to bind for 1 hour at 37°C.
- the microplate was thoroughly washed, and an avidin-conjugated Horse Radish Peroxidase was added and allowed to bind for 1 hour at 37°C.
- Enzyme substrate was then added, and the plate was developed for 30 minutes at 37°C. After the addition of stop solution, the absorbance was read at 450 nm and the concentration of MMP-13 calculated based on the absorbance readings of an MMP-13 standard curve.
- the level of cartilage regeneration biomarker PIIANP was measured using the Rat Procollagen Type IIA N-Prop (PIIANP) ELISA kit from Mybiosource (product#: MBS9399069) as follows: undiluted serum was added to a microplate coated with PIIANP antibody as well as an HRP-conjugated PIIANP antibody and allowed to bind for one hour at 37°C. The microplate was thoroughly washed, and a Chromagen solution was added and allowed to bind for 15 minutes at 37°C. After the addition of stop solution, the absorbance was read at 450 nm and the concentration of PIIANP calculated based on the absorbance readings of a PIIANP standard curve.
- PIIANP Rat Procollagen Type IIA N-Prop
- composition AP administered orally at 200 mg/kg for 3 weeks significantly reduced the serum catabolic biomarkers IL-6, TNF-a and MMP-13 levels when compared to vehicle-treated CIA rats.
- the most significant inhibition in proinflammatory and catabolic cytokines as a result of composition AP treatment was observed in IL-6, which was reduced by 58.7% in comparison to the vehicle-treated CIA rat group. This reduction was complemented by a 43.5% reduction in matrix degrading enzyme MMP-13 for the AP -treated rats.
- the IL-6 and MMP-13 data seem a true reflection of what was observed in the in-life study as far as clinical measurements and histopathology findings for the AP -treated rats.
- the positive drug control Methotrexate-treated rats experienced significantly reduced amounts of IL-6 and TNF-a in the serum.
- Example 57 Changes in histopathology readings by composition AlpiniarPepper (AP) in CIA rats
- rats treated with AP composition also showed statistically significant reductions in cartilage destruction, inflammation severity, bone erosion and GAG loss compared to CIA rats treated with vehicle.
- Cartilage protection and hence anti-catabolic activity of composition AP was found to be 57.7% with a 47.5% maintenance of matrix integrity in comparison to the vehicle-treated CIA rats.
- biomarker data such as reduced catabolic TNF-a and IL-6
- There was also a 61.0% reduction in bone erosion for the CIA rats treated with AP composition were statistically significant for each parameter monitored compared to vehicle-treated CIA rats.
- Cartilage destruction (0—6) Cartilage thickness/thinning, irregular surface frayed/fissure loss, degeneration, ulcerative necrosis/fragmentation, severe disorganization/chaotic; Bone damage (0—6): Subchondral bone thickness/volume and density, osteoclastic activity, subchondral bone damage; Inflammation/Cellular infiltration (0—6): Cellular Infiltration/Inflammation and Proliferation, hyper cellular, cluster Zhypocellular; Matrix HA (is loss (0—6): Matrix GAG reduction: radial, interterritorial to pericellular loss of staining, femoral condyle/tibial plateau integrity, and thickness of articular Cartilage.
- Example 58 Implications of the cartilage protection and symptom relief activities of AlpiniarPepper (AP) and Alpinia:Magnolia:Kochia (AMK) in collagen-induced arthritis (CIA)
- the CIA model in rats is the most commonly studied autoimmune model of RA with several pathological features resembling the immune-mediated polyarthritis in humans (Miyoshi et al., 2018). Its short duration between immunization and disease manifestation makes the model feasible for therapeutic efficacy evaluations.
- rats Following inoculation of heterogenic type II collagen (CII), rats mount both humoral and cellular responses to the antigen (Brand et al., 2003). This sensitization subsequently leads to the host animal attacking its own type II collagen, which is predominantly present in the joint cartilage and hence results in erosive or non-erosive joint destruction.
- the pathophysiology of the disease is highly orchestrated and complex. Upon induction, rats experience inflammatory pain and swelling, cartilage degradation, synovial hyperplasia, pannus formation, mononuclear cell infiltration, deformity, and immobility.
- rats started to show the pathognomonic signs of arthritis on day 9 post-priming followed by a progressive increase in severity that approached near plateau on days 19 to 21. These symptoms were mitigated by oral treatment of an immune suppressant-Methotrexate and also the novel natural compositions - Alpinia:Pepper (AP) and Alpinia:Magnolia:Kochia (AMK). All treatment groups (Methotrexate, AP and AMK) showed measurable relief in arthritis severity, swelling, ankle width, and pain sensitivity when compared to the vehicle-treated diseased rats.
- an immune suppressant-Methotrexate and also the novel natural compositions - Alpinia:Pepper (AP) and Alpinia:Magnolia:Kochia (AMK). All treatment groups (Methotrexate, AP and AMK) showed measurable relief in arthritis severity, swelling, ankle width, and pain sensitivity when compared to the vehicle-treated diseased rats.
- Catabolic TNF-a and IL-Ib are the two primary cytokines involved in the initiation and progression of arthritis (Kapoor et al ., 2011), mainly through (a) inhibition of anabolic activities of chondrocytes, leading to downregulation of extracellular matrix component biosynthesis, (Saklatvala et al., 1986; Goldring etal ., 1994); (b) induction of additional catabolic cytokines (such as IL-6), chemokines, and extracellular matrix degrading enzymes (MMPs and aggrecanases) (Lefebvre et al., 1990; Guerne et al ., 1990); (c) inhibition of anti-oxidant activity of the host (Mathy-Hartert,e/ al ., 2008); and (d) induction of reactive oxygen species (Lepetsos et al ., 2016).
- IL- 6 levels are also linked to the common clinical manifestations associated with rheumatoid arthritis pathology, such as fever, fatigue, and weight loss (Wei et al., 2015).
- rheumatoid arthritis pathology such as fever, fatigue, and weight loss (Wei et al., 2015).
- modulating these catabolic pro-inflammatory cytokines at various stages of disease progression could shift the balance of arthritis away from catabolic processes while alleviating the symptoms associated with arthritis and/or helping to modify the disease.
- MMP-13 has been found in increased levels at the sites of cartilage erosion in cases of rheumatoid arthritis and osteoarthritis (Rose et al ., 2016).
- MMP levels in OA patient’s blood and synovial fluid were higher than in healthy people and the level was consistent with the extent of cartilage damage (Yamanaka et al., 2000; Galil et al., 2016).
- MMPs secreted into the synovial fluid can directly degrade the cartilage and bone composition, leading to enhanced damage of surrounding articular structures (Ma et al., 2015).
- AMK and AP there was significant suppression of MMP-13 levels by AMK and AP, which provided protection of cartilage from degradation, improved pain relief and suppression of the phenotype of arthritis.
- the reduction in MMPs observed in this study could partially be explained by (a) the effect of treatment materials in reducing the catabolic pro-inflammatory cytokines and/or (b) the activity of treatment materials directly suppressing expression of these matrix degrading enzymes.
- Urine C-terminal telopeptide of type II collagen has been by far the most studied and frequently referred to biomarker of cartilage degradation that could be used for the purpose of diagnosis, determining the severity of disease or extent of disease progression, prognosis, and monitoring efficacy of treatment (Oestergaard et al., 2006).
- high levels of uCTX-II are a good predictor of increased risk of joint destruction (Garnero et al., 2001).
- Degradation and loss of articular cartilage are fundamental phenotypes of arthritis, whereby increased CTX-II levels directly correlated with the time course of paw swelling and arthritis severity indicated by the narrowing of joint space and loss of total cartilage volume.
- AMK and AP orally administered produced (a) reduced catabolic inflammation as reflected by reduced arthritis index, paw thickness, paw edema, and reduced catabolic cytokines (IL-Ib, IL-6, and TNF-a); (b) decreased pain sensitivity; (c) increased cartilage sparing activity and maintenance of articular structure as indicated by lower uCTX-II and cartilage degrading enzymes (MMP-13) and (d) improved cartilage synthesis and repair (as documented in the increased level of PIIANP).
- MMP-13 uCTX-II and cartilage degrading enzymes
- Example 59 Mono-iodoacetate (MIA)-induced experimental osteoarthritis model induction and AMK treatment
- the MIA-induced OA disease model in rats is a standardized model most frequently used to mimic human OA (Lee et al., 2014).
- the model involves inoculation of MIA into a femorotibial joint pocket that induces pain responses in the ipsilateral limb accompanied by progressive cartilage degradation.
- Intra-articular injection of MIA disrupts chondrocyte glycolysis by inhibiting glyceraldehyde-3 -phosphatase dehydrogenase and results in chondrocyte death, neovascularization, subchondral bone necrosis and collapse, as well as inflammation (Guzman et al., 2003).
- anesthetized rats were injected with 0.8 mg of MIA (Lot # A0352046, Acros Organics, New Jersey, USA) in 50 pL saline solution into the intra-articular pocket of left femorotibial (knee) joint using 26 G needle an hour after treatment.
- MIA Liot # A0352046, Acros Organics, New Jersey, USA
- Normal control rats were injected with an equal volume of saline.
- Paw withdrawal thresholds as a result of constant pressure applied to the affected joint as a measure of pain sensitivity were taken once a week using Randall-Salitto Anesthesiometer (IITC, USA) and treatment lasted for 6 weeks. Body weights were measured once a week to calculate the respective weekly dosage of each group.
- Urine was collected at the end of study using metabolic cages. Blood samples were collected to isolate serum for biomarker analysis. At necropsy, animals were asphyxiated with CO2 and the femorotibial joint was carefully dissected out, fixed in 10% buffered formalin and sent to Nationwide Histology (Veradale, WA, USA) for further histopathology analysis. The fixed specimens were then decalcified with Calci-Clear Rapid for 1 and a half days and embedded in paraffin. Standardized 5 pm serial sections were obtained at the medial and lateral mid-condylar level in the sagittal plane and were stained with hematoxylin and eosin (HE) and Safranin O-fast green to enable evaluation of proteoglycan content.
- HE hematoxylin and eosin
- Mankin system Mankin et ah, 1981 was used to score structural and cellular alterations of articular components as indications of disease progression and/or treatment efficacy.
- the histological analysis was conducted by a certified Pathologist at National Histology.
- Example 60 Anti-pain sensitivity activity of composition AMK in MIA-induced OA model
- Example 61 Cartilage protection and a reduction in proinflammatory cytokine activity by composition AMK in MIA-induced rat arthritis model
- Example 62 Improved histological findings as a result of composition Alpinia:Magnolia:Kochia (AMK) in MIA-induced OA model
- Example 63 Significance of outcome from the MIA model for Composition Alpinia:Magnolia:Kochia (AMK) and its implication in OA It is believed that at various stages of OA, all the three major structures of the joint (cartilage, subchondral bone and synovium) could be involved in the pathophysiology of the disease, which complicates the identification of a single biomarker that is indicative of a need for immediate therapeutic intervention at the early stage of the disease.
- ANK Alpinia:Magnolia:Kochia
- C-terminal telopeptide of type II collagen (CTX-II) has been by far the most studied and frequently referred to biomarker of cartilage degradation, and could be used for the purposes of diagnosis, determining the severity of disease or extent of disease progression, prognosis and monitoring the efficacy of treatment.
- CTX-II is primarily generated by matrix metalloproteinase activity during cartilage degradation in OA. It is known to show a close link with the catabolic/anabolic homeostasis and progression of articular cartilage degradation in OA patients.
- CTX-II levels increased in serum, urine or synovial fluid level and articular cartilage degradation were reported both in pre-clinical and clinical studies (Oestergaard et al ., 2006; Garnero et al, 2001), suggesting that plant extracts with inherent characteristics of reducing uCTX-II levels changed the phenotype of arthritis toward reduced catabolic degradation and increased anabolic regeneration and rebuilding by regulating homeostasis of chondrocytes, extracellular matrix, and articular cartilage.
- uCTX-II was found significantly increased corresponding to disease severity and was correlated with changes in joint space narrowing (Garnero et ah, 2001).
- Example 64 Anti-pain activity of topically applied plant extracts in a hot plate test
- the procedure was repeated 3 times, every 30 minutes, before placing the animals on a preheated hot plate set to 53°C.
- the paw withdrawal latency was calculated as the time elapsed from the initial placement of the rat onto the hotplate to the withdrawal (or licking or shaking) of the hind paw in response to the thermal stimulus. Animals were immediately removed when this response was observed. Those animals that did not display a response within 30 seconds were removed from the heated plate to prevent any tissue damage.
- Table 49 Paw withdrawal threshold as a measure of anti-pain activity of medicinal plants in a hot plate test
- V Vehilce-1 (VI) DMSO+PG+Aloe (2%) 10 7.13 ⁇ 1.25
- Example 65 A 7-day repeated oral acute Maximum Tolerable Dose (MTD) Study of AP
- Gl Vehicle control (0.5% CMC)
- G2 Alpin
- Table 50 Body weight measurements of mice treated with AP for 7-days
- percent body weight changes from the baseline were found decreased by 5.18 and 6.07% for the 500 and 750 mg/kg AP, respectively (i.e. i.e.
- mice physically appeared normal after each gavage for both genders.
- the mice continued normal exploratory activity and behavior. These normal behaviors were continued for the remaining doses for both genders. These mice showed no changes in behavior or activity for the whole duration of treatment.
- Necropsy once the abdominal cavity was opened, the organs were subjected to gross examination for the surviving animals. No macroscopic (grossly visible) deviations from normal were observed. The appearance and Necropsy findings were comparable to the vehicle group.
- Gl Vehicle control
- mice Both male and female mice were observed daily for 7 days for their physical appearances and behavior in both studies. Daily examination of mice for their physical condition and wellbeing showed no signs suggestive of toxicity or abnormality throughout the study period. Mice physically appeared normal after each gavage for both genders. The mice continued normal exploratory activity and behavior. These normal behaviors were continued for the remaining doses for both genders. The mice showed no changes in behavior or activity for the whole duration of treatment.
- mice in each group continued to maintain body weight for the duration of the study.
- the difference in body weight measurements between the baseline and the 7th day was insignificant (i.e. Male BL: 36.58 ⁇ 4.2 vs day7:36.96 ⁇ 4.5; Female BL: 30.37 ⁇ 2.0 vs day7:30.66 ⁇ 1.3).
- Table 53 Percent body weight changes of mice in a 7-day repeated daily oral MTD study
- Example 67 Human clinical study of the compositions from the individual extracts of Alpinia, Pepper, Magnolia and Kochia and/or at various combinations of 2 to 3 of those extracts with examples, but not limited to, compositions AlpiniarPepper (AP) and Alpinia:Magnolia:Kochia (AMK)
- the study population consists of male and female subjects older than 18 and younger than 75 years, and in general good health as determined by a medical history. Female subjects of childbearing potential must have a negative urine pregnancy test at baseline. The goal of the study is to enroll at least 40 subjects per arm for meaningful statistical power.
- the trial will have defined Inclusion criteria as follows: Male/Female healthy adults at 18 to 75 years of age; meet pain entry criteria; a history of knee joint pain for greater than 6 months; medial or lateral tibiofemoral joint line tenderness; unilateral knee pain 6/10 or greater, on average, on the visual analog scale (VAS), that interferes with function most days per week; Kellgren grade II or III radiographic changes of osteoarthritis; and willing to discontinue use of all analgesic medications (including over-the-counter [OTC] analgesics) except those provided as the study treatment and rescue medication specifically for study purposes.
- VAS visual analog scale
- Biomarkers of uCTX-II for cartilage degradation/protection; anabolic biomarkers ACAN, Sox- 9, PIIANP and TGFP; catabolic cytokines such as IL-1, IL-6, TNF-a, and MMP-13 from the serum and also synovial fluid will be measured.
- the global gene expression and protein expression profiles of cells/tissues from synovial fluid, synovial membrane, and cartilage for changes of catabolic and anabolic markers will be measured.
- the joint space narrowing and total joint space area for ultimate proof of disease-modifying effects will also be measured.
- IL-1 alpha beta blockade prevents cartilage and bone destruction in murine type II collagen- induced arthritis, whereas TNF-alpha blockade only ameliorates joint inflammation.
- C-terminal telopeptides of collagen type II (CTX-II) in serum and synovial fluid samples for estimation of articular cartilage status in experimental models of destructive joint diseases.
- Early elevation in circulating levels of C-telopeptides of type II collagen predicts structural damage in articular cartilage in the rodent model of collagen-induced arthritis.
- Topical therapies for knee osteoarthritis Postgrad Med. 2018 Sep;130(7):607-612. Stanos SP, Galluzzi KE. Topical therapies in the management of chronic pain. Postgrad Med. 2013 Jul; 125(4 Suppl l):25-33.
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