The role of phytopharmaceuticals in topical pain relief.
Natural ingredients (phytopharmaceuticals) have been used to treat muscle and joint inflammation, especially in Eastern countries. Although they possess fewer of the side effects observed with Western drugs, the Eastern formulations do not always provide long-lasting relief of pain and discomfort, or restore mobility of inflamed joints.
There is a growing interest in phytopharmaceuticals as complementary or alternative medicine in the U.S. that combines modern Western treatments with botanical and nutraceutical ingredients. Most phytopharmaceutical and nutraceutical-based arthritis and pain relief formulations are ingested. However, these oral-based formulations often have an unacceptable odor and taste, and may lose potency during digestion. Topical delivery systems circumvent some of the disadvantages of oral dosage forms due to their application near or at the site of affliction. These topical "pharmacosmetics" can be formulated to provide medicinal benefits in addition to their cosmetic and skin care attributes.
Product claims for pharmacosmetics must be worded carefully. The topical pharmacosmetics discussed in this article are not promulgated for drug marketing claims. The Food and Drug Administration (FDA) regulates some of the ingredients mentioned above under topical analgesic drugs monograph in the U.S. drug and cosmetic regulations vary from other countries. A guidebook on this topic, along with excellent recent articles on modern treatments for pain, is available. (1)
Most pain-relieving drugs are antipyretic, anti-inflammatory and analgesic agents that decrease prostaglandin production through their inhibition of cyclooxygenase-1 (COX-1), cyclooxygenase-2 (COX-2) and lipoxygenase-5 (LOX-5) enzymes. (1) The use of massage, or vasodilatory ingredients for the removal of lactic acid from sore muscle areas, are well-known therapies for pain. The initiation of inflammation by reactive oxygen species (such as superoxide anions) has been recognized. Recently, the role of Substance P in neurotransmission of pain has been reviewed. The inhibition of inflammatory cytokines in the development of new anti-arthritis therapies is actively being studied. In addition, excessive nitric oxide (NO) production by activated macrophages has been implicated in several inflammatory diseases including arthritis. (2)
This article details select phytopharmaceutical ingredients for the management of arthritis, muscular pain and inflammation, and key aspects of their formulation in topical pharmacosmetics are presented in this article. It is worthy of note that the anti-inflammatory property of a number of these ingredients has been discovered recently. Their increased commercial availability should stimulate further research.
When developing topical formulations, chemists should use a combination of ingredients that possess complementary pain remedial mechanisms such as analgesic, vasodilatory, Substance P inhibition, COX-inhibition and cytokine regulation. Such combinations generally provide enhanced benefits due to their frequently synergistic action. (2)
The incorporation of phytopharmaceutical or nutraceutical ingredients in topical pharmacosmetics requires a careful balance of criteria that include product appearance, cosmetic benefits, medicinal efficacy and claims, dosage level, bioavailability, storage stability, packaging and cost. A combination of cosmetic and pharmaceutical product development technologies is required, and are detailed in recent publications and patents. (3)
In the development of topical formulations, it should be recognized that medicinally important moieties present in these botanical extracts are usually poorly soluble in water. It is advantageous to first prepare a solution of such extracts in an appropriate cosmetically-acceptable solvent. The solubilized forms generally possess enhanced efficacy and improved stability. The oil-soluble ingredients are better formulated in a water-in-oil system; the water-soluble ingredients provide better bioavailability in an oil-in-water, or water/ glycol gel delivery system.
The possible chemical reactivity of the constituents of these botanical extracts should also be considered. Members of the ginger family usually contain chemical moieties with ketone functionality. Ketones are generally reactive toward primary and secondary amines. The innocuous addition of a hydrolyzed protein additive (usually containing amino acids) to enhance the skin feel attributes of a formulation that also contains extracts of the ginger family may cause the ketones to react with amino acids and result in chemical dismutation of both ingredients.
Similarly, the formulation conditions of pH and temperature, and chemical stability criteria of these ingredients need to be carefully evaluated. For example, the alkaloids present in some of phytopharmaceuticals may undergo chemical isomerization or transformation under conditions of formula processing. Here's a look at some unique natural ingredients with pain relief characteristics.
Corydalis: Well-known in Chinese and Tibetan herbal medicine, it contains several phenanthrene alkaloids that have pain-relieving, sedative and analgesic activity. These alkaloids have a combined efficacy of up to 40% of morphine. No addiction to corydalis has been reported, as the mechanism of its analgesic action does not involve the brain's opiate receptors. Yet, tolerance may develop with prolonged use. (4)
Corydalis extract is effective in both acute and chronic stages of inflammation and mechanisms for this activity have been studied. Corydalis should be used with other herbs that are complementary to each other via different pain alleviation biochemical mechanisms. This may also circumvent its tolerance-related concerns. (5)
Ginger: Ginger rhizomes contain some of the most well known antiarthritis and anti-inflammatory ingredients known to pharmacy. Ginger has been in use in Ayurvedic and Tibetan medicine for centuries. Ginger extracts increase peripheral blood flow with a warming and tingling sensation. Ginger contains essential oils and spicy substances such as gingerol, shogaol, zingerone and capsaicin; those spicy substances are principally responsible for its pain-relieving properties.
Recent scientific studies suggest that inhibiting the COX-2 enzyme may be an effective way to reduce inflammation without the side effects associated with irreversible COX-1 inhibition. Ginger inhibits COX-2 as well as 5-lipoxygenase (LOX-5) enzyme. The ameliorative effects of ginger in arthritis and muscular pain could be related to reduced formation of prostanoids and leukotrienes by the above biochemical mechanisms. A recent clinical study on ginger extract in the treatment of pain has been published. (6)
Turmeric (Curcuma longa) rhizomes contain curcumin and its derivatives (curcuminoids) that are bright yellow in color. Their hydrogenated derivatives, tetrahydrocurcuminoids, are nearly colorless materials. All possess excellent anti-inflammatory activity. Tetrahydrocurcuminoids offer advantages in topical cosmetic applications due to their lack of color. (7)
The steam distillation of turmeric rhizomes produces turmeric oil, which has excellent anti-inflammatory activity. In our research, turmeric oil provided good carrier function for the absorption of other anti-arthritis ingredients. Additionally, the antifungal and antibacterial activities of turmeric oil have been reported. A closely-related plant, Curcuma amada (mango ginger), commonly found in India, reportedly provides pain-relieving activity. (8)
Galanga (Alpinia officinarum), also known as Galangal or Chinese Ginger, is native to China, Thailand and India. It contains essential oils, gingerols and a group of pungent substances, diarylheptanoids. Diarylheptanoids and analogous phenyl alkyl ketones possess excellent anti-arthritic properties due to their arrest of prostaglandin biosynthesis via inhibition of 5-lipoxygenase. (9)
Capsicum, Capsaicin: The ancient Mayan folk-healers used cayenne pepper (Capsicum frutescence) for the treatment of toothache and general body pain. In modern Western medicine, capsaicin has been used to treat pain associated with neuralgia, neuropathy, osteoarthritis, rheumatoid arthritis, bladder pain, and stomach pain.
Capsaicin is the active analgesic ingredient present in capsicum preparations. It is a topical analgesic that may inhibit the synthesis, transport and release of substance P, a neurotransmitter of pain. Capsaicin is also a vasodilator. The medicinal attributes of capsicum, including its antinociceptive activity, were recently reviewed. (10) A new antioxidant glycoside, icaricide and five new antioxidant apocarotenoids have been isolated from capsicum annuum, (11) suggesting additional benefits of capsicum oleoresin.
The pain relieving attributes of capsaicin are enhanced when combined with other pain management ingredients. (12) However, quantitative capsaicinoid concentrations of capsicum oleoresin samples may not always relate to their Scoville Heat Units designations. This is an important consideration in the development of effective topical formulations. (13)
In its pure state, capsaicin is white. But capsicum oleoresin preparations are orange to red in color due to the presence of carotenoids, as mentioned above. The topical formulations that contain capsicum oleoresin also assume that color. For this reason, capsicum oleoresin is also used as a natural coloring agent in cosmetics.
Clove Family: Clove oil and clove buds have been in use for the treatment of toothache and muscular pains since ancient times. A number of plants in this family, notably Syzygium aromaticum, Syzygium corynocarpum and Syzygium mallacense, are known to contain pain-relieving constituents. Eugenol, a vasorelaxant and analgesic constituent of Syzygium aromaticum, also possesses strong anti-inflammatory activity. The extracts of Syzygium corynocarpum and Syzygium malaccense inhibit prostaglandin biosynthesis via blocking of COX-1 and COX-2 enzymes. (14)
More recently, the extract from the bark of Syzygium cumini has been shown to possess excellent anti-inflammatory activity without any gastric side effects. Acetyl eugenol, a component of clove oil, has recently been shown to alter arachidonic acid metabolism, resulting in reduced formation of thromboxane. This may open future applications of this ingredient in pain therapy. (15)
Evodia: This herb has been used for dysentery in Chinese medicine (Wu Zhu Yu) since ancient times. Rutaecarpine, obtained from Evodia rutaecarpa, is a new class of anti-inflammatory ingredients that inhibits COX-2 enzyme. The herb also has antinociceptive and anti-inflammatory activities. Evodiamine, and its analogs present in Evodia rutaecarpa, also possess vasodilatory and analgesic activity. (16)
Frankincense, Boswellia: Guggal (Boswellia serrata) has been used for the treatment of arthritis in Ayurvedic medicine for centuries. Frankincense, myrrh, and gold were presented by the wise men to the infant Christ. It is interesting to note that centuries ago, all three were used to treat gout and arthritis. Boswellia is currently one of the most popular alternative medicines for pain.
Four key ingredients, grouped as boswellic acids, are responsible for the anti-inflammatory action of boswellia serrata extracts. Recent research has firmly established that boswellic acids and their derivatives are specific inhibitors of leukotriene synthesis by their direct interaction with 5-lipoxygenase. Boswellia extracts provide enhanced arthritis and gout relief usually in combination with other herbal preparations. Piperine and essential oils enhance the bioavailability of boswellic acids. (17)
The preparation of therapeutically effective boswellic acids from the Boswellia serrata herb is critically dependent on its process methodology, requiring careful standardization. This chemical sensitivity of boswellic acids is key to the development of topical formulations relative to pH, excipients and process conditions. (17)
Since its discovery in 1952, SAMe has received wide interest for the treatment of osteoarthritis. This substance, present in all living organisms, is required for more than 40 biochemical functions in human body. SAMe enhances the formation of cartilage, and provides pain relieving anti-inflammatory action. Extensive clinical testing on this topic have been published. SAMe is one of the fastest growing nutraceuticals for the management of arthritis. (18)
According to some reports, however, SAMe becomes gummy and degrades in water-based topical formulations. Yet, our work has shown that this degradation is due to pH and temperature and formulations show improved stability under acidic pH conditions. SAMe should be added below 40 [degrees] C.
Eucomis: South African traditional medicine has extensively utilized the extracts of bulbs, leaves and roots of this plant for pain, inflammation and fever. Recent work has shown that the extracts from the bulb have the highest level of COX-1 inhibitory activity. This ingredient will attract greater attention for pain management. (19)
Celastrus: This Asian folk medicine has been used for rheumatoid arthritis. Recent work has identified strong COX-1 activity ascribed to epiafzelechin, a member of flavan-3-ols, present in this herb. (20)
Tithonia: Extracts of Tithonia are used in Central America to treat hematomas. Recent work has shown the constituents of this extract, diversifolin and tirotundin, possess anti-inflammatory activity. Interestingly, the anti-inflammatory activity was from the inhibition of the synthesis of inflammatory mediators such as cytokines and chemokines. (21)
Kochia: The extracts from dry fruits of Kochia scoparia possess peripheral antinociceptive activity, ascribed to its momordin content. (22)
Scoparia: The herb Scoparia dulcis is used in Brazilian folk medicine to treat bronchitis, gastric disorders, hemorrhoids, insect bites and skin wounds, and in Asian medicine to treat hypertension. Recent studies have shown that extracts of Scoparia dulcis have analgesic, anti-inflammatory and sympathomimetic activity. (23)
Qiang Huo: The root extracts of this Chinese medicinal herb traditionally used for arthritis and joint pain possess COX-1 and LOX-5 inhibitory activity. The chemical structures of its constituents and their anti-inflammatory activity have been established. The drug interaction of qiang huo with modern Western medicine has been discussed recently. A unique, traditional Chinese delivery system (Shen Gong Yuan Qi Dai) for external application of qiang huo and other herbal drugs have been patented. (24)
Cinnamon: Middle Eastern countries have long used cinnamon as a vasodilator for pain and inflammation. Recent work has confirmed the antinociceptive and anti-inflammatory activity of cinnamon extract via its direct scavenging of nitric oxide and peroxynitrite. The constituents of cinnamon oil have been identified. (25)
Polygonum: Also known as Mexican Bamboo (Mexico) and Hu Zhang (China), various species of polygonum contain anti-inflammatory constituents that modulate the production of NO by activated macrophages. Recent results suggest that polygonum tinctorium extract may be a potential therapeutic modulator of NO synthesis in various pathological conditions, including arthritis. Protykin, a high potency standardized extract derived from the dried rhizome of polygonum cuspidatum, has free radical scavenging and anti-inflammatory actions. The anti-inflammatory compounds from the dried rhizomes of polygonum bistorta are 5-glutinen-3-one and friedelanol An extract of polygonum hypoleucum has shown anti-inflammatory activity via its inhibition of cytokines. (26)
Ogon (Ougon): Scutellaria, used in Japanese Kampo herbal medicine (Ogon), China, (Sanhuang) and in the Baikal region of Russia, has anti-inflammatory, anti-hepatitis, antibacterial, antiviral, anti-tumor and antioxidant activity. The anti-inflammatory activity is ascribed to its active components, baicalin, baicalein and wogonin. In a recent study, wogonin tested as a direct inhibitor of COX-2 NO-production and prostaglandin production, indicating its potential use in the treatment of topical inflammatory diseases. In another study, baicalin inhibited chemokine activity. Baicalein has shown LOX-5 inhibiting activity. Recent patents have disclosed topical compositions containing scutellaria to treat arthritis. It is one of the most promising new botanicals awaiting commercialization. (27)
Coptis: Coptis, a Chinese herbal medicine (Xianglian) also used in Japan, possesses antibacterial properties due to its high berberine content. It also contains several lignans (isolariciresinol, lariciresinol glycoside, pinoresinol, pinoresinol glycoside and syringaresinol glycoside) with anti-inflammatory properties. Woorenosides, isolated from Coptis japonica, have anti-inflammatory activity via their inhibition of NO production. (28)
A Look at Anti-lnflammatories
A number of recently studied anti-inflammatory phytopharmaceuticals are worthy of mention for their future commercialization.
Psoralea glandulosa: An ancient Persian medicine, psoralea glandulosa contains bakuchiol, cyclobakuchiols, and angelicin that possess anti-pyretic and anti-inflammatory activities. Psoralea corylifolia, an Ayurvedic medicine in India (Babchi) and BuGuZhi in China, possesses anti-inflammatory, anti-pyretic and analgesic activity due to its bavachinin content. Bakuchiol, isolated from the same plant, inhibits NO synthase gene, with implications for its anti-inflammatory activity. (29)
Rumex patientia (dock) has shown anti-inflammatory activity. (30)
Baccharis: Several species of baccharis have shown analgesic and anti-inflammatory activity, principally due to their inhibition of prostaglandin biosynthesis. (31)
Feverfew: This phytopharmaceutical (Tanacetum parthenium) is wellknown for its fever and migraine alleviation benefits. Recently, its anti-nociceptive and anti-inflammatory activities, due to its LOX-5 and COX inhibition, have been reported. (32)
Vedic Vibration: Maharishi Vedic vibration technology is an ancient folk medicine practiced in India. Although not a phytopharmaceutical, this alternative medicine methodology has recently been evaluated in a randomized double-blind study with 176 arthritic patients of which a large percentage reported relief of pain and improvement in mobility. (33)
Vitis: The grape family is well known for its potent antioxidant constituents, especially procyanidins and resveratrol. Recently, tetramers of resveratrol found in Vitis amurensis, have been found to possess strong anti-inflammatory activity via their inhibition of leukotriene biosynthesis. This is not surprising, as several antioxidants are also known to possess anti-inflammatory activity: This property may be due to their inhibitory effect on LOX and COX enzymes. (34)
Stephania: Stephania has long been used in Korea as an analgesic and anti-inflammatory agent for joint swelling. Tetrandrine, an alkaloid found in Stephania japonica, has anti-inflammatory activity. Cepharanthine, an alkaloid found in Stephania cepharantha, has vasodilatory effects with enhanced microcirculation. (35)
Tinospora: Ayurvedic and Islamic practitioners in India have used Tinospora cardifolia for liver jaundice, various skin diseases, rheumatism, fever and syphilis. Clinical studies conducted with human arthritis have demonstrated its anti-inflammatory properties. The inhibition of nitric oxide synthesis appears to be a factor for this activity. (36) It has a nauseating bitter taste; its topical applications should provide a more appealing alternative delivery system.
Phytopharmaceutical Arthritis and Muscular Pain Relief Ingredients Common Name INCl/Botanical Designation Mechanism of Action Corydalis Corydalis Turtschaninovii Analgesic root extract Ginger Root Zingiber Officinale COX-2 inhibitor (Ginger) root extract Galanga Alpinia Officinarum LOX-5 inhibitor (Galanga) extract Turmeric Curcuma Longa (Turmeric) Superoxide inhibitor root extract Mango Ginger Curcuma amada Unknown Capsicum, Capsaicin Capsicum Annuum extract Substance P inhibitor Vasodilator, Superoxide inhibitor Clove Family Syzygium Aromaticum COX-1, COX-2 inhibitor extract Evodia Evodia Rutaecarpa fruit COX-2 inhibitor extract Boswellia, Olibanum Boswellia Serrata extract LOX-5 inhibitor SAMe S-Adenosylmethionine Catecholamine metabolism Eucomis Eucomis L'Herit COX-1 inhibitor Celastrus Celastrus orbiculatus COX-1 inhibitor Tithonia Tithonia diversifolia Cytokine inhibitor Kochia Kochia Scoparia extract COX-2 inhibitor Scoparia Scoparia dulcis extract Analgesic Qiang Huo Notopterygium incisum COX-1, LOX-5 inhibitor Cinnamon Cinnamomum cassia Nitric oxide (NO) scavenger Mexican Bamboo Polygonum Nitric Oxide (NO) cuspidatum scavenger Ogon, Baikal Scullcap Scutellaria baicalensis COX-2 inhibitor Coptis, Xianglian Coptis chinenesis NO inhibitor Miscellaneous Psoralea, Rumex, Baccharis, Feverfew, Vedic Vibration, Vitis, Stephania
This article is dedicated to Professor H.C. Brown on the occasion of his 90th birthday.
The contributions of Gary Grayson, Jesus San Miguel and Lori Murphy are also very much appreciated.
(1.) International Regulatory Resource Manual, 5th Edition, CTFA, Washington, DC (2001); R.L. Barkin and D. Barkin, Pharmacologic Management of Acute and Chronic Pain, South. Med. J., 94, 756 (2001); D.R.P. Guay, Adjunctive Agents in the Management of Chronic Pain, Pharmacotherapy, 21, 1070, (2001); J.R. Vane, Int. J. Tissue React., 20, 3 (1998); A.T. Borchers et al., Inflammation and Native American Medicine: The Role of Botanicals, Am. J. Clin. Nutr., 72, 339 (2000); C.C. Chan and I.W. Rodger, Selective Cyclooxygenase-2 Inhibitors as Potential Therapeutic Agents for Inflammatory Diseases, Adv. Exp. Med. Biol., 407,157 (1997); J.R. Vane and R.M. Botting, Mechanism of Action of Anti-inflammatory Drugs, Adv. Exp. Med. Biol., 433 131 (1997).
(2.) C.L. DeVane, Substance P: A New Era, A New Role, Pharmacotherapy, 21, 1061 (2001); C.A. Dinarello CA and N.H. Margolis, Cytokine-processing Enzymes. Stopping the Cuts, Curr. Biol.,5, 587 (1995); B. Joe and B.R. Lokesh, Role of Capsaicin, Curcumin and Dietary n-3 Fatty Acids in Lowering the Generation of Reactive Oxygen Species in rat Peritoneal Macrophages, Biochim. Biophys. Acta, 1224, 255 (1994); B. Patwardhan, U.S. Patent 5,494,668; B. Weisman, U.S. Patent 5,888,514; T.R. Laughlin and H.D. Holt, U.S. Patent 5,854,291; R. Rose and G.L. Chrisope, U.S. Patent 5,916,565.
(3.) S. Gupta, Nutraceuticals Based Topical Delivery Systems, Nutraceuticals World, (Nov. 2001); S. Gupta, Antioxidants: Formulation of Cosmetic Delivery Systems, Happi, 56 (July 2001); S.M. Niemiec et al., Topical Delivery Systems for Active Agents, U.S. Patent 6,284,234.
(4.) The Pharmacology of Chinese Herbs, II Edition, K.C. Huang, CRC Press, NY, USA (1999); Chinese Materia Medica: Chemistry, Pharmacology, and Applications, Y-P Zhu, Overseas Publishing Association, Amsterdam (1998)
(5.) Corydalis ambigua, Draco Herbs, San Jose, CA, USA; M. Kubo, et al., Anti-inflammatory Activities of Methanolic Extract and Alkaloidal Components from Corydalis Tuber, Biol. Pharm. Bull., 17, 262 (1994).
(6.) Ginger (Ginger Officinale), Sabinsa Corp., NJ, USA; Crodarom Ginger, Croda, NJ, USA; Study of Local Vasodilatory Effects of Topical Preparations Applied to Human Skin, Study No. 96103BS (1996), Croda, NJ, USA; Wu et al., U.S. Patent 6,274,177; T. Newmark and P. Schulick, U.S. Patent 6,264,995; H. Bliddal et al., A Randomized, Placebo-controlled, Crossover Study of Ginger Extracts and Ibuprofen in Osteoarthritis, Osteoarthritis Cartilage, 8, 9 (2000); K.C. Srivastava and T. Mustafa, Ginger (Ginger Officinale) in Rheumatism and Musculoskeletal Disorders, Medical Hypothesis, 39, 342 (1992).
(7.) Tetrahydrocurcuminoids, Sabinsa Corp., NJ, USA; T.S. Rao, et al., Anti-inflammatory Activity of Curcumin Analogs, Ind. J. Med. Res., 75,574 (1982).
(8.) Turmeric Oil, Sabinsa Corp., NJ, USA; D. Chandra and S.S. Gupta, Ind. J. Med. Res., 60, 138 (1972); G.K. Jayaprakasha, et al., Chemical Composition of Turmeric Oil - a Byproduct from Turmeric Oleoresin Industry and Its Inhibitory Activity Against Different Fungi, Z. Naturforsch (C), 56, 40 (2001); P.S. Negi et al., Antibacterial Activity of Turmeric Oil: A Byproduct from Curcumin Manufacture, J. Agric. Food Chem., 47, 4297 (1999); M.S. Weidner et al., Certain Diterpenes and Extracts or Concentrates of Curcuma amada Containing Them for Use as Medicaments, U.S. Patent 6,235,287.
(9.) Herbal Drugs and Phytopharmaceuticals, N.G. Bisset, ed., CRC Press, NY, USA (1994); R. Yamazaki et al., U.S. Patent 5,763,673.
(10.) Capsaicin, Sabinsa Corp., NJ, USA; P. Dasgupta and C.J. Fowler, Chillies: From Antiquity to Urology, Br. J. Urol., 80, 845 (1997); J.B. Calixto et al., Naturally Occurring Antinocicoptive Substances from Plants, Phytother Res., 14, 401 (2000); Y.J. Surh et al., Chemoprotective Properties of Some Pungent Ingredients Present in Red Pepper and Ginger, Mutat. Res., 402, 259 (1998).
(11.) M. Iorizzi et al., New Glycosides from Capsicum annuum. Isolation, Structure Determination, and Biological Activity, J. Agric. Food Res., 49, 2022 (2001); T. Maoka et al., Isolation of a Series of Apocarotenoids from the Fruits of Red Paprika Capsicum annuum, J. Agric Food Chem., 49, 1601 (2001).
(12.) F.S. Caruso, Analgesic Drug Composition Containing a Capsaicinoid and Potentiator Therefor, U.S. Patent 6,277,398; D.A. Rhodes, Topical Treatment of Pain and to Promote Healing, U.S. Patent 6,284,797; T.L. Barr and H.D. Holt, Pain Reliever and Method of Use, U.S. Patent 6,197,823; W.R. Robbins et al., Therapeutic Method with Capsaicin and Capsaicin Analogs, U.S. Patent 6,248,788.
(13.) C.A. Reilly et al., Quantitative Analysis of Capsaicinoids in Fresh Peppers, Oleoresin Capsicum, and Pepper Spray Products, J. Forensic Sci., 46, 502 (2001).
(14.) Sygygium, AHD International, GA, USA; H. Nishijima et al., Mechanisms Mediating the Vasorelaxing Action of Eugenol, a Pungent Oil, on Rabbit Arterial Tissue, Jpn. J. Pharmacol., 79, 327 (1999); M. Ahmed et al., Analgesic Principle from Abutilon indicum, Pharmazie, 55, 314 (2000); A.C. Reddy and B.R. Lokesh, Studies on Anti-inflammatory Activity of Spice Principles and Dietary n-3 Polyunsaturated fatty Acids on Carrageenaninduced Inflammation in Rats, Ann. Nutr. Metab. (Switzerland), 38, 349 (1994); Noreen et al., Flavan-3-ols Isolated from Some Medicinal Plants Inhibiting COX-1 and COX-2 Catalysed Prostaglandin Biosynthesis, Planta Med., 64, 520 (1998); M.A. Kelm, Antioxidant and Cyclooxygenase Inhibitory Phenolic Compounds from Ocimum sanctum, Phytomedicine, 7, 7 (2000).
(15.) S. Muruganandan et al., Anti-inflammatory Activity of Syzygium cumini Bark, Fitoterapia, 72,369 (2001); K.C. Srivastava and N. Malhotra, Acetyl Eugenol, a Component of Oil of Cloves (Syzygium aromaticum L.) Inhibits Aggregation and Alters Arachidonic Acid Metabolism in Human Blood Platelets, Prostaglandins Leukot. Essent. Fatty Acids (Scotland), 42, 73 (1991).
(16.) Evodia fructus, AHD International, GA, USA; T.C. Moon et al., A New Class of COX-2 Inhibitor, Rutaecarpine from Evodia rutaecarpa, Inflamm. Res., 48, 621 (1999); H. Matsuda et al., Antinociceptive and Anti-inflammatory Activities of Limonin Isolated from the Fruits of Evodia rutaecarpa, Planta Med., 64, 339 (1998); H. Matsuda et al., Antinociceptive Activities of 70% Methanol Extract of Evodiae Fructus (fruit of Evodia rutaecarpa) and its Alkaloidal Components, Bio.1 Pharm. Bull., 20, 243 (1997); W.F. Chiou et al., Comparative Study of the Vasodilatory Effects of Three Quinazoline Alkaloids Isolated from Evodia rutaecarpa, J. Nat. Prod., 59, 374 (1996).
(17.) Boswellin, Sabinsa Corp., NJ, USA; M. Majeed et al., Planta Medica, 64, 328 (1998); Boswellia serrata, Altern. Med. Rev., 3,306 (1998); U. Dahmen, et al., Boswellic Acid, a Potent Antiinflammatory Drug, Inhibits Rejection to the Same Extent as High Dose Steroids, Transplant Proc., 33, 539 (2001); H.P. Ammon et al., Mechanism of Antiinflammatory Actions of Curcumine and Boswellic acids, J. Ethnopharmacol., 38, 113 (1993); E.R. Sailer et al., Acetyl-11-keto-beta-boswellic Acid (AKBA): Structure Requirements for Binding and 5-Lipoxygenase Inhibitory Activity, Br. J. Pharmacol., 117, 615 (1996); H.P. Ammon, Salai Guggal - Boswellia serrata: from a Herbal Medicine to a Non-redox Inhibitor of Leukotriene Biosynthesis, Eur. J. Med. Res., 1,369 (1996); O.S. Tomer et al., Herbal Compositions and Their Use as Anti-inflammatory Agents for Alleviation of Arthritis and Gout, U.S.Patent 6,274,176; M. Majeed et al., Use of Piperine as a Bioavailability Enhancer, U.S. Patent 5,744,161; J.C. Fletcher et al., Essential Oil Composition,U.S. Patent 6,280,751; S. Schweizer, et al. Workup-Dependent Formation of 5-Lipoxygenase Inhibitory Boswellic Acid Analogues, J. Nat. Prod., 63, 1058 (2000); H. Safayhi, et al., Concentration-dependent Potentiating and Inhibitory Effects of Boswellia Extracts on 5-Lipoxygenase Product Formation in Stimulated PMNL, Planta Med., 66, 110 (2000).
(18.) S-Adenosylmethionine (SAMe), AHD International, GA, USA; Osteoarthritis: The New Clinical Picture, Pathogenesis, and Management with Studies on a New Therapeutic Agent, S-Adenosylmethionine, The American Journal of Medicine, 83, 11 et seq. (1988); H.W. Henderson et al., Aminosugar, Glycosaminoglycan, and S-Adenosylmethionine Composition for the Treatment and Repair of Connective Tissue, U.S. Patent 6,271,213; T.G. Boone et al., Composition and Method for Treating Infammatory Diseases, U.S. Patent 6,294,170.
(19.) J.L. Taylor and J. Stayden, COX-1 Inhibitory Activity in Extracts from Eucomis L'Herit. Species, J. Ethnopharmacol, 75, 257 (2001).
(20.) K.R. Min et al., (-)-Epiafzelechin: Cyclooxygenase-1 Inhibitor and Anti-inflammatory Agent from Aerial Parts of Celastrus orbiculatus, Planta Med., 65, 460 (1999).
(21.) P. Rungeler et al., Study of three sesquiterpene lactones from Tithonia diversifolia on their anti-inflammatory Activity Using the Transcription Factor NF-Kappa B and Enzymes of the Arachidonic Acid Pathway as Targets, Planta Med., 64, 588 (1998).
(22.) Kochia scoparia, AHD International, GA, USA; H. Matsuda et al., Studies on Kochiae Fructus. III. Antinociceptive and Antiinflammatory Effects of 70% Ethanol Extract and its Component, Momordin Ic from Dried Fruits of Kochia scoparia , Biol. Pharm. Bull., 20, 1086 (1997).
(23.) S.M. Freire et al., Sympathomimetic Effects of Scoparia dulcis L. and Catecholamines Isolated from Plant Extracts, J. Pharm. Pharmacol., 48, 624 (1996); S.M. Freire et al., Analgesic Activity of a Triterpene Isolated from Scoparia dulcis (Vassourinha), Mem Inst Oswaldo Cruz (Brazil), 86, 149 (1991).
(24.) S. Zschocke et al., 5-Lipoxygenase and Cyclooxygenase Inhibitory Active Constituents from Qianghuo (Notopterygium incisum), Planta. Med., 63, 203 (1997); E. Okuyama, et al., Analgesic Component of Notopterygium incisum., Chem. Pharm. Bull., 41, 926 (1993); X.W. Yang et al., Comparison of Anti-lipid Peroxidative Effects of the Underground Parts of Notopterygium incisum and N. forbesii in Mice, Planta Med., 57, 399 (1991); Y.F. Sun et al., Chemical Constituents of Notopterygium incisium, Zhongguo Zhong Yao Za Zhi., 19,100, 127(1994); Y. Qin et al., Determination of Nodakenin in the Rhizome or Root of Notopterygium incisum Ting by TLC-scanning, Zhongguo Zhong Yao Za Zhi., 21, 486, 511(1996); L.Q. Guo et al., Inhibitory Potential of Herbal Medicines on Human Cytochrome P450-mediated Oxidation: Properties of Umbelliferous or Citrus Crude Drugs and their Relative Prescriptions, Jpn. J. Pharmacol., 85, 399 (2001); L. Wei, Hygienic Bag and Preparation Thereof, U.S. Patent 6,123,946.
(25.) A.H. Atta and A. Alkofahi, Anti-nociceptive and Anti-inflammatory Effects of Some Jordanian Medicinal Plant Extracts, J. Ethnopharmacol., 60, 117 (1998); T. Yokozawa et al., Direct Scavenging of Nitric Oxide by Traditional Crude Drugs, Phytomedicine, 6, 453 (2000); G.K. Jayaprakasha et al.,Chemical Composition of the Flower Oil of Cinnamomum zeylanicum blume. J. Agric. Food. Chem., 48, 4294 (2000).
(26.) T. Ishihara, et al., Polygonum tinctorium Extract Suppresses Nitric Oxide Production by Activated Macrophages Through Inhibiting Inducible Nitric Oxide Synthase Expression, J. Ethnopharmacol., 72, 141 (2000); M. Sato et al., Myocardial Protection by Protykin, a Novel Extract of trans-Resveratrol and Emodin, Free Radic. Res., 32, 135 (2000); M. Duwiejua et al., The Anti-inflammatory Compounds of Polygonum bistorta: Isolation and Characterisation, Planta Med., 65, 371 (1999); Y.C. Kuo et al., Regulation of Cell Proliferation, Inflammatory Cytokine Production and Calcium Mobilization in Primary Human T Lymphocytes by Emodin from Polygonum hypoleucum, Inflamm Res., 50, 73 (2001).
(27.) C.C.Lin and D.E. Shieh, The Anti-inflammatory Activity of Scutellaria rivularis Extracts and its Active Components, Baicalin, Baicalein and Wogonin, Am. J. Chin. Med., 24, 31 (1996); Y.S. Chi et al., Effect of Wogonin, a Plant Flavone from Scutellaria radix, on the Suppression of Cyclooxygenase-2 and the Induction of Inducible Nitric Oxide Synthase in Lipopolysaccharide-Treated Cells, Biochem. Pharmacol., 61, 1195 (2001); B.K. Park et al., Inhibition of TPA-induced Cyclooxygenase-2 Expression and Skin Inflammation in Mice by Wogonin, a Plant Flavone from Scutellaria radix, Eur. J. Pharmacol., 425, 153 (2001); T. Nakajima et al., Inhibitory Effect of Baicalein, a Flavonoid in Scutellaria Root, on Eotaxin Production by Human Dermal Fibroblasts, Planta Med., 67, 132 (2001); M.J. Cuellar et all., Topical Anti-inflammatory Activity of Some Asian Medicinal Plants Used in Dermatological Disorders, Fitoterapia, 72, 221 (2001); I.G. Butenko et al., Anti-inflammatory Properties and Inhibition of Leukotriene C4 Biosynthesis in vitro by Flavonoid Baicalein from Scutellaria baicalensis georgy Roots, Agents Actions, 39, C49 (1993); T. Newmark et al., Herbal composition for reducing inflammation and methods of using same, U.S. Patent 6,264,995; A. Meybeck, Method of skin care utilizing liposomes containing Scutellaria extracts, U.S. Patent 5,643,598, U.S. Patent 5443,839.
(28.) J.Y. Cho et al., Lignans from the Rhizomes of Coptis japonica Differentially act as Anti-inflammatory Principles, Planta Med., 67, 312 (2001); J.Y. Cho et al., In vitro Antiinflammatory Effects of Neolignan Woorenosides from the Rhizomes of Coptis japonica, J. Nat. Prod., 63, 1205 (2000).
(29.) B.C. Nadine et al., Active Constituents Isolated from Psoralea glandulosa L. with Antiinflammatory and Antipyretic Activities, J. Ethnopharmacol., 78, 27 (2001); K.K. Anand et al., Antiinflamatory, Antipyretic & Analgesic Properties of Bavachinin-a Flavanone Isolated from Seeds of Psoralea corylifolia Linn. (Babchi), Indian J. Exp. Biol., 16, 1216 (1978); H.O. Pae et al., Bakuchiol from Psoralea corylifolia Inhibits the Expression of Inducible Nitric Oxide Synthase Gene via the Inactivation of Nuclear Transcription Factor-kappaB, Int. Immunophar- macol., 1, 1849 (2001).
(30.) H. Suleyman et al., Antiinfiammatory effect of the aqueous extract from Rumex patientia L. roots. J. Ethnopharmacol., 6, 141 (1999).
(31.) D.A. Cifuente et al., Antiinflammatory Activity from Aerial Parts of Baecharis medullosa, Baccharis rufescens and Laennecia sophiifolia in mice. Phytother. Res., 15, 529 (2001); R.M. Gene et al., Anti-inflammatory and Analgesic Activity of Baccharis trimera: Identification of its Active Constituents, Planta. Med., 62, 232 (1996).
(32.) N.K. Jain and S.K. Kulkarni, Antinociceptive and Anti-inflammatory Effects of Tanacetum parthenium Extract in Mice and Rats, J. Ethnopharmacol., 68, 251 (1999); H. Sumner et al.. Inhibition of 5-Lipoxygenase and Cyclo-oxygenase in Leukocytes by Feverfew. Involvement of Sesquiterpene Lactones and other Components, Biochem. Pharmacol., 43, 2313 (1992).
(33.) T.A. Nader, et al., A Double Blind Randomized Controlled Trial of Maharishi Vedic Vibration Technology in Subjects with Arthritis, Front. Biosci. (United States), 6, H7-H17 (2001).
(34.) K. Huang et al., Anti-inflammatory Tetramers of Resveratrol from the Roots of Vitis amurensis and the Conformations of the Seven-membered Ring in Some Oligostilbenes, Phytochemistry, 58, 357 (2001); J.N. Wang et al., Procyanidins from the Seeds of Vitis amurensis. Phytochemistry, 53, 1097 (2000); J.N. Wang et al., Antioxidant Activity of Polyphenols from Seeds of Vitis amurensis in vitro, Acta Pharmacol Sin., 21, 633 (2000).
(35.) K.H. Pyun et al., Method for Inhibiting Interleukin-6 Production by Administering Extracts from Root of Stephania tetrandra, U.S. Patent 6,162,437; L. Hou, Compositions with Analgesic, Antipyretic and Antiinflammatory Properties, U.S. Patent 5,908,628; T. Kamiya et al., Vasodilator Effects of Bisbenzylisoquinoline Alkaloids from Stephania cepharantha, Planta Med., 59, 475 (1993); M. Asano et al., Vasodilator Effects of Cepharanthine, a Biscoclaurine Alkaloid, on Cutaneous Microcirculation in the Rabbit, J. Ethnopharmacol., 20, 107 (1987).
(36.) Tinofolin, Sabinsa Corp., NJ, USA; T. Yokozawa et al., Inhibition of Nitric Oxide Release By an Aqueous Extract of Tinospora tuberculata, Phytother Res., 14, 51 (2000); Chavali et al., Formulation for Alleviating Symptoms Associated with Arthritis, U.S. Patent 5,683,698.
About the Author
Shyam Gupta is director of R&D at Arizona Natural Resources, a contract manufacturing company specializing in nutraceuticals and phytopharmaceuticals based cosmetics. He is also a consultant in topical delivery systems based on nutraceutical and phytopharmaceutical ingredients. Fax: 602-569-9697, Tel: 602-569-6900, email: firstname.lastname@example.org or email@example.com.