Ingredients for Unflame

1. Urtica Dioica: Stinging Nettle

Background

Found in Africa, Europe, the United States and Canada, stinging nettle is a perennial plant that has been used as a medicinal agent since ancient times. The genus name Urtica comes from the Latin verb urere, meaning, "to burn," because of its urticate (stinging) hairs that cover the stem and underside of the leaves, which can cause an inflammatory skin response. The species name dioica means "two houses" because the plant usually has male or female flowers. This herb, which grows ubiquitously, is often considered a weed, yet there is a great deal of research indicating it has very potent anti- inflammatory properties.

History:

According to secondary sources, nettle was used as a medicinal agent as early as 3 BC both internally and externally, mainly as a treatment or antidote for bites, wounds, and poisonings. Nettle was smoked to treat asthma. Native Americans used nettle tea for pregnancy complications and to stop uterine bleeding after childbirth. The early settlers adopted these uses and used it to increase breast milk production. The juice of the nettle leaf was believed to be a hair growth stimulant.

Constituents of Stinging Nettle

More than 100 chemical components have been identified in the hairs, roots, leaves and rhizomes of nettle. Amines, such as acetylcholine, 5-hydroxytryptamine (serotonin), and histamine are found in the stinging hairs; adrenaline and noradrenaline are in the chloroplasts. [29] Carotenoids, such as chlorophyll, xanthophyll, and beta-carotene have been identified in the herbage of fresh and dried plants [30] Vitamins A, B1, B2, B9, C, E, and K have been identified from fresh and/or dried plant sources. Other components, such as cytokines, leukotrienes, scopoletin, volatile oils, rutin, ketones, ceramides, amino acids, glucokinins, mucilages, phospholipids (betaine, choline, lecithin), and glucoquinones have all been identified in nettle preparations [31] [29] [30]. In the leaves of Urtica dioica, water-extractable magnesium, manganese, and copper have been identified.[32]

Mechanisms of Action:
Analgesic Effects
In a randomized controlled double-blind crossover study, stinging nettle demonstrated an analgesic effect and reduction of disability after one week of daily treatment. However the mechanism of action is unclear.[18].

 Anti-inflammatory Effects

The proposed use of stinging nettle in the treatment of arthritis and inflammation may be due to components found in the extract of the root. A fraction of an aqueous extract containing polysaccharides demonstrated prolonged anti-inflammatory activity in the rat paw edema test. Some of the polysaccharides isolated from this fraction stimulated T-lymphocyte proliferation or influenced the complement system [31] [33]. An ethanolic extract was found to potently suppress human leukocyte elastase (HLE). HLE is one of the most destructive enzymes released by polymorphonuclear granulocytes, which migrate into tissues during the inflammatory process [34].

The water-soluble fraction of stinging nettle leaf extract (IDS 23 - Rheuma-Hek ®, Germany) demonstrated a dose dependent inhibition of phytohemagglutinin-stimulated production of Th1- specific interleukin-2 and interferon-gamma in peripheral blood mononuclear cells. [35] Inflammatory responses are primarily mediated by Th1 cells. IDS 23 has also demonstrated inhibition of leukotriene and prostaglandin syntheses [36] reduction of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) in lipopolysaccharide-stimulated human whole blood [36] and inhibition of nuclear factor-kappaB (NF-kappaB) [17] The NF-kappaB family of transcription factors is critical for the inducible expression of many genes involved in inflammatory responses [17] and thus its use as a antirheumatic remedy may be dependent on its ability to inhibit the proinflammatory transcription factor NF-kB. A hydroalcoholic extract of stinging nettle was found to lower levels of interleukin-6 and high-sensitivity C-reactive protein (hs-CRP), but it lacked significant effects on TNF- alpha.[37]

Finally, Teucher et al. studied the effect of Urtica dioica extract on cytokine secretion in 20 volunteers and found out that ingesting two capsules of nettle leaf extract twice daily for 21 days resulted in a decrease of lipopolysaccharide-stimulated TNF-alpha and IL-1beta releases in whole blood.[38]

Safety

Stinging nettle root has been used safely for up to 2 years.[39] Stinging nettle root extract (Bazoton- uno) has been shown to be safe and effective in randomized, controlled long-term treatment study of benign prostatic syndrome (BPS).[40]

EVIDENCE
Arthritis
Summary: Nettle is widely used throughout Europe and in Australia as a folk remedy to treat arthritic and rheumatic conditions. Preclinical evidence and in vitro and in vivo effects suggests that certain constituents in the nettle plant have anti-inflammatory and/or immunomodulatory activity.[47] A combination trial evaluating Phytalgic (fish oil, vitamin E, and Urtica dioica) reported a decrease in NSAID and analgesic use and improvement in osteoarthritis (OA) symptoms. [48]
Christensen et al. commented on this trial and reported that the results from this trial are promising.[49] Well-designed, randomized controlled trials are needed to further support its use in humans.

Evidence: Rayburn et al. conducted a nonrandomized, uncontrolled, before-and-after comparison study to assess the effect of a prepared topical cream containing stinging nettle (Urtica dioica) on joint function due to osteoarthritis (OA) (N=23) [50] Stinging nettle cream for osteoarthritis. Individuals were included if they presented with radiologically confirmed OA. Further information on inclusion and exclusion criteria was lacking. Participants were instructed to apply a formulated topical stinging nettle cream twice daily for two weeks. The stinging nettle cream was prepared by compounding 13.33% (w/w) stinging nettle extract (Liquid Phyto-Caps Nettle Leaf®) in Lipobase® oil-in-water emulsion. The study reported that two participants experienced temporary tingling and mild discomfort. Information regarding toxic effects, dropouts, and interactions was lacking. The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) was used to measure any effect on the participants' joint function. Assessments were conducted at baseline and at the end of the two- week study period. A mean reduction in WOMAC score of 4.17 (95% CI: 1.87, 6.48) from a mean baseline score of 17.22 was observed following treatment with stinging nettle. Limitations of this study included the lack of a control group. Patient inclusion criteria and exclusion criteria were also inadequately described, thus further limiting the study's generalizability. Moreover, patient medication information was lacking. In addition, the sample size was small, and the treatment period was only two weeks.

Chrubasik et al. conducted an open, equivalence trial comparing diclofenac 50 mg plus stewed stinging nettles (D50+U) to diclofenac 200 mg (D200) in the treatment of an acute attack of chronic joint diseases (N=40). [51] Patients were randomly assigned to receive diclofenac 100 mg twice-daily plus misoprostol or diclofenac 50 mg (in capsules identical to the D200 group) plus placebo for 14 days. Study participants were offered the same nutrition, except that the diclofenac 50 mg patients also received 50 g of stewed nettle using the leaves of young Urtica dioica. The primary outcome measure was improvement in elevated C-reactive protein (CRP). Secondary outcomes were total joint scores for physical impairment, subjective pain, and pain on pressure as assessed by the patient, and stiffness assessed by the physician. The median CRP concentration decreased to 68% of baseline level in the diclofenac 200 mg group and to 71% in the diclofenac 50 mg-plus-nettle group (p=0.34). The change in the median scores of patient and physician assessments decreased similarly in both groups for the following: physical impairment (67% for D200 and 60% for D50+U, p=0.71); subjective pain (67% for D200 and 77% for D50+U, p=0.38); pressure pain (75% for D200 and 77% for D50+U, p=0.66); and stiffness (52% for D200 and 67% for D50+U, p=0.38). Diclofenac 50 mg with 50 g of stewed Urtica dioica produced an effect on CRP and clinical symptoms of acute arthritis similar to diclofenac 200 mg. The results of this study would have been stronger if a third group receiving only diclofenac 50 mg had been included to serve as a control group and establish diclofenac 50 mg as a subtherapeutic dose in the treatment of arthritis.

Select combination studies (not included in the Evidence Table): Jacquet et al. conducted a randomized, double-blind, placebo controlled clinical trial to evaluate the effects of Phytalgic® in patients with knee and hip OA (N=81).[48] Patients included in the trial had knee or hip OA and were using NSAIDs and/or analgesics. Patients randomly received Phytalgic® (fish oil, vitamin E, and Urtica dioica) vs. placebo daily for three months. The primary outcome measures included use of NSAIDs by defined daily doses per day (DDD/day), use of analgesics defined in 500 mg paracetamol (acetaminophen)-equivalent tablets per week (PET/week), and WOMAC function scales. Those taking Phytalgic® for three months significantly decreased their mean use of analgesics by 6.5 PET/week vs. 16.5 PET/week (p<0.001; mean difference of -10.0; 95% CI: -4.9 to -15.1), and decreased use of NSAIDs to 0.4 DDD/day vs. 1.0 DDD/day (p=0.02; mean difference of - 0.7 DDD/day; 95% CI: -0.2 to - 1.2). Mean WOMAC scores evaluating pain, stiffness, and function reported significant improvement in those taking Phytalgic® (86.5, 41.4, and 301.6, respectively) vs. placebo (235.3, 96.3, and 746.5, respectively) (p<0.001; mean differences, respectively, of -148.8 (95% CI: -97.7 to -199.9), -54.9 (95% CI: -27.9 to -81.9), and -444.8 (95% CI: -269.1 to -620.4)). Symptoms of osteoarthritis improved and NSAID and analgesic use decreased in patients taking Phytalgic®. Further details are lacking. The effect of Urtica dioica alone is unclear. Christensen et al. commented on this article and reported that the results from this trial are promising.[49]

Inflammation
Summary: According to a randomized clinical trial, 100 mg/kg of stinging nettle daily for eight weeks made a significant difference compared to placebo in lowering inflammatory markers such as IL-6 and hs-CRP, but not on TNF-alpha.[37] Further well-designed clinical trials are needed before conclusions can be made.

Evidence: Namazi et al. conducted a randomized, double-blind, placebo controlled trial to assess the effects of a hydroalcoholic extract of stinging nettle (Urtica dioica) on insulin sensitivity and markers of inflammation (N=50).[37] Participants were included if they were over the age of 30 years, had a glycosylated hemoglobin (HbAlc) level =10%, used common diabetes drugs, and had triglyceride levels <400 mg/dL. Participants with cardiovascular, kidney, liver or thyroid diseases; infections; allergies; or angina were excluded. Also, if individuals were taking nonsteroidal anti-inflammatory drugs (NSAIDs), warfarin, or insulin, as well as if they used alcohol, herbal teas, or dietary supplements, they were also excluded. Participants were randomized to receive 100 mg/kg of stinging nettle extract or placebo in three portions daily. Each portion was to be dissolved in one glass of water and consumed after a main meal for duration of eight weeks. Each liter of hydroalcoholic extract of stinging nettle contained 45% ethanol, 55% water, and 2.7g of dry matter. Water and alcohol percent in placebo was equal to the stinging nettle extract, with the additions of chlorophyll color to eliminate differences in appearance. Information regarding adverse and toxic effects was lacking. Five participants failed to complete the study, but information regarding the reasons for the dropouts was lacking. Interaction information was lacking. Biomarkers of inflammation, including interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), and high-sensitivity C-reactive protein (hs-CRP), were measured. In addition, concentrations of insulin were measured to assess insulin sensitivity, and changes in body mass index (BMI) and waist circumference were assessed. Compared to the placebo group following treatment, participants treated with stinging nettle had significantly lower levels of IL-6 (3.49 ± 0.54 vs. 1.19 ± 0.27 pg/mL, p<0.01) and hs-CRP (2.95 ± 0.87 vs. 1.37 ± 0.11 mg/dL, p=0.03). A statistically significant between-group difference regarding levels of TNF-alpha or insulin sensitivity was lacking after treatment. In addition, there was a lack of between-group difference regarding changes in BMI or waist circumference. Limitations of this study included the lack of information regarding dropouts, adverse and toxic effects, and interactions. This trial was also performed at one facility in Iran.

Moreover, further information regarding ethnicities, length of time of having type 2 diabetes, and concurrent diabetes medications used by participants was lacking, which may limit the generalizability of the results.

Joint pain
Summary: Nettle has historically been used in several different forms to treat pain of varying origins. Randall has conducted several studies that evaluated stinging nettle's effect on osteoarthritis pain, and although a recent trial did not show significant differences compared a the control group, the other trials had reduction in visual analog pain scores and pain relief experienced by most participants.[18, 52, 53]
However, well-controlled statistically significant clinical trials to support this use are lacking.

2. BOSWELLIA SERRATA

History

Boswellia serrata is an herb used for millennia and for good reason. In fact, its use is described in biblical texts written around 586 BCE. While used in religious ceremonies (it was used for its aromatic effects), it was very likely also used for its anti-inflammatory pain relieving effects.. Extracts from resins of Boswellia species have been used for years in African countries and in Ayurvedic medicine in India for the treatment of a variety of diseases. [55, 56] Frankincense is also derived from Boswellia species. Today, Boswellia is often used in complementary medicine, most commonly for inflammatory conditions such as rheumatoid arthritis.

Constituents

Boswellia is frequently standardized according to the boswellic acid content.[57] The gum resin typically contains 30% boswellic acids, while ethanol extracts contain 43% boswellic acids.[58] Some commercial sources contain up to 70% boswellic acids. The Boswellia serrata tree contains a gummy oleoresin found under the bark.[55]

The four major pentacyclic triterpene acids isolated from the gum resin of Boswellia serrata are beta- boswellic acid (the most abundant), 3-acteyl-beta-boswellic acid, 11-keto-beta-boswellic acid, and 3- acetyl-11-keto-beta-boswellic acid. These triterpenes are responsible for the pharmacologic effects.

Individual triterpenoids included lupeol, beta-boswellic acid, 11-keto-beta-boswellic acid, acetyl beta- boswellic acid, acetyl 11-keto-beta-boswellic acid, acetyl-alpha-boswellic acid, 3-oxo-tirucallic acid, and 3-hydroxy-tirucallic acid.

Mechanisms of Action

Analgesic effects: Acetyl-11-keto-beta-boswellic acid is one of the four major pentacyclic triterpenic acids found in the gum resin of Boswellia serrata.[59] Acetyl-11-beta-boswellic acid is a highly specific inhibitor of 5-lipoxygenase, an enzyme for leukotriene biosynthesis.[60] [61] In animal research, dose-dependent analgesic activity has been noted. [62] A study in rats showed that the nonphenolic ration of Boswellia serrata gum resin (20-300 mg/kg) exhibited an analgesic effect similar to morphine (4.5 mg/kg).[63]

Anti-inflammatory effects: Multiple pentacyclic triterpenic acids, referred to as boswellic acids, have been isolated from resins of the Boswellia species and identified as major anti-inflammatory components of Boswellia gum resin extract.[55] Busheled, B. and Simmet, T. Analysis of 12 different pentacyclic triterpenic acids from frankincense in human plasma by high-performance liquid chromatography and photodiode array detection.[64-66] Acetyl-11-keto-beta-boswellic acid from Boswellia has been identified as one of the primary anti-inflammatory triterpenoid acids in Boswellia resin extract. Acetyl-11-beta-boswellic acid is a highly specific inhibitor of 5-lipoxygenase, an enzyme for leukotriene biosynthesis [60] [61] Animal research shows that it inhibits the release of leukotrienes B4 (LTB4) [55] [67] [68] Additional studies have found that Boswellia inhibits human leukocyte elastase (HLE).[67]

Doses of 50-200 mg/kg of Boswellia extract given orally to mice following the injection of an inflammatory agent into the intrapleural cavity inhibited polymorphonuclear leukocyte (PMN) infiltration, similar to the effect seen with indomethacin. Similarly effective anti-inflammatory activity has been observed in studies of rats with laboratory-induced paw inflammation, and in animal models with arthritis, gouty arthritis, and polyarthritis. Antipyretic activity in rats and rabbits has also been noted.

Results of studies suggest that Boswellia extract may also inhibit TNF-alpha-induced inflammatory response [69]. [70]. The effects of acetyl-11-keto-beta-boswellic acid (AKBA) on TNF-alpha-inducible metalloproteinase expression in human microvascular endothelial cells (HMECs) were evaluated in vivo and in vivo.[70] Treatment of HMECs for two days with either a 3% or 30% formulation protected against arthritis by preventing TNF-alpha-induced expression and activity of matrix metalloprotease-3 (MMP-3), MMP-10, and MMP-12. The 30% formulation was consistently more effective than the 3% formulation.

Earlier studies showed that boswellic acids reduced enzymes that are elevated in inflammatory conditions like arthritis, such as glutamic pyruvic transaminase, glycohydrolase, and beta- glucuronidase.[71-73] Inhibition of glycosaminoglycan (GAG) synthesis and urinary excretion of connective tissue metabolites by boswellic acids may support the purported beneficial effects of Boswellia in the prevention of the degradation of connective tissue in inflammatory arthritic conditions.

In a study of mice with trinitrobenzene sulfonic acid-induced colitis, high doses of Boswellia extracts were ineffective at reducing inflammatory responses and were associated with hepatotoxic effects, including hepatomegaly and steatosis.[74] Based on these findings, the authors recommended that further research be conducted to elucidate the anti-inflammatory effects and potential hepatotoxic effects of Boswellia in humans.

Abdel-Tawab et al. published a review of Boswellia serrata.[75] The authors suggest that animal and pilot clinical research support its anti-inflammatory effects. They suggest that until recently, pharmacological effects of extracts were attributed to leukotriene formation suppression by the boswellic acids, 11-keto-ß-boswellic acid and acetyl-11-keto-ß-boswellic acid. This effect is lacking in human whole blood, and due to the poor pharmacokinetics, the authors suggest another mechanism is likely, such as the inhibition by beta-boswellic acid of microsomal prostaglandin E synthase-1 and the serine protease cathepsin G. In 2009, Tausch identified human cathepsin G as a potential functional target of boswellic acids using human blood ex vivo.[76]

According to a review, incensole acetate (a major component of Boswellia resin) is a nuclear factor (NF)-kappaB inhibitor.[77]

Pharmacokinetics

Food appeared to alter the pharmacokinetic profile of Boswellia.[78] Meals that are high in fat increased the concentration of beta-boswellic acid, 11-keto-beta-boswellic acid, and acetyl-11-keto- beta-boswellic acid, acetyl-alpha-boswellic acid, and alpha boswellic acid in plasma.

After a single 333 mg dose of Boswellia serrata extract, the mean elimination half-life was reported to be 5.97 ± 0.95 hours.[79] Metabolites of Boswellia appear to be excreted in urine.[80]

Pharmacokinetic tests of gum-resin of Boswellia carterii, Boswellia frereana, Boswellia sacra, and Boswellia serrata showed that they are moderate-to-potent inhibitors of CYP enzymes, with equal potency for inhibiting the major drug metabolizing enzymes 1A2, 2C8, 2C9, 2C19, 2D6, and 3A4.[81]In 12 healthy volunteers who took a single 333 mg dose of Boswellia serrata extract (BSE), peak plasma levels (2.72 x 10-3± 0.18 mm/mL) of BSE were reached at 4.5 ± 0.55 hours.[79]

Evidence of Efficacy:

There is good quality evidence in support of the use of Boswellia for OA.[84, 85, 87, 90-93]Ernst conducted a systematic review to assess evidence from randomized clinical trials about the effectiveness of extracts of Boswellia serrata (frankincense). [90] Electronic searches on MEDLINE, Embase, CINAHL, AMED, and the Cochrane Library were conducted, as were manual searches of conference proceedings, bibliographies, and departmental files. All randomized clinical trials of Boswellia serrata extract as a treatment for any human medical conditions were included, and studies of Boswellia serrata preparations combined with other ingredients were excluded. Selection of studies, data extraction, and validation were done by the author. The Jadad scoring system was used to evaluate the methodological quality of all included trials. Of 47 potentially relevant studies, seven met all inclusion criteria (five placebo controlled, two with active controls). The included trials related to osteoarthritis [84, 87, 93] and collagenous colitis.[94] The results of all trials indicated that

Boswellia serrata extracts were clinically effective. Three studies were of good methodological quality. Serious safety issues were not noted.

Sengupta et al. conducted a three-group, randomized, placebo controlled trial to evaluate the safety and efficacy of 5-Loxin® in treating OA of the knee (N=75).[84] Participants were outpatients who had OA for more than three months and were included if they were between 40 and 80 years of age, met the American College of Rheumatology classification criteria, were taking prescription strength nonsteroidal anti-inflammatory drugs (NSAIDs) or acetaminophen regularly for 30 days before the trial with benefit, and, after withdrawal from usual medication, had visual analogue scale (VAS) scores between 40 and 70 mm and a Lequesne's Functional Index (LFI) score greater than seven points. Subjects were excluded with a history of inflammatory arthropathy or rheumatoid arthritis (RA), hyperuricemia (>440 mcM/L), history of peptic ulcer or upper gastrointestinal bleed, or body mass index >30 kg/m2. Patients in the low dose 5-Loxin® group received 50 mg; patients in the high dose 5- Loxin® group received 125 mg; patients in the placebo group received one similar capsule filled with rice bran. All doses were in capsule form and were given twice daily by mouth for 90 days. 5-Loxin® is extracted from Boswellia serrata enriched to 30% 3-O-acetyl-11-keto-beta-boswellic acid (AKBA). Reports of toxic effects in study participants were lacking. The primary outcome measures were pain, physical function, and joint stiffness. Statistically significant improvements in the low dose group vs. placebo on the VAS, LFI and the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain scores were 48.83% (p<0.001), 23.79% (p<0.036), and 39.61% (p= 0.009), respectively. Statistically significant improvements in the high dose group vs. placebo on the VAS, LFI, WOMAC pain, WOMAC stiffness, and WOMAC function were 65.94% (p< 0.001), 31.34% (p<0.017), 52.05% (p< 0.001), 62.22% (p= 0.014), and 49.34% (p= 0.002), respectively. In general, this was a small, well-conducted, 90 day, double-blind, randomized, placebo controlled study.

Sengupta et al. also conducted a randomized, double-blinded, placebo controlled trial to determine the effects of 5-Loxin® and Aflapin® for OA of the knee (N=60) [92] Participants were included in the study if they were between the ages of 40 and 80 years with OA of the knee for three months or longer, and after a week without medication had a VAS score for pain of 40-70 mm. Compared to placebo, the Aflapin® treatment group had significantly superior improvements in VAS (47.3%, p<0.0001), LFI (35.8%, p=0.0004), WOMAC pain (61.7%, p<0.0001), WOMAC stiffness (60.1%, p=0.0001), and WOMAC functional ability (49.4%, p=0.0001) at the end of the study. The authors concluded that 5-Loxin® and Aflapin® were effective and safe for OA of the knee.

Kimmatkar et al. conducted a randomized, double-blind, placebo controlled, crossover trial in 30 patients to assess the safety and efficacy of Boswellia serrata in patients with osteoarthritis of the knee.[87] Subjects were administered either a placebo or a formulation of Boswellia serrata extract 333 mg three times daily (standardized to 40% to 40% total boswellic acid [87] Reduction in the severity of pa in and swelling and improvement in the loss of function were significant in the group receiving the Boswellia serrata treatment vs. the placebo (p<0.001). Decreased knee pain; increased knee flexion; increased walking distance; improvement in range of movement of the knee, walking up stairs, and squatting; and better ability to kneel and sit cross-legged were also noted in those receiving Boswellia.

Sontakke et al. conducted a randomized, prospective, open-label, comparative study to compare the efficacy, safety, and tolerability of Boswellia serrata extract to valdecoxib in patients with osteoarthritis.[93] Sixty-six subjects, aged between 40 and 70 years, were randomly assigned to receive Boswellia serrata extract (BSE) 333 mg three times daily (N=33) or valdecoxib 10 mg once daily (N=33) for six months. The WOMAC scale was used to assess patients at baseline and at one- month intervals until one month after drug discontinuation. In the BSE group, pain, stiffness, and difficulty in performing daily activities showed statistically significant improvement with two months of therapy; this even lasted until one month after stopping the intervention (p<0.001). In the valdecoxib group, the statistically significant improvement in all parameters was reported after one month of therapy, but the effect persisted only as long as the drug therapy continued (p<0.001).

3. EQUISETUM ARVENSAE (Horsetail)

Horsetail (Equisetum arvense) has traditionally been used in Europe as an oral diuretic for the treatment of edema. The German Commission E expert panel has approved horsetail for this indication. Horsetail is also occasionally used for osteoporosis, nephrolithiasis, urinary tract inflammation, and wound healing (topical). These uses have largely been based on anecdote and clinical tradition rather than scientific evidence. Orally, horsetail is used for diuresis, edema, kidney and bladder stones, urinary tract infections, incontinence, and general disturbances of the kidney and bladder. It is also used for alopecia; tuberculosis; jaundice; hepatitis; brittle fingernails; rheumatic diseases; gout; osteoarthritis; osteoporosis; frostbite; weight loss; menorrhagia; and nasal, pulmonary, and gastric hemorrhage.

Topically, horsetail is used for treatment of wounds and burns.

Constituents

The benzoic acid derivative hippuric acid and the quercetin derivative homovanillic acid are metabolites of Equisestum arvense.[95]

Drug Interactions:

Some evidence indicates horsetail may lower blood sugar.[97] Animal research suggests that horsetail has diuretic properties.[98] Theoretically, due to these potential diuretic effects, horsetail might reduce excretion and increase levels of lithium. The dose of lithium might need to be decreased. Horsetail contains chromium (0.0006%) and could increase the risk of chromium toxicity when taken with chromium supplements or chromium-containing herbs such as bilberry, brewer's yeast, or cascara.[99]

Mechanism of Action:
Antioxidant effects: Equisetum telmateia may be a useful source of antioxidants with huge scavenger ability.[100]

Diuretic Effect: Horsetail possesses weak diuretic properties, which are believed to be due to equisetonin and flavone glycosides. In one human trial examining patients with a history of nephrolithiasis, an 18-24% statistically significant increase in diuresis was noted in those taking horsetail vs. baseline after 8-12 weeks; these individuals had an increase in glomerular filtration rate (GFR) of 22%.[101] Horsetail was also noted to lower urine pH. Renal excretion of uric acid increased as did urine uric acid crystal formation.  

Hepatoprotective effects: The phenolic petrosin onitin and flavonoid luteolin isolated from Equisetum arvense L. (Equisetaceae) exhibited hepatoprotective activities on tacrine-induced cytotoxicity in human liver cells, displaying EC50 values of 85.8 ± 9.3 mcM and 20.2 ± 1.4 mcM, respectively.[102]

4. ALLIUM SATIVUM (Garlic)

Allium Sativum, commonly known as garlic is a culinary herb cultivated worldwide. It is related to onion, leeks, and chives. It is thought that garlic is native to Siberia but was spread to other parts of the world over 5000 years ago.

People Use Garlic for:

Garlic is used for exercise performance, exercise-induced muscle soreness, osteoarthritis, joint pain, gout, gastrointestinal disorders, immune enhancement, stress, and fatigue. Additionally, garlic is used for more than 50 other conditions.

Safety:

Garlic is safe when used orally and appropriately for up to 7 years. [104]

Constituents:

The applicable part of garlic is the bulb. The bulb of garlic contains the cysteine sulfoxide. Many of the pharmacological effects of garlic are attributed to the allicin, ajoene, and other alliin, also known as S- allyl-L-cysteine sulfoxide. Other garlic constituents include S-propylcysteinesulfoxide (PCSO) and S- methylcysteine-sulfoxide (MCSO), which can also be converted by alliinase to constituents such as allyl methane thiosulfinate, methyl methanethiosulfinate, and other thiosulfinates. Volatile constituents of garlic include diallyldisulfide (DADS), dimethyltrisulfide (DATS), and sulfur dioxide.[105]

Mechanisms of Action:

Antibacterial effects: Fresh garlic has shown activity against Escherichia coli, methicillin-resistant Staphylococcus aureus, and Salmonella enteritidis; it has been suggested as a food additive to prevent food poisoning.[106] The antimicrobial effects of garlic have been attributed to its allicin content.

Antioxidant effects: In various laboratory studies, garlic and its constituents displayed antioxidant activity, including increasing that activities of glutathione peroxidase, catalase, and superoxide dismutase; lowering xanthine oxidase activity; and inhibiting lipid peroxidation and prostaglandin production. [107-109]

Antiviral effects: Preliminary in vitro evidence suggests that garlic compounds, including ajoene, allicin, allyl methyl thiosulfinate, and methyl allyl thiosulfinate, might have activity against viruses such as cytomegalovirus, influenza B, herpes simplex virus type 1, herpes simplex virus type 2, parainfluenza virus type 3, vaccinia virus, vesicular stomatitis virus, and human rhinovirus type 2. [110-113]

Immunologic Actions: Some in vitro evidence suggests that garlic powder extract reduces lipopolysaccharide-induced production of IL-1beta and tumor necrosis factor (TNF)-alpha in human whole blood. Garlic powder extract also appears to reduce the activity of nuclear factor (NF)-kB, a transcription factor involved in inflammation associated with autoimmune diseases such as arthritis and inflammatory bowel disease, as well as atherosclerosis.[114]

Evidence from animal research suggests that garlic oil 100-200 mg/kg every other day for 2 weeks enhances lymphocyte proliferation rate and increase the production of the cytokines interleukin 2 (IL- 2), interferon gamma (IFN-gamma), IL-4, and IL-10 upon stimulation with concanavalin A.[115] At low doses, garlic oil appears to enhance T cell response toward the Th1 type cytokines (eg, IL-2 and INF-gamma).[115]

Garlic may also enhance natural killer (NK) cell number and activity.[116]

According to preliminary research, allicin (the major biologically active component of garlic) supplementation may reduce exercise induced muscle damage [117] Allicin supplementation for 14 days reduced plasma creatine kinase (CK), muscle-specific creatine kinase (CK-MM), interleukin-6 (IL- 6), and perceived muscle soreness after exercise. Sixteen subjects were randomized to allicin supplementation (80 mg daily) or a control group for 14 days. Allicin supplementation resulted in reduced exercise-induced plasma creatine kinase (CK), muscle-specific creatine kinase (CK-MM), interleukin-6 (IL-6), and perceived muscle soreness after exercise when compared to placebo. It was also found to reduce muscle soreness.[117]

Ince et al. conducted a randomized, double-blind, placebo controlled, crossover trial to evaluate the effects of a single dose of garlic on aerobic performance in college endurance athletes. Ten subjects participated in the study and were given 900 mg of odor-modified dried garlic or placebo in a single administration. Heart rate, VO2 max, and endurance time responses of each subject were recorded. VO2max and mean endurance performance time for treadmill running increased significantly five hours after the ingestion of a single dose of garlic compared to placebo (p<0.01 and p<0.001, respectively). This study received a Jadad score of 2.[118]

Circulation
Summary: In observational research, garlic supplementation increased calf blood flow in healthy individuals. Moreover, the improvement was associated with and possibly mediated by increased plasma levels of interleukin-6 (IL-6). In this study, increased IL-6 was independent of the activation of the NO pathway.[119] [120]

5. APIUM GRAVEOLENS (celery seed)

Apium graveolens, a herb from Europe and temperate parts of Asia, is a species in the family of Apiaceae. Wild celery (Apium) can be found throughout Europe, the Mediterranean, and parts of Asia. The leaves, stalks, root, and seeds can be eaten. Celery seed has also been used as a diuretic and to treat gout.

People Use This For

Orally, celery is used to treat rheumatism, gout, hysteria, nervousness, headache, weight loss due to malnutrition, loss of appetite, and exhaustion. Celery is also used as a sedative, mild diuretic, urinary antiseptic, digestive aid, menstrual stimulant, anti-flatulent, aphrodisiac, to reduce lactation, for regulating bowel movements, stimulating glands, for blood purification, dysmenorrhea. It was believed in Chinese folklore that Apium graveolens Linn alleviates hypertension, vertigo, headache, redness of the face and eyes, swelling and pain.

Safety

Celery seed has Generally Recognized as Safe (GRAS) status in the US (Electronic Code of Federal Regulations. Title 21. Part 182 -- Substances Generally Recognized As Safe.) [127]

Constituents:

L-3-n-butylphthalide (L-NBP) is the active component of the essential oil extracted from the seeds of Apium Graveolens.[128]
Celery contains phenols and furocoumarins (psoralens). Celery tuber also contains methoxsalen (8- methoxypsoralen) and 5-methoxypsoralen and the allergen profilin (Api g 1), which shows high homology to birch pollen profiling[129] and thus can cross react with those who are allergic to birch pollen. It also contains flavonols (luteolin and apigenin).[130] Celery seed oil contains the natural phthalides.[131] Celery contains high amounts of sodium.[132]

Mechanism of Action

The anti-inflammatory activities of celery extracts, some rich in flavone aglycones and others rich in flavone glycosides, were tested on the inflammatory mediators tumor necrosis factor α (TNF-α) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) in lipopolysaccharide- stimulated macrophages. Pure flavone aglycones and aglycone-rich extracts effectively reduced TNF-α production and inhibited the transcriptional activity of NF-κB, while glycoside-rich extracts showed no significant effects. These results demonstrate that deglycosylation increases absorption of dietary flavones in vivo and modulates inflammation by reducing TNF-α and NF-κB, suggesting the potential use of functional foods rich in flavones for the treatment and prevention of inflammatory diseases.[133]

Apigenin, a flavonoid abundantly found in fruits and vegetables, including celery, exhibits anti- proliferative and anti-inflammatory activities through inhibition of the production of proinflammatory cytokines IL-1beta, IL-8, and TNF in LPS-stimulated human monocytes and mouse macrophages. Apigenin inhibits the transcriptional activity of NF-kappaB in LPS-stimulated mouse macrophages as well. [134]

Food plants of the Apiaceae plant family such as carrots, celery and parsley, contain a group of bioactive aliphatic C17-polyacetylenes. These polyacetylenes have shown to be highly toxic towards fungi, bacteria, and mammalian cells, and to display anti-inflammatory and anti-platelet-aggregatory effects.[135]

Interactions with Drugs and other Supplements:

In vitro and in vivo research suggests that celery can inhibit cytochrome P450 1A2 (CYP1A2).[136] Theoretically concomitant use may increase the levels of CYP1A2 substrates. Some drugs metabolized by CYP1A2 include amitriptyline (Elavil), haloperidol (Haldol), ondansetron (Zofran), propranolol (Inderal), theophylline (Theo-Dur, others), verapamil (Calan, Isoptin, others), and others. Celery seed may decrease the effects of levothyroxine replacement therapy [137] when taken together. Celery is thought to have diuretic properties. Theoretically, due to these potential diuretic effects, celery might reduce excretion and increase levels of lithium. The dose of lithium might need to be decreased.

Celery contains the constituents falcarinol and falcarindiol. Laboratory research suggests that falcarinol and falcarindiol can inhibit platelet aggregation [135] [138]
Anecdotal evidence suggests that celery can decrease blood pressure.[139] Theoretically, concomitant use with herbs with hypotensive effects might have additive blood pressure lowering effects and increase the risk of hypotension; use with caution. Some of these herbs include andrographis, casein peptides, cat's claw, coenzyme Q-10, fish oil, L-arginine, lycium, stinging nettle, theanine, and others.

Celery tuber also contains methoxsalen (8-methoxypsoralen) and 5-methoxypsoralen and the allergen profilin (Api g 1), which shows high homology to birch pollen profiling, and thus can cross react with those who are allergic to birch pollen.