Grassfed Trachea by Ancestral Supplements

POSSIBLY EFFECTIVE

• Cataracts. Chondroitin sulfate in combination with sodium hyaluronate is approved as a medical device to be ophthalmically injected during cataract surgery. It is unknown if other routes of administration are beneficial. Details: Injecting ophthalmic viscosurgical devices (OVDs) containing a combination of chondroitin sulfate and sodium hyaluronate into the eye protects the corneal endothelium during small-incision cataract surgery. Various medical devices containing chondroitin sulfate and sodium hyaluronate (Viscoat, Alcon Laboratories) have been granted approval by US Food and Drug Administration (FDA) for use as an adjunct to cataract surgery (89436,89437). However, OVDs that cannot be easily removed after surgery can cause intraocular pressure (IOP) spikes and reduced visual acuity. A meta-analysis of small clinical studies shows that using a specific chondroitin sulfate 4% and sodium hyaluronate 3% solution (Viscoat, Alcon Laboratories) after small-incision cataract surgery increases IOP at postoperative days 1 and 2, but not at any later postoperative days for up to 1 month (104452).
• Osteoarthritis. Chondroitin sulfate seems to modestly reduce osteoarthritis pain and improve function. Pharmaceutical-grade chondroitin sulfate products have shown the most benefit. Details: Meta-analyses of randomized controlled trials in patients with mostly knee osteoarthritis show that taking chondroitin sulfate 800-2000 mg in single or divided doses daily for at least 3 months modestly reduces pain and disability when compared with placebo. However, included studies were heterogeneous and most had high attrition bias. A sub-group analysis of high-quality studies shows that 16 patients need to take chondroitin sulfate for 6 months for one patient to experience at least a 20% reduction in pain (94381,95792,99685,104446). When compared with conventional treatments like diclofenac 50 mg three times daily, chondroitin sulfate improves symptoms more slowly; however, the improvement seems to persist for up to 3 months after treatment cessation (322). Chondroitin also seems to have disease-modifying benefits. Clinical research in patients with osteoarthritis of the knee or hip shows that taking chondroitin sulfate 800 mg daily or more for 2 years might modestly reduce joint degeneration and narrowing when compared with placebo or celecoxib (42348,42398,94381,95516). Overall, most of the positive research involved pharmaceutical-grade chondroitin sulfate products, which are available as prescription products in some countries, such as Chondrosulf (IBSA Institut Biochimique SA) (17732,42348,42398,42536,89596,94360,104446), Chondrosan (Bioibérica, S.A.) (42463,42513), and Structum (Laboratoires Pierre Fabre) (22212,42520,89593). One clinical study shows that taking a pharmaceutical-grade chondroitin product (Chondrosulf) 800 mg daily seems to be comparable to taking celecoxib 200 mg daily for reducing pain and improving knee function (94360). Pharmaceutical-grade chondroitin products might demonstrate greater benefit due to higher quality (94360,102116). It is also important to note that most clinical studies using pharmaceutical-grade products are manufacturer-funded (94381). Furthermore, they may not be readily available for purchase in the US. Experts have conflicting stances on the use of chondroitin for osteoarthritis. The American College of Rheumatology (ACR) strongly recommends against the use of chondroitin for any form of osteoarthritis (102114). Conversely, the European Society of Clinical and Economic Aspects of Osteoarthritis (ESCEO) strongly recommends for the use of pharmaceutical-grade chondroitin products. Additionally, the ESCEO provides a weak recommendation against the use of chondroitin in combination with glucosamine (102141). These differing recommendations seem to be related to interpretation of the evidence for pharmaceutical-grade products. The ACR has determined that the inconsistent evidence may indicate the presence of industry bias; the ESCEO has determined that the inconsistent evidence is due to inconsistent product quality. Chondroitin is often used in combination with glucosamine and/or other products. Long-term studies in patients with osteoarthritis show that taking non-branded chondroitin sulfate with glucosamine sulfate modestly reduces joint-space narrowing when compared with control (89558,94380,95792). However, meta-analyses and individual clinical studies assessing non-branded preparations of chondroitin sulfate with glucosamine hydrochloride or glucosamine sulfate do not show reduced pain in patients with knee osteoarthritis when compared with control (13579,89558,95788,99683,99685). In contrast, pain reduction was reported for branded formulations such as chondroitin sulfate with glucosamine hydrochloride and manganese ascorbate (Cosamin DS, Nutramax Laboratories) (4237,7169); chondroitin sulfate with glucosamine hydrochloride (Droglican, Bioiberica, S.A.) (89516); or chondroitin sulfate with collagen peptides and hyaluronic acid (BioCell Collagen, BioCell Technology, LLC) (28678,28680). A large, prospective observational study in adults with knee or hip osteoarthritis suggests that taking glucosamine hydrochloride 500 mg and chondroitin sulfate 400 mg (Theraflex, Bayer) three times daily for the first 3 weeks, then twice daily thereafter for up to 64 weeks, is associated with reductions in pain, stiffness, and the need for concomitant analgesic therapy, and improvements in daily function and knee- or hip-related quality of life, when compared to baseline. The most pronounced improvements are from 16-24 weeks (111647). It is unclear if the benefit seen with these specific products is due to bias introduced by industry funding or due to higher quality. Limited research has also evaluated INTRAMUSCULAR and TOPICAL chondroitin. Some clinical research shows that receiving daily intramuscular injections of chondroitin sulfate for 6 months improves pain and function in patients with osteoarthritis (42396,42397). A topical preparation of chondroitin sulfate in combination with glucosamine sulfate, shark cartilage, and camphor also seems to reduce arthritis symptoms. However, any symptom relief is most likely due to the counterirritant effect of camphor and not the other ingredients (10327). There is no research showing that chondroitin is absorbed topically.

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Aging skin. Oral chondroitin sulfate has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in females with aging skin shows that taking a specific combination product (BioCell Collagen, BioCell Technology, LLC) containing chondroitin sulfate 200 mg, collagen peptides 600 mg, and hyaluronic acid 100 mg daily for 12 weeks reduces lines and wrinkles by about 13% when compared with baseline (28681). The validity of these findings is limited by the lack of a comparator group. It is also unclear if these improvements are due to chondroitin sulfate, other ingredients, or the combination. Furthermore, it should be noted that this study was funded by the product manufacturer.
• Aromatase inhibitor-induced arthralgia. Oral chondroitin sulfate has only been evaluated in combination with glucosamine sulfate; its effect when used alone is unclear. Details: A small open-label clinical study in postmenopausal females with early stage breast cancer shows that taking a combination of glucosamine sulfate 1500 mg and chondroitin sulfate 1200 mg in 2-3 divided doses daily for 24 weeks improves pain and symptoms associated with aromatase inhibitor-induced arthralgias when compared to baseline (89561). The validity of this finding is limited by the lack of a control group.
• Cancer. Some low-quality observational studies suggest that oral chondroitin use is not associated with a lower risk of cancer. Details: A meta-analysis of observational research has found that use of chondroitin with or without glucosamine is not associated with a lower risk of cancer when compared with no use (110625).
• Colorectal adenoma. Oral chondroitin has only been evaluated in combination with glucosamine; its effect when used alone is unclear. Details: An observational study in older adults has found that taking oral chondroitin and glucosamine is associated with a 26% reduced chance of high-risk adenoma and 10% reduced chance of conventional adenoma when compared with not using these supplements. This benefit was not seen in a subgroup of younger females (104444).
• Dry eye. It is unclear if ophthalmic chondroitin sulfate improves dry eye symptoms. Details: A small clinical study in patients with dry eye suggests that administering an ophthalmic preparation of chondroitin sulfate every two hours while awake for 2 weeks seems to improve symptoms when compared to baseline (1974). Chondroitin has also been used in combination with other ingredients. A large clinical trial in patients with mild to moderate dry eye disease shows that applying preservative-free eye drops containing chondroitin sulfate with sodium hyaluronate (Humylub Ofteno PF, Laboratorios Sophia), one drop into each eye four times daily for 90 days, seems to be no different for improving dry eye severity when compared with using polyethylene/propylene glycol eye drops (Systane Ultra, Alcon Laboratories) (104443). Another small clinical trial in patients with mild to moderate dry eye shows that using specific eye drops containing chondroitin sulfate and xanthan gum (PRO-148, Laboratorios Sophia) four times daily for 60 days does not improve tear stability, but might improve dry eye severity, when compared with using polyethylene/propylene glycol eye drops (Systane, Alcon Laboratories) (89591).
• Exercise-induced muscle soreness. It is unclear if oral chondroitin sulfate improves muscle soreness from exercise. Details: Preliminary clinical research in untrained males shows that taking chondroitin sulfate 1800 mg twice daily for 14 days before exercise does not reduce post-exercise muscle soreness when compared with placebo (42352). However, another small clinical study in healthy, recreationally active adults shows that a specific combination product (BioCell Collagen, BioCell Technology, LLC) containing chondroitin sulfate 300 mg, collagen peptides 900 mg, and hyaluronic acid 150 mg, taken twice daily for 6 weeks prior to two bouts of resistance exercise, attenuates muscle damage and decreases delayed-onset muscle soreness when compared with placebo (96301). It is unclear if these effects are due to chondroitin sulfate, the other ingredients, or the combination.
• Gastroesophageal reflux disease (GERD). Oral chondroitin sulfate has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Patients with non-erosive GERD are thought to be less responsive to conventional acid suppression with proton pump inhibiters (PPIs) and H-2 blockers. A small preliminary clinical study shows that taking a syrup containing hyaluronic acid and chondroitin sulfate along with PPIs, H2-receptor antagonists, and/or antacids, reduces the intensity of symptoms associated with non-erosive GERD by about 3.5-fold when compared with placebo (89592). A larger clinical study in patients with non-erosive GERD shows that taking the same combination agent (Esoxx by Alfa Wassermann) in addition to acid suppression with PPIs improves GERD symptom severity by 21%, heartburn by 15%, and regurgitation by 10% when compared with PPIs with a placebo (101271). This product is available in Canada as EsopH (Exzell Pharma). It is unclear if the benefit of this combination product is due to chondroitin sulfate, hyaluronic acid, or the combination. Chondroitin sulfate has also been evaluated in patients with GERD who experience extraesophageal symptoms. A small clinical study in patients reporting symptoms of cough, hoarseness, postnasal drip, sore throat, and/or throat clearing shows that taking a specific combination product (Gerdoff, SOFAR S.p.A.) containing chondroitin sulfate, hyaluronic acid, and aluminum hydroxide three times daily with omeprazole 40 mg once daily for 6 weeks does not reduce overall symptom scores, based on the Reflux Symptoms Index (RSI) score, when compared with omeprazole alone. However, it does increase the probability of treatment response, defined as a 50% or greater improvement in RSI score, by nearly 40% (109648). This product is available in Italy. It is unclear if these findings are due to chondroitin sulfate, other ingredients, or the combination.
• Gastritis. Oral chondroitin sulfate has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in patients with gastritis shows that taking a specific liquid product (Esoxx, Alfa Wasserman Spa) containing chondroitin sulfate and hyaluronic acid four times daily for 4 weeks modestly reduces upper abdominal pain when compared with placebo (99687). It is not clear if this effect is due to chondroitin sulfate, hyaluronic acid, or the combination.
• Hyperlipidemia. Although there is interest in using oral chondroitin for hyperlipidemia, there is insufficient reliable information about the clinical effects of chondroitin for this condition.
• Interstitial cystitis. Small clinical studies suggest that intravesical chondroitin sulfate may not improve interstitial cystitis symptoms. Oral chondroitin sulfate has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Several uncontrolled, open-label studies suggest that intravesical chondroitin sulfate, with or without hyaluronic acid, improves clinical symptoms of interstitial cystitis and reduces the problems caused by symptoms in these patients (42338,42371,42373,42385,42387). However, in controlled clinical trials, intravesical chondroitin sulfate 2%, instilled weekly for 6-7 weeks, does not significantly improve symptoms when compared with a placebo solution (42473,42517). Furthermore, a meta-analysis of clinical research shows that intravesical chondroitin sulfate with hyaluronic acid does not improve pain due to interstitial cystitis better than using hyaluronic acid solution alone (97054). Oral chondroitin has been evaluated in combination with other ingredients. Preliminary clinical research shows that taking a specific product (CystoProtek, Tischon Corporation) containing glucosamine sulfate 120 mg, sodium hyaluronate 10 mg, chondroitin sulfate 150 mg, quercetin 150 mg, and rutin 20 mg, as two capsules twice daily for 12 months, reduces symptoms of interstitial cystitis by 44% to 52% (42391). It is not clear if this effect is due to chondroitin, other ingredients, or the combination.
• Kashin-Beck disease. It is unclear if oral chondroitin sulfate improves Kashin-Beck disease symptoms such as pain. Details: A small clinical study in Chinese adults with Kashin-Beck disease shows that taking chondroitin sulfate 600 mg twice daily with or without glucosamine hydrochloride 480 mg three times daily for 6 months decreases pain and stiffness when compared with placebo (42516).
• Osteoporosis. Although there is interest in using oral chondroitin for osteoporosis, there is insufficient reliable information about the clinical effects of chondroitin for this condition.
• Overall mortality. Oral chondroitin has only been evaluated in combination with glucosamine; its effect when used alone is unclear. Details: A cross-sectional observational study suggests that using oral chondroitin and glucosamine for at least one year is associated with a 27% lower incidence of overall mortality and 58% lower incidence of cardiovascular mortality when compared with not using these supplements (104445). However, this study did not clarify the forms of chondroitin and glucosamine used, or the doses, frequencies, or durations of use. Furthermore, the adults that reported glucosamine and chondroitin use also reported overall healthier lifestyle habits than those that were not taking glucosamine and chondroitin. Another observational study suggests that regular use of chondroitin with glucosamine for an average of 8 years is associated with a 30% lower risk of mortality when compared with no use. However, when these findings are adjusted for differences in age, body mass index, and comorbidities, overall mortality risk does not seem to be reduced with chondroitin and glucosamine supplementation (110626). Higher quality, prospective research is needed to clarify the relationship, if any, with overall mortality. Additionally, it is unclear if the effects on mortality are due to chondroitin, glucosamine, or the combination.
• Psoriasis. It is unclear if oral chondroitin sulfate is beneficial for reducing psoriasis disease severity. Details: A clinical study in patients with plaque psoriasis and knee osteoarthritis shows that taking chondroitin sulfate (Condrosan, CS Bio-Active, Bioibérica S.A.) 800 mg daily for 3 months does not appear to reduce the extent or severity of plaque psoriasis when compared with placebo (42463).
• Stroke. It is unclear if oral chondroitin sulfate is beneficial for reducing stroke risk. Details: An observational study in Spanish patients found that chondroitin sulfate use is associated with 23% lower odds of ischemic stroke when compared with non-use; however, the benefit was only observed in patients taking at least 800 mg for no more than one year (109643).
• Temporomandibular disorders (TMD). Oral and topical chondroitin sulfate has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A meta-analysis of two small clinical studies in patients with TMD shows that taking chondroitin sulfate 1200 mg and glucosamine sulfate 1500 mg daily for 2 months does not reduce pain or increase maximum mouth opening when compared with tramadol 50-100 mg daily (109647). Another small clinical trial in children aged 10-13 years with class II malocclusion shows that application of a specific combination gel product containing glucosamine, chondroitin, and essential oils (Jointace Gel, Vitabiotics) with an expander device twice daily for 3 months does not improve pain, tension, or temporomandibular space measures when compared with placebo (110629).
• Urinary incontinence. Although there is interest in using intravesical chondroitin for urinary incontinence, there is insufficient reliable information about the clinical effects of chondroitin for this condition.
• Urinary tract infections (UTIs). It is unclear if intravesical administration of chondroitin sulfate alone is beneficial in patients with recurrent UTIs. Most research has evaluated the effects of chondroitin sulfate in combination with hyaluronic acid, with promising results. Details: One small observational study in patients with recurrent UTIs has found that intravesical administration of 40 mL of chondroitin sulfate 0.2% weekly for 6 weeks, then every 2 weeks for 2 months, then every 3 weeks for 2 months, and finally every 6 weeks for a total treatment duration of 1 year is associated with a lower number of UTIs and urologist visits when compared with low-dose long-term antibiotic therapy (109649). Most research on the use of chondroitin sulfate for UTIs has evaluated its effects when used in combination with hyaluronic acid. Several small clinical studies and a pooled analysis of the available clinical research show that intravesical administration of 50 mL of specific solutions containing chondroitin sulfate 2% and hyaluronic acid 1.6% (iAluRil, IBSA Farmaceutici; Cystistat, Bioniche) for up to 6 months reduces the rate of UTI recurrence by about 2-3 incidents per year and delays the time to the first UTI recurrence when compared with placebo or prophylaxis with sulfamethoxazole-trimethoprim (42511,42519,89590,89594,99688). However, the validity of these findings is limited by the low quality and high heterogeneity of the included studies, as well as concerns for publication bias (99688). More evidence is needed to rate chondroitin sulfate for these uses.

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POSSIBLY EFFECTIVE

• Osteoarthritis. Oral collagen type II seems to improve stiffness, pain, and function by a small amount in patients with knee osteoarthritis, but any benefit on joint space narrowing is unclear. Details: Clinical research in patients with knee osteoarthritis shows that taking a specific collagen type II (UC-II, InterHealth Nutraceuticals, Inc.) 40 mg daily for up to 6 months reduces symptoms, such as stiffness, pain, and physical functioning, by about 20% when compared with baseline (97238,97239). Taking this product might also improve some symptoms, such as pain and stiffness, when compared with glucosamine 1500 mg plus chondroitin 1200 mg (97239). A small clinical study in patients with knee osteoarthritis and type 2 diabetes shows that taking a specific collagen type II (UC II, SEMNL Biotechnology) 40 mg daily for 3 months improves pain by 36%, compared with 5% in those receiving placebo (107466). It is unclear if taking collagen type II is more beneficial than exercise. A small clinical study in females with knee osteoarthritis shows that taking a specific collagen type II (Motilex Caps, Aspen Pharmaceutics) at an unknown dose daily for 6 weeks may improve physical functioning and pain but does not improve range of motion when compared with usual care. However, physical functioning, rigidity, and pain were not improved when compared with twice-weekly standardized exercise (110734). Collagen type II is also studied in combination with other ingredients. A small clinical study shows that taking a specific combination product (AR7 Joint Complex, Robinson Pharma) containing collagen type II, methylsulfonylmethane (MSM), cetyl myristoleate, lipase, vitamin C, turmeric, and bromelain orally for 12 weeks reduces symptoms, with 43% and 46% of patients reporting joint pain and stiffness, respectively, compared with 71% and 71% in those receiving placebo. However, the combination product does not appear to improve joint space narrowing (19314).

POSSIBLY INEFFECTIVE

• Rheumatoid arthritis (RA). Despite some conflicting results, oral collagen type II does not seem to improve symptoms of RA when compared with standard treatments. Details: Three moderately large clinical studies in patients with RA, some of whom were using disease modifying antirheumatic drugs (DMARDs), show that taking chicken collagen type II 100-2500 mcg daily or bovine collagen type II 100-500 mcg daily for 6 months does not improve clinical response rates based on American College of Rheumatology (ACR) criteria when compared with placebo (3111,44446,101718). Other clinical research in patients stabilized on oral methotrexate shows that switching to chicken collagen type II 500 mcg orally daily actually increases disease activity when compared with continued treatment with methotrexate (44456). While some clinical research in patients not taking DMARDs shows that taking chicken collagen type II 100 mcg daily may reduce symptoms, the response rates based on ACR20 and ACR50 criteria are greater for patients treated with methotrexate 10 mg weekly when compared with chicken collagen type II (44451,101717). One clinical study shows that taking low dose chicken collagen type II 20 mcg daily for 24 weeks improves clinical response according to the Paulus criteria, but not according to the ACR criteria, when compared with placebo. Other preliminary research in patients who discontinued treatment with immunosuppressants and DMARDs shows that taking chicken collagen type II 100 mcg orally daily for 1 month, followed by 500 mcg daily for 2 months, improves symptoms in some patients when compared with placebo (44454).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Back pain. Although there has been interest in using oral collagen type II for back pain, there is insufficient reliable information about the clinical effects of collagen type II for this condition.
• Gout. Although there has been interest in using oral collagen type II for gout, there is insufficient reliable information about the clinical effects of collagen type II for this condition.
• Joint pain. Oral collagen type II may modestly reduce joint pain. Details: A small clinical study in patients with joint pain due to exercise shows that taking a specific collagen type II product (UC-II, InterHealth Nutraceuticals, Inc.) 40 mg daily for 4 months may increase the duration of pain-free exercise by about 1.5 minutes when compared with baseline (101744). Another small clinical study in patients with non-arthritic knee pain shows that taking a specific chicken-derived collagen type II product (NEXT-II, Ryusendo Co.) 3.2 mg daily for 12 weeks modestly improves knee pain, stiffness, and function when compared with placebo (110733). However, it is unclear whether these results apply to patients with overweight or obesity since they were excluded from this study.
• Juvenile idiopathic arthritis (JIA). It is unclear if oral collagen type II is beneficial for JIA. Details: Some small clinical studies show that taking chicken collagen type II may improve symptoms such as swollen and tender joint scores when compared with baseline in some patients. However, the lack of a control group in these studies limits the reliability of these results (3112,101719).
• Neck pain. Although there has been interest in using oral collagen type II for neck pain, there is insufficient reliable information about the clinical effects of collagen type II for this condition.
• Pain (acute). Although there has been interest in using oral collagen type II for acute pain after trauma, there is insufficient reliable information about the clinical effects of collagen type II for this condition.
• Postoperative pain. Although there has been interest in using oral collagen type II for joint pain after surgery, there is insufficient reliable information about the clinical effects of collagen type II for this condition.
• Range of motion. It is unclear if oral collagen type II improves range of motion; study results are in conflict. Details: Small clinical studies in healthy people with joint pain due to exercise who took a specific collagen type II product (UC-II, InterHealth Nutraceuticals, Inc.) have conflicting results (101744,110732). In one study, taking 40 mg daily for 4 months increases knee extension by about 6 degrees when compared with placebo, but does not improve knee flexion (101744). However, the other study shows that taking 40 mg daily for 6 months does not improve knee extension but increases knee flexion by about 3 degrees when compared with placebo (110732). Results are similar in a small clinical study in patients with non-arthritic knee pain. In this study, taking a specific chicken-derived collagen type II product (NEXT-II, Ryusendo Co.) 3.2 mg daily for 12 weeks does not improve knee extension but increases knee flexion by about 5 degrees when compared with placebo (110733).
• Urticaria. Although there has been interest in using oral collagen type II for urticaria associated with stress, there is insufficient reliable information about the clinical effects of collagen type II for this condition.
• Uveitis. It is unclear if oral collagen type II is beneficial for uveitis. Details: Preliminary clinical research in children with uveitis associated with juvenile idiopathic arthritis shows that taking collagen type II (Colloral, AutoImmune Inc.) 60 or 540 mcg daily for 6 months does not improve ophthalmic outcomes when compared with baseline (101719). More evidence is needed to rate collagen type II for these uses.

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POSSIBLY INEFFECTIVE

• Chronic fatigue syndrome (CFS). Daily injections of a combination of folic acid, bovine liver extract, and cyanocobalamin for 3 weeks appear to have no effect on CFS symptoms (7561).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Hepatitis C. Preliminary clinical research suggests that intravenous treatment with liver extract plus flavin adenine dinucleotide improves response to interferon-beta therapy in patients with hepatitis C (59952). Also, giving a specific combination of liver extract and flavin adenine dinucleotide (Adelavin) intravenously or intramuscularly appears to improve hepatitis C virus RNA levels in patients with hepatitis C who are being treated with interferon-alpha compared with those being treated with interferon-alpha alone. Researchers have attributed this effect to enhancement of 2'5'-oligoadenylate synthetase production (59964). More evidence is needed to rate liver extract for these uses.

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POSSIBLY EFFECTIVE

• Cerebrovascular disease. Preliminary clinical research in small groups of patients with cerebrovascular disease shows that taking mesoglycan 96-100 mg daily orally for 6 months seems to reduce ischemic events, improve quality of life, and provide subjective improvement when compared with baseline (6635,6637,6639). The validity of this finding is limited by the lack of a comparator group. There is also some preliminary evidence that mesoglycan might be comparable to standard antiplatelet drug therapy (6639).
• Peripheral arterial disease (PAD). The majority of preliminary clinical research shows that mesoglycan improves walking distance in patients with PAD, although it may not be as effective as other therapies. Alternating intravenous and oral mesoglycan seems to improve walking distance when compared with baseline in patients with intermittent claudication due to PAD (6629). Also, injecting mesoglycan 30 mg intramuscularly for 3 weeks then taking oral mesoglycan 100 mg daily for 20 weeks appears to improve clinical response and walking distance in patients with PAD when compared with placebo (31635). Taking mesoglycan 100 mg daily orally for a total of 120 days increases walking distance by approximately 39% when compared with baseline (97779). However, taking oral mesoglycan 48 mg daily for 6 months is less effective at improving pain-free walking distance and total walking distance than oral defibrotide 800 mg daily in patients with intermittent claudication due to PAD (31647).
• Venous insufficiency. There is some evidence from uncontrolled trials that administering mesoglycan orally or parenterally may improve the subjective and objective symptoms associated with various venous conditions, including varicose syndromes, post-phlebitic syndromes, and thrombophlebitis, when used over a 1-3 month period (6630,6638,6644,6645). Some research also shows that applying mesoglycan topically might be beneficial for treating leg ulcers in patients with chronic venous insufficiency (6627).
• Venous leg ulcers. Clinical research shows that administering a combination of intramuscular and oral mesoglycan as an adjunct to traditional chronic venous stasis ulcer therapy improves the rate of healing when compared with traditional therapy alone. At least 75% of patients taking mesoglycan were fully healed approximately 46 days earlier than patients taking traditional therapy alone (11479).

POSSIBLY INEFFECTIVE

• Venous thromboembolism (VTE). Clinical research shows that taking oral mesoglycan plus compression stockings following standard deep venous thrombosis (DVT) therapy is no better than placebo for preventing recurrent DVT and/or pulmonary embolism during a follow-up period ranging from 5 to 48 months (6640).
• Stroke. Clinical research in patients with acute ischemic stroke shows that adding intramuscular mesoglycan for 5 days, followed by 25 days of oral mesoglycan, to intravenous dexamethasone therapy is no more effective than dexamethasone alone (6641).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Atherosclerosis. Preliminary clinical research shows that taking oral mesoglycan 200 mg daily for 18 months might slow the progression of atherosclerosis by decreasing the rate of carotid and femoral artery intima-media thickening (6628,31649).
• Chronic venous insufficiency (CVI). Preliminary clinical research in adults with unilateral lower limb edema due to CVI shows that taking mesoglycan 100 mg daily for one month reduces pain and swelling by approximately 43% and 63%, respectively, when compared with placebo (97778).
• Cutaneous necrotizing venulitis. Preliminary clinical research shows that intramuscular mesoglycan 10 mg/kg daily for 20 days might be useful for treating cutaneous necrotizing venulitis in patients with reduced fibrinolytic activity (6634).
• Diabetic retinopathy. Preliminary clinical research in adults with diabetic retinopathy shows that taking mesoglycan 100 mg daily for 6 months reduces the occurrence of microhemorrhages, microaneurysms, and exudates, compared with no change in those taking placebo (97777).
• Hypertension. Preliminary clinical research shows that taking mesoglycan 100 mg daily orally for a total of 120 days reduces systolic blood pressure by 5 mmHg when compared to baseline in patients with hypertension (97779). The validity of this finding is limited by the lack of a comparator group.
• Hypertriglyceridemia. Preliminary clinical research in a small group of patients shows that taking mesoglycan 96 mg daily reduces total triglyceride and very low density lipoprotein (VLDL) levels when compared to baseline in patients with hypertriglyceridemia (6646).The validity of this finding is limited by the lack of a comparator group.
• Metabolic syndrome. Preliminary clinical research in a small group of patients with metabolic syndrome shows that taking mesoglycan 50 mg twice daily for 90 days improves vascular function, as measured by brachial flow-mediated dilation and arterial stiffness, when compared with placebo (103265).
• Postoperative pain. Preliminary, prospective clinical research in a small group of patients undergoing open excisional diathermy hemorrhoidectomy shows that intramuscular mesoglycan (Prisma, Mediolanum Farmaceutici) 60 mg daily for 5 days postoperatively, then 50 mg orally twice daily for 30 days, reduces pain after rectal examination, but not spontaneous pain or pain after defecation, and shortens the time to full resumption of normal daily activities, when compared with ketorolac 10 mg orally every 4-6 hours for 5 days (103263). A retrospective, observational study in a larger group of patients undergoing the same surgery shows that giving the same mesoglycan regimen in conjunction with the ketorolac regimen reduces pain on postoperative day 1 and after 1, 3, and 6 weeks of follow-up when compared with the ketorolac regimen alone. The addition of mesoglycan also reduces the incidence of postoperative rectal thromboses and the time to recovery of normal activities, but does not reduce postoperative bleeding or time to wound healing, when compared with ketorolac alone (109651).
• Tinnitus. Observational research in patients with tinnitus has found that taking mesoglycan 50 mg daily for 90 days is associated with an improvement in tinnitus when compared to baseline (103264). The validity of this finding is limited by the lack of a comparator group .
• Vertigo. Observational research in patients with vertigo has found that taking mesoglycan 50 mg daily for 90 days is associated with an improvement in vertigo symptoms when compared to baseline (103264). The validity of this finding is limited by the lack of a comparator group. More evidence is needed to rate mesoglycan for these uses.

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LIKELY SAFE ...when used orally and appropriately. Chondroitin sulfate has been used safely in doses of up to 2000 mg daily for up to 6 years (1955,2533,13579,17732,22212,42339,42343,42348,42389,42396)(42398,42463,42477,42513,42520,42536,42541,89516,89558,89592)(89596,94360,94381,95788,95792). However, since chondroitin is often derived from bovine cartilage, historically, there was concern about contamination with diseased animal parts (1825). So far, there are no reports of disease transmission to humans due to use of contaminated chondroitin preparations. ...when used topically and appropriately as an ophthalmic viscosurgical device (OVD). Various products containing chondroitin sulfate and sodium hyaluronate have been granted approval by the US Food and Drug Administration (FDA) for use as an adjunct to cataract surgery (89436,89437).

POSSIBLY SAFE ...when used intramuscularly (10149,42397). ...when used topically as eye drops, short-term. Eye drops containing chondroitin sulfate with xanthan gum or glucosamine have been used with apparent safety four times daily for up to 3 months (89591,104443). ...when administered intravesically under the supervision of a physician (42338,42371,42373,42385,42387,42473,42511,42517,42519,109649).

PREGNANCY AND LACTATION:
Insufficient reliable information available; avoid using.

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POSSIBLY SAFE ...when used orally in doses up to 40 mg daily for up to 24 weeks (3111,44446,97238,97239,101717,101718,101744,110732).

PREGNANCY AND LACTATION:
Insufficient reliable information available; avoid using.

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There is insufficient reliable information available about the safety of liver extract. However, since some preparations are derived from animals, there is concern about contamination with diseased animal parts (1825). So far, there are no reports of disease transmission to humans due to use of contaminated liver extract.

PREGNANCY AND LACTATION:
Insufficient reliable information available; avoid using.

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POSSIBLY SAFE ...when used orally and appropriately. Mesoglycan has been used safely at doses of up to 200 mg daily for up to 18 months (6635,6637,6638,6639,6644,6645,11479,31647,31649,97777)(97778,97779,103263,103264,103265). ...when used intramuscularly under the supervision of a healthcare provider. Mesoglycan has been used with apparent safety at doses of 60 mg daily for up to 5 days and doses up to 30 mg daily for up to 3 weeks (6630,11479,103263). Since mesoglycan products are derived from animals, there are concerns about contamination with diseased animal parts (1825). However, there are no reports of disease transmission to humans due to use of contaminated mesoglycan. There is insufficient reliable information available about the safety of mesoglycan when used topically or intravenously.

PREGNANCY AND LACTATION:
Insufficient reliable information available; avoid using.

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WARFARIN (Coumadin) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Unlikely •  Level of Evidence = D Taking chondroitin in combination with glucosamine might increase the anticoagulant effects of warfarin. However, the effect of chondroitin alone is unclear.  Details There have been multiple reports of increased international normalized ratio (INR) in patients taking warfarin with glucosamine, with or without chondroitin. The lack of reports with chondroitin alone seem to suggest that the interactions occurring in these reports may have been due to glucosamine. In two individual case reports, glucosamine/chondroitin combinations were associated with a significant increase in INR in patients previously stabilized on warfarin (11389,16130). Additionally, 20 voluntary case reports to the US Food & Drug Administration (FDA) have linked glucosamine plus chondroitin with increased INR, bruising, and bleeding in patients who were also taking warfarin (16130). There have also been 20 additional case reports to the World Health Organization (WHO) that link glucosamine alone, without chondroitin, to increased INR in patients taking warfarin (16131).

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General ...Orally and topically, chondroitin sulfate is generally well tolerated. Intramuscular and ophthalmic use also seems to be well tolerated.
Most Common Adverse Effects:
Orally: Abdominal pain, bloating, constipation, diarrhea, heartburn, nausea.
Serious Adverse Effects (Rare):
Orally: There have been rare reports of hepatotoxicity.

Cardiovascular ...One case of congestive heart failure and another case of myocardial infarction has been possibly attributed to use of glucosamine hydrochloride and chondroitin sulfate (13579,42477). Also, a case of mesenteric occlusion in one patient was considered possibly related to treatment with chondroitin sulfate and glucosamine (89520).

Dermatologic ...Orally, chondroitin sulfate has been associated with skin symptoms, such as eyelid edema, lower limb edema, alopecia, and skin rash (42513). Combinations of chondroitin sulfate along with glucosamine hydrochloride may also be associated with rash, water retention around eyes and scars, and hives on face, chest, torso, and legs when taken orally (42436,110628). A case of photosensitization that was reproducible with rechallenge has been reported following treatment with oral glucosamine-chondroitin products. However, it is not clear if this effect was due to glucosamine, chondroitin sulfate, or contaminants in the product (10408). A case of rash following treatment with intravesical chondroitin sulfate has been reported to be possibly related to the product (42385).

Gastrointestinal ...Orally, chondroitin might cause nausea, bloating, abdominal pain, diarrhea, constipation, vomiting, dyspepsia, and epigastric burning (42396,42436,42541,89561,110628,111647).

Genitourinary ...Intravesical chondroitin sulfate has been associated with cases of vulvar burning, vaginitis, urinary tract infection (UTI), dysuria, pelvic pain, and other bladder symptoms, such as increased frequency, urgency, or incontinence. However, these effects might be due to catheterization rather than chondroitin sulfate (42385,42387,42473).

Hematologic ...Concern has been expressed about possible anticoagulant activity of oral chondroitin sulfate. However, hematological changes have not occurred in patients taking chondroitin sulfate in clinical trials (760).

Hepatic ...Although relatively uncommon, combinations of glucosamine and chondroitin sulfate have been associated with acute liver injury that mimics autoimmune hepatitis. Two cases of elevated aminotransferase levels have been reported for patients taking glucosamine (form unspecified) and chondroitin sulfate at recommended doses. Aminotransferase levels, which were increased by four- to seven-fold, returned to normal following discontinuation of treatment (89515). Another case of abdominal pain, jaundice, fatigue, and elevated liver enzymes has been reported for a patient who used chondroitin sulfate (Condrosulf) for 2 years followed by a combination of glucosamine sulfate and chondroitin sulfate (Vita Mobility Complex) for 8 weeks. The patient required maintenance treatment with azathioprine to remain in remission (89518). A case of acute cholestatic hepatitis due to Glucosamine Forte, which contains glucosamine hydrochloride, chondroitin sulfate, Devil's claw, and shark cartilage, has been reported (89522). It is unclear whether these adverse events were related to chondroitin sulfate, other ingredients, or the combination.

Musculoskeletal ...Orally, chondroitin has been associated with musculoskeletal and connective-tissue events and disorders (13579,42520,95516).

Neurologic/CNS ...Rare cases of headache have been reported following treatment with products containing a combination of oral chondroitin sulfate and glucosamine hydrochloride or glucosamine sulfate (42436,89561). It is unclear if this effect was due to chondroitin, glucosamine, or the combination.
Patients should adhere to product directions when using chondroitin sulfate products that contain manganese. When taken at doses slightly higher than the recommended dose, these products can sometimes supply greater than the tolerable upper limit (UL) for manganese of 11 mg per day. Ingestion of more than 11 mg per day of manganese might cause significant central nervous system toxicity (7135).

Ocular/Otic ...A case of bilateral pinna chondritis (inflammation of the cartilage of the external ear) has been reported for a patient who received supplements containing glucosamine and chondroitin sulfate (42503).

Pulmonary/Respiratory ...A case of asthma exacerbation has been reported occurred following use of an oral glucosamine and chondroitin sulfate combination product (10002).

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General ...Orally, collagen type II seems to be well tolerated.
Most Common Adverse Effects:
Orally: Abdominal pain, constipation, nausea, and vomiting.

Cardiovascular ...Orally, one incident of mild hypertension was reported as being possibly related to collagen type II in a clinical trial of children (101719).

Dermatologic ...Orally, collagen type II might cause itching. In two cases, the itching was associated with skin eruption (44451,101717,101719).

Gastrointestinal ...Orally, the most common adverse effects of collagen type II reported in clinical studies are gastrointestinal and include constipation, nausea, vomiting, and abdominal pain. These occurred in up to 7% of patients taking collagen type II (44451,97238,97239,101717,101719). Anorexia was also reported, but this was much less common (44451).

Hematologic ...Orally, one incident each of blood in urine and a decrease in white blood cell count were reported for patients taking collagen type II in clinical research (101717).

Hepatic ...Orally, liver function abnormalities, including elevated transaminase levels, have been reported in some clinical research, but this is uncommon (3111,44451,101717).

Neurologic/CNS ...Orally, headache, dizziness, and insomnia have been reported for patients taking collagen type II in clinical studies, but these events are uncommon (44451,97238,97239,101717).

Renal ...Orally, one case of mild proteinuria was reported as being possibly related to use of collagen type II in a clinical trial of children (101719).

Other ...Orally, edema occurred in two patients taking collagen type II in clinical research (101717).

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General ...No adverse reactions have been reported. However, a thorough evaluation of safety outcomes has not been conducted, There is some concern about the possibility of contamination as liver extract is derived from raw animal liver gathered from slaughterhouses, possibly from sick or diseased animals (6616). There is also concern that liver extracts produced from cows in countries where bovine spongiform encephalitis (BSE) has been reported might be contaminated with diseased tissue (1825).

Immunologic ...There is concern that liver extracts produced from cows in countries where bovine spongiform encephalitis (BSE) has been reported might be contaminated with diseased tissue. Countries where BSE has been reported include Great Britain, France, The Netherlands, Portugal, Luxembourg, Ireland, Switzerland, Oman, and Belgium (1825). However, there have been no reports of BSE transfer to humans from contaminated liver extract products. Until more is known, tell patients to avoid these products unless the country of origin can be determined. Patients should avoid products that are produced in countries where BSE has been found.

Other ...There is some concern about the possibility of contamination of liver extract. Liver extract is derived from raw animal liver gathered from slaughterhouses, possibly from sick or diseased animals (6616). Products made from contaminated or diseased organs might present a human health hazard.

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General ...Orally, mesoglycan seems to be well tolerated. Some adverse effects reported in clinical studies include nausea, vomiting, epigastric pain, dyspepsia, heartburn, headache, diarrhea, and local cutaneous reactions (6629,97778,97779,103265).
However, there is some concern about potential contamination. Mesoglycan is derived from raw animal tissues gathered from slaughterhouses, possibly from sick or diseased animals (6620). Products made from contaminated or diseased organs might present a human health hazard. There is also concern that mesoglycan produced from cows in countries where bovine spongiform encephalitis (BSE) has been reported might be unsafe (1825). However, there are no reports of disease transfer to humans from contaminated mesoglycan.

Dermatologic ...Orally, mesoglycan has been reported to cause local cutaneous reactions (6629,97778).
Subcutaneously, injections of mesoglycan into the scalp were thought to result in edema, redness, and local hair loss in a 32-year-old female (97780).

Gastrointestinal ...Orally, mesoglycan has been reported to cause nausea, vomiting, epigastric pain, dyspepsia, heartburn, and diarrhea (6629,97779,103265).

Neurologic/CNS ...Orally, mesoglycan has been reported to cause headache (6629).

Other ...Mesoglycan is derived from raw animal tissues gathered from slaughterhouses, possibly from sick or diseased animals (6620). Products made from contaminated or diseased organs might present a human health hazard. However, there are no reports of disease transfer to humans from contaminated mesoglycan.
There is also some concern that mesoglycan that is obtained from cows in countries where bovine spongiform encephalopathy (BSE) has been reported might be unsafe. However, there are no reports of BSE transfer to humans from contaminated mesoglycan (1825).

(Read more about MESOGLYCAN)