Deflect AB by D'Adamo Personalized Nutrition

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

• Urinary tract infections (UTIs). Cranberry products may possibly reduce the risk of repeat, symptomatic UTI in females with recurrent UTI, in children, and in people susceptible to UTI following kidney transplant, urogenital surgery, or radiation therapy near the urogenital system. While some positive evidence exists, most research suggests that cranberry products do not seem to reduce the risk of UTI in older adults in institutions, pregnant patients, or adults with neuromuscular dysfunction of the bladder. Cranberry is not recommended for the treatment of UTI in any population. Details: Cranberry appears to reduce the risk of UTI in some populations but not others. In healthy females at an increased risk of UTI or history of recurrent UTI, meta-analyses of clinical trials show that cranberry products decrease the overall risk of recurrent or first-time UTI by 26% to 35% (46473,92578,96739,111407). In 2019, the American Urological Association published guidelines stating that, based on low certainty evidence, clinicians may offer cranberry tablets or juice as prophylaxis for females with recurrent UTIs. Due to a lack of compelling evidence for any specific product, the guidelines recommend choosing formulations based on availability and tolerability (100855). In 2020, the US Food and Drug Administration (FDA) approved qualified health claims stating that consuming cranberry juice in doses of at least 8 ounces daily, or cranberry supplements in doses of at least 500 mg daily, may help reduce the risk of recurrent UTI in healthy females. However, the FDA has concluded that there is limited scientific evidence to support these claims (103302). The benefits of cranberry for prevention of UTI during pregnancy are unclear. Subgroup analysis of meta-analyses suggest that cranberry supplementation does not reduce the risk of UTI in pregnant adults compared with placebo or no treatment (100855,111407). A preliminary clinical study shows that drinking cranberry juice 240 mL three times daily until delivery does not reduce the frequency of asymptomatic bacteriuria or symptomatic UTI during pregnancy, although the study was not adequately powered to detect a difference in these outcomes (16415). In contrast, one preliminary clinical trial shows that UTI frequency was reduced in 70.5% of those ingesting cranberry juice 250 mL four times daily, compared with only 32% of those taking placebo (93670). In children, a meta-analysis shows that taking cranberry products probably reduces the risk of subsequent symptomatic UTIs by up to 54% compared with placebo or no treatment, but does not specify a particular formulation (111407). Clinical trials show that daily consumption of cranberry syrup (Pharmatoka), cranberry juice (Cranberry UR-50, Kikkoman Company) 100 mL, cranberry-lingonberry juice 50 mL, and cranberry extract (Anthocran) 120 mg reduce the risk of UTI recurrence in children (46452,96733,96737,108055). In contrast, another clinical trial shows that drinking cranberry juice (Ocean Spray Cranberries, Inc) 5 mL/kg daily for 6 months does not reduce the incidence of recurrent UTI when compared with placebo, although it does decrease the total number of UTI episodes and length of antimicrobial therapy per child (46470). In older, institutionalized adults, a meta-analysis of 5 studies evaluating the effectiveness of cranberry products shows little or no benefit in preventing symptomatic, culture-verified UTIs (111407). A clinical study in females residing in long-term care (LTC) facilities shows that taking a specific cranberry supplement (Ellura, Pharmatoka) once daily for 1 year does not reduce the incidence of UTI or asymptomatic bacteriuria (92517). However, clinical trials of cranberry products in elderly patients in LTC facilities suggest that cranberry may be more effective in patients at a higher risk for UTIs, such as those with diabetes, long-term catheterization, or recurrent UTIs (90041,108055), and in patients with E. coli-related UTIs (46389,46472). In one small study, providing all patients living in a LTC facility with 4 ounces of cranberry juice or six tablets of a specific concentrated cranberry product (Azo-Cranberry, i-Health, Inc.) daily for 13 months decreased the facility's overall monthly UTI rate from 27.7 to 20.7 (46492). In another clinical trial, taking cranberry juice cocktail (Ocean Spray Cranberries, Inc) 300 mL daily for 6 months decreased the rate of asymptomatic bacteriuria plus pyuria by 13% in older females living in institutional settings (7008). In another clinical trial, taking a cranberry capsule 500 mg, standardized to 1.8% PACs, twice daily for 12 months decreased the risk of UTI by around 26% in patients at high-risk for UTI, including those with catheters, diabetes, or at least one UTI in the previous 12 months (90041). Meta-analyses and clinical research show that cranberry products do not reduce the risk of UTI associated with neurogenic bladder, neuromuscular dysfunction, or insufficient bladder emptying in adults or children (2811,6759,11980,46379,46425,46473,90044,92578,96737,108055,111407). However, one study found benefit in patients with neurogenic bladder due to spinal cord injury taking cranberry capsules (Cran-Max, Proprietary Nutritionals, Inc.) 500 mg daily (46443). Cranberry products have also been evaluated in a variety of other high-risk populations, with mixed results. A meta-analysis of 7 studies shows that cranberry products reduce the risk of UTIs in people with increased susceptibility to UTI due to an intervention (e.g., kidney transplant, radiotherapy to urogenital system, or urogenital surgery) when compared with placebo (111407). Cranberry extracts do not seem to reduce the risk of UTIs in individuals undergoing hysterectomy and/or anterior vaginal repair (46465), pelvic floor surgery (104245), or in patients with multiple sclerosis (46496,111407). Taking cranberry powder capsules (NurtiCran90, Petefa AB) 550 mg three times daily for 5 days does not reduce the UTI rate at days 5 or 14 when compared with placebo in postoperative females with hip fracture receiving a urinary catheter; however, the study was not adequately powered to detect a difference in this outcome (96734). Other preliminary clinical research in elderly males with benign prostatic hyperplasia and a recent UTI shows that taking a standardized cranberry extract (Anthocran) 120 mg daily for 60 days reduces the UTI recurrence rate by about 62% when compared with placebo (96735). Cranberry supplements have been studied in a variety of formulations, but it is unclear whether certain cranberry formulations are better than others (111407). Most positive studies utilized oral cranberry EXTRACTS in tablet, powder, or capsule form (6760,17210,46366,46432,93669,111407). Some products (Cranberry Supreme, GNC; Cranpac, IPCA Laboratories), taken as 200 mg twice daily, were standardized to provide 100-120 mg of proanthocyanidins (PACs) daily (46432). Some of these studies used capsules containing 400 mg cranberry solids twice daily (6760) or Natural Cranberry Extract (Solgar Vitamin and Herb Co.) 800 mg twice daily (17210). However, a clinical study in healthy females with a history of UTIs shows that taking a specific cranberry extract product (Urophenol; Diana Food) does not reduce the risk of symptomatic UTI when taken at a dose of 120 mg twice daily, standardized to 15% PACs, or at a dose of 1 mg twice daily, standardized to 1% PACs. A subgroup analysis suggests that the high dose may have modest benefit in those with less than 5 UTIs a year (108054). Cranberry JUICE or syrup has yielded mixed results for the prevention of UTI in patients with a history of recurrent UTIs, with some showing significant benefit (8253,46366,96736,111407). These studies used cranberry juice 240-250 mL 1-3 times daily (46366,96736), cranberry syrup, or a combination beverage containing cranberry juice plus lingonberry juice (Maija) 50 mL daily (8253). However, other studies found no significant improvement when compared with placebo (17524,46471,90047), although some of these studies may have been inadequately powered to detect a difference (17524,46471). Cranberry products have also been compared with other treatments including antibiotics and probiotics for preventing recurrent UTI, but the results are unclear. A meta-analysis suggests that cranberry products reduce the risk of symptomatic UTIs compared to probiotics. The analysis also showed no difference in the risk of UTI between cranberry products and antibiotics, but the precision of included studies was poor (111407). In one study, taking cranberry extract capsules (Cran-Max; Proprietary Nutritionals, Inc) 500 mg daily for 6 months was as effective as trimethoprim 100 mg daily in elderly females with recurrent UTI (16720). However, taking this same cranberry product twice daily for 12 months was less effective than trimethoprim-sulfamethoxazole 480 mg once daily in younger premenopausal individuals (17176). Additional research in children with vesicoureteral reflux (VUR) shows that daily consumption of cranberry products results in UTI recurrence rates equivalent to those obtained with prophylactic antibiotics. Cranberry juice (Cranberry UR-50, Kikkoman Company) 100 mL daily was equally effective to cefaclor 5-10 mg/kg daily; cranberry syrup (Pharmatoka) 0.2 mL/kg daily was equally effective to trimethoprim 0.2 mL/kg daily (96737).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Age-related cognitive decline. It is unclear if oral cranberry is beneficial for age-related cognitive decline. Oral cranberry may be beneficial for improving visual episodic memory in healthy, elderly adults, but its effects on other aspects of cognition are unclear. Details: A clinical study in healthy adults aged 50-80 years shows that taking a freeze-dried cranberry powder 4.5 grams twice daily (standardized to provide 281 mg proanthocyanidins daily), provided as a sachet and added to food or beverage for 12 weeks, improves visual episodic memory performance during a memory and recall test (Rey Complex Figure Test), but does not appear to affect other measures such as attention, orientation, fluency, language, processing speed, or short-term memory, when compared with placebo (108564). Cranberry supplementation also does not appear to affect grey matter structure; however, due to the low number of patients who completed a baseline and follow-up MRI, this study may not have been adequately powered to detect a difference between groups.
• Benign prostatic hyperplasia (BPH). Preliminary clinical research suggests that oral cranberry is beneficial for reducing BPH symptoms. Details: Preliminary clinical research shows that taking powdered dried cranberry fruit 500 mg three times daily for 6 months improves lower urinary symptoms and reduces prostate specific antigen (PSA) levels when compared with no treatment in patients 45 years of age or older with elevated PSA levels, a negative prostate biopsy, and clinically confirmed non-bacterial prostatitis (17126). Another small study in those 45 years of age and older without elevated PSA levels shows that taking a specific dried cranberry powder (Flowens, Naturex-DBS, LLC) 250-500 mg daily for 6 months reduces lower urinary tract symptoms and improves voiding and storage symptoms when compared with placebo (96738).
• Cancer. Although there has been interest in using oral cranberry for cancer, there is insufficient reliable information about the clinical effects of cranberry for this condition.
• Cardiovascular disease (CVD). Although some research suggests that oral cranberry may modestly improve some CVD risk factors, it is unclear if it is beneficial for CVD prevention. Details: A meta-analysis of 10 clinical studies shows that cranberry juice or cranberry extract seems to reduce systolic blood pressure by 3.6 mmHg and body mass index by 0.3 kg/m2 when compared with placebo. However, these improvements are unlikely to be clinically significant, and cranberry does not appear to improve diastolic blood pressure, lipid levels, glycemic control, or waist circumference (102849). The generalizability of these results is limited, as the study populations ranged from healthy adults to those with type 2 diabetes, metabolic syndrome, or coronary heart disease. A clinical crossover study in patients who are overweight or obese and have elevated blood pressure shows that drinking cranberry juice 250 mL twice daily for 8 weeks reduces ambulatory diastolic blood pressure by 2 mmHg during daytime hours, but does not improve systolic blood pressure, glycemic control, or lipid levels, when compared with placebo (108059). The validity of these findings is limited due to short duration of treatment and broad heterogeneity of patient baseline characteristics.
• Catheter-related infections. Although there has been interest in using oral cranberry for catheter-related infections, there is insufficient reliable information about the clinical effects of cranberry for this condition.
• Chronic fatigue syndrome (CFS). Although there has been interest in using oral cranberry for CFS, there is insufficient reliable information about the clinical effects of cranberry for this condition.
• Diabetes. It is unclear if oral cranberry is beneficial for diabetes. Details: A small clinical trial shows that taking cranberry supplements orally does not improve fasting serum glucose, glycated hemoglobin (HbA1C), fructosamine, triglycerides, high-density lipoprotein (HDL) cholesterol, or low-density lipoprotein (LDL) cholesterol levels in patients with type 2 diabetes (11328).
• Helicobacter pylori. There is conflicting evidence regarding the use of oral cranberry for Helicobacter pylori eradication, either as a standalone treatment or in combination with standard triple therapy. Details: Two small clinical studies show that taking cranberry juice 480-500 mL, containing 88 mg proanthocyanidins (PACs), daily in two divided doses for 2-3 months can modestly increase the H. pylori eradication rate at 8 weeks, but not at 2 weeks, when compared with placebo. However, the eradication rate was only 20% or less, which is much lower than that obtained with conventional triple therapy (46388,104248). Lower doses, as either cranberry juice or cranberry powder, do not seem to improve H. pylori eradication rates. Cranberry juice containing only 23 mg or 44 mg PACs or cranberry powder containing 36 mg or 72 mg PACs did not demonstrate benefit when compared with placebo (104248). Cranberry juice has also been studied in combination with standard triple therapy. Preliminary clinical research shows that taking cranberry juice 250 mL daily for 3 weeks along with omeprazole, amoxicillin, and clarithromycin for one week does not increase the eradication rate when compared with triple therapy plus placebo. However, the combination treatment increased the rate of H. pylori eradication when only females were considered (46439). A meta-analysis of 4 small clinical studies, including three studies already discussed, shows that taking cranberry, either as a juice or a dried powder, does not improve H. pylori eradication rate when compared with placebo, regardless of treatment duration (108060). The validity of these findings is limited by the high heterogeneity of the included studies and incomplete reporting. In asymptomatic children aged 6-16 years old with H. pylori, one clinical study shows that drinking cranberry juice 200 mL, with live or heat-killed Lactobacillus johnsonii 80 mL, daily for 3 weeks eradicates H. pylori in 15% to 22% of patients, compared with 1.5% of those receiving placebo. However, these rates are lower than those typically obtained with conventional triple therapy (46441).
• Hyperlipidemia. Oral cranberry has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Drinking a combination of cranberry, blueberry, apple, and chokeberry juice 300 mL daily for 6 weeks appears to decrease total cholesterol and increase high-density lipoprotein (HDL) cholesterol when compared to baseline in females with overweight or obesity and at least one risk factor for cardiovascular disease (111233). However, the validity of the study is limited by its small size, short duration, and lack of a comparator group. It is unclear if these effects are due to cranberry, other ingredients, or the combination.
• Kidney stones (nephrolithiasis). It is unclear if oral cranberry is beneficial for reducing the risk of kidney stones. Details: Although some preliminary clinical research shows that drinking cranberry juice 500 mL diluted in 1500 mL water daily for 2 weeks can decrease urinary excretion of oxalate in healthy males, which suggests a decreased risk of kidney stone formation (46371), other preliminary clinical research shows that both cranberry juice and concentrated cranberry extracts can increase urinary oxalate levels, suggesting an increased risk of stone formation (7074,46393).
• Memory. It is unclear if oral cranberry is beneficial for memory. Details: Preliminary clinical research in cognitively intact older adults shows that taking cranberry juice 16 ounces twice daily for 6 weeks does not improve memory when compared with placebo (46390).
• Metabolic syndrome. It is unclear if oral cranberry is beneficial for metabolic syndrome. Details: Preliminary clinical research shows that drinking cranberry juice 240 mL twice daily for 8 weeks can increase plasma antioxidant capacity when compared with placebo in adults with metabolic syndrome. However, cranberry juice does not appear to affect blood pressure, blood glucose, serum lipids, or markers of inflammation when compared with placebo in these patients (46467).
• Nonalcoholic fatty liver disease (NAFLD). It is unclear if oral cranberry is beneficial for NAFLD. Details: Preliminary clinical research in adults with NAFLD shows that adding cranberry extract 288 mg daily to a weight loss diet for 12 weeks does not appear to affect body weight, liver enzymes, lipid levels, or steatosis grade when compared with placebo. Cranberry extract may moderately reduce insulin levels and insulin resistance (104249). However, the clinical impact of these reductions is unclear. Another clinical trial in adults with NAFLD shows that taking dried cranberry powder 144 mg daily after lunch for 6 months improves steatosis grade as measured by ultrasound, insulin sensitivity, and levels of total cholesterol and triglycerides, but does not affect liver enzyme levels, when compared with placebo. All patients also consumed a reduced-calorie diet and an undefined dose of supplemental vitamin E (108058).
• Obesity. Oral cranberry has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in females with overweight or obesity and at least one risk factor for cardiovascular disease shows that drinking a combination of cranberry, blueberry, apple, and chokeberry juice 300 mL daily for 6 weeks does not reduce body weight, body mass index (BMI), or blood pressure but might improve total cholesterol and high-density lipoprotein (HDL) cholesterol when compared to baseline (111233). However, the validity of these findings is limited by the small study size, short duration, and lack of a comparator group. It is unclear if these effects are due to cranberry, other ingredients, or the combination.
• Overactive bladder. It is unclear if oral cranberry is beneficial for overactive bladder. Details: Preliminary clinical research in otherwise healthy females shows that taking dried cranberry powder 500 mg daily for 24 weeks can reduce daily micturition by 16% and urgency episodes by 57% when compared with placebo. Patients taking cranberry powder also reported an improvement in their own perception of their bladder condition when compared with placebo (104246). Limitations of this study include a short duration, lack of a run-in period, and high drop-out rate, which interfered with the ability to meet power.
• Peristomal lesions. Although there has been interest in using oral cranberry for peristomal lesions, there is insufficient reliable information about the clinical effects of cranberry for this condition.
• Prostate cancer. It is unclear if cranberry is beneficial for preventing prostate cancer recurrence. Details: Clinical research shows that taking cranberry powder (Pacran, Naturex) 1500 mg for a mean of 30 days prior to radical prostatectomy for prostate cancer does not improve prostate tissue markers when compared with taking placebo. However, levels of prostate tissue antigen decreased by approximately 22% when compared with baseline (105127).
• Radiation-induced cystitis. Evidence for the use of cranberry juice in the prevention of radiation-induced cystitis is conflicting. Details:One small clinical study in individuals with prostate cancer shows that taking 200 mg of a cranberry extract standardized to 30% proanthocyanidins (Monoselect Macrocarpon; PharmExtracta) once daily during external beam radiotherapy for 6-7 weeks reduces the risk of lower UTI by 64% when compared with placebo (92579). However, other preliminary clinical research shows that taking cranberry capsules, standardized to contain a total of 72 mg proanthocyanidins, daily during radiation treatment for prostate cancer and for two weeks post-treatment, does not improve pain, burning, nocturia, or urinary flow symptoms from radiation-induced cystitis when compared with a beetroot placebo (104247). Additionally, preliminary clinical research in patients receiving radiotherapy for bladder or cervical cancer shows that consuming cranberry juice 250 mL daily for 2 weeks does not seem to reduce the incidence of UTIs (46469).
• Rheumatoid arthritis (RA). It is unclear if cranberry juice is beneficial in RA. Details: A clinical study in adults with RA shows that drinking reduced-calorie cranberry juice 250 mL twice daily in addition to taking fish oil 1 gram three times daily for 90 days improves disease activity score (DAS28-CRP) when compared with no supplementation. However, this combination was similarly effective to patients taking fish oil alone, suggesting that any benefits may be due to fish oil, as opposed to cranberry juice (108057).
• Upper respiratory tract infection (URTI). It is unclear if oral cranberry is beneficial for the prevention or treatment of URTIs. Details: Clinical research shows that drinking a cranberry juice beverage 450 mL daily for 70 days does not decrease the incidence of cold or flu, but may reduce cold and flu symptoms, when compared with placebo in healthy adults (90046).
• Urinary odor. It is unclear if oral cranberry is beneficial for urinary odor. Details: Preliminary clinical research shows that cranberry juice cocktail might reduce urinary odors when given orally on a regular basis to patients with urinary incontinence (3333,3334,8254). Cranberry juice cocktail up to 237 mL three times daily for up to 4 weeks has been used (3334). More evidence is needed to rate cranberry for these uses.

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LIKELY EFFECTIVE

• Carbohydrate-deficient glycoprotein syndrome type 1b. Oral d-mannose prevents certain hematologic and gastrointestinal complications in patients with this condition. However, it's unclear if it helps to prevent liver complications. Details: Carbohydrate-deficient glycoprotein syndrome type 1b is a rare and often lethal congenital disorder of glycosylation (CDG). It is characterized by protein loss in the digestive tract, gastrointestinal symptoms, hypoglycemia, liver disease, and failure to thrive. The disorder is also called phosphomannose isomerase (PMI) deficiency or mannose-phosphate-isomerase CDG (MPI-CDG). Taking d-mannose 300-1020 mg/kg daily in 3-6 divided doses long-term can reduce protein loss, hypoglycemia, coagulation disorders, and gastrointestinal symptoms in patients, usually infants and children, with this disorder (13344,13345,13346,13348,100978,100979,100980,100981). While d-mannose seems to be effective for stabilizing the signs and symptoms of this condition, it is not clear whether it can prevent liver complications. In two cases, d-mannose reduced hepatomegaly after 6 months or 2 years of therapy (13348,100980). In other cases, however, hepatic fibrosis developed despite d-mannose treatment for up to 6 years (13345,100978). These discrepant finding are thought to be due to the variable levels of liver disease severity at the time of d-mannose treatment initiation (100977).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Urinary tract infections (UTIs). Small clinical studies suggest that oral d-mannose might reduce UTI recurrence, when used alone or in combination with other ingredients. It is unclear if d-mannose improves symptoms in patients with existing UTIs. Details: A systematic review of the available research concluded that there is no strong evidence for or against the use of d-mannose for UTI prevention or treatment and higher quality research is needed (110013). A meta-analysis of low-quality studies suggests that d-mannose may have a protective effect against UTI recurrence when compared with no prophylaxis and may be similarly effective to prophylactic antibiotics. However, it is difficult to draw strong conclusions from the meta-analysis because it included only 3 small studies, one of which was a prospective cohort study (104209). Two of these studies compared d-mannose powder 2 grams daily for 6 months to prophylactic antibiotics. In one study, d-mannose demonstrated comparable effectiveness to nitrofurantoin 50 mg daily (91141). However, the other study compared d-mannose to trimethoprim/sulfamethoxazole 160/800 mg twice daily for 5 days, followed by one dose daily at bedtime for one week of each month (99656). Although trimethoprim/sulfamethoxazole is commonly used to prevent UTI recurrence, the specific regimen studied here is not typically used for prophylaxis, limiting the validity of the findings from this meta-analysis. Additionally, a small clinical study of postmenopausal females with a history of recurrent UTI was halted early due to likely futility to show a reduction in recurrent UTI with taking 2 grams of d-mannose powder (Organic & Pure Powder D-Mannose Powder, NOW Foods Inc.) daily for 90 days in addition to using vaginal estrogen (111756). A small clinical study in older adults post-cystoscopy for suspected bladder cancer or post-transurethral resection of the bladder shows that taking D-mannose 500 mg plus Saccharomyces boulardii daily for 1 week reduces the incidence of positive urine cultures (0% vs. 19%) when compared with no treatment (112363). However, it is unclear if these effects are due to D-mannose, Saccharomyces boulardii, or the combination. Low-quality research also suggests that taking specific combination products containing d-mannose with other ingredients may be beneficial for UTI prevention. These products have combined d-mannose 250 mg with cranberry extract, tara gum, and probiotic bacteria (1-2.5 billion live cells of L. plantarum LP01, L. paracasei LPC09, and Streptococcus thermophilus ST10) (93884); d-mannose (dose unspecified) with cranberry, and L. paracasei (Lactoflorene Cist, Montefarmaco) (104210); and d-mannose 500 mg with noni fruit extract 200 mg and N-acetylcysteine 100 mg (97360). D-mannose has also been studied as a treatment for existing UTI alone and in combination with other ingredients. A small clinical study in females with an acute UTI shows that taking a specific d-mannose product (Mannocist, Laboratori Farmaceutici Krymi) 1.5 grams twice daily for 3 days, and then once daily for 10 days, improves some symptoms of UTI when compared to baseline (93883). The validity of this finding is limited by the lack of a comparator group. A moderate-size clinical study in females aged 18-45 with uncomplicated UTIs shows that taking a supplement containing d-mannose 2 grams, astragalus, citric acid, dandelion, and prebiotics as a sachet dissolved in water twice daily for 5 days improves complete resolution of UTI symptoms and clearance of bacteriuria at days 6 and 35 when compared with placebo (111757). However, it is unclear if these effects are due to d-mannose, other ingredients, or the combination. More evidence is needed to rate d-mannose for this use.

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INSUFFICIENT RELIABLE EVIDENCE to RATE

• Common cold. Preliminary clinical research shows that taking a specific larch arabinogalactan extract (ResistAid, Lonza Ltd.) 4.5 grams daily for 12 weeks does not significantly decrease the number, intensity, or symptoms of common colds when compared with placebo in patients who frequently suffer from colds. However, larch arabinogalactan appears to increase the percentage of patients who experience no cold episodes. About 42% of patients receiving larch arabinogalactan extract had no cold episodes, compared to only 28% of patients receiving placebo (93104).
• Hyperlipidemia. Preliminary clinical research shows that taking larch arabinogalactan 8.4 grams daily for 6 months, or 15-30 grams daily for 6 weeks, does not significantly lower total cholesterol, low-density lipoprotein (LDL) cholesterol, triglycerides, apolipoprotein B (apo B), apolipoprotein A-1, body weight, blood pressure, or glucose levels in healthy people (15617,15620). It is not known if larch arabinogalactan lowers lipid levels in patients with hyperlipidemia. More evidence is needed to rate larch arabinogalactan for these uses.

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POSSIBLY EFFECTIVE

• Hypercholesterolemia. Most clinical research shows that oral pectin at a dose of 15 grams daily can slightly lower total cholesterol and low-density lipoprotein (LDL) cholesterol levels in patients with hypercholesterolemia. Details: While some small studies in patients with or without hypercholesterolemia suggest that pectin 1-12 grams daily for up to 12 weeks does not reduce lipid levels (2215,2217), other research in patients with hypercholesterolemia shows that taking pectin 15 grams daily for 4 weeks consistently reduces total cholesterol and LDL cholesterol by around 7% to 10% when compared with baseline or placebo (2214,2216,92473). Some forms of pectin might lower cholesterol levels better than others. Pectin with a higher molecular weight and higher degree of esterification appears to be the most effective (92473). A larger clinical study also shows that taking 20 grams of pectin and guar gum, along with small amounts of insoluble fiber, reduces total cholesterol by nearly 8% and LDL cholesterol by nearly 11%, but does not improve high-density lipoprotein (HDL) cholesterol or triglycerides, when compared with placebo (12547).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Colorectal cancer. Although there has been interest in using oral pectin for the prevention of colorectal cancer, there is insufficient reliable information about the clinical effects of pectin for this purpose.
• Diarrhea. It is unclear if oral pectin is beneficial in children with persistent diarrhea. Details: A small clinical study in children aged 5-12 months in developing nations with persistent diarrhea shows that taking pectin 4 grams/kg reduces the duration of diarrhea and vomiting, and reduces the need for oral rehydration solution and intravenous fluid, when compared with a rice-diet control (12575). Pectin has also been evaluated in combination with other ingredients. One clinical study in children aged 6 months to 6 years with acute diarrhea shows that taking a combination of apple pectin and chamomile (Diarrhoesan, Dr. Loges + Co. GmbH) for up to 5 days reduces the frequency of stools by day 3 by about 1.36-fold when compared with placebo, with improvements maintained through day 5. This combination product was given hourly up to a maximum dose of 50 mL in children 6-12 months of age, 60 mL in children 1-3 years of age, and 80 mL in children 4-6 years of age (19705). It is unclear if these findings are due to pectin, chamomile, or the combination.
• Gastroesophageal reflux disease (GERD). It is unclear if oral pectin is beneficial in children with GERD. Details: A small clinical study in children with GERD and cerebral palsy shows that adding pectin to enteral nutrition in a 1:2 ratio for 4 weeks might reduce some symptoms of GERD. The number of vomiting episodes per week was reduced by 60% and the frequency of coughing/wheezing was reduced by 76% for children given the pectin diet when compared with those given a non-pectin diet (92476).
• Impaired glucose tolerance (Prediabetes). It is unclear if oral pectin is beneficial in patients with impaired glucose tolerance. Details: A small clinical study in middle-aged patients with impaired glucose tolerance or impaired fasting glucose shows that drinking 400 mL of a beverage containing 40 grams/L of sugar beet pectin in two divided doses daily for 12 weeks does not improve fasting or postprandial plasma glucose concentrations or serum lipid levels when compared to baseline (34118).
• Irritable bowel syndrome (IBS). Although there has been interest in using oral pectin for IBS, there is insufficient reliable information about the clinical effects of pectin for this purpose.
• Mercury toxicity. It is unclear if oral pectin is beneficial in patients with mercury toxicity. Details: A small clinical study in children with mercury poisoning shows that taking pectin 2.5 grams daily for 21 days and then 5 grams daily for 39 days increases mercury excretion in the urine, decreases the duration of mercury toxicity, and improves psychological symptoms when compared to baseline (31657). The validity of these findings is limited by the lack of a comparator group.
• Niacin-induced flushing. It is unclear if oral pectin is beneficial for the prevention or management of niacin-induced flushing. Details: A small clinical study shows that taking apple pectin 2 grams 30 minutes prior to taking niacin extended-release 1000 mg reduces the duration of flushing by about 35 minutes when compared with placebo. However, apple pectin does not reduce the incidence of flushing, the time to flush, or the maximum severity of flushing (92477).
• Peptic ulcers. It is unclear if oral pectin is beneficial for the prevention of peptic ulcers. Details: A small clinical study in patients with recently healed duodenal ulcers shows that taking apple pectin 10 grams twice daily for 6 months does not reduce the recurrence of duodenal ulcers when compared with placebo (31697).
• Prostate cancer. It is unclear if oral pectin is beneficial in patients with prostate cancer. Details: Two small clinical studies in patients with prostate cancer show that taking a specific modified citrus pectin product (Pectasol, Econugenics) 4.8 grams three times daily following prostatectomy, radiation, or cryosurgery for up to one year slows disease progression and increases the time to prostate specific antigen (PSA) doubling when compared to baseline (15020,108525). The validity of these findings is limited by the lack of a comparator group.
• Radiation exposure. Although there has been interest in using oral pectin to minimize exposure to environmental radiation, there is insufficient reliable information about the clinical effects of pectin for this purpose. More evidence is needed to rate pectin 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.

(Read more about CHONDROITIN SULFATE)

LIKELY SAFE . .when used orally and appropriately. Cranberry juice up to 300 mL daily and cranberry extracts in doses up to 800 mg twice daily have been safely used in clinical trials (3333,3334,6758,6760,7008,8252,8253,8254,8995,11328) (16415,16720,17100,17126,17176,17210,17524,46379,46388,46389)(46390,46425,46439,46443,46465,46456,46466,46467,46469,46471)(46496,46499,90044,102847,111407).

CHILDREN: LIKELY SAFE
when cranberry juice is consumed in amounts commonly found in the diet (2811,6759,46441,46452,46470,111407). There is insufficient reliable information available about the safety of cranberry when used in medicinal amounts in children.

PREGNANCY AND LACTATION: LIKELY SAFE
when consumed in amounts commonly found in the diet. There is insufficient reliable information available about the safety of cranberry when used therapeutically during pregnancy or lactation; avoid using.

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POSSIBLY SAFE ...when used orally and appropriately, short-term. D-mannose 3 grams daily for up to 2 weeks or 2 grams daily for up to 6 months has been used with apparent safety in clinical research (91141,93883,99656). There is insufficient reliable information available about the safety of taking d-mannose long-term.

CHILDREN: POSSIBLY SAFE
when used orally and appropriately in children with carbohydrate-deficient glycoprotein syndrome type 1b. D-mannose 300-1020 mg/kg daily, taken in 3-6 divided doses, has been used with apparent safety, long-term (13345,13346,13348,100978,100979,100980,100981). While total daily doses up to 1020 mg/kg have been used safely when taken in divided doses, single doses greater than 200 mg/kg are more likely to cause osmotic diarrhea (100977). There is insufficient reliable information available about the safety of using d-mannose in children with other conditions.

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

(Read more about D-MANNOSE)

LIKELY SAFE ...when used orally in amounts found in foods. Larch arabinogalactan has Generally Recognized As Safe (GRAS) status in the US (3529).

POSSIBLY SAFE ...when used orally and appropriately in medicinal amounts, short-term. Larch arabinogalactan has been safely used at doses of 1.5-8.4 grams daily for up to 6 months (15617,15618,17370,93102,93104,104281). Higher doses of 15-30 grams daily have been used with apparent safety for up to 6 weeks (15620). There is insufficient reliable information available about the safety of larch arabinogalactan when used long-term.

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

(Read more about LARCH ARABINOGALACTAN)

LIKELY SAFE ...when used in amounts commonly found in foods. Pectin has Generally Recognized as Safe (GRAS) status in the US (4912).

POSSIBLY SAFE ...when used orally in amounts greater than those typically found in food. Pectin 4.8 grams three times daily has been used for up to one year without serious adverse effects (12547,15019,15020,92481,108525).

CHILDREN: POSSIBLY SAFE
when used orally in amounts greater than those found in food, short-term. Pectin 4 grams/kg has been used daily for up to 7 days without reports of serious adverse effects (12575,19705).

PREGNANCY AND LACTATION: LIKELY SAFE
when used in amounts commonly found in foods. Pectin has Generally Recognized as Safe (GRAS) status in the US (4912).

PREGNANCY AND LACTATION: POSSIBLY SAFE
when used orally in medicinal amounts (12577).

(Read more about PECTIN)

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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ATORVASTATIN (Lipitor) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, cranberry might increase levels and adverse effects of atorvastatin.  Details In one case report, a patient taking atorvastatin experienced upper back pain, rhabdomyolysis, and abnormal liver function after drinking cranberry juice 16 ounces daily for 2 weeks. Theoretically, this may have been caused by inhibition of cytochrome P450 3A4 (CYP3A4) enzymes by cranberry juice, as atorvastatin is a CYP3A4 substrate. Creatinine kinase and liver enzymes normalized within 2 weeks of stopping cranberry juice (90042). Patients taking atorvastatin should avoid large quantities of cranberry juice.

CYTOCHROME P450 2C9 (CYP2C9) SUBSTRATES Interaction Rating = Minor Be watchful with this combination. Severity = Moderate •  Occurrence = Unlikely •  Level of Evidence = B Theoretically, cranberry might increase the levels and adverse effects of CYP2C9 substrates. However, research is conflicting.  Details There is contradictory evidence about the effect of cranberry on CYP2C9 enzymes. In vitro evidence suggests that flavonoids in cranberry inhibit CYP2C9 enzymes (10452,11115,90048). However, clinical research shows that cranberry juice does not significantly affect the levels, metabolism, or elimination of the CYP2C9 substrates flurbiprofen or diclofenac (11094,90048). Also, in patients stabilized on warfarin, drinking cranberry juice 250 mL daily for 7 days does not significantly increase the anticoagulant activity of warfarin, a CYP2C9 substrate (15374). Additional pharmacokinetic research shows that cranberry juice does not increase peak plasma concentrations or area under the concentration-time curve of warfarin (15393).

CYTOCHROME P450 3A4 (CYP3A4) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, cranberry might increase the levels and adverse effects of CYP3A4 substrates.  Details A case of upper back pain, rhabdomyolysis, and abnormal liver function has been reported for a patient taking atorvastatin, a CYP3A4 substrate, in combination with cranberry juice 16 ounces daily for 2 weeks. Creatinine kinase and liver enzymes normalized within 2 weeks of stopping cranberry juice (90042). Also, animal research suggests that cranberry juice, administered intraduodenally 30 minutes prior to nifedipine, a CYP3A4 substrate, inhibits nifedipine metabolism and increases the area under the concentration-time curve by 1.6-fold compared to control (46420).

DICLOFENAC (Voltaren, others) Interaction Rating = Minor Be watchful with this combination. Severity = Moderate •  Occurrence = Unlikely •  Level of Evidence = B Theoretically, cranberry might modestly increase the levels and adverse effects of diclofenac.  Details In vitro evidence suggests that cranberry juice inhibits diclofenac metabolism by human liver microsomes (90048). However, drinking cranberry juice does not seem to affect diclofenac metabolism in humans (90048).

NIFEDIPINE (Procardia) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, cranberry might increase the levels and adverse effects of nifedipine.  Details Animal research suggests that cranberry juice, administered intraduodenally 30 minutes prior to nifedipine treatment, inhibits nifedipine metabolism and increases the area under the concentration-time curve by 1.6-fold compared to control (46420). This interaction has not been reported in humans.

WARFARIN (Coumadin) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = B Theoretically, cranberry might increase the levels and adverse effects of warfarin. However, research is conflicting.  Details There is contradictory evidence about the effect of cranberry juice on warfarin. Case reports have linked cranberry juice consumption to increases in the international normalized ratio (INR) in patients taking warfarin, resulting in severe spontaneous bleeding and excessive postoperative bleeding (10452,12189,12668,21187,21188,21189,46378,46396,46411)(46415,90043). Daily consumption of cranberry sauce for one week has also been linked to an increase in INR in one case report (16816). In a small study in healthy young males, taking a high dose of 3 grams of cranberry juice concentrate capsules, equivalent to 57 grams of fruit daily, for 2 weeks produced a 30% increase in the area under the INR-time curve after a single 25-mg dose of warfarin (16416). However, 3 very small clinical studies in patients stabilized on warfarin reported that cranberry juice 250 mL once or twice daily for 7 days (27% cranberry juice or pure cranberry juice) or 240 mL once daily for 14 days does not significantly increase INR or affect plasma warfarin levels (15374,17124,90045). The reasons for these discrepant findings are unclear. It is possible that the form and dose of cranberry may play a role, as cranberry extracts and juices contain different constituents. Additionally, an in vitro study evaluating 5 different cranberry juices found varying effects, with only a cranberry concentrate, and not diluted cranberry juices, inhibiting CYP2C9. However, this concentrate did not inhibit CYP2C9 activity in humans (108062).

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DIGOXIN (Lanoxin) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, pectin might reduce the absorption of digoxin, potentially decreasing its effectiveness.  Details A small clinical study shows that taking digoxin with a kaolin-pectin suspension reduces the absorption of digoxin by about 62% (2212). It is unclear if these effects are due to pectin, kaolin, or the combination.

LOVASTATIN (Mevacor) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, pectin might reduce the absorption of lovastatin, potentially decreasing its effectiveness.  Details Case reports suggest that concomitant use of pectin and lovastatin might reduce the cholesterol-lowering effect of lovastatin, possibly due to reduced intestinal absorption of lovastatin (615).

TETRACYCLINE ANTIBIOTICS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, pectin might reduce the absorption of tetracycline antibiotics, potentially decreasing their effectiveness.  Details A small clinical study shows that taking tetracycline with bismuth subsalicylate in a kaolin-pectin suspension reduces the absorption of tetracycline by about 34% (2213). It is unclear if these effects are due to pectin, kaolin, bismuth subsalicylate, or the combination.

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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).

(Read more about CHONDROITIN SULFATE)

General ...Orally, cranberry seems to be well tolerated.
Most Common Adverse Effects:
Orally: Diarrhea and gastrointestinal discomfort.

Dermatologic ...Orally, skin redness and itching has been reported in one patient (46389).

Gastrointestinal ...In very large doses, for example 3-4 L per day of juice, cranberry can cause gastrointestinal upset and diarrhea, particularly in young children (46364). There are reports of abdominal and gastrointestinal discomfort after taking cranberry tablets, extracts, and juice in clinical trials (16720,46379,111407). Nausea, vomiting, and diarrhea have also been reported with consumption of lower doses of cranberry juice cocktail, 16 ounces per day, equivalent to about 4 ounces cranberry juice, for several weeks (16415).

Genitourinary ...Vulvovaginal candidiasis has been associated with ingestion of cranberry juice (46374). Clinical research suggests that ingestion of cranberry juice may be associated with vaginal itching and vaginal dryness (46471). One patient in clinical research stopped taking dried cranberry juice due to excessive urination (46437), and an isolated case of nocturia following ingestion of cranberry tablets has been reported (16720).

Hematologic ...Thrombocytopenia has been reported as an adverse event to cranberry juice (46459).

Other ...An isolated case of sensitive swollen nipples after taking cranberry tablets has been reported (16720).

(Read more about CRANBERRY)

General ...Orally, d-mannose seems to be well tolerated.
Most Common Adverse Effects:
Orally: Bloating, diarrhea, and nausea.

Gastrointestinal ...Orally, d-mannose can cause loose stools, diarrhea, abdominal bloating, and nausea (13344,91141,100979,100981,104209). In children, loose stools and abdominal bloating have been reported at d-mannose doses ranging from 100 mg/kg three times daily to 150 mg/kg five times daily (13344,100979). Diarrhea has been reported in adults taking d-mannose 2 grams daily for 6 months (91141). While diarrhea and loose stools have been reported at lower doses, taking a single d-mannose dose greater than 200 mg/kg is more likely to cause osmotic diarrhea (100977).

Renal ...Orally, there is concern that excessive doses (toxic amounts unspecified) of d-mannose might be toxic to the kidneys (13348).

(Read more about D-MANNOSE)

General ...Orally, larch arabinogalactan is generally well tolerated (3530,17370,93102). Some people can experience bloating and flatulence (3530).

Gastrointestinal ...Orally, larch arabinogalactan can cause bloating and flatulence (3530).

(Read more about LARCH ARABINOGALACTAN)

General ...Orally, pectin seems to be well tolerated.
Most Common Adverse Effects:
Orally: Diarrhea, gas, loose stools, and mild cramps.
Serious Adverse Effects (Rare):
All routes of administration: Allergic reactions, including anaphylaxis, in sensitive individuals.

Gastrointestinal ...Orally, pectin alone or in combination with guar gum and insoluble fiber can cause gastrointestinal adverse effects such as mild cramps, diarrhea, gas, and loose stools (12547,15020,92473).

Immunologic ...Orally and topically, pectin may cause allergic reactions in sensitive individuals. In one case, a 7-year-old boy with a history of oral allergy syndrome after consuming a pectin-containing beverage experienced anaphylaxis after taking a citrus bath containing pectin. Allergy testing confirmed sensitivity to pectin (106928).

Pulmonary/Respiratory ...The occupational inhalation of pectin dust can cause asthma (580,581,582,583,584).

(Read more about PECTIN)