Hyaluronic Acid [Discontinued] by GNC Women's

POSSIBLY EFFECTIVE

• Dry eye. Applying eye drops containing hyaluronic acid alone or in combination with other ingredients, seems to improve symptoms of dry eye. Details: A large meta-analysis of clinical studies in patients with dry eye disease shows that using eye drops containing hyaluronic acid 0.1% to 0.4% for at least 14 days modestly improves tear production when compared with artificial tears or saline control, with a more significant improvement when compared with saline control. Tear stability is also modestly improved when compared with saline control (108622). Several individual clinical studies using specific hyaluronic acid eye drops have also demonstrated improvement. One clinical study in patients with dry eye disease shows that applying eye drops containing hyaluronic acid 0.1% to 0.3% 5-6 times daily for 12 weeks might improve symptoms to a similar degree as cyclosporine 0.05% eye drops. The products used in this study included Hyalein ophthalmic solution 0.1%, New Hyaluni ophthalmic solution 0.15%, and Hyaluni ophthalmic solution 0.3% (97885). Another clinical study shows similar efficacy between hyaluronic acid 0.15% eye drops (New Hyaluni), applied 6 times daily for 12 weeks, and eye drops containing cyclosporine 0.05% and carboxymethylcellulose 0.5%, applied twice daily (110555). A smaller clinical study in patients with dry eye disease shows that applying specific eye drops containing hyaluronic acid 0.2% (Hyalistil) seems to have similar efficacy as using tamarind seed polysaccharide eye drops (16301). Furthermore, adding hyaluronic acid to conventional treatment seems to offer additional benefit. A large multicenter clinical trial in patients with dry eye disease shows that applying 1-2 drops of artificial tears containing carboxymethylcellulose 0.5% and hyaluronic acid 0.1% (Optive Fusion, Allergan) at least 2 times daily for 3 months seems to further improve pain and discomfort when compared with using artificial tears containing carboxymethylcellulose alone (104384). One small clinical study also shows that hyaluronic acid 0.3% ocular gel and hyaluronic acid 0.18% eye drops, applied 4-6 times daily for 12 weeks, are equally effective for improving dry eye symptoms (110556). Hyaluronic acid has also been studied in combination with other ingredients. Several small clinical studies in patients with dry eye syndrome ranging from mild to severe shows that applying eye drops containing hyaluronic acid 0.2% or 0.3%, polyvinylpyrrolidone, and glycerin (Visaid 0.2% or 0.3%, Avizor S.A.), administered as one drop 3-8 times daily for one month, improves some signs and symptoms of dry eye when compared with sodium chloride 0.9% (97894,97895). Conversely, a large clinical study in patients with mild to moderate dry eye disease shows that applying preservative-free eye drops containing sodium hyaluronate with chondroitin sulfate (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 (104443).
• Venous leg ulcers. Topical application of hyaluronic acid-impregnated gauze reduces wound size and promotes wound healing. Details: Clinical studies in patients with at least one leg ulcer of venous or mixed arterial/venous origin show that once daily application of a specific hyaluronic acid-impregnated gauze (Ialuset, Laboratoires Genévrier) reduces wound size at 45 days by 73% and produces complete wound healing at or before 20 weeks in 40% of patients. In those receiving a neutral vehicle gauze, these improvements occurred in 46% and 19% of patients, respectively (108627,108640).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Aging skin. Oral hyaluronic acid has only been evaluated in combination with other ingredients; its effect when used alone is unclear. It is also unclear if topical hyaluronic acid is beneficial for aging skin. Details: A very small study shows that taking a specific combination product (GliSODin Skin Nutrients Advanced Anti-Aging Formula, Isocell North America Inc.) containing hyaluronic acid, krill oil, sea buckthorn berry oil, and cacao bean extract orally three times daily for 90 days, along with applying tazarotene 0.1% cream, moderately decreases wrinkling and photodamage and improves skin moisture and elasticity when compared with tazarotene cream alone (91778). Another small clinical study in females with aging skin shows that taking a specific combination product (BioCell Collagen, BioCell Technology, LLC) containing hyaluronic acid 100 mg, chondroitin sulfate 200 mg, and collagen peptides 600 mg daily for 12 weeks reduces lines and wrinkles by about 13% when compared with baseline (28681). The validity of this finding is limited by the lack of a comparator group. Furthermore, it should be noted that both studies were funded by the product manufacturer. A small open-label clinical study in females with mild to moderate lip dryness and mild to severe lip condition shows that three daily applications of a two-step lip treatment containing hyaluronic acid for 4 weeks improves the overall condition of lips, as well as texture/visual roughness, plumpness, color/rosiness, definition/contour, and lines/wrinkles when compared with baseline (108634). The validity of these findings is limited by the lack of a comparator group.
• Allergic rhinitis (hay fever). It is unclear if nasal irrigation with sodium hyaluronate is beneficial in patients with mild, persistent seasonal allergic rhinitis. Details: A small clinical study in patients with mild, persistent seasonal allergic rhinitis receiving an oral antihistamine and an intranasal corticosteroid shows that nasal irrigation with sodium hyaluronate twice daily for 1 month improves mucociliary clearance time by 3 minutes, compared with 1 minute with the use of isotonic saline and 5 minutes with the use of surfactant (108630). It is unclear if this change is associated with clinically relevant symptom improvement.
• Burns. It is unclear if topical hyaluronic acid is beneficial in patients with burns. Details: A meta-analysis of small clinical trials suggests that topical hyaluronic acid and hyaluronic acid derivatives might improve the healing of wounds, including burns, when compared with control (104389). A small nonrandomized clinical study in patients with partial- to full-thickness burns shows that hyaluronic acid 0.2% gel daily for 12 weeks during the re-epithelialization phase reduces erythema, tension, pruritus, burning, and neoangiogenesis when compared with baseline (108636). The lack of statistical comparison to the ozonated oil group and the single-blinded nature of the study limit the validity of these findings.
• Canker sores. It is unclear if topical hyaluronic acid is beneficial for canker sores. Details: A clinical study in adults with recurrent canker sores shows that applying a gel containing hyaluronic acid 0.2% two to three times daily for 7 days reduces soreness immediately and for up to 30 minutes after application when compared with baseline. However, these improvements are numerically similar to those seen with placebo (108637). The lack of statistical comparison to placebo limits the validity of this finding. A small observational study in children with recurrent canker sores has found that applying a gel containing hyaluronic acid 0.2% twice daily for 7 days is similarly effective to dexamethasone topical ointment applied three times daily for 5 days for reducing pain and ulcer size (104388).
• Corneal abrasion. It is unclear if eye drops containing hyaluronic acid are beneficial in preventing recurrence in patients with a history of traumatic corneal abrasion. Details: A small clinical study in patients with fully healed traumatic corneal abrasion at risk for recurrence shows that administration of eye drops containing hyaluronic acid 0.3% five times daily for 3 months does not reduce the incidence rate of major symptomatic episodes at 12 months when compared with observation alone (108623).
• Diabetic foot ulcers. Oral hyaluronic acid has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A meta-analysis of results from 4 clinical studies shows that applying hyaluronic acid combination gels or hyaluronic acid-based biomaterials to diabetic foot ulcers increases the odds of complete healing at 12 weeks by about 1.7-fold when compared to control treatment. Forms of hyaluronic acid assessed in the evaluated studies included zinc hyaluronate, hyaluronic acid-based biomaterial (Hyalograft 3D autograft), and a gel containing hyaluronic acid and amino acids (Vulnamin Gel, Errekappa) (91776). It is not clear if the beneficial effects were due to hyaluronic acid or other components of the treatments.
• Exercise-induced muscle soreness. Oral hyaluronic acid has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A very small clinical study in healthy, recreationally active adults shows that a specific product (BioCell Collagen, BioCell Technology, LLC) containing hyaluronic acid 150 mg, chondroitin sulfate 300 mg, and collagen peptides 900 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 hyaluronic acid, the other ingredients, or the combination. Furthermore, it should be noted that both studies were funded by the product manufacturer.
• Gastroesophageal reflux disease (GERD). Oral hyaluronic acid 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 a different formulation of the same combination of chondroitin sulfate and hyaluronic acid (Esoxx, Alfa Wassermann) 4 times daily for 14 days, in conjunction with a PPI, improves GERD symptom severity by 21%, heartburn by 15%, and regurgitation by 10% when compared with using a PPI and placebo (101271). Hyaluronic acid has also been evaluated in combination with chondroitin sulfate in patients with extraesophageal symptoms of GERD. A small, open-label study shows that taking a specific combination product (Gerdoff, SOFAR S.p.A.) containing hyaluronic acid and chondroitin sulfate three times daily with omeprazole 40 mg daily for 6 weeks increases the rate of treatment response, defined as a 50% or greater improvement in reflux symptoms index scores, by around 40% when compared with omeprazole alone. While average symptom scores were not significantly improved with the combination product over omeprazole, the need for omeprazole as rescue therapy for breakthrough symptoms was reduced in the treatment group (109648). It is unclear if the findings described above are due to hyaluronic acid, chondroitin sulfate, or the combination.
• Gingivitis. It is unclear if hyaluronic acid used in a mouthwash reduces gingivitis severity. Details: A small clinical study in patients with biofilm-induced gingivitis shows that rinsing with 10 mL of hyaluronic acid 0.025% mouth wash (Gengigel, RICERFARMA SRL) for 1 minute twice daily reduces probing index and bleeding when compared with rinsing with a placebo solution, but is less effective when compared with chlorhexidine 0.12% solution (104383). Another small clinical study in patients with plaque-induced gingivitis shows that rinsing with 10 mL of a mouthwash containing hyaluronic acid 0.1% and hydrogen peroxide 1.8% for 30 seconds twice daily for 21 days reduces gingival index scores but not plaque index scores when compared with placebo (110554). It is unclear if these findings are due to hyaluronic acid, hydrogen peroxide, or the combination.
• Intranasal surgery. It is unclear if topical hyaluronic acid irrigation improves recovery in patients after nasal surgery. Details: A small clinical study in patients that underwent nasal surgery for chronic rhinosinusitis shows that performing nasal irrigation with high molecular weight sodium hyaluronate 9 mg twice daily for 6 weeks improves sinus scarring, crusting, and headache when compared with nasal irrigation with saline. However, the sodium hyaluronate irrigation did not improve sinus inflammation or secretions, nasal obstruction, or facial pain (101288).
• Intrauterine adhesions. Several small studies suggest that intrauterine administration of hyaluronic acid gel seems to prevent intrauterine adhesions after uterine surgery. Details: Meta-analyses of 11-12 small clinical studies in patients undergoing uterine surgery shows that intrauterine application of 1-10 mL of hyaluronic acid gel after surgery reduces the risk of intrauterine adhesions by around 50% and increases pregnancy rates when compared with no treatment (110551,110552). One analysis suggests that hyaluronic acid is most effective for prevention of intrauterine adhesions when at least 5 mL of gel is applied (110551).
• Lichen planus. It is unclear if topical hyaluronic acid is beneficial in patients with oral lichen planus. Details: A clinical study in patients with oral lichen planus shows that application of a gel containing hyaluronic acid 0.2% four to five times daily for 28 days reduces soreness in as little as 5 minutes for up to 4 hours when compared with baseline. These findings are numerically similar to those seen with placebo; however, the lack of statistical comparison to placebo limits the validity of this finding (108635). A small clinical study in patients with symptomatic oral lichen planus (including mixed forms) shows that application of a gel containing hyaluronic acid 0.2% three times daily for 4 weeks is similarly effective to triamcinolone for improving pain, erythema, and lesion size (108633). It is unclear if the improvement from baseline differed between groups.
• Melasma. It is unclear if topical hyaluronic acid is beneficial in patients with moderate to severe facial melasma. Details: A small clinical study in patients with mostly mixed-type, moderate to severe facial melasma shows that twice daily application of hyaluronic acid along with isobutylamido thiazolyl resorcinol reduces melasma severity similarly to isobutylamido thiazolyl resorcinol alone (108628). The single-blinded nature of the study limits the validity of these findings.
• Oral mucositis. Topical hyaluronic acid has only been evaluated in combination with other ingredients; its effects when used alone is unclear. Details: A small clinical study in children aged 5 years or older with chemotherapy-induced oral mucositis shows that using a solution containing sodium hyaluronate, verbascoside, and polyvinylpyrrolidone (Mucosyte; Biopharm) three times daily is more effective than placebo for improving pain and other symptoms (97890). Another small clinical study in adults in recovery from hematopoietic stem cell transplantation shows that using a spray product containing sodium hyaluronate with synthetic amino acid precursors of collagen (Mucosamin) attenuates the development of severe oral mucositis when compared with chlorhexidine 0.2% (97889).
• Osteoarthritis. It is unclear if oral hyaluronic acid is beneficial in patients with osteoarthritis of the knee. Details: A small study in patients with knee osteoarthritis shows that taking chicken comb extract (Hyal-Joint, Bioibérica) 80 mg, standardized to contain hyaluronic acid 60% to 70%, once daily for 8 weeks does not reduce pain when compared with placebo (55742). This study was limited by small size and a significant placebo effect. Another small study in patients with knee osteoarthritis shows that taking a different supplement (Oralvisc, Bioibérica) 80 mg standardized to contain hyaluronic acid 70% and glycosaminoglycans once daily for 3 months modestly reduces pain when compared with placebo (91779). Reasons for these differing findings may relate to hyaluronic acid formulation, study funding sources, or the magnitude of placebo effect. Hyaluronic acid has also been studied in combination with chondroitin and collagen peptides (BioCell Collagen, BioCell Technology, LLC) with some evidence of benefit (28680).
• Otitis media. It is unclear if using intranasal hyaluronic acid solution is beneficial for otitis media in children. Details: Preliminary clinical research in children 3-12 years of age who have recurrent or chronic middle ear inflammation and adenoiditis shows that using a compound (Yabro, IBSA Farmaceutici Italia S.r.l.) containing hyaluronic acid in saline intranasally 15 days per month for 3 months modestly reduces the number of patients with impaired otoscopy or middle ear function when compared to baseline (97888). It is unclear if this effect is due to the hyaluronic acid product or to the natural resolution of inflammation over time.
• Radiation dermatitis. It is unclear if topical hyaluronic acid is beneficial for the prevention of radiation dermatitis. Details: A small clinical study in patients with breast cancer undergoing adjuvant radiation therapy following lumpectomy shows that three daily applications of a specific hyaluronic acid gel (RadiaPlex, MPM Medical) to one side of the breast results in a grade 2 or greater dermatitis occurrence rate of 62%, compared with a rate of 48% on the side receiving petrolatum-based gel. A review of a planned interim analysis led to early trial discontinuation (108638).
• Rhinosinusitis. It is unclear if hyaluronic acid solution is beneficial for acute or chronic rhinosinusitis when used in an intranasal saline rinse. Details: A small clinical study in adults with acute rhinosinusitis who are being treated with levofloxacin and prednisone shows that using a 3% hyaluronic acid in saline nasal douche twice daily improves smell, obstruction, and discharge within 14 days when compared with saline alone (97886). A very small clinical study in patients with chronic rhinosinusitis without nasal polyps shows that receiving micronized nasal hyaluronic acid douches twice daily for 30 days improves nasal symptoms, nasal obstruction, and ability to smell to a similar degree as normal saline (104387).
• Sexual dysfunction. It is unclear if vaginal hyaluronic acid is beneficial for improving sexual function in adults with dyspareunia. Details: A small nonrandomized clinical study in females with dyspareunia while taking oral hormonal contraceptives shows that once daily vaginal application of a hyaluronic acid gel for 12 weeks reduces pain and improves sexual function at 12 weeks when compared baseline. Though patients treated with twice weekly vaginal estrogen therapy had better 12-week scores than patients treated with hyaluronic acid, it is unclear if the improvements from baseline differed between groups (108639).
• Tooth extraction. It is unclear if topical hyaluronic acid is beneficial for wound healing after tooth extraction. Details: A small clinical study in patients undergoing tooth extraction shows that application of hyaluronic acid 0.2% gel or hyaluronic acid 0.1% spray to the extraction socket twice daily for 7 days increases the rate of wound closure when compared with no treatment (110553). The validity of these findings is limited by a lack of placebo control group.
• Urinary tract infections (UTIs). Oral and intravesical hyaluronic acid have been evaluated for the prevention of UTI in combination with other ingredients; its effect when used alone is unclear. Details: A meta-analysis of prospective and retrospective studies shows that intravesical administration of 50 mL of specific solutions containing chondroitin sulfate 2% and hyaluronic acid 1.6% (iAluRil, IBSA Farmaceutici; Cystistat, Bioniche), once weekly to once monthly 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 (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. Also, the effect of hyaluronic acid alone is unclear. Oral hyaluronic acid has also been evaluated in combination with other ingredients for the prevention of recurrent UTI. A small prospective observational study shows that taking 1-2 capsules of a combination of hyaluronic acid, chondroitin sulfate, curcumin, and quercetin daily for 15 days each month, in conjunction with the use of local topical estrogen therapy for up to 12 months, reduces the number of women with recurrent UTIs when compared with taking the oral combination product or the vaginal estrogen product alone (96781). It is unclear if this effect is due to hyaluronic acid, other ingredients, or the combination.
• Vaginal atrophy. It is unclear if topical hyaluronic acid is beneficial for improving symptoms of vaginal atrophy. Details: A small, open-label clinical trial in patients going through menopause with symptoms of vaginal atrophy shows that applying 3 grams of a topical vaginal preparation of hyaluronic acid (Hyalo Gyn, Fidia Farmaceutici) every 3 days for 30 days improves vaginal health scores and reduces vaginal itching, vaginal burning, and pain during intercourse when compared to baseline. However, it does not appear to be any more effective than a polycarbophil vaginal gel (110549). Also, a small observational study in postmenopausal patients with vulvovaginal atrophy has found that applying a topical vaginal preparation containing hyaluronic acid (Justgin, JustPharma) three times weekly for 8 weeks is associated with improved symptoms of vaginal dryness, burning, and itching, as well as pain during intercourse, when compared to baseline (97887). The validity of these findings is limited by the lack of a comparator group and retrospective nature of the study. Some research has evaluated combination products containing hyaluronic acid for vaginal atrophy. A clinical trial in patients with cervical cancer shows that intravaginal administration of a specific suppository (Santes, Lo.Li. Pharma) containing hyaluronic acid, vitamin E, and vitamin A, once daily for the 5 week duration of radiotherapy reduces vaginal dryness, inflammation, and dyspareunia when compared with no additional treatment (101283). Also, a small, open-label clinical study in patients with vaginal atrophy after treatment for breast cancer shows that intravaginal application of a suppository containing hyaluronic acid and extract of aloe, marigold, tiger grass, and tea tree daily for 10 days then every 3 days for 80 days improves vaginal health scores and reduces vaginal dryness and pain during intercourse when compared to baseline, with no difference between the hyaluronic acid-containing suppository and vaginal laser therapy (110550). It is unclear if these findings are due to hyaluronic acid, other ingredients, or the combination.
• Wound healing. Small clinical studies show that topical hyaluronic acid and hyaluronic acid derivatives may improve the healing of various types of wounds. Details: A meta-analysis of small clinical trials suggest that topical hyaluronic acid and hyaluronic acid derivatives might improve the healing of burns, wounds, and skin ulcers when compared with control (104389). More evidence is needed to rate hyaluronic acid for these uses.

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LIKELY EFFECTIVE

• Cystic fibrosis. Long-term nebulized hypertonic sodium chloride improves lung function and reduces pulmonary exacerbations in patients with cystic fibrosis. Details: Meta-analyses of clinical research in adults with cystic fibrosis show that, when taken along with a bronchodilator and other standard therapies, nebulized hypertonic sodium chloride in concentrations of 3% to 7%, up to 10 mL twice daily for 4 weeks, increases forced expiratory volume at one second (FEV1) when compared with isotonic saline (sodium chloride 0.9%) (26230,26230). This benefit was not seen at 48 weeks. Other clinical research in adults with cystic fibrosis shows that inhaling sodium chloride 7%, 4 mL twice daily for 48 weeks, does not improve FEV1 when compared with isotonic saline. However, chronic treatment with hypertonic saline does reduce the number of pulmonary exacerbations and increase the number of patients without pulmonary exacerbations when compared with isotonic saline (29402). It is not clear if this benefit occurs in children with cystic fibrosis. The Pulmonary Clinical Practice Guidelines Committee of the Cystic Fibrosis Foundation recommends that individuals with cystic fibrosis aged 6 years or older use nebulized hypertonic saline long-term to improve lung function, reduce the number of exacerbations, and improve quality of life (29403).

POSSIBLY EFFECTIVE

• Amphotericin B nephrotoxicity. Oral sodium chloride seems to prevent nephrotoxicity associated with use of amphotericin B. Details: Clinical research shows that administering oral or intravenous sodium chloride 150 mEq daily during treatment with amphotericin B can attenuate the rise in serum creatinine levels and preserve renal function when compared to treatment with amphotericin B alone (26226).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Bipolar disorder. It is unclear if oral sodium is beneficial in preventing lithium level fluctuations in patients with bipolar disorder. Details: A moderate-sized open-label clinical study in adults with type I bipolar disorder receiving lithium carbonate shows that taking sodium chloride 1 gram daily for 12 weeks along with dietary salt restriction of 1 gram daily reduces the percentage of patients with lithium level fluctuations above 0.8 mEq/L, but does not significantly affect serum sodium, potassium, aldosterone, or creatinine levels when compared with controls who were not salt restricted, but were advised not to consume additional salt at the table (112909). However, the interpretation of these findings is limited by missing data in both groups.
• Canker sores. Although there is interest in using topical sodium chloride for canker sores, there is insufficient reliable information about the clinical effects of sodium chloride for this condition.
• Congestive heart failure. It is unclear if oral sodium is beneficial in patients with acute decompensated heart failure requiring decongestive therapy with diuretics. Details: A moderate-sized clinical study in adults hospitalized with acute decompensated heart failure requiring high-dose intravenous furosemide shows that taking sodium chloride 2 grams three times daily for up to 96 hours does not affect patient weight or serum creatinine levels when compared with placebo (112911). However, the clinical relevance of this study is unclear and it may have been inadequately powered to detect a difference between groups.
• Conjunctivitis. Although there is interest in using ophthalmic sodium chloride for conjunctivitis, there is insufficient reliable information about the clinical effects of sodium chloride for this condition.
• Hyponatremia. Although there is interest in using oral sodium chloride for hyponatremia, there is insufficient reliable information about the clinical effects of oral sodium chloride for this condition.
• Pharyngitis. Although there is interest in using topical sodium chloride for pharyngitis, there is insufficient reliable information about the clinical effects of sodium chloride for this condition.
• Prematurity. It is unclear if oral sodium is beneficial for premature infants. Details: Preliminary clinical research in infants born at less than 32 weeks' gestation shows that adding sodium 4 mEq/kg daily to enteral feedings, starting from the 7th day after birth and continuing through the 35th day, reduces the risk of developing hyponatremia and improves weight gain when compared with adding water (98180). A small, open-label clinical study in newborns less than 35 weeks gestation shows that high sodium intake, defined as an average of 0.25% sodium in maintenance fluids, for 48 hours on day 2 and 3 after birth results in less weight loss within the first 72 hours of life when compared with control, but does not improve mortality, length of hospital stay, or complications from prematurity (112908). However, interpretation of these findings is limited by varied concentrations of sodium as an intervention. More evidence is needed to rate sodium for these uses.

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LIKELY SAFE ...when used orally and appropriately. Supplements standardized to contain hyaluronic acid 70%, in an 80 mg daily dose, have been used daily for up to 3 months with no reports of adverse effects (55742,91779). ...when used topically and appropriately. Hyaluronic acid, in a gel or impregnated gauze, has been safely applied to the skin in clinical trials (7889,7892,104389,108627,108640). ...when eye drop preparations containing up to 0.3% hyaluronic acid are used multiple times per day for up to 3 months (97885,97894,97895,110555).

PREGNANCY:
There is insufficient reliable information available about the safety of hyaluronic acid; avoid using.

LACTATION:
There is insufficient reliable information available about the safety of hyaluronic acid. It is not known if hyaluronic acid is excreted in breast milk (7890); avoid using.

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LIKELY SAFE ...when used orally and appropriately. Sodium is safe in amounts that do not exceed the Chronic Disease Risk Reduction (CDRR) intake level of 2.3 grams daily (100310). Higher doses can be safely used therapeutically with appropriate medical monitoring (26226,26227).

POSSIBLY UNSAFE ...when used orally in high doses. Tell patients to avoid exceeding the CDRR intake level of 2.3 grams daily (100310). Higher intake can cause hypertension and increase the risk of cardiovascular disease (26229,98176,98177,98178,98181,98183,98184,100310,109395,109396,109398,109399). There is insufficient reliable information available about the safety of sodium when used topically.

CHILDREN: LIKELY SAFE
when used orally and appropriately (26229,100310). Sodium is safe in amounts that do not exceed the CDRR intake level of 1.2 grams daily for children 1 to 3 years, 1.5 grams daily for children 4 to 8 years, 1.8 grams daily for children 9 to 13 years, and 2.3 grams daily for adolescents (100310).

CHILDREN: POSSIBLY UNSAFE
when used orally in high doses. Tell patients to avoid prolonged use of doses exceeding the CDRR intake level of 1.2 grams daily for children 1 to 3 years, 1.5 grams daily for children 4 to 8 years, 1.8 grams daily for children 9 to 13 years, and 2.3 grams daily for adolescents (100310). Higher intake can cause hypertension (26229).

PREGNANCY AND LACTATION: LIKELY SAFE
when used orally and appropriately. Sodium is safe in amounts that do not exceed the CDRR intake level of 2.3 grams daily (100310).

PREGNANCY AND LACTATION: POSSIBLY UNSAFE
when used orally in higher doses. Higher intake can cause hypertension (100310). Also, both the highest and the lowest pre-pregnancy sodium quintile intakes are associated with an increased risk of hypertensive disorders of pregnancy, including gestational hypertension and pre-eclampsia, and the delivery of small for gestational age (SGA) infants when compared to the middle intake quintile (106264).

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ANTIHYPERTENSIVE DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = A Theoretically, a high intake of dietary sodium might reduce the effectiveness of antihypertensive drugs.  Details High intake of dietary sodium can increase systolic and diastolic blood pressure (26222). Also, high intake of sodium may necessitate increased use of antihypertensive medications to achieve blood pressure control in some patients, such as those with chronic kidney disease (26223).

CORTICOSTEROIDS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Concomitant use of mineralocorticoids and some glucocorticoids with sodium supplements might increase the risk of hypernatremia.  Details Mineralocorticoids and some glucocorticoids (corticosteroids) cause sodium retention. This effect is dose-related and depends on mineralocorticoid potency. It is most common with hydrocortisone, cortisone, and fludrocortisone, followed by prednisone and prednisolone (4425).

LITHIUM Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Altering dietary intake of sodium might alter the levels and clinical effects of lithium.  Details High sodium intake can reduce plasma concentrations of lithium by increasing lithium excretion (26225). Reducing sodium intake can significantly increase plasma concentrations of lithium and cause lithium toxicity in patients being treated with lithium carbonate (26224,26225). Stabilizing sodium intake is shown to reduce the percentage of patients with lithium level fluctuations above 0.8 mEq/L (112909). Patients taking lithium should avoid significant alterations in their dietary intake of sodium.

SODIUM-CONTAINING DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Concomitant use of sodium-containing drugs with additional sodium from dietary or supplemental sources may increase the risk of hypernatremia and long-term sodium-related complications.  Details The Chronic Disease Risk Reduction (CDRR) intake level of 2.3 grams of sodium daily indicates the intake at which it is believed that chronic disease risk increases for the apparently healthy population (100310). Some medications contain high quantities of sodium. When used in conjunction with sodium supplements or high-sodium diets, the CDRR may be exceeded. Additionally, concomitant use may increase the risk for hypernatremia; this risk is highest in the elderly and people with other risk factors for electrolyte disturbances.

TOLVAPTAN (Samsca) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = C Theoretically, concomitant use of tolvaptan with sodium might increase the risk of hypernatremia.  Details Tolvaptan is a vasopressin receptor 2 antagonist that is used to increase sodium levels in patients with hyponatremia (29406). Patients taking tolvaptan should use caution with the use of sodium salts such as sodium chloride.

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General ...Orally and topically, hyaluronic acid appears to be well tolerated.
Most Common Adverse Effects:
Topically: Eczema, erythema, itching, wound hemorrhage, wound infection (e.g., erysipelas).

Dermatologic ...The use of needle-free devices to inject hyaluronic acid for cosmetic purposes has been reported to cause serious injury, and in some cases permanent harm, to the skin, lips, and eyes (108613).
Topically, hyaluronic acid application has been reported to cause eczema, erythema, itching, wound hemorrhage, and wound infection (e.g., erysipelas) (108628,108640).

Ocular/Otic ...Ocular pain has been reported rarely in patients using eye drops containing up to 0. 3% hyaluronic acid (97885).

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General ...Orally, sodium is well tolerated when used in moderation at intakes up to the Chronic Disease Risk Reduction (CDRR) intake level. Topically, a thorough evaluation of safety outcomes has not been conducted.
Serious Adverse Effects (Rare):
Orally: Worsened cardiovascular disease, hypertension, kidney disease.

Cardiovascular ...Orally, intake of sodium above the CDRR intake level can exacerbate hypertension and hypertension-related cardiovascular disease (CVD) (26229,98176,100310,106263). A meta-analysis of observational research has found a linear association between increased sodium intake and increased hypertension risk (109398). Observational research has also found an association between increased sodium salt intake and increased risk of CVD, mortality, and cardiovascular mortality (98177,98178,98181,98183,98184,109395,109396,109399). However, the existing research is unable to confirm a causal relationship between sodium intake and increased cardiovascular morbidity and mortality; high-quality, prospective research is needed to clarify this relationship (100312). As there is no known benefit with increased salt intake that would outweigh the potential increased risk of CVD, advise patients to limit salt intake to no more than the CDRR intake level (100310).
A reduction in sodium intake can lower systolic blood pressure by a small amount in most individuals, and diastolic blood pressure in patients with hypertension (100310,100311,106261). However, post hoc analysis of a small crossover clinical study in White patients suggests that 24-hour blood pressure variability is not affected by high-salt intake compared with low-salt intake (112910). Additionally, the available research is insufficient to confirm that a further reduction in sodium intake below the CDRR intake level will lower the risk for chronic disease (100310,100311). A meta-analysis of clinical research shows that reducing sodium intake increases levels of total cholesterol and triglycerides, but not low-density lipoprotein (LDL) cholesterol, by a small amount (106261).
It is unclear whether there are safety concerns when sodium is consumed in amounts lower than the adequate intake (AI) levels. Some observational research has found that the lowest levels of sodium intake might be associated with increased risk of death and cardiovascular events (98181,98183). However, this finding has been criticized because some of the studies used inaccurate measures of sodium intake, such as the Kawasaki formula (98177,98178,101259). Some observational research has found that sodium intake based on a single 24-hour urinary measurement is inversely correlated with all-cause mortality (106260). The National Academies Consensus Study Report states that there is insufficient evidence from observational studies to conclude that there are harmful effects from low sodium intake (100310).

Endocrine ...Orally, a meta-analysis of observational research has found that higher sodium intake is associated with an average increase in body mass index (BMI) of 1. 24 kg/m2 and an approximate 5 cm increase in waist circumference (98182). It has been hypothesized that the increase in BMI is related to an increased thirst, resulting in an increased intake of sugary beverages and/or consumption of foods that are high in salt and also high in fat and energy (98182). One large observational study has found that the highest sodium intake is not associated with overweight or obesity when compared to the lowest intake in adolescents aged 12-19 years when intake of energy and sugar-sweetened beverages are considered (106265). However, in children aged 6-11 years, usual sodium intake is positively associated with increased weight and central obesity independently of the intake of energy and/or sugar-sweetened beverages (106265).

Gastrointestinal ...In one case report, severe gastritis and a deep antral ulcer occurred in a patient who consumed 16 grams of sodium chloride in one sitting (25759). Chronic use of high to moderately high amounts of sodium chloride has been associated with an increased risk of gastric cancer (29405).

Musculoskeletal ...Observational research has found that low sodium levels can increase the risk for osteoporosis. One study has found that low plasma sodium levels are associated with an increased risk for osteoporosis. Low levels, which are typically caused by certain disease states or chronic medications, are associated with a more than 2-fold increased odds for osteoporosis and bone fractures (101260).
Conversely, in healthy males on forced bed rest, a high intake of sodium chloride (7.7 mEq/kg daily) seems to exacerbate disuse-induced bone and muscle loss (25760,25761).

Oncologic ...Population research has found that high or moderately high intake of sodium chloride is associated with an increased risk of gastric cancer when compared with low sodium chloride intake (29405). Other population research in patients with gastric cancer has found that a high intake of sodium is associated with an approximate 65% increased risk of gastric cancer mortality when compared with a low intake. When zinc intake is taken into consideration, the increased risk of mortality only occurred in those with low zinc intake, but the risk was increased to approximately 2-fold in this sub-population (109400).

Pulmonary/Respiratory ...In patients with hypertension, population research has found that sodium excretion is modestly and positively associated with having moderate or severe obstructive sleep apnea. This association was not found in normotensive patients (106262).

Renal ...Increased sodium intake has been associated with impaired kidney function in healthy adults. This effect seems to be independent of blood pressure. Observational research has found that a high salt intake over approximately 5 years is associated with a 29% increased risk of developing impaired kidney function when compared with a lower salt intake. In this study, high salt intake was about 2-fold higher than low salt intake (101261).

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