| Ingredients | Amount Per Serving |
|---|---|
|
Calories
|
15 {Calories} |
|
Total Carbohydrates
|
3 Gram(s) |
|
(Ascorbic Acid)
|
60 mg |
|
(as Manganese Sulfate)
(Manganese (Form: as Manganese Sulfate) )
|
2 mg |
|
(Na)
|
40 mg |
|
(1,500 mg)
(Glucosamine HCl Note: 1,500 mg )
|
1.5 Gram(s) |
|
Proprietary Blend
(Proprietary Blend Note: 1,250 mg )
|
1.25 Gram(s) |
|
(MSM)
|
|
|
(Boswellia serrata )
(wood)
|
|
|
Boswellia serrata AKBA standardized extract (wood) resin
(Boswellia serrata )
(wood)
|
100 mg |
|
(Sodium Borate)
(Boron (Form: as Sodium Borate) )
|
3 mg |
Crospovidone, Povidone, Microcrystalline Cellulose, Polyvinyl Alcohol, Titanium Dioxide, Polyethylene Glycol, Stearic Acid (Alt. Name: C18:0), Talc, Magnesium Stearate, Silicon Dioxide (Alt. Name: SiO2), Caramel color
Below is general information about the effectiveness of the known ingredients contained in the product Triple Strength Glucosamine Chondroitin. Some ingredients may not be listed. This information does NOT represent a recommendation for or a test of this specific product as a whole.
INSUFFICIENT RELIABLE EVIDENCE to RATE
INSUFFICIENT RELIABLE EVIDENCE to RATE
INSUFFICIENT RELIABLE EVIDENCE to RATE
INSUFFICIENT RELIABLE EVIDENCE to RATE
INSUFFICIENT RELIABLE EVIDENCE to RATE
INSUFFICIENT RELIABLE EVIDENCE to RATE
INSUFFICIENT RELIABLE EVIDENCE to RATE
INSUFFICIENT RELIABLE EVIDENCE to RATE
INSUFFICIENT RELIABLE EVIDENCE to RATE
INSUFFICIENT RELIABLE EVIDENCE to RATE
Below is general information about the safety of the known ingredients contained in the product Triple Strength Glucosamine Chondroitin. Some ingredients may not be listed. This information does NOT represent a recommendation for or a test of this specific product as a whole.
LIKELY SAFE ...when used orally and appropriately. Boron is safe in amounts that do not exceed the tolerable upper intake level (UL) 20 mg daily (7135). ...when used vaginally. Boric acid, the most common form of boron, has been safely used for up to six months (15443,15444,15445,15446,15458,15449,15451,15453,15454). ...when used topically. Boron, in the form of sodium pentaborate pentahydrate 3% gel, has been applied to the skin with apparent safety up to four times daily for up to 5 weeks (95660,109557).
POSSIBLY UNSAFE ...when used orally in doses exceeding the UL of 20 mg daily. Higher doses might adversely affect the testes and male fertility (7135). Poisoning has occurred after ingestion of boron 2.12 grams daily for 3-4 weeks (17). Death has occurred after ingesting a single dose of 30 grams (36848,36863).
CHILDREN: LIKELY SAFE
when used orally and appropriately.
Boron is safe in amounts that do not exceed the tolerable upper intake level (UL). The UL by age is 3 mg daily at 1-3 years, 6 mg daily at 4-8 years, 11 mg daily at 9-13 years, and 17 mg daily at 14 years or older (7135). The UL for infants has not been determined (7135).
CHILDREN: POSSIBLY UNSAFE
when used orally in doses exceeding the age-based UL (7135).
...when applied topically in large quantities. Infant deaths have occurred after the use of topical boric acid powder to prevent diaper rash (36873,36874).
PREGNANCY AND LACTATION: LIKELY SAFE
when used orally and appropriately.
Boron is safe in amounts that do not exceed the UL during pregnancy or lactation, which is 20 mg daily in those 19-50 years of age or 17 mg daily for those 14-18 years of age (7135).
PREGNANCY AND LACTATION: POSSIBLY UNSAFE
when used orally in doses exceeding the UL.
Higher doses might impair growth and cause adverse effects in the developing fetus (7135,102058). ...when used vaginally. Intravaginal boric acid has been associated with a 2.7- to 2.8-fold increased risk of birth defects when used during the first 4 months of pregnancy (15443,15645).
LIKELY SAFE ...when used orally and appropriately. Boswellia serrata extract in doses up to 1000 mg daily has been safely used in several clinical trials lasting up to 6 months (1708,1709,12432,12434,12438,17948,17949,17950,91379)(100699,100713,102089,109568). Boswellia serrata extract has been used with apparent safety at a dose of 2400 mg for up to 1 month (102092).
PREGNANCY AND LACTATION: LIKELY SAFE
when used orally in amounts commonly found in foods (4912).
There is insufficient reliable information available about the safety of using Boswellia serrata in medicinal amounts; avoid using.
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.
LIKELY SAFE ...when used orally in amounts commonly found in foods. Gelatin has Generally Recognized as Safe (GRAS) status in the US (4912).
POSSIBLY SAFE ...when used orally and appropriately in medicinal amounts, short-term . A specific type of gelatin from donkey hide, called colla corii asini, has been safely used in doses of 6-10 grams orally daily for 6-8 weeks. Higher doses of 15 grams daily have been associated with an increased risk of inflammatory adverse effects, including sore throat, swollen gums, local eczema, and oral ulcers (97634,107011). Since gelatin is often derived from bovine bones and skin, there is some concern about contamination with diseased animal parts (1825). So far, there are no reports of disease transmission to humans due to use of contaminated gelatin preparations.
CHILDREN: POSSIBLY SAFE
when gelatin tannate is used orally and appropriately in medicinal amounts, short-term.
In children under 15 kg or under 3 years of age, gelatin tannate has been used with apparent safety at doses up to 250 mg four times daily for up to 5 days. In children over 15 kg or over 3 years of age, it has been used with apparent safety at doses up to 500 mg four times daily for up to 5 days (103296). There is insufficient reliable information available about the safety of other forms of gelatin in children.
PREGNANCY: LIKELY SAFE
when used orally in the amounts commonly found in foods.
PREGNANCY: POSSIBLY SAFE
when a specific type of gelatin from donkey hide, called colla corii asini, is used orally in doses of 10 grams daily for 6 weeks.
Higher doses of 15 grams daily have been associated with an increased risk of inflammatory adverse effects, including sore throat, swollen gums, local eczema, and ulcers in the oral cavity (97634).
There is insufficient reliable information available about the safety of other types of gelatin when used during pregnancy in medicinal amounts.
LACTATION: LIKELY SAFE
when used orally in the amounts commonly found in foods.
There is insufficient reliable information available about the safety of using larger amounts of gelatin during lactation; avoid using.
LIKELY SAFE ...when glucosamine sulfate is used orally and appropriately. Glucosamine sulfate has been used safely in multiple clinical trials at a dose of 1000-1500 mg daily for 4 weeks to 3 years (2604,7026,8942,11340,12461)(14305,16717,89558,89567,94380,94382,95785).
POSSIBLY SAFE ...when glucosamine hydrochloride is used orally and appropriately. Glucosamine hydrochloride has been used with apparent safety at a dose of 1400-1600 mg daily for up to 2 years (4237,13579,14809,18344,42477,89516,89519,95784). Glucosamine hydrochloride 2 grams daily has also been used with apparent safety for up to 3 weeks (103281). ...when N-acetyl glucosamine is used orally and appropriately. N-acetyl glucosamine 100 mg daily has been used with apparent safety for up to 24 weeks (95795). ...when N-acetyl glucosamine is applied topically and appropriately. A 2% N-acetyl glucosamine cream has been safely used for up to 10 weeks (92721). ...when N-acetyl glucosamine is used rectally and appropriately. N-acetyl glucosamine 3-4 grams daily in 2 divided doses has been safely used (10234). ...when glucosamine sulfate is used intramuscularly and appropriately, short-term. Intramuscular glucosamine sulfate seems to be well tolerated when given twice weekly for up to 6 weeks (2605).
PREGNANCY AND LACTATION:
Insufficient reliable information available; avoid using.
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.
LIKELY SAFE ...when used orally and appropriately. Oral manganese is safe when used in doses below the tolerable upper intake level (UL) of 11 mg daily for adults 19 years and older (1994,7135). ...when used parenterally and appropriately. Parenteral manganese chloride and manganese sulfate are FDA-approved prescription products.
POSSIBLY UNSAFE ...when used orally in high doses. Doses exceeding 11 mg daily can cause significant adverse effects (7135). ...when used parenterally in moderate or high doses, long-term. Reports of neurotoxicity and Parkinson-like symptoms have been reported with parenteral nutrition manganese doses above 60 mcg daily. It is recommended that adults on long-term parenteral nutrition receive manganese in doses of no more than 55 mcg daily (99302).
LIKELY UNSAFE ...when inhaled in moderate doses, long-term. According to the US Occupational Safety and Health Administration (OSHA), the permissible exposure limit (PEL) for manganese is 5 mg/m3. Exposure to higher amounts of manganese dust or fumes has been associated with central nervous system toxicity, Parkinson-like symptoms, and poor bone health (61296,102516).
CHILDREN: LIKELY SAFE
when used orally and appropriately.
Manganese is safe in children when used in daily doses less than the tolerable upper intake level (UL) of 2 mg in children 1-3 years, 3 mg in children 4-8 years, 6 mg in children 9-13 years, and 9 mg in children 14-18 years (7135).
CHILDREN: POSSIBLY UNSAFE
when used orally in excessive doses.
Daily doses greater than the UL are associated with a greater risk of toxicity (7135).
CHILDREN: LIKELY UNSAFE
when inhaled at moderate doses, long-term.
Exposure to high amounts of manganese dust has been associated with central nervous system toxicity and Parkinson-like symptoms (61296).
PREGNANCY AND LACTATION: LIKELY SAFE
when used orally and appropriately.
Manganese is safe when used in doses below the tolerable upper intake level (UL) of 11 mg daily during pregnancy or lactation in those aged 19 or older. However, those under 19 years of age should limit doses to less than 9 mg daily (7135).
PREGNANCY AND LACTATION: POSSIBLY UNSAFE
when used orally in excessive doses.
Doses over the UL are associated with a greater risk of toxicity (7135). Additionally, observational research shows that adults with higher blood manganese levels have greater odds of delivering low birth weight or small for gestational age (SGA) male, but not female, infants (102515).
PREGNANCY AND LACTATION: LIKELY UNSAFE
when inhaled at moderate doses, long-term.
Manganese salts can cross the placenta, and animal research suggests that large amounts of manganese may be teratogenic (61296).
POSSIBLY SAFE ...when used orally and appropriately, short term. MSM in doses of 1.5-6 grams daily or 50 mg/kg daily has been used safely in studies lasting up to 6 months (8574,12469,14335,17127,19312,96446,96448,102555). One specific product (OptiMSM, Bergstrom Nutrition) is Generally Recognized As Safe (GRAS) by the United States Food and Drug Administration (FDA) (102555). ...when used topically. Topical cream containing MSM and silymarin, as well as topical gel containing MSM, hyaluronic acid, and tea tree oil, have been used with apparent safety for up to 20 days (19318,19319).
PREGNANCY AND LACTATION:
Insufficient reliable information available; avoid using.
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).
LIKELY SAFE ...when used orally, topically, intramuscularly, or intravenously and appropriately. Vitamin C is safe when taken orally in doses below the tolerable upper intake level (UL). Tell patients not to exceed the UL of 2000 mg daily (1959,4713,4714,4844). ...when used intravenously or intramuscularly and appropriately. Injectable vitamin C is an FDA-approved prescription product (15).
POSSIBLY UNSAFE ...when used orally in excessive doses. Doses greater than the tolerable upper intake level (UL) of 2000 mg daily can significantly increase the risk of adverse effects such as osmotic diarrhea and gastrointestinal upset (4844).
CHILDREN: LIKELY SAFE
when used orally and appropriately (4844,10352,14443).
CHILDREN: POSSIBLY UNSAFE
when used orally in excessive amounts.
Tell patients not to use doses above the tolerable upper intake level (UL) of 400 mg daily for children ages 1 to 3 years, 650 mg daily for children 4 to 8 years, 1200 mg daily for children 9 to 13 years, and 1800 mg daily for adolescents 14 to 18 years. Higher doses can cause osmotic diarrhea and gastrointestinal upset (4844).
PREGNANCY AND LACTATION: LIKELY SAFE
when used orally and appropriately (4844).
PREGNANCY AND LACTATION: POSSIBLY UNSAFE
when used orally in excessive doses.
Tell patients over age 19 not to use doses exceeding the UL of 2000 mg daily when pregnant or breast-feeding and for those 14-18 years of age not to use doses exceeding 1800 mg daily when pregnant or breast-feeding. Higher doses can cause osmotic diarrhea and gastrointestinal upset. Large doses of vitamin C during pregnancy can also cause newborn scurvy (4844); avoid using.
Below is general information about the interactions of the known ingredients contained in the product Triple Strength Glucosamine Chondroitin. Some ingredients may not be listed. This information does NOT represent a recommendation for or a test of this specific product as a whole.
Theoretically, Boswellia serrata might increase the levels of CYP1A2 substrates.
 Details
In vitro research shows that Boswellia serrata gum resin inhibits CYP1A2 enzymes (21178).
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Theoretically, Boswellia serrata might increase the levels of CYP2C19 substrates.
Details
In vitro research shows that Boswellia serrata gum resin inhibits CYP2C19 enzymes (21178).
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Theoretically, Boswellia serrata might increase the levels of CYP2C9 substrates.
Details
In vitro research shows that Boswellia serrata gum resin inhibits CYP2C9 enzymes (21178).
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Theoretically, Boswellia serrata might increase the levels of CYP2D6 substrates.
Details
In vitro research shows that Boswellia serrata gum resin inhibits CYP2D6 enzymes (21178).
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Theoretically, Boswellia serrata might increase the levels of CYP3A4 substrates.
Details
In vitro research shows that Boswellia serrata gum resin inhibits CYP3A4 enzymes (21178).
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Theoretically, Boswellia serrata might alter the effects of immunosuppressive drugs.
Details
Some in vitro research suggests that Boswellia serrata extracts might inhibit mediators of autoimmune disorders such as leukotrienes and reduce production of antibodies and cell-mediated immunity (12432,12435,12437,12438). However, other in vitro research suggests that, when coupled with calcium ions, boswellic acids containing the keto group have immunostimulant properties within specific cell signaling pathways (21180).
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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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Acetaminophen might interfere with the activity of glucosamine sulfate by interacting with the sulfate portion.
Details
Anecdotal reports suggest that adding glucosamine to an acetaminophen regimen might decrease pain control in patients with osteoarthritis (14806). Some research suggests that the sulfate portion of glucosamine sulfate might contribute to its effect in osteoarthritis. Since acetaminophen metabolism requires sulfur and reduces serum sulfate concentrations, acetaminophen could theoretically interfere with the action of glucosamine sulfate. Conversely, the administration of sulfate could theoretically decrease the effectiveness of acetaminophen in sulfate-deficient people by increasing its clearance (10313).
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Despite initial concerns, it is unlikely that glucosamine will interfere with the effects of antidiabetes drugs.
Details
In vitro and animal research has suggested that glucosamine might increase insulin resistance or decrease insulin production (371,372,3406,18342,18343). This has raised concerns that taking glucosamine might worsen diabetes and decrease the effectiveness of diabetes drugs. However, clinical research suggests that glucosamine does not have adverse effects on blood glucose or glycated hemoglobin (HbA1C) in healthy, obese, or type 2 diabetes patients (7026,7075,8942,10311,10317,15111).
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Theoretically glucosamine may induce resistance to topoisomerase II inhibitors.
Details
In vitro research suggests that glucosamine might induce resistance to etoposide (VP16, VePesid) and doxorubicin (Adriamycin) by reducing inhibition of topoisomerase II, an enzyme required for DNA replication in tumor cells (7639). This effect has not been reported in humans.
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Glucosamine might increase the anticoagulant effects of warfarin and increase the risk of bruising and bleeding.
Details
In two individual case reports, glucosamine/chondroitin combinations were associated with a significant increase in international normalized ratio (INR) in patients previously stabilized on warfarin (11389,16130). In one case, the increase in INR occurred only after tripling the dose of a glucosamine/chondroitin supplement from 500 mg/400 mg daily to 1500/1200 mg daily (16130). Additionally, 20 voluntary case reports to the U.S. 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 to increased INR in patients taking warfarin (16131). The mechanism of this interaction is unclear. Glucosamine is a small component of heparin, but is not thought to have anticoagulant activity; however, animal research suggests that it might have antiplatelet activity (16131).
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Theoretically, the risk for manganese toxicity might increase when taken with antipsychotic drugs.
Details
Hallucinations and behavioral changes have been reported in a patient with liver disease who was taking haloperidol and manganese. Researchers speculate that taking manganese along with haloperidol, phenothiazine-derivatives, or other antipsychotic medications might increase the risk of manganese toxicity in some patients (61493).
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Theoretically, manganese might reduce the absorption of quinolone antibiotics.
Details
Manganese is a multivalent cation. Interactions resulting in reduced quinolone absorption have been reported between quinolones and other multivalent cations, such as calcium and iron (488).
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Theoretically, manganese might reduce the absorption of tetracycline antibiotics.
Details
Manganese is a multivalent cation. Interactions resulting in reduced tetracycline absorption have been reported between tetracyclines and other multivalent cations, such as calcium and iron (488).
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Theoretically, a high intake of dietary sodium might reduce the effectiveness of antihypertensive drugs.
Details
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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).
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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.
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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.
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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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High-dose vitamin C might slightly prolong the clearance of acetaminophen.
Details
A small pharmacokinetic study in healthy volunteers shows that taking high-dose vitamin C (3 grams) 1.5 hours after taking acetaminophen 1 gram slightly increases the apparent half-life of acetaminophen from around 2.3 hours to 3.1 hours. Ascorbic acid competitively inhibits sulfate conjugation of acetaminophen. However, to compensate, elimination of acetaminophen glucuronide and unconjugated acetaminophen increases (6451). This effect is not likely to be clinically significant.
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Theoretically, antioxidant effects of vitamin C might reduce the effectiveness of alkylating agents.
Details
The use of antioxidants like vitamin C during chemotherapy is controversial. There is concern that antioxidants could reduce the activity of chemotherapy drugs that generate free radicals, such as cyclophosphamide, chlorambucil, carmustine, busulfan, and thiotepa (391). In contrast, some researchers theorize that antioxidants might make chemotherapy more effective by reducing oxidative stress that could interfere with apoptosis (cell death) of cancer cells (14012,14013). More evidence is needed to determine what effect, if any, antioxidants such as vitamin C have on chemotherapy.
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Vitamin C can increase the amount of aluminum absorbed from aluminum compounds.
Details
Research in animals and humans shows that vitamin C increases aluminum absorption, theoretically by chelating aluminum and keeping it in solution where it is available for absorption (10549,10550,10551,21556). In people with normal renal function, urinary excretion of aluminum will likely increase, making aluminum retention and toxicity unlikely (10549). Patients with renal failure who take aluminum-containing compounds such as phosphate binders should avoid vitamin C supplements in doses above the recommended dietary allowances.
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Theoretically, the antioxidant effects of vitamin C might reduce the effectiveness of antitumor antibiotics.
Details
The use of antioxidants like vitamin C during chemotherapy is controversial. There is concern that antioxidants could reduce the activity of chemotherapy drugs which generate free radicals, such as doxorubicin (391). In contrast, some researchers theorize that antioxidants might make chemotherapy more effective by reducing oxidative stress that could interfere with apoptosis (cell death) of cancer cells (14012,14013). More evidence is needed to determine what effects, if any, antioxidants such as vitamin C have on chemotherapy.
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Acidification of the urine by vitamin C might increase aspirin levels.
Details
It has been suggested that acidification of the urine by vitamin C could increase reabsorption of salicylates by the renal tubules, and increase plasma salicylate levels (3046). However, short-term use of up to 6 grams daily of vitamin C does not seem to affect urinary pH or salicylate excretion (10588,10589), suggesting this interaction is not clinically significant.
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Acidification of the urine by vitamin C might increase choline magnesium trisalicylate levels.
Details
It has been suggested that acidification of the urine by vitamin C could increase reabsorption of salicylates by the renal tubules, and increase plasma salicylate levels (3046,4531). However, short-term use of up to 6 grams daily of vitamin C does not seem to affect urinary pH or salicylate excretion (10588,10589), suggesting this interaction probably is not clinically significant.
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Vitamin C might increase blood levels of estrogens.
Details
Increases in plasma estrogen levels of up to 55% occur under some circumstances when vitamin C is taken concurrently with oral contraceptives or hormone replacement therapy, including topical products (129,130,11161). It is suggested that vitamin C prevents oxidation of estrogen in the tissues, regenerates oxidized estrogen, and reduces sulfate conjugation of estrogen in the gut wall (129,11161). When tissue levels of vitamin C are high, these processes are already maximized and supplemental vitamin C does not have any effect on estrogen levels. Increases in plasma estrogen levels may occur when patients who are deficient in vitamin C take supplements (11161). Monitor these patients for estrogen-related side effects.
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Theoretically, vitamin C might decrease levels of fluphenazine.
Details
In one patient there was a clinically significant decrease in fluphenazine levels when vitamin C (500 mg twice daily) was started (11017). The mechanism is not known, and there is no further data to confirm this interaction.
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Vitamin C can modestly reduce indinavir levels.
Details
One pharmacokinetic study shows that taking vitamin C 1 gram orally once daily along with indinavir 800 mg orally three times daily reduces the area under the concentration-time curve of indinavir by 14%. The mechanism of this interaction is unknown, but it is unlikely to be clinically significant in most patients. The effect of higher doses of vitamin C on indinavir levels is unknown (11300,93578).
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Vitamin C can increase levothyroxine absorption.
Details
Two clinical studies in adults with poorly controlled hypothyroidism show that swallowing levothyroxine with a glass of water containing vitamin C 500-1000 mg in solution reduces thyroid stimulating hormone (TSH) levels and increases thyroxine (T4) levels when compared with taking levothyroxine alone. This suggests that vitamin C increases the oral absorption of levothyroxine, possibly due to a reduction in pH (102978).
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Vitamin C might decrease the beneficial effects of niacin on high-density lipoprotein (HDL) cholesterol levels.
Details
A combination of niacin and simvastatin (Zocor) effectively raises HDL cholesterol levels in patients with coronary disease and low HDL levels. Clinical research shows that taking a combination of antioxidants (vitamin C, vitamin E, beta-carotene, and selenium) along with niacin and simvastatin (Zocor) attenuates this rise in HDL, specifically the HDL-2 and apolipoprotein A1 fractions, by more than 50% in patients with coronary disease (7388,11537). It is not known whether this adverse effect is due to a single antioxidant such as vitamin C, or to the combination. It also is not known whether it will occur in other patient populations.
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Acidification of the urine by vitamin C might increase salsalate levels.
Details
It has been suggested that acidification of the urine by vitamin C could increase reabsorption of salicylates by the renal tubules, and increase plasma salicylate levels (3046). However, short-term use of up to 6 grams/day vitamin C does not seem to affect urinary pH or salicylate excretion (10588,10589), suggesting this interaction probably is not clinically significant.
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High-dose vitamin C might reduce the levels and effectiveness of warfarin.
Details
Vitamin C in high doses may cause diarrhea and possibly reduce warfarin absorption (11566). There are reports of two people who took up to 16 grams daily of vitamin C and had a reduction in prothrombin time (9804,9806). Lower doses of 5-10 grams daily can also reduce warfarin absorption. In many cases, this does not seem to be clinically significant (9805,9806,11566,11567). However, a case of warfarin resistance has been reported for a patient who took vitamin C 500 mg twice daily. Cessation of vitamin C supplementation resulted in a rapid increase in international normalized ratio (INR) (90942). Tell patients taking warfarin to avoid taking vitamin C in excessively high doses (greater than 10 grams daily). Lower doses may be safe, but the anticoagulation activity of warfarin should be monitored. Patients who are stabilized on warfarin while taking vitamin C should avoid adjusting vitamin C dosage to prevent the possibility of warfarin resistance.
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Below is general information about the adverse effects of the known ingredients contained in the product Triple Strength Glucosamine Chondroitin. Some ingredients may not be listed. This information does NOT represent a recommendation for or a test of this specific product as a whole.
General
...Orally, boron is generally well tolerated when used in doses below the tolerable upper intake level (UL) of 20 mg.
Vaginally, boron is well tolerated.
Most Common Adverse Effects:
Orally: Anorexia, dermatitis, erythema, indigestion.
Vaginally: Burning and pain.
Dermatologic
...Orally, chronic use of 1 gram daily of boric acid or 25 grams daily of boric tartrate can cause dermatitis and alopecia (7135).
Larger doses can result in acute poisoning. Symptoms of poisoning in adults and children may include skin erythema, desquamation, and exfoliation (17).
Gastrointestinal
...Orally, chronic use of 1 gram daily of boric acid or 25 grams daily of boric tartrate can cause anorexia and indigestion (7135).
Larger doses can result in acute poisoning. Children who have ingested 5 grams or more of borates can have persistent nausea, vomiting, and diarrhea leading to acute dehydration, shock, and coma. Adults who have ingested 15-20 grams of borate can exhibit nausea, vomiting, diarrhea, epigastric pain, hematemesis, and a blue-green discoloration of feces and vomit (17).
Genitourinary ...Vaginally, boric acid can cause vulvovaginal burning and dyspareunia in males if intercourse occurs shortly after vaginal treatment (15447).
Neurologic/CNS ...Orally, large doses can result in acute poisoning. Poisoning with boron can cause hyperexcitability, irritability, tremors, convulsions, weakness, lethargy, and headaches (17).
Ocular/Otic ...Exposure to boric acid or boron oxide dust has been reported to cause eye irritation (36852).
Pulmonary/Respiratory ...Exposure to boric acid and boron oxide dust has been reported to cause mouth and nasal passage irritation, sore throat, and productive cough (36852).
General
...Orally, Boswellia serrata extract is generally well-tolerated.
For information on the safety of Boswellia serrata when applied topically or used as aromatherapy, see the Frankincense monograph.
Most Common Adverse Effects:
Orally: Abdominal pain, diarrhea, headache, heartburn, itching, nausea.
Serious Adverse Effects (Rare):
Orally: Large amounts of Boswellia serrata gum resin can cause bezoar formation.
Dermatologic ...Orally, Boswellia serrata extract (5-Loxin) has been associated with itching at doses of 100-250 mg daily (17948).
Gastrointestinal ...Orally, Boswellia serrata extract may cause diarrhea, nausea, abdominal pain, and heartburn (1708,12432,12438,17948,17949,17950,21149,109567). A case of a large gastrointestinal bezoar has been reported in a 17-year-old female who chewed and swallowed large quantities of boswellia gum resin (Boswellia species not specified) for celiac disease (36914).
Musculoskeletal ...Orally, Boswellia serrata extract (5-Loxin) has been associated with one case of foot edema and four cases of generalized weakness in one clinical study (17948).
Neurologic/CNS ...Orally, Boswellia serrata extract may cause dizziness, headache, and vertigo. In one clinical study, nearly 11% of patients taking a specific Boswellia serrata extract (K-Vie) reported headache. Dizziness and vertigo were also reported, but at lower rates (109567). In another study, headache was reported in one patient taking a specific Boswellia serrata extract (5-Loxin) (17948).
Psychiatric ...Orally, one case of mania is reported in a 73-year-old male who took Boswellia powder mixed with honey for 3 days. The patient recovered after hospitalization and treatment with olanzapine (110526).
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).
General
...Orally, gelatin seems to be well tolerated.
Most Common Adverse Effects:
Oral: Belching, bloating, and dyspepsia.
Serious Adverse Effects (Rare):
Injection: IgE-mediated allergic reactions, Kounis syndrome.
Gastrointestinal ...Orally, gelatin can cause unpleasant taste, sensation of heaviness in the stomach, bloating, dyspepsia, and belching (7704).
Immunologic
...Gelatin can cause allergic reactions.
Gelatin in foods can cause initial sensitization (7703). Gelatin-containing medicines including oral medications, suppositories, vaccines, and injectable products can cause IgE-mediated allergic reactions, including urticaria, angioedema, wheezing, hypotension, and anaphylaxis (7708,7709,7710,97633,111345). In the US, gelatin is used as a stabilizer in some vaccines such as measles, mumps, and rubella (MMR), and diphtheria, pertussis, tetanus (DPT) (7711). In one case report, a 73-year-old male experienced anaphylactic symptoms within 10 minutes of receiving gelatin lysate as a plasma expander during a routine surgery. The patient proceeded to develop heart, respiratory, and kidney failure and died 76 days after receiving the gelatin infusion (97633). At least 12 case reports describe life-threatening anaphylaxis after administration of gelatin-containing hemostatic agents during surgery. In these cases, hypotension, tachycardia, and increased airway pressure occurred shortly after injection of the agent into the pedicle tract (111345).
There are at least two cases of Kounis syndrome, an acute coronary syndrome related to a massive mast cell activation, after the use of a gelatin infusion during general anesthesia. In one case, immediate symptoms included bradycardia and hypotension, followed by myocardial ischemia and coronary vasospasm (97631).
Other ...Since gelatin is sometimes produced from bovine bones and skin, there is some concern about the potential risk of contamination with diseased animals and transmission of bovine spongiform encephalopathy (BSE, mad cow disease) and other diseases (1825). So far, there are no reports of BSE or other disease transmission to humans from gelatin products.
General
...Orally, all forms of glucosamine seem to be well tolerated.
Topically and rectally, N-acetyl glucosamine also seems to be well tolerated. Intramuscularly, glucosamine sulfate seems to be well tolerated. However, a thorough evaluation of safety outcomes has not been conducted for non-oral routes of administration.
Most Common Adverse Effects:
Orally: Bloating, constipation, cramps, diarrhea, heartburn, nausea.
Serious Adverse Effects (Rare):
Orally: There have been rare reports of severe allergic reactions and hepatotoxicity.
Cardiovascular
...One case of mesenteric occlusion in a clinical trial was considered possibly related to use of oral glucosamine hydrochloride and chondroitin sulfate (89520).
Some observational research has found that glucosamine use in patients with osteoarthritis is associated with a higher risk of cardiovascular disease (CVD) events when compared with non-use (109642). However, glucosamine users tended to be older, have multiple comorbidities, and be on antihyperlipidemic or antiplatelet therapy. Furthermore, other observational research in healthy adults has found that glucosamine use is associated with a reduced risk of fatal and non-fatal CVD events (99682). Higher quality, prospective research is needed to clarify the relationship, if any, between glucosamine and CVD risk.
Dermatologic ...Orally, glucosamine might cause skin reactions, including itching, rash, and erythema (2608,20084,89567,110628,113636). Also, fingernail and toenail toughening, with an increased rate of growth, has been reported (89572). Topically, N-acetyl glucosamine 2% with niacinamide 4% cream might cause rare skin reactions (92721). Photosensitization that was reproducible with re-challenge was reported in a case report of an individual using glucosamine (form unknown) and chondroitin (10408).
Endocrine ...Orally, glucosamine does not seem to impact blood glucose. Preliminary research and anecdotal reports have found that various forms of glucosamine might increase insulin resistance or decrease insulin production, increasing fasting plasma glucose levels (22,371,372,1203,3406,5059,7637,14810). This has raised concerns that taking glucosamine sulfate might worsen diabetes and decrease the effectiveness of diabetes drugs. However, clinical research suggests that various forms of glucosamine do not have adverse effects on blood glucose or glycated hemoglobin (HbA1C) in healthy, obese, patients with type 2 diabetes or impaired glucose tolerance (7026,7075,7638,8942,10311,10317,12107,14808,15111,89563).
Gastrointestinal ...Orally, glucosamine has been associated with gastrointestinal problems, including epigastric and abdominal pain, cramps, heartburn, diarrhea, nausea, dyspepsia, vomiting, constipation, and flatulence (1520,2608,16717,20084,20104,20105,89561,89562,89567,89568)(108897,110628,111647,113636). In older persons, use of glucosamine sulfate is associated with oral dryness (89564). In a clinical trial, a case of Helicobacter pylori gastritis was considered probably related to the use of glucosamine hydrochloride (89516).
Hepatic ...Although relatively uncommon, combinations of glucosamine and chondroitin sulfate have been associated with acute liver injury that mimics autoimmune hepatitis. Of 151 patients at an outpatient clinic for liver diseases, 23 acknowledged use of products containing glucosamine (form unspecified) and/or chondroitin. However, only 2 cases had an apparent relationship between transaminase elevation and the use of recommended doses of glucosamine and chondroitin sulfate. Aminotransferase levels, which were increased by four- to seven-fold, returned to normal following discontinuation of treatment (89515). In another case, a 65-year-old male presented to the hospital with signs and symptoms of drug-induced autoimmune hepatitis. The patient had used Condrosulf, containing chondroitin sulfate, for two years, followed by Vita Mobility Complex, containing chondroitin sulfate and glucosamine sulfate, 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 glucosamine, other ingredients, or the combination.
Immunologic ...There is some concern that glucosamine products might cause allergic reactions in sensitive individuals. One review of glucosamine-related adverse events in Australia found that 72% of all reports involved hypersensitivity reactions. Of these reactions, 35% were mild, including pruritis, urticaria, and lip edema, 49% were moderate, including dyspnea, and 16% were severe, including gait disturbance, somnolence, and hypotension. Anaphylaxis was reported in 1.5% of cases (102115). Also, in one clinical trial, a single patient developed allergic dermatitis considered to be likely due to glucosamine hydrochloride (89516). Glucosamine is derived from the exoskeletons of shrimp, lobster, and crabs. However, it is unclear if these adverse reactions were due to a shellfish sensitivity or general atopy. Additionally, shellfish allergies are caused by IgE antibodies to antigens in the meat of shellfish, not to antigens in the exoskeleton. Regardless, it is possible that some glucosamine products might be contaminated by this allergen during production (102115).
Neurologic/CNS ...Orally, glucosamine has been reported to cause drowsiness and headache (2608,89561,113636). Glucosamine plus chondroitin combination products that also contain manganese (e.g., CosaminDS) should always be taken according to product directions. When taken at doses slightly higher than the recommended dose, these products can sometimes supply greater than the tolerable upper limit (UL) for manganese which is 11 mg/day. Ingestion of more than 11 mg/day of manganese might cause significant central nervous system toxicity (7135).
Ocular/Otic ...In older persons, use of glucosamine sulfate has been associated with ocular dryness (89564). Increased intraocular pressure has occurred with glucosamine sulfate supplementation (89573,112460). Data from the FDA MedWatch adverse event reporting system shows that 0.21% of subjects taking glucosamine reported glaucoma, which is significantly greater than the 0.08% of subjects who reported glaucoma while using any other drug (112460).
Pulmonary/Respiratory ...Cases of asthma exacerbations associated with the use of glucosamine (form unknown)-chondroitin products have been reported (10002).
Renal ...Anecdotal reports have associated glucosamine with nephrotoxicity signals such as modestly elevated creatine phosphokinase and 1+ to 2+ proteinuria, but changes in kidney function have not been reported in long-term studies (7026,8942,10408,10409). It was also noted that effects may have been due to other concurrent medications or impurities in glucosamine-chondroitin products. Cases of acute interstitial nephritis induced by glucosamine (form unknown) have also been reported (89523).
Other ...There has been concern that glucosamine might increase the risk of metabolic disturbances resulting in increased cholesterol levels and blood pressure. However, glucosamine does not appear to increase the risk of these adverse effects. Taking glucosamine sulfate for up to 3 years does not significantly increase blood glucose or lipid levels, or cause any other disturbances in metabolism (7026,7075,8942,10311,10317).
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).
General
...Orally and parenterally, manganese is generally well tolerated when used in appropriate doses.
High doses might be unsafe.
Serious Adverse Effects (Rare):
All routes of administration: Neurotoxicity, including Parkinson-like extrapyramidal symptoms, when used in high doses.
Cardiovascular ...Chronic occupational exposure to manganese dust or fumes can cause orthostatic hypotension, and heart rate and rhythm disturbances (61363).
Endocrine ...Chronic occupational exposure to manganese dust or fumes can cause elevations in thyrotropin-releasing hormone (TRH), follicle-stimulating hormone (FSH), and luteinizing hormone (LH) levels (61378).
Hepatic ...Manganese intoxication may cause cirrhosis and hepatic steatosis. In one case, a 13-year-old female with manganese intoxication developed severe, life-threatening neurological symptoms, with liver biopsy indicating incomplete cirrhosis and microvesicular steatosis. Chelation therapy and multiple rounds of therapeutic plasma exchange were required before symptoms resolved. The source of manganese exposure was not identified, and it is not clear if the impaired liver function contributed to the manganese accumulation or if elevated manganese exposure led to the liver damage.
Musculoskeletal ...Chronic occupational exposure to manganese dust or fumes has been associated with lower bone quality in females, but not males, suggesting that prolonged manganese exposure might increase the risk of osteoporosis in females (102516). A meta-analysis of 11 observational studies in adults also suggests that increased environmental exposure to airborne manganese sources is associated with lower motor function scores (108537).
Neurologic/CNS
...Orally, there is concern that higher doses of manganese might increase the risk of neurotoxicity, including Parkinson-like extrapyramidal symptoms (7135,10665,10666).
One severe case of irreversible Parkinson disease possibly related to taking manganese 100 mg daily for 2-4 years has been reported (96418). In another case, a 13-year-old female with manganese intoxication (diagnosed from blood manganese levels and cranial MRI evidence) developed severe neurological symptoms including loss of consciousness, decorticate posture, clonus, increased reflexes in the extremities, isochoric pupils, and no painful stimulus response. Liver biopsy also showed incomplete cirrhosis and microvesicular steatosis. The patient was intubated, and chelation therapy and multiple rounds of therapeutic plasma exchange were required before symptoms resolved. The source of the child's manganese exposure was not identified (112137). Individuals with impaired manganese excretion can also experience these effects even with very low manganese intake. Manganese accumulation due to chronic liver disease seems to cause Parkinson-like extrapyramidal symptoms, encephalopathy, and psychosis (1992,7135). One review recommends stopping supplementation if aminotransferase or alkaline phosphatase levels rise beyond twice normal (99302).
Chronic occupational exposure to manganese dust or fumes can also cause extrapyramidal reactions (1990,7135). In 1837, Couper observed that exposure to manganese dust particles produces a neurological syndrome characterized by muscle weakness, tremor, bent posture, whispered speech, and excess salivation (61264). Additionally, observational research in children has found that elevated manganese levels detected in the hair and fingernails due to environmental exposure may be associated with impaired neurocognitive function or development (108535). A meta-analysis of 11 observational studies in adults also suggests that increased environmental exposure to airborne manganese sources is associated with lower cognitive function scores (108537).
Intravenously, manganese might increase the risk of neurotoxicity when administered at high doses or for an extended duration. Cases of Parkinson-like symptoms have been reported in patients receiving parenteral nutrition containing more than 60 mcg of manganese daily. Moderate MRI intensity uptake for manganese in the globus pallidus and basal ganglion areas of the brain has been shown in patients receiving parenteral manganese (96416,99302).
Psychiatric ...Chronic occupational exposure to manganese dust or fumes can cause mood disturbance and dementia (1990,7135). A case report describes a man who presented with confusion, psychosis, dystonic limb movements, and cognitive impairment after chronic industrial manganese exposure (99415). Symptoms of manganese toxicity from inhalational exposure develop slowly with initial fatigue and personality changes, progressing to hallucinations, delusions, hyperexcitability, Parkinson-like symptoms, dystonia, and dementia (99415). Additionally, observational research has found that chronic environmental exposure to manganese sources such as mining operations and various industrial processes may be associated with a greater risk for developing symptoms of depression (108536).
Pulmonary/Respiratory ...Chronic occupational exposure to manganese dust or fumes can cause acute chemical pneumonitis, pulmonary edema, or acute tracheobronchitis (61495).
General
...Orally, MSM is generally well tolerated.
Most Common Adverse Effects:
Orally: Bloating, diarrhea, gastrointestinal discomfort, nausea.
Dermatologic ...In rare cases, MSM has caused pruritus when taken orally (8574).
Gastrointestinal ...Orally, MSM may cause mild gastrointestinal discomfort, nausea, bloating, and diarrhea (8574,12469).
Immunologic ...Orally, MSM may increase allergy symptoms (8574).
Neurologic/CNS ...Orally, MSM may cause headache, fatigue, insomnia, and difficulty concentrating (8574,14335).
Ocular/Otic ...In a case report, a 35-year-old female presented with bilateral acute angle closure glaucoma, which resolved 4 days after discontinuing a multi-ingredient product. Although the product contained over 35 vitamins, minerals, and other ingredients, only MSM contained sulfur, which the authors suggest acted like a sulfa-drug to cause acute angle closure glaucoma (90613).
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).
General
...Orally, intravenously, and topically, vitamin C is well-tolerated.
Most Common Adverse Effects:
Orally: Abdominal cramps, esophagitis, heartburn, headache, osmotic diarrhea, nausea, vomiting. Kidney stones have been reported in those prone to kidney stones. Adverse effects are more likely to occur at doses above the tolerable upper intake level of 2 grams daily.
Topically: Irritation and tingling.
Serious Adverse Effects (Rare):
Orally: There have been rare case reports of carotid inner wall thickening after large doses of vitamin C.
Intravenously: There have been case reports of hyperoxalosis and oxalate nephropathy following high-dose infusions of vitamin C.
Cardiovascular
...Evidence from population research has found that high doses of supplemental vitamin C might not be safe for some people.
In postmenopausal adults with diabetes, supplemental vitamin C intake in doses greater than 300 mg per day is associated with increased risk of cardiovascular mortality. However, dietary intake of vitamin C is not associated with this risk. Also, vitamin C intake is not associated with an increased risk of cardiovascular mortality in patients without diabetes (12498).
Oral supplementation with vitamin C has also been associated with an increased rate of carotid inner wall thickening in men. There is preliminary evidence that supplemental intake of vitamin C 500 mg daily for 18 months can cause a 2.5-fold increased rate of carotid inner wall thickening in non-smoking men and a 5-fold increased rate in men who smoked. The men in this study were 40-60 years old (1355). This effect was not associated with vitamin C from dietary sources (1355).
There is also some concern that vitamin C may increase the risk of hypertension in some patients. A meta-analysis of clinical research suggests that, in pregnant patients at risk of pre-eclampsia, oral intake of vitamin C along with vitamin E increases the risk of gestational hypertension (83450). Other clinical research shows that oral intake of vitamin C along with grape seed polyphenols can increase both systolic and diastolic blood pressure in hypertensive patients (13162).
Dental ...Orally, vitamin C, particularly chewable tablets, has been associated with dental erosion (83484).
Dermatologic ...Topically, vitamin C might cause tingling or irritation at the site of application (6166). A liquid containing vitamin C 20%, red raspberry leaf cell culture extract 0.0005%, and vitamin E 1% (Antioxidant and Collagen Booster Serum, Max Biocare Pty Ltd.) has been reported to cause mild tingling and skin tightness (102355). It is unclear if these effects are due to vitamin C, the other ingredients, or the combination.
Gastrointestinal ...Orally, the adverse effects of vitamin C are dose-related and include nausea, vomiting, esophagitis, heartburn, abdominal cramps, gastrointestinal obstruction, and diarrhea. Doses greater than the tolerable upper intake level (UL) of 2000 mg per day can increase the risk of adverse effects such as osmotic diarrhea and severe gastrointestinal upset (3042,4844,96707,104450). Mineral forms of vitamin C, such as calcium ascorbate (Ester-C), seem to cause fewer gastrointestinal adverse effects than regular vitamin C (83358). In a case report, high dose intravenous vitamin C was associated with increased thirst (96709).
Genitourinary ...Orally, vitamin C may cause precipitation of urate, oxalate, or cysteine stones or drugs in the urinary tract (10356). Hyperoxaluria, hyperuricosuria, hematuria, and crystalluria have occurred in people taking 1 gram or more per day (3042,90943). Supplemental vitamin C over 250 mg daily has been associated with higher risk for kidney stones in males. There was no clear association found in females, but the analysis might not have been adequately powered to evaluate this outcome (104029). In people with a history of oxalate kidney stones, supplemental vitamin C 1 gram per day appears to increase kidney stone risk by 40% (12653). A case of hematuria, high urine oxalate excretion, and the presence of a ureteral stone has been reported for a 9-year-old male who had taken about 3 grams of vitamin C daily since 3 years of age. The condition resolved with cessation of vitamin C intake (90936).
Hematologic ...Prolonged use of large amounts of vitamin C can result in increased metabolism of vitamin C; subsequent reduction in vitamin C intake may precipitate the development of scurvy (15). In one case, a patient with septic shock and a large intraperitoneal hematoma developed moderate hemolysis and increased methemoglobin 12 hours after a high-dose vitamin C infusion. The patient received a blood transfusion and the hemolysis resolved spontaneously over 48 hours (112479).
Neurologic/CNS ...Orally, the adverse effects of vitamin C are dose-related and include fatigue, headache, insomnia, and sleepiness (3042,4844,83475,83476).
Renal ...Hyperoxalosis and oxalate nephropathy have been reported following high-dose infusions of vitamin C. Hyperoxalosis and acute kidney failure contributed to the death of a 76-year-old patient with metastatic adenocarcinoma of the lung who received 10 courses of intravenous infusions containing vitamins, including vitamin C and other supplements over a period of 1 month. Dosages of vitamin C were not specified but were presumed to be high-dose (106618). In another case, a 34-year-old patient with a history of kidney transplant and cerebral palsy was found unresponsive during outpatient treatment for a respiratory tract infection. The patient was intubated for acute hypoxemic respiratory failure, initiated on vasopressors, hydrocortisone, and antibacterial therapy, and received 16 doses of vitamin C 1.5 grams. Serum creatinine level peaked at greater than 3 times baseline and the patient required hemodialysis for oliguria and uncontrolled acidosis. Kidney biopsy revealed oxalate nephropathy with concomitant drug-induced interstitial nephritis (106625). In another case, a 41-year-old patient with a history of kidney transplant presented with fever, nausea, and decreased urine output 4 days after receiving intravenous vitamin C 7 grams for urothelial carcinoma. Serum creatinine levels increased from 1.7 mg/dL to 7.3 mg/dL over those 4 days, and hemodialysis was initiated 3 days after admission due to anuria. Renal biopsy confirmed the diagnosis of acute oxalate nephropathy (109962).
Other ...Intravenously, hypernatremia and falsely elevated ketone levels is reported in a patient with septic shock and chronic kidney disease after a high-dose vitamin C infusion. The hypernatremia resolved over 24 hours after cessation of the infusion (112479).
