Bio-Gro Chocolate Ice Cream [Discontinued] by iSatori

EFFECTIVE

• Dyspepsia. Oral calcium carbonate is approved by the US Food and Drug Administration (FDA) as an antacid. Details: Taking calcium carbonate orally as an antacid is effective for treating dyspepsia (1843). Calcium carbonate has FDA approval as an antacid.
• Hyperkalemia. Intravenous calcium gluconate is approved by the US Food and Drug Administration (FDA) for preventing hyperkalemia-induced cardiac abnormalities. Details: Administering calcium gluconate intravenously can reverse electrocardiographic changes and arrhythmias induced by hyperkalemia (12946). Intravenous calcium gluconate is FDA-approved for preventing hyperkalemia-induced cardiac abnormalities.
• Hypocalcemia. Oral calcium treats and prevents hypocalcemia. Intravenous calcium is used to treat severe hypocalcemia. Details: Taking calcium orally is effective for treating and preventing hypocalcemia. Intravenous calcium gluconate, acetate, gluceptate, or chloride is effective for severe hypocalcemia or hypocalcemic tetany (12928).
• Kidney failure. Oral calcium carbonate or calcium acetate is used as a phosphate binder during kidney failure. Details: Taking calcium carbonate or calcium acetate orally is effective as a phosphate binder. Calcium acetate (PhosLo) appears to control hyperphosphatemia better than sevelamer (Renagel) (12943,12944,38990). Calcium citrate is not recommended for this purpose because it increases aluminum absorption and does not bind phosphate as efficiently as calcium acetate or calcium carbonate (21631). Some clinical research also shows that taking calcium orally reduces blood pressure in patients with kidney failure (975).

LIKELY EFFECTIVE

• Corticosteroid-induced osteoporosis. Oral calcium in combination with vitamin D prevents bone density loss that occurs during long-term treatment with corticosteroids. Details: Taking calcium in combination with vitamin D as adjunctive therapy seems to be effective for reducing bone mineral density loss in people using corticosteroids long-term (982,1046,1830,1831,1832,4462,4463,4464,4465,4466)(4467,12945,38493). One specific product used in clinical research is Oscal (Marion Merrel Dow Inc.), which contains elemental calcium 500 mg per tablet plus vitamin D 125 IU per tablet (982). Another product used is Oscal 250 + D (SmithKline Beecham Healthcare), which contains elemental calcium 250 mg and vitamin D 125 IU per tablet (1046).
• Hyperparathyroidism. Oral calcium reduces parathyroid hormone levels in patients with secondary hyperparathyroidism due to kidney failure. Details: Taking calcium orally reduces parathyroid hormone levels in patients with kidney failure and secondary hyperparathyroidism (1827,1828,1829,39174,39425). In elderly women, the combination of calcium and vitamin D reverses secondary hyperparathyroidism and reduces hip fracture risk (8818). Also, population research suggests increased calcium intake from the diet and supplements reduces the risk of primary hyperparathyroidism in women. Supplemental intakes of at least 500 mg/day and dietary intakes of approximately 1100 mg/day are considered to be protective (91353).
• Osteoporosis. Adequate calcium intake, from the diet and/or supplements, is recommended for the prevention and treatment of osteoporosis. Details: The Bone Health and Osteoporosis Foundation (BHOF) recommends ensuring adequate calcium intake in line with the recommended dietary allowance (RDA) by age, along with adequate vitamin D intake, for the prevention and treatment of osteoporosis in adults over 50 years of age. Supplementation can be used to augment dietary intake when adequate dietary intake is not feasible (109425). In the US and Canada, foods containing at least 200 mg calcium with less phosphorous content than calcium can be labelled with a health claim regarding the relationship between adequate calcium intake and a reduced risk for osteoporosis (11940,102148). However, calcium supplementation is not recommended specifically for the primary prevention of osteoporosis. The US Preventive Task Force (USPSTF) states that the current evidence is insufficient to assess the balance of benefits and harms of vitamin D and calcium supplementation, alone or in combination, for the primary prevention of fractures in community dwelling adults without osteoporosis (95695). Also, calcium supplements do not seem to be effective for preventing loss of bone mineral density (BMD) during lactation (988), in patients who have had bone marrow transplantation (1817), or in patients who have had renal transplantation (4823,38736,38871). Maximal bone growth occurs in the teenage years, and then BMD in females remains relatively constant until age 30-40. After age 40, bone loss typically occurs at rates of 0.5% to 1% per year. In males, this occurs several decades later. Bone loss is more pronounced if dietary calcium intake is below the RDA, which is the case for many Americans (2571,2578). One meta-analysis of randomized controlled trials in healthy children 7-14 years old shows that fortifying food with calcium 250-1000 mg daily for up to 24 months modestly improves femoral neck BMD, but not hip or spine BMD. However, the included trials did not supplement vitamin D (107232). During the 5 years immediately after menopause, calcium supplementation has very little effect on bone loss (2569,2570,2575,2576). The rapid loss of estrogen causes a high bone resorption rate, which increases serum calcium levels and therefore decreases intestinal absorption of calcium (2570). After this period, the typical rate of bone loss is 2% per year (2572,2576). Taking calcium 1000-1600 mg daily as carbonate, citrate, lactate gluconate, or citrate malate salt decreases this rate by 0.25% to 1% annually (977,979,981,2569,2571,2572,2575,2576,2578,6850)(38978,38980,39064). The greatest reductions (1% or more) are seen in the first 1-2 years of supplementation when bone remodeling foci can be filled (2569,2576). After this period, the differences in rate of loss between supplemented and non-supplemented females are closer to 0.25% per year (2569,2577). A meta-analysis of clinical evidence suggests that there is no additional benefit after 4 years (38980). Small clinical studies have found that continuous calcium supplementation at an average daily dose of 1050 mg, started after menopause and continued for 1.5-4 years, may reduce fracture rates by 26% when compared with no calcium supplementation. The largest of these studies was conducted in nursing home residents who also received daily vitamin D; the benefits of calcium, specifically, are unclear (39386). Some research also suggests that calcium and vitamin D improves primary prevention of osteoporotic fractures in some older individuals with osteoporosis, particularly the elderly and those who are no longer community dwelling (12930,38875,38849,39026,109471). However, not all research is positive. One large clinical trial in elderly adults with a low-trauma fracture show that taking calcium 1000 mg daily with or without vitamin D 800 IU daily for 2-7 years does not reduce the risk of a second fracture when compared with placebo (13073). Another clinical study shows that taking calcium 1000 mg daily plus vitamin D 800 IU daily does not prevent a second fracture in elderly patients, or prevent a first fracture in elderly patients with other risk factors such as low body weight (less than 58 kg, 127.6 pounds), smoking, family history of hip fracture, or fair or poor self-reported health (12929). Also, some exploratory research suggests that supplements may need to be continued indefinitely; in adults over 68 years of age, any effects of 2 years of calcium supplements on BMD appear to be lost within 2 years after discontinuing supplements (6853). Calcium has additive effects when used with other agents such as vitamin D, estrogens, or calcitonin. Whereas calcium alone generally reduces or prevents loss of BMD, combination with other agents can produce small increases in BMD ranging from 0.3% to 3.3% depending on the combination and dosages used (978,980,1836,2570,2571,2572,2576). However, one meta-analysis in healthy adults shows that fortifying foods with calcium 250-1000 mg daily, in conjunction with vitamin D supplementation, for up to 24 months does not improve BMD when compared with control (107232). The full potential of osteoporosis treatments cannot be realized without adequate calcium intake (2569,2570,2571,2572). Advise patients taking agents such as estrogens, calcitonin, bisphosphonates, or raloxifene (Evista) to ensure that their daily calcium intake meets the RDA. Use supplements if necessary. The usefulness of calcium in preventing osteoporosis in males is not as well-studied. Some observational research has found that calcium 870 mg daily is not associated with changes in BMD and bone loss in males (97201). However, clinical evidence suggests that taking calcium 1000 mg daily for 2 years might improve trabecular or cortical bone mass by 2% to 4% (980,8827,8873). Dietary supplementation with calcium and vitamin D seems to moderately reduce bone loss measured in the femoral neck, spine, and total body, and seems to reduce the incidence of nonvertebral fractures in older patients with osteopenia or low BMD (980).
• Premenstrual syndrome (PMS). Adequate calcium intake seems to prevent symptoms of PMS. Details: There seems to be a link between low dietary calcium intake and symptoms of PMS (2004,6847,39007). Taking calcium 1000-1336 mg daily seems to significantly reduce depressed mood, water retention, and pain, especially if daily calcium intake is inadequate (1822,1823,1824,2004,95821). Calcium carbonate 1200 mg daily seems to decrease PMS symptom scores by about 18% when compared with placebo (1822). Increasing dietary calcium intake is also associated with a decreased risk of developing PMS. Consuming an average of 1283 mg of calcium per day from foods is associated with about a 30% lower risk of developing PMS compared with consuming an average of 529 mg daily (13094); however, taking calcium supplements does not appear to be associated with the risk of developing PMS.

POSSIBLY EFFECTIVE

• Colorectal cancer. Oral calcium seems to be beneficial for preventing colorectal cancer, especially in those with adequate vitamin D levels and normal body mass index (BMI). Details: Population studies have found that increased intake of dietary or supplemental calcium is associated with a reduced risk of colorectal cancer and colorectal adenomas (1047,8820,12120,38951,98898,98899). Clinical trials and meta-analyses of clinical research also show that taking calcium supplements 1.2-2 grams daily for up to 4 years can reduce the risk of colorectal adenoma recurrence by up to 29% (970,12118,12950,15267,34596,38718,39042,95817). However, not all research has been positive. Some meta-analyses of clinical research or observational studies suggest that taking calcium does not reduce the risk of familial adenomatous polyposis or colorectal cancer (34596,39042,39349). Other contradictory research suggests that postmenopausal females who take calcium 1000 mg daily plus vitamin D 400 IU daily do not have a reduced risk of developing colorectal cancer (14290); however, this finding may not be reliable due to the high baseline intake of calcium in study participants. The reason for these conflicting findings is not entirely clear. Vitamin D might be an important factor. People with lower than average vitamin D levels do not seem to get any benefit from calcium supplements (12118). Also, one meta-analysis of previous trials suggests that taking calcium 1200 mg daily reduces the risk of colorectal adenomas in people with a normal BMI, but not in those who are overweight or obese (99715). Despite this conflicting evidence, the US Food and Drug Administration (FDA) approved a qualified health claim in 2005 stating that calcium supplements may reduce the risk of colorectal cancer and colorectal adenomas. However, the FDA has determined that there is little scientific evidence to support this claim (102366).
• Fetal bone mineralization. If calcium intakes are low during pregnancy, oral calcium seems to be beneficial for increasing fetal bone density. Details: With low dietary calcium intake (less than 562 mg elemental calcium daily) during pregnancy, calcium supplementation increases fetal bone mineralization and density. However, calcium supplementation does not offer any additional benefit if calcium intakes are adequate (3263,3264).
• Hypertension. Oral calcium seems to reduce blood pressure by a small amount. However, it is unclear if this reduction is clinically significant. Details: Many clinical trials and observational studies show that intake of calcium supplements or dietary calcium modestly reduces blood pressure in patients with or without hypertension, usually around 1-2 mmHg. Calcium seems to be more effective for certain subpopulations of patients, such as salt-sensitive people and patients with low baseline dietary calcium intake (945,972,974,976,984,1818,1819,1820,1821,6852)(13138,14406,38803,39063,39094,39221). Also, a meta-analysis of clinical research shows that calcium intake during pregnancy reduces systolic blood pressure in offspring by 1-2 mmHg (38852). However, a large-scale clinical trial in postmenopausal females shows that taking vitamin D (cholecalciferol) 400 IU daily in combination with elemental calcium 1000 mg daily does not lower blood pressure or reduce the risk of developing hypertension (16714). Additionally, a meta-analysis of 8 clinical trials shows that taking calcium in combination with vitamin D for up to 7 years has no effect on blood pressure (98861). The validity of this finding is limited by the poor methodological quality of the included studies. Some observational research suggests that calcium can reduce the risk for hypertension. Population research in females aged 45 years and older suggests that higher intake of calcium from both diet and supplement sources is linked to a lower risk of developing hypertension when compared to lower calcium intake (14265). In 2005, the US Food and Drug Administration (FDA) approved a qualified health claim stating that calcium supplements may reduce the risk of hypertension. However, the FDA has concluded that this claim is based on supporting, rather than conclusive, evidence (102367).
• Osteomalacia. Oral calcium seems to reverse osteomalacia caused by very low calcium intakes. Details: Osteomalacia is commonly caused by vitamin D deficiency; however, very low calcium intake can also lead to osteomalacia in children and adults. Calcium supplementation can reverse osteomalacia caused by calcium deficiency. Along with appropriate vitamin D supplementation, individuals at risk of osteomalacia need sufficient calcium intake (94819).
• Pre-eclampsia. Oral calcium seems to reduce the risk of pre-eclampsia in high risk pregnancies, especially if calcium intakes are low. Details: Although there is some conflicting evidence (971,38756), most clinical research shows that taking calcium orally 1-2 grams daily reduces pregnancy-related hypertension and pre-eclampsia (973,1833,8828,39043,39319,39426,96480). Calcium appears to reduce the risk of pre-eclampsia by about 50% when compared with placebo. One meta-analysis of 19 controlled trials involving over 29,000 pregnancies found that for every 19 females treated with calcium, one episode of pre-eclampsia would be avoided (96480). Calcium appears to have the greatest effect in individuals at high-risk of pre-eclampsia or with low calcium levels, and when taken at greater than or equal to 20 weeks of gestation (15029,38497,96480,99714). In 2005, the US Food and Drug Administration (FDA) approved a qualified health claim regarding the use of calcium supplements to reduce the risk of pregnancy-induced hypertension and pre-eclampsia. However, due to the limited and conflicting research available at that time, the FDA stated that this outcome was highly unlikely. Since then, large, high-quality clinical research has supported this finding. In fact, in 2016 the World Health Organization (WHO) released a recommendation to prescribe oral calcium supplementation 1.5-2 grams daily during pregnancies at high risk of pre-eclampsia if dietary calcium intakes are low, in order to prevent pre-eclampsia (97347).
• Rickets. Oral calcium seems to reverse rickets caused by very low calcium intakes. Details: Rickets is commonly caused be vitamin D deficiency; however, very low calcium intake can also lead to rickets. Calcium supplementation can reverse rickets caused by calcium deficiency (94819). A small clinical study in children with nutritional rickets shows that taking calcium 500-2000 mg daily for 24 weeks improves radiographically measured rickets caused by calcium deficiency. Rickets seems to improve more rapidly with calcium 1000 mg compared to calcium 500 mg. However, increasing the calcium dose to 2000 mg daily is not more beneficial than calcium 1000 mg daily (98904).
• Tooth retention. Oral calcium with vitamin D seems to help with tooth retention in the elderly population. Details: A clinical trial in the elderly population shows that taking calcium citrate malate 500 mg daily along with vitamin D3 (cholecalciferol) 700 IU daily orally for 3 years reduces the risk of tooth loss by about 52% when compared with placebo (8816).

POSSIBLY INEFFECTIVE

• Breast cancer. Oral calcium does not seem to be beneficial for breast cancer prevention. Details: Although some population research disagrees (15631,39041,95811,107237), most research shows that increased calcium intake is not associated with a reduced risk of breast cancer (15631,16715,98895,107236,107237). Subgroup analyses of population research suggest that calcium intake may reduce the risk of breast cancer in postmenopausal, but not pre-menopausal, adults (15631,107237). Another subgroup analysis in a large meta-analysis of population research also suggests that dietary intake may reduce estrogen receptor(ER)-negative breast cancer, but not ER-positive breast cancer (107236). However, most other research has not evaluated the effects of calcium supplementation or intake on breast cancer subtypes. The best evidence to date, from a large scale clinical trial (Women's Health Initiative), shows that taking vitamin D (cholecalciferol) 400 IU daily plus calcium 1000 mg daily for 7 years after menopause does not reduce the risk of developing invasive breast cancer at the end of the study and 5 years after the end of the intervention (16715,98895).
• Fractures. Although oral calcium prevents fractures in osteoporosis, most evidence shows that calcium does NOT prevent factures in people who do not have osteoporosis. See Osteoporosis discussion for more information on the use of calcium for this purpose. Details: The most recent and robust meta-analysis of clinical research shows that calcium supplementation with or without vitamin D is NOT associated with reduced fractures in older adults without osteoporosis (95822). A large-scale study in postmenopausal females aged 50-79 years suggests calcium 1000 mg plus vitamin D 400 IU daily for 7 years only modestly improves bone mineral density (BMD) and does not significantly reduce fracture risk. This lack of effect may have been due to low adherence to the treatment regimen. In those who were 80% adherent, the combination of calcium plus vitamin D reduced the risk of hip fracture by about 29% (14282). Also, some clinical research shows that taking calcium carbonate 1000 mg and vitamin D 400 IU for 5 years does not attenuate loss of height after menopause when compared with placebo (95810). Additional meta-analyses of clinical and observational evidence suggest that calcium supplementation is not associated with a reduced risk of vertebral or nonvertebral fractures, such as hip fractures (38589,38888,98895). Some other research has suggested that calcium in combination with vitamin D reduces fracture risk in older patients without osteoporosis (980,1836,8818,12930,12933,12952,38849,102145,107235); however, this research is confounded by a number of variables, including the presence of hormonal therapy and differing levels of fracture risk at baseline (1836,8818,95822). Conflicting findings on this topic might also be due to genetic differences in patient populations. A population analysis of the Women's Health Initiative study found that, in older females with the lowest genetic susceptibility to low bone mineral density (BMD), taking calcium with vitamin D is associated with a reduction in fracture risk. However, in females with a higher genetic susceptibility to low BMD, there is no association between supplementation and fracture risk. This might be because individuals with a lower susceptibility to low BMD are also more responsive to calcium and vitamin D supplementation (97357). As of April 2018, the U.S. Preventative Services Task Force (USPSTF) concludes that there is insufficient evidence to determine whether supplementing with vitamin D >400 IU daily along with calcium >1000 mg daily is safe and effective for preventing fractures in community dwelling adults without vitamin D deficiency, osteoporosis, or a history of fracture. USPSTF recommends against supplementing with calcium 1000 mg daily or less along with vitamin D 400 IU daily or less for preventing primary fractures in community-dwelling postmenopausal females (95695).
• Obesity. Oral calcium does not seem to improve weight loss. Details: Observational research has found that adults and children with low calcium intake are more likely to gain weight, have a higher body mass index (BMI), and be overweight or obese when compared to people with high calcium intake (12124,12125,12126,12127,14265). Additional observational research has found that increasing calcium intake is associated with weight loss in females; the results in males have been conflicting (12127,15602,15603). Despite these findings from observational research and a few small clinical studies (12128,15397,14438,98905), most clinical research has found that increased calcium intake does not increase weight loss (12052,13138,15396,15399,38985,39004,97356). The most recent meta-analysis of 20 clinical studies shows that daily dietary and supplemental calcium intake that meets the dietary reference intake (DRI) of 1000 mg or more daily does not increase weight loss in overweight individuals or patients with obesity when compared with intake below the DRI (95813). An older meta-analysis of 13 clinical trials also shows that increased dietary and supplemental calcium intake does not increase weight loss (15605).
• Overall mortality. Oral calcium does not seem to reduce overall mortality. Details: While some population research has found that calcium taken in combination with vitamin D in older females is associated with a lower risk of death (97353), most evidence shows that calcium, with or without vitamin D, has no effect on all-cause mortality (93533,97308).

INEFFECTIVE

• Cardiovascular disease (CVD). Oral calcium does not reduce the risk of developing CVD and may actually increase risk in some patients. Details: Clinical research shows that calcium does not decrease CVD risk. Several separate meta-analyses of clinical and population research involving over 50,000 patients show that taking calcium 600-1200 mg daily for up to 7 years does not reduce the risk of CVD-related outcomes, including stroke and myocardial infarction, cardiovascular death, or overall mortality (39018,91350,92994,93533,97308,98902,107231,107233). No association was found between total dietary or supplemental calcium intake with or without vitamin D and the risk of CVD or mortality (91350,93533,97308). In fact, some population and clinical research has found that when calcium is used alone or with vitamin D, there is an INCREASED risk of CVD and coronary heart disease (38077,107233). However, other clinical research disagrees (93533). One meta-analysis of high-quality randomized controlled trials shows that taking calcium for 2-7 years increases the risk of CVD and coronary heart disease by 1.1-1.2 times when compared with control. However, the majority of the included research evaluated postmenopausal females and it is unclear if this finding is applicable to other populations (107233).
• Chemotherapy-induced peripheral neuropathy. Intravenous calcium does not prevent nerve pain in patients given oxaliplatin. Oral calcium has not been evaluated for this purpose. Details: While pooled analyses of cohort studies and randomized controlled trials suggest that calcium and magnesium infusion decreases the incidence of oxaliplatin-induced neurotoxicity, a meta-analysis of only randomized controlled trials shows that the infusion has no effect in preventing neurotoxicity (90028,90029,90031). Additionally, clinical trials show that administering calcium gluconate 1 gram with magnesium sulfate 1 gram intravenously immediately before, or before and after, the administration of a single oxaliplatin cycle (90005), or over the entire 6-cycle course of oxaliplatin, does not improve symptoms of neurotoxicity when compared with placebo (96474).
• Myocardial infarction (MI). Oral calcium does not prevent MI. When taken in the absence of vitamin D, oral calcium may increase the risk of MI. Details: Population research has found that increased dietary intake of calcium is associated with a decreased risk of MI (91350). However, a 2010 meta-analysis of clinical research shows that taking calcium at a dose of at least 500 mg daily is associated with an approximate 30% INCREASE in the risk of MI in patients over the age of 40. According to this analysis, one additional case of MI will occur for every 69 patients that take calcium for 5 years (17482). A more recent meta-analysis of high-quality randomized controlled trials shows that taking calcium for 2-7 years increases the risk of MI by 1.2 times when compared with control. However, the majority of the included research studied postmenopausal females and it is unclear if this finding is applicable to other populations (107233) In contrast, other meta-analyses of clinical research have shown that taking calcium for up to 7 years is NOT associated with an increased risk of MI, including a meta-analysis that only included postmenopausal females (93533,107231). Reasons for these discrepancies are not entirely clear. It may relate to whether calcium is taken as monotherapy or in combination with vitamin D. When taken with vitamin D, which is commonly recommended, calcium supplementation does not appear to be associated with an increased risk of MI in postmenopausal females (93533). Also, the association between calcium supplementation and MI risk may be influenced by the amount of calcium consumed as part of the diet. Supplementation with calcium may be associated with an increased risk of MI in people with dietary calcium intake above 805 mg daily, but not in those with dietary calcium intake below 805 mg daily (17482)

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Alcohol use disorder. It is unclear if oral calcium is beneficial for alcohol use disorder. Details: Preliminary clinical research shows that taking calcium carbonate 800 mg and vitamin D 200 IU orally daily for 14 days modestly reduces alcohol craving scores and withdrawal scores when compared with placebo in adults with alcohol dependence that are undergoing withdrawal. Taking calcium carbonate did not reduce the need for diazepam; however, the study may have been inadequately powered to detect a difference between groups (107234).
• Atherosclerosis. It is unclear if oral calcium is beneficial for atherosclerosis. Details: A population study has found that taking calcium 1.2 grams daily for 3 years has no effect on carotid intima thickness or carotid atherosclerosis incidence. A total calcium intake (dietary and supplemental) of at least 1794 mg daily in older females may be associated with a decreased risk of carotid atherosclerosis when compared with a total calcium intake below 1010 mg daily (97351).
• Autism spectrum disorder. It is unclear if oral calcium during pregnancy is beneficial for reducing the odds of autism spectrum disorder in the offspring. Details: A small observational study found that calcium supplementation during pregnancy is associated with a 52% reduced odds of an autism spectrum disorder in the offspring (98900).
• Cancer. Oral calcium alone does not seem to prevent cancer. It is unclear if oral calcium with vitamin D is beneficial for preventing cancer. Details: Taking calcium alone does not seem to significantly reduce the risk of cancer (12118,15629). The role of calcium in cancer prevention when taken along with vitamin D is controversial, as conflicting results exist. One clinical trial shows that healthy postmenopausal females who take supplemental calcium 1400-1500 mg daily plus vitamin D3 (cholecalciferol) 1100 IU daily have a 60% lower relative risk for developing cancer of any type. Approximately 25 postmenopausal females would need to take this combination for 4 years to prevent one occurrence of cancer (15629). However, a more recent clinical study shows that healthy postmenopausal females who take supplemental calcium 1500 mg daily plus vitamin D3 (cholecalciferol) 2000 IU daily do not have a reduced risk of cancer at 4 years (93943). Reasons for the disparate results are not entirely clear. The discrepancies do not appear to be related to baseline vitamin D levels or different study populations. It is possible that, given the 10-year time lapse between the two publications, the discrepancies result from differences in cancer detection capability. Also, since cancer risk was a secondary outcome measure in the earlier study and a primary outcome measure in the more recent study, it is possible that the discrepancies result from differences in statistical methodologies. The effect of vitamin D and calcium on cancer risk in males and younger patients is not known. There is also interest in using calcium for reducing the risk of hematological malignancies. An analysis of the Women's Health Initiative study shows that taking calcium 1000 mg daily in combination with vitamin D3 400 IU for up to 10 years is associated with a 20% reduction in the risk of hematologic malignancies when compared with placebo. However, no effect on hematologic malignancy related mortality was seen (97354).
• Depression. It is unclear if oral calcium is beneficial for depression prevention. Details: Population research has found no association between a higher dietary intake of calcium and the risk of depression when compared with a lower dietary intake of calcium (96480).
• Diabetes. It is unclear if oral calcium is beneficial for type 2 diabetes prevention. Details: Some population research has found that a higher intake of calcium from diet or supplements, alone or in combination with vitamin D, is associated with a lower risk of developing type 2 diabetes when compared with lower calcium intake (14265,16713,96473). However, population research is often limited by confounding variables. For example, one analysis found that any beneficial effect might be influenced by concomitant magnesium intake (96473). Furthermore, other population research has found that serum calcium levels higher than 9.6 mg/dL are associated with greater risk of developing diabetes in Chinese adults with osteoporosis. This study is limited because it was not determined whether increased serum calcium was due to increased calcium intake or another factor such as parathyroid function (95815).
• Dysmenorrhea. It is unclear if oral calcium is beneficial for reducing pain associated with dysmenorrhea. Details: Clinical research shows that taking calcium carbonate 1000 mg with vitamin D 5000 IU daily for three menstrual cycles does not reduce pain when compared with placebo in patients with primary dysmenorrhea (95821). However, calcium carbonate 1000 mg taken alone seems to reduce pain when compared with placebo.
• Endometrial cancer. It is unclear if oral calcium is beneficial for endometrial cancer prevention. Details: A meta-analysis of population research suggests that calcium supplements may reduce the risk of endometrial cancer, but dietary calcium does not seem to have any effect (38893).
• Fall prevention. It is unclear if oral calcium with vitamin D is beneficial for preventing falls. Details: Research suggests that calcium in combination with vitamin D, but not calcium alone, might prevent falls by decreasing body sway and normalizing systolic blood pressure (6362,11939,39038). Some experts think the combination of calcium and vitamin D may be important (11916). Preliminary clinical research in adults residing in a health care facility shows that taking vitamin D supplements while increasing dietary calcium and protein for 2 years reduces falls by 11% when compared with standard diets. Intervention diets were supplemented with milk, yogurt, and cheese to provide calcium 1142 mg and protein 69 grams daily (107235). There might also be different effects in females compared to males. In one study, females aged 65 years or older who took vitamin D 700 IU plus calcium citrate 500 mg daily over a 3-year period had a 46% lower risk of falling. However, this combination did not decrease falls in males (14291).
• Fluorosis. Oral calcium has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Taking calcium orally, in combination with ascorbic acid (vitamin C) and vitamin D, seems to be effective for reducing excessive fluoride levels in children and improving symptoms of fluorosis in children aged 6-12 years (990).
• Heart failure. It is unclear if oral calcium in combination with vitamin D is beneficial for preventing heart failure. Details: Based on a secondary analysis of a large-scale clinical trial (Women's Health Initiative), taking calcium 1000 mg with vitamin D 400 IU daily does not reduce the risk of heart failure in the overall population or in individuals at high risk. However, in a subgroup of postmenopausal females without risk factors for heart failure, calcium and vitamin D supplementation might reduce the risk of developing heart failure by about 37% (97307).
• Hypercholesterolemia. It is unclear if oral calcium is beneficial for hypercholesterolemia. Details: Some evidence shows that taking calcium carbonate 400 mg three times daily reduces low-density lipoprotein (LDL) cholesterol levels by 4% and increases high-density lipoprotein (HDL) cholesterol levels by 4% after 6 weeks of treatment when used in combination with a low-fat diet (American Heart Association Step 1) (2557). In contrast, a study in females with dyslipidemia shows that taking calcium 800 mg daily for 2 years might INCREASE total cholesterol levels by about 12 mg/dL when compared with placebo. This same study showed an association between calcium supplementation and an increase in total cholesterol levels and carotid intimal thickness in postmenopausal females, but not premenopausal females (97350). A recent meta-analysis of randomized controlled trials which included both healthy patients and patients with dyslipidemia shows that taking calcium 500-2000 mg daily and vitamin D 200-7142 IU daily modestly improves HDL cholesterol and triglyceride levels, but not LDL cholesterol levels, when compared with placebo. Subgroup analyses suggest that calcium and vitamin D supplementation is more effective in patients with dyslipidemia at baseline. It is unclear if this effect is due to calcium, vitamin D, or the combination (107227). However, other research shows that taking a specific supplement containing calcium 600 mg plus vitamin D 200 IU (Caltrate 600 D, Wyeth Consumer Healthcare Inc.) twice daily in combination with calorie restriction does not reduce total or LDL cholesterol levels when compared with placebo (15601).
• Lead toxicity. It is unclear if oral calcium is beneficial for reducing blood levels of lead. Details: Lead is mobilized along with calcium from bone during pregnancy and lactation, resulting in increased serum concentrations of lead. One clinical study suggests that calcium supplementation does not significantly decrease these elevated lead concentrations (1586). However, another clinical study suggests that taking calcium reduces blood lead levels by 11% when compared with placebo, with greatest effects observed in those with high baseline levels of lead (38957).
• Lyme disease. Although there is interest in using oral calcium for Lyme disease, there is insufficient reliable information about the clinical effects of calcium for this condition.
• Metabolic syndrome. It is unclear if oral calcium alone or with vitamin D is beneficial for metabolic syndrome prevention. Details: Population research has found that a higher intake of calcium from diet and supplements alone, or in combination with vitamin D, is associated with a lower risk of developing metabolic syndrome when compared with lower calcium intake (14265,16713).
• Nephrotic syndrome. It is unclear if oral calcium with vitamin D is beneficial for preventing nephrotic syndrome. Details: Clinical research shows that taking calcium 500-1000 mg daily for 3 months in combination with vitamin D3 60,000 IU daily or weekly for 4 weeks has no effect on bone mineral density or the risk of relapse in children with steroid-sensitive nephrotic syndrome (97355).
• Nonmelanoma skin cancer. It is unclear if oral calcium is beneficial for preventing keratinocyte carcinomas. Details: In middle aged and older adults recently diagnosed with a colorectal adenoma, clinical research shows that taking calcium 1200 mg daily as calcium carbonate for 3-5 years does not reduce the incidence of keratinocyte cancer when compared with placebo over a median of 8 years. A sub-group analysis shows that taking calcium alone or with vitamin D3 1000 IU daily reduced the risk of invasive cutaneous squamous cell carcinoma by a moderate amount, but had no effect on the risk of basal cell carcinoma (104622).
• Oral mucositis. When used in combination with fluoride treatments, a calcium phosphate mouth rinse seems to prevent and reduce mucositis-related pain in patients undergoing hematopoietic stem cell transplantation (HSCT). Details: A small clinical study in patients undergoing HSCT shows that using a particular mouth rinse (Caphosol, EUSA Pharma) containing calcium phosphate, in combination with fluoride treatments, reduces days of mucositis, the duration of pain, and the dose and days of morphine used when compared with placebo and fluoride treatment (38611).
• Ovarian cancer. It is unclear if oral calcium is beneficial for ovarian cancer prevention. Details: An older meta-analysis of 12 cohort studies found that dietary calcium intake is not associated with a reduced risk of ovarian cancer (38792). However, a more recent pooled analysis of 15 cohort and case-control studies has found that the highest intake of dietary or dairy calcium is associated with a 20% lower risk of ovarian cancer when compared to the lowest intake (97349).
• Postpartum depression. It is unclear if oral calcium is beneficial for reducing postpartum depression risk. Details: Preliminary clinical research shows that taking calcium 2 grams daily beginning at 11-21 weeks gestation reduces depression at 12 weeks postpartum when compared with placebo. However, no benefit is seen at 6 weeks postpartum (39447).
• Pregnancy-related leg cramps. It is unclear if oral calcium is beneficial for preventing leg cramps during pregnancy. Details: A small clinical study shows that taking calcium 1 gram twice daily (as a mixture of salts) for 2 weeks can reduce pregnancy-related leg cramps during the second half of pregnancy when compared with no treatment (2567).
• Prostate cancer. It is unclear if oral calcium is beneficial for prostate cancer prevention. Details: Some clinical research shows that taking calcium 1200 mg daily might decrease the risk of developing prostate cancer (14133). However, some epidemiological research suggests that consuming very high doses of calcium, over 2000 mg daily, might actually increase the risk of developing prostate cancer (14134). Some epidemiological research also suggests that doses greater than 1500 mg daily increase the risk of poorly differentiated, clinically advanced, and fatal prostate cancer (14132). Consumption of dairy products has also been weakly linked to a modest increase in risk of prostate cancer (98894). However, contradictory research suggests that there is no association between dietary intake of calcium and overall risk of prostate cancer (14131,14132,104630).
• Stroke. It is unclear if oral calcium is beneficial for stroke prevention. Details: Some population research has found that increasing dietary calcium intake is associated with a decreased risk of ischemic stroke (4822,38678). However, other population research has found that increasing dietary calcium intake is not associated with a decreased risk of stroke (91350). One meta-analysis of high-quality randomized controlled trials shows that taking calcium for 2-7 years does not affect the risk of stroke when compared with control. However, the majority of the included research evaluated postmenopausal females, and it is unclear if this finding is applicable to other populations (107233).
• Vertigo. Oral calcium with vitamin D might reduce positional vertigo; the effect of calcium when used alone is unclear. Details: A large clinical study in adults with recurrent benign paroxysmal positional vertigo shows that taking calcium 500 mg and vitamin D 400 IU twice daily for one year reduces annual recurrence of vertigo by 27% when compared with no treatment. The number needed to treat to prevent vertigo was 3.7 (103681). It is unclear if this benefit is due to vitamin D, calcium, or the combination. More evidence is needed to rate calcium for these uses.

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POSSIBLY EFFECTIVE

• Pregnancy-related iron deficiency. Oral lactoferrin seems to improve hemoglobin levels similarly to oral or parenteral iron therapy in patients with pregnancy-related iron deficiency. Details: A meta-analysis of 4 clinical studies in patients with pregnancy-related iron deficiency anemia shows that taking bovine lactoferrin 200-250 mg daily for 4-8 weeks during the second or third trimester is equally effective to ferrous sulfate 150-520 mg for improving hemoglobin levels (97788). Another meta-analysis of 6 mostly small, low-quality clinical studies in pregnant patients with iron deficiency anemia, iron deficiency, or hereditary thrombophilia shows that taking lactoferrin improves hemoglobin and serum iron, but not serum ferritin, when compared with ferrous sulfate (110773). However, the validity of these findings is limited by the heterogeneity of the included studies and lack of information about lactoferrin and iron doses.
• Sepsis. Oral lactoferrin seems to reduce the risk of late-onset sepsis in some premature infants. However, the optimal dosing regimen and patient population is unclear. Details: A meta-analysis of 12 clinical studies in premature infants shows that lactoferrin 150-200 mg/kg daily reduces the risk of late-onset sepsis by 20%, largely due to reductions in fungal infections specifically (104868). In contrast, other meta-analyses have reported conflicting findings (97783,104856) and some suggest that any benefits may be relegated to certain sub-groups of premature infants, including infants fed with bovine formula (104856,104868) or those with very low birth weight or extremely low birth weight (104856,104868,104869). These groups seemed to obtain greater benefits than other premature infants or those fed exclusively or almost exclusively with breast milk. Early data from one meta-analysis also suggests that lactoferrin may be more effective at preventing late-onset sepsis when combined with probiotics (104868). Fixed doses of 100-250 mg daily and weight-based doses up to 300 mg/kg daily have been studied (97783,104856,104868,104869,104870). However, many individual clinical studies, including 3 large studies, have failed to demonstrate clear benefits of lactoferrin. These clinical trials, one in very premature infants and the others in very low birthweight infants, show that lactoferrin 150 mg/kg daily, 200 mg/kg daily, or 100 mg daily does not reduce late-onset sepsis when compared with control (104857,104858,110771). Two of these trials had very few infants exclusively fed bovine formula, which may have limited potential benefits. Subgroup analyses from these trials also suggest that extremely low birth weight and/or extremely premature infants may have benefited from lactoferrin (104857,104858).

LIKELY INEFFECTIVE

• Fetal and premature infant mortality. Oral lactoferrin does not reduce the risk of all-cause mortality in premature infants. Details: Many meta-analyses and large clinical trials show that taking lactoferrin does not reduce the risk of mortality from any cause in premature infants (104856,104857,104858,104868,110771).
• Necrotizing enterocolitis (NEC). Most research shows that oral lactoferrin does not reduce the incidence of NEC in premature infants. Details: Many meta-analyses and large clinical studies show that lactoferrin does not reduce the incidence of NEC in premature infants (104856,104857,104858,104868,110771). Exploratory data from one meta-analysis suggest that lactoferrin combined with probiotics may reduce the incidence of NEC when compared with control (104868). However, since probiotics alone have demonstrated benefit for the prevention of NEC in clinical trials, it is unclear if lactoferrin confers any additional benefit.

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Acne. Oral lactoferrin has only been studied in combination with other ingredients; its effect when used alone is unclear. Details: A large clinical study in adult females with acne shows that taking an oral supplement containing lactoferrin, zinc, niacinamide, and prebiotics once daily for 12 weeks, in addition to applying a topical combination retinoid-based cream, modestly improves the number of acne lesions (i.e., non-inflammatory, inflammatory, and total) when compared with the topical combination retinoid-based cream alone (112915). It is unclear if these effects are due to lactoferrin, other ingredients, or the combination.
• Anemia of chronic disease. Oral lactoferrin might improve hemoglobin levels in some patients with anemia of chronic disease. However, the optimal patient population is unclear. Details: One nonrandomized clinical study evaluated bovine lactoferrin in patients with anemia of chronic disease. In pregnant patients with anemia related to beta-thalassemia or hereditary thrombophilia, taking a specific bovine lactoferrin 100 mg capsule (Lattoglobina, Aqma Italia) twice daily with meals, starting at 6-8 weeks' gestation and continuing until delivery, improves hemoglobin levels by 50% and 15%, respectively, when compared with baseline. In non-pregnant patients, taking this same product twice daily for 30 days improves hemoglobin levels by 18% in patients with hereditary thrombophilia, but not in those with beta-thalassemia. The study may have been inadequately powered to detect a difference from baseline (104865).
• Antibiotic-associated diarrhea. It is unclear if oral lactoferrin is beneficial for preventing antibiotic-associated diarrhea in children or adults. Details: A very small clinical study in long-term care patients shows that adding lactoferrin at an unspecified dose to 600 mL of gastronomy tube solution daily for 56 days reduces the risk for antibiotic-associated diarrhea when compared with placebo (97782). Conversely, a clinical study in children aged 1-18 years receiving antibiotic therapy for an acute respiratory or urinary tract infection shows that those taking bovine lactoferrin 100 mg twice daily are more than twice as likely to develop antibiotic-associated diarrhea during or for the two weeks following antibiotic therapy when compared with those taking placebo (106729). However, the validity of these findings is limited by differences in baseline characteristics between groups.
• Atopic dermatitis (eczema). Oral lactoferrin has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A very small clinical study in adults with atopic dermatitis shows that taking a combination of lactoferrin 250 mg and a whey derived immunoglobulin-rich fraction 250 mg daily for 56 days improves symptoms in 13 of 22 patients, compared with 4 of 13 patients taking placebo (97789).
• Bacterial vaginosis. Oral lactoferrin has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in adults with recurrent bacterial vaginosis shows that adding a specific combination capsule (Respecta, Giellepi Spa Health Science) containing bovine lactoferrin 50 mg and 5 billion colony-forming units of Lactobacillus acidophilus GLA-14 and Lactobacillus rhamnosus HN001 on a varying schedule over 6 months, in conjunction with metronidazole 500 mg twice daily for the first 7 days, reduces the proportion of patients with vaginal discharge by 63%, itching by 57%, and a recurrent episode by 50% when compared with placebo. Patients took 2 capsules daily for 5 days, then 1 capsule daily for 10 days, followed by 1 capsule daily for 10 days of each month, beginning on the first day of the menstrual cycle. It is unclear if these effects are due to lactoferrin, other ingredients, or the combination (104872).
• Chemotherapy-induced anemia. It is unclear if oral lactoferrin is beneficial for chemotherapy-induced anemia. Details: An open-label clinical study in adults with advanced cancer and chemotherapy-induced anemia who are receiving treatment with recombinant human erythropoietin shows that taking oral lactoferrin (Lattoglobina, Grunenthal-Formenti) 200 mg daily for 12 weeks is as effective as intravenous ferric gluconate 125 mg weekly for improving hemoglobin and iron levels (97781).
• Cognitive function. Oral lactoferrin has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical trial in healthy adults shows that taking a product containing a combination of lactoferrin 10 mg, probiotics, prebiotics, minerals, and glutathione (Puraflor, GSK Consumer Healthcare, Milano, Italy) daily for 4 weeks does not affect cognitive performance during acute stress when compared with placebo (110923). It is unclear if this effect is due to lactoferrin, other ingredients, or the combination.
• Common cold. It is unclear if oral lactoferrin is beneficial for preventing the common cold. Details: A clinical study in healthy adults shows that taking bovine lactoferrin 200 mg or 600 mg daily for 12 weeks does not reduce the frequency or duration of self-reported symptoms of the common cold when compared with placebo (104859). Another clinical study in adults with frequent colds shows that taking a combination of bovine lactoferrin 400 mg and whey protein immunoglobulin-rich fraction 200 mg daily for 90 days reduces the number of colds by 57% when compared with placebo. There was no effect on cold severity (97786). It is not clear if this effect is due to lactoferrin, whey protein fraction, or the combination.
• Coronavirus disease 2019 (COVID-19). It is unclear if oral lactoferrin is beneficial for the treatment or prevention of COVID-19. Details: A small clinical study in adults hospitalized with mild-to-moderate COVID-19 receiving hydroxychloroquine, vitamin C, zinc, and acetylcysteine shows that taking lactoferrin 200 mg once or twice daily does not improve symptoms when compared with placebo (106731). Similarly, a large clinical study in adults hospitalized with moderate-to-severe COVID-19 receiving standard therapy shows that taking a specific product containing bovine lactoferrin (Mosaic, Pharmaguida) 400 mg twice daily for 30 days does not reduce intensive care unit admission or death, nor improve illness severity scores or discharge within 2 weeks when compared with placebo (112913). However, observational research with this product in outpatient adults with asymptomatic to moderately symptomatic COVID-19 suggests that taking 200-1000 mg daily is associated with a median of 15 days to a negative SARS-CoV-2 test, compared with 24 days in a historical control group (106732). The validity of these findings is limited by the retrospective nature of the study and differences in symptom severity between the groups at baseline. There is also interest in oral lactoferrin for prevention of COVID-19. A large clinical study conducted in healthcare workers in Peru who were screened and tested for COVID-19 shows that taking bovine lactoferrin 600 mg once daily for 65 days does not reduce the number of SARS-CoV-2 cases when compared with placebo (112914). However, the study was stopped prematurely due to vaccine availability; it may not have been powered to detect a difference between groups.
• Diarrhea. It is unclear if oral lactoferrin is beneficial for reducing the incidence of diarrhea in children or adults. Details: A large clinical study in weaned children 12-18 months of age shows that taking bovine lactoferrin 500 mg twice daily for 6 months does not reduce the incidence of diarrhea when compared with placebo (97787). However, a clinical study in infants with anemia who were exclusively breast-fed from 4-6 months before weaning and transitioning to infant formula from 6-9 months shows that fortification of each 100 grams of formula with 38 mg of bovine lactoferrin for 3 months improves vomiting and nausea when compared with formula without fortification. Similarly, fortification of each 100 grams of formula with 76 mg of bovine lactoferrin for 3 months improves diarrhea-related illness, diarrhea, vomiting, and nausea when compared with formula without fortification (106726). Lactoferrin has also been evaluated in adults. A large clinical study in healthy adults working at kindergartens or nursery schools in the winter shows that taking bovine lactoferrin 600 mg daily for 12 weeks is associated with a 1-day duration of diarrhea, compared with 2 days in those taking placebo (106728).
• Gastroenteritis-associated nausea and vomiting. It is unclear if oral lactoferrin prevents the development of gastroenteritis-associated nausea and vomiting in children or adults. Details: A large clinical study in children aged 3-6 years shows that consuming yogurt fortified with bovine lactoferrin 100 mg 3-5 days weekly for 15 weeks reduces the odds of school absence due to vomiting by 19% when compared with consuming the yogurt less than 3 days per week. However, consuming the yogurt did not reduce absences due to gastroenteritis, the presumed cause of vomiting (104862). A large clinical study in healthy adults working at kindergartens or nursery schools in the winter shows that taking bovine lactoferrin 200 or 600 mg daily for 12 weeks is associated with a 12% prevalence of acute gastrointestinal symptoms, compared with a prevalence of 22% in those taking placebo (106728).
• Gingivitis. Oral lactoferrin has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A clinical study in adults with mild gingivitis shows that taking bovine lactoferrin 60 mg, bovine lactoperoxidase 7.8 mg, and glucose oxidase 7.8 mg daily for 12 weeks improves gingival health and plaque index scores when compared with placebo. A lower dose product containing bovine lactoferrin 20 mg, bovine lactoperoxidase 2.6 mg, and glucose oxidase 2.6 mg daily for 12 weeks improves plaque index scores, but not gingival health scores, when compared with placebo. It is unclear if these effects are due to lactoferrin, other ingredients, or the combination (104867).
• Helicobacter pylori. Research on the use of oral lactoferrin as an adjunct for H. pylori eradication is inconclusive and conflicting. Details: Monotherapy with human recombinant lactoferrin, even at high doses of 5 grams daily, does not suppress or eradicate H. pylori infection (13317). However, research on its use as an adjunct to standard therapy is conflicting. Some studies suggest that lactoferrin improves efficacy when added to a triple therapy regimen of rabeprazole, clarithromycin, and tinidazole (13316,13332). However, research using lactoferrin with a triple therapy regimen of esomeprazole, clarithromycin, and amoxicillin found no difference in eradication rates. It is possible that lactoferrin activity on the bacterial cell wall interferes with the cell wall activity of amoxicillin (13315). Other research shows that using lactoferrin in addition to a sequential therapy regimen of esomeprazole, amoxicillin, metronidazole, and clarithromycin or a triple therapy regimen of esomeprazole, amoxicillin, and clarithromycin is associated with eradication rates of 95% or 86%, respectively, compared with eradication rates of 83% and 70%, respectively, with the use of either regimen alone (106730). However, using lactoferrin in addition to a sequential therapy regimen (esomeprazole, amoxicillin, tinidazole, and clarithromycin) and probiotics does not increase eradication more than sequential therapy and probiotics alone (97790).
• Hepatitis C. It is unclear if oral lactoferrin is beneficial for hepatitis C. Details: Some clinical research shows that lactoferrin decreases serum levels of hepatitis C virus RNA and alanine aminotransferase (ALT) in adults with hepatitis C (13320,13321). Some experts recommend starting lactoferrin 1 to 3 months before starting interferon to identify lactoferrin responders (13321,13322,13323,13324). Lactoferrin doses of 1.8 or 3.6 grams daily appear to be necessary for efficacy (13323,13324); lower doses don't seem to have any effect (13313,13314).
• Infant development. Oral lactoferrin has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A clinical study in healthy, full-term, exclusively formula-fed infants shows that taking a formula fortified with bovine lactoferrin 0.6 grams/L and bovine milk fat globule membrane 5 grams/L for 12 months improves cognitive development scores by about 8% after 12 months, but not after 18 months, when compared with control formula. This study may have been inadequately powered to detect a difference between groups at 18 months. It is unclear if any effect is due to lactoferrin, milk fat globule membrane, or the combination (104866).
• Iron deficiency anemia. It is unclear if oral lactoferrin is beneficial for the treatment or prevention of iron deficiency anemia in infants and children. Details: An open-label clinical study in children aged 1-10 years with cerebral palsy and iron deficiency anemia shows that taking bovine lactoferrin (Pravotin, Hygint) 100 mg twice daily for 4 weeks improves hemoglobin by 1.4 grams/dL, compared with 0.8 grams/dL in those taking iron hydroxide polymaltose complex providing elemental iron 3 mg/kg twice daily. Lactoferrin also improves serum ferritin, but not the rest of the serum iron profile (106725). Conversely, a small open-label clinical study in children aged 1-18 years with iron deficiency anemia in Egypt shows that the improvement in hemoglobin, serum iron, ferritin, or transferrin saturation is less with lactoferrin 100 mg daily, or twice daily if over age 3, when compared with iron bisglycinate chelate 0.75 mg/kg daily or iron polymaltose complex 6 mg/kg daily for a month. However, improvement in hemoglobin and iron studies was similar when comparing 30% iron saturated lactoferrin (100 mg lactoferrin and 30 mg iron) daily, or twice daily if over age 3 years, with iron bisglycinate chelate or iron polymaltose complex (110189). Lactoferrin has also been evaluated for the prevention of iron deficiency anemia. A clinical study in healthy, full-term formula-fed infants aged 6 weeks to 6 months shows that feeding a low-iron infant formula supplemented with lactoferrin has no effect on iron status or incidence of iron deficiency when compared with the low-iron formula alone (106724).
• Preterm labor. It is unclear if vaginal lactoferrin is beneficial for preventing preterm labor. Details: Observational research in patients diagnosed with bacterial vaginosis in the first trimester of pregnancy and a previous history of preterm labor has found that using a lactoferrin vaginal tablet 300 mg daily for 21 days is associated with a 44% reduced incidence of preterm birth when compared with no intervention. The validity of this study is limited by the use of a retrospective chart review (105405).
• Psoriasis. It is unclear if topical lactoferrin is beneficial in psoriasis. Details: A small open-label clinical study in patients with mild to moderate stable plaque-type psoriasis shows that applying lactoferrin 10% or 20% ointment topically daily in addition to taking bovine lactoferrin 100 mg orally daily (Lattoglobina, Grünenthal-Formenti) for 4 weeks improves symptoms of psoriasis, such as redness and scaling, by up to 37% when compared with use of oral lactoferrin alone (97784).
• Respiratory tract infections. It is unclear if oral lactoferrin is beneficial for treating or preventing respiratory tract infections. Details: A clinical study in healthy children aged 12-32 months shows that taking bovine lactoferrin 48 mg daily for 13 weeks does not reduce symptoms of respiratory tract infections when compared with placebo (104861). However, a clinical study in infants with anemia who were exclusively breast-fed from 4-6 months before weaning and transitioning to infant formula from 6-9 months shows that fortification of each 100 grams of formula with 38 mg of bovine lactoferrin for 3 months improves rhinorrhea, wheezing, and skin rash when compared with formula without fortification. Similarly, fortification of each 100 grams of formula with 76 mg of bovine lactoferrin for 3 months improves respiratory-related illness and wheezing when compared with formula without fortification (106726). There is also interest in oral lactoferrin for prevention of respiratory tract infections. However, two meta-analyses that each included 6 clinical studies in infants, children, and adults who consumed a bovine lactoferrin supplement or bovine lactoferrin enhanced formula, with some studies included in both analyses, have conflicting results. One meta-analysis of 1194 patients shows that lactoferrin reduces the risk of developing a respiratory infection by 43% when compared with placebo or various controls (110774). Conversely, the second meta-analysis of 1157 patients shows that lactoferrin does not reduce the risk of developing a respiratory infection in adults but may reduce the risk by 22% in infants and children when compared with placebo or unenhanced formula (110775). The validity of the findings from these meta-analyses is limited by the heterogeneity of the included studies, which enrolled patients of a broad age range and utilized widely varying dosing regimens. Furthermore, some studies are of poor quality.
• Vaginal candidiasis. Oral lactoferrin has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in adults with recurrent vaginal candidiasis shows that taking a specific combination capsule (Respecta, Giellepi Spa Health Science) containing bovine lactoferrin 50 mg and 5 billion colony-forming units of Lactobacillus acidophilus GLA-14 and Lactobacillus rhamnosus HN001 on a varying schedule over 6 months, in conjunction with clotrimazole 100 mg daily for the first 7 days, reduces the proportion of patients with vaginal discharge by 63%, itching by 100%, and a recurrent infection by 71% when compared with placebo. Patients took 2 capsules daily for 5 days, then 1 capsule daily for 10 days, followed by 1 capsule daily for 10 days of each month, beginning during the premenstrual phase. It is unclear if these effects are due to lactoferrin, other ingredients, or the combination (104863).
• Ventilator-associated pneumonia (VAP). It is unclear if oral lactoferrin is beneficial for preventing VAP. Details: A clinical study in critically ill, mechanically ventilated adults shows that taking lactoferrin 500 mg four times daily for up to 28 days does not reduce the incidence of VAP or other infections, or increase antibiotic-free days, when compared with placebo (104873). More evidence is needed to rate lactoferrin for these uses.

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LIKELY SAFE ...when used orally or intravenously and appropriately. Calcium is safe when used in appropriate doses (7555,12928,12946,95817). However, excessive doses should be avoided. The Institute of Medicine sets the daily tolerable upper intake level (UL) for calcium according to age as follows: Age 0-6 months, 1000 mg; 6-12 months, 1500 mg; 1-8 years, 2500 mg; 9-18 years, 3000 mg; 19-50 years, 2500 mg; 51+ years, 2000 mg (17506). Doses over these levels can increase the risk of side effects such as kidney stone, hypercalciuria, hypercalcemia, and milk-alkali syndrome. There has also been concern that calcium intake may be associated with an increased risk of cardiovascular disease (CVD) and coronary heart disease (CHD), including myocardial infarction (MI). Some clinical research suggests that calcium intake, often in amounts over the recommended daily intake level of 1000-1300 mg daily for adults, is associated with an increased risk of CVD, CHD, and MI (16118,17482,91350,107233). However, these studies, particularly meta-analyses, have been criticized for excluding trials in which calcium was administered with vitamin D (94137). Many of these trials also only included postmenopausal females. Other analyses report conflicting results, and have not shown that calcium intake affects the risk of CVD, CHD, or MI (92994,93533,97308,107231). Advise patients not to consume more than the recommended daily intake of 1000-1200 mg per day and to consider total calcium intake from both dietary and supplemental sources (17484). Also, advise patients taking calcium supplements to take calcium along with vitamin D (93533).

POSSIBLY UNSAFE ...when used orally in excessive doses. The National Academy of Medicine sets the daily tolerable upper intake level (UL) for calcium according to age as follows: 19-50 years, 2500 mg; 51 years and older, 2000 mg (17506). Doses over these levels can increase the risk of side effects such as kidney stones, hypercalciuria, hypercalcemia, and milk-alkali syndrome. There has also been concern that calcium intake may be associated with an increased risk of cardiovascular disease (CVD) and coronary heart disease (CHD), including myocardial infarction (MI). Some clinical research suggests that calcium intake, often in amounts over the recommended daily intake level of 1000-1300 mg daily for adults, is associated with an increased risk of CVD, CHD, and MI (16118,17482,91350,107233). However, these studies, particularly meta-analyses, have been criticized for excluding trials in which calcium was administered with vitamin D (94137). Many of these trials also only included postmenopausal females. Other analyses report conflicting results, and have not shown that calcium intake affects the risk of CVD, CHD, or MI (92994,93533,97308,107231). Advise patients to not consume more than the recommended daily intake of 1000-1200 mg per day and to consider total calcium intake from both dietary and supplemental sources (17484). Also, advise patients taking calcium supplements to take calcium along with vitamin D (93533).

CHILDREN: LIKELY SAFE
when used orally and appropriately. Calcium is safe when used in appropriate doses (17506).

CHILDREN: POSSIBLY UNSAFE
when used orally in excessive doses. The Institute of Medicine sets the daily tolerable upper intake level (UL) for calcium according to age as follows: 0-6 months, 1000 mg; 6-12 months, 1500 mg; 1-8 years, 2500 mg; 9-18 years, 3000 mg (17506). Doses over these levels can increase the risk of side effects such as kidney stones, hypercalciuria, hypercalcemia, and milk-alkali syndrome.

PREGNANCY AND LACTATION: LIKELY SAFE
when used orally and appropriately (945,1586,3263,3264,17506). The World Health Organization (WHO) recommends prescribing oral calcium supplementation 1.5-2 grams daily during pregnancy to those with low dietary calcium intake to prevent pre-eclampsia (97347).

PREGNANCY AND LACTATION: POSSIBLY UNSAFE
when used orally in excessive doses. The Institute of Medicine sets the same daily tolerable upper intake level (UL) for calcium according to age independent of pregnancy status: 9-18 years, 3000 mg; 19-50 years, 2500 mg (17506). Doses over these amounts might increase the risk of neonatal hypocalcemia-induced seizures possibly caused by transient neonatal hypoparathyroidism in the setting of excessive calcium supplementation during pregnancy, especially during the third trimester. Neonatal hypocalcemia is a risk factor for neonatal seizures (97345).

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LIKELY SAFE ...when used orally in amounts commonly found in foods. Lactoferrin has Generally Regarded as Safe (GRAS) status in the US (13312).

POSSIBLY SAFE ...when used orally in medicinal amounts. Bovine lactoferrin has been safely used at doses of up to 600 mg daily for up to 12 months (13313,13314,13315,13316,13320,13321,13322,13323,97786,104859,104860). Recombinant human lactoferrin has been used with apparent safety at a dose of 5 grams daily for up to 14 days (13317,13318,13319). There is insufficient reliable information available about the safety of lactoferrin when used topically.

CHILDREN: POSSIBLY SAFE
when used enterally in infants and children up to 6 years of age. Lactoferrin has been used safely as a part of enteral feeds in preterm infants at a dose of 250 mg daily or up to 300 mg/kg daily for up to 30 days (97783,97787,104857,104858,104870). Formula fortified with bovine lactoferrin 0.6 grams/L and bovine milk fat globule membrane 5 grams/L has also been used safely in infants for up to 12 months (104866). Bovine and recombinant human lactoferrin 1000 mg daily for up to 6 months has been used with apparent safety in weaned infants up to 18 months of age (97783,97787). Bovine lactoferrin 336-500 mg per week has been used with apparent safety in children 1-6 years of age for 13-15 weeks (104861,104862). There is insufficient reliable information available about the safety of lactoferrin in children over 6 years of age.

PREGNANCY: LIKELY SAFE
when used orally in amounts commonly found in foods. Lactoferrin has Generally Regarded as Safe (GRAS) status in the US (13312).

PREGNANCY: POSSIBLY SAFE
when used orally in medicinal amounts. Lactoferrin has been used with apparent safety during the second or third trimester of pregnancy at doses of up to 250 mg daily for up to 8 weeks (97788). Also, bovine lactoferrin has been used with apparent safety throughout all trimesters of pregnancy at doses of up to 200 mg daily (104865). There is insufficient reliable information available about the safety of intravaginal lactoferrin during pregnancy and lactation; avoid using.

LACTATION: LIKELY SAFE
when used orally in amounts commonly found in foods. Lactoferrin has Generally Regarded as Safe (GRAS) status in the US (13312). There is insufficient reliable information available about the safety of lactoferrin when used medicinally during lactation; avoid using.

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ALUMINUM Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Calcium citrate might increase aluminum absorption and toxicity. Other types of calcium do not increase aluminum absorption.  Details Calcium citrate can increase the absorption of aluminum when taken with aluminum hydroxide. The increase in aluminum levels may become toxic, particularly in individuals with kidney disease (21631). However, the effect of calcium citrate on aluminum absorption is due to the citrate anion rather than calcium cation. Calcium acetate does not appear to increase aluminum absorption (93006).

BISPHOSPHONATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = C Calcium reduces the absorption of bisphosphonates.  Details Advise patients to take bisphosphonates at least 30 minutes before calcium, but preferably at a different time of day. Calcium supplements decrease absorption of bisphosphonates (12937).

CALCIPOTRIENE (Dovonex) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Taking calcipotriene with calcium might increase the risk for hypercalcemia.  Details Calcipotriene is a vitamin D analog used topically for psoriasis. It can be absorbed in sufficient amounts to cause systemic effects, including hypercalcemia (12938). Theoretically, combining calcipotriene with calcium supplements might increase the risk of hypercalcemia.

CALCIUM CHANNEL BLOCKERS Interaction Rating = Minor Be watchful with this combination. Severity = Moderate •  Occurrence = Unlikely •  Level of Evidence = D Intravenous calcium may decrease the effects of calcium channel blockers; oral calcium is unlikely to have this effect.  Details Intravenous calcium is used to decrease the effects of calcium channel blockers in the management of overdose. Intravenous calcium gluconate has been used before intravenous verapamil (Isoptin) to prevent or reduce the hypotensive effects without affecting the antiarrhythmic effects (6124). But there is no evidence that dietary or supplemental calcium when taken orally interacts with calcium channel blockers (12939,12947).

CEFTRIAXONE (Rocephin) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = D Co-administration of intravenous calcium and ceftriaxone can result in precipitation of a ceftriaxone-calcium salt in the lungs and kidneys.  Details Avoid administering intravenous calcium in any form, such as parenteral nutrition or Lactated Ringers, within 48 hours of intravenous ceftriaxone. Case reports in neonates show that administering intravenous ceftriaxone and calcium can result in precipitation of a ceftriaxone-calcium salt in the lungs and kidneys. In several cases, neonates have died as a result of this interaction (15794,21632). So far there are no reports in adults; however, there is still concern that this interaction might occur in adults.

DIGOXIN (Lanoxin) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = B Using intravenous calcium with digoxin might increase the risk of fatal cardiac arrhythmias.  Details Hypercalcemia increases the risk of fatal cardiac arrhythmias with digoxin (12940). However, one retrospective analysis of clinical data suggests that intravenous calcium does not increase the risk of dysrhythmias or mortality in patients receiving digoxin (38960).

DILTIAZEM (Cardizem, others) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = D Theoretically, calcium may reduce the therapeutic effects of diltiazem.  Details Hypercalcemia can reduce the effectiveness of verapamil in atrial fibrillation (10574). Theoretically, calcium might increase this risk of hypercalcemia and reduce the effectiveness of diltiazem.

DOLUTEGRAVIR (Tivicay) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = B Calcium seems to reduce levels of dolutegravir.  Details Advise patients to take dolutegravir either 2 hours before or 6 hours after taking calcium supplements. Pharmacokinetic research suggests that taking calcium carbonate 1200 mg concomitantly with dolutegravir 50 mg reduces plasma levels of dolutegravir by almost 40%. Calcium appears to decrease levels of dolutegravir through chelation (93578).

ELVITEGRAVIR (Vitekta) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = B Calcium seems to reduce levels of elvitegravir.  Details Advise patients to take elvitegravir either 2 hours before or 2 hours after taking calcium supplements. Pharmacokinetic research suggests that taking calcium along with elvitegravir can reduce blood levels of elvitegravir through chelation (94166).

LEVOTHYROXINE (Synthroid, others) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Calcium seems to reduce the absorption and effectiveness of levothyroxine.  Details Advise patients to take levothyroxine and calcium supplements at least 4 hours apart. Calcium reduces levothyroxine absorption, probably by forming insoluble complexes (5082). Calcium carbonate supplements reduce effectiveness of levothyroxine in patients with hypothyroidism (5081,5082,6137).

LITHIUM Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, concomitant use of calcium and lithium may increase this risk of hypercalcemia.  Details Clinical research suggests that long-term use of lithium may cause hypercalcemia in 10% to 60% of patients (38953). Theoretically, concomitant use of lithium and calcium supplements may further increase this risk.

QUINOLONE ANTIBIOTICS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Calcium seems to reduce the absorption of quinolone antibiotics.  Details Advise patients to take oral quinolones at least 2 hours before or 4-6 hours after calcium supplements or calcium-fortified foods. Taking calcium at the same time as oral quinolones can reduce quinolone absorption. Calcium binds to quinolones in the gut (4412,10339,21638,38570).

RALTEGRAVIR (Isentress) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = B Calcium may reduce levels of raltegravir.  Details Pharmacokinetic research shows that taking a single dose of calcium carbonate 3000 mg along with raltegravir 400 mg twice daily modestly decreases the mean area under the curve of raltegravir, but the decrease does not necessitate a dose adjustment of raltegravir (94164). However, a case of elevated HIV-1 RNA levels and documented resistance to raltegravir has been reported for a patient taking calcium carbonate 1 gram three times daily plus vitamin D3 (cholecalciferol) 400 IU three times daily in combination with raltegravir 400 mg twice daily for 11 months. It is thought that calcium reduced raltegravir levels by chelation, leading to treatment failure (94165).

SOTALOL (Betapace) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Calcium seems to reduce the absorption of sotalol.  Details Advise patients to separate doses by at least 2 hours before or 4-6 hours after calcium. Calcium appears to reduce the absorption of sotalol, probably by forming insoluble complexes (10018).

TETRACYCLINE ANTIBIOTICS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = C Calcium seems to reduce the absorption of tetracycline antibiotics.  Details Advise patients to take oral tetracyclines at least 2 hours before, or 4-6 hours after calcium supplements. Taking calcium at the same time as oral tetracyclines can reduce tetracycline absorption. Calcium binds to tetracyclines in the gut (1843).

THIAZIDE DIURETICS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = C Taking calcium along with thiazides might increase the risk of hypercalcemia and renal failure.  Details Thiazides reduce calcium excretion by the kidneys (1902). Using thiazides along with moderately large amounts of calcium carbonate increases the risk of milk-alkali syndrome (hypercalcemia, metabolic alkalosis, renal failure). Patients may need to have their serum calcium levels and/or parathyroid function monitored regularly.

VERAPAMIL (Calan, others) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = D Theoretically, calcium may reduce the therapeutic effects of verapamil.  Details Hypercalcemia can reduce the effectiveness of verapamil in atrial fibrillation (10574). Theoretically, use of calcium supplements may increase this risk of hypercalcemia and reduce the effectiveness of verapamil.

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General ...Orally and intravenously, calcium is well-tolerated when used appropriately.
Most Common Adverse Effects:
Orally: Belching, constipation, diarrhea, flatulence, and stomach upset.
Serious Adverse Effects (Rare):
Orally: Case reports have raised concerns about calciphylaxis and kidney stones.

Cardiovascular ...There has been concern that calcium intake may be associated with an increased risk of cardiovascular disease (CVD) and coronary heart disease (CHD), including myocardial infarction (MI). Some clinical research suggests that calcium intake, often in amounts over the recommended daily intake level of 1000-1300 mg daily for adults, is associated with an increased risk of CVD, CHD, and MI (16118,17482,91350,107233). However, these results, particularly meta-analyses, have been criticized for excluding trials in which calcium was administered with vitamin D (94137). Many of these trials also only included postmenopausal females. Other analyses report conflicting results, and have not shown that calcium intake affects the risk of CVD, CHD, or MI (92994,93533,97308,107231). Reasons for these discrepancies are not entirely clear. It may relate to whether calcium is taken as monotherapy or in combination with vitamin D. When taken with vitamin D, which is commonly recommended, calcium supplementation does not appear to be associated with an increased risk of CVD, CHD, or MI (93533,107231). Also, the association between calcium supplementation and CVD, CHD, or MI risk may be influenced by the amount of calcium consumed as part of the diet. Supplementation with calcium may be associated with an increased risk of MI in people with dietary calcium intake above 805 mg daily, but not in those with dietary calcium intake below 805 mg daily (17482). To minimize the possible risk of CVD, CHD, or MI, advise patients not to consume more than the recommended daily intake of 1000-1200 mg and to consider total calcium intake from both dietary and supplemental sources (17484). While dietary intake of calcium is preferred over supplemental intake, advise patients who require calcium supplements to take calcium along with vitamin D, as this combination does not appear to be associated with an increased risk of MI (93533).
Rarely, calcium intake can increase the risk of calciphylaxis, which usually occurs in patients with kidney failure. Calciphylaxis is the deposition of calcium phosphate in arterioles, which causes skin ulcers and skin necrosis. In a case report, a 64-year-old female with a history of neck fracture, sepsis, and ischemic colitis presented with painful leg ulcers due to calciphylaxis. She discontinued calcium and vitamin D supplementation and was treated with sodium thiosulfate and supportive care (95816).

Gastrointestinal ...Orally, calcium can cause belching, flatulence, nausea, gastrointestinal discomfort, and diarrhea (1824,1843,12950,38803). Although constipation is frequently cited as an adverse effect of calcium, there is no scientific substantiation of this side effect (1824,1843,1844,1845,12950,38978). Calcium carbonate has been reported to cause acid rebound, but this is controversial (12935,12936).

Oncologic ...There is some concern that very high doses of calcium might increase the risk of prostate cancer. Some epidemiological evidence suggests that consuming over 2000 mg/day of dietary calcium might increase the risk for prostate cancer (4825,12949). Additional research suggests that calcium intake over 1500 mg/day might increase the risk of advanced prostate cancer and prostate cancer mortality (14132). Consumption of dairy products has also been weakly linked to a small increase in prostate cancer risk (98894). However, contradictory research suggests no association between dietary intake of calcium and overall prostate cancer risk (14131,14132,104630). More evidence is needed to determine the effect of calcium, if any, on prostate cancer risk.

Renal ...Kidney stones have been reported in individuals taking calcium carbonate 1500 mg daily in combination with vitamin D 2000 IU daily for 4 years (93943).

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General ...Orally, bovine and human recombinant lactoferrin are well tolerated when used in typical doses. However, hjgher doses of 7.2 grams daily increase the risk of side effects and decrease tolerability.
Topically, there is a limited amount of information on the adverse effects of lactoferrin.
Intravaginally, no adverse effects have been reported. However, a thorough evaluation of safety outcomes has not been conducted.
Most Common Adverse Effects:
Orally: Constipation, diarrhea, epigastric pain, and nausea.
Topically: Burning sensation.
Serious Adverse Effects (Rare):
Orally: Bowel obstruction, intestinal perforation.

Dermatologic ...Orally, at higher doses of 7. 2 grams daily, lactoferrin has been reported to cause skin rash (13323). Topically, burning sensation has been reported (97784).

Gastrointestinal ...Orally, lactoferrin has been reported to cause diarrhea in some patients. At higher doses of 7.2 grams daily, anorexia and constipation have been reported (13323). However, gastrointestinal effects of lactoferrin, including epigastric pain, constipation, nausea, and diarrhea, are less common than with other sources of iron such as ferrous sulfate (97788). In neonates, single cases of jaundice, bloody stool, bowel obstruction, and intestinal perforation have been reported in clinical trials (104857,104858).

Neurologic/CNS ...Orally, at higher doses of 7. 2 grams daily, lactoferrin has been reported to cause fatigue and chills (13323).

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