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Literature Review & Commentary.

Omega-3 Fatty Acids for Dry Eyes

One hundred five patients (mean age, 57 years) with dry eye syndrome (keratoconjunctivitis sicca) were randomly assigned to receive, in double-blind fashion, 4 capsules per day of an omega-3 fatty acid preparation (providing a daily total of 1,680 mg of eicosapentaenoic acid and 560 mg of docosahexaenoic acid) or placebo (linoleic acid) for 12 weeks. Compared with placebo, the omega-3 fatty acids significantly increased tear break-up time (indicating slower evaporation of tears) and significantly decreased (improved) the mean Ocular Surface Disease Index score.

Comment: The findings from this study are consistent with those from numerous other studies in which oral administration of fish oil or the omega-3 fatty acids present in fish oil (eicosapentaenoic acid and docosahexaenoic acid) was moderately effective for relieving dry eye symptoms, including in patients with dry eyes associated with the use of contact lenses. In most of these studies, omega-3 fatty acids also increased tear secretion and decreased the rate of tear evaporation. In contrast, one study found that fish oil in combination with other nutrients was not more effective than placebo, although symptoms improved significantly in both groups. The dosage of omega-3 fatty acids used in the present study is equivalent to around 5-9 g per day of fish oil, but fish oil doses as low as 2 g per day were effective in some studies. Omega-3 fatty acids may work by an anti-inflammatory mechanism.

Epitropoulos AT, et al. Effect of oral re-esterified omega-3 nutritional supplementation on dry eyes. Cornea. 2016;35:1185-1191.

Topical Vitamin B12-Containing Ointment for Psoriasis

Twenty-four adults (mean age, 48.2 years) with mild-to-moderate plaque psoriasis were randomly assigned to apply, in single-blind fashion, a vitamin B12-containing ointment to affected areas on one side of the body and a control cream to affected areas on the other side twice a day for 12 weeks. The active treatment (Mavena B12 ointment) is a registered medication in the European Union; it contains 0.07% cyanocobalamin, 20% avocado oil, polyunsaturated fatty acids, and moisturizing factors. The control treatment was a glycerol and petrolatum-based hydrating cream. Mean disease severity (as determined by the Psoriasis Area Severity Index) decreased to a significantly greater extent with active treatment than with control treatment (86% vs. 12.3%; p < 0.001). The difference between active and control treatment became statistically significant within two weeks of the start of treatment.

Comment: In this study, topical application of a vitamin B12-containing ointment resulted in marked improvement in patients with mild-to-moderate plaque psoriasis. These findings confirm the results of a previous trial in which twice-daily application of a cream containing 0.07% vitamin B12 and an unspecified concentration of avocado oil for 12 weeks improved the mean Psoriasis Area Severity Index in patients with chronic plaque psoriasis. (1) It is not clear how much of the benefit (if any) in these studies was due to the avocado oil. While avocado oil has been reported anecdotally to improve psoriasis, it has not, to my knowledge, been investigated in a controlled trial.

Del Duca E, et al. Superiority of a vitamin [B.sub.12]-containing emollient compared to a standard emollient in the maintenance treatment of mild-to-moderate plaque psoriasis. Int J Immunopathol Pharmacol. 2017;30:439-444.

Topical Vitamin B12-Containing Cream for Atopic Dermatitis

Twenty-two adults (ages not specified) with mild atopic dermatitis were randomly assigned to apply, in single-blind fashion, a vitamin B12-containing barrier cream to affected areas on one side of the body twice a day and a control cream to affected areas on the other side of the body three times per day for 12 weeks. The vitamin B12-containing cream (Mavena B12 barrier cream) contained 0.07% cyanocobalamin, a polysorbate carrier system to enhance penetration into the skin, and 1% urea. The control cream was a glycerol and petrolatum-based emollient cream. The mean percent improvement (as determined by the SCORing Atopic Dermatitis [SCORAD] index) was significantly greater at two weeks (53% vs. 12%; p < 0.001) and at 12 weeks (82% vs. 20%; p < 0.01) on the vitamin B12 side than on the control side.

Comment: This study found that topical application of a vitamin B12-containing barrier cream was an effective treatment for mild atopic dermatitis in adults. The findings are consistent with previous randomized controlled trials in which topical preparations containing 0.07% vitamin B12 improved atopic dermatitis in both adults (2) and children. (3) While the mechanism of action of vitamin B12 is not clear, it has been shown to prevent the production of certain inflammatory cytokines, an effect that might help prevent flare-ups of atopic dermatitis.

Nistico SP, et al. Superiority of a vitamin B12-barrier cream compared with standard glycerol-petrolatum-based emollient cream in the treatment of atopic dermatitis: A randomized, left-to-right comparative trial. Dermatol Tber. 2017 Jul 4 [Epub ahead of print].

Multi-Strain Probiotic for Atopic Dermatitis

Fifty children (aged 4-17 years; mean, 9.2 years) in Spain with moderate atopic dermatitis were randomly assigned to receive, in double-blind fashion, a daily capsule containing 10 (9) total colony-forming units of Bifidobacterium lactis CECT 8145, B. longum CECT 7347, and Lactobacillus casei CECT 9104 or placebo for 12 weeks. The mean improvement in the SCORing Atopic Dermatitis (SCORAD) index was significantly greater in the probiotic group than in the placebo group (83% vs. 24%; p < 0.001). In addition, the use of topical steroids to treat flares was significantly lower by 29% in the probiotic group than in the placebo group (7.7% vs. 10.8% of patient-days; p < 0.001).

Comment: In this study, a multi-strain probiotic preparation was effective in the treatment of moderate atopic dermatitis in children. The study was funded by Biopolis, a company that develops and manufactures probiotics, and three of the study authors were employees of the company. The results should therefore be interpreted with caution. Numerous other randomized controlled trials have invested the effect of various probiotic agents in children with atopic dermatitis. About half of those studies found a beneficial effect, while the others did not. The conflicting results might be due in part to the presence of small amounts of cow's milk proteins in probiotic preparations that were grown on milk or casein (a milk protein). In a case report, an infant who was allergic to cow's milk had a moderately severe allergic reaction to a probiotic preparation that had been grown on casein. (4)

Further research is needed to identify patient characteristics that might predict a positive response to probiotics, and what probiotic strains are most effective. Milk-allergic children with atopic dermatitis should not use probiotics that were grown on culture media that contain milk proteins.

Navarro-Lopez V, et al. Effect of oral administration of a mixture of probiotic strains on SCORAD index and use of topical steroids in young patients with moderate atopic dermatitis: a randomized clinical trial. JAMA Dermatol. 2017 Nov 8 [Epub ahead of print].

High-Dose Intravenous Magnesium for Severe Asthma

Thirty-eight children (aged 6-16 years) in Paraguay presenting to an emergency department with severe non-infection-mediated asthma that had failed to improve after two hours of standard therapy were randomly assigned to receive intravenous magnesium sulfate at a bolus dose of 50 mg per kg of body weight given over one hour, or a more prolonged infusion with a higher total dose (50 mg per kg per hour for 4 hours; maximum dose, 8 g over 4 hours). Patients were monitored for cardiorespiratory complications. The proportion of patients who were discharged to home within 24 hours was significantly higher in the prolonged-infusion group than in the bolus group (47% vs. 10%; p = 0.032). The number-needed-to-treat to facilitate one discharge at or before 24 hours was 2.7. The mean length of hospital stay (34 vs. 48 hours; p = 0.013) and the mean cost per patient ($603 vs. $834; p < 0.02) was significantly lower in the prolonged-treatment group than in the bolus group. There were no adverse events serious enough to require intervention or discontinuation of treatment.

Comment: Magnesium is a potent bronchodilator. Intravenous magnesium has been reported in many, though not all, randomized controlled trials to be an effective treatment for acute exacerbations of asthma. Studies conducted in children typically used magnesium sulfate at a dosage of 40-50 mg per kg of body weight, administered over 20 minutes. The results of the present study suggest that a more prolonged infusion with a larger total dose, as compared with the usual treatment protocol, can accelerate discharge from the emergency department and reduce healthcare costs in children with treatment-resistant non-infection-mediated asthma. High-dose intravenous magnesium can cause potentially serious adverse effects such as hypotension and bradycardia, so it should be used with caution and patients should be monitored closely.

Irazuzta JE, et al. High-dose magnesium sulfate infusion for severe asthma in the emergency department: efficacy study. Pediatr Crit Care Med. 2016;17:e29-e33.

Vitamin D During Pregnancy Prevents Allergies in Children

Two hundred sixty pregnant women in New Zealand were randomly assigned to receive, in double-blind fashion, 1,000 or 2,000 IU per day of vitamin D or placebo from week 27 of gestation until delivery. The infants then received 400 or 800 IU per day of vitamin D or placebo, corresponding to low-dose vitamin D, high-dose vitamin D, or placebo, respectively, during the mother's pregnancy. Specific IgE was measured at 18 months of age. Compared with placebo, both doses of vitamin D significantly decreased the proportion of children sensitized to mites at 18 months of age. The proportion of children who had primary care visits for asthma was 11% with placebo, 0% with low-dose vitamin D, and 4% with high-dose vitamin D (p = 0.002).

Comment: In this study, vitamin D supplementation during pregnancy and infancy reduced the proportion of children sensitized to mites at 18 months of age and decreased the number of primary care visits due to asthma. The infant dose of 800 IU per day was not more effective than 400 IU per day for decreasing the number of visits for asthma. A previous randomized controlled trial found that vitamin D in doses of 800 or 1,200 IU per day, as compared with 400 IU per day, resulted in subtle impairments in motor development in breastfed infants. (5) The American Academy of Pediatrics recommends that all breastfed infants receive 400 IU per day of supplemental vitamin D. However, the available evidence does not support the routine use of larger vitamin D doses in the infant population.

Grant CC, et al. Vitamin D supplementation during pregnancy and infancy reduces aeroallergen sensitization: a randomized controlled trial. Allergy. 2016;71:1325-1334.

Beetroot Juice Enhances Athletic Performance

Thirty-two trained male soccer players (mean age, 23 years) were randomly assigned to receive, in double-blind fashion, 140 ml per day of nitrate-rich beetroot juice (providing 800 mg per day of nitrate) or nitrate-depleted beetroot juice (placebo) for six days. After a washout period of at least eight days, each person consumed the alternate drink for an additional six days. All subjects performed a high-intensity intermittent running test (the Yo-Yo IR1 test) on the last day of each supplementation period. In this test, which assesses both aerobic and anaerobic performance, subjects perform repeated 2 times 20 m sprints at progressively increasing speeds, with a 10-second recovery period between each sprint. The test ends the second time a subject fails to cross the finish line in the required time. The primary outcome measure was the total distance covered during the test. Compared with placebo, nitrate-rich beetroot juice increased the mean distance covered during the Yo-Yo IR1 test by 3.4% (p < 0.03).

In a second study, eight trained male runners completed two 1,500 m and two 10,000 m time trials on a treadmill. Three hours before each test, the subjects received 140 ml of nitrate-rich or nitrate-depleted (placebo) beetroot juice. Performance in the 1,500 m trial was significantly faster with nitrate-rich beetroot juice than with placebo (mean, 320 vs. 326 seconds; p<0.05). In the 10,000 m trial, nitrate-rich beetroot juice resulted in a nonsignificantly faster performance (mean, 2,643 vs. 2,650 seconds).

Comment: These studies demonstrate that supplementation with nitrate-rich beetroot juice can improve performance in high-intensity intermittent exercise and middle-distance running events. The results are also consistent with improved performance in long-distance running events, although that improvement was not statistically significant. The effect of nitrate may be mediated by its conversion to nitric oxide, which functions as a vasodilator and a regulator of cellular activity.

While short-term administration of nitrate is probably safe for most people, its long-term safety has not been adequately studied. Nitric oxide is an unstable molecule that promotes the formation of reactive oxidants such as peroxynitrite. Peroxynitrite and other nitric oxide-derived oxidants are inflammatory mediators that may promote the development of atherosclerosis. The substance that has been shown most clearly to scavenge reactive nitrogen molecules is gamma-tocopherol, which is one of the naturally occurring forms of vitamin E. (6) In the process of quenching nitric oxide-derived oxidants, gamma-tocopherol is converted to 5-nitro-gamma-tocopherol, (7) which appears to be an inactive metabolite. (8) If long-term nitrate administration has potential adverse effects, they might be preventable by supplementing with gamma-tocopherol in the form of mixed tocopherols.

Nyakayiru J, et al. Beetroot juice supplementation improves high-intensity intermittent type exercise performance in trained soccer players. Nutrients. 2017;9:E314.

Shannon OM, et al. Dietary nitrate supplementation enhances short but not longer duration running time-trial performance. Eur J Appl Physiol. 2017;117:775-785.

Probiotic for Functional Abdominal Pain in Children

Fifty-five children (aged 5-17 years) with functional abdominal pain or irritable bowel syndrome were randomly assigned to receive, in double-blind fashion, Lactobacillus reuteri DSM 17938 (10 (8) colony-forming units per day) or placebo for 12 weeks, and were then followed for an additional four weeks. During the treatment and follow-up period, the median number of days with pain was significantly lower by 60% in the probiotic group than in the placebo group (26 vs. 65; p < 0.03).

Comment: These results indicate that administration of Lactobacillus reuteri DSM 17938 significantly decreased pain in children with functional abdominal pain or irritable bowel syndrome. This probiotic preparation is commercially available as L. reuteri Protectis, under the brand name Gerber Soothe Colic Drops. Its temperature should not exceed 77[degrees] F.; it should therefore be shipped cold during the summer.

Jadresin O, et al. Lactobacillus reuteri DSM 17938 in the treatment of functional abdominal pain in children: RCT study. J Pediatr Gastroenterol Nutr. 2017;64::925-929.


(1.) Stucker M, et al. Vitamin B12 cream containing avocado oil in the therapy of plaque psoriasis. Dermatology. 2001;203:141-147.

(2.) Stucker M, et al. Topical vitamin B12 - a new therapeutic approach in atopic dermatitis - evaluation of efficacy and tolerability in a randomized placebo-controlled multicentre clinical trial. Br J Dermatol. 2004;150:977-983.

(3.) Januchowski R. Evaluation of topical vitamin B12 for the treatment of childhood eczema. J Altern Complement Med. 2009;15:387-389.

(4.) Moneret-Vautrin DA, et al. Probiotics may be unsafe in infants allergic to cow's milk. Allergy. 2006;61:507-508.

(5.) Wicklow B, et al. Impact of vitamin D supplementation on gross motor development of healthy term infants: a randomized dose-response trial. Phys Occup Ther Pediatr. 2016;36:300-342.

(6.) Christen S, et al. Gamma-tocopherol traps mutagenic electrophiles such as NOx and complements alpha-tocopherol: physiological implications. Proc Natl Acad Sci. 1997;94:3217-3222.

(7.) Hensley K, et al. Measurement of 3-nitrotyrosine and 5-nitro-gamma-tocopherol by high-performance liquid chromatography with electrochemical detection. Free Radic Biol Med. 2000;28:520-528.

(8.) Wu JH, Hodgson JM, Ward NC, et al. Nitration of gamma-tocopherol prevents its oxidative metabolism by HepG2 cells. Free Radic Biol Med. 2005;39:483-494.

by Alan R. Gaby, MD
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Title Annotation:omega-3 fatty acids for dry eye, vitamin B-12 for psoriasis and atopic dermatitis
Author:Gaby, Alan R.
Publication:Townsend Letter
Date:Apr 1, 2018
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