Corticosteroid sparing effects of vitamin C and magnesium in asthma: a randomised trial

Open ArchivePublished:April 27, 2005DOI:https://doi.org/10.1016/j.rmed.2005.03.038

      Summary

      Aim

      The study aims to assess the a priori hypothesis that regular supplementation with vitamin C or magnesium will permit a reduction in the corticosteroid dose required to maintain asthma control in adults.

      Methods

      We invited all participants recruited from primary care centres who completed a parallel-group, randomised, placebo-controlled, 16-week supplementation trial of 1g/day vitamin C or 450mg/day magnesium to continue and participate in a structured corticosteroid reduction protocol over 10 weeks.

      Results

      A total of 92 participants (29 vitamin C, 31 magnesium and 32 placebo) entered the study. Assuming no reduction in corticosteroid dose in the 10 who subsequently withdrew, the geometric mean reductions in inhaled corticosteroid dose achieved with vitamin C, magnesium and placebo were 49, 13 and 11μg, respectively. Relative to placebo, the unadjusted effect of vitamin C was significant, and remained at borderline significance after adjustment for baseline corticosteroid dose (relative reduction ratio=4.03, 95% CI 0.95 to 17.1, P=0.06).

      Conclusions

      We conclude that while vitamin C supplements may have modest corticosteroid sparing effects and hence the potential to reduce exposure to their side effects, magnesium supplements have no effect on the inhaled corticosteroid dose required to maintain asthma control.

      Keywords

      Introduction

      Epidemiological evidence suggests that dietary factors may have an important influence on the incidence and severity of asthma,
      • Fogarty A.
      • Britton J.
      The role of diet in the aetiology of asthma.
      and both vitamin C
      • Bodner C.
      • Godden D.
      • Brown K.
      • Little J.
      • Ross S.
      • Seaton A.
      Antioxidant intake and adult-onset wheeze: a case-control study.
      • Soutar A.
      • Seaton A.
      • Brown K.
      Bronchial reactivity and dietary antioxidants.
      and magnesium
      • Soutar A.
      • Seaton A.
      • Brown K.
      Bronchial reactivity and dietary antioxidants.
      • Britton J.
      • Pavord I.
      • Richards K.
      • Wisniewski A.
      • Knox A.
      • Lewis S.
      • Tattersfield A.E.
      • Weiss S.
      Dietary magnesium, lung function, wheezing, and airway hyper-reactivity in a random adult population sample.
      are nutrients that have been particularly implicated in this respect. To date, several studies using short-term supplementation with these agents have indicated that they may be effective as therapies for asthma.
      • Schachter E.
      • Schlesinger A.
      The attenuation of exercise-induced bronchospasm by ascorbic acid.
      • Ogilvy C.
      • Dubois A.
      • Douglas J.
      Effects of ascorbic acid and indomethacin on the airways of healthy male subjects with and without induced bronchoconstriction.
      • Mohsenin V.
      • Dubois A.
      • Douglas J.
      Effect of ascorbic acid on response to methacholine challenge in asthmatic subjects.
      • Chatham M.
      • Eppler J.
      • Sauder L.
      • Green D.
      • Kulle T.
      Evaluation of the effects of vitamin C on ozone-induced bromchoconstriction in normal subjects.
      • Mohsenin V.
      Effect of vitamin C on NO2-induced airway hyperresponsiveness in normal subjects.
      However, with the exception of a placebo-controlled study that reported a decrease in clinical exacerbations of asthma during the Nigerian rainy season after regular vitamin C supplements,
      • Anah C.
      • Jarike L.
      • Baig H.
      High dose ascorbic acid in nigerian asthmatics.
      there is little evidence on the effects of longer-term supplementation with either magnesium or vitamin C. We have recently completed a double-blind, placebo-controlled, parallel group intervention study of 16 weeks vitamin C or magnesium supplementation in 300 adults with a physician diagnosis of asthma maintained on regular inhaled corticosteroids, which found no evidence of an effect on the clinical control of their disease.
      • Fogarty A.
      • Lewis S.
      • Scrivener S.
      • Antoniak M.
      • Pacey S.
      • Pringle M.
      • Britton J.
      Oral magnesium and vitamin C supplements in asthma: a parallel group randomised placebo-controlled trial.
      One explanation for the discrepancy between our negative intervention study and the observational epidemiological studies suggesting an effect of dietary vitamin C and magnesium intake on asthma control is that participants in our study were adults with asthma on regular inhaled corticosteroids. This has resulted in a study population with good asthma control as demonstrated by their low baseline level of asthma symptoms, and hence with only a small potential for improvement while remaining on maintenance corticosteroid medication. At the end of this study, in accordance with the original protocol, we invited participants to continue with their allocated supplement for a further 10 weeks, while undergoing a staged corticosteroid reduction protocol to determine whether either supplement had significant corticosteroid sparing effects. This was to see if there is a beneficial effect of either supplement that was masked by good asthma control attained by inhaled corticosteroid therapy. We report the results of this trial of the corticosteroid sparing effect of 26 weeks supplementation with vitamin C or magnesium in adults with asthma.

      Materials and methods

       Study subjects

      Men and women aged 18–60 with a physician diagnosis of asthma who had been using at least one dose of an inhaled corticosteroid daily for 6 months or more were identified from computerised records in 24 General Practices in the Nottingham area. Exclusion criteria were the current use of oral corticosteroids or diuretics, use of vitamin C, magnesium or calcium supplements in the past 3 months, an exacerbation of asthma requiring a change in regular medication within the past 4 weeks, a cumulative smoking history of more than 10 pack years, current pregnancy or planned pregnancy during the proposed trial period. Consenting individuals who met the entry criteria at an initial screening visit were randomised to one of the three study groups and entered a 3-week run-in period in which they completed a daily record of morning and evening peak flow measurements, asthma symptom score and bronchodilator use. Participants who did not satisfactorily complete this asthma diary or had unstable asthma (defined as any change in prophylactic medication use) during the run-in period were excluded from proceeding into the intervention period.

       Study design

      The intervention study used a double-blind, randomised, parallel-group, placebo-controlled design in a two-phase study over a total of 26 weeks. In the first phase we compared the effects of 16 weeks of daily supplements with magnesium (450mg), vitamin C (1g) or placebo given in addition to regular asthma medication, on the clinical control of asthma. Participants were randomly assigned (using a random number generator using blocks of nine units) to one of the three treatment groups by allocation of an individual code number, after the first (screening) visit. The code for randomisation was only broken after the final participant had left the trial. All randomisation, tablet preparation and dispensing were carried out independently from the recruitment and assessment of participants and were supervised by Sarah Pacey in Nottingham City Hospital Pharmacy. This study, which has been described and reported elsewhere, found no evidence of benefit from either supplement.
      • Fogarty A.
      • Lewis S.
      • Scrivener S.
      • Antoniak M.
      • Pacey S.
      • Pringle M.
      • Britton J.
      Oral magnesium and vitamin C supplements in asthma: a parallel group randomised placebo-controlled trial.

       Methods

      For the current study, we invited all participants completing the first phase to continue with their allocated blinded supplement and enter a staged inhaled corticosteroid reduction protocol adapted from a previous investigation.
      • Wong C.S.
      • Cooper S.
      • Britton J.
      • Tattersfield A.E.
      Steroid sparing effect of nedocromil sodium in asthmatic patients on high doses of inhaled steroids.
      The primary outcome was the decrease in individual inhaled corticosteroid dose achieved in each active supplement group relative to placebo. Participants were assessed at 2-week intervals for a total of 10 weeks, and on each occasion, in the absence of evidence of deterioration in clinical control, were asked to reduce their regular inhaled corticosteroid dose by approximately 25% of their initial regular maintenance dose. These incremental reductions in dose were scaled to the baseline inhaled corticosteroid dose in each individual, and designed to achieve complete withdrawal of inhaled corticosteroids within 8 weeks.
      Deterioration in asthma control was defined as one or more of:
      • (1)
        an increase in average daily bronchodilator usage by 6 or more inhalations over the 3 days preceding the study visit,
      • (2)
        a decrease in mean average morning and evening peak flow over the 3 days preceding the study visit of 15% or more below the average values recorded during the 2 weeks prior to the start of the steroid reduction protocol,
      • (3)
        a positive response to the question “are you aware of any deterioration in your asthma?”
      At each visit, participants who remained well controlled were asked to reduce their inhaled corticosteroid dose by the next planned increment. Those who did not, either then or at any time between visits, were asked to return and maintain their inhaled corticosteroid dose at that at which they had last felt well controlled, and remain on that dose for the remainder of the study. The daily dose of inhaled corticosteroid at the end of the corticosteroid reduction stage (week 10 of the present study, 26 weeks after starting the nutrient supplements) was used as the final dose for analysis.

       Statistical analysis and power

      The primary outcome was the decrease in individual inhaled corticosteroid dose achieved in each active supplement group relative to placebo. Reductions in inhaled corticosteroid doses were normalised by log10 transformation, after adding 1μg to all reductions to remove zero values. All fluticasone doses were doubled before transformation to reflect the relative potency of this agent compared to beclomethasone and budesonide.
      • Barnes N.
      • Marone G.
      • Maria G.
      • Visser S.
      • Utama I.
      • Payne S.
      A comparison of fluticasone propionate, 1mg daily, with beclomethasone dipropionate, 2mg daily, in the treatment of severe asthma.
      We compared the reduction in corticosteroid in the vitamin C and magnesium supplemented groups with placebo on an intention-to-treat basis in all participants who entered the steroid reduction phase, assuming no reduction in all who withdrew, initially using t-tests, and then corrected for the baseline inhaled corticosteroid dose using analysis of covariance. All analyses were carried out using the Statistical Package for the Social Sciences (version 9.0). Our initial power calculations were based on recruiting 300 participants to the first phase of the study, and assumed that 240 of these would enter the corticosteroid reduction phase of the study. This would have provided 87% power to detect an increase in the proportion of participants able to halve their inhaled corticosteroid dose from 60% to 80%.

      Results

      Of the 300 participants who entered the first phase of supplementation (full details on recruitment and compliance reported elsewhere
      • Fogarty A.
      • Lewis S.
      • Scrivener S.
      • Antoniak M.
      • Pacey S.
      • Pringle M.
      • Britton J.
      Oral magnesium and vitamin C supplements in asthma: a parallel group randomised placebo-controlled trial.
      ), 95 were randomised to vitamin C, 99 to magnesium and 106 to placebo. A total of 234 participants completed 16 weeks of supplementation, and of these, 92 (29 randomised to vitamin C, 31 to magnesium and 32 to placebo) consented to continue taking their allocated supplements and enter the inhaled corticosteroid reduction protocol. The treatment groups were similar at baseline (Table 1), except that baseline inhaled corticosteroid dose tended to be higher in those receiving vitamin C supplements. The main reason given for non-participation was lack of time to complete a further five visits and those who did not participate in the controlled corticosteroid reduction had a slightly higher requirement for inhaled corticosteroids compared to those who did.
      Table 1Baseline characteristics of participants.
      Total eligible to enter studyParticipants who entered corticosteroid reduction protocolParticipants who did not enter corticosteroid reduction protocol
      Vit CMagPlacebo
      Demographics
      Number300293132208
      Male (%)112 (37%)1481872
      Mean age (years) [sd]41 (11)45434140
      Mean daily corticosteroid dose (μg) [sd]646 (506)626593502679
      Number on high dose corticosteroid (%)28 (9)13123
      Number on long acting β-agonists (%)50 (17)86531
      Allergen sensitised (%)229 (79)232226158
      Current smokers (%)12 (4)01011
      Mean pack years [sd]1.3 (2.6)1.01.00.61.5
      Mean dietary vit C (mg) [sd]83 (36)84828983
      Mean dietary magnesium (mg) [sd]322 (87)317309350321
      Biological markers
      Mean serum mag (mmol) [sd] n=790.8 (0.07)0.80.80.80.8
      Mean 24h mag excretion (mmol) [sd] n=743.5 (1.9)3.63.43.53.4
      Mean serum vit C (μmol/L) [sd] n=7948.4 (23.3)50424450
      Baseline measures
      Mean FEV1 (L) [sd]2.8 (0.8)2.92.73.02.7
      Mean FVC (L) [sd]3.7 (1.0)3.93.54.23.6
      Mean log10 PD20 [sd]0.28 (0.73)0.370.380.350.23
      am peak flow (L/min) [sd]429 (92)454423435425
      pm peak flow (L/min) [sd]438 (91)455429441436
      Daily symptom score [sd]0.6 (0.7)0.20.60.40.7
      Inhaler use (puffs/day) [sd]2.0 (2.5)1.31.91.02.3
      All measurements taken at baseline prior to nutrient supplementation.
      Ten participants (1 from the vitamin C group, 3 from magnesium and 6 from placebo) withdrew from corticosteroid reduction, in most cases also giving reasons relating to time. Assuming no reduction in inhaled corticosteroids in these individuals, the geometric mean reductions in corticosteroid use achieved in the three groups were equivalent to 49 (95% CI 18–132)μg beclomethasone/day with vitamin C, 13 (95% CI 5–38)μg with magnesium and 11 (95% CI 4–30)μg with placebo (Table 2). The unadjusted geometric mean reduction in the vitamin C group was greater than that in the placebo group by a ratio of 4.37 (95% CI 1.06–18.20, P=0.04), and after adjustment of this difference for baseline inhaled corticosteroid dose the effects remained at borderline statistical significance (adjusted ratio=4.03, 95% CI 0.95–17.06, P=0.06). There was no difference in corticosteroid reduction between magnesium and placebo (unadjusted reduction ratio=1.22, 95% CI 0.28–5.25).
      Table 2Mean decrease in inhaled corticosteroid dose in participants (intention to treat analysis).
      GroupNumber of participantsGeometric mean decrease in corticosteroid [μg]
      Using the daily dose of inhaled corticosteroid at the final visit compared to baseline (μg), expressed as dose standardised to beclomethasone equivalent dose.
      (95% CI)
      Reduction ratio compared to placebo
      Calculated using multiple linear regression correcting for baseline inhaled corticosteroid dose.
      95%CI of reduction ratio compared to placebo
      Calculated using multiple linear regression correcting for baseline inhaled corticosteroid dose.
      P value
      Calculated using multiple linear regression correcting for baseline inhaled corticosteroid dose.
      Placebo3211 (4–30)
      Vitamin C2949 (18–132)4.030.95–17.060.06
      Magnesium3113 (5–38)1.030.23–4.300.97
      low asterisk Using the daily dose of inhaled corticosteroid at the final visit compared to baseline (μg), expressed as dose standardised to beclomethasone equivalent dose.
      Calculated using multiple linear regression correcting for baseline inhaled corticosteroid dose.

      Discussion

      There have been relatively few randomised controlled trials of the potential therapeutic benefits of vitamin C and magnesium in the control of asthma, and the present study of 26 weeks of supplementation is the longest reported to date. Our study has demonstrated no clear evidence of benefit from regular oral magnesium supplements, but found an effect, at the borderline of statistical significance, on regular inhaled corticosteroid requirement in participants allocated to vitamin C.
      With an intervention such as dietary manipulation using vitamin C and magnesium supplementation, any benefit is likely to be small and difficult to detect in patients with asthma that are already controlled. That our patients’ asthma was well controlled is demonstrated by the fact that their mean baseline peak flow levels were high, and their average subjective score on a scale from 0 to 5 was only 0.4. The corticosteroid reduction study was therefore designed to determine whether this good level of asthma control could be maintained on a lower regular dose of inhaled corticosteroids. In most studies of an experimental treatment the optimal duration and study population of the intervention is unknown, and as a consequence of the paucity of previous longer-term studies of the therapeutic benefits of vitamin C and magnesium on asthma control the duration of intervention for our study was a maximum of 26 weeks, a decision made due to logistic considerations. Thus we are unable to exclude the possibility that a different study design using a longer duration of intervention or a different study population such as children may demonstrate a marked benefit of vitamin C or magnesium supplementation on asthma control. Another limitation of our study is the reduction in the power of the study as a consequence of the lower than anticipated recruitment rate achieved from those eligible who completed the original 16-week intervention study; we had expected over 200 to participate when in the event only 92 did. However, examination of the confidence intervals around our estimates permits estimation of the size of any treatment effects. Although we conclude that our study provides no evidence for a beneficial effect of magnesium, we are unable to exclude the possibility that magnesium supplementation may result in up to a four-fold reduction in steroid dose demonstrated by the 95% confidence intervals. The interpretation of the potential therapeutic benefits of vitamin C supplementation on the requirement for inhaled corticosteroid is again limited by the low power of the study, but those who received vitamin C were able to reduce their inhaled corticosteroid dosage fourfold more than those who received placebo, with a lower 95% confidence interval of 0.95 and a higher 95% confidence interval of 17 times more than placebo, just outside the conventional criteria for statistical significance (P=0.06). Those who elected to continue in the study were generally similar to those who did not, but they had a marginally lower average daily inhaled baseline corticosteroid dose than participants in the original trial, particularly in the placebo group. Adjusting for baseline steroid dose therefore reduced the size of effect of vitamin C compared to placebo, but it remained of borderline statistical significance, suggesting that differential participation does not explain this effect. Adherence to the supplements, as reported in our original paper was good.
      • Fogarty A.
      • Lewis S.
      • Scrivener S.
      • Antoniak M.
      • Pacey S.
      • Pringle M.
      • Britton J.
      Oral magnesium and vitamin C supplements in asthma: a parallel group randomised placebo-controlled trial.
      While recent work has demonstrated that nebulised magnesium has a significant bronchodilator effect in acute asthma,
      • Hughes R.
      • Goldkorn A.
      • Masoli M.
      • Weatherall M.
      • Burgess C.
      • Beasley R.
      Use of isotonic nebulised magnesium sulphate as an adjuvant to salbutamol in treatment of severe asthma in adults: randomised placebo-controlled trial.
      while intravenous magnesium is of recognised benefit in this patient group,
      • Rowe B.
      • Bretzlaff J.
      • Bourdon C.
      • Bota G.
      • Camargo C.
      Magnesium sulfate is effective for severe acute asthma treated in the emergency department.
      our findings indicate that this beneficial effect is limited to the context of acute severe disease. We are not aware of any studies using oral magnesium supplements in acute asthma, but our pilot studies suggested that the limited efficiency of magnesium absorption would limit the applicability of this approach.
      • Fogarty A.
      • Christie S.
      • Lewis S.
      • Britton J.
      Alterations in serum magnesium after an acute dose of magnesium citrate or magnesium amino acid chelate.
      The benefits of vitamin C on asthma control have however been demonstrated elsewhere, and in diverse populations such as Nigeria, Mexico and The Netherlands. In Nigeria, Anah demonstrated a reduction in asthma attacks in patients with asthma in the rainy season using 1g vitamin C over 14 weeks.
      • Anah C.
      • Jarike L.
      • Baig H.
      High dose ascorbic acid in nigerian asthmatics.
      In Mexico City, Romieu and colleagues have shown a benefit of vitamin C on bronchoconstriction secondary to ozone in both street workers (with vitamin E and β-carotene) over an 18-week period
      • Romieu I.
      • Meneses F.
      • Ramirez M.
      • Ruiz S.
      • Padilla R.
      • Sienra J.
      • Gerber M.
      • Grievink L.
      • Dekker R.
      • Walda I.
      • Brunekreef B.
      Antioxidant supplementation and respiratory functions among workers exposed to high levels of ozone.
      and also children with asthma (with vitamin E) over a 12-week period.
      • Romieu I.
      • Sienra-Monge J.
      • Ramirez-Aguilar M.
      • Tellez-Rojo M.
      • Moreno-Macias H.
      • Reyes-Ruiz N.
      • Rio-Navarro B.
      • Ruiz-Navarro M.
      • Hatch G.
      • Slade R.
      • Hernandez-Avila M.
      Antioxidant supplementation and lung function among children with asthma exposed to high levels of air pollutants.
      Similar findings of a protective effect of vitamin C, in combination with vitamin E and β-carotene, on ozone-induced bronchoconstriction have also been reported in cyclists in The Netherlands.
      • Grievink L.
      • Jansen S.
      • Van’t Veer P.
      • Brunekreef B.
      Acute effects of ozone on pulmonary function of cyclists receiving antioxidant supplements.
      • Grievink L.
      • Zijlstra A.
      • Ke X.
      • Brunekreef B.
      Double-blind intervention trial on modulation of ozone effects on pulmonary function by antioxidant supplements.
      Thus, our observation of small decrement in daily inhaled corticosteroids after 26 weeks vitamin C supplementation is, albeit of borderline significance, consistent with the existing literature.
      We conclude therefore that regular oral supplementation for 26 weeks with magnesium has no significant effect on the requirement for inhaled corticosteroids in adults with asthma, but that vitamin C may have a modest corticosteroid sparing effect equivalent to a decrease in 38μg beclomethasone per day. As the side effects of inhaled corticosteroids are dose related,
      • Israel E.
      • Banerjee T.
      • Fitzmaurice G.
      • Kotlov T.
      • LaHive K.
      • LeBoff M.
      Effects of inhaled glucocorticoids on bone density in premenopausal women.
      further adequately powered studies are necessary to determine whether our findings can be confirmed, and hence whether patients with asthma should be recommended to use regular oral vitamin C supplements.

      Acknowledgements

      The authors thank Vicky Hammersley of Trent Focus and the General Practitioners of Nottingham for their help with patient recruitment, to Tony Hitch for biochemical analyses, Janet Oborne for assistance with data collection, and all the participants who took part in the study. Funding from the NHS National Research and Development Programme on Asthma Management administered by the National Asthma Campaign (Grant No. AM1/02/002) is gratefully acknowledged.

      References

        • Fogarty A.
        • Britton J.
        The role of diet in the aetiology of asthma.
        Clin Exp Allergy. 2000; 30: 615-627
        • Bodner C.
        • Godden D.
        • Brown K.
        • Little J.
        • Ross S.
        • Seaton A.
        Antioxidant intake and adult-onset wheeze: a case-control study.
        Eur Resp J. 1999; 13: 22-30
        • Soutar A.
        • Seaton A.
        • Brown K.
        Bronchial reactivity and dietary antioxidants.
        Thorax. 1997; 52: 166-170
        • Britton J.
        • Pavord I.
        • Richards K.
        • Wisniewski A.
        • Knox A.
        • Lewis S.
        • Tattersfield A.E.
        • Weiss S.
        Dietary magnesium, lung function, wheezing, and airway hyper-reactivity in a random adult population sample.
        Lancet. 1994; 344: 357-362
        • Schachter E.
        • Schlesinger A.
        The attenuation of exercise-induced bronchospasm by ascorbic acid.
        Ann Allergy. 1982; 49: 146-150
        • Ogilvy C.
        • Dubois A.
        • Douglas J.
        Effects of ascorbic acid and indomethacin on the airways of healthy male subjects with and without induced bronchoconstriction.
        J Allergy Clin Immunol. 1981; 67: 363-369
        • Mohsenin V.
        • Dubois A.
        • Douglas J.
        Effect of ascorbic acid on response to methacholine challenge in asthmatic subjects.
        Am Rev Resp Dis. 1983; 127: 143-147
        • Chatham M.
        • Eppler J.
        • Sauder L.
        • Green D.
        • Kulle T.
        Evaluation of the effects of vitamin C on ozone-induced bromchoconstriction in normal subjects.
        Ann NY Acad Sci. 1987; 498: 269-279
        • Mohsenin V.
        Effect of vitamin C on NO2-induced airway hyperresponsiveness in normal subjects.
        Am Rev Resp Dis. 1987; 136: 1408-1411
        • Anah C.
        • Jarike L.
        • Baig H.
        High dose ascorbic acid in nigerian asthmatics.
        Trop Geogr Med. 1980; 32: 132-137
        • Fogarty A.
        • Lewis S.
        • Scrivener S.
        • Antoniak M.
        • Pacey S.
        • Pringle M.
        • Britton J.
        Oral magnesium and vitamin C supplements in asthma: a parallel group randomised placebo-controlled trial.
        Clin Exp Allergy. 2003; 33: 1355-1359
        • Wong C.S.
        • Cooper S.
        • Britton J.
        • Tattersfield A.E.
        Steroid sparing effect of nedocromil sodium in asthmatic patients on high doses of inhaled steroids.
        Clin Exp Allergy. 1993; 23: 370-376
        • Barnes N.
        • Marone G.
        • Maria G.
        • Visser S.
        • Utama I.
        • Payne S.
        A comparison of fluticasone propionate, 1mg daily, with beclomethasone dipropionate, 2mg daily, in the treatment of severe asthma.
        Eur Resp J. 2001; 6: 877-884
        • Hughes R.
        • Goldkorn A.
        • Masoli M.
        • Weatherall M.
        • Burgess C.
        • Beasley R.
        Use of isotonic nebulised magnesium sulphate as an adjuvant to salbutamol in treatment of severe asthma in adults: randomised placebo-controlled trial.
        Lancet. 2003; 361: 2114-2117
        • Rowe B.
        • Bretzlaff J.
        • Bourdon C.
        • Bota G.
        • Camargo C.
        Magnesium sulfate is effective for severe acute asthma treated in the emergency department.
        Evidence-Based Med. 1999; : 138
        • Fogarty A.
        • Christie S.
        • Lewis S.
        • Britton J.
        Alterations in serum magnesium after an acute dose of magnesium citrate or magnesium amino acid chelate.
        Clin Drug Invest. 2002; 22: 469-471
        • Romieu I.
        • Meneses F.
        • Ramirez M.
        • Ruiz S.
        • Padilla R.
        • Sienra J.
        • Gerber M.
        • Grievink L.
        • Dekker R.
        • Walda I.
        • Brunekreef B.
        Antioxidant supplementation and respiratory functions among workers exposed to high levels of ozone.
        Am J Resp Crit Care Med. 1998; 158: 226-232
        • Romieu I.
        • Sienra-Monge J.
        • Ramirez-Aguilar M.
        • Tellez-Rojo M.
        • Moreno-Macias H.
        • Reyes-Ruiz N.
        • Rio-Navarro B.
        • Ruiz-Navarro M.
        • Hatch G.
        • Slade R.
        • Hernandez-Avila M.
        Antioxidant supplementation and lung function among children with asthma exposed to high levels of air pollutants.
        Am J Resp Crit Care Med. 2002; 166: 703-709
        • Grievink L.
        • Jansen S.
        • Van’t Veer P.
        • Brunekreef B.
        Acute effects of ozone on pulmonary function of cyclists receiving antioxidant supplements.
        Occup Environ Med. 1998; 55: 13-17
        • Grievink L.
        • Zijlstra A.
        • Ke X.
        • Brunekreef B.
        Double-blind intervention trial on modulation of ozone effects on pulmonary function by antioxidant supplements.
        Am J Epidemiol. 1999; 149: 306-314
        • Israel E.
        • Banerjee T.
        • Fitzmaurice G.
        • Kotlov T.
        • LaHive K.
        • LeBoff M.
        Effects of inhaled glucocorticoids on bone density in premenopausal women.
        New Engl J Med. 2001; 345: 941-947