SunGold Kiwifruit Consumption Restores Adequate to Optimal Vitamin C Status in People with a History of Severe Respiratory Infections.

Severe respiratory infections are characterised by depleted vitamin C and elevated inflammation and oxidative stress. The aim of this study was to recruit people with a history of severe respiratory infections to undergo a six-week intervention with SunGold kiwifruit to determine if this could restore adequate vitamin C status. Secondary outcomes included changes in inflammatory and oxidative stress biomarkers, self-reported fatigue and subjective mood, and the incidence, duration and severity of respiratory symptoms. The total cohort comprised 20 adults (65% female, age range 31-84 years). The participants had a low median fruit and vegetable intake of 2.3 servings/day and a correspondingly low vitamin C intake of 46 mg/day. Circulating vitamin C status was a median of 45 µmol/L and was in the hypovitaminosis range in 25% of the cohort. Following intervention with two SunGold kiwifruit/day (equivalent to ~300 mg vitamin C), there was an increase in plasma vitamin C concentrations to >60 µmol/L (p < 0.05). Approximately 20% of the participants were unable to reach adequate vitamin C status (≥50 µmol/L), possibly due to current smoking, which enhances vitamin C turnover, and a strong inverse correlation between body weight and vitamin C status (r = -0.734, p < 0.05). Following the intervention, there were indications towards decreases in the inflammatory biomarkers C-reactive protein and TNFα (p > 0.05), but no changes in oxidative stress biomarkers (F2isoprostanes, protein carbonyls). There were decreases in fatigue and depression (p < 0.05) and a lower number of individual respiratory symptoms reported during the kiwifruit intervention phase (8.5 vs. 10, p = 0.05). Overall, the consumption of two SunGold kiwifruit per day for six weeks was able to restore adequate to saturating vitamin C status in ~80% of the participants. Smokers and people with higher body weight may need larger doses and/or longer duration of supplementation. The contribution of vitamin C to reducing fatigue, depression, and number of respiratory symptoms warrants further investigation.

Low Vitamin C Concentrations in Patients with Community-Acquired Pneumonia Resolved with Pragmatic Administration of Intravenous and Oral Vitamin C.

Community-acquired pneumonia (CAP) is characterized by elevated markers of inflammation and oxidative stress and depleted circulating concentrations of the antioxidant nutrient vitamin C. A feasibility trial of intravenous and oral vitamin C supplementation, matched to the timing of intravenous and oral antibiotic formulations, was carried out and changes in vitamin C status were monitored to determine whether saturating status could be achieved throughout the administration period. Patients with moderate and severe CAP (CURB-65 ≥ 2; n = 75) who were receiving intravenous antimicrobial therapy were randomized to placebo (n = 39) or intravenous vitamin C (2.5 g per 8 h; n = 36) before moving to oral vitamin C (1 g three times daily) when prescribed oral antimicrobials. Blood samples were collected at baseline and then daily whilst in the hospital. Vitamin C concentrations were determined by high-performance liquid chromatography. The inflammatory and infection biomarkers C-reactive protein and procalcitonin were elevated at baseline (158 (61, 277) mg/L and 414 (155, 1708) ng/L, respectively), and vitamin C concentrations were depleted (15 (7, 25) µmol/L). There was an inverse association between vitamin C and C-reactive protein concentrations (r = -0.312, p = 0.01). Within one day of intervention initiation, plasma vitamin C concentrations in the vitamin C group reached median concentrations of 227 (109, 422) µmol/L, and circulating concentrations remained at ≥150 µmol/L for the duration of the intervention, whilst median vitamin C concentrations in the placebo group remained low (≤35 µmol/L). There was a trend toward decreased duration of hospital stay (p = 0.07) and time to clinical stability (p = 0.08) in the vitamin C group. In conclusion, patients with moderate to severe CAP have inadequate plasma vitamin C concentrations for the duration of their hospital stay. The administration of intravenous or oral vitamin C, titrated to match the antimicrobial formulation, provided saturating plasma vitamin C concentrations whilst in the hospital. There were trends toward shorter duration of hospital stay and time to clinical stability. Thus, larger trials assessing the impact of intravenous and oral vitamin C intervention on CAP clinical outcomes are indicated.

Adjunctive intravenous then oral vitamin C for moderate and severe community-acquired pneumonia in hospitalized adults: feasibility of randomized controlled trial.

Patients hospitalised with community acquired pneumonia (CAP) have low peripheral blood vitamin C concentrations and limited antioxidant capacity. The feasibility of a trial of vitamin C supplementation to improve patient outcomes was assessed. Participants with moderate and severe CAP (CURB-65 ≥ 2) on intravenous antimicrobial treatment were randomised to either intravenous vitamin C (2.5 g 8 hourly) or placebo before switching to oral intervention (1 g tds) for 7 days when they were prescribed oral antimicrobial therapy. Of 344 patients screened 75 (22%) were randomised and analysed. The median age was 76 years, and 43 (57%) were male. In each group, one serious adverse event that was potentially intervention related occurred, and one subject discontinued treatment. Vitamin C concentrations were 226 µmol/L in the vitamin C group and 19 µmol/L in the placebo group (p < 0.001) after 3 intravneous doses. There were no signficant differences between the vitamin C and placebo groups for death within 28 days (0 vs. 2; p = 0.49), median length of stay (69 vs. 121 h; p = 0.07), time to clinical stability (22 vs. 49 h; p = 0.08), or readmission within 30 days (1 vs. 4; p = 0.22). The vitamin C doses given were safe, well tolerated and saturating. A randomised controlled trial to assess the efficacy of vitamin C in patients with CAP would require 932 participants (CURB-65 ≥ 2) to observe a difference in mortality and 200 participants to observe a difference with a composite endpoint such as mortality plus discharge after 7 days in hospital. These studies are feasible in a multicentre setting.

Supplementation with Oral Vitamin C Prior to and during Myeloablative Chemotherapy and Autologous Haematopoietic Stem Cell Transplantation: A Pilot Study.

Chemotherapy-related side effects are common in patients undergoing myeloablative chemotherapy and haematopoietic stem cell transplantation. Some, such as oral mucositis, are believed to be due to enhanced oxidative stress and inflammation. Vitamin C, a potent antioxidant with anti-inflammatory properties, becomes severely depleted following myeloablative chemotherapy. The aim of our study was to assess the feasibility and efficacy of oral vitamin C supplementation to restore and maintain adequate vitamin C concentrations in patients undergoing myeloablative chemotherapy and stem cell transplantation. We carried out a pilot randomized controlled trial in 20 patients with myeloma and lymphoma. Placebo or vitamin C tablets (1 g twice daily) were initiated one week prior to transplantation and continued for 4 weeks post-transplantation. Blood samples were collected weekly for analysis of plasma vitamin C concentrations using high-performance liquid chromatography. The patients' symptoms and quality of life parameters were monitored using the World Health Organization oral toxicity scale and the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ). Pre-supplementation with oral vitamin C doubled vitamin C concentrations relative to placebo by day 0 (median 61 vs. 31 µmol/L), with 60% of those in the vitamin C group achieving concentrations ≥ 50 µmol/L, compared with only 10% in the placebo group. Following chemotherapy and transplantation, significance between the vitamin C and placebo groups was lost by day 7, with only 30% of the patients in the vitamin C group having plasma concentrations ≥ 50 µmol/L. This was partly due to intolerance of the oral intervention due to nausea/vomiting and diarrhoea (40% of the participants in each group). Oral mucositis was also observed in 40% of the participants at day 7 or 14. Overall, our study showed that whilst short-term oral vitamin C pre-supplementation was able to restore adequate vitamin C status by day 0, ongoing supplementation could not maintain adequate vitamin C concentrations following chemotherapy and transplantation. Thus, intravenous vitamin C should be trialled as this bypasses the gastrointestinal system, negating intolerance issues and improving bioavailability of the vitamin.

Patients with Community Acquired Pneumonia Exhibit Depleted Vitamin C Status and Elevated Oxidative Stress.

Pneumonia is a severe lower respiratory tract infection that is a common complication and a major cause of mortality of the vitamin C-deficiency disease scurvy. This suggests an important link between vitamin C status and lower respiratory tract infections. Due to the paucity of information on the vitamin C status of patients with pneumonia, we assessed the vitamin C status of 50 patients with community-acquired pneumonia and compared these with 50 healthy community controls. The pneumonia cohort comprised 44 patients recruited through the Acute Medical Assessment Unit (AMAU) and 6 patients recruited through the Intensive Care Unit (ICU); mean age 68 ± 17 years, 54% male. Clinical, microbiological and hematological parameters were recorded. Blood samples were tested for vitamin C status using HPLC with electrochemical detection and protein carbonyl concentrations, an established marker of oxidative stress, using ELISA. Patients with pneumonia had depleted vitamin C status compared with healthy controls (23 ± 14 µmol/L vs. 56 ± 24 µmol/L, p < 0.001). The more severe patients in the ICU had significantly lower vitamin C status than those recruited through AMAU (11 ± 3 µmol/L vs. 24 ± 14 µmol/L, p = 0.02). The pneumonia cohort comprised 62% with hypovitaminosis C and 22% with deficiency, compared with only 8% hypovitaminosis C and no cases of deficiency in the healthy controls. The pneumonia cohort also exhibited significantly elevated protein carbonyl concentrations compared with the healthy controls (p < 0.001), indicating enhanced oxidative stress in the patients. We were able to collect subsequent samples from 28% of the cohort (mean 2.7 ± 1.7 days; range 1-7 days). These showed no significant differences in vitamin C status or protein carbonyl concentrations compared with baseline values (p = 0.6). Overall, the depleted vitamin C status and elevated oxidative stress observed in the patients with pneumonia indicates an enhanced requirement for the vitamin during their illness. Therefore, these patients would likely benefit from additional vitamin C supplementation to restore their blood and tissue levels to optimal. This may decrease excessive oxidative stress and aid in their recovery.

Effect of adjunctive single high-dose vitamin D3 on outcome of community-acquired pneumonia in hospitalised adults: The VIDCAPS randomised controlled trial.

Low vitamin D status is associated with increased risk of pneumonia, greater disease severity and poorer outcome. However, no trials have examined the effect of adjunctive vitamin D therapy on outcomes in adults with community-acquired pneumonia (CAP). We conducted a randomised, double-blind, placebo-controlled trial examining the effects of adjunctive vitamin D in adults hospitalised with CAP. Participants were randomised to either a single oral dose of 200,000 IU vitamin D3 or placebo. The primary outcome was the complete resolution of chest radiograph infiltrate at 6 weeks post-study treatment. Secondary outcomes included length of hospital stay, intensive care admission and return to normal activity. Only participants who completed the study or died within the 6 week period were included in the analysis (n = 60 vitamin D, n = 57 placebo). Adjunctive vitamin D did not have any effect on the primary outcome (OR 0.78, 95% CI 0.31 to 1.86, p = 0.548). However, there was evidence it increased the complete resolution of pneumonia in participants with baseline vitamin D levels <25 nmol/L (OR 17.0, 95% CI 1.40-549.45, P = 0.043), but this did not reach statistical significance using exact methods (OR 13.0, 95%CI 0.7-960.4, P = 0.083). There were no significant effects for any secondary outcome.

Effect of monthly vitamin D3 supplementation in healthy adults on adverse effects of earthquakes: randomised controlled trial.

OBJECTIVE: To determine whether supplementation with vitamin D improves resilience to the adverse effects of earthquakes. DESIGN: Opportunistic addition to an established randomised double blind placebo controlled trial. SETTING: Christchurch, New Zealand, where a prolonged series of catastrophic earthquakes beginning on 4 September 2010 occurred, which caused widespread destruction, fatalities, and extensive psychological damage. PARTICIPANTS: 322 healthy adults (241 women; 81 men) aged 18-67 who were already participating in the vitamin D and acute respiratory infections study (VIDARIS) between February 2010 and November 2011. INTERVENTION: Participants were randomised to receive an oral dose of either 200,000 IU vitamin D3 monthly for two months then 100,000 IU monthly (n=161) or placebo (n=161) for a total of 18 months. MAIN OUTCOME MEASURE: This is a post hoc analysis from the previously published VIDARIS trial. The primary endpoint in the current analysis was the self reported effects and overall adverse impact of the Christchurch earthquakes as assessed by questionnaire four months after the most destructive earthquake on 22 February 2011, which was used as the index event. The secondary end point was the number of "psychological" adverse events that participants reported at their usual monthly appointments as part of the original VIDARIS trial. RESULTS: 308 participants completed the earthquake impact questionnaire (n=152 in the vitamin D group and 156 in the placebo group). There was no significant difference in the number of self reported adverse effects between those receiving vitamin D supplementation and those receiving placebo. There was also no difference in the overall adverse impact score between treatment groups (χ(2) P=0.44). The exception was that those in the vitamin D group experienced more adverse effects on family relationships (22% v 13%; χ(2) P=0.03). The number of psychological adverse events-such as fatigue, stress, anxiety, and insomnia-that participants reported at their usual monthly appointments was significantly higher after the earthquake (χ(2) P=0.007) but did not differ between treatment groups. CONCLUSION: In this trial, vitamin D supplementation did not reduce the adverse impact of earthquakes in healthy adults. Trial registration Australian New Zealand Clinical Trials Registry (anzctr.org.au) ACTRN12609000486224.

Fenofibrate causes elevation of betaine excretion but not excretion of other osmolytes by healthy adults.

BACKGROUND: Cross-sectional data suggest that bezafibrate increases betaine excretion in dyslipidemic patients. OBJECTIVE: We aimed to demonstrate that fenofibrate induces increased betaine excretion in normal subjects and explore whether other 1-carbon metabolites and osmolytes are similarly affected. METHODS: Urine was collected from 26 healthy adults before and after treatment with fenofibrate (145 mg/day for 6 weeks). Excretions of betaine, N,N-dimethylglycine, free choline, myo-inositol, taurine, trimethylamine-N-oxide, carnitine, and acetylcarnitine were measured by liquid chromatography with mass spectrometric detection. RESULTS: Fenofibrate increased the median betaine excretion from 7.5 to 25.8 mmol/mole creatinine (median increase 3-fold), P < .001. The median increase in N,N-dimethylglycine excretion was 2-fold (P < .001). Median choline excretion increased 12% (significant, P = .029). Participants with higher initial excretions tended to have larger increases (P < .001 in all 3 cases). Fenofibrate did not significantly change the median excretions of myo-inositol, taurine, trimethylamine-N-oxide, and carnitine. The excretion of acetylcarnitine decreased 4-fold on treatment, with no correlation between the baseline and after-treatment excretions. Changes in all urine components tested, except trimethylamine-N-oxide, positively correlated with changes in betaine excretion even when the median excretions before and after were not significantly different. CONCLUSIONS: Fibrates increase betaine, and to a lesser extent N,N-dimethylglycine and choline, excretion. Other osmolytes are not elevated. Because the increase in betaine excretion depends on the baseline excretion, large increases in excretion in the metabolic syndrome and diabetes (where baseline excretions are high) could be expected. Replacement with betaine supplements may be considered.

Long-term high-dose vitamin D3 supplementation and blood pressure in healthy adults: a randomized controlled trial.

Previous randomized controlled trials of vitamin D supplementation and blood pressure (BP) mainly have given vitamin D for short periods (<6 months) or at low doses (400 IU per day). This study aims to determine whether long-term high-dose vitamin D taken for 18 months lowers BP. Adults were recruited from a healthcare organization or university into a double-blind controlled trial and randomized to receive either vitamin D3 200 000 IU for 2 months followed by 100 000 IU monthly up to 18 months (n=161) or placebo (n=161). BP was measured at baseline, 5, and 18 months. Subjects had a mean (SD) age of 47.6 (9.7) years, 75% were women, and 94% were of European ancestry (white). Mean (SD) 25-hydroxyvitamin D3 changed from 73 (22) nmol/L at baseline to 124 (28) nmol/L at 18 months in the vitamin D group, and from 71 (22) nmol/L to 56 (22) nmol/L in the placebo group. Mean BP was similar for the vitamin D and placebo groups at baseline (123.4/76.3 versus 122.6/75.6 mm Hg; respectively). The mean change (95% confidence interval) in BP at 18 months minus baseline in the vitamin D group compared with placebo group was -0.6 (-2.8 to 1.6) mm Hg for systolic (P=0.61) and 0.5 (-1.1, 2.2) mm Hg for diastolic (P=0.53). Long-term vitamin D supplementation, which increased mean 25-hydroxyvitamin D3 concentration >100 nmol/L for 18 months, had no effect on systolic or diastolic BP in predominantly white, healthy adults without severe vitamin D deficiency. Beneficial effects on BP cannot be ruled out for other populations.

Extreme urinary betaine losses in type 2 diabetes combined with bezafibrate treatment are associated with losses of dimethylglycine and choline but not with increased losses of other osmolytes.

PURPOSE: Betaine deficiency is a probable cardiovascular risk factor and a cause of elevated homocysteine. Urinary betaine excretion is increased by fibrate treatment, and is also often elevated in diabetes. Does fibrate further increase betaine excretion in diabetes, and does it affect the plasma concentrations and excretions of related metabolites and of other osmolytes? METHODS: Samples from a previous study of type 2 diabetes were selected if participants were taking bezafibrate (n = 32). These samples were compared with participants matched for age and gender and not on a fibrate (comparator group, n = 64). Betaine, related metabolites, and osmolytes were measured in plasma and urine samples from these 96 participants. RESULTS: Median urinary betaine excretion in those on bezafibrate was 5-fold higher than in the comparator group (p < 0.001), itself 3.5-fold higher than the median reported for healthy populations. In the bezafibrate group, median dimethylglycine excretion was higher (9-fold, p < 0.001). Excretions of choline, and of the osmolytes myo-inositol, taurine and glycerophosphorylcholine, were not significantly different between groups. Some participants excreted more betaine than usual dietary intakes. Several betaine fractional clearances were >100 %. Betaine excretion correlated with excretions of the osmolytes myo-inositol and glycerophosphorylcholine, and also with the excretion of choline and N,N-dimethylglycine, but it was inconclusive whether these relationships were affected by bezafibrate therapy. CONCLUSIONS: Increased urinary betaine excretions in type 2 diabetes are further increased by fibrate treatment, sometimes to more than their dietary intake. Concurrent betaine supplementation may be beneficial.

Effect of vitamin D3 supplementation on upper respiratory tract infections in healthy adults: the VIDARIS randomized controlled trial.

CONTEXT: Observational studies have reported an inverse association between serum 25-hydroxyvitamin D (25-OHD) levels and incidence of upper respiratory tract infections (URTIs). However, results of clinical trials of vitamin D supplementation have been inconclusive. OBJECTIVE: To determine the effect of vitamin D supplementation on incidence and severity of URTIs in healthy adults. DESIGN, SETTING, AND PARTICIPANTS: Randomized, double-blind, placebo-controlled trial conducted among 322 healthy adults between February 2010 and November 2011 in Christchurch, New Zealand. INTERVENTION: Participants were randomly assigned to receive an initial dose of 200,000 IU oral vitamin D3, then 200,000 IU 1 month later, then 100,000 IU monthly (n = 161), or placebo administered in an identical dosing regimen (n = 161), for a total of 18 months. MAIN OUTCOME MEASURES: The primary end point was number of URTI episodes. Secondary end points were duration of URTI episodes, severity of URTI episodes, and number of days of missed work due to URTI episodes. RESULTS: The mean baseline 25-OHD level of participants was 29 (SD, 9) ng/mL. Vitamin D supplementation resulted in an increase in serum 25-OHD levels that was maintained at greater than 48 ng/mL throughout the study. There were 593 URTI episodes in the vitamin D group and 611 in the placebo group, with no statistically significant differences in the number of URTIs per participant (mean, 3.7 per person in the vitamin D group and 3.8 per person in the placebo group; risk ratio, 0.97; 95% CI, 0.85-1.11), number of days of missed work as a result of URTIs (mean, 0.76 days in each group; risk ratio, 1.03; 95% CI, 0.81-1.30), duration of symptoms per episode (mean, 12 days in each group; risk ratio, 0.96; 95% CI, 0.73-1.25), or severity of URTI episodes. These findings remained unchanged when the analysis was repeated by season and by baseline 25-OHD levels. CONCLUSION: In this trial, monthly administration of 100,000 IU of vitamin D did not reduce the incidence or severity of URTIs in healthy adults. TRIAL REGISTRATION: anzctr.org.au Identifier: ACTRN12609000486224.

Betaine and secondary events in an acute coronary syndrome cohort.

BACKGROUND: Betaine insufficiency is associated with unfavourable vascular risk profiles in metabolic syndrome patients. We investigated associations between betaine insufficiency and secondary events in acute coronary syndrome patients. METHODS: Plasma (531) and urine (415) samples were collected four months after discharge following an acute coronary event. Death (34), secondary acute myocardial infarction (MI) (70) and hospital admission for heart failure (45) events were recorded over a median follow-up of 832 days. PRINCIPAL FINDINGS: The highest and lowest quintiles of urinary betaine excretion associated with risk of heart failure (p = 0.0046, p = 0.013 compared with middle 60%) but not with subsequent acute MI. The lowest quintile of plasma betaine was associated with subsequent acute MI (p = 0.014), and the top quintile plasma betaine with heart failure (p = 0.043), especially in patients with diabetes (p<0.001). Top quintile plasma concentrations of dimethylglycine (betaine metabolite) and top quintile plasma homocysteine both associated with all three outcomes, acute MI (p = 0.004, <0.001), heart failure (p = 0.027, p<0.001) and survival (p<0.001, p<0.001). High homocysteine was associated with high or low betaine excretion in >60% of these subjects (p = 0.017). Median NT-proBNP concentrations were lowest in the middle quintile of plasma betaine concentration (p = 0.002). CONCLUSIONS: Betaine insufficiency indicates increased risk of secondary heart failure and acute MI. Its association with elevated homocysteine may partly explain the disappointing results of folate supplementation. In some patients, especially with diabetes, elevated plasma betaine also indicates increased risk.

Plasma lipids and betaine are related in an acute coronary syndrome cohort.

BACKGROUND: Low plasma betaine has been associated with unfavorable plasma lipid profiles and cardiovascular risk. In some studies raised plasma betaine after supplementation is associated with elevations in plasma lipids. We aimed to measure the relationships between plasma and urine betaine and plasma lipids, and the effects of lipid-lowering drugs on these. METHODOLOGY: Fasting plasma samples were collected from 531 subjects (and urine samples from 415) 4 months after hospitalization for an acute coronary syndrome episode. In this cross-sectional study, plasma betaine and dimethylglycine concentrations and urine excretions were compared with plasma lipid concentrations. Subgroup comparisons were made for gender, with and without diabetes mellitus, and for drug treatment. PRINCIPAL FINDINGS: Plasma betaine negatively correlated with triglyceride (Spearman's r(s) = -0.22, p<0.0001) and non-high-density lipoprotein cholesterol (r(s) = -0.27, p<0.0001). Plasma betaine was a predictor of BMI (p<0.05) and plasma non-high-density lipoprotein cholesterol and triglyceride (p<0.001) independently of gender, age and the presence of diabetes. Using data grouped by plasma betaine decile, increasing plasma betaine was linearly related to decreases in BMI (p = 0.008) and plasma non-HDL cholesterol (p = 0.002). In a non-linear relationship betaine was negatively associated with elevated plasma triglycerides (p = 0.004) only for plasma betaine >45 µmol/L. Subjects taking statins had higher plasma betaine concentrations (p<0.001). Subjects treated with a fibrate had lower plasma betaine (p = 0.003) possibly caused by elevated urine betaine loss (p<0.001). The ratio of coenzyme Q to non-high-density lipoprotein cholesterol was higher in subjects with higher plasma betaine, and in subjects taking a statin. CONCLUSION: Low plasma betaine concentrations correlated with an unfavourable lipid profile. Betaine deficiency may be common in the study population. Controlled clinical trials of betaine supplementation should be conducted in appropriate populations to determine whether correction affects cardiovascular risk.

Fibrates may cause an abnormal urinary betaine loss which is associated with elevations in plasma homocysteine.

PURPOSE: Betaine is an osmolyte, supplies methyl groups, and controls plasma homocysteine. Abnormal urinary loss of betaine is common in patients with the metabolic syndrome or diabetes mellitus. These patients are often treated with fibrates which alter renal function and raise plasma homocysteine concentrations. We suggest there is a connection between fibrate treatment and betaine excretion. METHODS: We identified 32 fibrate-treated patients in several studies (total of 740 subjects) and compared the betaine excretion by these with the excretion by other patients, both in the separate studies and in the combined group. We investigated the correlation of betaine excretion with homocysteine in these groups. RESULTS: Patients taking bezafibrate had higher betaine excretion than patients not taking fibrates, p < 0.00001 in some studies with n < 10. Of 32 patients taking bezafibrate, 20 had abnormal (>97.5 %-ile) betaine excretion. Plasma homocysteine correlated positively with betaine excretion in male patients with lipid disorders who were not taking fibrate (n = 68, p = 0.043), but the relationship was stronger if patients taking bezafibrate were included (n = 76, p < 0.00001). In elderly (>65 years) subjects with hypertension there was a similar correlation (n = 19, p = 0.047), which was stronger when a subject taking bezafibrate was included (n = 20, p = 0.013). CONCLUSIONS: Abnormal betaine excretion is common in patients treated with bezafibrate. Bezafibrate appears to exacerbate betaine loss, which will cause a rise in plasma homocysteine. Betaine supplementation could be considered in conjunction with fibrate therapy.

Plasma and urine betaine and dimethylglycine variation in healthy young male subjects.

OBJECTIVES: We aimed to compare the individuality (within subject consistency) of plasma and urine betaine and N,N-dimethylglycine. DESIGN AND METHODS: In two separate groups of 8 males (ages 19 to 40), plasma (10) and urine (6) samples were collected either over a single day or over an 8 week period. The individuality of the betaine and N,N-dimethylglycine plasma concentrations and excretions were estimated by one-way repeated measures analysis of variance. The reliability coefficients and indices of individuality were calculated. The between-subject variation in the study population was compared with that in a normal population (n=192 for plasma, 205 for urine). RESULTS: Plasma betaine concentrations were significantly different between subjects over 24 h and 8 weeks (p<0.00001). Plasma dimethylglycine concentrations were different over 24 h. Urine betaine and dimethylglycine excretions were different in both (p<0.0001). Betaine was more individual than dimethylglycine in both plasma and urine. Compared with a normal healthy population, the between-subject variation in plasma betaine was less (p<0.001) in the study group, but similar for dimethylglycine and for urine betaine. CONCLUSIONS: Plasma betaine and urinary betaine excretions are more individual than dimethylglycine. Plasma and urine betaine are highly individual in the general population.

Dietary and supplementary betaine: acute effects on plasma betaine and homocysteine concentrations under standard and postmethionine load conditions in healthy male subjects.

BACKGROUND: Betaine comes from the diet and from choline, and it is associated with vascular disease in some patient groups. Betaine supplementation lowers plasma total homocysteine. OBJECTIVE: We compared the acute effects of dietary and supplementary betaine and choline on plasma betaine and homocysteine under standard conditions and after a methionine load. DESIGN: In a randomized crossover study, 8 healthy men (19-40 y) consumed a betaine supplement (approximately 500 mg), high-betaine meal (approximately 517 mg), choline supplement (500 mg), high-choline meal (approximately 564 mg), high-betaine and -choline meal (approximately 517 mg betaine, approximately 622 mg choline), or a low-betaine and -choline control meal under standard conditions or postmethionine load. Plasma betaine, dimethylglycine, and homocysteine concentrations were measured hourly for 8 h and at 24 h after treatment. RESULTS: Dietary and supplementary betaine raised plasma betaine concentrations relative to control (P < 0.001) under standard conditions. This was not associated with raised plasma dimethylglycine concentration, and no significant betaine appeared in the urine. A small increase in dimethylglycine excretion was observed when either betaine or choline was supplied (P = 0.011 and < 0.001). Small decreases in plasma homocysteine 6 h after ingestion under standard conditions (P < or = 0.05) were detected after a high-betaine meal and after a high-betaine and high-choline meal. Dietary betaine and choline and betaine supplementation attenuated the increase in plasma homocysteine at both 4 and 6 h after a methionine load (P < or = 0.001). CONCLUSIONS: Dietary betaine and supplementary betaine acutely increase plasma betaine, and they and choline attenuate the postmethionine load rise in homocysteine concentrations.

Effects of orange juice and proline betaine on glycine betaine and homocysteine in healthy male subjects.

BACKGROUND: Proline betaine (PB), a glycine betaine (GB) analogue found in citrus foods, increases urinary GB loss and plasma total homocysteine (tHcy) concentrations in rats. Its presence in human plasma is associated with increased GB excretion. AIM: To compare the effects of dietary levels of PB on GB excretion, and on plasma tHcy and GB concentrations in healthy volunteers. METHODS: In a randomized crossover study, eight healthy males (18-50 years) ingested either 750 mL orange juice (containing 0.545 g PB), a PB supplement (0.545 g PB dissolved in 750 mL apple juice), or 750 mL apple juice (control). Plasma PB, GB and tHcy, and urine PB, GB and creatinine concentrations were measured hourly for 6 h and at 24 h post-treatment. RESULTS: Plasma tHcy concentrations were not increased (relative to control) following ingestion of either orange juice or PB supplement. Both treatments produced a significant increase in plasma PB concentrations (P < 0.001), this effect being greater following orange juice compared with PB supplement (P < 0.05, 1-2 h). Urinary excretion of PB was greater than the control following both orange juice (P < 0.001) and PB supplement (P < 0.001), from 2 to 24 h post-treatment. This increase in PB excretion was significantly greater following orange juice compared with PB supplement with higher peak excretion (Cmax difference, P = 0.008). GB excretion was significantly greater following ingestion of orange juice compared with PB in apple juice (P = 0.007) and apple juice control (P < 0.001) in the first 2 h post-ingestion. CONCLUSIONS: PB administered in dietary doses had little effect on plasma tHcy concentrations in healthy humans. Ingestion of PB in orange juice compared with PB alone resulted in greater increases in the urinary excretion of PB and GB.

Dimethylglycine supplementation does not affect plasma homocysteine concentrations in pre-dialysis chronic renal failure patients.

OBJECTIVE: To determine whether daily dimethylglycine supplementation affects plasma homocysteine concentrations. DESIGN AND METHODS: A randomized, blinded, crossover design was used. Seven pre-dialysis chronic renal failure patients consumed 400 mg of dimethylglycine or placebo daily for 28 days. Fasting blood samples and 12-h urine samples were collected at baseline and at the end of each treatment period for analysis. RESULTS: No significant differences were observed in plasma homocysteine (P = 0.624), glycine betaine (P = 0.452) and methionine (P = 0.457) concentrations between dimethylglycine and placebo treatments. CONCLUSION: Daily supplementation with dimethylglycine does not affect plasma homocysteine.

Betaine supplementation decreases post-methionine hyperhomocysteinemia in chronic renal failure.

BACKGROUND: Fasting and post-methionine load hyperhomocysteinemia are independent risk factors for vascular disease that are common in chronic renal failure. Folate decreases but seldom normalizes fasting total homocysteine (tHcy) concentrations in such patients. Glycine betaine (GB) is known to decrease tHcy in other clinical settings, but whether it is beneficial in chronic renal failure has not been established. METHODS: We conducted a crossover-controlled trial in 36 patients with chronic renal failure to determine if oral GB decreased fasting or post-methionine tHcy concentrations. All subjects received, in randomized sequence, 5-mg folic acid and 50-mg pyridoxine daily, with or without GB 4-g daily, for three months each. Fasting plasma tHcy, GB, folate, B vitamins, serum lipids and creatinine were measured at one and three months, and methionine load tests were performed at the end of each three-month treatment phase. RESULTS: GB and N,N-dimethylglycine (DMG) levels in plasma and urine increased markedly during GB treatment. Fasting tHcy decreased from baseline with both treatments but did not differ between treatments. Post-methionine tHcy decreased with both treatments and was 18% lower on GB than on folate and pyridoxine alone (P < 0.001). There were small increases in lipids during treatment with GB but the ratio of total: HDL cholesterol was unchanged. CONCLUSIONS: GB supplementation had no effect on fasting tHcy in patients with chronic renal failure who were folate and pyridoxine replete, but it significantly decreased tHcy concentrations after methionine loading.