Re: Folate and chemical trials

Hi Thomas,
thanks for the collection of refs.  An encouraging set of results for both
combination therapy and isolated high dose (5mg/d) folate.  I've never
heard of any contraindications for folate and believe 5mg/d is often
prescribed for recovering alcoholics.

Riboflavin (vitamin B2) is also important for 10-15% of the
population as part of a homeocysteine-busting regime.

[115a] Impaired functioning of thermolabile methylenetetrahydrofolate
reductase is dependent on riboflavin status: implications for riboflavin
requirements.  McNulty H, McKinley MC, Wilson B, McPartlin J, Strain JJ,
Weir DG, Scott JM in Am J Clin Nutr 2002 Aug;76(2):436-41   PMID: 12145019
"The high tHcy concentration typically associated with homozygosity for the
677C-->T variant of MTHFR occurs only with poor riboflavin status."  The
mutant, thermolabile version of MTHFR, present in 10-15% of the European
genotype renders the co-enzyme FAD prosthetic group ~10 times more likely to
disassociate.  Extra riboflavin stabilises MTHFR.

[115b] Riboflavin as a determinant of plasma total homocysteine: effect
modification by the methylenetetrahydrofolate reductase C677T polymorphism.
Hustad S, Ueland PM, Vollset SE, Zhang Y, Bjorke-Monsen AL, Schneede J in
Clin Chem 2000 Aug;46(8 Pt 1):1065-71   PMID: 10926884
"The riboflavin-tHcy relationship was modified by genotype (P = 0.004) and
was essentially confined to subjects with the C677T transition of the MTHFR
gene. CONCLUSIONS: Plasma riboflavin is an independent determinant of plasma
tHcy."

[115c] Methylenetetrahydrofolate reductase polymorphism, plasma homocysteine
and age.  Todesco L, Angst C, Litynski P, Loehrer F, Fowler B, Haefeli WE in
Eur J Clin Invest 1999 Dec;29(12):1003-9   PMID: 10583447
"In the healthy younger subjects the mutant allele was 1.4 times more
frequent compared to the older subjects (P = 0.01)."

[124] High-dose vitamin therapy stimulates variant enzymes with decreased
coenzyme binding affinity (increased K(m)): relevance to genetic disease and
polymorphisms.  Ames BN, Elson-Schwab I, Silver EA in Am J Clin Nutr 2002
Apr;75(4):616-58   PMID: 11916749

Cheers,
Michael C Price
----------------------------------------
http://mcp.longevity-report.com
http://www.hedweb.com/manworld.htm

"Thomas Carter" <[EMAIL PROTECTED]> wrote in message
news:[EMAIL PROTECTED]
> Hi,
>     The epidemiology of folate, B6, and B12 is just great, so are the
> in vitro results. I decided to check the clinical trials. Immagine my
> supprise to find them even better. Does anyone know of a
> contraindication to taking 5mG/day of folic acid?
>
> Thomas
>
> PS Be sure to read all the way to the bottom, Nelson. I may have
> something on NO that you don't. And it ain't too shabby.
>
> J Am Coll Cardiol. 2003 Jun 18;41(12):2105-13.
> Secondary prevention with folic acid: effects on clinical outcomes.
> Liem A, Reynierse-Buitenwerf GH, Zwinderman AH, Jukema JW, van
> Veldhuisen DJ.
> Department of Cardiology, Oosterschelde Ziekenhuizen, Goes, The
> Netherlands.
> [EMAIL PROTECTED]
>      OBJECTIVES: We sought to conduct a randomized trial with folic
> acid 0.5 mg/day
> in a patient population with stable coronary artery disease (CAD).
> BACKGROUND:
> Folic acid has favorable effects on vascular endothelium and lowers
> plasma
> homocysteine levels. In addition, homocysteine appears to be an
> independent risk
> factor for atherosclerotic disease. However, the value of folic acid
> in
> secondary prevention had seldom been tested. METHODS: In this
> open-label study,
> 593 patients were included; 300 were randomized to folic acid and 293
> served as
> controls. Mean follow-up time was 24 months. At baseline all patients
> had been
> on statin therapy for a mean of 3.2 years. RESULTS: In patients
> treated with
> folic acid, plasma homocysteine levels decreased by 18%, from 12.0 +/-
> 4.8 to
> 9.4 +/- 3.5 micromol/l, whereas these levels remained unaffected in
> the control
> group (p < 0.001 between groups). The primary end point (all-cause
> mortality and
> a composite of vascular events) was encountered in 31 (10.3%) patients
> in the
> folic acid group and in 28 (9.6%) patients in the control group
> (relative risk
> 1.05; 95% confidence interval: 0.63 to 1.75). In a multifactorial
> survival model
> with adjustments for clinical factors, the most predictive laboratory
> parameters
> were, in order of significance, levels of creatinine clearance, plasma
> fibrinogen, and homocysteine. CONCLUSIONS: Within two years, folic
> acid does not
> seem to reduce clinical end points in patients with stable coronary
> artery
> disease (CAD) while on statin treatment. Homocysteine might therefore
> merely be
> a modifiable marker of disease. Thus, low-dose folic acid
> supplementation should
> be treated with reservation, until more trial outcomes become
> available.
> PMID: 12821232.....................
> JAMA. 2002 Aug 28;288(8):973-9.
> Comment in:
>     ACP J Club. 2003 Mar-Apr;138(2):33.
>     J Fam Pract. 2003 Jan;52(1):16-8.
> Effect of homocysteine-lowering therapy with folic acid, vitamin B12,
> and vitamin
> B6 on clinical outcome after percutaneous coronary intervention: the
> Swiss Heart
> study: a randomized controlled trial.
> Schnyder G, Roffi M, Flammer Y, Pin R, Hess OM.
> Division of Cardiology, Swiss Cardiovascular Center Bern, University
> Hospital,
> Switzerland. [EMAIL PROTECTED]
> CONTEXT: Plasma homocysteine level has been recognized as an important
> cardiovascular risk factor that predicts adverse cardiac events in
> patients with
> established coronary atherosclerosis and influences restenosis rate
> after
> percutaneous coronary intervention. OBJECTIVE: To evaluate the effect
> of
> homocysteine-lowering therapy on clinical outcome after percutaneous
> coronary
> intervention. DESIGN, SETTING, AND PARTICIPANTS: Randomized,
> double-blind
> placebo-controlled trial involving 553 patients referred to the
> University
> Hospital in Bern, Switzerland, from May 1998 to April 1999 and
> enrolled after
> successful angioplasty of at least 1 significant coronary stenosis (>
> or = 50%).
> INTERVENTION: Participants were randomly assigned to receive a
> combination of
> folic acid (1 mg/d), vitamin B12 (cyanocobalamin, 400 micro g/d), and
> vitamin B6
> (pyridoxine hydrochloride, 10 mg/d) (n = 272) or placebo (n = 281) for
> 6 months.
> MAIN OUTCOME MEASURE: Composite end point of major adverse events
> defined as
> death, nonfatal myocardial infarction, and need for repeat
> revascularization,
> evaluated at 6 months and 1 year. RESULTS: After a mean (SD) follow-up
> of 11 (3)
> months, the composite end point was significantly lower at 1 year in
> patients
> treated with homocysteine-lowering therapy (15.4% vs 22.8%; relative
> risk [RR],
> 0.68; 95% confidence interval [CI], 0.48-0.96; P =.03), primarily due
> to a
> reduced rate of target lesion revascularization (9.9% vs 16.0%; RR,
> 0.62; 95%
> CI, 0.40-0.97; P =.03). A nonsignificant trend was seen toward fewer
> deaths
> (1.5% vs 2.8%; RR, 0.54; 95% CI, 0.16-1.70; P =.27) and nonfatal
> myocardial
> infarctions (2.6% vs 4.3%; RR, 0.60; 95% CI, 0.24-1.51; P =.27) with
> homocysteine-lowering therapy. These findings remained unchanged after
> adjustment for potential confounders. CONCLUSION:
> Homocysteine-lowering therapy
> with folic acid, vitamin B12, and vitamin B6 significantly decreases
> the
> incidence of major adverse events after percutaneous coronary
> intervention.
> PMID: 12190367...........................
> Circulation. 2002 Jan 1;105(1):22-6.
> Comment in:
>     Circulation. 2002 Aug 13;106(7):e33.
> Folic acid improves endothelial function in coronary artery disease
> via
> mechanisms largely independent of homocysteine lowering.
> Doshi SN, McDowell IF, Moat SJ, Payne N, Durrant HJ, Lewis MJ,
> Goodfellow J.
> Cardiovascular Sciences Research Group, Wales Heart Research
> Institute,
> Department of Pharmacology, University of Wales College of Medicine,
> Heath Park,
> Cardiff, UK.
>     BACKGROUND: Homocysteine is a risk factor for coronary artery
> disease (CAD),
> although a causal relation remains to be proven. The importance of
> determining
> direct causality rests in the fact that plasma homocysteine can be
> safely and
> inexpensively reduced by 25% with folic acid. This reduction is
> maximally
> achieved by doses of 0.4 mg/d. High-dose folic acid (5 mg/d) improves
> endothelial function in CAD, although the mechanism is controversial.
> It has
> been proposed that improvement occurs through reduction in total
> (tHcy) or free
> (non-protein bound) homocysteine (fHcy). We investigated the effects
> of folic
> acid on endothelial function before a change in homocysteine in
> patients with
> CAD. METHODS AND RESULTS: A randomized, placebo-controlled study of
> folic acid
> (5 mg/d) for 6 weeks was undertaken in 33 patients. Endothelial
> function,
> assessed by flow-mediated dilatation (FMD), was measured before, at 2
> and 4
> hours after the first dose of folic acid, and after 6 weeks of
> treatment. Plasma
> folate increased markedly by 1 hour (200 compared with 25.8 nmol/L;
> P<0.001).
> FMD improved at 2 hours (83 compared with 47 microm; P<0.001) and was
> largely
> complete by 4 hours (101 compared with 51 microm; P<0.001). tHcy did
> not
> significantly differ acutely (4-hour tHcy, 9.56 compared with 9.79
> micromol/L;
> P=NS). fHcy did not differ at 3 hours but was slightly reduced at 4
> hours (1.55
> compared with 1.78 micromol/L; P=0.02). FMD improvement did not
> correlate with
> reductions in either fHcy or tHcy at any time. CONCLUSIONS: These data
> suggest
> that folic acid improves endothelial function in CAD acutely by a
> mechanism
> largely independent of homocysteine. (and that 5 mG/day should be
> considered)
> PMID: 11772871....................
> Lancet. 2000 Feb 12;355(9203):517-22.  Comment in:
>     Lancet. 2000 Feb 12;355(9203):511-2.
>     Lancet. 2000 Jun 24;355(9222):2249; discussion 2250.
> Effect of homocysteine-lowering treatment with folic acid plus vitamin
> B6 on
> progression of subclinical atherosclerosis: a randomised,
> placebo-controlled
> trial.
> Vermeulen EG, Stehouwer CD, Twisk JW, van den Berg M, de Jong SC,
> Mackaay AJ,
> van Campen CM, Visser FC, Jakobs CA, Bulterjis EJ, Rauwerda JA.
> Department of General Surgery, University Hospital and Institute for
> Cardiovascular Research Vrije Universiteit, Amsterdam, The
> Netherlands.
>        BACKGROUND: A high plasma homocysteine concentration is
> associated with
> increased risk of atherothrombotic disease. We investigated the
> effects of
> homocysteine-lowering treatment (folic acid plus vitamin B6) on
> markers of
> subclinical atherosclerosis among healthy siblings of patients with
> premature
> atherothrombotic disease. METHODS: We did a randomised,
> placebo-controlled trial
> among 158 healthy siblings of 167 patients with premature
> atherothrombotic
> disease. 80 were assigned placebo and 78 were assigned 5 mg folic acid
> and 250
> mg vitamin B6 daily for 2 years. The primary endpoint was the
> development or
> progression of subclinical atherosclerosis as estimated from exercise
> electrocardiography, the ankle-brachial pressure index, and carotid
> and femoral
> ultrasonography. FINDINGS: Ten participants in the treatment group,
> and 14 in
> the placebo group dropped out. Vitamin treatment, compared with
> placebo, was
> associated with a decrease in fasting homocysteine concentration (from
> 14.7 to
> 7.4 micromol/L vs from 14.7 to 12.0 micromol/L), and in postmethionine
> homocysteine concentration (from 64.9 to 34.9 micromol/L vs from 64.8
> to 50.3
> micromol/L). It was also associated with a decreased rate of abnormal
> exercise
> electrocardiography tests (odds ratio 0.40 [0.17-0.93]; p=0.035).
> There was no
> apparent effect of vitamin treatment on ankle-brachial pressure
> indices (0.87
> [0.56-1.33]), or on carotid and peripheral-arterial outcome variables
> (1.02
> [0.26-4.05] and 0.86 [0.47-1.59], respectively). (Yes there was, these
> are important
>  and apparent altho not significant reductions.) INTERPRETATION:
> Homocysteine-lowering treatment with folic acid plus vitamin B6 in
> healthy
> siblings of patients with premature atherothrombotic disease is
> associated with
> a decreased occurrence of abnormal exercise electrocardiography tests,
> which is
> consistent with a decreased risk of atherosclerotic coronary events.
> PMID: 10683000..........................
> N Engl J Med. 2001 Nov 29;345(22):1593-600.
> Comment in:
>     N Engl J Med. 2002 Apr 4;346(14):1093-5.
>     N Engl J Med. 2002 Apr 4;346(14):1093-5.
> Decreased rate of coronary restenosis after lowering of plasma
> homocysteine
> levels.
> Schnyder G, Roffi M, Pin R, Flammer Y, Lange H, Eberli FR, Meier B,
> Turi ZG,
> Hess OM.
> Division of Cardiology, Swiss Cardiovascular Center Bern, University
> Hospital.
> [EMAIL PROTECTED]
>      BACKGROUND: We have previously demonstrated an association
> between elevated
> total plasma homocysteine levels and restenosis after percutaneous
> coronary
> angioplasty. We designed this study to evaluate the effect of lowering
> plasma
> homocysteine levels on restenosis after coronary angioplasty. METHODS:
> A
> combination of folic acid (1 mg), vitamin B12 (400 microg), and
> pyridoxine (10
> mg)--referred to as folate treatment--or placebo was administered to
> 205
> patients (mean [+/-SD] age, 61+/-11 years) for six months after
> successful
> coronary angioplasty in a prospective, double-blind, randomized trial.
> The
> primary end point was restenosis within six months as assessed by
> quantitative
> coronary angiography. The secondary end point was a composite of major
> adverse
> cardiac events. RESULTS: Base-line characteristics and initial
> angiographic
> results after coronary angioplasty were similar in the two study
> groups. Folate
> treatment significantly lowered plasma homocysteine levels from
> 11.1+/-4.3 to
> 7.2+/-2.4 micromol per liter (P<0.001). At follow-up, the minimal
> luminal
> diameter was significantly larger in the group assigned to folate
> treatment
> (1.72+/-0.76 vs. 1.45+/-0.88 mm, P=0.02), and the degree of stenosis
> was less
> severe (39.9+/-20.3 vs. 48.2+/-28.3 percent, P=0.01). The rate of
> restenosis was
> significantly lower in patients assigned to folate treatment (19.6 vs.
> 37.6
> percent, P=0.01), as was the need for revascularization of the target
> lesion
> (10.8 vs. 22.3 percent, P=0.047). CONCLUSIONS: Treatment with a
> combination of
> folic acid, vitamin B12, and pyridoxine significantly reduces
> homocysteine
> levels and decreases the rate of restenosis and the need for
> revascularization
> of the target lesion after coronary angioplasty. This inexpensive
> treatment,
> which has minimal side effects, should be considered as adjunctive
> therapy for
> patients undergoing coronary angioplasty.PMID:
> 11757505..................
> Arterioscler Thromb Vasc Biol. 2001 Jul;21(7):1196-202.
> Folate improves endothelial function in coronary artery disease: an
> effect
> mediated by reduction of intracellular superoxide?
> Doshi SN, McDowell IF, Moat SJ, Lang D, Newcombe RG, Kredan MB, Lewis
> MJ,
> Goodfellow J.
> Department of Pharmacology, Cardiovascular Sciences Research Group,
> Wales Heart
> Research Institute, University of Wales College of Medicine, Heath
> Park,
> Cardiff, UK.
>       Homocysteine is a risk factor for coronary artery disease (CAD).
> Folic acid
> lowers homocysteine and may improve endothelial function in CAD,
> although the
> mechanism is unclear. We investigated the effect of folic acid on
> endothelial
> function, homocysteine, and oxidative stress in patients with CAD. We
> also
> examined the acute effect of 5-methyltetrahydrofolate (5-MTHF), the
> principal
> circulating folate, on endothelial function in vivo and on
> intracellular
> superoxide in cultured endothelial cells. A randomized crossover study
> of folic
> acid (5 mg daily) for 6 weeks was undertaken in 52 patients with CAD.
> Ten
> further patients were given intra-arterial 5-MTHF. Endothelial
> function was
> assessed by flow-mediated dilatation (FMD). Folic acid increased
> plasma folate
> (P<0.001), lowered homocysteine by 19% (P<0.001), and improved FMD
> (P<0.001).
> FMD improvement did not correlate with homocysteine reduction.
> Malondialdehyde
> and total plasma antioxidant capacity, markers of oxidative stress,
> were
> unchanged. 5-MTHF acutely improved FMD (P<0.001) without altering
> homocysteine
> (P=0.47). In vitro, 5-MTHF abolished homocysteine-induced
> intracellular
> superoxide increase (P<0.001); this effect was also observed with
> folic acid and
> tetrahydrobiopterin. Our data support the beneficial effect of folic
> acid on
> endothelial function in CAD but suggest that the mechanism is
> independent of
> homocysteine. Reduction of intracellular endothelial superoxide may
> have
> contributed to the effect.PMID: 11451751...........
> Ann Nutr Metab. 2002;46(2):73-9.
> Effect of vegetarian diet on homocysteine levels.
> Bissoli L, Di Francesco V, Ballarin A, Mandragona R, Trespidi R,
> Brocco G,
> Caruso B, Bosello O, Zamboni M.
> Cattedra di Geriatria, Universita di Verona, Italy.
> [EMAIL PROTECTED]
>    OBJECTIVE: To compare fasting total plasma homocysteine (tHcy)
> levels in vegans,
> lacto-ovovegetarians and control subjects, and to evaluate the
> relationships
> between tHcy levels and nutritional variables in vegetarians. METHODS:
> The study
> was conducted on 45 vegetarian subjects: 31 vegans (19 males, 12
> females, mean
> age 45.8 +/- 15.8 years); 14 lacto-ovovegetarians (6 males, 8 females,
> mean age
> 48.5 +/- 14.5 years), and 29 control subjects (19 males, 10 females,
> mean age
> 43.4 +/- 16.7 years). tHcy was evaluated by high-performance liquid
> chromatography. Serum vitamin B(12) and folate were analyzed by
> automated
> chemiluminescence systems. Clinical records, nutritional and
> anthropometric
> variables were collected for all vegetarian subjects. RESULTS: tHcy
> was
> significantly higher in vegetarian subjects than in controls (23.9 +/-
> 21.3 vs.
> 11.6 +/- 4.9 micromol/l, p < 0.001). The prevalence of
> hyperhomocysteinemia was
> higher in vegetarians than in controls (53.3 vs. 10.3%, p < 0.001).
> Serum
> vitamin B(12) levels were lower in vegetarians than in control
> subjects (171.2
> +/- 73.6 vs. 265.0 +/- 52.2 pmol/l, p < 0.01; normal range 220-740
> pmol/l). In
> vegetarian subjects, significant inverse correlations were found
> between tHcy
> and serum vitamin B(12) levels (r = -0.776, p < 0.001) and between
> tHcy and
> serum folate levels (r = -0.340, p < 0.05). Positive correlations were
> found
> between tHcy and mean red cell volume (r = 0.44, p < 0.01) and between
> tHcy and
> fat-free mass (r = 0.36, p < 0.05). CONCLUSION: Vegetarian subjects
> presented
> significantly higher tHcy levels, higher prevalence of
> hyperhomocysteinemia, and
> lower serum vitamin B(12) levels than controls. Copyright 2002 S.
> Karger AG,
> Basel PMID: 12011576 (The related articles button corroborates this as
> well as the B12 link, which is due to B12 acting in the MTHFR
> pathway.)
> XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX
> 1:  Vasa M, Breitschopf K, Zeiher AM, Dimmeler S.
>  Nitric oxide activates telomerase and delays endothelial cell
> senescence.
> Circ Res. 2000 Sep 29;87(7):540-2. No abstract available.
> PMID: 11009557 [PubMed - indexed for MEDLINE] full text available
>
> 2:  Xu D, Neville R, Finkel T.
>  Homocysteine accelerates endothelial cell senescence.
> FEBS Lett. 2000 Mar 17;470(1):20-4.
> PMID: 10722838 [PubMed - indexed for MEDLINE]
>
> 3:  Fenech M.
>  Chromosomal damage rate, aging, and diet.
> Ann N Y Acad Sci. 1998 Nov 20;854:23-36. Review.
> PMID: 9928417 [PubMed - indexed for MEDLINE]
> XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX