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Marissa B Guzzo, Hoa T Nguyen, Thanh H Pham, Monika Wyszczelska-Rokiel, Hieronim Jakubowski, Kerstin A Wolff, Sam Ogwang, Joseph L Timpona, Soumya Gogula, Michael R Jacobs, Markus Ruetz, Bernhard Kräutler, Donald W Jacobsen, Guo-Fang Zhang, Liem Nguyen
The methylfolate trap, a metabolic blockage associated with anemia, neural tube defects, Alzheimer's dementia, cardiovascular diseases, and cancer, was discovered in the 1960s, linking the metabolism of folate, vitamin B12, methionine and homocysteine. However, the existence or physiological significance of this phenomenon has been unknown in bacteria, which synthesize folate de novo. Here we identify the methylfolate trap as a novel determinant of the bacterial intrinsic death by sulfonamides, antibiotics that block de novo folate synthesis...
October 2016: PLoS Pathogens
J Hara, W R Shankle, L W Barrentine, M V Curole
OBJECTIVES: Studies have produced conflicting results assessing hyperhomocysteinemia (HYH) treatment with B vitamins in patients with normal cognition, Alzheimer's disease and related disorders (ADRD). This study examined the effect of HYH management with L-methylfolate (LMF), methylcobalamin (MeCbl; B12), and N-acetyl-cysteine (CFLN: Cerefolin®/Cerefolin-NAC®) on cognitive decline. DESIGN: Prospective, case-control study of subjects followed longitudinally. SETTING: Outpatient clinic for cognitive disorders...
2016: Journal of Nutrition, Health & Aging
William R Shankle, Junko Hara, Lori W Barrentine, Melanie V Curole
We examined whether using a medical food therapy for hyperhomocysteinemia (HHcy) in patients with Alzheimer's disease (AD) or cognitive impairment due to cerebrovascular disease (CVD) with Cerefolin®/CerefolinNAC® (CFLN: L-methylfolate, methylcobalamin, and N-acetyl-cysteine) slowed regional brain atrophy. Thirty HHcy patients with AD and related disorders (ADRD) received CFLN (HHcy+CFLN: duration [μ ±  σ] = 18.6±16.1 months); a sub-sample of this group did not receive CFLN for varying periods of time (HHcy+NoCFLN: duration [μ ±  σ] = 12...
October 4, 2016: Journal of Alzheimer's Disease: JAD
Shailesh Jha, Pankaj Kumar, Rajesh Kumar, Aparna Das
The 5,10-methylenetetrahydrofolate reductase (MTHFR) gene plays a central role in folate metabolism. Many studies have demonstrated an association between MTHFR C677 T variant with depression, schizophrenia and bipolar disorder as one of them being comorbid to other. This has justified the use of folate supplement in psychiatric disorders mainly depression but still not in various other comorbid complex psychiatric disorders. Here we have tried to show how the l-methylfolate in conjunction with the conventional psychotropic drugs can be useful in a state of such complex psychiatric phenomenon and comorbid diagnosis with genetic polymorphism of MTHFR C677 T mutation...
August 2016: Asian Journal of Psychiatry
Jerome Sarris, Jenifer Murphy, David Mischoulon, George I Papakostas, Maurizio Fava, Michael Berk, Chee H Ng
OBJECTIVE: There is burgeoning interest in augmentation strategies for improving inadequate response to antidepressants. The adjunctive use of standardized pharmaceutical-grade nutrients, known as nutraceuticals, has the potential to modulate several neurochemical pathways implicated in depression. While many studies have been conducted in this area, to date no specialized systematic review (or meta-analysis) has been conducted. METHOD: A systematic search of PubMed, CINAHL, Cochrane Library, and Web of Science was conducted up to December 2015 for clinical trials using adjunctive nutrients for depression...
June 1, 2016: American Journal of Psychiatry
John M Zajecka, Maurizio Fava, Richard C Shelton, Lori W Barrentine, Page Young, George I Papakostas
OBJECTIVE: To evaluate remission and recovery, safety, and tolerability for up to 12 months of open-label adjunctive L-methylfolate calcium 15 mg. METHOD: Subjects in this analysis were adult outpatients (18-65 years) enrolled from 2 acute, double-blind, placebo-controlled trials comparing adjunctive L-methylfolate and placebo for DSM-IV major depressive disorder (MDD) with an inadequate response to monotherapy selective serotonin reuptake inhibitor (SSRI). Subjects who completed the acute trial were offered to enroll in a 12-month, open-label treatment phase with L-methylfolate and continued SSRI treatment, with scheduled visits for efficacy, safety, and tolerability every 12 weeks...
May 2016: Journal of Clinical Psychiatry
Craig J Brown
Cilioretinal artery occlusion is a cause of sudden, often catastrophic loss of central vision. There are no established effective treatments. Recently, a patient presented 24 hours after a cilioretinal artery occlusion, following a cardiac catheterization prior to which her blood thinners had been discontinued. Lacking an effective way to address the severe retinal ischemic oxidative stress, she was offered, under compassionate use, a multivitamin complex designed to address retinal ischemia and oxidative stress...
2016: International Medical Case Reports Journal
Richard C Shelton, Michael J Pencina, Lori W Barrentine, Juan A Ruiz, Maurizio Fava, John M Zajecka, George I Papakostas
OBJECTIVE: Adjunctive treatment with L-methylfolate calcium significantly improved treatment outcomes in patients with major depressive disorder (MDD) and an inadequate response to antidepressants. This post hoc exploratory analysis evaluated baseline concentrations of cytokines (interleukin [IL]-1α, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12p70, IL-13, and IL-17; tumor necrosis factor α [TNF-α]; and interferon γ [IFN-γ]), high-sensitivity C-reactive protein (hsCRP), insulin, adiponectin and leptin and body mass index (BMI [kg/m2]) on L-methylfolate calcium treatment response...
December 2015: Journal of Clinical Psychiatry
Yi-Cheng Wang, Ming-Tsung Wu, Yan-Jun Lin, Feng-Yao Tang, Hsin-An Ko, En-Pei Chiang
Folate-mediated one-carbon metabolism is an important therapeutic target of human diseases. We extensively investigated how gene-nutrient interactions may modulate human cancer risk in 2 major folate metabolic genes, MTHFR and GNMT. The biochemical impacts of MTHFR and GNMT on methyl group supply, global DNA methylation, nucleotide biosynthesis, DNA damage, and partitioning of the folate dependent 1-carbon group were carefully studied. The distinct model systems used included: EB virus-transformed lymphoblasts expressing human MTHFR polymorphic genotypes; liver-derived GNMT-null cell-lines with and without GNMT overexpression; and HepG2 cells with stabilized inhibition of MTHFR using shRNA, GNMT wildtype, heterozygotous (GNMT(het)) and knockout (GNMT(nul)) mice...
2015: Journal of Nutritional Science and Vitaminology
Bruce S Trippe, Lori W Barrentine, Melanie V Curole, Eleanor Tipa
OBJECTIVE: Current therapies for diabetic peripheral neuropathy with pain mask the painful symptoms while the underlying pathology continues to progress. This study assessed changes in symptoms and quality of life in patients taking a novel prescription medical food, L-methylfolate-methylcobalamin-pyridoxal-5-phosphate (LMF-MC-PP, Metanx ), intended to address the underlying metabolic needs of patients with diabetic peripheral neuropathy. RESEARCH DESIGN AND METHODS: Between November 2010 and April 2012, patients rated their experiences before and after using LMF-MC-PP through an automated telephone system that included symptomatic items from the Neuropathy Total Symptom Score-6 (NTSS-6) questionnaire and questions related to quality of life and medication satisfaction...
2016: Current Medical Research and Opinion
Hua Jiang, K Joseph Hurt, Kelsey Breen, Sally P Stabler, Robert H Allen, David J Orlicky, Kenneth N Maclean
In addition to its role in the endogenous synthesis of cysteine, cystathionine gamma-lyase (CGL) is a major physiological source of the vasorelaxant hydrogen sulfide. Cgl null mice are potentially useful for studying the influence of this compound upon vascular tone and endothelial function. Here, we confirm a previous report that female Cgl null mice exhibit an approximate 45-fold increase in plasma total homocysteine compared to wild type controls. This level of homocysteine is approximately 3.5-fold higher than that observed in male Cgl null mice and is essentially equivalent to that observed in mouse models of cystathionine beta synthase deficient homocystinuria...
2015: Biology Open
Jeong-Hwa Choi, Zoe Yates, Charlotte Martin, Lyndell Boyd, Xiaowei Ng, Virginia Skinner, Ron Wai, Jeongseon Kim, Hae Dong Woo, Martin Veysey, Mark Lucock
BACKGROUND: The C1561T variant of the glutamate carboxypeptidase II (GCPII) gene is critical for natural methylfolylpolyglutamte (methylfolate) absorption, and has been associated with perturbations in folate metabolism and disease susceptibility. However, little is known on C1561T-GCPII as a risk factor for colorectal cancer. Therefore, this study examined whether C1561T-GCPII influences folate metabolism and adenomatous polyp occurrence. MATERIALS AND METHODS: 164 controls and 38 adenomatous polyp cases were analysed to determine blood folate and plasma homocysteine (Hcy) level, dietary intake of natural methylfolate, synthetic pteroylglutamic acid (PteGlu), vitamin C and C1561T-GCPII genotype...
2015: Asian Pacific Journal of Cancer Prevention: APJCP
Joseph N Trachtman, Vincent Pagano
We describe a patient who developed symptoms of headache, fatigue, and dizziness after administration of terbinafine (Lamisil). Laboratory tests revealed that he is heterozygous for the C677T variation of the methylenetetrahydrofolate reductase genetic mutation. The prescription of Deplin (L-methylfolate) greatly reduced the symptoms. It was later noted that Lamisil's mechanism of action interferes with cells' methylation cycle, which we suspect compromises cellular function in people with the methylenetetrahydrofolate reductase genetic mutation...
December 2015: Therapeutic Drug Monitoring
Haitao Liu, Jie Tang, Chieh Allen Lee, Timothy S Kern
PURPOSE: l-Methylfolate, pyridoxal 5'-phosphate, and methylcobalamin, individually have been reported to have beneficial effects on diabetes-induced defects. The possibility that combining these therapeutic approaches might have additional benefit led us to investigate the effect of Metanx against development of early stages of diabetic retinopathy in a mouse model. METHODS: C57BL/6J mice were made diabetic with streptozotocin, and some were given Metanx (a combination food product) mixed in the food at a dose of 5 mg/kg of body weight...
January 2015: Investigative Ophthalmology & Visual Science
Emma Bedson, Diana Bell, Daniel Carr, Ben Carter, Dyfrig Hughes, Andrea Jorgensen, Helen Lewis, Keith Lloyd, Andrew McCaddon, Stuart Moat, Joshua Pink, Munir Pirmohamed, Seren Roberts, Ian Russell, Yvonne Sylvestre, Richard Tranter, Rhiannon Whitaker, Clare Wilkinson, Nefyn Williams
BACKGROUND: Folate deficiency is associated with depression. Despite the biological plausibility of a causal link, the evidence that adding folate enhances antidepressant treatment is weak. OBJECTIVES: (1) Estimate the clinical effectiveness and cost-effectiveness of folic acid as adjunct to antidepressant medication (ADM). (2) Explore whether baseline folate and homocysteine predict response to treatment. (3) Investigate whether response to treatment depends on genetic polymorphisms related to folate metabolism...
July 2014: Health Technology Assessment: HTA
George I Papakostas, Richard C Shelton, John M Zajecka, Teodoro Bottiglieri, Joshua Roffman, Clair Cassiello, Stephen M Stahl, Maurizio Fava
OBJECTIVE: Specific genetic or biological markers may predict inadequate response to therapy for major depressive disorder (MDD). The objective of the current post hoc analysis was to evaluate the effect of specific biological and genetic markers on the antidepressant efficacy of adjunctive L-methylfolate 15 mg versus placebo from a trial of inadequate responders to selective serotonin reuptake inhibitors (SSRIs). METHOD: The double-blind, randomized, placebo-controlled trial used the sequential parallel comparison design...
August 2014: Journal of Clinical Psychiatry
R T Owen
The use of two antidepressants from the initiation of treatment in major depressive disorder has been investigated in several recent studies and forms a paradigm shift in the pharmacotherapy of the condition. Several, but not all, trials have claimed improved response and remission rates with the combinations as opposed to monotherapy. The use of folate preparations (folic and folinic acid and l-meth-ylfolate) have shown effective augmentation of antidepressant response in a variety of controlled and open-label settings in patients with normo- and hypofolatemic status...
December 2013: Drugs of Today
S Erbe, U N Pellert
Depression is an important and often recurrent illness. An initial antidepressant trial is effective at achieving remission for about 30 % of patients when prescribed as monotherapy, with the majority of patients returning as partial or non-responders. Suboptimal serum and red blood cell folate levels have been associated with a poorer response to antidepressant therapy, a greater severity of symptoms, later onset of clinical improvement, and overall treatment resistance. This article reviews the evidence for L-methylfolate and folic acid as antidepressive agents in depression and discusses their clinical use...
February 2014: Fortschritte der Neurologie-Psychiatrie
Richard C Shelton, J Sloan Manning, Lori W Barrentine, Eleanor V Tipa
OBJECTIVE: l-Methylfolate has been shown in retrospective and prospective studies to enhance antidepressant response. The aim of this study was to prospectively assess change in depression severity and medication satisfaction in patients prescribed l-methylfolate within a naturalistic setting. METHOD: Between November 2010 and April 2012, patients who reported being treated for major depressive disorder rated their experiences before and after 3 months on the prescription medical food l-methylfolate (Deplin) 7...
2013: Primary Care Companion to CNS Disorders
Rolin L Wade, Sylvia L Kindermann, Qingjiang Hou, Michael E Thase
BACKGROUND: Antidepressant monotherapy is effective in achieving treatment remission in only approximately one third of patients with depression, and even switching to a second antidepressant brings the cumulative remission rate to only 50%-55%. This has led to an interest in augmentation therapy for the management of treatment-resistant depression. OBJECTIVES: To assess (a) selective serotonin reuptake inhibitor/selective norepinephrine reuptake inhibitor (SSRI/SNRI) adherence when augmented with second-generation atypical antipsychotics (SGAs) or L-methylfolate using a modified application of the Healthcare Effectiveness Data and Information Set (HEDIS) acute medication management (AMM) measures at the time of augmentation, and (b) the depression-specific and total health care cost, comparing the 2 forms of augmentation therapy in the treatment of depressive disorder...
January 2014: Journal of Managed Care Pharmacy: JMCP
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