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Frontiers in Endocrinology 2021Vitamins B12 and folate participate in the one-carbon metabolism cycle and hence regulate fetal growth. Though vitamin B12 deficiency is widely prevalent, the current...
Maternal Vitamin B12 Status During Pregnancy and Its Association With Outcomes of Pregnancy and Health of the Offspring: A Systematic Review and Implications for Policy in India.
BACKGROUND
Vitamins B12 and folate participate in the one-carbon metabolism cycle and hence regulate fetal growth. Though vitamin B12 deficiency is widely prevalent, the current public health policy in India is to supplement only iron and folic acid for the prevention of anaemia. Prompted by our research findings of the importance of maternal vitamin B12 status for a healthy pregnancy, birth and offspring health outcomes, we evaluated available literature evidence using a systematic review approach, to inform policy.
METHODS
A systematic search was performed for relevant Indian studies in the MEDLINE/PubMed and IndMed databases. We selected studies reporting maternal vitamin B12 status (dietary intake or blood concentrations), and/or metabolic markers of vitamin B12 deficiency (homocysteine, methylmalonic acid) or haematological indices during pregnancy and their associations with outcomes of pregnancy, infancy or in later life. Intervention trials of vitamin B12 during pregnancy were also included. Quality of evidence was assessed on the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system. We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement.
RESULTS
Of the 635 articles identified, 46 studies met the inclusion criteria (cohort studies-26, case-control studies-13, RCT's -7). There is a high prevalence of vitamin B12 deficiency in Indian women during pregnancy (40-70%) (3 studies). Observational studies support associations (adjusted for potential sociodemographic confounders, maternal body size, postnatal factors) of lower maternal B12, higher homocysteine or an imbalance between vitamin B12-folate status with a higher risk of NTDs (6 studies), pregnancy complications (recurrent pregnancy losses, gestational diabetes, pre-eclampsia) (9 studies), lower birth weight (10 studies) and adverse longer-term health outcomes in the offspring (cognitive functions, adiposity, insulin resistance) (11 studies). Vitamin B12 supplementation (7 RCT's) in pregnancy showed a beneficial effect on offspring neurocognitive development and an effect on birth weight was inconclusive. There is a high quality evidence to support the role of low maternal vitamin B12 in higher risk for NTD and low birth weight and moderate-quality evidence for higher risk of gestational diabetes and later life adverse health outcomes (cognitive functions, risk for diabetes) in offspring.
CONCLUSION
In the Indian population low maternal vitaminB12 status, is associated with adverse maternal and child health outcomes. The level of evidence supports adding vitamin B12 to existing nutritional programs in India for extended benefits on outcomes in pregnancy and offspring health besides control of anaemia.
SYSTEMATIC REVIEW REGISTRATION
[website], identifier [registration number].
Topics: Female; Folic Acid; Humans; India; Pregnancy; Pregnancy Outcome; Vitamin B 12
PubMed: 33912132
DOI: 10.3389/fendo.2021.619176 -
Journal of Affective Disorders May 2018Nutritional requirements need to be met in order to adapt to pre- and postnatal changes. Our aim was to systematically review the evidence of associations between... (Review)
Review
BACKGROUND
Nutritional requirements need to be met in order to adapt to pre- and postnatal changes. Our aim was to systematically review the evidence of associations between nutritional biomarkers and psychological distress during pregnancy and in the first postnatal year.
METHODS
MEDLINE, EMBASE, PsycINFO, Scielo, LILACS, clinicaltrials.gov, International Clinical Trials Registry, Cochrane Library, Scopus and Web of Science databases were searched for articles from inception to 4/15/2016. Studies of maternal nutritional biomarkers in blood (fatty acids/micronutrients/amino acids) and associations with psychological distress (depression/anxiety/stress) were included. Two independent reviewers extracted data based on study designs, participants, outcomes, exposures, and association measures.
RESULTS
Thirty-eight studies were included. A total of 13 studies showed divergent or no associations between serum/plasma/erythrocyte fatty acid concentrations and depression/anxiety during pregnancy and postpartum. Changes in serum cholesterol levels from pregnancy to postpartum showed a significant inverse correlation with depression in one out of three studies. Five out of seven studies found an inverse association between serum vitamin D levels and pre- and postnatal depression. Plasma tryptophan levels were inversely correlated with postnatal depression scores in three out of four studies. We identified that one out of two studies presented no significant association between vitamin B/folate/ferritin concentrations and depression in postpartum.
LIMITATIONS
There was higher variability between association measures, time and scales of depression and anxiety assessments.
CONCLUSIONS
The majority of high-quality studies suggest that lower vitamin D levels may be associated with postpartum depression. However, further evidence is needed for guiding clinical practice on nutritional biomarkers.
Topics: Adult; Anxiety Disorders; Biomarkers; Depression, Postpartum; Depressive Disorder; Female; Folic Acid; Humans; Maternal Nutritional Physiological Phenomena; Micronutrients; Postpartum Period; Pregnancy; Pregnancy Complications; Vitamin B 12; Vitamin D; Vitamin D Deficiency
PubMed: 29494902
DOI: 10.1016/j.jad.2018.02.004 -
Scientific Reports Jul 2015Contrasting results have been reported regarding the associations between plasma total homocysteine (tHcy) and B vitamin levels and age-related macular degeneration... (Meta-Analysis)
Meta-Analysis Review
Contrasting results have been reported regarding the associations between plasma total homocysteine (tHcy) and B vitamin levels and age-related macular degeneration (AMD) risk. Thus, we aimed to systematically evaluate these associations. Relevant case control studies in English were identified via a thorough search of the PubMed, Medline, and Embase databases from inception to June 2014. The results were pooled using Review Manager 5.2.1. Eleven studies (including 1072 cases and 1202 controls) were eligible for analysis of tHcy levels; additionally, 3 studies (including 152 cases and 98 controls) were eligible for analysis of folic acid and vitamin B12 levels. The cumulative results demonstrated that the plasma tHcy level among the AMD cases was 2.67 μmol/L (95% confidence interval [CI], 1.60-3.74) higher than that among the controls. In contrast, the vitamin B12 level among the AMD cases was 64.16 pg/mL (95% CI, 19.32-109.00) lower than that among the controls. Subgroup analyses showed that the folic acid level was 1.66 ng/mL (95% CI, 0.10-3.21) lower for the wet type. Together, the results demonstrated that AMD is associated with elevated tHcy levels and decreased vitamin B12 levels. Plasma tHcy may act as a modulator of the risk for AMD based on the current evidence.
Topics: Aged; Aged, 80 and over; Female; Folic Acid; Homocysteine; Humans; Macular Degeneration; Male; Middle Aged; Risk Factors; Vitamin B 12
PubMed: 26194346
DOI: 10.1038/srep10585 -
Journal of the National Cancer Institute Jan 2016Little is known about the total patient burden associated with clinical development and where burdens fall most heavily during a drug development program. Our goal was... (Review)
Review
BACKGROUND
Little is known about the total patient burden associated with clinical development and where burdens fall most heavily during a drug development program. Our goal was to quantify the total patient burden/benefit in developing a new drug.
METHODS
We measured risk using drug-related adverse events that were grade 3 or higher, benefit by objective response rate, and trial outcomes by whether studies met their primary endpoint with acceptable safety. The differences in risk (death rate) and benefit (overall response rate) between industry and nonindustry trials were analyzed with an inverse-variance weighted fixed effects meta-analysis implemented as a weighted regression analysis. All statistical tests were two-sided.
RESULTS
We identified 103 primary publications of sunitinib monotherapy, representing 9092 patients and 3991 patient-years of involvement over 10 years and 32 different malignancies. In total, 1052 patients receiving sunitinib monotherapy experienced objective tumor response (15.7% of intent-to-treat population, 95% confidence interval [CI] = 15.3% to 16.0%), 98 died from drug-related toxicities (1.08%, 95% CI = 1.02% to 1.14%), and at least 1245 experienced grade 3-4 drug-related toxicities (13.7%, 95% CI = 13.3% to 14.1%). Risk/benefit worsened as the development program matured, with several instances of replicated negative studies and almost no positive trials after the first responding malignancies were discovered.
CONCLUSIONS
Even for a successful drug, the risk/benefit balance of trials was similar to phase I cancer trials in general. Sunitinib monotherapy development showed worsening risk/benefit, and the testing of new indications responded slowly to evidence that sunitinib monotherapy would not extend to new malignancies. Research decision-making should draw on evidence from whole research programs rather than a narrow band of studies in the same indication.
Topics: Angiogenesis Inhibitors; Antineoplastic Agents; Clinical Trials as Topic; Drug Approval; Humans; Indoles; Neoplasms; Pyrroles; Risk Assessment; Sunitinib; United States; United States Food and Drug Administration
PubMed: 26547927
DOI: 10.1093/jnci/djv292 -
The Cochrane Database of Systematic... Aug 2017Cardiovascular disease, which includes coronary artery disease, stroke and peripheral vascular disease, is a leading cause of death worldwide. Homocysteine is an amino... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Cardiovascular disease, which includes coronary artery disease, stroke and peripheral vascular disease, is a leading cause of death worldwide. Homocysteine is an amino acid with biological functions in methionine metabolism. A postulated risk factor for cardiovascular disease is an elevated circulating total homocysteine level. The impact of homocysteine-lowering interventions, given to patients in the form of vitamins B6, B9 or B12 supplements, on cardiovascular events has been investigated. This is an update of a review previously published in 2009, 2013, and 2015.
OBJECTIVES
To determine whether homocysteine-lowering interventions, provided to patients with and without pre-existing cardiovascular disease are effective in preventing cardiovascular events, as well as reducing all-cause mortality, and to evaluate their safety.
SEARCH METHODS
We searched the Cochrane Central Register of Controlled Trials (CENTRAL 2017, Issue 5), MEDLINE (1946 to 1 June 2017), Embase (1980 to 2017 week 22) and LILACS (1986 to 1 June 2017). We also searched Web of Science (1970 to 1 June 2017). We handsearched the reference lists of included papers. We also contacted researchers in the field. There was no language restriction in the search.
SELECTION CRITERIA
We included randomised controlled trials assessing the effects of homocysteine-lowering interventions for preventing cardiovascular events with a follow-up period of one year or longer. We considered myocardial infarction and stroke as the primary outcomes. We excluded studies in patients with end-stage renal disease.
DATA COLLECTION AND ANALYSIS
We performed study selection, 'Risk of bias' assessment and data extraction in duplicate. We estimated risk ratios (RR) for dichotomous outcomes. We calculated the number needed to treat for an additional beneficial outcome (NNTB). We measured statistical heterogeneity using the I statistic. We used a random-effects model. We conducted trial sequential analyses, Bayes factor, and fragility indices where appropriate.
MAIN RESULTS
In this third update, we identified three new randomised controlled trials, for a total of 15 randomised controlled trials involving 71,422 participants. Nine trials (60%) had low risk of bias, length of follow-up ranged from one to 7.3 years. Compared with placebo, there were no differences in effects of homocysteine-lowering interventions on myocardial infarction (homocysteine-lowering = 7.1% versus placebo = 6.0%; RR 1.02, 95% confidence interval (CI) 0.95 to 1.10, I = 0%, 12 trials; N = 46,699; Bayes factor 1.04, high-quality evidence), death from any cause (homocysteine-lowering = 11.7% versus placebo = 12.3%, RR 1.01, 95% CI 0.96 to 1.06, I = 0%, 11 trials, N = 44,817; Bayes factor = 1.05, high-quality evidence), or serious adverse events (homocysteine-lowering = 8.3% versus comparator = 8.5%, RR 1.07, 95% CI 1.00 to 1.14, I = 0%, eight trials, N = 35,788; high-quality evidence). Compared with placebo, homocysteine-lowering interventions were associated with reduced stroke outcome (homocysteine-lowering = 4.3% versus comparator = 5.1%, RR 0.90, 95% CI 0.82 to 0.99, I = 8%, 10 trials, N = 44,224; high-quality evidence). Compared with low doses, there were uncertain effects of high doses of homocysteine-lowering interventions on stroke (high = 10.8% versus low = 11.2%, RR 0.90, 95% CI 0.66 to 1.22, I = 72%, two trials, N = 3929; very low-quality evidence).We found no evidence of publication bias.
AUTHORS' CONCLUSIONS
In this third update of the Cochrane review, there were no differences in effects of homocysteine-lowering interventions in the form of supplements of vitamins B6, B9 or B12 given alone or in combination comparing with placebo on myocardial infarction, death from any cause or adverse events. In terms of stroke, this review found a small difference in effect favouring to homocysteine-lowering interventions in the form of supplements of vitamins B6, B9 or B12 given alone or in combination comparing with placebo.There were uncertain effects of enalapril plus folic acid compared with enalapril on stroke; approximately 143 (95% CI 85 to 428) people would need to be treated for 5.4 years to prevent 1 stroke, this evidence emerged from one mega-trial.Trial sequential analyses showed that additional trials are unlikely to increase the certainty about the findings of this issue regarding homocysteine-lowering interventions versus placebo. There is a need for additional trials comparing homocysteine-lowering interventions combined with antihypertensive medication versus antihypertensive medication, and homocysteine-lowering interventions at high doses versus homocysteine-lowering interventions at low doses. Potential trials should be large and co-operative.
Topics: Angina Pectoris; Cardiovascular Diseases; Cause of Death; Folic Acid; Humans; Hyperhomocysteinemia; Myocardial Infarction; Randomized Controlled Trials as Topic; Risk Factors; Stroke; Vitamin B 12; Vitamin B 6; Vitamin B Complex
PubMed: 28816346
DOI: 10.1002/14651858.CD006612.pub5 -
Cells Oct 2022Major depressive disorder (MDD) and bipolar disorder (BD) with melancholia and psychotic features and suicidal behaviors are accompanied by activated immune-inflammatory... (Meta-Analysis)
Meta-Analysis Review
The Tryptophan Catabolite or Kynurenine Pathway in a Major Depressive Episode with Melancholia, Psychotic Features and Suicidal Behaviors: A Systematic Review and Meta-Analysis.
Major depressive disorder (MDD) and bipolar disorder (BD) with melancholia and psychotic features and suicidal behaviors are accompanied by activated immune-inflammatory and oxidative pathways, which may stimulate indoleamine 2,3-dioxygenase (IDO), the first and rate-limiting enzyme of the tryptophan catabolite (TRYCAT) pathway resulting in increased tryptophan degradation and elevated tryptophan catabolites (TRYCTAs). The purpose of the current study is to systematically review and meta-analyze levels of TRP, its competing amino acids (CAAs) and TRYCATs in patients with severe affective disorders. Methods: PubMed, Google Scholar and SciFinder were searched in the present study and we recruited 35 studies to examine 4647 participants including 2332 unipolar (MDD) and bipolar (BD) depressed patients and 2315 healthy controls. Severe patients showed significant lower ( < 0.0001) TRP (standardized mean difference, SMD = -0.517, 95% confidence interval, CI: -0.735; -0.299) and TRP/CAAs (SMD = -0.617, CI: -0.957; -0.277) levels with moderate effect sizes, while no significant difference in CAAs were found. Kynurenine (KYN) levels were unaltered in severe MDD/BD phenotypes, while the KYN/TRP ratio showed a significant increase only in patients with psychotic features (SMD = 0.224, CI: 0.012; 0.436). Quinolinic acid (QA) was significantly increased (SMD = 0.358, CI: 0.015; 0.701) and kynurenic acid (KA) significantly decreased (SMD = -0.260, CI: -0.487; -0.034) in severe MDD/BD. Patients with affective disorders with melancholic and psychotic features and suicidal behaviors showed normal IDO enzyme activity but a lowered availability of plasma/serum TRP to the brain, which is probably due to other processes such as low albumin levels.
Topics: Albumins; Amino Acids; Depressive Disorder, Major; Humans; Indoleamine-Pyrrole 2,3,-Dioxygenase; Kynurenic Acid; Kynurenine; Quinolinic Acids; Suicidal Ideation; Tryptophan
PubMed: 36231075
DOI: 10.3390/cells11193112 -
BMJ Open May 2023To evaluate the association between bilirubin levels and stroke risk. (Meta-Analysis)
Meta-Analysis
OBJECTIVE
To evaluate the association between bilirubin levels and stroke risk.
DESIGN
Systematic review and meta-analysis, reported in accordance with Meta-analysis Of Observational Studies in Epidemiology guidelines.
DATA SOURCES
The PubMed, Embase, Cochrane Central Register of Controlled Trials and China National Knowledge Infrastructure Databases were searched from inception up to 27 February 2022.
ELIGIBILITY CRITERIA
Cohort studies assessing the dose-response relationship between bilirubin levels and risk of stroke were eligible for inclusion. There were no language restrictions.
DATA EXTRACTION AND SYNTHESIS
All data from eligible studies were collected and assessed by two independent investigators. We generated pooled relative risks (RRs) with 95% CIs. We used a restricted cubic spline model for the dose-response analyses. Subsequent subgroup analyses were conducted according to stroke outcomes, follow-up duration, geographical area and size of the cohort.
RESULTS
Nine articles including results from 11 cohort studies with 7835 cases of stroke and 263 596 participants met the inclusion criteria. The summarised RR of stroke comparing the highest and lowest bilirubin level was 0.85 (95% CI 0.72 to 0.99). The dose-response analysis indicated that a 15 µmol/L increment of bilirubin level was associated with an 18% lower risk of stroke (RR=0.82, 95% CI 0.67 to 0.99). For ischaemic stroke, the RR was 0.76 (95% CI 0.58 to 0.99). Significant publication bias was not detected.
CONCLUSIONS
Elevated bilirubin levels were associated with a decreased risk of stroke among adults.
PROSPERO REGISTRATION NUMBER
CRD42017071497.
Topics: Adult; Humans; Brain Ischemia; Stroke; Cohort Studies; Ischemic Stroke; Bilirubin
PubMed: 37164466
DOI: 10.1136/bmjopen-2022-064433 -
The Cochrane Database of Systematic... May 2017Since the mid-2000s, the field of metastatic renal cell carcinoma (mRCC) has experienced a paradigm shift from non-specific therapy with broad-acting cytokines to... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Since the mid-2000s, the field of metastatic renal cell carcinoma (mRCC) has experienced a paradigm shift from non-specific therapy with broad-acting cytokines to specific regimens, which directly target the cancer, the tumour microenvironment, or both.Current guidelines recommend targeted therapies with agents such as sunitinib, pazopanib or temsirolimus (for people with poor prognosis) as the standard of care for first-line treatment of people with mRCC and mention non-specific cytokines as an alternative option for selected patients.In November 2015, nivolumab, a checkpoint inhibitor directed against programmed death-1 (PD-1), was approved as the first specific immunotherapeutic agent as second-line therapy in previously treated mRCC patients.
OBJECTIVES
To assess the effects of immunotherapies either alone or in combination with standard targeted therapies for the treatment of metastatic renal cell carcinoma and their efficacy to maximize patient benefit.
SEARCH METHODS
We searched the Cochrane Library, MEDLINE (Ovid), Embase (Ovid), ISI Web of Science and registers of ongoing clinical trials in November 2016 without language restrictions. We scanned reference lists and contacted experts in the field to obtain further information.
SELECTION CRITERIA
We included randomized controlled trials (RCTs) and quasi-RCTs with or without blinding involving people with mRCC.
DATA COLLECTION AND ANALYSIS
We collected and analyzed studies according to the published protocol. Summary statistics for the primary endpoints were risk ratios (RRs) and mean differences (MD) with their 95% confidence intervals (CIs). We rated the quality of evidence using GRADE methodology and summarized the quality and magnitude of relative and absolute effects for each primary outcome in our 'Summary of findings' tables.
MAIN RESULTS
We identified eight studies with 4732 eligible participants and an additional 13 ongoing studies. We categorized studies into comparisons, all against standard therapy accordingly as first-line (five comparisons) or second-line therapy (one comparison) for mRCC.Interferon (IFN)-α monotherapy probably increases one-year overall mortality compared to standard targeted therapies with temsirolimus or sunitinib (RR 1.30, 95% CI 1.13 to 1.51; 2 studies; 1166 participants; moderate-quality evidence), may lead to similar quality of life (QoL) (e.g. MD -5.58 points, 95% CI -7.25 to -3.91 for Functional Assessment of Cancer - General (FACT-G); 1 study; 730 participants; low-quality evidence) and may slightly increase the incidence of adverse events (AEs) grade 3 or greater (RR 1.17, 95% CI 1.03 to 1.32; 1 study; 408 participants; low-quality evidence).There is probably no difference between IFN-α plus temsirolimus and temsirolimus alone for one-year overall mortality (RR 1.13, 95% CI 0.95 to 1.34; 1 study; 419 participants; moderate-quality evidence), but the incidence of AEs of 3 or greater may be increased (RR 1.30, 95% CI 1.17 to 1.45; 1 study; 416 participants; low-quality evidence). There was no information on QoL.IFN-α alone may slightly increase one-year overall mortality compared to IFN-α plus bevacizumab (RR 1.17, 95% CI 1.00 to 1.36; 2 studies; 1381 participants; low-quality evidence). This effect is probably accompanied by a lower incidence of AEs of grade 3 or greater (RR 0.77, 95% CI 0.71 to 0.84; 2 studies; 1350 participants; moderate-quality evidence). QoL could not be evaluated due to insufficient data.Treatment with IFN-α plus bevacizumab or standard targeted therapy (sunitinib) may lead to similar one-year overall mortality (RR 0.37, 95% CI 0.13 to 1.08; 1 study; 83 participants; low-quality evidence) and AEs of grade 3 or greater (RR 1.18, 95% CI 0.85 to 1.62; 1 study; 82 participants; low-quality evidence). QoL could not be evaluated due to insufficient data.Treatment with vaccines (e.g. MVA-5T4 or IMA901) or standard therapy may lead to similar one-year overall mortality (RR 1.10, 95% CI 0.91 to 1.32; low-quality evidence) and AEs of grade 3 or greater (RR 1.16, 95% CI 0.97 to 1.39; 2 studies; 1065 participants; low-quality evidence). QoL could not be evaluated due to insufficient data.In previously treated patients, targeted immunotherapy (nivolumab) probably reduces one-year overall mortality compared to standard targeted therapy with everolimus (RR 0.70, 95% CI 0.56 to 0.87; 1 study; 821 participants; moderate-quality evidence), probably improves QoL (e.g. RR 1.51, 95% CI 1.28 to 1.78 for clinically relevant improvement of the FACT-Kidney Symptom Index Disease Related Symptoms (FKSI-DRS); 1 study, 704 participants; moderate-quality evidence) and probably reduces the incidence of AEs grade 3 or greater (RR 0.51, 95% CI 0.40 to 0.65; 1 study; 803 participants; moderate-quality evidence).
AUTHORS' CONCLUSIONS
Evidence of moderate quality demonstrates that IFN-α monotherapy increases mortality compared to standard targeted therapies alone, whereas there is no difference if IFN is combined with standard targeted therapies. Evidence of low quality demonstrates that QoL is worse with IFN alone and that severe AEs are increased with IFN alone or in combination. There is low-quality evidence that IFN-α alone increases mortality but moderate-quality evidence on decreased AEs compared to IFN-α plus bevacizumab. Low-quality evidence shows no difference for IFN-α plus bevacizumab compared to sunitinib with respect to mortality and severe AEs. Low-quality evidence demonstrates no difference of vaccine treatment compared to standard targeted therapies in mortality and AEs, whereas there is moderate-quality evidence that targeted immunotherapies reduce mortality and AEs and improve QoL.
Topics: Antineoplastic Agents; Bevacizumab; Cancer Vaccines; Carcinoma, Renal Cell; Clinical Trials, Phase III as Topic; Humans; Immunologic Factors; Immunotherapy; Indoles; Interferon-alpha; Kidney Neoplasms; Longevity; Pyrroles; Quality of Life; Randomized Controlled Trials as Topic; Sirolimus; Sunitinib
PubMed: 28504837
DOI: 10.1002/14651858.CD011673.pub2 -
The Cochrane Database of Systematic... Jun 2019Diabetic peripheral neuropathy (DPN) is a common and severe complication that affects 50% of people with diabetes. Painful DPN is reported to occur in 16% to 24% of... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Diabetic peripheral neuropathy (DPN) is a common and severe complication that affects 50% of people with diabetes. Painful DPN is reported to occur in 16% to 24% of people with diabetes. A complete and comprehensive management strategy for the prevention and treatment of DPN, whether painful or not, has not yet been defined.Research into treatment for DPN has been characterised by a series of failed clinical trials, with few noteworthy advances. Strategies that support peripheral nerve regeneration and restore neurological function in people with painful or painless DPN are needed. The amino acid acetyl-L-carnitine (ALC) plays a role in the transfer of long-chain fatty acids into mitochondria for β-oxidation. ALC supplementation also induces neuroprotective and neurotrophic effects in the peripheral nervous system. Therefore, ALC supplementation targets several mechanisms relevant to potential nerve repair and regeneration, and could have clinical therapeutic potential. There is a need for a systematic review of the evidence from clinical trials.
OBJECTIVES
To assess the effects of ALC for the treatment of DPN.
SEARCH METHODS
On 2 July 2018, we searched the Cochrane Neuromuscular Specialised Register, CENTRAL, MEDLINE, Embase, LILACS, ClinicalTrials.gov, and the World Health Organization International Clinical Trials Registry Platform. We checked references, searched citations, and contacted study authors to identify additional studies.
SELECTION CRITERIA
We included randomised controlled trials (RCTs) and quasi-RCTs of ALC compared with placebo, other therapy, or no intervention in the treatment of DPN. Participants could be of any sex and age, and have type 1 or type 2 diabetes mellitus, of any severity, with painful or painless DPN. We accepted any definition of minimum criteria for DPN, in accordance with the Toronto Consensus. We imposed no language restriction.Pain was the primary outcome, measured as the proportion of participants with at least 30% (moderate) or 50% (substantial) decrease in pain over baseline, or as the score on a visual analogue scale (VAS) or Likert scale for pain.
DATA COLLECTION AND ANALYSIS
We followed standard Cochrane methods.
MAIN RESULTS
We included four studies with 907 participants, which were reported in three publications. Three trials studied ALC versus placebo (675 participants); in one trial the dose of ALC was 2000 mg/day, and in the other two trials, it was 1500 mg/day or 3000 mg/day. The fourth trial studied ALC 1500 mg/day versus methylcobalamin 1.5 mg/day (232 participants). The risk of bias was high in both trials of different ALC doses and low in the other two trials.No included trial measured the proportion of participants with at least moderate (30%) or substantial (50%) pain relief. ALC reduced pain more than placebo, measured on a 0- to 100-mm VAS (MD -9.16, 95% CI -16.76 to -1.57; three studies; 540 participants; P = 0.02; I² = 56%; random-effects; very low-certainty evidence; a higher score indicating more pain). At doses of 1500 mg/day or less, the VAS score after ALC treatment was little different from placebo (MD -0.05, 95% CI -10.00 to 9.89; two studies; 159 participants; P = 0.99; I² = 0%), but at doses greater than 1500 mg/day, ALC reduced pain more than placebo (MD -14.93, 95% CI -19.16 to -10.70; three studies; 381 participants; P < 0.00001; I² = 0%). This subgroup analysis should be viewed with caution as the evidence was even less certain than the overall analysis, which was already of very low certainty.Two placebo-controlled studies reported that vibration perception improved after 12 months. We graded this evidence as very low certainty, due to inconsistency and a high risk of bias, as the trial authors did not provide any numerical data. The placebo-controlled studies did not measure functional impairment and disability scores. No study used validated symptom scales. One study performed sensory testing, but the evidence was very uncertain.The fourth included study compared ALC with methylcobalamin, but did not report effects on pain. There was a reduction from baseline to 24 weeks in functional impairment and disability, based on the change in mean Neuropathy Disability Score (NDS; scale from zero to 10), but there was no important difference between the ALC group (mean score 1.66 ± 1.90) and the methylcobalamin group (mean score 1.35 ± 1.65) groups (P = 0.23; low-certainty evidence).One placebo-controlled study reported that six of 147 participants in the ALC > 1500 mg/day group (4.1%) and two of 147 participants in the placebo group (1.4%) discontinued treatment because of adverse events (headache, facial paraesthesia, and gastrointestinal disorders) (P = 0.17). The other two placebo-controlled studies reported no dropouts due to adverse events, and more pain, paraesthesia, and hyperaesthesias in the placebo group than the 3000 mg/day ALC group, but provided no numerical data. The overall certainty of adverse event evidence for the comparison of ALC versus placebo was low.The study comparing ALC with methylcobalamin reported that 34/117 participants (29.1%) experienced adverse events in the ALC group versus 33/115 (28.7%) in the methylcobalamin group (P = 0.95). Nine participants discontinued treatment due to adverse events (ALC: 4 participants, methylcobalamin: 5 participants), which were most commonly gastrointestinal symptoms. The certainty of the adverse event evidence for ALC versus methylcobalamin was low.Two studies were funded by the manufacturer of ALC and the other two studies had at least one co-author who was a consultant for an ALC manufacturer.
AUTHORS' CONCLUSIONS
We are very uncertain whether ALC causes a reduction in pain after 6 to 12 months' treatment in people with DPN, when compared with placebo, as the evidence is sparse and of low certainty. Data on functional and sensory impairment and symptoms are lacking, or of very low certainty. The evidence on adverse events is too uncertain to make any judgements on safety.
Topics: Acetylcarnitine; Adult; Aged; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Female; Humans; Male; Middle Aged; Neuralgia; Pain Measurement; Placebos; Randomized Controlled Trials as Topic; Sensation; Vibration; Vitamin B 12
PubMed: 31201734
DOI: 10.1002/14651858.CD011265.pub2 -
The Cochrane Database of Systematic... May 2020Sexual dysfunction following stroke is common but often is poorly managed. As awareness of sexual dysfunction following stroke increases as an important issue, a clearer...
BACKGROUND
Sexual dysfunction following stroke is common but often is poorly managed. As awareness of sexual dysfunction following stroke increases as an important issue, a clearer evidence base for interventions for sexual dysfunction is needed to optimise management.
OBJECTIVES
To evaluate the effectiveness of interventions to reduce sexual dysfunction following stroke, and to assess adverse events associated with interventions for sexual dysfunction following stroke.
SEARCH METHODS
We conducted the search on 27 November 2019. We searched the Cochrane Central Register of Controlled Trials (CENTRAL; from June 2014), in the Cochrane Library; MEDLINE (from 1950); Embase (from 1980); the Cumulative Index to Nursing and Allied Health Literature (CINAHL; from 1982); the Allied and Complementary Medicine Database (AMED; from 1985); PsycINFO (from 1806); the Physiotherapy Evidence Database (PEDro; from 1999); and 10 additional bibliographic databases and ongoing trial registers.
SELECTION CRITERIA
We included randomised controlled trials (RCTs) that compared pharmacological treatments, mechanical devices, or complementary medicine interventions versus placebo. We also included other non-pharmacological interventions (such as education or therapy), which were compared against usual care or different forms of intervention (such as different intensities) for treating sexual dysfunction in stroke survivors.
DATA COLLECTION AND ANALYSIS
Two review authors independently selected eligible studies, extracted data, and assessed study quality. We determined the risk of bias for each study and performed a 'best evidence' synthesis using the GRADE approach.
MAIN RESULTS
We identified three RCTs with a total of 212 participants. We noted significant heterogeneity in interventions (one pharmacological, one physiotherapy-based, and one psycho-educational), and all RCTs were small and of 'low' or 'very low' quality. Based on these RCTs, data are insufficient to provide any reliable indication of benefit or risk to guide clinical practice in terms of the use of sertraline, specific pelvic floor muscle training, or individualised sexual rehabilitation.
AUTHORS' CONCLUSIONS
Use of sertraline to treat premature ejaculation needs to be tested in further RCTs. The lack of benefit with structured sexual rehabilitation and pelvic floor physiotherapy should not be interpreted as proof of ineffectiveness. Well-designed, randomised, double-blinded, placebo-controlled trials of long-term duration are needed to determine the effectiveness of various types of interventions for sexual dysfunction. It should be noted, however, that it may not be possible to double-blind trials of complex interventions.
Topics: Adult; Aged; Aged, 80 and over; Antidepressive Agents; Female; Humans; Male; Middle Aged; Orgasm; Pelvic Floor; Premature Ejaculation; Quality of Life; Randomized Controlled Trials as Topic; Resistance Training; Sertraline; Sex Education; Sexual Dysfunction, Physiological; Sexual Partners; Stroke; Vitamin B 12; Vitamin B Complex; Young Adult
PubMed: 32356377
DOI: 10.1002/14651858.CD011189.pub2