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Vascular Pharmacology Aug 2015Dark chocolate contains many biologically active components, such as catechins, procyanidins and theobromine from cocoa, together with added sucrose and lipids. All of... (Review)
Review
Dark chocolate contains many biologically active components, such as catechins, procyanidins and theobromine from cocoa, together with added sucrose and lipids. All of these can directly or indirectly affect the cardiovascular system by multiple mechanisms. Intervention studies on healthy and metabolically-dysfunctional volunteers have suggested that cocoa improves blood pressure, platelet aggregation and endothelial function. The effect of chocolate is more convoluted since the sucrose and lipid may transiently and negatively impact on endothelial function, partly through insulin signalling and nitric oxide bioavailability. However, few studies have attempted to dissect out the role of the individual components and have not explored their possible interactions. For intervention studies, the situation is complex since suitable placebos are often not available, and some benefits may only be observed in individuals showing mild metabolic dysfunction. For chocolate, the effects of some of the components, such as sugar and epicatechin on FMD, may oppose each other, or alternatively in some cases may act together, such as theobromine and epicatechin. Although clearly cocoa provides some cardiovascular benefits according to many human intervention studies, the exact components, their interactions and molecular mechanisms are still under debate.
Topics: Animals; Blood Pressure; Cacao; Cardiovascular Diseases; Catechin; Endothelium, Vascular; Flavonoids; Humans; Theobromine
PubMed: 26026398
DOI: 10.1016/j.vph.2015.05.011 -
The New England Journal of Medicine Apr 2015Alcoholic hepatitis is a clinical syndrome characterized by jaundice and liver impairment that occurs in patients with a history of heavy and prolonged alcohol use. The... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Alcoholic hepatitis is a clinical syndrome characterized by jaundice and liver impairment that occurs in patients with a history of heavy and prolonged alcohol use. The short-term mortality among patients with severe disease exceeds 30%. Prednisolone and pentoxifylline are both recommended for the treatment of severe alcoholic hepatitis, but uncertainty about their benefit persists.
METHODS
We conducted a multicenter, double-blind, randomized trial with a 2-by-2 factorial design to evaluate the effect of treatment with prednisolone or pentoxifylline. The primary end point was mortality at 28 days. Secondary end points included death or liver transplantation at 90 days and at 1 year. Patients with a clinical diagnosis of alcoholic hepatitis and severe disease were randomly assigned to one of four groups: a group that received a pentoxifylline-matched placebo and a prednisolone-matched placebo, a group that received prednisolone and a pentoxifylline-matched placebo, a group that received pentoxifylline and a prednisolone-matched placebo, or a group that received both prednisolone and pentoxifylline.
RESULTS
A total of 1103 patients underwent randomization, and data from 1053 were available for the primary end-point analysis. Mortality at 28 days was 17% (45 of 269 patients) in the placebo-placebo group, 14% (38 of 266 patients) in the prednisolone-placebo group, 19% (50 of 258 patients) in the pentoxifylline-placebo group, and 13% (35 of 260 patients) in the prednisolone-pentoxifylline group. The odds ratio for 28-day mortality with pentoxifylline was 1.07 (95% confidence interval [CI], 0.77 to 1.49; P=0.69), and that with prednisolone was 0.72 (95% CI, 0.52 to 1.01; P=0.06). At 90 days and at 1 year, there were no significant between-group differences. Serious infections occurred in 13% of the patients treated with prednisolone versus 7% of those who did not receive prednisolone (P=0.002).
CONCLUSIONS
Pentoxifylline did not improve survival in patients with alcoholic hepatitis. Prednisolone was associated with a reduction in 28-day mortality that did not reach significance and with no improvement in outcomes at 90 days or 1 year. (Funded by the National Institute for Health Research Health Technology Assessment program; STOPAH EudraCT number, 2009-013897-42 , and Current Controlled Trials number, ISRCTN88782125 ).
Topics: Adult; Analysis of Variance; Double-Blind Method; Female; Glucocorticoids; Hepatitis, Alcoholic; Humans; Infections; Kaplan-Meier Estimate; Male; Middle Aged; Pentoxifylline; Phosphodiesterase Inhibitors; Prednisolone; Treatment Failure
PubMed: 25901427
DOI: 10.1056/NEJMoa1412278 -
The Cochrane Database of Systematic... Aug 2020A couple may be considered to have fertility problems if they have been trying to conceive for over a year with no success. This may affect up to a quarter of all... (Meta-Analysis)
Meta-Analysis
BACKGROUND
A couple may be considered to have fertility problems if they have been trying to conceive for over a year with no success. This may affect up to a quarter of all couples planning a child. It is estimated that for 40% to 50% of couples, subfertility may result from factors affecting women. Antioxidants are thought to reduce the oxidative stress brought on by these conditions. Currently, limited evidence suggests that antioxidants improve fertility, and trials have explored this area with varied results. This review assesses the evidence for the effectiveness of different antioxidants in female subfertility.
OBJECTIVES
To determine whether supplementary oral antioxidants compared with placebo, no treatment/standard treatment or another antioxidant improve fertility outcomes for subfertile women.
SEARCH METHODS
We searched the following databases (from their inception to September 2019), with no language or date restriction: Cochrane Gynaecology and Fertility Group (CGFG) specialised register, CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL and AMED. We checked reference lists of relevant studies and searched the trial registers.
SELECTION CRITERIA
We included randomised controlled trials (RCTs) that compared any type, dose or combination of oral antioxidant supplement with placebo, no treatment or treatment with another antioxidant, among women attending a reproductive clinic. We excluded trials comparing antioxidants with fertility drugs alone and trials that only included fertile women attending a fertility clinic because of male partner infertility.
DATA COLLECTION AND ANALYSIS
We used standard methodological procedures expected by Cochrane. The primary review outcome was live birth; secondary outcomes included clinical pregnancy rates and adverse events.
MAIN RESULTS
We included 63 trials involving 7760 women. Investigators compared oral antioxidants, including: combinations of antioxidants, N-acetylcysteine, melatonin, L-arginine, myo-inositol, carnitine, selenium, vitamin E, vitamin B complex, vitamin C, vitamin D+calcium, CoQ10, and omega-3-polyunsaturated fatty acids versus placebo, no treatment/standard treatment or another antioxidant. Only 27 of the 63 included trials reported funding sources. Due to the very low-quality of the evidence we are uncertain whether antioxidants improve live birth rate compared with placebo or no treatment/standard treatment (odds ratio (OR) 1.81, 95% confidence interval (CI) 1.36 to 2.43; P < 0.001, I = 29%; 13 RCTs, 1227 women). This suggests that among subfertile women with an expected live birth rate of 19%, the rate among women using antioxidants would be between 24% and 36%. Low-quality evidence suggests that antioxidants may improve clinical pregnancy rate compared with placebo or no treatment/standard treatment (OR 1.65, 95% CI 1.43 to 1.89; P < 0.001, I = 63%; 35 RCTs, 5165 women). This suggests that among subfertile women with an expected clinical pregnancy rate of 19%, the rate among women using antioxidants would be between 25% and 30%. Heterogeneity was moderately high. Overall 28 trials reported on various adverse events in the meta-analysis. The evidence suggests that the use of antioxidants makes no difference between the groups in rates of miscarriage (OR 1.13, 95% CI 0.82 to 1.55; P = 0.46, I = 0%; 24 RCTs, 3229 women; low-quality evidence). There was also no evidence of a difference between the groups in rates of multiple pregnancy (OR 1.00, 95% CI 0.63 to 1.56; P = 0.99, I = 0%; 9 RCTs, 1886 women; low-quality evidence). There was also no evidence of a difference between the groups in rates of gastrointestinal disturbances (OR 1.55, 95% CI 0.47 to 5.10; P = 0.47, I = 0%; 3 RCTs, 343 women; low-quality evidence). Low-quality evidence showed that there was also no difference between the groups in rates of ectopic pregnancy (OR 1.40, 95% CI 0.27 to 7.20; P = 0.69, I = 0%; 4 RCTs, 404 women). In the antioxidant versus antioxidant comparison, low-quality evidence shows no difference in a lower dose of melatonin being associated with an increased live-birth rate compared with higher-dose melatonin (OR 0.94, 95% CI 0.41 to 2.15; P = 0.89, I = 0%; 2 RCTs, 140 women). This suggests that among subfertile women with an expected live-birth rate of 24%, the rate among women using a lower dose of melatonin compared to a higher dose would be between 12% and 40%. Similarly with clinical pregnancy, there was no evidence of a difference between the groups in rates between a lower and a higher dose of melatonin (OR 0.94, 95% CI 0.41 to 2.15; P = 0.89, I = 0%; 2 RCTs, 140 women). Three trials reported on miscarriage in the antioxidant versus antioxidant comparison (two used doses of melatonin and one compared N-acetylcysteine versus L-carnitine). There were no miscarriages in either melatonin trial. Multiple pregnancy and gastrointestinal disturbances were not reported, and ectopic pregnancy was reported by only one trial, with no events. The study comparing N-acetylcysteine with L-carnitine did not report live birth rate. Very low-quality evidence shows no evidence of a difference in clinical pregnancy (OR 0.81, 95% CI 0.33 to 2.00; 1 RCT, 164 women; low-quality evidence). Low quality evidence shows no difference in miscarriage (OR 1.54, 95% CI 0.42 to 5.67; 1 RCT, 164 women; low-quality evidence). The study did not report multiple pregnancy, gastrointestinal disturbances or ectopic pregnancy. The overall quality of evidence was limited by serious risk of bias associated with poor reporting of methods, imprecision and inconsistency.
AUTHORS' CONCLUSIONS
In this review, there was low- to very low-quality evidence to show that taking an antioxidant may benefit subfertile women. Overall, there is no evidence of increased risk of miscarriage, multiple births, gastrointestinal effects or ectopic pregnancies, but evidence was of very low quality. At this time, there is limited evidence in support of supplemental oral antioxidants for subfertile women.
Topics: Abortion, Spontaneous; Administration, Oral; Antioxidants; Female; Humans; Infertility, Female; Live Birth; Minerals; Oxidative Stress; Pentoxifylline; Placebos; Pregnancy; Pregnancy Rate; Pregnancy, Multiple; Randomized Controlled Trials as Topic; Vitamins
PubMed: 32851663
DOI: 10.1002/14651858.CD007807.pub4 -
Human Molecular Genetics Dec 2016Caffeine is the most widely consumed psychoactive substance in the world and presents with wide interindividual variation in metabolism. This variation may modify...
Caffeine is the most widely consumed psychoactive substance in the world and presents with wide interindividual variation in metabolism. This variation may modify potential adverse or beneficial effects of caffeine on health. We conducted a genome-wide association study (GWAS) of plasma caffeine, paraxanthine, theophylline, theobromine and paraxanthine/caffeine ratio among up to 9,876 individuals of European ancestry from six population-based studies. A single SNP at 6p23 (near CD83) and several SNPs at 7p21 (near AHR), 15q24 (near CYP1A2) and 19q13.2 (near CYP2A6) met GW-significance (P < 5 × 10-8) and were associated with one or more metabolites. Variants at 7p21 and 15q24 associated with higher plasma caffeine and lower plasma paraxanthine/caffeine (slow caffeine metabolism) were previously associated with lower coffee and caffeine consumption behavior in GWAS. Variants at 19q13.2 associated with higher plasma paraxanthine/caffeine (slow paraxanthine metabolism) were also associated with lower coffee consumption in the UK Biobank (n = 94 343, P < 1.0 × 10-6). Variants at 2p24 (in GCKR), 4q22 (in ABCG2) and 7q11.23 (near POR) that were previously associated with coffee consumption in GWAS were nominally associated with plasma caffeine or its metabolites. Taken together, we have identified genetic factors contributing to variation in caffeine metabolism and confirm an important modulating role of systemic caffeine levels in dietary caffeine consumption behavior. Moreover, candidate genes identified encode proteins with important clinical functions that extend beyond caffeine metabolism.
Topics: Antigens, CD; Basic Helix-Loop-Helix Transcription Factors; Caffeine; Coffee; Cytochrome P-450 CYP1A2; Cytochrome P-450 CYP2A6; Female; Genome-Wide Association Study; Humans; Immunoglobulins; Male; Membrane Glycoproteins; Polymorphism, Single Nucleotide; Receptors, Aryl Hydrocarbon; Theobromine; Theophylline; White People; CD83 Antigen
PubMed: 27702941
DOI: 10.1093/hmg/ddw334 -
Nutrients Feb 2021Methylxanthines (MTX) are purine derived xanthine derivatives. Whereas naturally occurring methylxanthines like caffeine, theophylline or theobromine are widely consumed... (Review)
Review
Methylxanthines (MTX) are purine derived xanthine derivatives. Whereas naturally occurring methylxanthines like caffeine, theophylline or theobromine are widely consumed in food, several synthetic but also non-synthetic methylxanthines are used as pharmaceuticals, in particular in treating airway constrictions. Besides the well-established bronchoprotective effects, methylxanthines are also known to have anti-inflammatory and anti-oxidative properties, mediate changes in lipid homeostasis and have neuroprotective effects. Known molecular mechanisms include adenosine receptor antagonism, phosphodiesterase inhibition, effects on the cholinergic system, wnt signaling, histone deacetylase activation and gene regulation. By affecting several pathways associated with neurodegenerative diseases via different pleiotropic mechanisms and due to its moderate side effects, intake of methylxanthines have been suggested to be an interesting approach in dealing with neurodegeneration. Especially in the past years, the impact of methylxanthines in neurodegenerative diseases has been extensively studied and several new aspects have been elucidated. In this review we summarize the findings of methylxanthines linked to Alzheimer´s disease, Parkinson's disease and Multiple Sclerosis since 2017, focusing on epidemiological and clinical studies and addressing the underlying molecular mechanisms in cell culture experiments and animal studies in order to assess the neuroprotective potential of methylxanthines in these diseases.
Topics: Alzheimer Disease; Animals; Caffeine; Coffee; Humans; Multiple Sclerosis; Neurodegenerative Diseases; Neuroprotective Agents; Parkinson Disease; Theobromine; Theophylline; Xanthines
PubMed: 33671099
DOI: 10.3390/nu13030803 -
The Cochrane Database of Systematic... Sep 2015Intermittent claudication (IC) is a symptom of peripheral arterial disease (PAD) and is associated with high morbidity and mortality. Pentoxifylline, one of many drugs... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Intermittent claudication (IC) is a symptom of peripheral arterial disease (PAD) and is associated with high morbidity and mortality. Pentoxifylline, one of many drugs used to treat IC, acts by decreasing blood viscosity, improving erythrocyte flexibility and promoting microcirculatory flow and tissue oxygen concentration. Many studies have evaluated the efficacy of pentoxifylline in treating individuals with PAD, but results of these studies are variable. This is an update of a review first published in 2012.
OBJECTIVES
To determine the efficacy of pentoxifylline in improving the walking capacity (i.e. pain-free walking distance and total (absolute, maximum) walking distance) of individuals with stable intermittent claudication, Fontaine stage II.
SEARCH METHODS
For this update, the Cochrane Vascular Group Trials Search Co-ordinator searched the Specialised Register (last searched April 2015) and the Cochrane Register of Studies (2015, Issue 3).
SELECTION CRITERIA
All double-blind, randomised controlled trials (RCTs) comparing pentoxifylline versus placebo or any other pharmacological intervention in patients with IC Fontaine stage II.
DATA COLLECTION AND ANALYSIS
Two review authors separately assessed included studies,. matched data and resolved disagreements by discussion. Review authors assessed the methodological quality of studies by using the Cochrane 'Risk of bias' tool and collected results related to pain-free walking distance (PFWD) and total walking distance (TWD). Comparison of studies was based on duration and dose of pentoxifylline.
MAIN RESULTS
We included in this review 24 studies with 3377 participants. Seventeen studies compared pentoxifylline versus placebo. In the seven remaining studies, pentoxifylline was compared with flunarizine (one study), aspirin (one study), Gingko biloba extract (one study), nylidrin hydrochloride (one study), prostaglandin E1 (two studies) and buflomedil and nifedipine (one study). The quality of the evidence was generally low, with large variability in reported findings.. Most included studies did not report on random sequence generation and allocation concealment, did not provide adequate information to allow selective reporting to be judged and did not report blinding of assessors. Heterogeneity between included studies was considerable with regards to multiple variables, including duration of treatment, dose of pentoxifylline, baseline walking distance and participant characteristics; therefore, pooled analysis was not possible.Of 17 studies comparing pentoxifylline with placebo, 14 reported TWD and 11 reported PFWD; the difference in percentage improvement in TWD for pentoxifylline over placebo ranged from 1.2% to 155.9%, and in PFWD from -33.8% to 73.9%. Testing the statistical significance of these results generally was not possible because data were insufficient. Most included studies suggested improvement in PFWD and TWD for pentoxifylline over placebo and other treatments, but the statistical and clinical significance of findings from individual trials is unclear. Pentoxifylline generally was well tolerated; the most commonly reported side effects consisted of gastrointestinal symptoms such as nausea.
AUTHORS' CONCLUSIONS
Given the generally poor quality of published studies and the large degree of heterogeneity evident in interventions and in results, the overall benefit of pentoxifylline for patients with Fontaine class II intermittent claudication remains uncertain. Pentoxifylline was shown to be generally well tolerated.Based on total available evidence, high-quality data are currently insufficient to reveal the benefits of pentoxifylline for intermittent claudication.
Topics: Ankle Brachial Index; Humans; Intermittent Claudication; Pentoxifylline; Platelet Aggregation Inhibitors; Quality of Life; Randomized Controlled Trials as Topic; Vasodilator Agents; Walking
PubMed: 26417854
DOI: 10.1002/14651858.CD005262.pub3 -
Nutrients May 2022This study aimed to assess the content of caffeine and its metabolites-paraxanthine, theophylline, and theobromine-in breast milk according to selected factors. Samples...
This study aimed to assess the content of caffeine and its metabolites-paraxanthine, theophylline, and theobromine-in breast milk according to selected factors. Samples of human milk were collected from 100 women living in the east-northeast region of Poland. Information on the consumption of beverages and foods containing caffeine was collected using a 3 day food record. The determination of caffeine and its metabolite content was performed using liquid chromatography-mass spectrometry (LC-MS/MS). This study research showed that more caffeine was found in the milk of women living in cities, with secondary education, aged 34-43, and also in milk from the 3rd and 4th lactation periods ( ≤ 0.05). Factors such as place of residence, level of education, age, and stage of lactation influenced the nutritional choices of breastfeeding women, which had an impact on the level of caffeine and its metabolites in breast milk. A positive correlation was found between the consumption of caffeine with food and drinks and its level in human milk.
Topics: Caffeine; Chromatography, Liquid; Female; Humans; Milk, Human; Tandem Mass Spectrometry; Theobromine; Theophylline
PubMed: 35683994
DOI: 10.3390/nu14112196 -
International Journal of Molecular... Jun 2023Uric acid lithiasis accounts for about 10% of all types of renal lithiasis. The most common causes of uric acid lithiasis are low urinary pH, followed by high...
Uric acid lithiasis accounts for about 10% of all types of renal lithiasis. The most common causes of uric acid lithiasis are low urinary pH, followed by high concentration of urinary uric acid, and low diuresis. Treatment of patients consists of alkalinization of urine, reducing the consumption of purine-rich foods, and administration of xanthine oxidase inhibitors, because there are no established therapeutic inhibitors of uric acid crystallization. We recently found that theobromine inhibited uric acid crystallization in vitro, and that the increased urinary level of theobromine following its oral consumption was associated with the prevention of uric acid crystallization. In this study, we evaluated the inhibitory effects of theobromine metabolites and other methylxanthine-related compounds on uric acid crystallization. We also measured the urinary concentrations of theobromine and its metabolites in samples from healthy individuals and patients with uric acid stones and compared the extent of uric acid supersaturation and uric acid crystal formation in these different samples. Theobromine and other methylxanthines that lacked a substituent at position 1 inhibited uric acid crystallization, but other methylxanthines did not have this effect. Individuals with clinical parameters that favored uric acid crystallization did not develop uric acid crystals when theobromine and its metabolites were in the urine at high levels. Thus, theobromine and its metabolites reduced the risk of uric acid lithiasis.
Topics: Humans; Uric Acid; Theobromine; Lithiasis; Nephrolithiasis; Pharmaceutical Preparations
PubMed: 37446053
DOI: 10.3390/ijms241310879 -
PloS One 2022To evaluate the efficacy and safety of cilostazol, pentoxifylline, beraprost for intermittent claudication due to lower extremity arterial occlusive disease. (Meta-Analysis)
Meta-Analysis
OBJECTIVE
To evaluate the efficacy and safety of cilostazol, pentoxifylline, beraprost for intermittent claudication due to lower extremity arterial occlusive disease.
METHODS
Randomized controlled clinical trials were identified from PubMed, Scopus, EMbase, Cochrane Library, Web of Science, China National Knowledge Infrastructure, SinoMed, Wanfang and Chongqing VIP databases, from the database inception to 31/12/2021. The outcome measures were walking distance measured by treadmill (maximum and pain-free walking distance), ankle-brachial index and adverse events. The quality of included studies was assessed by the Cochrane bias risk assessment tool. A network meta-analysis was carried out with Stata 16.0 software.
RESULTS
There were 29 RCTs included in the study, covering total 5352 patients. Cilostazol was ranked first for both maximum and pain-free walking distance, followed by beraprost and pentoxifylline. For cilostazol, pentoxifylline and beraprost, maximum walking distance increased by 62.93 95%CI(44.06, 81.79), 32.72 95%CI(13.51, 55.79) and 43.90 95%CI(2.10, 85.71) meters, respectively relative to placebo, and pain-free walking distance increased by 23.92 95%CI(11.24, 36.61), 15.16 95%CI(2.33, 27.99) and 19.78 95%CI(-3.07, 42.62) meters. For cilostazol, pentoxifylline, beraprost and cilostazol combined with beraprost, ankle-brachial index increased by 0.06 95%CI(0.04, 0.07), -0.01 95%CI(-0.08, 0.05), 0.18 95%CI(0.12, 0.23) and 0.23 95%CI(0.18, 0.27), respectively relative to placebo. The pentoxifylline and cilostazol was associated with a lower ratio of adverse events than beraprost and cilostazol combined with beraprost.
CONCLUSION
Cilostazol, pentoxifylline and beraprost were all effective treatments for intermittent claudication; cilostazol with good tolerance was likely to be the most effective in walking distance, while beraprost and cilostazol combined with beraprost were more prominent in the ankle-brachial index.
Topics: Humans; Cilostazol; Intermittent Claudication; Network Meta-Analysis; Pentoxifylline; Vasodilator Agents; Randomized Controlled Trials as Topic
PubMed: 36318524
DOI: 10.1371/journal.pone.0275392 -
British Medical Journal (Clinical... Apr 1986
Topics: Aged; Aorta, Abdominal; Endarterectomy; Femoral Artery; Humans; Intermittent Claudication; Nafronyl; Pentoxifylline; Physical Exertion; Popliteal Artery; Smoking
PubMed: 3083974
DOI: 10.1136/bmj.292.6526.970