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Frontiers in Nutrition 2020Interactions are occurring in the course of liberation, absorption, distribution, metabolism, and excretion of active ingredients, or at the target receptors. They are...
Interactions are occurring in the course of liberation, absorption, distribution, metabolism, and excretion of active ingredients, or at the target receptors. They are causing therapy failures and undesirable events. Forty-seven of fifty-seven human hepatic isoenzymes are specific and relevant in hormone and vitamin metabolism and biosynthesis. Aromatase (syn. CYP19A1) is one of the specific CYP450 isoenzymes so far not elucidated in detail. As aromatase-inhibiting phytochemicals are currently recommended for breast cancer prevention and as add-on accompanying aromatase-inhibitor pharmacotherapy, it was the aim of this literature review to assess whether a common interpretation on genetic and -omics basis could be found. Articles retrieved showed that traditional antioxidation diet is one of the most approved explanations of inhibition of aromatase by phytonutrients of flavonoid derivatives. Flavonoids compete for the oxygen provided by the heme moiety of aromatase in the course of aromatase-catalyzed conversion of steroid precursors to estrogens. Flavonoids are therefore promoted for breast cancer prevention. A further explanation of flavonoids' mechanism of action proposed was related to enzymatic histone deacetylation. By keeping DNA-structure wide through a high acetylation degree, acetylated histones favor transcription and replication. This mechanism corresponds to a procedure of switching genes on. Inhibiting acetylation and therefore switching genes off might be an important regulation of repressing cancer genes. Aromatase expression depends on the genotype and phenotype of a person. Aromatase itself depends on the expression of the heme moiety encoded in the genotype. Biosynthesis of porphyrins in turn depends on the substrates succinate and glycine, as well as on a series of further enzymes, with ALA synthetase as the rate-limiting step. The effect of the heme moiety as prosthetic group of aromatase further depends on the absorption of iron as a function of pH and redox state. To assess the function of aromatase precisely, multiple underlying biochemical pathways need to be evaluated. As a conclusion, the genetic regulation of metabolism is a complex procedure affecting multiple pathways. To understand a metabolic step, multiple underlying individually performing reactions need to be considered if personalized (nutritional) medicine should bring an advantage for a patient. Nutrition sciences need to consider the genome of an individual to truly find answers to nutrition-derived non-communicable diseases. With current GWAS (genome-wide association study) approaches, inherited errors of metabolism are identified and ideally treated effectively. It is much more difficult to get a precise genetic profile for non-communicable diseases stemming from multifactorial causes. Polygenic risks evaluation is feasible but diagnostic tools are not yet available in a desired extent. Neither flavonoid researchers nor providers of genetic testing kits are going into the details needed for a truly personalized nutritional medicine. The next step with profiling the exome and then the whole genome is on the threshold of becoming routine diagnosis and of bringing the desired details.
PubMed: 32328497
DOI: 10.3389/fnut.2020.00037 -
Phytomedicine : International Journal... Jul 2019Photoactivity, though known for centuries, is only recently shifting back into focus as a treatment option against cancer and microbial infections. The external factor...
BACKGROUND
Photoactivity, though known for centuries, is only recently shifting back into focus as a treatment option against cancer and microbial infections. The external factor light is the ingenious key-component of this therapy: Since light activates the drug locally, a high level of selectivity is reached and side effects are avoided. The first reported photoactive medicines were plant extracts. Synthetic entities (so-called photosensitizers PSs), however, paved the route towards the clinical approval of the so-called photodynamic therapy (PDT), and thus natural PSs took a backseat in the past.
HYPOTHESIS
Many isolated bioactive phytochemicals hold a hidden photoactive potential, which is overlooked due to the reduced common awareness of photoactivity.
METHODS
A systematic review of reported natural PSs and their supposed medicinal application was conducted by employing PubMed, Scifinder, and Web of Science. The identified photoactive natural products were compiled including information about their natural sources, their photoyield, and their pharmacological application. Furthermore, the common chemical scaffolds of natural PS are shown to enable the reader to recognize potentially overlooked natural PSs.
RESULTS
The literature review revealed over 100 natural PS, excluding porphyrins. The PSs were classified according to their scaffold. Thereby it was shown that some PS-scaffolds were analyzed in a detailed way, while other classes were only scarcely investigated, which leaves space for future discoveries. In addition, the literature revealed that many PSs are phytoalexins, thus the selection of the starting material significantly matters in order to find new PSs.
CONCLUSION
Photoactive principles are ubiquitous and can be found in various plant extracts. With the increasing availability of light-irradiation setups for the identification of photoactive natural products, we anticipate the discovery of many new natural PSs in the near future. With the accumulation of chemically diverse PSs, PDT itself might finally reach its clinical breakthrough as a promising alternative treatment against multi-resistant microbes and cancer types.
Topics: Biological Products; Humans; Neoplasms; Photochemotherapy; Photosensitizing Agents; Phytochemicals; Sesquiterpenes; Phytoalexins
PubMed: 31257117
DOI: 10.1016/j.phymed.2019.152985 -
BMC Cancer Jun 2019Iron has been shown to promote breast carcinogenesis in animal models through generation of oxidative stress and interaction with estrogen. Heme iron, which is found... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Iron has been shown to promote breast carcinogenesis in animal models through generation of oxidative stress and interaction with estrogen. Heme iron, which is found exclusively in animal-sourced foods, is suggested to have a more detrimental effect. Epidemiological evidence of the association between iron and breast cancer risk remains inconclusive and has not been comprehensively summarized. This systematic review and meta-analysis evaluated associations between both iron intake and body iron status and breast cancer risk.
METHODS
Four electronic databases (MEDLINE, EMBASE, CINAHL, and Scopus) were searched up to December 2018 for studies assessing iron intake and/or biomarkers of iron status in relation to breast cancer risk. Using random-effects meta-analyses, pooled relative risks (RRs) and 95% confidence intervals (CIs) were calculated comparing the highest vs. lowest category of each iron measure. Dose-response meta-analyses were also performed to investigate linear and nonlinear associations.
RESULTS
A total of 27 studies were included in the review, of which 23 were eligible for meta-analysis of one or more iron intake/status measures. Comparing the highest vs. lowest category, heme iron intake was significantly associated with increased breast cancer risk, with a pooled RR of 1.12 (95% CI: 1.04-1.22), whereas no associations were found for dietary (1.01, 95% CI: 0.89-1.15), supplemental (1.02, 95% CI: 0.91-1.13), or total (0.97, 95% CI: 0.82-1.14) iron intake. Associations of iron status indicators with breast cancer risk were generally in the positive direction; however, a significant pooled RR was found only for serum/plasma levels (highest vs. lowest) of iron (1.22, 95% CI: 1.01-1.47), but not for ferritin (1.13, 95% CI: 0.78-1.62), transferrin saturation (1.16, 95% CI: 0.91-1.47), or total iron-binding capacity (1.10, 95% CI: 0.97-1.25). In addition, a nonlinear dose-response was observed for heme iron intake and serum iron (both P < 0.05).
CONCLUSIONS
Heme iron intake and serum iron levels may be positively associated with breast cancer risk. Although associations were modest, these findings may have public health implications given the widespread consumption of (heme) iron-rich foods. In light of methodological and research gaps identified, further research is warranted to better elucidate the relationship between iron and breast cancer risk.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Breast Neoplasms; Carcinogenesis; Female; Ferritins; Heme; Humans; Iron; Iron, Dietary; Meat; Middle Aged; Nutritional Status; Postmenopause; Risk; Transferrin; Young Adult
PubMed: 31170936
DOI: 10.1186/s12885-019-5642-0 -
BMC Women's Health Aug 2018Since the publication over 50 years ago of the alkaline hematin method for quantifying menstrual blood loss (MBL) many new approaches have been developed to assess MBL....
BACKGROUND
Since the publication over 50 years ago of the alkaline hematin method for quantifying menstrual blood loss (MBL) many new approaches have been developed to assess MBL. The aim of this systematic review is to determine for methods of measuring MBL: ability to distinguish between normal and heavy menstrual bleeding (HMB); practicalities and limitations in the research setting; and suitability for diagnosing HMB in routine clinical practice.
METHODS
Embase®™, MEDLINE®, and ClinicalTrials.gov were screened for studies on the development/validation of MBL assessment methods in women with self-perceived HMB, actual HMB or uterine fibroids, or patients undergoing treatment for HMB. Studies using simulated menstrual fluid and those that included women with normal MBL as controls were also eligible for inclusion. Extracted data included study population, results of validation, and advantages/disadvantages of the technique.
RESULTS
Seventy-one studies fulfilled the inclusion criteria. The sensitivity and/or specificity of diagnosing HMB were calculated in 16 studies of methods involving self-perception of MBL (11 pictorial), and in one analysis of the menstrual-fluid-loss (MFL) method; in 13 of these studies the comparator was the gold standard alkaline hematin technique. Sensitivity and specificity values by method were, respectively: MFL model, 89, 98%; pictorial blood loss assessment chart (PBAC), 58-99%, 7.5-89%; menstrual pictogram, 82-96%, 88-94%; models/questionnaires, 59-87%, 62-86%, and complaint of HMB, 74, 74%. The power of methods to identify HMB was also assessed using other analyses such as comparison of average measurements: statistical significance was reported for the PBAC, MFL, subjective complaint, and six questionnaires. In addition, PBAC scores, menstrual pictogram volumes, MFL, pad/tampon count, iron loss, and output from three questionnaires correlated significantly with values from a reference method in at least one study. In general, pictorial methods have been more comprehensively validated than questionnaires and models.
CONCLUSIONS
Every method to assess MBL has limitations. Pictorial methods strike a good balance between ease of use and validated accuracy of MBL determination, and could complement assessment of HMB using quality of life (QoL) in the clinical and research setting.
TRIAL REGISTRATION
PRISMA registration number: CRD42016032956 .
Topics: Adult; Diagnostic Techniques, Obstetrical and Gynecological; Female; Hemin; Humans; Menorrhagia; Middle Aged; Sensitivity and Specificity; Surveys and Questionnaires
PubMed: 30134884
DOI: 10.1186/s12905-018-0627-8 -
American Journal of Reproductive... Feb 2018Parturition at term is characterized by inflammatory overload in both feto-maternal tissues. Despite the large number of individual studies on changes in inflammatory... (Review)
Review
Parturition at term is characterized by inflammatory overload in both feto-maternal tissues. Despite the large number of individual studies on changes in inflammatory biomarkers linked to labor, a comprehensive profile of them in each of the uterine compartments is not available to better understand their mechanistic contributions to labor. This systematic review investigated the pro- and anti-inflammatory biomarkers reported in intra-uterine tissues (amnion, chorion, decidua, placenta, and myometrium) at term labor. We conducted a systematic review of studies on pro- and anti-inflammatory biomarkers (mRNA and/or protein) reported in feto-maternal tissues during normal human term labor, published in English (1980-2016), in 3 electronic data bases. From a total of 3712 citations, 172 were included for final review. Each tissue expresses a unique set of biomarkers at the time of term labor, but there is significant overlap between tissues. All tissues had IL-6, IL-8, IL-1β, COX-2, PGE-2, TNF-α, and hCAP18 in common at term labor. Common and unique inflammatory biomarkers are expressed in various feto-maternal compartments at term labor. Increase in pro-inflammatory markers in all gestational tissue signifies their harmonious functional role in promoting labor. Anti-inflammatory markers at term labor are hardly reported.
Topics: Animals; Antimicrobial Cationic Peptides; Biomarkers; Cathelicidins; Cyclooxygenase 2; Female; Humans; Inflammation; Inflammation Mediators; Metalloporphyrins; Parturition; Pregnancy; Uterus
PubMed: 29076197
DOI: 10.1111/aji.12776 -
Asia Pacific Journal of Clinical... 2017Some potential role of iron overload in the development of diabetes mellitus have been suggested. Our study aimed to systematically assess the association between the... (Meta-Analysis)
Meta-Analysis
BACKGROUND AND OBJECTIVES
Some potential role of iron overload in the development of diabetes mellitus have been suggested. Our study aimed to systematically assess the association between the risk of gestational diabetes mellitus (GDM) and iron intakes/body iron status.
METHODS AND STUDY DESIGN
PubMed and Web of Science were searched for relevant articles. Relative risks (RR) of GDM in relation to dietary iron intakes and body iron stores were pooled with the random-effects model. Weighted mean differences of iron blood markers between GDM and non-GDM individuals were also analyzed.
RESULTS
Twenty-five studies were included in the qualitative analysis, and 23 studies with 29,378 participants and 3,034 GDM patients were included in the quantitative analysis. Dietary intake of heme iron was significantly associated with GDM risk (RR=1.65, 95% CI: 1.28 to 2.12), and the pooled RR for each 1mg/day increment of heme iron intake was 1.38 (95% CI: 1.19 to 1.61). No association between GDM and the intakes of nonheme iron, total iron, or supplemental iron was detected. Body iron stores, as represented by serum ferritin level, were correlated with GDM risk (RR=1.64, 95% CI: 1.27 to 2.11). Moreover, the concentrations of both serum ferritin and serum iron were increased in GDM patients, compared with non-GDM individuals.
CONCLUSIONS
Increased dietary intake of heme iron and body iron status are positively associated with the risk of GDM development in pregnant women. Future studies are warranted to better understand the role of iron in GDM development.
Topics: Diabetes, Gestational; Female; Heme; Humans; Iron, Dietary; Nutritional Status; Pregnancy
PubMed: 28917236
DOI: 10.6133/apjcn.022017.09 -
Experimental Biology and Medicine... Apr 2017A role for red and processed meat in the development of colorectal cancer has been proposed based largely on evidence from observational studies in humans, especially in... (Review)
Review
A role for red and processed meat in the development of colorectal cancer has been proposed based largely on evidence from observational studies in humans, especially in those populations consuming a westernized diet. Determination of causation specifically by red or processed meat is contingent upon identification of plausible mechanisms that lead to colorectal cancer. We conducted a systematic review of the available evidence to determine the availability of plausible mechanistic data linking red and processed meat consumption to colorectal cancer risk. Forty studies using animal models or cell cultures met specified inclusion criteria, most of which were designed to examine the role of heme iron or heterocyclic amines in relation to colon carcinogenesis. Most studies used levels of meat or meat components well in excess of those found in human diets. Although many of the experiments used semi-purified diets designed to mimic the nutrient loads in current westernized diets, most did not include potential biologically active protective compounds present in whole foods. Because of these limitations in the existing literature, there is currently insufficient evidence to confirm a mechanistic link between the intake of red meat as part of a healthy dietary pattern and colorectal cancer risk. Impact statement Current recommendations to reduce colon cancer include the reduction or elimination of red or processed meats. These recommendations are based on data from epidemiological studies conducted among cultures where meat consumption is elevated and consumption of fruits, vegetables, and whole grains are reduced. This review evaluated experimental data exploring the putative mechanisms whereby red or processed meats may contribute to colon cancer. Most studies used levels of meat or meat-derived compounds that were in excess of those in human diets, even in cultures where meat intake is elevated. Experiments where protective dietary compounds were used to mitigate the extreme levels of meat and meat-derived compounds showed protection against colon cancer, with some essentially negating the impact of meat in the diet. It is essential that better-designed studies be conducted that use relevant concentrations of meat or meat-derived compounds in complex diets representative of the foods consumed by humans.
Topics: Animals; Colonic Neoplasms; Cooking; Diet, Western; Heme; Humans; Iron; Meat; Mutagens; Observational Studies as Topic
PubMed: 28205448
DOI: 10.1177/1535370217693117 -
The Cochrane Database of Systematic... Dec 2016Choroidal neovascularisation (CNV) is a common complication of pathological myopia. Once developed, most eyes with myopic CNV (mCNV) experience a progression to macular... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Choroidal neovascularisation (CNV) is a common complication of pathological myopia. Once developed, most eyes with myopic CNV (mCNV) experience a progression to macular atrophy, which leads to irreversible vision loss. Anti-vascular endothelial growth factor (anti-VEGF) therapy is used to treat diseases characterised by neovascularisation and is increasingly used to treat mCNV.
OBJECTIVES
To assess the effects of anti-vascular endothelial growth factor (anti-VEGF) therapy for choroidal neovascularisation (CNV), compared with other treatments, sham treatment or no treatment, in people with pathological myopia.
SEARCH METHODS
We searched a number of electronic databases including CENTRAL and Ovid MEDLINE, ClinicalTrials.gov and the World Health Organization (WHO) International Clinical Trials Registry Platform ICTRP). We did not use any date or language restrictions in the electronic searches for trials. Electronic databases were last searched on 16 June 2016.
SELECTION CRITERIA
We included randomised controlled trials (RCTs) and quasi-RCTs comparing anti-VEGF therapy with another treatment (e.g. photodynamic therapy (PDT) with verteporfin, laser photocoagulation, macular surgery, another anti-VEGF), sham treatment or no treatment in participants with mCNV.
DATA COLLECTION AND ANALYSIS
We used standard methodological procedures expected by Cochrane. Two authors independently screened records, extracted data, and assessed risk of bias. We contacted trial authors for additional data. We analysed outcomes as risk ratios (RRs) or mean differences (MDs). We graded the certainty of the evidence using GRADE.
MAIN RESULTS
The present review included six studies which provided data on the comparison between anti-VEGF with PDT, laser, sham treatment and another anti-VEGF treatment, with 594 participants with mCNV. Three trials compared bevacizumab or ranibizumab with PDT, one trial compared bevacizumab with laser, one trial compared aflibercept with sham treatment, and two trials compared bevacizumab with ranibizumab. Pharmaceutical companies conducted two trials. The trials were conducted at multiple clinical centres across three continents (Europe, Asia and North America). In all these six trials, one eye for each participant was included in the study.When compared with PDT, people treated with anti-VEGF agents (ranibizumab (one RCT), bevacizumab (two RCTs)), were more likely to regain vision. At one year of follow-up, the mean visual acuity (VA) in participants treated with anti-VEGFs was -0.14 logMAR better, equivalent of seven Early Treatment Diabetic Retinopathy Study (ETDRS) letters, compared with people treated with PDT (95% confidence interval (CI) -0.20 to -0.08, 3 RCTs, 263 people, low-certainty evidence). The RR for proportion of participants gaining 3+ lines of VA was 1.86 (95% CI 1.27 to 2.73, 2 RCTs, 226 people, moderate-certainty evidence). At two years, the mean VA in people treated with anti-VEGFs was -0.26 logMAR better, equivalent of 13 ETDRS letters, compared with people treated with PDT (95% CI -0.38 to -0.14, 2 RCTs, 92 people, low-certainty evidence). The RR for proportion of people gaining 3+ lines of VA at two years was 3.43 (95% CI 1.37 to 8.56, 2 RCTs, 92 people, low-certainty evidence). People treated with anti-VEGFs showed no obvious reduction (improvement) in central retinal thickness at one year compared with people treated with PDT (MD -17.84 μm, 95% CI -41.98 to 6.30, 2 RCTs, 226 people, moderate-certainty evidence). There was low-certainty evidence that people treated with anti-VEGF were more likely to have CNV angiographic closure at 1 year (RR 1.24, 95% CI 0.99 to 1.54, 2 RCTs, 208 people). One study allowed ranibizumab treatment as of month 3 in participants randomised to PDT, which may have led to an underestimate of the benefits of anti-VEGF treatment.When compared with laser photocoagulation, there was more improvement in VA among bevacizumab-treated people than among laser-treated people after one year (MD -0.22 logMAR, equivalent of 11 ETDRS letters, 95% CI -0.43 to -0.01, 1 RCT, 36 people, low-certainty evidence) and after two years (MD -0.29 logMAR, equivalent of 14 ETDRS letters, 95% CI -0.50 to -0.08, 1 RCT, 36 people, low-certainty evidence).When compared with sham treatment, people treated with aflibercept had better vision at one year (MD -0.19 logMAR, equivalent of 9 ETDRS letters, 95% CI -0.27 to -0.12, 1 RCT, 121 people, moderate-certainty evidence). The fact that this study allowed for aflibercept treatment at 6 months in the control group might cause an underestimation of the benefit with anti-VEGF.People treated with ranibizumab had similar improvement in VA recovery compared with people treated with bevacizumab after one year (MD -0.02 logMAR, equivalent of 1 ETDRS letter, 95% CI -0.11 to 0.06, 2 RCTs, 80 people, moderate-certainty evidence).Of the included six studies, two studies reported no adverse events in either group and two industry-sponsored studies reported both systemic and ocular adverse events. In the control group, there were no systemic or ocular adverse events reported in 149 participants. Fifteen people reported systemic serious adverse events among 359 people treated with anti-VEGF agents (15/359, 4.2%). Five people reported ocular adverse events among 359 people treated with anti-VEGF agents (5/359, 1.4%). The number of adverse events was low, and the estimate of RR was uncertain regarding systemic serious adverse events (4 RCTs, 15 events in 508 people, RR 4.50, 95% CI 0.60 to 33.99, very low-certainty evidence) and serious ocular adverse events (4 RCTs, 5 events in 508 people, RR 1.82, 95% CI 0.23 to 14.71, very low-certainty evidence). There were no reports of mortality or cases of endophthalmitis or retinal detachment.There was sparse reporting of data for vision-related quality of life (in favour of anti-VEGF) in only one trial at one year of follow-up. The studies did not report data for other outcomes, such as percentage of participants with newly developed chorioretinal atrophy.
AUTHORS' CONCLUSIONS
There is low to moderate-certainty evidence from RCTs for the efficacy of anti-VEGF agents to treat mCNV at one year and two years. Moderate-certainty evidence suggests ranibizumab and bevacizumab are equivalent in terms of efficacy. Adverse effects occurred rarely and the trials included here were underpowered to assess these. Future research should be focused on the efficacy and safety of different drugs and treatment regimens, the efficacy on different location of mCNV, as well as the effects on practice in the real world.
Topics: Angiogenesis Inhibitors; Bevacizumab; Choroidal Neovascularization; Humans; Laser Coagulation; Macula Lutea; Myopia, Degenerative; Photochemotherapy; Photosensitizing Agents; Porphyrins; Randomized Controlled Trials as Topic; Ranibizumab; Receptors, Vascular Endothelial Growth Factor; Recombinant Fusion Proteins; Vascular Endothelial Growth Factor A; Verteporfin
PubMed: 27977064
DOI: 10.1002/14651858.CD011160.pub2 -
The Cochrane Database of Systematic... Aug 2014Age-related macular degeneration (AMD) is the most common cause of uncorrectable severe vision loss in people aged 55 years and older in the developed world. Choroidal... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Age-related macular degeneration (AMD) is the most common cause of uncorrectable severe vision loss in people aged 55 years and older in the developed world. Choroidal neovascularization (CNV) secondary to neovascular AMD accounts for most AMD-related severe vision loss. Anti-vascular endothelial growth factor (anti-VEGF) agents, injected intravitreally, aim to block the growth of abnormal blood vessels in the eye to prevent vision loss and, in some instances, improve vision.
OBJECTIVES
To investigate: (1) the ocular and systemic effects of, and quality of life associated with, intravitreally injected anti-VEGF agents (pegaptanib, ranibizumab, and bevacizumab) for the treatment of neovascular AMD compared with no anti-VEGF treatment; and (2) the relative effects of one anti-VEGF agent compared with another when administered in comparable dosages and regimens.
SEARCH METHODS
We searched Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Group Trials Register) (2014, Issue 3), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to March 2014), EMBASE (January 1980 to March 2014), Latin American and Caribbean Health Sciences Literature Database (LILACS) (January 1982 to March 2014), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com), ClinicalTrials.gov (www.clinicaltrials.gov) and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We used no date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 27 March 2014.
SELECTION CRITERIA
We included randomized controlled trials (RCTs) that evaluated pegaptanib, ranibizumab, or bevacizumab versus each other or a control treatment (e.g., sham treatment or photodynamic therapy). All trials followed participants for at least one year.
DATA COLLECTION AND ANALYSIS
Two review authors independently screened records, extracted data, and assessed risks of bias. We contacted trial authors for additional data. We analyzed outcomes as risk ratios (RRs) or mean differences (MDs). We used the standard methodological procedures expected by The Cochrane Collaboration.
MAIN RESULTS
We included 12 RCTs including a total of 5496 participants with neovascular AMD (the number of participants per trial ranged from 28 to 1208). One trial compared pegaptanib, three trials ranibizumab, and two trials bevacizumab versus controls; six trials compared bevacizumab with ranibizumab. Four trials were conducted by pharmaceutical companies; none of the eight studies which evaluated bevacizumab were funded by pharmaceutical companies. The trials were conducted at various centers across five continents (North and South America, Europe, Asia and Australia). The overall quality of the evidence was very good, with most trials having an overall low risk of bias.When compared with control treatments, participants who received any of the three anti-VEGF agents were more likely to have gained 15 letters or more of visual acuity, lost fewer than 15 letters of visual acuity, and had vision 20/200 or better after one year of follow up. Visual acuity outcomes after bevacizumab and ranibizumab were similar when the same regimens were compared in the same RCTs, despite the substantially lower cost for bevacizumab compared with ranibizumab. No trial directly compared pegaptanib with other anti-VEGF agents; however, when compared with controls, ranibizumab or bevacizumab yielded larger improvements in visual acuity outcomes than pegaptanib.Participants treated with anti-VEGFs showed improvements in morphologic outcomes (e.g., size of CNV or central retinal thickness) compared with participants not treated with anti-VEGF agents. There was less reduction in central retinal thickness among bevacizumab-treated participants than among ranibizumab-treated participants after one year (MD -13.97 μm; 95% confidence interval (CI) -26.52 to -1.41); however, this difference is within the range of measurement error and we did not interpret it as being clinically meaningful.Ocular inflammation and increased intraocular pressure after intravitreal injection were the most frequently reported serious ocular adverse events. Endophthalmitis was reported in fewer than 1% of anti-VEGF treated participants; no cases were reported in control groups. The occurrence of serious systemic adverse events was comparable across anti-VEGF-treated groups and control groups; however, the numbers of events and trial participants may have been insufficient to detect a meaningful difference between groups. Data for visual function, quality of life, and economic outcomes were sparsely measured and reported.
AUTHORS' CONCLUSIONS
The results of this review indicate the effectiveness of anti-VEGF agents (pegaptanib, ranibizumab, and bevacizumab) in terms of maintaining visual acuity; ranibizumab and bevacizumab were also shown to improve visual acuity. The information available on the adverse effects of each medication do not suggest a higher incidence of potentially vision-threatening complications with intravitreal injection compared with control interventions; however, clinical trial sample sizes may not have been sufficient to detect rare safety outcomes. Research evaluating variable dosing regimens with anti-VEGF agents, effects of long-term use, combination therapies (e.g., anti-VEGF treatment plus photodynamic therapy), and other methods of delivering the agents should be incorporated into future Cochrane reviews.
Topics: Aged; Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Aptamers, Nucleotide; Choroidal Neovascularization; Humans; Intravitreal Injections; Macular Degeneration; Middle Aged; Porphyrins; Randomized Controlled Trials as Topic; Ranibizumab; Vascular Endothelial Growth Factor A; Verteporfin; Visual Acuity
PubMed: 25170575
DOI: 10.1002/14651858.CD005139.pub3