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Brain Communications 2024New treatments are needed to improve the prognosis of pneumococcal meningitis. We performed a systematic review on adjunctive treatments in animal models of pneumococcal... (Review)
Review
New treatments are needed to improve the prognosis of pneumococcal meningitis. We performed a systematic review on adjunctive treatments in animal models of pneumococcal meningitis in order to identify treatments with the most potential to progress to clinical trials. Studies testing therapy adjunctive to antibiotics in animal models of pneumococcal meningitis were included. A literature search was performed using Medline, Embase and Scopus for studies published from 1990 up to 17 February 2023. Two investigators screened studies for inclusion and independently extracted data. Treatment effect was assessed on the clinical parameters disease severity, hearing loss and cognitive impairment and the biological parameters inflammation, brain injury and bacterial load. Adjunctive treatments were evaluated by their effect on these outcomes and the quality, number and size of studies that investigated the treatments. Risk of bias was assessed with the SYRCLE risk of bias tool. A total of 58 of 2462 identified studies were included, which used 2703 experimental animals. Disease modelling was performed in rats (29 studies), rabbits (13 studies), mice (12 studies), gerbils (3 studies) or both rats and mice (1 study). Meningitis was induced by injection of into the subarachnoid space. Randomization of experimental groups was performed in 37 of 58 studies (64%) and 12 studies (12%) were investigator-blinded. Overall, 54 treatment regimens using 46 adjunctive drugs were evaluated: most commonly dexamethasone (16 studies), daptomycin (5 studies), complement component 5 (C5; 3 studies) antibody and Mn(III)tetrakis(4-benzoicacid)porphyrin chloride (MnTBAP; 3 studies). The most frequently evaluated outcome parameters were inflammation [32 studies (55%)] and brain injury [32 studies (55%)], followed by disease severity [30 studies (52%)], hearing loss [24 studies (41%)], bacterial load [18 studies (31%)] and cognitive impairment [9 studies (16%)]. Adjunctive therapy that improved clinical outcomes in multiple studies was dexamethasone (6 studies), C5 antibodies (3 studies) and daptomycin (3 studies). HMGB1 inhibitors, matrix metalloproteinase inhibitors, neurotrophins, antioxidants and paquinimod also improved clinical parameters but only in single or small studies. Evaluating the treatment effect of adjunctive therapy was complicated by study heterogeneity regarding the animal models used and outcomes reported. In conclusion, 24 of 54 treatment regimens (44%) tested improved clinically relevant outcomes in experimental pneumococcal meningitis but few were tested in multiple well-designed studies. The most promising new adjunctive treatments are with C5 antibodies or daptomycin, suggesting that these drugs could be tested in clinical trials.
PubMed: 38707710
DOI: 10.1093/braincomms/fcae131 -
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 -
PloS One 2022Actovegin is a hemodialysate of calf's blood and has been used for several decades in the countries of Central Asia, East Asia, Russia and some European countries. It...
BACKGROUND
Actovegin is a hemodialysate of calf's blood and has been used for several decades in the countries of Central Asia, East Asia, Russia and some European countries. It has been used to treat patients with various neurological conditions, vascular disorders, and ischemic stroke.
OBJECTIVES
To perform a systematic review to evaluate the effect of Actovegin in patients who have suffered an ischemic stroke.
METHODS
A search of MEDLINE, PubMed, Cochrane and Embase was carried out from inception to October 10, 2021 for clinical trials and observational studies with a control group, published in English or Russian.
RESULTS
Of 220 identified unique records, 84 full-text articles were screened, and 5 studies were selected that met the inclusion criteria. This included 4 observational studies with control groups and one randomized, placebo-controlled clinical trial. These studies enrolled a total of 3879 patients of which 720 patients received Actovegin administered intravenously and/or orally for a duration ranging from 10 to 180 days. Because of study heterogeneity, meta-analysis was not performed. No consistent evidence on improved survival, quality of life, neurologic symptoms, activities of daily living or disability was identified. One study showed statistically significant improvements in the Alzheimer's Disease Assessment Scale, cognitive subscale, extended version (ADAS-cog+) for Actovegin compared with placebo at 6 months but the clinical relevance of this change is uncertain. One study reported a higher incidence of recurrent ischemic stroke, transient ischemic attack or intracerebral hemorrhage in patients taking Actovegin compared to placebo.
CONCLUSIONS
The benefits of Actovegin are uncertain and that there is potential risk of harm in patients with stroke. More evidence is needed from rigorously designed clinical trials to justify the role of Actovegin in patients with ischemic stroke.
Topics: Activities of Daily Living; Heme; Humans; Ischemic Attack, Transient; Ischemic Stroke; Observational Studies as Topic; Quality of Life; Randomized Controlled Trials as Topic; Stroke
PubMed: 35771887
DOI: 10.1371/journal.pone.0270497 -
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 -
Biomedicine & Pharmacotherapy =... Feb 2023Erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP) are characterized by skin photosensitivity caused by accumulation of protoporphyrin IX. We aimed to... (Review)
Review
Erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP) are characterized by skin photosensitivity caused by accumulation of protoporphyrin IX. We aimed to review the clinical evidence of efficacy and safety of skin photosensitivity treatments in individuals with EPP or XLP. We systematically searched MEDLINE, Embase, the Cochrane Library, and ClinicalTrials.gov. A total of 40 studies with data on 18 treatment modalities were included. Comprehensive treatment safety data were obtained from the European Medicines Agency and the United States Food and Drug Administration. The studies used different outcome measures to evaluate the sensitivity without a generally accepted method to assess treatment effect on skin photosensitivity. Of the included studies, 13 were controlled trials. Gathered, the trials showed moderate positive effect of inorganic sunscreen application and subcutaneous implant of afamelanotide and no effect of organic sunscreen application, or oral treatment with beta-carotene, cysteine, N-acetylcysteine, vitamin C, or warfarin. Studies without control groups suggested treatment effect of foundation cream, dihydroxyacetone/lawsone cream, narrow-band ultraviolet B phototherapy, erythrocyte transfusion, extracorporeal erythrocyte photodynamic therapy, or oral treatment with zinc sulphate, terfenadine, cimetidine, or canthaxanthin, but the real effect is uncertain. Assessment of treatment effect on photosensitivity in patients with EPP or XLP carries a high risk of bias since experienced photosensitivity varies with both weather conditions, exposure pattern, and pigmentation. Controlled trials of promising treatment options are important although challenging in this small patient population.
Topics: United States; Humans; Protoporphyria, Erythropoietic; Sunscreening Agents; Photosensitivity Disorders; Genetic Diseases, X-Linked; Protoporphyrins
PubMed: 36525819
DOI: 10.1016/j.biopha.2022.114132 -
International Journal of Molecular... Apr 2020Stroke is one of the largest problems and clinical-social challenges within neurology and, in general, pathology. Here, we briefly reviewed the main pathophysiological...
BACKGROUND
Stroke is one of the largest problems and clinical-social challenges within neurology and, in general, pathology. Here, we briefly reviewed the main pathophysiological mechanisms of ischemic stroke, which represent targets for medical interventions, including for a calf blood deproteinized hemodialysate/ultrafiltrate.
METHODS
We conducted a systematic review of current related literature concerning the effects of Actovegin, of mainly the pleiotropic type, applied to the injury pathways of ischemic stroke.
RESULTS
The bibliographic resources regarding the use of Actovegin in ischemic stroke are scarce. The main Actovegin actions refer to the ischemic stroke lesion items' ensemble, targeting tissue oxidation, energy metabolism, and glucose availability through their augmentation, combating ischemic processes and oxidative stress, and decreasing inflammation (including with modulatory connotations, by the nuclear factor-κB pathway) and apoptosis-like processes, counteracting them by mitigating the caspase-3 activation induced by amyloid β-peptides.
CONCLUSION
Since no available therapeutic agents are capable of curing the central nervous system's lesions, any contribution, such as that of Actovegin (with consideration of a positive balance between benefits and risks), is worthy of further study and periodic reappraisal, including investigation into further connected aspects.
Topics: Amyloid beta-Peptides; Animals; Antioxidants; Brain Ischemia; Heme; Humans; Stroke
PubMed: 32365943
DOI: 10.3390/ijms21093181 -
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 -
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