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Drugs Nov 2009Fabry disease is a progressive and life-threatening glycolipid storage disorder affecting both males and females. The primary driver of the disease is the accumulation... (Review)
Review
Fabry disease is a progressive and life-threatening glycolipid storage disorder affecting both males and females. The primary driver of the disease is the accumulation of glycolipids (globotriaosylceramide [GL-3]) in a variety of cell types, including vascular endothelial cells, a range of renal cell types, cardiomyocytes and neurons, which is caused by deficient activity of the lysosomal enzyme, alpha-galactosidase. The disease typically presents during childhood or adolescence. First manifestations reflect involvement of small nerve fibres of the peripheral and autonomic nervous systems. With age, severe complications involving the kidneys, heart and brain cause considerable morbidity and premature death. Outside the US, enzyme replacement therapy (ERT) with agalsidase alfa 0.2 mg/kg every other week (EOW) and agalsidase beta 1.0 mg/kg EOW is available for the treatment of patients with Fabry disease, while agalsidase beta 1.0 mg/kg EOW is the only approved drug in the US. To analyse the evidence for ERT, a systematic review of the literature was performed to identify prospectively designed randomized, controlled trials (RCTs) and open-label studies on the efficacy of agalsidase alfa and agalsidase beta. MEDLINE and EMBASE databases were searched; inclusion criteria for the systematic review were prospectively designed clinical studies evaluating ERT with quantifiable endpoints: double-blind and open-label studies were eligible. Exclusion criteria were review articles, case reports, case studies, letters to the editor and articles based on registry data (Fabry Outcome Survey or Fabry Registry). In addition, any studies with a retrospective design or data based on post hoc analyses were excluded. The evidence was reviewed with respect to the clinical benefits of ERT at the level of the end organ. A total of 9 RCTs and 23 open-label studies were identified for inclusion. The efficacy of ERT in Fabry disease has been measured against a variety of endpoints, the majority of which were subclinical parameters rather than clinical outcomes. Plasma levels of GL-3 together with accumulation in the kidney, heart and skin were the most commonly studied endpoints, followed by renal endpoints of proteinuria and glomerular filtration rate, whereas cardiac and neurological endpoints were not commonly studied. To date, only one RCT with ERT defined hard clinical outcomes in the form of cardiac, renal or cerebrovascular events, or death as its primary endpoint. The currently available data from prospective RCTs and open-label studies in patients with Fabry disease are more robust for ERT at a dose of 1 mg/kg EOW than a dose of 0.2 mg/kg EOW, although the beneficial effects of ERT with either dose or preparation are variable.
Topics: Child; Clinical Trials as Topic; Enzyme Replacement Therapy; Fabry Disease; Female; Humans; Isoenzymes; Male; Recombinant Proteins; Trihexosylceramides; alpha-Galactosidase
PubMed: 19852524
DOI: 10.2165/11318300-000000000-00000 -
Annals of Emergency Medicine May 2001We sought to evaluate quantitatively the evidence on the diagnostic performance of presentation and serial biochemical markers for emergency department diagnosis of... (Meta-Analysis)
Meta-Analysis Review
STUDY OBJECTIVE
We sought to evaluate quantitatively the evidence on the diagnostic performance of presentation and serial biochemical markers for emergency department diagnosis of acute cardiac ischemia (ACI), including acute myocardial infarction (AMI) and unstable angina.
METHODS
We conducted a systematic review and meta-analysis of the English-language literature published between 1966 and December 1998. We examined the diagnostic performance of creatine kinase, creatine kinase-MB, myoglobin, and troponin I and T testing. Diagnostic performance was assessed by using estimates of test sensitivity and specificity and was summarized by summary receiver-operating characteristic curves.
RESULTS
Only 4 studies were found that evaluated all patients with ACI; 73 were found that focused only on a diagnosis of AMI. To diagnose ACI, presentation biomarker tests had sensitivities of 16% to 19% and specificities of 96% to 100%; serial biomarker tests had sensitivities of 31% to 45% and specificities of 95% to 98%. Considering only the diagnosis of AMI, presentation biomarker tests had summary sensitivities of 37% to 49% and summary specificities of 87% to 97%; serial biomarker tests had summary sensitivities of 79% to 93% and summary specificities of 85% to 96%. Variation of test sensitivity was best explained by test timing. Longer symptom duration or time between serial tests yielded higher sensitivity.
CONCLUSION
The limited evidence available to evaluate the diagnostic accuracy of biomarkers for ACI suggests that biomarkers have very low sensitivity to diagnose ACI. Thus, biomarkers alone will greatly underdiagnose ACI and will be inadequate to make triage decisions. For AMI diagnosis alone, multiple testing of individual biomarkers over time substantially improves sensitivity, while retaining high specificity, at the expense of additional time. Further high-quality studies are needed on the clinical effect of using biomarkers for patients with ACI in the ED and on optimal timing of serial testing and in combination with other tests.
Topics: Acute Disease; Angina, Unstable; Bias; Biomarkers; Creatine Kinase; Creatine Kinase, MB Form; Emergency Treatment; Evidence-Based Medicine; Humans; Isoenzymes; Myocardial Infarction; Myocardial Ischemia; Myoglobin; Reproducibility of Results; Research Design; Sensitivity and Specificity; Time Factors; Triage; Troponin I; Troponin T
PubMed: 11326184
DOI: 10.1067/mem.2001.114905 -
Journal of Clinical Medicine Oct 2020Cardiovascular diseases (CVD) remain a global pandemic and leading cause of deaths worldwide. While several guidelines have been developed to control the development of... (Review)
Review
Cardiovascular diseases (CVD) remain a global pandemic and leading cause of deaths worldwide. While several guidelines have been developed to control the development of CVDs, its prevalence keeps on increasing until this day. Cardiovascular risk factors, such as reduced exercises and high fat or glucose diets, culminate in the development of the metabolic syndrome and eventually atherosclerosis, which is driven by high blood lipid and cholesterol levels, and by endothelial dysfunction. Late complications of atherosclerosis give rise to serious clinical cardiovascular manifestations such as myocardial infarction and hypertension. Therefore, endothelial functions and the lipid metabolism play critical roles in the pathogenesis of CVDs. Fatty acid-binding proteins are a family of intracellular proteins expressed in many cell types known mainly for their interaction with and trafficking of cellular lipids. The roles of a number of isoforms in this family have been implicated in lipid metabolic homeostasis, but their influence on endothelial function and vascular homeostasis remain largely unknown. This review's purpose is to update fundamentals about the connection between cardiovascular disease, metabolism, endothelial function, and mainly the roles of fatty acid-binding proteins.
PubMed: 33105856
DOI: 10.3390/jcm9113390 -
Glia Aug 2019Gliomas are a heterogenous group of malignant primary brain tumors that arise from glia cells or their progenitors and rely on accurate diagnosis for prognosis and...
Gliomas are a heterogenous group of malignant primary brain tumors that arise from glia cells or their progenitors and rely on accurate diagnosis for prognosis and treatment strategies. Although recent developments in the molecular biology of glioma have improved diagnosis, classical histological methods and biomarkers are still being used. The glial fibrillary acidic protein (GFAP) is a classical marker of astrocytoma, both in clinical and experimental settings. GFAP is used to determine glial differentiation, which is associated with a less malignant tumor. However, since GFAP is not only expressed by mature astrocytes but also by radial glia during development and neural stem cells in the adult brain, we hypothesized that GFAP expression in astrocytoma might not be a direct indication of glial differentiation and a less malignant phenotype. Therefore, we here review all existing literature from 1972 up to 2018 on GFAP expression in astrocytoma patient material to revisit GFAP as a marker of lower grade, more differentiated astrocytoma. We conclude that GFAP is heterogeneously expressed in astrocytoma, which most likely masks a consistent correlation of GFAP expression to astrocytoma malignancy grade. The GFAP positive cell population contains cells with differences in morphology, function, and differentiation state showing that GFAP is not merely a marker of less malignant and more differentiated astrocytoma. We suggest that discriminating between the GFAP isoforms GFAPδ and GFAPα will improve the accuracy of assessing the differentiation state of astrocytoma in clinical and experimental settings and will benefit glioma classification.
Topics: Animals; Astrocytoma; Biomarkers, Tumor; Central Nervous System Neoplasms; Glial Fibrillary Acidic Protein; Humans; Protein Isoforms
PubMed: 30667110
DOI: 10.1002/glia.23594 -
Journal of Cancer Research and Clinical... May 2012Osteosarcoma is a primary malignancy of bone. Although new therapies continue to emerge, osteosarcoma-related morbidity and mortality remain high. Various studies have... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Osteosarcoma is a primary malignancy of bone. Although new therapies continue to emerge, osteosarcoma-related morbidity and mortality remain high. Various studies have evaluated the prognostic value of VEGF levels in osteosarcoma patients, but they have yielded conflicting results.
METHODS
The 5-year survival of each study was aggregated following a methodological assessment, and a systematic review of eligible studies with meta-analysis and univariate analysis was performed to quantitatively review the correlation of VEGF overexpression with 5-year survival in patients with osteosarcoma.
RESULTS
A total of 387 patients in eleven papers were finally considered to be eligible for inclusion in our analysis. Aggregation of the 6 positive results in Kaplan-Meier curve showed a risk ratio of 2.84 (95% CI: 1.39-5.83, P = 0.004) associated with VEGF-positive conditions in comparison with VEGF-negative conditions, suggesting that there was significant association between VEGF positive and the 5-year mortality. But univariate analysis of eleven studies showed that there was a small inverse but not significant relationship between VEGF expression level and the 5-year survival of osteosarcoma patients, but stage III, neo-chemotherapy, the primary tumor location, osteoblastic histological subtype and the source of patients showed a significant impact on the 5-year survival of patients.
CONCLUSIONS
The prognostic significance of VEGF expression in all its isoforms is still unknown based on the limited data available, but we find VEGF165 may play an important role. Future studies should examine the relationship between VEGF isoform expression and patients' survival and the relationship between VEGF isoform expression and EMMPRIN expression, which could be helpful for predicting the prognosis of patients with osteosarcoma. Once the conclusion of whether the VEGF and its isoforms playing a role in osteosarcoma were reached, it would help guide clinical decision-making regarding therapy and outcomes. In addition, we recommend a >25% positive staining of the cells as a VEGF-positive cut-off value in immunohistochemistry, since we find a relatively strict detecting method is likely to yield significant result in the 5-year survival of patients.
Topics: Algorithms; Biomarkers, Tumor; Bone Neoplasms; Gene Expression Regulation, Neoplastic; Humans; Osteosarcoma; Predictive Value of Tests; Prognosis; Protein Isoforms; Survival Analysis; Up-Regulation; Vascular Endothelial Growth Factor A
PubMed: 22274866
DOI: 10.1007/s00432-012-1149-7 -
Pharmacological Research Jul 2017UDP-glucuronosyltransferases (UGTs) are the primary phase II enzymes catalyzing the conjugation of glucuronic acid to the xenobiotics with polar groups for facilitating... (Review)
Review
UDP-glucuronosyltransferases (UGTs) are the primary phase II enzymes catalyzing the conjugation of glucuronic acid to the xenobiotics with polar groups for facilitating their clearance. The UGTs belong to a superfamily that consists of diverse isoforms possessing distinct but overlapping metabolic activity. The abnormality or deficiency of UGTs in vivo is highly associated with some diseases, efficacy and toxicity of drugs, and precisely therapeutic personality. Despite the great effects and fruitful results achieved, to date, the expression and functions of individual UGTs have not been well clarified, the inconsistency of UGTs is often observed in human and experimental animals, and the complex regulation factors affecting UGTs have not been systematically summarized. This article gives an overview of updated reports on UGTs involving the various regulatory factors in terms of the genetic, environmental, pathological, and physiological effects on the functioning of individual UGTs, in turn, the dysfunction of UGTs induced disease risk and endo- or xenobiotic metabolism-related toxicity. The complex cross-talk effect of UGTs with internal homeostasis is systematically summarized and discussed in detail, which would be of great importance for personalized precision medicine.
Topics: Animals; Gene Expression Regulation; Glucuronosyltransferase; Homeostasis; Humans; Metabolic Diseases; Neoplasms; Polymorphism, Genetic; Precision Medicine; Protein Isoforms
PubMed: 28479371
DOI: 10.1016/j.phrs.2017.05.001 -
Annals of Internal Medicine May 2003Rofecoxib and celecoxib (coxibs) effectively treat chronic arthritis pain and reduce ulcer complications by 50% compared with nonselective nonsteroidal anti-inflammatory... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Rofecoxib and celecoxib (coxibs) effectively treat chronic arthritis pain and reduce ulcer complications by 50% compared with nonselective nonsteroidal anti-inflammatory drugs (NSAIDs). However, their absolute risk reduction is small and the cost-effectiveness of treatment is uncertain.
OBJECTIVE
To determine whether the degree of risk reduction in gastrointestinal complications by coxibs offsets their increased cost compared with a generic nonselective NSAID.
DESIGN
Cost-utility analysis.
DATA SOURCES
Systematic review of MEDLINE and published abstracts.
TARGET POPULATION
Patients with osteoarthritis or rheumatoid arthritis who are not taking aspirin and who require long-term NSAID therapy for moderate to severe arthritis pain.
PERSPECTIVE
Third-party payer.
INTERVENTIONS
Naproxen, 500 mg twice daily, and coxib, once daily. Patients intolerant of naproxen were switched to a coxib.
TIME HORIZON
Lifetime.
OUTCOME MEASURES
Incremental cost per quality-adjusted life-year (QALY) gained.
RESULTS OF BASE-CASE ANALYSIS
Using a coxib instead of a nonselective NSAID in average-risk patients cost an incremental 275 809 dollars per year to gain 1 additional QALY.
RESULTS OF SENSITIVITY ANALYSIS
The incremental cost per QALY gained decreased to 55 803 dollars when the analysis was limited to the subset of patients with a history of bleeding ulcers. The coxib strategy became dominant when the cost of coxibs was reduced by 90% of the current average wholesale price. In probabilistic sensitivity analysis, if a third-party payer was willing to pay 150 000 dollars per QALY gained, then 4.3% of average-risk patients would fall within the budget.
CONCLUSIONS
The risk reduction seen with coxibs does not offset their increased costs compared with nonselective NSAIDs in the management of average-risk patients with chronic arthritis. However, coxibs may provide an acceptable incremental cost-effectiveness ratio in the subgroup of patients with a history of bleeding ulcers.
Topics: Anti-Inflammatory Agents, Non-Steroidal; Arthritis, Rheumatoid; Cardiovascular Diseases; Celecoxib; Chronic Disease; Cost-Benefit Analysis; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Decision Support Techniques; Humans; Isoenzymes; Lactones; Membrane Proteins; Osteoarthritis; Peptic Ulcer; Prostaglandin-Endoperoxide Synthases; Pyrazoles; Quality-Adjusted Life Years; Recurrence; Risk Factors; Sensitivity and Specificity; Sulfonamides; Sulfones
PubMed: 12755551
DOI: 10.7326/0003-4819-138-10-200305200-00007 -
Diabetes, Obesity & Metabolism Feb 2012Insulin secretagogues promote insulin release by binding to sulfonylurea receptors on pancreatic β-cells (SUR1). However, these drugs also bind to receptor isoforms on... (Review)
Review
AIM
Insulin secretagogues promote insulin release by binding to sulfonylurea receptors on pancreatic β-cells (SUR1). However, these drugs also bind to receptor isoforms on cardiac myocytes (SUR2A) and vascular smooth muscle (SUR2B). Binding to SUR2A/SUR2B may inhibit ischaemic preconditioning, an endogenous protective mechanism enabling cardiac tissue to survive periods of ischaemia. This study was designed to identify insulin secretagogues that selectively bind to SUR1 when given at therapeutic doses.
METHODS
Using accepted systematic review methods, three electronic databases were searched from inception to 13 June 2011. Original studies measuring the half-maximal inhibitory concentration (IC(50)) for an insulin secretagogue on K(ATP) channels using standard electrophysiological techniques were included. Steady-state concentrations (C(SS)) were estimated from the usual oral dose and clearance values for each drug.
RESULTS
Data were extracted from 27 studies meeting all inclusion criteria. IC(50) values for SUR1 were below those for SUR2A/SUR2B for all insulin secretagogues and addition of C(SS) values identified three distinct patterns. The C(SS) for gliclazide, glipizide, mitiglinide and nateglinide lie between IC(50) values for SUR1 and SUR2A/SUR2B, suggesting that these drugs bind selectively to pancreatic receptors. The C(SS) for glimepiride and glyburide (glibenclamide) was above IC(50) values for all three isoforms, suggesting these drugs are non-selective. Tolbutamide and repaglinide may have partial pancreatic receptor selectivity because IC(50) values for SUR1 and SUR2A/SUR2B overlapped somewhat, with the C(SS) in the midst of these values.
CONCLUSIONS
Insulin secretagogues display different tissue selectivity characteristics at therapeutic doses. This may translate into different levels of cardiovascular risk.
Topics: ATP-Binding Cassette Transporters; Animals; Carbamates; Cardiovascular Diseases; Cricetinae; Cyclohexanes; Diabetes Mellitus, Type 2; Gliclazide; Glipizide; Glyburide; Humans; Hypoglycemic Agents; Ischemic Preconditioning, Myocardial; Isoindoles; Mice; Muscle, Smooth, Vascular; Myocytes, Cardiac; Nateglinide; Phenylalanine; Piperidines; Potassium Channels, Inwardly Rectifying; Rats; Receptors, Drug; Risk Factors; Sulfonylurea Compounds; Sulfonylurea Receptors; Tolbutamide
PubMed: 21923736
DOI: 10.1111/j.1463-1326.2011.01496.x -
Journal of the American College of... May 2010The purpose of this study was to assess the association of apolipoprotein(a) (apo[a]) isoforms with cardiovascular disease risk. (Meta-Analysis)
Meta-Analysis Review
OBJECTIVES
The purpose of this study was to assess the association of apolipoprotein(a) (apo[a]) isoforms with cardiovascular disease risk.
BACKGROUND
Although circulating lipoprotein(a) (Lp[a]) is likely to be a causal risk factor in coronary heart disease (CHD), the magnitude of this association is modest. Lipoprotein(a) particles with smaller, rather than larger, apo(a) isoforms may be stronger risk factors.
METHODS
Information was collated from 40 studies published between January 1970 and June 2009 that reported on associations between apo(a) isoforms and risk of CHD or ischemic stroke (involving a total of 11,396 patients and 46,938 controls).
RESULTS
Thirty-six studies used broadly comparable phenotyping and analytic methods to assess apo(a) isoform size. These studies yielded a combined relative risk for CHD of 2.08 (95% confidence intervals [CI]: 1.67 to 2.58) for individuals with smaller versus larger apo(a) isoforms (corresponding approximately to 22 or fewer kringle IV type 2 repeats vs. >22 repeats or analogously an apo[a] molecular weight of <640 kDa vs. > or =640 kDa). There was substantial heterogeneity among these studies (I(2) = 85%, 80% to 89%), which was mainly explained by differences in the laboratory methods and analytic approaches used. In the 6 studies of ischemic stroke that used comparable phenotypic methods, the combined relative risk was 2.14 (1.85 to 2.97). Overall, however, only 3 studies made allowances for Lp(a) concentration.
CONCLUSIONS
People with smaller apo(a) isoforms have an approximately 2-fold higher risk of CHD or ischemic stroke than those with larger proteins. Further studies are needed to determine whether the impact of smaller apo(a) isoforms is independent from Lp(a) concentration and other risk factors.
Topics: Apoprotein(a); Biomarkers; Humans; Molecular Weight; Particle Size; Protein Isoforms; Risk Factors; Vascular Diseases
PubMed: 20447543
DOI: 10.1016/j.jacc.2009.10.080 -
Brain and Nerve = Shinkei Kenkyu No... Aug 2009Prion diseases are fatal infectious neurodegenerative disorders; examples include the Creutzfeldt-Jakob disease affecting humans and bovine spongiform encephalopathy in... (Review)
Review
Prion diseases are fatal infectious neurodegenerative disorders; examples include the Creutzfeldt-Jakob disease affecting humans and bovine spongiform encephalopathy in cattle. The causative agents of these diseases--the prions--are thought to consist of the pathogenic isoform of the prion protein PrP(Sc), which is produced by the conformational conversion of the normal isoform PrP(c). Many lines of evidence indicate that the constitutive conversion of PrP(c) to PrP(Sc), resulting in a marked accumulation of PrP(Sc) in the brain, is a central event in the pathogenesis of prion diseases. A large number of compounds have been identified as anti-prion agents and capable of reducing the PrP(Sc) levels in infected cells. Some of these compounds have been found to be partially effective in infected animals, thus resulting in the prolongation of the incubation or survival times and a few of these compounds were or are under clinical trials. However, none of these compounds have proven to be therapeutically effective against this group of diseases. This is probably because (1) these compounds fail to cross the blood-brain barrier and (2) their effectiveness is reduced because they are administered only to patients with clinically advanced disease owing to a lack of diagnostic indicators for presymptomatic individuals. In this communication, we systematically list these anti-prion compounds and summarize their effectiveness and possible mechanisms of action.
Topics: Aminopyridines; Animals; Antibodies, Monoclonal; Blood-Brain Barrier; Brain; Cattle; Clinical Trials as Topic; Drug Discovery; Gene Silencing; Humans; Pentosan Sulfuric Polyester; Polyelectrolytes; Polymers; PrPC Proteins; PrPSc Proteins; Prion Diseases; Protein Isoforms; Quinacrine; Species Specificity
PubMed: 19697882
DOI: No ID Found