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Systematic Reviews Jan 2024Up to 40% of UDCA-treated patients do not have an adequate clinical response. Farnesoid X receptor agonists, peroxisome proliferator-activated receptor agonists, and... (Meta-Analysis)
Meta-Analysis
Optimal drug regimens for improving ALP biochemical levels in patients with primary biliary cholangitis refractory to UDCA: a systematic review and Bayesian network meta-analysis.
BACKGROUND
Up to 40% of UDCA-treated patients do not have an adequate clinical response. Farnesoid X receptor agonists, peroxisome proliferator-activated receptor agonists, and fibroblast growth factor 19 analogs were developed as adjunctive therapy. The aim of this network meta-analysis was to compare the efficacy of these drugs as add-on therapy for patients with primary biliary cholangitis (PBC) refractory to UDCA in improving ALP levels.
METHODS
We searched PubMed, Embase, Web of Science, and the Cochrane Library for eligible studies until 1 December 2023. Randomized controlled trials, cohort studies, and case-control studies comparing the efficacy of different combination treatments and UDCA monotherapy in UDCA-refractory PBC patients were included in the analysis. Cumulative probability was used to rank the included treatments.
RESULTS
A total of 23 articles were eligible for our network meta-analysis. In terms of improving ALP levels, In terms of improving ALP biochemical levels, bezafibrate combined with UDCA (MD 104.49, 95% CI 60.41, 161.92), fenofibrate combined with UDCA (MD 87.81, 95% CI (52.34, 129.79), OCA combined with UDCA (MD 65.21, 95% CI 8.99, 121.80), seladelpar combined with UDCA (MD 117.39, 95% CI 19.97, 213.95), elafibranor combined with UDCA (MD 140.73, 95% CI 74.34, 209.98), saroglitazar combined with UDCA (MD 132.09, 95% CI 13.99, 247.04) was more effective than UDCA monotherapy. Elafibranor in combination with UDCA was the most likely (32%) to be the optimal drug regimen.
CONCLUSION
As second-line therapy for UDCA-refractory PBC, PPAR agonists were more effective than any other drugs with other mechanisms in improving ALP biochemical levels, with elafibranor being the best.
Topics: Humans; Liver Cirrhosis, Biliary; Ursodeoxycholic Acid; Bayes Theorem; Network Meta-Analysis; Drug Therapy, Combination; Treatment Outcome; Randomized Controlled Trials as Topic; Propionates; Chalcones
PubMed: 38287391
DOI: 10.1186/s13643-024-02460-0 -
Acta Pharmaceutica Sinica. B Nov 2015Cysteine proteases continue to provide validated targets for treatment of human diseases. In neurodegenerative disorders, multiple cysteine proteases provide targets for... (Review)
Review
Cysteine proteases continue to provide validated targets for treatment of human diseases. In neurodegenerative disorders, multiple cysteine proteases provide targets for enzyme inhibitors, notably caspases, calpains, and cathepsins. The reactive, active-site cysteine provides specificity for many inhibitor designs over other families of proteases, such as aspartate and serine; however, a) inhibitor strategies often use covalent enzyme modification, and b) obtaining selectivity within families of cysteine proteases and their isozymes is problematic. This review provides a general update on strategies for cysteine protease inhibitor design and a focus on cathepsin B and calpain 1 as drug targets for neurodegenerative disorders; the latter focus providing an interesting query for the contemporary assumptions that irreversible, covalent protein modification and low selectivity are anathema to therapeutic safety and efficacy.
PubMed: 26713267
DOI: 10.1016/j.apsb.2015.08.001 -
Journal of Clinical and Translational... Sep 2016To systematically evaluate the literature for evidence to support the use of bile acids in non-cholestatic liver conditions. Searches were conducted on the databases...
To systematically evaluate the literature for evidence to support the use of bile acids in non-cholestatic liver conditions. Searches were conducted on the databases of Medline (1948-March 31, 2015), Embase (1980-March 31, 2015) and the Cochrane Central Register of Controlled Trials, and on Google and Google Scholar to identify articles describing ursodeoxycholic acid (UDCA) and its derivatives for non-cholestatic hepatic indications. Combinations of the following search terms were used: ursodeoxycholic acid, ursodiol, bile acids and/or salts, non alcoholic fatty liver, non alcoholic steatohepatitis, fatty liver, alcoholic hepatitis, alcohol, liver disease, autoimmune, autoimmune hepatitis, liver transplant, liver graft, transplant rejection, graft rejection, ischemic reperfusion injury, reperfusion injury, hepatitis B, hepatitis C, viral hepatitis, chronic hepatitis, acute hepatitis, transaminases, alanine transaminase, liver enzymes, aspartate aminotransferase, gamma-glutamyl transferase, gamma-glutamyl transpeptidase, bilirubin, alkaline phosphatase. No search limits were applied. Additionally, references of the included studies were reviewed to identify additional articles. The literature search yielded articles meeting inclusion criteria for the following indications: non-alcoholic fatty liver disease (n = 5); alcoholic liver disease (n = 2); autoimmune hepatitis (n = 6), liver transplant (n = 2) and viral hepatitis (n = 9). Bile acid use was associated with improved normalization of liver biochemistry in non-alcoholic fatty liver disease, autoimmune hepatitis and hepatitis B and C infections. In contrast, liver biochemistry normalization was inconsistent in alcoholic liver disease and liver transplantation. The majority of studies reviewed showed that normalization of liver biochemistry did not correlate to improvement in histologic disease. In the prospective trials reviewed, adverse effects associated with the bile acids were limited to minor gastrointestinal complaints (most often, diarrhea) and did not occur at increased frequency as compared to controls. As administration of bile acids was often limited to durations of 12 months or less, long-term side effects for non-cholestatic indications cannot be excluded. Based on the available literature, bile acids cannot be widely recommended for non-cholestatic liver diseases at present.
PubMed: 27777888
DOI: 10.14218/JCTH.2016.00023 -
Cells Nov 2020Cardiovascular calcification is highly prevalent and associated with increased morbidity in chronic kidney disease (CKD). This review examines the impact of uremic...
Cardiovascular calcification is highly prevalent and associated with increased morbidity in chronic kidney disease (CKD). This review examines the impact of uremic toxins, which accumulate in CKD due to a failing kidney function, on cardiovascular calcification. A systematic literature search identified 41 uremic toxins that have been studied in relation to cardiovascular calcification. For 29 substances, a potentially causal role in cardiovascular calcification was addressed in in vitro or animal studies. A calcification-inducing effect was revealed for 16 substances, whereas for three uremic toxins, namely the guanidino compounds asymmetric and symmetric dimethylarginine, as well as guanidinosuccinic acid, a calcification inhibitory effect was identified in vitro. At a mechanistic level, effects of uremic toxins on calcification could be linked to the induction of inflammation or oxidative stress, smooth muscle cell osteogenic transdifferentiation and/or apoptosis, or alkaline phosphatase activity. For all middle molecular weight and protein-bound uremic toxins that were found to affect cardiovascular calcification, an increasing effect on calcification was revealed, supporting the need to focus on an increased removal efficiency of these uremic toxin classes in dialysis. In conclusion, of all uremic toxins studied with respect to calcification regulatory effects to date, more uremic toxins promote rather than reduce cardiovascular calcification processes. Additionally, it highlights that only a relatively small part of uremic toxins has been screened for effects on calcification, supporting further investigation of uremic toxins, as well as of associated post-translational modifications, on cardiovascular calcification processes.
Topics: Alkaline Phosphatase; Animals; Apoptosis; Calcinosis; Cardiomyopathies; Humans; Inflammation; Molecular Weight; Osteogenesis; Oxidative Stress; Renal Insufficiency, Chronic; Signal Transduction; Toxins, Biological; Uremia
PubMed: 33172085
DOI: 10.3390/cells9112428 -
Experimental and Therapeutic Medicine Apr 2022Paget's disease of bone (PDB) is characterized by abnormal osteoclastic bone resorption with disorganized bone neo-formation, primarily affecting elderly (>55 years)...
Paget's disease of bone (PDB) is characterized by abnormal osteoclastic bone resorption with disorganized bone neo-formation, primarily affecting elderly (>55 years) patients. Although the majority of patients are asymptomatic, some patients may experience bone pain due to local periosteal involvement or osteoarthritic lesions in the spine; in addition, limb deformities may lead to secondary gait problems or degenerative joint changes. Anemia has an overall prevalence of 12-17% in elderly adults (>65 years old), with macrocytic anemia being the less common type. Megaloblastic anemia is a macrocytic anemia characterized by the presence of large, immature, nucleated cells (megaloblasts) in the blood, with the most common cause being a deficiency of folate and/or vitamin B12. We herein report the rare case of a 72-year-old male patient exhibiting both these conditions, with the aim of discussing the possible association between the two and, most importantly, the clinical management of the patient in a real-life setting over a period of 10 years. The patient was diagnosed based on clinical symptoms (bone pain), radiological imaging and specific laboratory tests, and received discontinuous courses of bisphosphonates and cyanocobalamin supplementation therapy, based mainly on aggravated symptomatology. A systematic literature review was also performed and revealed not only the scarcity of reports on similar cases, but also the mechanisms that may underlie the possible association of PDB with macrocytic anemia due to vitamin B12 deficiency in elderly patients.
PubMed: 35251335
DOI: 10.3892/etm.2022.11195 -
Renal Failure Dec 2021Inconsistent investigations of the risk factors for all-cause mortality in patients undergoing peritoneal dialysis (PD) were reported. The present meta-analysis aimed to... (Meta-Analysis)
Meta-Analysis
Inconsistent investigations of the risk factors for all-cause mortality in patients undergoing peritoneal dialysis (PD) were reported. The present meta-analysis aimed to assess the impact of some clinical characteristics on the risk of mortality in PD patients. PubMed and Embase were systematically searched for studies evaluating the risk factors for all-cause mortality in PD patients. Hazard ratio (HR) and 95% confidence interval (CI) were derived using a random-effect or fixed-effect model considering the heterogeneity across studies. A total of 26 studies were included in this meta-analysis in accordance with the inclusion and exclusion criteria. Age, primary cardiovascular diseases, diabetes mellitus, and high level of alkaline phosphatase showed significant positive associations with elevated risk of all-cause and cardiovascular mortality in PD patients, while hemoglobin acted as a benefit factor. Furthermore, early onset of peritonitis, high peritoneal transport status, elevated body mass index and high-sensitivity C-reactive protein could also considerably increase the risk of all-cause mortality. The absolute serum level of magnesium, potassium, and uric acid required to improve survival in PD patients should be verified further. Multiple factors could affect the risk of mortality in PD patients.
Topics: Alkaline Phosphatase; Cardiovascular Diseases; Cause of Death; Humans; Kidney Failure, Chronic; Mortality; Peritoneal Dialysis; Risk Assessment; Risk Factors
PubMed: 33913381
DOI: 10.1080/0886022X.2021.1918558 -
Fitoterapia Apr 2021Members of the botanical families Apiaceae/Umbelliferae, Asteraceae, Fabaceae/Leguminosae, and Thymelaeaceae are rich in coumarins and have traditionally been used as...
BACKGROUND
Members of the botanical families Apiaceae/Umbelliferae, Asteraceae, Fabaceae/Leguminosae, and Thymelaeaceae are rich in coumarins and have traditionally been used as ethnomedicines in many regions including Europe, Asia, and South America. Coumarins are a class of secondary metabolites that are widely present in plants, fungi, and bacteria and exhibit several pharmacological, biochemical, and therapeutic effects. Recently, many plants rich in coumarins and their derivatives were found to affect bone metabolism.
OBJECTIVE
To review scientific literature describing the mechanisms of action of coumarins in osteoclastogenesis and bone resorption.
MATERIALS AND METHODS
For this systematic review, the PubMed, Scopus, and Periodical Capes databases and portals were searched. We included in vitro research articles published between 2010 and 2020 that evaluated coumarins using osteoclastogenic markers.
RESULTS
Coumarins have been reported to downregulate RANKL-RANK signaling and various downstream signaling pathways required for osteoclast development, such as NF-κB, MAPK, Akt, and Ca signaling, as well as pathways downstream of the nuclear factor of activated T-cells (NFATc1), including tartrate-resistant acid phosphatase (TRAP), cathepsin K (CTSK), and matrix metalloproteinase 9 (MMP-9).
CONCLUSIONS
Coumarins primarily inhibit osteoclast differentiation and activation by modulating different intracellular signaling pathways; therefore, they could serve as potential candidates for controlled randomized clinical trials aimed at improving human bone health.
Topics: Animals; Bone Resorption; Cells, Cultured; Coumarins; Humans; Osteogenesis; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Signal Transduction
PubMed: 33556550
DOI: 10.1016/j.fitote.2021.104842 -
Frontiers in Pharmacology 2024Gukang Capsule has been used as a complementary and alternative medicine (CAM) for the treatment of primary osteoporosis (POP) in China. The primary aim of this study...
Gukang Capsule has been used as a complementary and alternative medicine (CAM) for the treatment of primary osteoporosis (POP) in China. The primary aim of this study was to assess the clinical effectiveness and safety of Gukang Capsule in POP patients. A systematic search was conducted across multiple academic databases including PubMed, Web of science, Cochrane Library, China National Knowledge Infrastructure, Chongqing VIP Information, and Wanfang database to identify randomized controlled trials investigating the Gukang Capsule in the treatment of POP. The screening process, data extraction, and assessment of methodological quality were conducted independently by two reviewers. Statistical analysis was performed using the Rev Man 5.3 software. Subgroup analysis was carried out through the combination of OPF. Subgroup analysis was performed according to whether OPF were combined. Stata 12.0 was used for sensitivity and bias analysis. Nineteen studies were assessed that included 1804 participants. It was found that compared with the control group, the total effective rate (RR = 1.26, 95% CI, 1.20, 1.33), the Medical Outcomes Study Short-form 36 [RR = 1.26, 95% CI(1.20, 1.33)], the bone mineral density (BMD) of lumbar vertebra (SMD = 0.77, 95% CI, 0.48, 1.07), the BMD of femoral neck [SMD = 0.84, 95% CI(0.53, 1.14)], and the BMD of Ward's triangle (SMD = 0.64, 95% CI, 0.44, 0.85) of the Gukang Capsule experimental group were higher. Compared with the control group, the fracture healing time (SMD = -2.14, 95% CI, -2.45, -1.84), the bone specific alkaline phosphatase (BALP) levels in serum (SMD = -2.00, 95% CI, -2.83, -1.17), the tartrate resistant acid phosphatase 5b (TRACP-5b) levels in serum (SMD = -2.58, 95% CI, -3.87, -1.29) of the Gukang Capsule experimental group were lower. The bone glaprotein (BGP) levels in serum (SMD = -0.22, 95% CI, -1.86, 1.43) and the adverse events (RR = 0.80, 95% CI, 0.40, 1.63) of the experimental group and the control group have no difference. Gukang Capsule, as a CAM for the management of POP, exhibits the potential to enhance BMD and quality of life, expedite the healing time of OPF, diminish levels of BALP and TRACP-5b, and improve the total effective rate without increasing the adverse events. https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42023477774, PROSPERO CRD42023477774.
PubMed: 38915472
DOI: 10.3389/fphar.2024.1394537 -
Journal of Clinical and Experimental... 2021Hemophagocytic lymphohistiocytosis is a life-threatening disorder characterized by persistent pathologic activation of cytotoxic T lymphocytes, natural killer cells, and...
Hemophagocytic lymphohistiocytosis is a life-threatening disorder characterized by persistent pathologic activation of cytotoxic T lymphocytes, natural killer cells, and macrophages. We present details of a young patient who presented with high-grade fever, jaundice, and breathlessness. On investigations, he had hepatitis, anemia, neutropenia, and coagulopathy. He also had hypertriglyceridemia, hypofibrinogenemia, and hyperferritinemia. Bone marrow aspiration revealed histiocytosis, and transjugular liver biopsy revealed necrotizing granulomas positive for on acid-fast bacilli staining. He was successfully managed with a combination of immunosuppressants and antitubercular therapy. Tuberculosis associated hemophagocytosis syndrome is rare and should be considered in patients with unexplained hemophagocytosis syndrome, especially in tuberculosis-endemic regions. Prompt recognition and treatment with antitubercular treatment and immunosuppressants are associated with good outcomes.
PubMed: 33679052
DOI: 10.1016/j.jceh.2020.05.007 -
British Journal of Clinical Pharmacology Aug 2020The objective of this meta-analysis was to evaluate the effect of ursodeoxycholic acid (UDCA) therapy on serum liver function tests. (Meta-Analysis)
Meta-Analysis
AIM
The objective of this meta-analysis was to evaluate the effect of ursodeoxycholic acid (UDCA) therapy on serum liver function tests.
METHODS
PubMed, Web of Science, Scopus and Google Scholar databases were searched to identify randomized placebo-controlled trials assessing the impact of UDCA on hepatic parameters. Meta-analysis was conducted using a random-effects model and sensitivity analysis through the leave-one-out method in the Review Manager statistical software version 5.3.
RESULTS
After UDCA treatment, meta-analysis revealed a significant reduction of alanine aminotransferase (weighted mean difference [WMD]: -15.28 U/L, 95% confidence interval [CI]: -23.42, -7.15, P = 0.0002, I = 97%), aspartate aminotransferase (WMD: -16.13 U/L, 95% CI: -23.84, -8.42, P < 0.0001, I = 97%), gamma-glutamyl transferase (WMD: -23.29 U/L, 95% CI: -33.97, -12.61, P < 0.0001, I = 97%), alkaline phosphatase (WMD: -93.80 U/L, 95% CI: -126.36, -61.25, P < 0.0001, I = 95%) and bilirubin (WMD: -0.18 U/L, 95% CI: -0.35, -0.01, P = 0.04, I = 93%), but not significant changes in albumin levels (WMD: 0.10 U/L, 95% CI: -0.05, 0.24, P = 0.18, I = 80%).
CONCLUSION
The results of the present meta-analysis suggest a hepatoprotective effect of UDCA by reducing serum liver parameters.
Topics: Alanine Transaminase; Biomarkers; Humans; Liver; Randomized Controlled Trials as Topic; Ursodeoxycholic Acid
PubMed: 32285958
DOI: 10.1111/bcp.14311