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Biomolecules Mar 2022Proteases and protease inhibitors (P/PIs) are involved in many biological processes in human skin, yet often only specific families or related groups of P/PIs are...
Proteases and protease inhibitors (P/PIs) are involved in many biological processes in human skin, yet often only specific families or related groups of P/PIs are investigated. Proteomics approaches, such as mass spectrometry, can define proteome signatures (including P/PIs) in tissues; however, they struggle to detect low-abundance proteins. To overcome these issues, we aimed to produce a comprehensive proteome of all P/PIs present in normal and diseased human skin, in vivo, by carrying out a modified systematic review using a list of P/PIs from MEROPS and combining this with key search terms in Web of Science. Resulting articles were manually reviewed against inclusion/exclusion criteria and a dataset constructed. This study identified 111 proteases and 77 protease inhibitors in human skin, comprising the serine, metallo-, cysteine and aspartic acid catalytic families of proteases. P/PIs showing no evidence of catalytic activity or protease inhibition, were designated non-peptidase homologs (NPH), and no reported protease inhibitory activity (NRPIA), respectively. MMP9 and TIMP1 were the most frequently published P/PIs and were reported in normal skin and most skin disease groups. Normal skin and diseased skin showed significant overlap with respect to P/PI profile; however, MMP23 was identified in several skin disease groups, but was absent in normal skin. The catalytic profile of P/PIs in wounds, scars and solar elastosis was distinct from normal skin, suggesting that a different group of P/PIs is responsible for disease progression. In conclusion, this study uses a novel approach to provide a comprehensive inventory of P/PIs in normal and diseased human skin reported in our database. The database may be used to determine either which P/PIs are present in specific diseases or which diseases individual P/PIs may influence.
Topics: Antiviral Agents; Humans; Peptide Hydrolases; Protease Inhibitors; Proteome; Proteomics
PubMed: 35327667
DOI: 10.3390/biom12030475 -
British Journal of Clinical Pharmacology Aug 2022To update our previously reported systematic review and meta-analysis of observational studies on cardiovascular drug exposure and COVID-19 clinical outcomes by focusing... (Meta-Analysis)
Meta-Analysis Review
AIMS
To update our previously reported systematic review and meta-analysis of observational studies on cardiovascular drug exposure and COVID-19 clinical outcomes by focusing on newly published randomized controlled trials (RCTs).
METHODS
More than 500 databases were searched between 1 November 2020 and 2 October 2021 to identify RCTs that were published after our baseline review. One reviewer extracted data with other reviewers verifying the extracted data for accuracy and completeness.
RESULTS
After screening 22 414 records, we included 24 and 21 RCTs in the qualitative and quantitative syntheses, respectively. The most investigated drug classes were angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin receptor blocker (ARBs) and anticoagulants, investigated by 10 and 11 studies respectively. In meta-analyses, ACEI/ARBs did not affect hospitalization length (mean difference -0.42, 95% confidence interval [CI] -1.83; 0.98 d, n = 1183), COVID-19 severity (risk ratio/RR 0.90, 95% CI 0.71; 1.15, n = 1661) or mortality (risk ratio [RR] 0.92, 95% CI 0.58; 1.47, n = 1646). Therapeutic anticoagulation also had no effect (hospitalization length mean difference -0.29, 95% CI -1.13 to 0.56 d, n = 1449; severity RR 0.86, 95% CI 0.70; 1.04, n = 2696; and, mortality RR 0.93, 95% CI 0.77; 1.13, n = 5689). Other investigated drug classes were antiplatelets (aspirin, 2 trials), antithrombotics (sulodexide, 1 trial), calcium channel blockers (amlodipine, 1 trial) and lipid-modifying drugs (atorvastatin, 1 trial).
CONCLUSION
Moderate- to high-certainty RCT evidence suggests that cardiovascular drugs such as ACEIs/ARBs are not associated with poor COVID-19 outcomes, and should therefore not be discontinued. These cardiovascular drugs should also not be initiated to treat or prevent COVID-19 unless they are needed for an underlying currently approved therapeutic indication.
Topics: Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Cardiovascular Agents; Humans; Observational Studies as Topic; Randomized Controlled Trials as Topic; COVID-19 Drug Treatment
PubMed: 35322889
DOI: 10.1111/bcp.15331 -
Scientific Reports May 2021Although a considerable volume of data supporting induction or aggravation of psoriasis because of angiotensin-converting enzyme (ACE) inhibitor use exists, it remains... (Meta-Analysis)
Meta-Analysis
Although a considerable volume of data supporting induction or aggravation of psoriasis because of angiotensin-converting enzyme (ACE) inhibitor use exists, it remains insufficient for definitive conclusions. Therefore, we aimed to evaluate the association between ACE inhibitor use and psoriasis incidence through a systematic literature review and meta-analysis. We searched for qualifying studies across PubMed, Web of Science, and Embase. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to evaluate the strength of the association between ACE inhibitor use and psoriasis incidence. Eight studies with a total of 54,509 patients with a psoriasis diagnosis were included in this meta-analysis. The pooled OR for psoriasis incidence among ACE inhibitor users was 1.52 (95% CI, 1.16-2.00) compared to that among non-users. From subgroup analysis by continent, the OR for ACE inhibitor users versus non-users was 2.37 (95% CI 1.28-4.37) in Asia. Per the subgroup analysis by climate, the OR for ACE inhibitor users vs non-users in dry climate was 3.45 (95% CI: 2.05-5.79) vs 1.32 (95% CI 1.01-1.73) in temperate climate. Our results reveal a significant association between ACE inhibitor use and psoriasis incidence.
Topics: Angiotensin-Converting Enzyme Inhibitors; Humans; Incidence; Psoriasis
PubMed: 33976340
DOI: 10.1038/s41598-021-89490-z -
Pharmacoepidemiology and Drug Safety Feb 2023Some early reports in the medical literature have raised concern about a possible increased risk of pancreatic cancer associated with the use of two broad classes of... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Some early reports in the medical literature have raised concern about a possible increased risk of pancreatic cancer associated with the use of two broad classes of incretin-based therapies, dipeptidyl peptidase-4 inhibitors, and glucagon-like peptide-1 receptor agonists. This possibility has been somewhat mitigated by the null findings meta-analyses of randomized controlled trials, but the usefulness of their findings was hampered by serious shortcomings of lack of power and representativeness. These shortcomings can typically be addressed by observational studies, but observational studies on the topic have yielded conflicting findings. A systematic review and meta-analysis of observational studies was performed to qualitatively and quantitatively appraise the totality of evidence on the association between the use of incretin-based therapies and the risk of pancreatic cancer in routine clinical practice.
METHODS
The PubMed, Web of Science, Embase, and Google Scholar databases were searched. The study quality was appraised using the ROBINS-I tool and based on the presence of pharmacoepidemiology biases. A random-effects model was used to estimate the summary relative risks with corresponding CIs.
RESULTS
A total of 14 studies were included. The qualitative assessment revealed that all studies had inadequate follow-up (≤5 years), 12 studies were suspected to suffer from time-lag bias (due to inappropriate choice of comparator group) to varying extent, five studies included prevalent users, five studies did not implement exposure lag period, five studies had a serious risk of bias due to confounding, and one study had a time-window bias. The quantitative assessment showed no indication of an increased risk when all studies were pooled together (RR 1.04, 95% CI 0.87, 1.24) and when the analysis was restricted to the studies with the least bias (RR 0.77, 95% CI 0.51, 1.17). However, the pooled RRs were more frequently higher in the studies with less rigorous design and analysis. Specifically, a tendency toward an increased risk was observed in the studies with (RR 1.34, 95% CI 1.04, 1.72) or possibly with (RR 1.10, 95% CI 0.89, 1.36) time-lag bias, in the studies that did not apply (RR 1.23, 95% CI 0.93, 1.63) or with potentially inadequate exposure lag period of 6 months (RR 1.13, 95% CI 0.66, 1.94), in the studies that inappropriate comparator group of a combination of unspecified (RR 1.49, 95% CI 1.25, 1.78) or non-insulin (RR 1.15, 95% CI 0.93, 1.42) antidiabetic drugs, and in the studies with serious risk of bias due to confounding (RR 1.18, 95% CI 0.56, 2.49).
CONCLUSIONS
In summary, the totality of evidence from observational studies does not support the claim that the use of incretin-based therapies is associated with an increased risk of pancreatic cancer in routine clinical practice. The increased risk of pancreatic cancer observed in observational studies reflects bias resulting from suboptimal methodological approaches, which need to be avoided by future studies.
Topics: Humans; Incretins; Hypoglycemic Agents; Pancreatic Neoplasms; Dipeptidyl-Peptidase IV Inhibitors
PubMed: 36224724
DOI: 10.1002/pds.5550 -
The Journal of Trauma and Acute Care... Feb 2016Ulinastatin (UTI) and thymosin α1 (Tα1) have been investigated for their immunoregulatory properties in patients with severe sepsis. However, it is unclear whether... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
Ulinastatin (UTI) and thymosin α1 (Tα1) have been investigated for their immunoregulatory properties in patients with severe sepsis. However, it is unclear whether immunomodulatory therapy using UTI combined with Tα1 (UCT), UTI alone (UA), or Tα1 alone (TA) improves the disease outcome. The objective of this study was to analyze the effectiveness of UCT, UA, and TA for the treatment of severe sepsis.
METHODS
PubMed, EMBASE, and Cochrane Library databases were investigated from inception to September 2015. Randomized controlled trials (RCTs) examining the treatment of patients with severe sepsis by UCT, UA, and TA were defined as eligible. Data were analyzed using Review Manager 5.3, and the RCTs were evaluated by the Cochrane Handbook 5.1.0. The quality of the evidence was evaluated according to the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE).
RESULTS
Ten articles and 12 studies were included in this systematic review and meta-analysis. The primary outcome measures indicated that UCT was associated with significantly lower 28-day mortality (risk ratio [RR], 0.67; 95% confidence interval [CI], 0.57-0.80; p < 0.00001; n = 915; GRADE rating, moderate) and 90-day mortality (RR, 0.75; 95% CI, 0.61-0.93; p = 0.009; n = 547; GRADE rating, moderate); UA was associated with no significant difference in the 28-day mortality (RR, 0.60; 95% CI, 0.30-1.20; p = 0.15; n = 182; GRADE rating, low), and there was no report on 90-day mortality; TA was associated with significantly lower 28-day mortality (RR, 0.72; 95% CI, 0.55-0.93; p = 0.01; n = 494; GRADE rating, low), but there was no significant difference in the 90-day mortality (RR, 0.84; 95% CI, 0.54-1.31; p = 0.45; n = 91; GRADE rating, very low). In the secondary outcome measures, there was obvious heterogeneity in the length of the intensive care unit stay and that of the mechanical ventilation, length of the antibiotics and vasopressor use, and 28-day Acute Physiology and Chronic Health Evaluation II (APACHE II) scores.
CONCLUSION
Treatment of severe sepsis with UCT reduced both the 28-day and the 90-day mortality, whereas treatment with TA reduced only the 28-day mortality. The effects of UCT, UA, and TA on intensive care unit stay, mechanical ventilation, antibiotics and vasopressor use, and 28-day APACHE II scores of septic patients are still unclear. Additional high-quality RCTs are needed to define clearly the guidelines for the treatment of severe sepsis.
LEVEL OF EVIDENCE
Systematic review, level IV.
Topics: Adjuvants, Immunologic; Drug Therapy, Combination; Glycoproteins; Humans; Sepsis; Thymalfasin; Thymosin; Trypsin Inhibitors
PubMed: 26517783
DOI: 10.1097/TA.0000000000000909 -
Diabetes & Metabolism Dec 2017The US Food and Drug Administration has warned that treatment with dipeptidyl peptidase (DPP)-4 inhibitors may promote serious arthralgia. However, the clinical evidence... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
The US Food and Drug Administration has warned that treatment with dipeptidyl peptidase (DPP)-4 inhibitors may promote serious arthralgia. However, the clinical evidence for this is relatively lacking.
OBJECTIVE
For this reason, a systematic review and meta-analysis of randomized controlled trials (RCTs) were carried out to determine the relationship between DPP-4 inhibitors and risk of arthralgia, and also to investigate any potential risk factors.
METHODS
An extensive electronic search for RCTs comparing DPP-4 inhibitors with any comparators was performed up to July 2016. Outcomes of interest were overall and serious arthralgia. Summary risk ratios (RRs) with 95% confidence intervals (CIs) were calculated.
RESULTS
A total of 67 RCTs (involving 79,110 patients) was ultimately included. Pooled results showed that DPP-4 inhibitors were associated with a slightly but significantly increased risk of overall arthralgia (RR: 1.13, 95% CI: 1.04-1.22; P=0.003) and a non-significant increased risk of serious arthralgia (RR: 1.44, 95% CI: 0.83-2.51; P=0.20). Also, subgroup analyses showed that add-on/combination therapy and longer diabetes duration (>5years) were possible factors associated with the increased risk of overall arthralgia.
CONCLUSION
These findings suggest that DPP-4 inhibitors can increase the risk of arthralgia. Thus, the benefits of glycaemic control must be weighed against the risk of arthralgia when prescribing DPP-4 inhibitors. Further studies are now needed to identify and confirm these risk factors.
Topics: Aged; Arthralgia; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Humans; Middle Aged; Randomized Controlled Trials as Topic; Risk; Treatment Outcome
PubMed: 28778563
DOI: 10.1016/j.diabet.2017.05.013 -
Diabetes, Obesity & Metabolism Jul 2015To summarize evidence from and assess the quality of published systematic reviews evaluating the safety, efficacy and effectiveness of incretin-based medications used in... (Review)
Review
AIMS
To summarize evidence from and assess the quality of published systematic reviews evaluating the safety, efficacy and effectiveness of incretin-based medications used in the treatment of type 2 diabetes.
METHODS
We identified systematic reviews of randomized controlled trials or observational studies published in any language that evaluated the safety and/or effectiveness of glucagon-like peptide-1 (GLP-1) receptor agonists or dipeptidyl-peptidase-4 (DPP-4) inhibitors. Data sources used include the Cochrane Library, PubMed, EMBASE, Web of Science, International Pharmaceutical Abstracts, table of contents of diabetes journals, and hand-searching of reference lists and clinical practice guidelines. The methodological quality of systematic reviews was independently assessed by two reviewers using the Assessment of Multiple Systematic Reviews (AMSTAR) checklist. Our study protocol was registered with PROSPERO (2013:CRD42013005149). The primary outcomes were pooled treatment effect estimates for glycaemic control, macrovascular and microvascular complications, and hypoglycaemic events.
RESULTS
We identified 467 unique citations of which 84 systematic reviews met our inclusion criteria. There were 51 reviews that evaluated GLP-1 receptor agonists and 64 reviews that evaluated DPP-4 inhibitors. The median (interquartile range) AMSTAR score was 6 (3) out of 11 for quantitative and 1 (1) for non-quantitative reviews. Among the 66 quantitative systematic reviews, there were a total of 718 pooled treatment effect estimates reported for our primary outcomes and 1012 reported pooled treatment effect estimates for secondary outcomes.
CONCLUSIONS
Clinicians and policy makers, when using the results of systematic reviews to inform decision-making with regard to round clinical care or healthcare policies for incretin-based medications, should consider the variability in quality of reviews.
Topics: Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide-1 Receptor; Humans; Incretins; Observational Studies as Topic; Randomized Controlled Trials as Topic; Review Literature as Topic
PubMed: 25772666
DOI: 10.1111/dom.12465 -
Phytomedicine : International Journal... Jan 2023The therapeutic benefits of Niaoduqing granules (NDQG) in kidney diseases has been comprehensively studied, but its adverse drug reactions remain unexplored. (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
The therapeutic benefits of Niaoduqing granules (NDQG) in kidney diseases has been comprehensively studied, but its adverse drug reactions remain unexplored.
OBJECTIVE
To evaluate the safety of NDQG in kidney disease treatment.
METHODS
The literature was searched in Embase, Medline via PubMed, Cochrane Library database, Wanfang database, Chinese National Knowledge Infrastructure, SinoMed, and Chinese VIP Database from inception to January 15, 2022, for randomized controlled trials (RCTs) and observational studies. The ClinicalTrials.gov website was searched for ongoing trials. The frequency and characteristics of adverse drug reactions (ADRs) were the primary and secondary outcomes, respectively. Subgroup analysis were conducted to explore the effects of clinical trial types, different kidney diseases, drug combinations and dosage on the safety of NDQG.
RESULTS
This review included 132 trials comprising 115 RCTs and 17 cohort studies. Additionally, 118 studies reported ADR rates with complete data, including 10381 participants. Regarding ADR frequency, no significant difference was observed between NDQG (7.26%) and control (8.39%) groups (RR = 0.890, 95% confidence interval (CI): 0.788-1.007); with no heterogeneity among the studies (I = 0.0%, P = 0.958). ADR frequency in patients with chronic kidney disease (65 trials, n = 5823) was significantly lower in the NDQG treatment group than in the control group (RR = 0.810, 95% CI: 0.67-0.969, I = 0.0%, P = 0.993); however, for patients with diabetic nephropathy there was no difference between both groups (26 trials, n = 2166, RR = 1.077, 95% CI: 0.802-1.446, I = 0.0%, P = 0.611). Similarly, the incidence of ADR in patients on dialysis and patients with pyelonephritis and nephrotic syndrome was the same for both groups, with 95% CI overlapping the line. For different interventions, including NDQG monotherapy or its combination with other commonly used drugs (including angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, statin drugs, and compound α-keto acid) or dialysis, the incidence of ADR showed no significant difference between the experimental and control arms. The ADR in the NDQG group primarily affected the gastrointestinal system (64.74%), central and peripheral nervous system (9.07%), whole body (5.79%), and skin and appendages (4.53%). The most common clinical manifestations were diarrhea, nausea, and vomiting.
CONCLUSIONS
Our meta-analysis showed that compared with supportive therapy, the incidence of ADR was similar when NDQG was added. However, current evidence is not definitive and more well-designed and conducted RCTs are warranted to definitively establish the reliable evidence.
PROTOCOL REGISTRATION NUMBER
PROSPERO CRD 42018104227.
Topics: Humans; Angiotensin-Converting Enzyme Inhibitors; Renal Insufficiency, Chronic; Nephrotic Syndrome; Skin; Drug-Related Side Effects and Adverse Reactions
PubMed: 36610168
DOI: 10.1016/j.phymed.2022.154535 -
International Journal of Antimicrobial... Jul 2023Data indicate that certain combination antiretroviral treatment (cART) regimens, particularly protease inhibitor (PI)-based regimens, and cART initiation before... (Meta-Analysis)
Meta-Analysis Review
Maternal antiretroviral treatment for HIV infection and risk of small-for-gestational-age birth: A systematic review and meta-analysis of protease inhibitor-based treatment and timing of treatment.
BACKGROUND
Data indicate that certain combination antiretroviral treatment (cART) regimens, particularly protease inhibitor (PI)-based regimens, and cART initiation before conception may be associated with adverse pregnancy outcomes. The risk of having a small-for-gestational-age (SGA) infant was examined among pregnant HIV-infected mothers on 1) PI-based compared to non-PI-based cART, and 2) any cART initiated before compared to after conception.
METHODS
A search was conducted using PubMed, Embase, and the Cochrane Library, and a systematic review was performed of studies published since Dec 1, 1995. Effect estimates with 95% confidence intervals (CIs) were extracted and meta-analyses with random-effects models were conducted. The certainty of evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation tool.
FINDINGS
Of 783 identified studies, 28 fulfilled the inclusion criteria. Meta-analysis indicated that PI-based cART was associated with a possible slightly increased risk of SGA compared with non-PI-based cART (pooled odds ratio [OR]: 1·09; CI: 0·76, 1·55). Initiation of cART before conception was also associated with a possible slightly increased risk of SGA compared with after conception (pooled OR: 1·08; CI: 0·95, 1·22). The overall certainty of evidence was very low and low for the first and second research questions, respectively.
INTERPRETATION
Although the benefits of cART largely outweigh the risks, these findings indicate the possibility of slightly increased risks of having an SGA infant. This indicates that careful monitoring of fetuses exposed to PI-based cART or cART before pregnancy might be reasonable. Based on the uncertainty of evidence, further research may change this conclusion.
Topics: Pregnancy; Infant; Female; Humans; HIV Infections; Anti-HIV Agents; Pregnancy Outcome; Protease Inhibitors
PubMed: 37121443
DOI: 10.1016/j.ijantimicag.2023.106823 -
British Journal of Cancer Jan 2023The association between the use of angiotensin-converting enzyme inhibitors (ACEIs) and lung cancer risk remains controversial. This study evaluated the association... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
The association between the use of angiotensin-converting enzyme inhibitors (ACEIs) and lung cancer risk remains controversial. This study evaluated the association between the use of ACEIs and lung cancer risk.
METHODS
Records from five databases were searched from inception to 26 January 2022. Clinical studies involving persons aged ≥18 years with at least one year of follow-up and reporting adverse events, including lung cancer, were recorded with separate outcome reports supplied for the ACEIs and control groups. Data were extracted independently by three authors and pooled using a random-effects model. The primary outcome was lung cancer development. Odds ratios (ORs) with 95% confidence intervals (CIs) and lung cancer-related morbidity were calculated.
RESULTS
Of 2400 records screened, 13,061,226 patients were included from seven cohort studies and four case-control studies. Pooled results showed that ACEIs use was linked to increased lung cancer risk (OR 1.19, 95% CI 1.05-1.36; P = 0.008), with high heterogeneity (I = 98%).
CONCLUSIONS
ACEI usage is a greater risk factor for lung carcinogenesis than angiotensin receptor blocker use, especially in Asian patients. Further randomised controlled trials are needed to confirm the causal association between the use of ACEIs and lung cancer risk.
Topics: Humans; Adolescent; Adult; Angiotensin-Converting Enzyme Inhibitors; Angiotensin Receptor Antagonists; Risk Factors; Lung Neoplasms; Case-Control Studies
PubMed: 36396817
DOI: 10.1038/s41416-022-02029-5