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Contemporary Clinical Trials Feb 2021The nucleotide analogue prodrug remdesivir was among the first antiviral therapies to be tested in randomized controlled trials (RCTs) for COVID-19. We performed a... (Meta-Analysis)
Meta-Analysis
BACKGROUND
The nucleotide analogue prodrug remdesivir was among the first antiviral therapies to be tested in randomized controlled trials (RCTs) for COVID-19. We performed a meta-analysis to understand efficacy and safety.
METHODS
We searched PubMed, EMBASE, Cochrane library, and ClinicalTrials.gov databases (from January 1, 2020 to November 5, 2020). We included RCTs comparing the efficacy and safety of remdesivir to control/placebo in COVID-19. Two independent investigators abstracted data, assessed the quality of evidence, and rated the certainty of evidence.
RESULTS
A total of 4 RCTs with 7334 patients with COVID-19 were included. At a follow-up of 28-29 days from randomization, very low certainty evidence showed that use of remdesivir compared with control group (placebo and/or standard of care) was not associated with a significant decrease in time to clinical improvement (standardized mean difference -0.80 day; [CI, -2.12, 0.53]). However, moderate certainty of evidence showed that remdesivir was associated with higher rates of recovered patients (risk difference [RD] 0.07 [0.05, 0.08]) and discharged patients (RD 0.07 [0.03, 0.11]) and lower rates of developing serious adverse events (RD -0.05 [-0.10, -0.01]) compared with control. Moderate and very low certainty of evidence showed there was no significant difference in deaths at 28-29 days follow-up (RD -0.01 [-0.03, 0.01]) and developing any adverse events (RD 0.01 [-0.17, 0.19]) between both groups, respectively.
CONCLUSION
Patients given remdesivir are more likely to demonstrate recovery and were associated with higher rates of hospital discharge, but not with significant reduction in mean time to clinical improvement or mortality.
Topics: Adenosine Monophosphate; Alanine; Antiviral Agents; COVID-19; Humans; Randomized Controlled Trials as Topic; SARS-CoV-2; Treatment Outcome; COVID-19 Drug Treatment
PubMed: 33422642
DOI: 10.1016/j.cct.2021.106272 -
Drugs of Today (Barcelona, Spain : 1998) Feb 2010Cyclooxygenase (COX) enzymes mediate prostaglandin generation. COX-1 is expressed in all cells, producing prostaglandins that maintain cellular homeostasis, and COX-2 is... (Review)
Review
Cyclooxygenase (COX) enzymes mediate prostaglandin generation. COX-1 is expressed in all cells, producing prostaglandins that maintain cellular homeostasis, and COX-2 is an inducible enzyme that generates inflammatory prostaglandins at sites of inflammation and healing. Nonsteroidal antiinflammatory drugs (NSAIDs) that nonselectively inhibit COX-1 and COX-2 continue to be an important option for the management of pain. However, despite the potential advantages of NSAIDs, including their opioid-sparing effect and reduced opioid-related side effects, improved analgesia, and attenuation of the inflammatory pain response, several side effects limit their use. NSAIDs predispose to ulcer formation and upper gastrointestinal bleeding, impaired coagulation, cardiovascular effects and renal dysfunction. Selective cyclooxygenase-2 (COX-2) inhibitors were designed based on the hypothesis that selective inhibition of the COX-2 isoform should reduce pain and inflammation without compromising the integrity of the gastric mucosa. Celecoxib and parecoxib are two COX-2 inhibitors (coxibs) that are approved for the relief of acute postoperative pain and symptoms of chronic inflammatory conditions such as osteoarthritis and rheumatoid arthritis. They have similar pharmacological properties but a slightly improved gastrointestinal safety profile compared with traditional NSAIDs. Celecoxib is an orally administered coxib. Agents such as celecoxib, which are highly COX-2 specific and have shown excellent efficacy in relieving inflammation and associated pain, unfortunately exhibit only modest aqueous solubility, thus restricting dosing options. Parecoxib is the sulfonamide-based prodrug of valdecoxib and is the only parenterally administered coxib available to date. There is no evidence demonstrating any greater degree of pain relief between these two coxibs. However, parenteral preparations may be especially useful in the immediate postoperative period, when patients are unable to take oral medication or are experiencing nausea and vomiting.
Topics: Animals; Celecoxib; Cyclooxygenase 2 Inhibitors; Drug Administration Routes; Evidence-Based Medicine; Humans; Inflammation; Isoxazoles; Pain; Pain Measurement; Pyrazoles; Structure-Activity Relationship; Sulfonamides; Treatment Outcome
PubMed: 20224826
DOI: No ID Found -
Annals of Medicine and Surgery (2012) Feb 2024Hypertension has significantly contributed to morbidity and mortality, necessitating effective management. Angiotensin receptor blockers (ARBs) have emerged as a... (Review)
Review
BACKGROUND
Hypertension has significantly contributed to morbidity and mortality, necessitating effective management. Angiotensin receptor blockers (ARBs) have emerged as a cornerstone in hypertension treatment. Azilsartan, a relatively recent addition to the ARB family, offers unique characteristics, including prodrug activation. This systematic review and meta-analysis aimed to evaluate Azilsartan's role in reducing clinical blood pressure compared to other ARBs and determine the most effective dosage.
METHODS
Following PRISMA guidelines, a comprehensive literature search was conducted in Medline, Web of Science, Cochrane Library, and clinicaltrials.gov. Eligible studies included adult hypertensive patients receiving Azilsartan compared to other ARBs, with clinical systolic blood pressure (SBP) and diastolic blood pressure (DBP) outcomes. Data extraction and quality assessment were performed, and statistical analysis employed comprehensive meta-analysis (CMA) software.
RESULTS
Eleven randomized controlled trials encompassing 18 studies involving 6024 patients were included. Azilsartan demonstrated significant reductions in clinical SBP (mean difference=-2.85 mmHg) and DBP (mean difference=-2.095 mmHg) compared to other ARBs. Higher doses of Azilsartan showed greater efficacy, with 80 mg exhibiting the most substantial reduction in SBP. The analysis emphasized the need for more studies investigating lower Azilsartan doses (10 and 20 mg).
CONCLUSION
This systematic review and meta-analysis underscore Azilsartan's effectiveness in reducing SBP and DBP. Dose-dependent effects emphasize the importance of optimal dosing when prescribing Azilsartan. These findings provide valuable insights for clinicians in managing hypertension effectively and call for further research, primarily focusing on lower Azilsartan doses and a more diverse patient population.
PubMed: 38333313
DOI: 10.1097/MS9.0000000000001547 -
Antiviral Therapy 2019Tenofovir disoproxil fumarate (TDF), the oral prodrug of tenofovir (TFV), is advocated in pregnancy for prevention of mother-to-child transmission (PMCT) with failure of...
BACKGROUND
Tenofovir disoproxil fumarate (TDF), the oral prodrug of tenofovir (TFV), is advocated in pregnancy for prevention of mother-to-child transmission (PMCT) with failure of hepatitis B immunoglobulin and vaccination. The pharmacokinetics of TDF monotherapy for PMCT-HBV is important if deployment is to emulate the success of multiple antiretrovirals (ARVs) for PMCT-HIV in resource-constrained settings.
METHODS
This systematic review followed a protocol and is reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement (PRISMA) guidelines. We included studies that enrolled pregnant women who received oral TDF therapy as monotherapy or in combination with other ARVs: irrespective of the reason for receiving the drug (for example, HIV, HBV or pre-exposure prophylaxis); and reported pharmacokinetics.
RESULTS
The area under the concentration-time curve (AUC), maximum plasma concentrations (C) and last measurable plasma concentration (C) of TFV were decreased in the second and third trimester compared with first trimester or post-partum. In none of the manuscripts was the non-pregnant HBV threshold of C of 300 ng/ml reached, but the 50% effective concentration (EC) of TFV is lower for treatment of HBV compared with HIV. The TFV concentration in breastfed infants was 0.03% of the recommended infant dose.
CONCLUSIONS
Most knowledge of pharmacokinetics of TFV in pregnancy results from studies on HIV involving multiple ARVs. Increased TFV clearance occurred in the second and third trimester when optimal TFV concentrations are required to maximize suppression of HBV in the window before birth. Dose or duration adjustments will be better conceptualized with concurrent analysis of the pharmacokinetics of TFV monotherapy and hepatitis B pharmacodynamics in pregnancy.
Topics: Antiviral Agents; Female; HIV Infections; HIV-1; Humans; Lactation; Pregnancy; Pregnancy Complications, Infectious; Tenofovir
PubMed: 31868655
DOI: 10.3851/IMP3341 -
The Cochrane Database of Systematic... Apr 2018Heavy menstrual bleeding (HMB) is an important physical and social problem for women. Oral treatment for HMB includes antifibrinolytic drugs, which are designed to... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Heavy menstrual bleeding (HMB) is an important physical and social problem for women. Oral treatment for HMB includes antifibrinolytic drugs, which are designed to reduce bleeding by inhibiting clot-dissolving enzymes in the endometrium.Historically, there has been some concern that using the antifibrinolytic tranexamic acid (TXA) for HMB may increase the risk of venous thromboembolic disease. This is an umbrella term for deep venous thrombosis (blood clots in the blood vessels in the legs) and pulmonary emboli (blood clots in the blood vessels in the lungs).
OBJECTIVES
To determine the effectiveness and safety of antifibrinolytic medications as a treatment for heavy menstrual bleeding.
SEARCH METHODS
We searched the Cochrane Gynaecology and Fertility (CGF) Group trials register, CENTRAL, MEDLINE, Embase, PsycINFO and two trials registers in November 2017, together with reference checking and contact with study authors and experts in the field.
SELECTION CRITERIA
We included randomized controlled trials (RCTs) comparing antifibrinolytic agents versus placebo, no treatment or other medical treatment in women of reproductive age with HMB. Twelve studies utilised TXA and one utilised a prodrug of TXA (Kabi).
DATA COLLECTION AND ANALYSIS
We used standard methodological procedures expected by Cochrane. The primary review outcomes were menstrual blood loss (MBL), improvement in HMB, and thromboembolic events.
MAIN RESULTS
We included 13 RCTs (1312 participants analysed). The evidence was very low to moderate quality: the main limitations were risk of bias (associated with lack of blinding, and poor reporting of study methods), imprecision and inconsistency.Antifibrinolytics (TXA or Kabi) versus no treatment or placeboWhen compared with a placebo, antifibrinolytics were associated with reduced mean blood loss (MD -53.20 mL per cycle, 95% CI -62.70 to -43.70; I² = 8%; 4 RCTs, participants = 565; moderate-quality evidence) and higher rates of improvement (RR 3.34, 95% CI 1.84 to 6.09; 3 RCTS, participants = 271; moderate-quality evidence). This suggests that if 11% of women improve without treatment, 43% to 63% of women taking antifibrinolytics will do so. There was no clear evidence of a difference between the groups in adverse events (RR 1.05, 95% CI 0.93 to 1.18; 1 RCT, participants = 297; low-quality evidence). Only one thromboembolic event occurred in the two studies that reported this outcome.TXA versus progestogensThere was no clear evidence of a difference between the groups in mean blood loss measured using the Pictorial Blood Assessment Chart (PBAC) (MD -12.22 points per cycle, 95% CI -30.8 to 6.36; I² = 0%; 3 RCTs, participants = 312; very low quality evidence), but TXA was associated with a higher likelihood of improvement (RR 1.54, 95% CI 1.31 to 1.80; I² = 32%; 5 RCTs, participants = 422; low-quality evidence). This suggests that if 46% of women improve with progestogens, 61% to 83% of women will do so with TXA.Adverse events were less common in the TXA group (RR 0.66, 95% CI 0.46 to 0.94; I² = 28%; 4 RCTs, participants = 349; low-quality evidence). No thromboembolic events were reported in any group.TXA versus non-steroidal anti-inflammatory drugs (NSAIDs)TXA was associated with reduced mean blood loss (MD -73.00 mL per cycle, 95% CI -123.35 to -22.65; 1 RCT, participants = 49; low-quality evidence) and higher likelihood of improvement (RR 1.43, 95% CI 1.18 to 1.74; 1 = 0%; 2 RCTs, participants = 161; low-quality evidence). This suggests that if 61% of women improve with NSAIDs, 71% to 100% of women will do so with TXA. Adverse events were uncommon and no comparative data were available. No thromboembolic events were reported.TXA versus ethamsylateTXA was associated with reduced mean blood loss (MD 100 mL per cycle, 95% CI -141.82 to -58.18; 1 RCT, participants = 53; low-quality evidence), but there was insufficient evidence to determine whether the groups differed in rates of improvement (RR 1.56, 95% CI 0.95 to 2.55; 1 RCT, participants = 53; very low quality evidence) or withdrawal due to adverse events (RR 0.78, 95% CI 0.19 to 3.15; 1 RCT, participants = 53; very low quality evidence).TXA versus herbal medicines (Safoof Habis and Punica granatum)TXA was associated with a reduced mean PBAC score after three months' treatment (MD -23.90 pts per cycle, 95% CI -31.92 to -15.88; I² = 0%; 2 RCTs, participants = 121; low-quality evidence). No data were available for rates of improvement. TXA was associated with a reduced mean PBAC score three months after the end of the treatment phase (MD -10.40 points per cycle, 95% CI -19.20 to -1.60; I² not applicable; 1 RCT, participants = 84; very low quality evidence). There was insufficient evidence to determine whether the groups differed in rates of adverse events (RR 2.25, 95% CI 0.74 to 6.80; 1 RCT, participants = 94; very low quality evidence). No thromboembolic events were reported.TXA versus levonorgestrel intrauterine system (LIUS)TXA was associated with a higher median PBAC score than TXA (median difference 125.5 points; 1 RCT, participants = 42; very low quality evidence) and a lower likelihood of improvement (RR 0.43, 95% CI 0.24 to 0.77; 1 RCT, participants = 42; very low quality evidence). This suggests that if 85% of women improve with LIUS, 20% to 65% of women will do so with TXA. There was insufficient evidence to determine whether the groups differed in rates of adverse events (RR 0.83, 95% CI 0.25 to 2.80; 1 RCT, participants = 42; very low quality evidence). No thromboembolic events were reported.
AUTHORS' CONCLUSIONS
Antifibrinolytic treatment (such as TXA) appears effective for treating HMB compared to placebo, NSAIDs, oral luteal progestogens, ethamsylate, or herbal remedies, but may be less effective than LIUS. There were too few data for most comparisons to determine whether antifibrinolytics were associated with increased risk of adverse events, and most studies did not specifically include thromboembolism as an outcome.
Topics: Anti-Inflammatory Agents, Non-Steroidal; Antifibrinolytic Agents; Ethamsylate; Female; Hemostatics; Humans; Intrauterine Devices, Medicated; Lythraceae; Menorrhagia; Norethindrone; Plant Extracts; Progestins; Randomized Controlled Trials as Topic; Tranexamic Acid
PubMed: 29656433
DOI: 10.1002/14651858.CD000249.pub2 -
Frontiers in Oncology 2021Hypoxia is an important characteristic of most solid malignancies, and is closely related to tumor prognosis and therapeutic resistance. Hypoxia is one of the most...
Hypoxia is an important characteristic of most solid malignancies, and is closely related to tumor prognosis and therapeutic resistance. Hypoxia is one of the most important factors associated with resistance to conventional radiotherapy and chemotherapy. Therapies targeting tumor hypoxia have attracted considerable attention. Hypoxia-activated prodrugs (HAPs) are bioreductive drugs that are selectively activated under hypoxic conditions and that can accurately target the hypoxic regions of solid tumors. Both single-agent and combined use with other drugs have shown promising antitumor effects. In this review, we discuss the mechanism of action and the current preclinical and clinical progress of several of the most widely used HAPs, summarize their existing problems and shortcomings, and discuss future research prospects.
PubMed: 34395270
DOI: 10.3389/fonc.2021.700407 -
The New Zealand Medical Journal Nov 2005To determine the risk of serious cardiovascular events associated with the use of the COX-2 inhibitor valdecoxib and its prodrug parecoxib following major surgery. (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
To determine the risk of serious cardiovascular events associated with the use of the COX-2 inhibitor valdecoxib and its prodrug parecoxib following major surgery.
METHODS
A systematic review and meta-analysis of placebo-controlled randomised double-blind clinical trials of IV parecoxib followed by oral valdecoxib treatment, that presented data on serious cardiovascular events. Studies were identified from six databases including Medline and the FDA website on parecoxib/valdecoxib. The main outcome measure was major cardiovascular events. The pooled fixed effects estimates for the odds ratio for risk of cardiovascular events for the use of parecoxib/valdecoxib were calculated using the inverse variance weighting method.
RESULTS
Three studies with a total of 2,604 subjects were included in the meta-analysis. Parecoxib/valdecoxib was associated with a significantly increased risk of major cardiovascular events, with an odds ratio of 2.3 (95% CI: 1.1-4.7).
CONCLUSION
There is an increased cardiovascular risk associated with parecoxib/valdecoxib therapy in the post-surgical situation. These findings are consistent with a class effect for COX-2 inhibitors increasing the risk of cardiovascular events.
Topics: Cardiac Surgical Procedures; Cardiovascular Diseases; Cerebrovascular Disorders; Cyclooxygenase Inhibitors; Humans; Isoxazoles; Myocardial Infarction; Odds Ratio; Outcome and Process Assessment, Health Care; Pain, Postoperative; Risk Factors; Sulfonamides; Survival Analysis
PubMed: 16311613
DOI: No ID Found -
Open Heart Nov 2023Clopidogrel is a P2Y inhibitor that has become a mainstay treatment following percutaneous intervention with drug-eluting stent placement to decrease restenosis and its...
INTRODUCTION
Clopidogrel is a P2Y inhibitor that has become a mainstay treatment following percutaneous intervention with drug-eluting stent placement to decrease restenosis and its potential complications, including sudden cardiac death and ischaemic strokes in patients with significant vascular disease.
AREAS COVERED
As a prodrug, the metabolism and efficacy of clopidogrel are contingent on the presence of wild-type CYP450 (CYP2C19) alleles. Genetic polymorphisms and variants are well known to impair its ability to prevent major adverse cardiovascular events in these patients, with inadequate response rates as high as 30% in previous publications. Patterns of allelic frequencies are expected to exhibit similarities between individuals of the same ancestry, ethnic group or geographic region. Accordingly, we seek to further elucidate worldwide prevalence rates for genetic polymorphisms in the CYP2C19-dependent metabolism of clopidogrel and review the potential of personalised CYP2C19 genotyping in clinical practice to mitigate this high treatment resistance and its associated burden on patients.
EXPERTS' COMMENTARY
Our findings support the consideration of genotyping before initiation of therapy to guide adequate dosage or substitutions of other P2Y inhibitors to promote personalised, precision medicine and to prevent adverse events when these therapies may inevitably fail in patients with variants of the CYP450 (CYP2C19) system.
Topics: Humans; Clopidogrel; Platelet Aggregation Inhibitors; Cytochrome P-450 CYP2C19; Drug-Eluting Stents; Polymorphism, Genetic
PubMed: 37963685
DOI: 10.1136/openhrt-2023-002436 -
The Canadian Journal of Hospital... 2022Status epilepticus (SE) is a neurologic emergency with potential for substantial mortality and morbidity. Parenteral benzodiazepine is the established first-line... (Review)
Review
BACKGROUND
Status epilepticus (SE) is a neurologic emergency with potential for substantial mortality and morbidity. Parenteral benzodiazepine is the established first-line treatment but fails to control SE in about one-third of patients. Levetiracetam may be used for SE that is refractory to benzodiazepine therapy.
OBJECTIVE
To examine, by means of a systematic review, the role of IV levetiracetam for the treatment of SE in adults.
DATA SOURCES
MEDLINE, Embase, CENTRAL, and CINAHL databases were searched, from inception to August 18, 2020.
STUDY SELECTION AND DATA EXTRACTION
Included in this review were prospective randomized controlled trials comparing levetiracetam with another antiepileptic drug, given with or after a benzodiazepine, in adult patients with SE. The primary outcome was cessation of SE. Quality of evidence was assessed with the Cochrane risk-of-bias tool. Characteristics of the included studies were reported using descriptive statistics.
DATA SYNTHESIS
Five studies compared IV levetiracetam with valproic acid, phenytoin (or its prodrug fosphenytoin), or both. All 5 studies found no statistically significant differences in efficacy or safety end points. There were numerically more cases of hypotension and respiratory failure with phenytoin, and more cases of psychiatric adverse effects (e.g., post-ictal psychosis) with levetiracetam.
CONCLUSIONS
Available evidence suggests that levetiracetam is as effective as valproic acid or phenytoin for the cessation of SE in adults. Other factors should therefore dictate the choice of antiepileptic drug for patients with SE, such as adverse effect profile, logistics of administration, drug cost, inclusion on hospital formularies, and drug availability.
PubMed: 34987263
DOI: 10.4212/cjhp.v75i1.3254 -
Addiction (Abingdon, England) Nov 2011To assess the effectiveness of methamphetamine precursor regulations in reducing illicit methamphetamine supply and use. (Review)
Review
AIMS
To assess the effectiveness of methamphetamine precursor regulations in reducing illicit methamphetamine supply and use.
METHODS
A systematic review of 12 databases was used to identify studies that had evaluated the impact of methamphetamine precursor regulations on methamphetamine supply and/or use. The guidelines of the Effective Practice and Organization of Care Group (EPOC) of The Cochrane Collaboration were used to determine which study designs were included and assess their quality.
RESULTS
Ten studies met the inclusion criteria. These studies evaluated 15 interventions (13 regulations and two related interdiction efforts), all of which were located in North America. Interventions had consistent impacts across various indicators of methamphetamine supply and use. Seven of the 15 interventions produced reductions in methamphetamine indicators (ranging from 12% to 77%). Two of the largest impacts were seen following interdiction efforts, involving the closure of rogue pharmaceutical companies. There was no evidence of a shift into other types of drug use, or injecting use, although the impact on the synthetic drug market was not examined. Null effects were related largely to the existence of alternative sources of precursor chemicals or the availability of imported methamphetamine.
CONCLUSIONS
Methamphetamine precursor regulations can reduce indicators of methamphetamine supply and use. Further research is needed to determine whether regulations can be effective outside North America, particularly in developing countries, and what impact they have on the broader synthetic drug market. Improved data on precursor diversion are needed to facilitate the evaluation of precursor regulations.
Topics: Amphetamine-Related Disorders; Central Nervous System Stimulants; Commerce; Designer Drugs; Developing Countries; Drug and Narcotic Control; Humans; Illicit Drugs; Law Enforcement; Methamphetamine; Nasal Decongestants; North America; Prodrugs; Program Evaluation; Pseudoephedrine
PubMed: 21895829
DOI: 10.1111/j.1360-0443.2011.03582.x