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The Cochrane Database of Systematic... Mar 2022This is an updated version of the Cochrane Review previously published in 2019. Epilepsy is one of the most common neurological disorders. It is estimated that up to 30%... (Review)
Review
BACKGROUND
This is an updated version of the Cochrane Review previously published in 2019. Epilepsy is one of the most common neurological disorders. It is estimated that up to 30% of individuals with epilepsy continue to have epileptic seizures despite treatment with an antiepileptic drug. These patients are classified as drug-resistant and require treatment with a combination of multiple antiepileptic drugs. Brivaracetam is a third-generation antiepileptic drug that is a high-affinity ligand for synaptic vesicle protein 2A. In this review we investigated the use of brivaracetam as add-on therapy for epilepsy.
OBJECTIVES
To evaluate the efficacy and tolerability of brivaracetam when used as add-on treatment for people with drug-resistant epilepsy.
SEARCH METHODS
For the latest update we searched the following databases on 7 September 2021: the Cochrane Register of Studies (CRS Web); MEDLINE (Ovid) 1946 to 3 September 2021. CRS Web includes randomised controlled trials (RCTs) and quasi-RCTs from PubMed, Embase, ClinicalTrials.gov, the World Health Organization International Clinical Trials Registry Platform, the Cochrane Central Register of Controlled Trials (CENTRAL), and the specialised registers of Cochrane Review Groups including Cochrane Epilepsy.
SELECTION CRITERIA
We searched for parallel-group RCTs that recruited people of any age with drug-resistant epilepsy. We accepted studies with any level of blinding (double-blind, single-blind, or unblinded).
DATA COLLECTION AND ANALYSIS
In accordance with standard Cochrane methodological procedures, two review authors independently assessed trials for inclusion before evaluating trial quality and extracting relevant data. The primary outcome to be assessed was 50% or greater reduction in seizure frequency. Secondary outcomes were: seizure freedom, treatment withdrawal for any reason, treatment withdrawal due to adverse events, the proportion of participants who experienced any adverse events, and drug interactions. We used an intention-to-treat population for all primary analyses, and presented results as risk ratios (RRs) with 95% confidence intervals (CIs).
MAIN RESULTS
We did not identify any new studies for this update, therefore the results and conclusions of the review are unchanged. The previous review included six studies involving a total of 2411 participants. Only one study included participants with both focal and generalised onset seizures; the other five trials included participants with focal onset seizures only. Study participants were aged 16 to 80 years. Treatment periods ranged from 7 to 16 weeks. We judged two studies to have low risk of bias and four to have unclear risk of bias. Details on the method used for allocation concealment and how blinding was maintained were insufficient in one study each. One study did not report all outcomes prespecified in the trial protocol, and there were discrepancies in reporting in a further study. Participants receiving brivaracetam add-on were more likely to experience a 50% or greater reduction in seizure frequency than those receiving placebo (RR 1.81, 95% CI 1.53 to 2.14; 6 studies; moderate-certainty evidence). Participants receiving brivaracetam were more likely to attain seizure freedom; however, the evidence is of low certainty (RR 5.89, 95% CI 2.30 to 15.13; 6 studies). The incidence of treatment withdrawal for any reason was slightly greater for participants receiving brivaracetam compared to those receiving placebo (RR 1.27, 95% CI 0.94 to 1.74; 6 studies; low-certainty evidence). The risk of participants experiencing one or more adverse events did not differ significantly following treatment with brivaracetam compared to placebo (RR 1.08, 95% CI 1.00 to 1.17; 5 studies; moderate-certainty evidence). However, participants receiving brivaracetam did appear to be more likely to withdraw from treatment due to adverse events compared with those receiving placebo (RR 1.54, 95% CI 1.02 to 2.33; 6 studies; low-certainty evidence).
AUTHORS' CONCLUSIONS
When used as add-on therapy for individuals with drug-resistant epilepsy, brivaracetam may be effective in reducing seizure frequency and may aid patients in achieving seizure freedom. However, add-on brivaracetam is probably associated with a greater proportion of treatment withdrawals due to adverse events compared with placebo. It is important to note that only one of the eligible studies included participants with generalised epilepsy. None of the included studies involved participants under the age of 16, and all studies were of short duration. Consequently, the findings of this review are mainly applicable to adult patients with drug-resistant focal epilepsy. Future research should focus on investigating the tolerability and efficacy of brivaracetam during longer-term follow-up, as well as assess the efficacy and tolerability of add-on brivaracetam in managing other types of seizures and in other age groups.
Topics: Adult; Anticonvulsants; Drug Resistant Epilepsy; Drug Therapy, Combination; Epilepsy, Generalized; Humans; Pyrrolidinones; Randomized Controlled Trials as Topic; Seizures
PubMed: 35285519
DOI: 10.1002/14651858.CD011501.pub3 -
Psychopharmacology Nov 2022While one of the basic axioms of pharmacology postulates that there is a relationship between the concentration and effects of a drug, the value of measuring blood... (Meta-Analysis)
Meta-Analysis Review
RATIONALE
While one of the basic axioms of pharmacology postulates that there is a relationship between the concentration and effects of a drug, the value of measuring blood levels is questioned by many clinicians. This is due to the often-missing validation of therapeutic reference ranges.
OBJECTIVES
Here, we present a prototypical meta-analysis of the relationships between blood levels of aripiprazole, its target engagement in the human brain, and clinical effects and side effects in patients with schizophrenia and related disorders.
METHODS
The relevant literature was systematically searched and reviewed for aripiprazole oral and injectable formulations. Population-based concentration ranges were computed (N = 3,373) and pharmacokinetic influences investigated.
RESULTS
Fifty-three study cohorts met the eligibility criteria. Twenty-nine studies report blood level after oral, 15 after injectable formulations, and nine were positron emission tomography studies. Conflicting evidence for a relationship between concentration, efficacy, and side effects exists (assigned level of evidence low, C; and absent, D). Population-based reference ranges are well in-line with findings from neuroimaging data and individual efficacy studies. We suggest a therapeutic reference range of 120-270 ng/ml and 180-380 ng/ml, respectively, for aripiprazole and its active moiety for the treatment of schizophrenia and related disorders.
CONCLUSIONS
High interindividual variability and the influence of CYP2D6 genotypes gives a special indication for Therapeutic Drug Monitoring of oral and long-acting aripiprazole. A starting dose of 10 mg will in most patients result in effective concentrations in blood and brain. 5 mg will be sufficient for known poor metabolizers.
Topics: Humans; Aripiprazole; Schizophrenia; Reference Values; Antipsychotic Agents; Cytochrome P-450 CYP2D6
PubMed: 36195732
DOI: 10.1007/s00213-022-06233-2 -
British Journal of Clinical Pharmacology Apr 2020Amisulpride, a first-line schizophrenia treatment, has shown large interindividual variability in plasma/serum levels, often outside the reference range (100-320 ng/mL).... (Meta-Analysis)
Meta-Analysis Review
AIMS
Amisulpride, a first-line schizophrenia treatment, has shown large interindividual variability in plasma/serum levels, often outside the reference range (100-320 ng/mL). This study aims to clarify the impact of dose, sex, age and related factors for the interpatient variability in amisulpride plasma/serum concentration.
METHODS
Both English and Chinese databases were searched from their inception to May 16, 2019, using the terms: amisulpride and (plasma OR serum OR blood OR "drug monitoring" OR concentration). Studies reporting concentrations and either a dose, associated factor, clinical outcome or side effect were included.
RESULTS
Fourteen studies with 1628 participants were eventually included. Eligible articles yielded data on drug concentration and dose, averaging 333.9 (95% confidence interval [CI]: 294.5-373.3) ng/mL and 636.2 (95% CI: 549.7-722.6) mg/d, respectively. The calculated mean concentration-to-dose (C/D) ratio was 0.60 (95% CI: 0.52-0.67) (ng/mL)/mg. Subgroup analysis suggested that female patients on combined lithium-amisulpride have higher concentration levels and C/D ratios. Age was slight positive associated with C/D ratio while not for plasma level. Smoker patients have high concentration level than nonsmoking patients but not for C/D. Responsive and nonresponsive groups did not differ in concentration and C/D.
CONCLUSION
Pooled concentration levels of amisulpride were higher than recommended with wide individual variation, especially in older patients, female patients and patients taking amisulpride combined with lithium. The specific therapeutic reference range for amisulpride may require reconstruction, which should consider the influence of age, sex, kidney function, drug-drug interactions, different dose regimens and sampling times in future study.
Topics: Aged; Amisulpride; Antipsychotic Agents; Drug Monitoring; Female; Humans; Schizophrenia; Sulpiride
PubMed: 32090363
DOI: 10.1111/bcp.14246 -
Frontiers in Neuroendocrinology Oct 2023Substance use disorder (SUD) is a chronic condition characterized by pathological drug-taking and seeking behaviors. Remarkably different between males and females,... (Review)
Review
Substance use disorder (SUD) is a chronic condition characterized by pathological drug-taking and seeking behaviors. Remarkably different between males and females, suggesting that drug addiction is a sexually differentiated disorder. The neurobiological bases of sex differences in SUD include sex-specific reward system activation, influenced by interactions between gonadal hormone level changes, dopaminergic reward circuits, and epigenetic modifications of key reward system genes. This systematic review, adhering to PICOS and PRISMA-P 2015 guidelines, highlights the sex-dependent roles of estrogens, progesterone, and testosterone in SUD. In particular, estradiol elevates and progesterone reduces dopaminergic activity in SUD females, whilst testosterone and progesterone augment SUD behavior in males. Finally, SUD is associated with a sex-specific increase in the rate of opioid and monoaminergic gene methylation. The study reveals the need for detailed research on gonadal hormone levels, dopaminergic or reward system activity, and epigenetic landscapes in both sexes for efficient SUD therapy development.
Topics: Female; Humans; Male; Dopamine; Epigenesis, Genetic; Gonadal Steroid Hormones; Meta-Analysis as Topic; Progesterone; Sex Characteristics; Substance-Related Disorders; Systematic Reviews as Topic; Testosterone
PubMed: 37543184
DOI: 10.1016/j.yfrne.2023.101085 -
Cancer Treatment Reviews Apr 2023The anti-tumor activity of WEE1 inhibitors (WEE1i) in gynecological malignancies has recently been demonstrated in clinical trials and its rationale is based on... (Review)
Review
INTRODUCTION
The anti-tumor activity of WEE1 inhibitors (WEE1i) in gynecological malignancies has recently been demonstrated in clinical trials and its rationale is based on biological/molecular features of gynecological cancers. With this systematic review, we aim to outline the clinical development and current evidence regarding the efficacy and safety of these targeted agents in in this patient group.
METHODS
Systematic literature review of trials including patients with gynecological cancers treated with a WEE1i. The primary objective was to summarize the efficacy of WEE1i in gynecological malignancies regarding objective response rate (ORR), clinical benefit rate (CBR), overall survival (OS) and progression-free survival (PFS). Secondary objectives included toxicity profile, Maximum Tolerated Dose (MTD), pharmacokinetics, drug-drug interactions and exploratory objectives such as biomarkers for response.
RESULTS
26 records were included for data extraction. Almost all trials used the first-in-class WEE1i adavosertib; one conference abstract reported about Zn-c3. The majority of the trials included diverse solid tumors (n = 16). Six records reported efficacy results of WEE1i in gynecological malignancies (n = 6). Objective response rates of adavosertib monotherapy or in combination with chemotherapy ranged between 23% and 43% in these trials. Median PFS ranged from 3.0 to 9.9 months. The most common adverse events were bone marrow suppression, gastrointestinal toxicities and fatigue. Mainly alterations in cell cycle regulator genes TP53 and CCNE1 were potential predictors of response.
CONCLUSION
This report summarizes encouraging clinical development of WEE1i in gynecological cancers and considers its application in future studies. Biomarker-driven patient selection might be essential to increase the response rates.
Topics: Female; Humans; Genital Neoplasms, Female; Antineoplastic Agents; Protein-Tyrosine Kinases; Cell Cycle Proteins
PubMed: 36893690
DOI: 10.1016/j.ctrv.2023.102531 -
BMC Cancer Nov 2023RAS mutations affect prognosis in patients with metastatic colorectal cancer (mCRC) and have been identified as strong negative predictive markers for anti-epidermal... (Meta-Analysis)
Meta-Analysis
BACKGROUND
RAS mutations affect prognosis in patients with metastatic colorectal cancer (mCRC) and have been identified as strong negative predictive markers for anti-epidermal growth factor receptor monoclonal antibody (anti-EGFR mAb) therapy, but many tumors containing wild-type RAS genes still do not respond to these therapies. Some additional biomarkers may have prognostic or predictive roles, but conclusions remain controversial.
METHODS
We performed a meta-analysis and systematic review of randomized controlled trials comparing anti-EGFR mAb therapy with alternative therapy that investigated the prognostic and predictive impact of additional biomarkers in RAS wild-type (wt) mCRC patients. Hazard ratios (HRs) and 95% confidence intervals (CIs) for progression-free survival (PFS) and overall survival (OS) and odds ratios (ORs) for objective response rate (ORR) were calculated. The prognostic value of biomarkers was investigated by separately pooling HR and OR for different treatment groups in an individual study. The predictive value was assessed by pooling study interactions between treatment effects and biomarker subgroups.
RESULTS
Thirty publications reporting on eighteen trials were selected, including a total of 13,507 patients. In prognostic analysis, BRAF mutations were associated with poorer PFS [HRs = 3.76 (2.47-5.73) and 2.69 (1.82-3.98)] and OS [HRs = 2.66 (1.95-3.65) and 2.45 (1.55-3.88)] in both the experimental and control arms; low miR-31-3p expression appeared to have longer PFS and OS. In terms of predictive effect, a lack of response to anti-EGFR therapy was observed in patients with BRAF mutant tumors (P < 0.01 for PFS). Patients with tumors with any mutation in the KRAS/NRAS/BRAF/PIK3CA gene also showed similar results compared with all wild-type tumors (P for PFS, OS, and ORR were < 0.01, < 0.01 and 0.01, respectively). While low miR-31-3p expression could predict PFS (P = 0.01) and OS (P = 0.04) benefit. The prognostic and predictive value regarding PIK3CA mutations, PTEN mutations or deletions, EGFR, EREG/AREG, HER2, HER3, and HER4 expression remains uncertain.
CONCLUSIONS
In RAS wt mCRC patients receiving EGFR-targeted therapy, BRAF mutation is a powerful prognostic and therapy-predictive biomarker, with no effect found for PIK3CA mutation, PTEN mutation or deletion, but the combined biomarker KRAS/NRAS/BRAF/PIK3CA mutations predict resistance to anti-EGFR therapy. Low miR-31-3p expression may have positive prognostic and therapy predictive effects. Evidence on the prognostic and predictive roles of EGFR and its ligands, and HER2/3/4 is insufficient.
Topics: Humans; Prognosis; Proto-Oncogene Proteins B-raf; Colorectal Neoplasms; Proto-Oncogene Proteins p21(ras); ErbB Receptors; Antibodies, Monoclonal; Colonic Neoplasms; Rectal Neoplasms; Biomarkers; Class I Phosphatidylinositol 3-Kinases; Mutation; MicroRNAs; Biomarkers, Tumor
PubMed: 37974093
DOI: 10.1186/s12885-023-11600-z -
European Journal of Hospital Pharmacy :... Jan 2021The prevalence of drug-drug interactions (DDIs) in hospital settings is variable, and elderly patients are considered a high risk population for DDIs. There are no... (Review)
Review
BACKGROUND
The prevalence of drug-drug interactions (DDIs) in hospital settings is variable, and elderly patients are considered a high risk population for DDIs. There are no systematic reviews describing the prevalence of DDIs in hospitalised elderly patients.
OBJECTIVES
To assess and summarise the available data on the prevalence of DDIs in hospitalised elderly patients and to describe which drugs, drug classes and drug combinations are most commonly involved in DDIs.
DATA SOURCE
A systematic electronic literature search was conducted on Medline/PubMed, Embase, Lilacs, SciElo, Web of Science, Cinahl, Scopus, Cochrane, OpenGrey, Capes Thesis Bank, OasisBR, OpenAire and abstracts from scientific events, without limitation on language or period of publication. Study selection was completed on 21 September 2018.
STUDY ELIGIBILITY CRITERIA, PARTICIPANTS AND INTERVENTIONS
Original observational studies that reported the prevalence of actual or potential DDIs during hospitalisation in patients aged 60 years or older were included. The main outcome measure was prevalence of DDIs and number of DDIs per patient. Subgroup analysis was performed in studies that reported the prevalence of DDIs in geriatric units.
STUDY APPRAISAL AND SYNTHESIS METHODS
Study quality was assessed using the Agency for Healthcare Research and Quality methodological checklist for cross sectional and prevalence studies.
RESULTS
34 studies were included, involving 9577 patients. The prevalence of DDIs ranged from 8.34% to 100%. In studies conducted in geriatric units, the prevalence ranged from 80.5% to 90.5%. The number of DDIs per patient ranged from 1.2 to 30.6. Single drugs most commonly involved in DDIs were furosemide, captopril, warfarin and dipyrone. Drug classes mostly involved were potassium sparing diuretics and angiotensin converting enzyme inhibitors.
LIMITATIONS
The main limitation is the heterogeneity between the included studies that precluded a meta-analysis. Several different methods were used to identify DDIs, majorly, and potential DDIs. Few studies have reported measures to control the quality of the collected data.
CONCLUSIONS AND IMPLICATIONS OF KEY FINDINGS
The prevalence of DDIs ranged widely, and the variation may reflect differences in the conditions of the elderly patients and level of attention (or complexity of care), as well as methodological differences, especially the methods and/or software used to identify DDIs.
SYSTEMATIC REVIEW REGISTRATION NUMBER
CRD42018096720.
Topics: Aged; Cross-Sectional Studies; Drug Interactions; Hospitalization; Humans; Middle Aged; Prevalence; United States
PubMed: 33355278
DOI: 10.1136/ejhpharm-2019-002111 -
Journal of Nanobiotechnology Aug 2023Lymph nodes targeted drug delivery is an attractive approach to improve cancer immunotherapy outcomes. Currently, the depth of understanding of afferent and efferent... (Review)
Review
Lymph nodes targeted drug delivery is an attractive approach to improve cancer immunotherapy outcomes. Currently, the depth of understanding of afferent and efferent arms in brain immunity reveals the potential clinical applications of lymph node targeted drug delivery in brain tumors, e.g., glioblastoma. In this work, we systematically reviewed the microenvironment of glioblastoma and its structure as a basis for potential immunotherapy, including the glial-lymphatic pathway for substance exchange, the lymphatic drainage pathway from meningeal lymphatic vessels to deep cervical lymph nodes that communicate intra- and extracranial immunity, and the interaction between the blood-brain barrier and effector T cells. Furthermore, the carriers designed for lymph nodes targeted drug delivery were comprehensively summarized. The challenges and opportunities in developing a lymph nodes targeted delivery strategy for glioblastoma using nanotechnology are included at the end.
Topics: Humans; Glioblastoma; Lymph Nodes; Brain Neoplasms; Brain; Drug Delivery Systems; Tumor Microenvironment
PubMed: 37542241
DOI: 10.1186/s12951-023-02011-0 -
Drugs & Aging Feb 2023Drug-drug interactions (DDIs) can lead to medication-related harm, and the older population is at greatest risk. We conducted a systematic review and meta-analysis to... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Drug-drug interactions (DDIs) can lead to medication-related harm, and the older population is at greatest risk. We conducted a systematic review and meta-analysis to estimate DDI prevalence and identify common DDIs in older community-dwelling adults.
METHODS
PubMed and EMBASE were searched for observational studies published between 01/01/2010 and 10/05/2021 reporting DDI prevalence in community-dwelling individuals aged ≥ 65 years. Nursing home and inpatient hospital studies were excluded. Study quality was assessed using the Joanna Briggs Institute critical appraisal tool. Meta-analysis was performed using a random-effects model with logit transformation. Heterogeneity was evaluated using Cochran's Q and I. DDI prevalence and 95% confidence intervals (CIs) are presented. All analyses were performed in R (version 4.1.2).
RESULTS
There were 5144 unique articles identified. Thirty-three studies involving 17,011,291 community-dwelling individuals aged ≥ 65 years met inclusion criteria. Thirty-one studies reported DDI prevalence at the study-participant level, estimates ranged from 0.8% to 90.6%. The pooled DDI prevalence was 28.8% (95% CI 19.3-40.7), with significant heterogeneity (p < 0.10; I = 100%; tau = 2.13) largely explained by the different DDI identification methods. Therefore, 26 studies were qualitatively synthesised and seven studies were eligible for separate meta-analyses. In a meta-analysis of three studies (N = 1122) using Micromedex, pooled DDI prevalence was 57.8% (95% CI 52.2-63.2; I = 69.6%, p < 0.01). In a meta-analysis of two studies (N = 809,113) using Lexi-Interact, pooled DDI prevalence was 30.3% (95% CI 30.2-30.4; I = 6.8%). In a meta-analysis of two studies (N = 947) using the 2015 American Geriatrics Society Beers criteria, pooled DDI prevalence was 16.6% (95% CI 5.6-40.2; I = 97.5%, p < 0.01). Common DDIs frequently involved cardiovascular drugs, including ACE inhibitor-potassium-sparing diuretic; amiodarone-digoxin; and amiodarone-warfarin.
CONCLUSIONS
DDIs are prevalent among older community-dwelling individuals; however, the methodology used to estimate these events varies considerably. A standardised methodology is needed to allow meaningful measurement and comparison of DDI prevalence.
Topics: Humans; Aged; Independent Living; Prevalence; Drug Interactions; Nursing Homes; Skilled Nursing Facilities
PubMed: 36692678
DOI: 10.1007/s40266-022-01001-5 -
Nucleic Acids Research Jun 2022At the time of writing, although siRNA therapeutics are approved for human use, no official regulatory guidance specific to this modality is available. In the absence of...
At the time of writing, although siRNA therapeutics are approved for human use, no official regulatory guidance specific to this modality is available. In the absence of guidance, preclinical development for siRNA followed a hybrid of the small molecule and biologics guidance documents. However, siRNA differs significantly from small molecules and protein-based biologics in its physicochemical, absorption, distribution, metabolism and excretion properties, and its mechanism of action. Consequently, certain reports typically included in filing packages for small molecule or biologics may benefit from adaption, or even omission, from an siRNA filing. In this white paper, members of the 'siRNA working group' in the IQ Consortium compile a list of reports included in approved siRNA filing packages and discuss the relevance of two in vitro reports-the plasma protein binding evaluation and the drug-drug interaction risk assessment-to support siRNA regulatory filings. Publicly available siRNA approval packages and the literature were systematically reviewed to examine the role of siRNA plasma protein binding and drug-drug interactions in understanding pharmacokinetic/pharmacodynamic relationships, safety and translation. The findings are summarized into two decision trees to help guide industry decide when in vitro siRNA plasma protein binding and drug-drug interaction studies are warranted.
Topics: Biological Products; Blood Proteins; Decision Trees; Drug Interactions; Humans; Protein Binding; RNA, Small Interfering
PubMed: 35687098
DOI: 10.1093/nar/gkac456