BACKGROUND: Identification of real-time adverse drug reactions [ADRs] (as opposed to the risk of ADRs) in older poly-medicated people in primary care is a challenging task, often undertaken without an explicit strategy. This systematic review aims to evaluate replicable instruments and methods for identifying and addressing ADRs. METHODS: A systematic search was conducted in Medline, CINAHL, Scopus, Web of Science and Cochrane library, using controlled vocabulary (MeSH) and free-text terms. Randomised controlled trials (RCTs) implementing strategies to identify or resolve ADRs experienced by patients in primary care were included. Two reviewers independently screened studies, extracted data, and assessed the risk of bias using the Cochrane Risk of Bias tool. Discrepancies were resolved by discussion. RESULTS: From 2,182 unique records, 49 studies were identified for full review. Eight papers reporting results from 6 RCTs were included. All six trials utilised a list of medicine-related unwanted symptoms to identify ADRs. Two of three studies using adverse drug reaction questionnaires reported statistically significant increased rates of ADR reporting. Two of three studies that combined symptom questionnaires with prescriber consultations reported reductions in the number of health problems. Overall, results suggest that the three studies that described multidisciplinary collaborations using lists of ADRs plus prescriber reviews enhanced patient safety. However, the RCTs were unblinded and reported suboptimal retention. When considered as a whole, findings are equivocal and the data are too heterogenous to warrant any firm conclusions, beyond the need for more research to optimise strategies to safeguard patient wellbeing. IMPLICATIONS: Adaptable and scalable instruments with decision support are needed in primary care to identify and mitigate medicine-related harm in older poly-medicated people. The effectiveness of adverse drug reaction identification instruments, the value of comprehensive instruments, and the optimum method of delivery should be explored in multicentre trials.
BACKGROUND: Immune checkpoint inhibitors (ICIs) are an important therapeutic pillar in metastatic urothelial carcinoma (mUC). The occurrence of immune-related adverse events (irAEs) appears to be associated with improved outcomes in observational studies. However, these associations are likely affected by immortal time bias and do not represent causal effects. The aim of this study was to assess the effect of irAEs on outcomes while correcting for immortal time bias, using target trial emulation (TTE). METHODS: TTE was contrasted to adjusted naïve and time-updated Cox models. We performed a multi-institutional retrospective study involving mUC patients under ICI. The primary objective was to assess the impact of irAEs on progression-free survival (PFS) and overall survival (OS). Secondary endpoints included the influence of irAEs on objective response rates (ORRs) to ICI and the influence of systemic corticosteroids on outcomes. RESULTS: Among 335 patients (median age: 69 yrs), 69.6% received ICI in the second line or further lines. During a median follow-up of 21.1 months, 122 (36.4%) patients developed irAEs of any grade (grade ≥ 3: 14.9%). Hazard ratios (HRs) for PFS ranged from 0.37 for naïve adjusted Cox model to 0.88 (95% confidence interval (CI), 0.59-1.30) with time-updated covariates, and from 0.41 to 1.10 (95% CI, 0.69-1.75) for OS. TTE accounting for immortal time bias yielded a HR of 1.02 (95% CI, 0.72-1.44) for PFS, and 0.90 (95% CI, 0.62-1.30) for OS. In contrast to the naïve Cox model (HR = 2.26, 95% CI 1.26-4.05), the presence of irAEs was no longer a predictive factor for improved ORR in time-updated Cox models (HR = 1.27, 95% CI 0.68-2.36) and TTE (HR = 1.43, 95% CI 0.89-2.29). In patients with irAEs, systemic corticosteroids did not negatively impact survival. CONCLUSION: Using TTE, we were able to show that the occurrence of irAEs is no longer associated with better survival or improved response rates to ICI in mUC patients, in contrast to the naïve analysis. These findings demonstrate that TTE is a suitable formal framework to avoid immortal time bias in studies with time-dependent non-interventional exposures.
- Klíčová slova
- Adverse events, Immortal time bias, Immune checkpoint inhibitors, Immunotherapy, Metastatic, Target trial emulation, Urothelial cancer,
- MeSH
- inhibitory kontrolních bodů * škodlivé účinky terapeutické užití MeSH
- karcinom z přechodných buněk farmakoterapie mortalita imunologie MeSH
- lidé středního věku MeSH
- lidé MeSH
- metastázy nádorů MeSH
- nádory močového měchýře farmakoterapie mortalita imunologie patologie MeSH
- nežádoucí účinky léčiv etiologie MeSH
- retrospektivní studie MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- urologické nádory farmakoterapie mortalita imunologie patologie MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- multicentrická studie MeSH
- Názvy látek
- inhibitory kontrolních bodů * MeSH
Drug induced akathisia is classified as an extrapyramidal adverse effect. Although akathisia is quite common extrapyramidal adverse effect, it is often overlooked or mistaken for restlessness or agitation of another etiology. Drugs associated with the risk of extrapyramidal adverse effects (antipsychotics, antiemetics, antidepressants) belong to frequently used pharmacotherapy. The use of these drugs is often complicated by serious condition of a patient and several other comorbidities, which increase the risk of the aforementioned adverse effects. In many situations, akathisia can be more difficult to recognize and more easily attributed to non-drug etiology, especially outside the fields of psychiatry and neurology. The variability of the clinical symptoms and the similarity to other clinical entities that occur frequently (anxiety, delirium, agitated depression, restless legs syndrome, etc.) can lead to difficult determination of the etiology and to the administration of medication, which tends to worsen the problem. At the same time, akathisia can be a source of very strong distress for a patient and fundamentally reduce his quality of life.
- Klíčová slova
- drug-induced movement disorders, akathisia, antipsychotics, antidepressants, antiemetics,
- MeSH
- antipsychotika škodlivé účinky MeSH
- lidé MeSH
- poléková akatizie * etiologie diagnóza MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
- Názvy látek
- antipsychotika MeSH
This current study seeks to examine the pre-protective function of Quercetin in Cadmium (Cd)-induced liver damage, along with its modulation of the PI3K/Akt/NF-kappaB signaling pathway. A total of 60 male C57BL/6J mice were randomly assigned to four groups: control (C), quercetin (Q, 100 mg/kg/day), Cd (Cd, 2.5 mg/kg/day), and quercetin and Cd (Q+Cd). Before receiving Cd treatment, quercetin was administered intragastrically for 4 weeks. In the present study, liver markers, oxidative stress parameters, pro-inflammatory cytokines, liver histopathology, apoptotic markers and PI3K/Akt/NF-kappaB signaling molecules were examined. We observed that the body weight of the Cd-treated mice dramatically rise after 4 weeks of quercetin pre-administration, and the Cd concentration was significantly decreased. Liver function markers like alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP), and lactate dehydrogenase (LDH) were significantly reduced in quercetin treatment in Cd-induced mice. Additionally, we observed that quercetin reduced Cd-mediated liver injury in mice by assessing the level of malondialdehyde (MDA), and the activities of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and glutathione (GSH) concentrations and the histological alterations. By monitoring tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and interleukin-1beta (IL-1beta), quercetin successfully reduced the inflammatory cytokines that the Cd metal caused in the liver. Additionally, in the liver tissues of Cd-mediated, quercetin could enhance the expression of Bcl-2 and decrease the expression of p-Akt, p-PI3K, Bax, Caspase-9, Caspase-3, NF-kappaB. In conclusion, quercetin protects against Cd induced liver injury via several pathways, including oxidative stress, inflammation and apoptosis, and its protective effect correlates with antioxidant activity.
- MeSH
- antioxidancia * farmakologie MeSH
- fosfatidylinositol-3-kinasy * metabolismus MeSH
- játra účinky léků patologie metabolismus MeSH
- kadmium * toxicita MeSH
- lékové postižení jater * prevence a kontrola metabolismus patologie MeSH
- myši inbrední C57BL * MeSH
- myši MeSH
- NF-kappa B * metabolismus MeSH
- oxidační stres účinky léků MeSH
- protoonkogenní proteiny c-akt * metabolismus MeSH
- quercetin * farmakologie terapeutické užití MeSH
- signální transdukce * účinky léků MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- antioxidancia * MeSH
- fosfatidylinositol-3-kinasy * MeSH
- kadmium * MeSH
- NF-kappa B * MeSH
- protoonkogenní proteiny c-akt * MeSH
- quercetin * MeSH
Acute generalized exanthematous pustulosis (AGEP) is a rare, usually drug-induced, acute pustular rash. Despite the lack of strong data supporting the effectiveness of topical or systemic corticosteroids in this drug reaction, they are widely used. More generally, there is no consensus on the diagnostic modalities and the management of patients with AGEP. We aimed to provide European expert recommendations for the diagnosis and management or patients with AGEP. Members of the ToxiTEN group of the European Reference Network (ERN)-skin, all dermatologists and/or allergologists with expertise in drug reactions, elaborated these recommendations based on their own experience and on a review of the literature. Recommendations were separated into the following categories: professionals involved, assessment of the diagnosis of AGEP, management of the patient and allergological work-up after the acute phase. Consensus was obtained among experts for the list of professionals involved for the diagnosis and management of AGEP, including the minimum diagnostic work-up, the setting of management, the treatments, the modalities and the timing of allergological work-up and follow-up. European experts in drug allergies propose herein consensus on the diagnosis and management of patients with AGEP. A multidisciplinary approach is warranted, including dermatologists, allergologists and pharmacovigilance services.
- MeSH
- akutní generalizovaná exantematózní pustulóza * diagnóza etiologie terapie MeSH
- konsensus * MeSH
- lidé MeSH
- přehledová literatura jako téma MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- směrnice pro lékařskou praxi MeSH
- Geografické názvy
- Evropa MeSH
The effects of alpha-pinene (AP), a monoterpenoid, known for its antioxidant, anti-inflammatory, and anti-apoptotic properties, on methotrexate (MTX)-induced cardiac and hepatic damage were investigated in this study. Male Sprague-Dawley rats were divided into Control, Vehicle, AP, MTX, and AP+MTX groups (n=7). AP (50 mg/kg/day, 14 days) was applied subcutaneously in the AP and AP+MTX groups. MTX (20 mg/kg) was injected three days before sacrification. Serum CK-MB, troponin T, ALT, and AST levels, as well as cardiac and hepatic MDA, GSH, caspase-3, and p53 levels, were measured by ELISA. Histological changes in tissues were evaluated by scoring in terms of tissue damage and cellular degeneration parameters after hematoxylin-eosin staining. MTX caused significant increase in serum CK-MB, troponin T, ALT, and AST levels, hepatic and cardiac lipid peroxidation, GSH depletion, and caspase-3 level. However, tissue levels of p53 did not change significantly. MTX-induced histological deterioration was observed in both tissues. These MTX-induced changes were significantly reduced in the AP+MTX group. Present results show that MTX-induced cardiac and hepatic damage is prevented by AP pretreatment. This protection can be attributed to the antioxidant and anti-apoptotic properties of AP. Considering the importance of MTX in cancer treatment, AP appears to have highly promising potential as a cardioprotective and hepatoprotective agent in anti-tumoral therapy. Key words: MDA, GSH, Caspase-3, p53, Oxidative stress, Apoptosis.
- MeSH
- antioxidancia farmakologie MeSH
- bicyklické monoterpeny * farmakologie MeSH
- játra účinky léků patologie metabolismus MeSH
- krysa rodu Rattus MeSH
- lékové postižení jater prevence a kontrola patologie metabolismus MeSH
- methotrexát * toxicita MeSH
- monoterpeny farmakologie terapeutické užití MeSH
- myokard patologie metabolismus MeSH
- oxidační stres účinky léků MeSH
- potkani Sprague-Dawley * MeSH
- zvířata MeSH
- Check Tag
- krysa rodu Rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- alpha-pinene MeSH Prohlížeč
- antioxidancia MeSH
- bicyklické monoterpeny * MeSH
- methotrexát * MeSH
- monoterpeny MeSH
Linoleic acid (LA) not only functions as an essential nutrient, but also profoundly modulates oxidative stress and inflammatory response. However, the potential mechanisms have not been adequately researched. Hence, this study examined the potential pharmacological roles of LA and the underlying mechanisms in mice with lipopolysaccharide (LPS)-associated acute liver injury (ALI). The results indicated that treatment with LA alleviated the histopathological abnormalities in the hepatic and plasma levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and glutathione-S-transferase (GST) in mice with LPS exposure. In addition, LA inhibited the LPS-associated generation of proinflammatory factors, such as tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6), and downregulated the hepatic myeloperoxidase (MPO) level. In addition, the administration of LA resulted in a reduction in hepatic malondialdehyde (MDA) levels and an elevation in liver superoxide dismutase (SOD), reduced glutathione (GSH), catalase (CAT), and glutathione peroxidase (GSH-PX) levels. Further investigations revealed that LA promoted the expression of nuclear factor E2-related factor (Nrf2) and NAD(P)H: quinone oxidoreductase 1 (NQO1). In addition, the beneficial outcomes of LA on LPS-induced acute liver failure were revered when Nrf2 was pharmacologically suppressed by ML385. These experimental results demonstrated that LA supplementation attenuated LPS-associated acute hepatic impairment in mice via the activation of Nrf2.
- MeSH
- faktor 2 související s NF-E2 * metabolismus MeSH
- játra účinky léků metabolismus patologie MeSH
- kyselina linolová * farmakologie MeSH
- lékové postižení jater * metabolismus farmakoterapie patologie prevence a kontrola MeSH
- lipopolysacharidy * toxicita MeSH
- myši MeSH
- oxidační stres účinky léků MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- faktor 2 související s NF-E2 * MeSH
- kyselina linolová * MeSH
- lipopolysacharidy * MeSH
- Nfe2l2 protein, mouse MeSH Prohlížeč
The liver is a vital organ in human physiology positioned in the upper right quadrant of the peritoneal cavity, which plats a critical role in metabolic processes, detoxification of various substances and overall homeostasis. Along with these critical functions, hepatic diseases impose as significant global health threat. Liver illness is the cause of two million fatalities every year, or 4% of all deaths. Traditionally, healthcare providers have prescribed antibacterial and antiviral medications to address liver illness. Nephrotoxicity is a frequently observed negative reaction to drugs, with the majority of such events happening in individuals who have advanced cirrhosis. Thus, recognizing this gap, there is a dire need of exploration of pharmaceutical alterative for hepatic diseases, with special focus on their efficacy and reduced toxicity. Fruits have long been known to therapeutic impact on human health, thus exploration of fruits components namely pulp, seeds and peels containing phytochemicals have emerged as a promising avenue for hepatoprotective interventions. Thus, review comprehends the information about worldwide burden of chemical induced toxicity and injuries as well as highlight the on-going challenges in hepatic disease management. It also shed light on the valuable contributions fruit parts and their phytocompounds obtained from different components of fruits. Fruit pulp, especially when rich in flavonoids, has demonstrated significant potential in animal model studies. It has been observed to enhance the activity of antioxidant enzymes and reduce the expression of pro-inflammatory markers. The methanolic and ethanolic extracts have demonstrated the most favorable outcomes. Further, this review also discusses about the safety assessments of fruits extracts for their utilization as hepatoprotective agents.
- Klíčová slova
- Apoptosis, Extracts, Hepatoprotective, Inflammation, Liver damage, Polyphenols,
- MeSH
- játra účinky léků metabolismus MeSH
- lékové postižení jater prevence a kontrola MeSH
- lidé MeSH
- ochranné látky farmakologie MeSH
- ovoce * chemie MeSH
- rostlinné extrakty farmakologie MeSH
- semena rostlinná * chemie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
- Názvy látek
- ochranné látky MeSH
- rostlinné extrakty MeSH
OBJECTIVES: To compare the prevalence, regulations, and pharmacovigilance practices of clozapine use in Eastern European countries (except Russia). METHODS: Questionnaires and data from administrative databases (2016 and 2021), package inserts and national guidelines were collected from 21 co-authors from 21 countries. Reports of clozapine adverse drug reactions (ADRs) sent to the global pharmacovigilance database (VigiBase™) were analyzed from introduction to December 31, 2022. RESULTS: Clozapine prescription among antipsychotics in 2021 varied six-fold across countries, from 2.8 % in the Czech Republic to 15.8 % in Montenegro. The utilization of antipsychotics in both 2016 and 2021 was highest in Croatia, and lowest in Serbia in 2016, and Montenegro in 2021, which had half the defined daily dose (DDD)/1000/day compared to the Croatian data. From 2016 to 2021, the prevalence of antipsychotic use increased in almost all countries; the proportion of clozapine use mainly remained unchanged. Differences were detected in hematological monitoring requirements and clozapine approved indications. Only a few national schizophrenia guidelines mention clozapine-induced myocarditis or individual titration schemes. The VigiBase search indicated major underreporting regarding clozapine and its fatal outcomes. By comparison, the United Kingdom had less than half the population of these Eastern European countries but reported to VigiBase more clozapine ADRs by 89-fold and clozapine fatal outcomes by almost 300-fold. CONCLUSION: Clozapine is under-utilized in Eastern European countries. Introducing individualized clozapine treatment schedules may help to maximize clozapine benefits and safety. Major improvement is needed in reporting clozapine ADRs and fatal outcomes in Eastern European countries.
- Klíčová slova
- Clozapine/administration and dosage, Clozapine/adverse effects, Clozapine/therapeutic use, Drug labeling, Europe, Eastern, Schizophrenia,
- MeSH
- antipsychotika * škodlivé účinky MeSH
- databáze faktografické MeSH
- farmakovigilance * MeSH
- klozapin * škodlivé účinky MeSH
- lidé MeSH
- nežádoucí účinky léčiv epidemiologie MeSH
- schizofrenie farmakoterapie MeSH
- systémy pro sběr zpráv o nežádoucích účincích léků statistika a číselné údaje MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Geografické názvy
- východní Evropa epidemiologie MeSH
- Názvy látek
- antipsychotika * MeSH
- klozapin * MeSH
BACKGROUND: The study aimed to evaluate the agreement of prescribed drug dosages with renal dosing recommendations and describe adverse drug events (ADEs) contributing to hospital admissions of patients with chronic kidney disease (CKD). METHODS: This cross-sectional study focused on CKD patients admitted to University Hospital Hradec Králové, with an estimated glomerular filtration rate below 60 ml/min. The necessity for renal dosage adjustments was determined using the Summary of Product Characteristics (SmPC). For medications requiring renal dosage adjustment according to SmPC, agreement between the prescribed and recommended renal dosage was assessed. ADEs were adjudicated using the OPERAM drug-related hospital admissions adjudication guide. RESULTS: Of 375 CKD patients, 112 (30%, 95% CI 25-34) were prescribed drug dosages in disagreement with SmPC renal dosage recommendations. Perindopril, metformin, and ramipril were most frequently dosed in disagreement with SmPC. ADE-related hospital admissions occurred in 20% (95% CI 16-24) of CKD patients. CONCLUSION: CKD patients are often prescribed medication dosages in disagreement with SmPC renal dosing recommendations. Besides explicit factors, treatment goals, feasibility of monitoring and alternative treatment must be weighed when assessing drug and dosage appropriateness. Gastrointestinal bleeding was the most frequent ADE that contributed to hospital admissions of CKD patients.
- Klíčová slova
- Adverse drug event, adverse drug reaction, chronic kidney disease, hospitalization, medication error,
- MeSH
- chronická renální insuficience * komplikace MeSH
- hodnoty glomerulární filtrace MeSH
- ledviny MeSH
- lidé MeSH
- nemocnice MeSH
- nežádoucí účinky léčiv * epidemiologie etiologie MeSH
- průřezové studie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
