Polypharmacy in the elderly complicates therapy, increases cost, and is a challenge for healthcare agencies. In the context of the evolving role of the pharmacist, this systematic review examines the ...effectiveness of interventions led by pharmacists in reducing polypharmacy. A computerised search was conducted using Medline, Embase geriatrics and gerontology (2001 edition), the Cochrane Library and International Pharmaceutical Abstracts (IPA) databases. A manual search of articles on polypharmacy and the role of pharmacists in the therapy of the elderly and of the reference sections of all retrieved articles was also carried out. Search terms used were 'polypharmacy', 'elderly', 'aged', 'intervention' and 'pharmacist(s)'. Articles that fulfilled the following criteria were included: only elderly people were included in the study, or all ages were included but the study gave separate results for the elderly; the outcome was expressed as a reduction in the number of medications; a pharmacist participated in the study; and the study was a controlled or a randomised controlled study. We initially identified 106 articles, but only 14 studies met our four inclusion criteria. Reduction in the number of medications was not the major purpose of most selected studies but often a secondary outcome. Objectives differed, the general aim being to enhance the quality of prescribing in elderly patients. These controlled studies argued in favour of the effectiveness of pharmacists' interventions, even though the number of medications eliminated was small. Most studies were not designed to demonstrate the impact of reducing the number of drugs on the clinical consequences of polypharmacy (nonadherence, adverse drug reactions, drug-drug interactions, increased risk of hospitalisation, and medication errors). The most frequently reported outcome related to cost savings. It was therefore difficult to assess whether the interventions benefited the patient. The methodological quality of many identified studies was poor. In particular, the study objectives were often very broad and ill-defined. Polypharmacy itself has been defined in different ways and the appropriate definition may differ according to the patient population and the study setting. Further studies are needed to find the most effective way to reduce polypharmacy, especially in the frail elderly population, and to quantify the real advantages of simplifying their drug regimens in terms of improved quality of life.
Background and Objective
Cytochromes P450 (CYP) are the major enzymes involved in hepatic metabolism of drugs. Personalization of treatment in pediatrics is a major challenge, as it must not only ...take into account genetic, environmental, and physiological factors but also ontogeny. Published data in adults show that inflammation had an isoform-specific impact on CYP activities and we aimed to evaluate this impact in the pediatric population.
Methods
Articles listed in PubMed through 7 January, 2021 that studied the impact of inflammation on CYP activities in pediatrics were included in this systematic review. Sources of inflammation, victim drugs (CYP involved), effect of drug–disease interactions, number and age of subjects, and study design were extracted.
Results
Twenty-seven studies and case reports were included. The impact of inflammation on CYP activities appeared to be age dependent and isoform-specific, with some drug–disease interactions having significant pharmacokinetic and clinical impact. For example, midazolam clearance decreases by 70%, while immunosuppressant and theophylline concentrations increase three-fold and two-fold with intensive care unit admission and infection. Cytochrome P450 activity appears to return to baseline level when the disease is resolved.
Conclusions
Studies that have assessed the impact of inflammation on CYP activity are lacking in pediatrics, yet it is a major factor to consider to improve drug efficacy or safety. The scarce current data show that the impact of inflammation is isoform and age dependent. An effort must be made to improve the understanding of the impact of inflammation on CYP activities in children to better individualize treatment.
Cytochromes P450 (CYP) are subject to important interindividual variability in their activity due to genetic and environmental factors and some diseases. Limited human data support the idea that ...inflammation downregulates CYP activities. Our study aimed to evaluate the impact of orthopedic surgery (acute inflammation model) on the activity of six human CYP. This prospective observational study was conducted in 30 patients who underwent elective hip surgery at the Geneva University Hospitals in Switzerland. The Geneva phenotyping cocktail containing caffeine, bupropion, flurbiprofen, omeprazole, dextromethorphan, and midazolam as probe drugs respectively assessing CYP1A2, 2B6, 2C9, 2C19, 2D6, and 3A activities was administered orally before surgery, day 1 (D1) and 3 (D3) postsurgery and at discharge. Capillary blood samples were collected 2 hours after cocktail intake to assess metabolic ratios (MRs). Serum inflammatory markers (CRP, IL‐6, IL‐1β, TNF‐α, and IFN‐γ) were also measured in blood. CYP1A2 MRs decreased by 53% (P < 0.0001) between baseline and the nadir at D1. CYP2C19 and CYP3A activities (MRs) decreased by 57% (P = 0.0002) and 61% (P < 0.0001), respectively, with the nadir at D3. CYP2B6 and CYP2C9 MRs increased by 120% (P < 0.0001) and 79% (P = 0.018), respectively, and peaked at D1. Surgery did not have a significant impact on CYP2D6 MR. Hip surgery was a good acute inflammation model as CRP, IL‐6, and TNF‐α peak levels were reached between D1 and day 2 (D2). Acute inflammation modulated CYP activity in an isoform‐specific manner, with different magnitudes and kinetics. Acute inflammation may thus have a clinically relevant impact on the pharmacokinetics of these CYP substrates.
Coronavirus disease 2019 (COVID‐19), caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection, is a severe acute respiratory syndrome with an underlying inflammatory state. We ...have previously demonstrated that acute inflammation modulates cytochromes P450 (CYPs) activity in an isoform‐specific manner. We therefore hypothesized that COVID‐19 might also impact CYP activity, and thus aimed to evaluate the impact of acute inflammation in the context of SARS‐CoV‐2 infection on the six main human CYPs activity. This prospective observational study was conducted in 28 patients hospitalized at the Geneva University Hospitals (Switzerland) with a diagnosis of moderate to severe COVID‐19. They received the Geneva phenotyping cocktail orally during the first 72 hours of hospitalization and after 3 months. Capillary blood samples were collected 2 hours after cocktail administration to assess the metabolic ratios (MRs) of CYP1A2, 2B6, 2C9, 2C19, 2D6, and 3A. C‐reactive protein (CRP), interleukin 6 (IL‐6), and tumor necrosis factor‐α (TNF‐α) levels were also measured in blood. CYP1A2, CYP2C19, and CYP3A MRs decreased by 52.6% (P = 0.0001), 74.7% (P = 0.0006), and 22.8% (P = 0.045), respectively, in patients with COVID‐19. CYP2B6 and CYP2C9 MRs increased by 101.1% (P = 0.009) and 55.8% (P = 0.0006), respectively. CYP2D6 MR variation did not reach statistical significance (P = 0.072). As expected, COVID‐19 was a good acute inflammation model as mean serum levels of CRP, IL‐6, and TNF‐α were significantly (P < 0.001) higher during SARS‐CoV‐2 infection. CYP activity are modulated in an isoform‐specific manner by SARS‐CoV‐2 infection. The pharmacokinetics of CYP substrates, whether used to treat the disease or as the usual treatment of patients, could be therefore clinically impacted.
Apixaban, a direct oral anticoagulant, has emerged over the past few years because it is considered to have a low risk of drug‐drug interactions compared to vitamin K antagonists. To better ...characterize these interactions, we systematically reviewed studies evaluating the drug‐drug interactions involving apixaban and analyzed the drug‐drug interactions resulting in an adverse drug reaction reported in case reports and VigiBase. We systematically searched Medline, Embase, and Google Scholar up to 20 August 2018 for articles that investigated the occurrence of an adverse drug reaction due to a potential drug interacting with apixaban. Data from VigiBase came from case reports retrieved up to the 2 January 2018, where identification of potential interactions is performed in terms of two drugs, one adverse drug reaction triplet and potential signal detection using Omega, a three‐way measure of disproportionality. We identified 15 studies and 10 case reports. Studies showed significant variations in the area under the curve for apixaban and case reports highlighted an increased risk of hemorrhage or thromboembolic events due to a drug‐drug interaction. From VigiBase, a total of 1617 two drugs and one adverse drug reaction triplet were analyzed. The most reported triplet were apixaban—aspirin—gastrointestinal hemorrhage. Sixty‐seven percent of the drug‐drug interactions reported in VigiBase were not described or understood. In the remaining 34%, the majority were pharmacodynamic drug‐drug interactions. These data suggest that apixaban has significant potential for drug‐drug interactions, either with CYP3A/P‐gp modulators or with drugs that may impair hemostasis. The most described adverse drug reactions were adverse drug reactions related to hemorrhage or thrombosis, mostly through pharmacodynamic interactions. Pharmacokinetic drug‐drug interactions seem to be poorly detected.
Background
Bisphosphonate drugs can be used to prevent and treat osteoporosis and to reduce symptoms and complications of metastatic bone disease; however, they are associated with a rare but serious ...adverse event: osteonecrosis of the maxillary and mandibular bones. This condition is called bisphosphonate‐related osteonecrosis of the jaw or BRONJ. BRONJ is diagnosed when people who are taking, or have previously taken, bisphosphonates have exposed bone in the jaw area for more than eight weeks in the absence of radiation treatment. There is currently no "gold standard" of treatment for BRONJ. The three broad categories of intervention are conservative approaches (e.g. mouth rinse, antibiotics), surgical interventions and adjuvant non‐surgical strategies (e.g. hyperbaric oxygen therapy, platelet‐rich plasma), which can be used in combination.
Objectives
To determine the efficacy and safety of any intervention aimed at treating BRONJ.
Search methods
We searched the following databases to 15 December 2015: the Cochrane Oral Health Group Trials Register, the Cochrane Breast Cancer Group Trials Register (20 September 2011), the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE via Ovid, EMBASE via Ovid, CancerLit via PubMed, CINAHL via EBSCO and AMED via Ovid. We scanned the references cited in retrieved articles and contacted experts in the field, the first authors of included papers, study sponsors, other bisphosphonates investigators and pharmaceutical companies. We searched for ongoing trials through contact with trialists and by searching the US National Institutes of Health Trials Register (clinicaltrials.gov) and the World Health Organization Clinical Trials Registry Platform. We also conducted a grey literature search to September 2015.
Selection criteria
Randomised controlled trials (RCTs) comparing the effects of any treatment for BRONJ with another treatment or placebo.
Data collection and analysis
Two review authors independently screened the search results, assessed the risk of bias in the included trials and extracted data. When in dispute, we consulted a third review author.
Main results
One small trial at high risk of bias met the inclusion criteria. The trial randomised 49 participants, most of whom had cancer. It compared standard care (defined as surgery, antibiotics and oral rinses at the discretion of the oral‐maxillofacial surgeon) to standard care plus hyperbaric oxygen therapy (2 atmospheres twice a day for 40 treatments). The trial measured the percentage of participants who improved or healed at three, six, 12 and 18 months and last contact. It also measured mean weekly pain scores.
At three months, the study found that the participants in intervention group were more likely to have an improvement in their osteonecrosis than the standard care group participants (risk ratio (RR) 1.94, 95% confidence interval (CI) 1.01 to 3.74). There was no clear difference between the groups for the outcome 'healed' at three months (RR 3.60, 95% CI 0.87 to 14.82). There was no clear difference between the groups for improvement or healing when they were evaluated at six, 12 and 18 months and last contact.
The study did not give any information on adverse events.
Although the findings suggest adjunctive hyperbaric oxygen improved BRONJ, the quality of the evidence is very low since the only study was underpowered and was at high risk of bias due to lack of blinding, cross‐over of participants between groups and very high attrition (50% at 12 months and 80% at 18 months in this study, which was designed for an intended follow‐up of 24 months).
Authors' conclusions
There is a lack of evidence from randomised controlled trials to guide treatment of bisphosphonate‐related osteonecrosis of the jaw (BRONJ). One small trial at high risk of bias evaluated hyperbaric oxygen therapy (HBO) as an adjunct to "standard" care and could not confirm or refute the effectiveness of HBO. There are two ongoing trials of teriparatide treatment for BRONJ. We found no randomised controlled trials of any other BRONJ treatments. High quality randomised controlled trials are needed. We provide recommendations for their focus and design.
Trazodone is indicated for the treatment of major depressive disorder, but more frequently prescribed off-label at lower doses for insomnia in women of childbearing age. The aim of this study was to ...assess the risks linked to trazodone exposure during pregnancy for which limited safety data are available.
This multicenter, observational prospective cohort study compared pregnancy outcomes in women exposed to trazodone in early pregnancy against those in a reference group of women exposed to a selective serotonin reuptake inhibitors (SSRIs) between 1996 and 2021.
The sample included 221 trazodone and 869 SSRI-exposed pregnancies. Exposure to trazodone in the first trimester was not associated with a significant difference in the risk of major congenital anomalies (trazodone 1/169, 0.6%; SSRI 19/730, 2.6%; adjusted odds ratio, 0.2; 95% confidence interval, 0.03-1.77). The cumulative incidences of live birth were 61% and 73% in the trazodone and reference group, respectively (25% vs 18% for pregnancy loss and 14% vs 10% for pregnancy termination). Trazodone exposure was not associated with a significantly increased risk of pregnancy termination and pregnancy loss. The rate of small for gestational age infants did not differ between the groups.
This study did not reveal a significant difference in the risk of major congenital anomalies after first trimester exposure to trazodone, compared with SSRI exposure. Although this study is the largest so far, these results call for confirmation through further studies.
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