Cornelis Kramers

Efficacy and safety of medical cannabinoids in older subjects: a systematic review.

This systematic review aims to integrate the evidence on indications, efficacy, safety and pharmacokinetics of medical cannabinoids in older subjects. The literature search was conducted using PubMed, EMBASE, CINAHL and Cochrane Library. We selected controlled trials including solely older subjects (≥65 years) or reporting data on older subgroups. 105 (74%) papers, on controlled intervention trials, reported the inclusion of older subjects. Five studies reported data on older persons separately. These were randomized controlled trials, including in total 267 participants (mean age 47-78 years). Interventions were oral tetrahydrocannabinol (THC) (n=3) and oral THC combined with cannabidiol (n=2). The studies showed no efficacy on dyskinesia, breathlessness and chemotherapy induced nausea and vomiting. Two studies showed that THC might be useful in treatment of anorexia and behavioral symptoms in dementia. Adverse events were more common during cannabinoid treatment compared to the control treatment, and were most frequently sedation like symptoms. Although trials studying medical cannabinoids included older subjects, there is a lack of evidence of its use specifically in older patients. Adequately powered trials are needed to assess the efficacy and safety of cannabinoids in older subjects, as the potential symptomatic benefit is especially attractive in this age group.

Adherence to biochemical monitoring recommendations in patients starting with renin angiotensin system inhibitors: a retrospective cohort study in the Netherlands.

Background: Renin angiotensin system inhibitors (RASIs) are frequently involved in serious adverse events. These events principally occur in high-risk patients and often arise within the first days after treatment initiation; therefore, guidelines recommend biochemical monitoring within 3 weeks after the start of therapy with RASIs.Objective: The purpose of this study was to examine the level of biochemical monitoring directly after treatment initiation with RASIs in patients with different risk profiles and to study the attitudes of the physicians involved towards biochemical monitoring.Methods: We carried out a retrospective analysis of 202 patients who started RASI therapy in 2006 in Groesbeek, the Netherlands. We determined the rate of serum creatinine and potassium monitoring within 3 weeks after the start of therapy. In addition, we studied the intentions and attitudes towards biochemical monitoring during RASI therapy among 68 general practitioners and medical specialists by way of a brief questionnaire.Results: Serum creatinine and potassium monitoring after treatment initiation was performed in 34% and 28% of patients, respectively. Of all the patients, 29% had two or more additional risk factors for renal function deterioration. In these high-risk patients, creatinine was significantly less often monitored compared with low-risk patients (22% vs 39%). In contrast to these findings, the prescribing physicians claimed to check serum creatinine within 2 weeks after treatment initiation in 85% of their patients. Most of the prescribing physicians (88%) rated this monitoring as (very) important.Conclusions: We demonstrated that, despite positive intentions of physicians, the biochemical monitoring recommendation in patients treated with RASIs is poorly met. In addition, serum creatinine monitoring was significantly less often performed in high-risk patients compared with low-risk patients.

Safety and pharmacokinetics of oral delta-9-tetrahydrocannabinol in healthy older subjects: A randomized controlled trial

There is a great concern about the safety of THC-based drugs in older people (≥65 years), as most of THC-trials did not include such group. In this phase 1, randomized, double-blind, double-dummy, placebo-controlled, cross-over trial, we evaluated the safety and pharmacokinetics of three oral doses of Namisol(®), a novel THC in tablet form, in older subjects. Twelve healthy older subjects (6 male; mean age 72±5 years) randomly received a single oral dose of 3mg, 5mg, or 6.5mg of THC or matching placebo, in a crossover manner, on each intervention day. The data for 11 subjects were included in the analysis. The data of 1 subject were excluded due to non-compliance to study medication. THC was safe and well tolerated. The most frequently reported adverse events (AEs) were drowsiness (27%) and dry mouth (11%). Subjects reported more AEs with THC 6.5mg than with 3mg (p=0.048), 5mg (p=0.034) and placebo (p=0.013). There was a wide inter-individual variability in plasma concentrations of THC. Subjects for whom the Cmax fell within the sampling period (over 2h), Cmax was 1.42-4.57ng/mL and Tmax was 67-92min. The AUC0-2h (n=11) was 1.67-3.51ng/mL. Overall, the pharmacodynamic effects of THC were smaller than effects previously reported in young adults. In conclusion, THC appeared to be safe and well tolerated by healthy older individuals. Data on safety and effectiveness of THC in frail older persons are urgently required, as this population could benefit from the therapeutic applications of THC.

Metamizole (Dipyrone) as an Alternative Agent in Postoperative Analgesia in Patients with Contraindications for Nonsteroidal Anti-Inflammatory Drugs.

Nonsteroidal anti‐inflammatory drugs (NSAIDs) play an important role in multimodal pain management. In patients with a contraindication for NSAIDs, pain management is challenging. A recent Dutch anesthesiology guideline propagates the use of metamizole (dipyrone) in these patients. Metamizole is a controversial drug, its use being previously discouraged because of the risk for agranulocytosis. We discuss whether metamizole could be an alternative to classical NSAIDs and opioids in postoperative pain management despite this drawback.

Acute intoxications: Differences in management between six Dutch hospitals

Abstract Context. Acute intoxications are frequently seen in Dutch hospitals. Based on single-centre studies and the fact that there are no clear guidelines, we hypothesised that hospital admission of acute intoxications may vary. Furthermore, decontamination treatment of poisonings may differ between hospitals, as earlier studies showed that adherence to international guidelines concerning decontamination may be poor. Objective. We aim to identify possible variations in Dutch hospital admission and decontamination treatment of patients with acute intoxications. Materials and methods. Data on acute intoxications was retrospectively collected from patient records from the emergency departments of six Dutch hospitals. All patients older than 14 years who presented between 1 January 2008 and 31 December 2008 were included in the study. Results. The percentage of suicide attempts differed significantly between the hospitals (25–73%, p < 0.0001) as equally the percentage of intoxications with drugs of abuse (18–61%, p < 0.0001). Marked differences in admission rates were found (27–78%, p < 0.0001) and these differences remained even when intoxications because of suicide attempts and drugs of abuse were analysed separately (admission rate of 52–87%, p < 0.0001 and 8–71%, p < 0.0001 respectively). Reported consultation with the National Poisons Information Centre differed between hospitals (range 0% to 80–100%). No statistical differences were found between hospitals for the use of activated charcoal (16.1–42.5%, p = 0.037). Gastric lavage was used infrequently in all hospitals. (6.6–16.7%, p = 0.614). Discussion and conclusion. The admission rate of patients with an acute intoxication varies considerably, especially in the case of intoxications with drugs of abuse. Consultations with the National Poisons Information Centre differed between the six hospitals. Rates of decontamination did not vary, which may indicate adherence to guidelines by the American Academy of Clinical Toxicology, European Association of Poisons Centres and Clinical Toxicologists. National guidelines or admission algorithms may reduce variations in poisoning management and make the care for these patients more efficient.

Potentially inappropriate prescribing in older patients admitted to psychiatric hospital

The objectives of this study are to determine the prevalence of potentially inappropriate prescribing including potentially inappropriate medications (PIMs) and potential prescription omissions (PPOs) and to assess related risk factors in older people with major psychiatric illness.

Pharmacovigilance Skills, Knowledge and Attitudes in our Future Doctors - A Nationwide Study in the Netherlands

Pharmacovigilance centres monitor the safety of drugs, based on adverse drug reactions (ADRs) reported by doctors, pharmacists and pharmaceutical companies. However, the under‐reporting of ADRs remains a major problem. Our aim was to investigate preparedness of future doctors for their role in pharmacovigilance, by assessing their pharmacovigilance awareness, skills and knowledge. The study was a nationwide e‐survey among medical students (third to sixth year) of all eight medical schools in the Netherlands. The survey consisted of questions regarding pharmacovigilance awareness, skills and knowledge. Overall, 874 students provided informed consent and participated (response 12%). Almost all students (96%) intended to report serious ADRs in their future practice. Almost half (44%) of the students did not know where to report an ADR, and 78% did not know which items were necessary for a good‐quality ADR report. While more than 78% of the students agreed that pharmacovigilance is an important topic in their medical education, only 26% found that their current curriculum covered pharmacovigilance adequately. Although ADR reporting is considered relevant and important among future doctors, many do not know where and what to report. This is highly undesirable and should have consequences for pharmacotherapy teaching.

Individualizing Pharmacotherapy in Patients with Renal Impairment: The Validity of the Modification of Diet in Renal Disease Formula in Specific Patient Populations with a Glomerular Filtration Rate below 60 Ml/Min. A Systematic Review

Background The Modification of Diet in Renal Disease (MDRD) formula is widely used in clinical practice to assess the correct drug dose. This formula is based on serum creatinine levels which might be influenced by chronic diseases itself or the effects of the chronic diseases. We conducted a systematic review to determine the validity of the MDRD formula in specific patient populations with renal impairment: elderly, hospitalized and obese patients, patients with cardiovascular disease, cancer, chronic respiratory diseases, diabetes mellitus, liver cirrhosis and human immunodeficiency virus. Methods and Findings We searched for articles in Pubmed published from January 1999 through January 2014. Selection criteria were (1) patients with a glomerular filtration rate (GFR) < 60 ml/min (/1.73m2), (2) MDRD formula compared with a gold standard and (3) statistical analysis focused on bias, precision and/or accuracy. Data extraction was done by the first author and checked by a second author. A bias of 20% or less, a precision of 30% or less and an accuracy expressed as P30% of 80% or higher were indicators of the validity of the MDRD formula. In total we included 27 studies. The number of patients included ranged from 8 to 1831. The gold standard and measurement method used varied across the studies. For none of the specific patient populations the studies provided sufficient evidence of validity of the MDRD formula regarding the three parameters. For patients with diabetes mellitus and liver cirrhosis, hospitalized patients and elderly with moderate to severe renal impairment we concluded that the MDRD formula is not valid. Limitations of the review are the lack of considering the method of measuring serum creatinine levels and the type of gold standard used. Conclusion In several specific patient populations with renal impairment the use of the MDRD formula is not valid or has uncertain validity.

Drug therapy management in patients with renal impairment: how to use creatinine-based formulas in clinical practice

PurposeThe use of estimated glomerular filtration rate (eGFR) in daily clinical practice.MethodseGFR is a key component in drug therapy management (DTM) in patients with renal impairment. eGFR is routinely reported by laboratories whenever a serum creatinine testing is ordered. In this paper, we will discuss how to use eGFR knowing the limitations of serum creatinine-based formulas.ResultsBefore starting a renally excreted drug, an equally effective drug which can be used more safely in patients with renal impairment should be considered. If a renally excreted drug is needed, the reliability of the eGFR should be assessed and when needed, a 24-h urine creatinine clearance collection should be performed. After achieving the best approximation of the true GFR, we suggest a gradual drug dose adaptation according to the renal function. A different approach for drugs with a narrow therapeutic window (NTW) is recommended compared to drugs with a broad therapeutic window. For practical purposes, a therapeutic window of 5 or less was defined as a NTW and a list of NTW drugs is presented. Considerations about the drug dose may be different at the start of the therapy or during the therapy and depending on the indication. Monitoring effectiveness and adverse drug reactions are important, especially for NTW drugs. Dose adjustment should be based on an ongoing assessment of clinical status and risk versus the benefit of the used regimen.ConclusionWhen determining the most appropriate dosing regimen serum creatinine-based formulas should never be used naively but always in combination with clinical and pharmacological assessment of the individual patient.

Application of urine proteomics for biomarker discovery in drug-induced liver injury

Abstract The leading cause of hepatic damage is drug-induced liver injury (DILI), for which currently no adequate predictive biomarkers are available. Moreover, for most drugs related to DILI, the mechanisms underlying the adverse reaction have not yet been elucidated. Urinary protein biomarker candidates for DILI have emerged in the past few years and correlate well with clinical studies for serum DILI biomarkers. The goal of this review was to investigate the use of urine as a source of protein biomarkers for drug-induced liver injury. Finally, we discuss some of the current strategies required to advance the field of biomarker discovery for DILI with respect to appropriate clinical biobanking and adequate translational research.