Influence of Intravenous S-Ketamine on the Pharmacokinetics of Oral Morphine in Healthy Volunteers.

BACKGROUND: Subanesthetic ketamine may reduce perioperative consumption of opioids. We studied whether intravenous S-ketamine alters the pharmacokinetics of oral morphine in healthy volunteers. METHODS: In this paired, randomized, double-blind, crossover trial, 12 participants under a 2-hour intravenous S-ketamine (0.57 mg/kg/h) or placebo infusion received oral morphine (0.2 mg/kg) at 30 minutes. Plasma concentrations of ketamine, morphine, and their major metabolites were quantified for 24 hours. The primary end point was area under the curve (AUC) 0-24 of morphine. Other pharmacokinetic variables for morphine and its metabolites were studied as secondary end points. The data were analyzed as between-phase comparisons for each participant using Wilcoxon matched-pairs signed-rank tests ( tmax ) or paired t -tests on log-transformed variables (other variables). RESULTS: While the AUC 0-24 was similar between the 2 phases, S-ketamine reduced the AUC 0-1.5 of oral morphine by 69% (ratio to control, 0.31; 90% confidence interval [CI], 0.15-0.65; P = .0171) and increased its tmax from 0.5 (range, 0.50-1.5) to 1.0 hour (range, 0.50-4.0; P = .010). The AUC 0-1.5 of morphine-6-glucuronide (M6G) was reduced by 84% (0.16; 90% CI, 0.07-0.37; P = .0025) and maximum plasma concentration ( Cmax ) by 43% (0.57; 90% CI, 0.40-0.81; P = .0155), while its tmax was increased from 1.5 (range, 1.0-2.0) to 4.0 (range, 1.0-8.0; P = .0094) hours by S-ketamine. Similarly, the AUC 0-1.5 of morphine-3-glucuronide (M3G) was reduced by 85% (0.15; 90% CI, 0.05-0.43; P = .0083), and tmax increased from 1.0 (range, 0.5-1.5) to 4.0 hours (range, 1.0-8.0; P = .0063). In addition, the M6G-to-morphine and M3G-to-morphine metabolic AUC ratios were decreased by 47% (0.53; 90% CI, 0.39-0.71; P = .0033) and 52% (0.48; 90% CI, 0.27-0.85; P = .0043) during 0 to 1.5 hours and by 15% (0.85; 90% CI, 0.78-0.92; P = .0057) and 10% (0.90; 90% CI, 0.83-0.98; P = .0468) during 0 to 24 hours, respectively. One participant was excluded from the analyses due to vomiting in the S-ketamine phase. CONCLUSIONS: Intravenous S-ketamine inhibited the metabolism of oral morphine and delayed its absorption, resulting in a net reduction in the exposure to morphine during the first 1.5 hours. Intravenous S-ketamine may delay the absorption and impair the efficacy of orally administered analgesics and other drugs.

Ticagrelor Increases Exposure to the Breast Cancer Resistance Protein Substrate Rosuvastatin.

Ticagrelor and rosuvastatin are often used concomitantly after atherothrombotic events. Several cases of rhabdomyolysis during concomitant ticagrelor and rosuvastatin have been reported, suggesting a drug-drug interaction. We showed recently that ticagrelor inhibits breast cancer resistance protein (BCRP) and organic anion transporting polypeptide (OATP) 1B1, 1B3, and 2B1-mediated rosuvastatin transport in vitro. The aim of this study was to investigate the effects of ticagrelor on rosuvastatin pharmacokinetics in humans. In a randomized, crossover study, 9 healthy volunteers ingested a single dose of 90 mg ticagrelor or placebo, followed by a single 10 mg dose of rosuvastatin 1 hour later. Ticagrelor 90 mg or placebo were additionally administered 12, 24, and 36 hours after their first dose. Ticagrelor increased rosuvastatin area under the plasma concentration-time curve (AUC) and peak plasma concentration 2.6-fold (90% confidence intervals: 1.8-3.8 and 1.7-4.0, P = 0.001 and P = 0.003), and prolonged its half-life from 3.1 to 6.6 hours (P = 0.009). Ticagrelor also decreased the renal clearance of rosuvastatin by 11% (3%-19%, P = 0.032). The N-desmethylrosuvastatin:rosuvastatin AUC0-10h ratio remained unaffected by ticagrelor. Ticagrelor had no effect on the plasma concentrations of the endogenous OATP1B substrates glycodeoxycholate 3-O-glucuronide, glycochenodeoxycholate 3-O-glucuronide, glycodeoxycholate 3-O-sulfate, and glycochenodeoxycholate 3-O-sulfate, or the sodium-taurocholate cotransporting polypeptide substrate taurocholic acid. These data indicate that ticagrelor increases rosuvastatin concentrations more than twofold in humans, probably mainly by inhibiting intestinal BCRP. Because the risk for rosuvastatin-induced myotoxicity increases along with rosuvastatin plasma concentrations, using ticagrelor concomitantly with high doses of rosuvastatin should be avoided.

Drug-related deaths in a university hospital: Comparison to previous decades.

The incidence of fatal adverse drug reactions (ADRs) in hospitals varies widely, and ADRs are often underreported. The impact of medical safety processes is not easily evaluated, and although medical practice changes constantly, little is known about ADR trends. This study concentrated on the current incidence and properties of fatal ADRs occurring in a university hospital and compared the results with two previous studies performed in the same hospital. We investigated retrospectively all 1236 deaths that occurred during 2019 in the Helsinki University Hospital. All the cases were evaluated by a team of experts, and the causality was assessed using the categories by World Health Organization and Uppsala monitoring centre. Suicides were excluded. Among death cases, we identified 65 certain or probable ADR cases (5.3%), representing 0.011% of all hospital admissions. Cytostatics and antithrombotics remained the largest drug classes, with neutropenia or sepsis and bleedings as the most common fatal ADRs. Compared with our earlier studies, warfarin caused less, and direct oral anticoagulants caused more fatal bleedings, reflecting the drug usage among the population. In contrast to earlier studies, contrast media and insulin did not cause any fatal ADRs, which may reflect an improvement in pharmacovigilance awareness among healthcare workers.

Posaconazole-ibrutinib interaction cannot be avoided by staggered dosing: How to optimize ibrutinib dose during posaconazole treatment.

AIMS: Ibrutinib is used in the treatment of certain B-cell malignancies. Due to its CYP3A4-mediated metabolism and highly variable pharmacokinetics, it is prone to potentially harmful drug-drug interactions. METHODS: In a randomized, placebo-controlled, three-phase crossover study, we examined the effect of the CYP3A4-inhibiting antifungal posaconazole on ibrutinib pharmacokinetics. Eleven healthy participants ingested repeated doses of 300 mg of posaconazole either in the morning or in the evening, or placebo. A single dose of ibrutinib (30, 70 or 140 mg, respectively) was administered at 9 AM, 1 or 12 h after the preceding posaconazole/placebo dose. RESULTS: On average, morning posaconazole increased the dose-adjusted geometric mean area under the plasma concentration-time curve from zero to infinity (AUC0-∞ ) and peak plasma concentration (Cmax ) of ibrutinib 9.5-fold (90% confidence interval [CI] 6.3-14.3, P < 0.001) and 8.5-fold (90% CI 5.7-12.8, P < 0.001), respectively, while evening posaconazole increased those 10.3-fold (90% CI 6.7-16.0, P < 0.001) and 8.2-fold (90% CI 5.2-13.2, P < 0.001), respectively. Posaconazole had no significant effect on the half-life of ibrutinib, but substantially reduced the metabolite PCI-45227 to ibrutinib AUC0-∞ ratio. There were no significant differences in ibrutinib pharmacokinetics between morning and evening posaconazole phases. CONCLUSIONS: Posaconazole increases ibrutinib exposure substantially, by about 10-fold. This interaction cannot be avoided by dosing the drugs 12 h apart. In general, a 70-mg daily dose of ibrutinib should not be exceeded during posaconazole treatment to avoid potentially toxic systemic ibrutinib concentrations.

Benefits and challenges of electronic package leaflet (ePL) - review of ePL pilots in hospital settings in Europe.

Inclusion of package leaflets in paper format is a legal requirement in European Union (EU), therefore the electronic package leaflet (ePL) is a relatively unknown phenomenon in medicinal products in Europe. Introduction of ePL only would be a more sustainable format of providing the product information than paper package leaflet. Furthermore, ePL would support health care professionals' comprehension of product use through electronic searchability and facilitate access to up-to-date product information in respective language used. It could also help us to tackle the availability issues and be a further step towards common packages. With this commentary, our aim is to review the ongoing ePL pilots in hospital settings in Europe and identify the benefits and challenges of ePL. Based on our review, there is a broad general support for the removal of paper package leaflets from hospital products. Packages without paper package leaflets are considered more sustainable due to savings in production and materials. Furthermore, ePL could be a facilitator for common packages in EU-countries with the benefit of reducing pharmaceutical waste and drug shortages. The most important benefit from both pharmaceutical industry and healthcare professionals' interest is that current and on-line updated product information is always electronically available, especially from drug safety perspective.

Medicines, environment and clinical pharmacology.

Medical associations and other societies have announced their theses on protection of the climate and environmental aspects in medicine. The challenges with climate change and sustainability are complex, and no quick solutions are to be found. However, basic knowledge on these issues should be available to everyone, and environmental aspects of drugs are important to all healthcare professionals. We present here a study with medical students who were introduced for the first time to environmental aspects of medicines. The results confirmed the suitability and feasibility of the approach to introduce this subject to students, and we propose that the same method can be used also when explaining the issue to medical professionals. We would like to encourage particularly clinical pharmacologists, pharmacologists and pharmacists to take a more apparent position in this field and to participate in the discussions where the strategies for the choice of medicines are considered.

How to Identify Organizational High-Alert Medications.

OBJECTIVES: High-alert medications may cause significant patient harm when used in error. Hospital-specific safety data should be used to customize high-alert medication lists to fit the local context. The aim of this study was to identify organizational high-alert medications by evaluating university hospital's data on adverse drug reaction (ADR) and medication error (ME). METHODS: The Anatomical Therapeutic Chemical (ATC) codes and top active substances in ADR (n = 401) and ME (n = 11,668) reports of Helsinki University Hospital from 2015-2016 were analyzed and compared with hospitals' drug consumption and the Institute for Safe Medication Practices' (ISMP) list of high-alert medications. RESULTS: The top ATC groups and active substances in ADR and ME reports were not similar. The most numerous ATC groups were L, antineoplastic and immunomodulating agents (30%) in ADRs and N, nervous system (26%) in MEs. According to ADR and ME reports, several high-alert medications from Institute for Safe Medication Practices' lists, such as antineoplastic agents, antithrombotics, opioids, and insulins, should be considered high-alert medications also in Helsinki University Hospital. Although no ADR reports of amphotericin B existed, it had the highest number of MEs causing severe/moderate harm or unexpected reactions relative to its consumption. CONCLUSIONS: To identify organizational high-alert medications, both drug safety information and medication safety information should be used. Adverse drug reaction and ME data are needed to recognize high-alert medications, but these should also be combined with a literature search and local expert opinions.

Incidence, preventability, and causality of adverse drug reactions at a university hospital emergency department.

PURPOSE: To investigate the characteristics of ADRs in patients admitting at the emergency room of a tertiary hospital. METHODS: We collected the patient records of 1600 emergency room visits of a university hospital in 2018. The patient files were studied retrospectively and all possible ADRs were identified and registered. Patient characteristics, drugs associated with ADRs, causality, severity, preventability, and the role of pharmacogenetics were assessed. RESULTS: There were 125 cases with ADRs, resulting in a 7.8% overall incidence among emergency visits. The incidence was greatest in visits among elderly patients, reaching 14% (men) to 19% (women) in the 80-89 years age group. The most common causative drugs were warfarin, acetylsalicylic acid (ASA), apixaban, and docetaxel, and the most common ADRs were bleedings and neutropenia and/or severe infections. Only two of the cases might have been prevented by pharmacogenetic testing, as advised in Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines. CONCLUSION: The same ATC classes, antithrombotics and cytostatics, were involved in ADRs causing university clinic hospitalizations as those identified previously in drug-related hospital fatalities. It seems difficult to prevent these events totally, as the treatments are vitally important and their risk-benefit-relationships have been considered thoroughly, and as pharmacogenetic testing could have been useful in only few cases.

Febuxostat, But Not Allopurinol, Markedly Raises the Plasma Concentrations of the Breast Cancer Resistance Protein Substrate Rosuvastatin.

Xanthine oxidase inhibitors febuxostat and allopurinol are commonly used in the treatment of gout. Febuxostat inhibits the breast cancer resistance protein (BCRP) in vitro. Rosuvastatin is a BCRP substrate and genetic variability in BCRP markedly affects rosuvastatin pharmacokinetics. In this study, we investigated possible effects of febuxostat and allopurinol on rosuvastatin pharmacokinetics. In a randomized crossover study with 3 phases, 10 healthy volunteers ingested once daily placebo for 7 days, 300 mg allopurinol for 7 days, or placebo for 3 days, followed by 120 mg febuxostat for 4 days, and a single 10 mg dose of rosuvastatin on day 6. Febuxostat increased the peak plasma concentration and area under the plasma concentration-time curve of rosuvastatin 2.1-fold (90% confidence interval 1.8-2.6; P = 5 × 10-5 ) and 1.9-fold (1.5-2.5; P = 0.001), but had no effect on rosuvastatin half-life or renal clearance. Allopurinol, on the other hand, did not affect rosuvastatin pharmacokinetics. In vitro, febuxostat inhibited the ATP-dependent uptake of rosuvastatin into BCRP-overexpressing membrane vesicles with a half-maximal inhibitory concentration of 0.35 µM, whereas allopurinol showed no inhibition with concentrations up to 200 µM. Taken together, the results suggest that febuxostat increases rosuvastatin exposure by inhibiting its BCRP-mediated efflux in the small intestine. Febuxostat may, therefore, serve as a useful index inhibitor of BCRP in drug-drug interaction studies in humans. Moreover, concomitant use of febuxostat may increase the exposure to BCRP substrate drugs and, thus, the risk of dose-dependent adverse effects.

Strategies for improving medication safety in hospitals: Evolution of clinical pharmacy services.

BACKGROUND: Medication safety risks are the most important preventable factors jeopardizing patient safety. To manage these risks, extending pharmacists' involvement in patient care and patient safety work has been systematically addressed in patient safety initiatives since the early 2000s. OBJECTIVE: To explore the extent and range of clinical pharmacy services in Finnish hospitals to promote medication safety: 1) in 2011, when the first National Patient Safety Strategy, the new Health Care Act and the Medicines Policy 2020 had been recently enacted; and 2) five years later in 2016. METHODS: The study was conducted in 2011 and 2016 as a national online survey targeted to hospital pharmacies (n = 24) and medical dispensaries (n = 131 in 2011; n = 28 in 2016). The questions were analyzed using descriptive statistics and qualitative content analysis. RESULTS: Overall response rate was 60% in 2011 and 52% in 2016. Clinical pharmacy services were provided by 51% of the responding units in 2011, whereas by 85% in 2016. The reported number of clinical pharmacists had increased during the five years. The most notable increase in reported tasks occurred in conducting medication reconciliations (+63% increase in the number of providing units). By 2016 pharmacists had extended their tasks particularly towards system-based medication safety work: e.g. developing instructions for medication-use (91% of the responding units), creating and updating medication safety plans (87%) and using medication error reports in developing the process of medication use safer (78%). Pharmacists' participation in long-term continuing education became more common in 2016, which was perceived as helpful in extending their responsibilities to improve medication safety. CONCLUSION: Pharmacists' involvement in patient care and system-based medication safety work was reported to become more common in Finnish hospitals during 2011-2016. This development is in line with patient safety policy initiatives and its impact on patient care outcomes should be followed up.

Clopidogrel Increases Dasabuvir Exposure With or Without Ritonavir, and Ritonavir Inhibits the Bioactivation of Clopidogrel.

Dasabuvir is mainly metabolized by cytochrome P450 (CYP) 2C8 and is predominantly used in a regimen containing ritonavir. Ritonavir and clopidogrel are inhibitors of CYP3A4 and CYP2C8, respectively. In a randomized, crossover study in 12 healthy subjects, we examined the impact of clinical doses of ritonavir (for 5 days), clopidogrel (for 3 days), and their combination on dasabuvir pharmacokinetics, and the effect of ritonavir on clopidogrel. Clopidogrel, but not ritonavir, increased the geometric mean AUC0-∞ of dasabuvir 4.7-fold; range 2.0-10.1-fold (P = 8·10-7 ), compared with placebo. Clopidogrel and ritonavir combination increased dasabuvir AUC0-∞ 3.9-fold; range 2.1-7.9-fold (P = 2·10-6 ), compared with ritonavir alone. Ritonavir decreased the AUC0-4h of clopidogrel active metabolite by 51% (P = 0.0001), and average platelet inhibition from 51% without ritonavir to 31% with ritonavir (P = 0.0007). In conclusion, clopidogrel markedly elevates dasabuvir concentrations, and patients receiving ritonavir are at risk for diminished clopidogrel response.

Medication reconciliation and review for older emergency patients requires improvement in Finland.

BACKGROUND: 10-30% of hospital stays by older patients are drug-related. The admission phase is important for identifying drug-related problems, but taking an incorrect medication history often leads to medication errors. OBJECTIVES: To enhance medication history recording and identify drug-related problems (DRPs) of older patients admitted to emergency departments (EDs). METHODS: DRPs were identified by pharmacists-led medication reconciliation and review procedures in two EDs in Finland; Helsinki University Hospital (HUS), and Kuopio University Hospital (KUH). One-hundred-and-fifty patients aged ≥65-years, living at home and using ≥6 medicines were studied. RESULTS: 100% of patients (N = 75) in HUS and 99% in KUH (N = 75), had discrepancies in their admission-medication chart recorded by the nurse or physician. Associations between admission-diagnosis and drug-related problems were found in 12 patients (16%) in HUS and 22 patients (29%) in KUH. Of these, high-alert medications (e.g. antithrombotics, cytostatics, opioids) were linked to eight patients (11%) in HUS and six patients (8%) in KUH. Other acute DRPs were identified in 19 patients (25%) in HUS and 54 patients (72%) in KUH. Furthermore, 67 patients (89%) in HUS and all patients in KUH had non-acute DRPs. CONCLUSIONS: Medication reconciliation and review at admission of older ED patients requires improvement in Finland.

Drug-Related Inadvertent Deaths in a University Hospital--A Declining Trend.

We studied the incidence of fatal adverse drug reactions (ADRs) in a tertiary hospital to find out which drugs were involved. The secondary objective was to compare the data from the same hospital published 12 years earlier. All 1708 death cases in the Helsinki University Central Hospital during the year 2012 were retrospectively evaluated. All suspected drug-related deaths, excluding suicides, were scrutinized by an expert panel using the WHO ADR probability classification. Of all cases, 52 (3.0%) were classified as certainly or probably drug related and 24 (1.4%) as possibly drug related. Together, these corresponded to 0.02% of all hospital admissions. The most commonly involved drugs in certain or probable cases were cytostatics (18 cases, 1.1% of all cases) and antithrombotics (17, 1.0%). Twelve years earlier, these caused 27 (1.8%) and 22 (1.5%) cases, respectively. Non-steroidal anti-inflammatory drugs (NSAIDs) and glucocorticoids caused less (2 and 0 cases) fatal ADRs than earlier (12 and 4 cases, p = 0.048 and p = 0.005, respectively). Most of the ADRs leading to death were present already in admission and affected seriously ill or elderly patients. Hospital-born fatal ADRs occurred in 0.003% of patients. In conclusion, cytostatics and antithrombotics are still the leading causes of fatal ADRs, but NSAIDs and glucocorticoids seem to cause fatal ADRs less often than previously. The incidence of fatal ADRs in 2012 was 3.0% of all deaths, suggesting a decline compared to the 2000 value (5.0%). Improved awareness, prevention and treatment of ADRs and safer medicines may explain these declining trends.

[Adder bites in Turku region in 2000 to 2010]. / Kyynpuremat Turun seudulla vuosina 2000-2010.

Adder bites cause dozens of hospital visits and complications in Finland each year Some of the patients also suffer from troublesome late symptoms. We established the number of adder bites, use of antivenin, and degree of severity of the bites in child and adult patients treated at TYKS in 2000 to 2010. Antivenin was given to 9.6% of the bitten adults and 17.3% of the children. The number of adder bites was highest in July. Accidental stepping on an adder or hitting an adder-inhabited tussock with the berry picker's hand were the most common cases. Severe cases were rare.

[Drug-associated hyperthermic syndromes]. / Lääkkeisiin liittyvät hypertermiset oireyhtymät.

Drug-associated hyperthermic syndromes include the serotonin syndrome, neuroleptic malignant syndrome, neuroleptic-induced catatonia, anticholinergic syndrome, sympatomimetic syndrome and malignant hyperthermia. Discontinuation of medication is a sufficient treatment for mild serotonin syndrome. In a more severe situation the patient's spasticity and hyperthermia are treated with drugs. In neuroleptic malignant syndrome discontinuation of medication does not suffice, but the patient needs active therapy. Many of the drugs causing these syndromes are common in clinical use. Starting an effective treatment early enough is more important than a precise diagnosis.

[Surrogate alcohol poisonings]. / Korvikealkoholimyrkytykset.

Surrogate alcohols, i.e., methanol, ethylene glycol and isopropanol, still cause some dozens of deaths in Finland every year. Assessment of the severity of the intoxication is often hampered by the presence of ethanol. If ingestion of surrogate alcohol is suspected and the patient is diagnosed with metabolic acidosis, treatment should be initiated immediately, without waiting for the result of concentration analysis. Ethanol is commonly utilized as an antidote in Finland, whereas the use of a specific antidote, fomepizole, is slowly increasing. Reversal of acidosis and hemodialysis are also essential measures in the treatment of methanol and ethylene glycol poisoning.