Value of Pharmacogenetic Testing Assessed with Real-World Drug Utilization and Genotype Data.

Implementation of pharmacogenetic testing in clinical care has been slow and with few exceptions is hindered by the lack of real-world evidence on how to best target testing. In this retrospective register-based study, we analyzed a nationwide cohort of 1,425,000 patients discharged from internal medicine or surgical wards and a cohort of 2,178 university hospital patients for purchases and prescriptions of pharmacogenetically actionable drugs. Pharmacogenetic variants were obtained from whole genome genotype data for a subset (n = 930) of the university hospital patients.

Digital Care Pathway for Patients With Sleep Apnea in Specialized Care: Mixed Methods Study.

Background: Sleep apnea is a significant public health disorder in Finland, with a prevalence of 3.7%. Continuous positive airway pressure (CPAP) therapy is the first-line treatment for moderate or severe sleep apnea.

Implementation of a new Digi-HTA process for digital health technologies in Finland.

Objectives: There has been a lack of health technology assessment (HTA) methods for novel digital health technologies (DHTs) such as mHealth, artificial intelligence, and robotics in Finland. The Digi-HTA method has been developed for this purpose. The aim of this study is to determine whether it would be possible to use Digi-HTA recommendations to support healthcare decision-makers.

Characteristics and predictors of off-label use of antipsychotics in general population sample.

Objective: Increasing number of people have been prescribed antipsychotics (APs) off-label in recent decades. This study aimed to identify the characteristics and predictors of receiving prescription of antipsychotics off-label.

Methods: The study sample was part of the Northern Finland Birth Cohort 1966 (n = 7071).

Detecting Patient Safety Errors by Characterizing Incidents Reported by Medical Imaging Staff.

The objectives of the study were to characterize events related to patient safety reported by medical imaging personnel in Finland in 2007-2017, the number and quality of reported injuries, the risk assessment, and the planned improvement of operations. The information was collected from a healthcare patient safety incident register system. The data contained information on the nature of the patient safety errors, harms and near-misses in medical imaging, the factors that lead to the events, the consequences for the patient, the level of risks, and future measures.

Investigating errors in medical imaging: medical malpractice cases in Finland.

Objective: The objectives of the study were to survey patient injury claims concerning medical imaging in Finland in 1991-2017, and to investigate the nature of the incidents, the number of claims, the reasons for the claims, and the decisions made concerning the claims.

Materials And Methods: The research material consisted of patient claims concerning imaging, sent to the Finnish Patient Insurance Centre (PVK). The data contained information on injury dates, the examination code, the decision code, the description of the injury, and the medical grounds for decisions.

Inhibition and induction of CYP enzymes in humans: an update.

The cytochrome P450 (CYP) enzyme family is the most important enzyme system catalyzing the phase 1 metabolism of pharmaceuticals and other xenobiotics such as herbal remedies and toxic compounds in the environment. The inhibition and induction of CYPs are major mechanisms causing pharmacokinetic drug-drug interactions. This review presents a comprehensive update on the inhibitors and inducers of the specific CYP enzymes in humans.

CYP-associated drug-drug interactions: A mission accomplished?

On the basis of official Finnish Medicines Authority (Fimea)-approved drug monographs, less than half of the approved small-molecule drugs between 2007 and 2016 were substrates, inhibitors or inducers of CYP enzymes, predominantly of CYP3A4. No significant unexpected, life-threatening, CYP-associated drug-drug interactions (CYP-DDIs) of newly approved drug entities have been observed in the last 10-15 years. The present analysis seems to suggest that tools to study and predict potentially significant CYP-DDIs are working and efficient.

Single-Arm Clinical Trials as Pivotal Evidence for Cancer Drug Approval: A Retrospective Cohort Study of Centralized European Marketing Authorizations Between 2010 and 2019.

The traditional drug development paradigm, consisting of sequential phases and randomized studies, has been challenged in oncology and hemato-oncology. In the regulatory context, a number of new products have been authorized based on nonrandomized efficacy and safety data. We retrospectively analyzed the European public assessment reports for anticancer treatments authorized between 2010 and 2019 to describe the data behind such approvals.

The Risks and Outcomes Resulting From Medication Errors Reported in the Finnish Tertiary Care Units:: A Cross-Sectional Retrospective Register Study.

Hospital-acquired medication errors (MEs) are common in health care. Although voluntary reporting is criticized for not producing reliable estimates on ME frequency, it provides valuable knowledge on errors occurring in the medication process. The purpose of this study was to analyze and determine the risks and outcomes resulting from MEs related to the TOP15 medicines in the Finnish tertiary care units from July 2016 to July 2017.

Quantitative analysis of 4β- and 4α‑hydroxycholesterol in human plasma and serum by UHPLC/ESI-HR-MS.

Cholesterol oxidation product 4β‑hydroxycholesterol (4β‑OHC) may possibly be used as an endogenous biomarker of CYP3A enzyme activity and as CYP3A4 is involved in the metabolism of approximately 50% of the drugs in clinical use, the monitoring of CYP3A activity by 4β‑OHC plasma or serum levels, may be of clinical significance. The plasma and serum concentrations of 4α‑hydroxycholesterol (4α‑OHC), an isomer of 4β‑OHC, increase during uncontrolled storage conditions and therefore serve as an indicator of proper handling of samples. A sensitive and simple high-throughput method for the simultaneous quantification of both 4α‑OHC and 4β‑OHC in human plasma and serum was developed utilizing ultrahigh performance liquid chromatography coupled with high resolution mass spectrometry (UHPLC/ESI-HR-MS).

Oral diabetes medications other than dipeptidyl peptidase 4 inhibitors are not associated with bullous pemphigoid: A Finnish nationwide case-control study.

Background: Dipeptidyl peptidase 4 inhibitors (DPP4is) used to treat diabetes have been reported to be associated with an increased risk of bullous pemphigoid (BP). There are no previous reports analyzing the risk of BP in patients who are using other diabetes medications.

Objective: To evaluate the association between diabetes medications other than DPP4i and development of BP.

New study designs in clinical drug development.

Clinical development of a novel drug has traditionally been seen as a series of four phases, each having its own objectives in establishing the efficacy and safety of the drug. Increasingly individualized medicine and the changing mechanisms of drug action are also changing the designs of clinical drug testing. The borders of development phases become blurred and the traditional large, controlled multicenter studies may in part be replaced by individual and risk-based approaches.

Hospitalizations Due to Adverse Drug Events in the Elderly-A Retrospective Register Study.

Adverse drug events (ADEs) are more likely to affect geriatric patients due to physiological changes occurring with aging. Even though this is an internationally recognized problem, similar research data in Finland is still lacking. The aim of this study was to determine the number of geriatric medication-related hospitalizations in the Finnish patient population and to discover the potential means of recognizing patients particularly at risk of ADEs.

Tandem mass spectrometric analysis of S- and N-linked glutathione conjugates of pulegone and menthofuran and identification of P450 enzymes mediating their formation.

Rationale: Menthofuran is a hepatotoxin and a major metabolite of pulegone, a monoterpene found in the essential oils of many mint species. It is bioactivated by cytochrome P450 (CYP) enzymes to reactive metabolites, which may further react with glutathione to form S-linked and N-linked conjugates. The tandem mass spectrometric (MS/MS) fragmentation pathways of rarely observed N-linked conjugates, and the differences to fragmentation of S-linked conjugates, have not been reported in the literature previously, although this information is essential to enable comprehensive MS/MS-based screening methods covering the both types of conjugates.

Peroxisome proliferator-activated receptor alpha, PPARα, directly regulates transcription of cytochrome P450 CYP2C8.

The cytochrome P450, CYP2C8, metabolizes more than 60 clinically used drugs as well as endogenous substances including retinoic acid and arachidonic acid. However, predictive factors for interindividual variability in the efficacy and toxicity of CYP2C8 drug substrates are essentially lacking. Recently we demonstrated that peroxisome proliferator-activated receptor alpha (PPARα), a nuclear receptor primarily involved in control of lipid and energy homeostasis directly regulates the transcription of CYP3A4.

Metabolism and metabolite profiles in vitro and in vivo of ospemifene in humans and preclinical species.

Background: Metabolite profiles of ospemifene, a novel nonsteroidal selective estrogen receptor modulator, were surveyed as part of its development.

Methods: The pharmacokinetics of ospemifene and its two major, pharmacologically active metabolites 4-hydroxyospemifene and 4'-hydroxyospemifene, was elucidated in studies of volunteer humans given various doses of ospemifene and in experiments of several animal species (rat, mouse, dog, and cynomolgus monkey), which had been used either for pharmacological or toxicological studies of ospemifene. Metabolites produced in in vitro human and animal liver preparations were compared between species and with the metabolite profiles in the in vivo investigations.

Toxicity of Carboxylic Acid-Containing Drugs: The Role of Acyl Migration and CoA Conjugation Investigated.

Many carboxylic acid-containing drugs are associated with idiosyncratic drug toxicity (IDT), which may be caused by reactive acyl glucuronide metabolites. The rate of acyl migration has been earlier suggested as a predictor of acyl glucuronide reactivity. Additionally, acyl Coenzyme A (CoA) conjugates are known to be reactive.

Formation of GSH-trapped reactive metabolites in human liver microsomes, S9 fraction, HepaRG-cells, and human hepatocytes.

The objective was to compare several in vitro human liver-derived subcellular and cellular incubation systems for the formation of GSH-trapped reactive metabolites. Incubations of pooled human liver microsomes, human liver S9 fractions, HepaRG-cells, and human hepatocytes were performed with glutathione as a trapping agent. Experiments with liver S9 were performed under two conditions, using only NADPH and using a full set of cofactors enabling also conjugative metabolism.

Glutathione trapping of reactive drug metabolites produced by biomimetic metalloporphyrin catalysts.

Rationale: Metalloporphyrins can be useful in the production of drug metabolites, as they enable easier production of oxidative metabolites usually produced by the cytochrome P450 enzymes. Our aim was to test metalloporphyrin-based biomimetic oxidation (BMO) methods for production and S-glutathione trapping of reactive drug metabolites in addition to phase I metabolites.

Methods: Clozapine, ticlopidine and citalopram were selected as model compounds.