Conventional synthetic (cs) and targeted synthetic (ts) disease-modifying antirheumatic drugs (DMARD) have potential interactions with a multitude of drugs. Furthermore, they sometimes have a lower therapeutic index, particularly in cases of limited organ functions. The aim of this work was to establish evidence-based recommendations on the therapeutic use of DMARDs in the context of drug interactions and dosage recommendations. A systematic literature search was carried out on the issue of drug interactions and dosages in cases of patients with limited kidney function and higher age and suffering from rheumatoid arthritis. A total of 2756 scientific publications were screened and 154 selected of which 68 were scrutinized in detail. Furthermore, the respective product information was also analyzed. A multitude of possible interactions of synthetic DMARDs with different drugs were detected, which were then assessed with respect to the clinical significance and consequences. A consensus process led to making recommendations with which the interactions were classified: A: dangerous combination, B: avoid combination (if possible, pausing DMARD treatment), C: possible combination requiring increased monitoring and potential adjustments in dosage and D: pharmacological interaction without relevance in DMARD standard doses. Apart from that dosage recommendations were established for each csDMARD and tsDMARD depending on kidney function and age. There are 3 primary recommendations and 11 core recommendations on interactions and dosages of csDMARDs and tsDMARDs meant as a practical help for therapeutic decision making and to improve safety in the treatment of rheumatoid arthritis.
UNASSIGNED: Konventionelle synthetische („conventional synthetic“ [cs]) und gezielte synthetische („targeted synthetic“ [ts]) DMARDs haben potenzielle Wechselwirkungen mit einer Vielzahl von Medikamenten. Darüber hinaus haben sie insbesondere bei eingeschränkten Organfunktionen teilweise eine geringe therapeutische Breite. Ziel der Arbeit war eine systematische Erarbeitung von evidenzbasierten Empfehlungen zur Therapie mit DMARDs im Kontext von Arzneimittelinteraktionen und Dosierungsempfehlungen. Es wurde eine systematische Literaturrecherche zur Frage nach Wechselwirkungen sowie Dosierungen bei eingeschränkter Nierenfunktion und höherem Lebensalter bei rheumatoider Arthritis durchgeführt. Insgesamt wurden 2756 wissenschaftliche Publikationen gescreent und 154 ausgewählt, wobei 68 Publikationen in eine detaillierte Analyse eingingen. Darüber hinaus wurden die Informationen der jeweiligen Fachinformationen analysiert. Es fand sich eine Vielzahl von möglichen Wechselwirkungen von synthetischen DMARDs mit verschiedenen Medikamenten, welche bezüglich klinischer Bedeutung und Konsequenz bewertet wurden. In einem Konsensprozess wurden Empfehlungen erarbeitet, wobei eine Graduierung der Wechselwirkungen erfolgte: A: gefährliche Kombination, B: Kombination meiden (wenn möglich DMARD-Pause), C: mögliche Kombination mit erhöhtem Überwachungsbedarf und evtl. Dosisanpassung, D: pharmakologische Interaktion ohne Relevanz in Standarddosierungen des DMARD. Es wurden darüber hinaus Dosierungsempfehlungen nach Nierenfunktion und Alter für jedes cs- und tsDMARD erarbeitet. Drei übergeordnete Empfehlungen und 11 Kernempfehlungen zu Wechselwirkungen und Dosierung von cs- und tsDMARDs sollen praktische Hilfestellung für therapeutische Entscheidungen geben und die Sicherheit der Therapie der rheumatoiden Arthritis verbessern.

BACKGROUND: No drug interaction between the guideline-directed medical therapy (GDMT) for heart failure (HF) with reduced ejection fraction (HFrEF) and glucose-dependent insulinotropic polypeptide (GIP)-glucagon-like peptide-1 (GLP-1) agonists is currently indexed in available drug interaction databases or package inserts for tirzepatide, the first dual GIP/GLP-1 agonist. The objective of our case series is to present 3 patients with HF who required modification in GDMT regimens for HFrEF or loop diuretic therapy after tirzepatide initiation.
METHODS: Three patients older than 60 years with HFrEF receiving GDMT agents (angiotensin receptor neprilysin inhibitors, beta blockers, mineralocorticoid receptor antagonists, and sodium-glucose cotransporter 2 inhibitors) were initiated on tirzepatide for weight loss management. After initiating tirzepatide therapy, all 3 patients developed symptomatic hypotension. Two cases had acute kidney injury owing to tirzepatide\'s direct vasodilation, natriuresis, reduction in extracellular volume, and weight loss. GDMT regimens and diuretic therapy were significantly modified to improve these adverse reactions.
CONCLUSIONS: Clinicians must closely monitor vital signs and volume status after initiating tirzepatide for potential need to modify GDMT regimens. Authors request a call to action to index the drug interaction between GDMT agents and tirzepatide in major drug interaction databases for a potential hypotension or dehydration risk.

BACKGROUND: Concomitant administration of enteral nutrition (EN) and phenytoin decreases phenytoin absorption. Concerns over impaired nutrition, however, may prevent EN from being held surrounding phenytoin administration. This study aimed to evaluate whether EN holding guidelines impacted nutrition goal achievement in patients taking phenytoin.
METHODS: Adult patients administered enteral phenytoin for acute or chronic seizures while receiving EN during a neurocritical care admission 6 months before and after EN holding guideline implementation were eligible. Patients without phenytoin concentrations or a clinical registered dietitian assessment were excluded. The primary outcome was the percentage of nutrition daily goals attained before and after implementation. Secondary end points included the incidence of hypoglycemia, differences in measured phenytoin concentrations, and rates of therapeutic (10-20 mcg/ml) and high-therapeutic (15-20 mcg/ml) concentration attainment. Concentrations were adjusted for hypoalbuminemia using the Winter-Tozer equation.
RESULTS: Fifty-five patients representing 412 patient days and 1110 phenytoin administrations were included with 29 preimplementation and 26 postimplementation patients. Median percent attainment of daily EN goals was consistent preimplementation and postimplementation (86% vs 83%, P = 0.48). No significant change in rates of days with hypoglycemia was observed. Adjusted phenytoin concentrations were similar before and after implementation (14.1 vs 15.2 mcg/ml, P = 0.45), but the preimplementation cohort had a lower proportion of high-therapeutic concentrations (23% vs 36%, P = 0.018).
CONCLUSIONS: Holding EN for phenytoin did not impact attainment of daily nutrition goals and was not associated with increased rates of hypoglycemia. This is the first study to evaluate the effect of EN holding on nutrition goals in patients receiving phenytoin.

Poly ADP-ribose polymerase inhibitors (PARPi), which approved in recent years, are recommended for ovarian cancer, breast cancer, pancreatic cancer, prostate cancer and other cancers by The National Comprehensive Cancer Network (NCCN) and Chinese Society of Clinical Oncology (CSCO) guidelines. Because most of PARPi are metabolized by cytochrome P450 enzyme system, there are extensive interactions with other drugs commonly used in cancer patients. By setting up a consensus working group including pharmaceutical experts, clinical experts and methodology experts, this paper forms a consensus according to the following steps: determine clinical problems, data retrieval and evaluation, Delphi method to form recommendations, finally formation expert opinion on PARPi interaction management. This paper will provide practical reference for clinical medical staff.
聚腺苷二磷酸核糖聚合酶抑制剂(PARPi)是近年上市被美国国立综合癌症网络(NCCN)和中国临床肿瘤学会(CSCO)指南推荐用于上皮性卵巢癌、乳腺癌、胰腺癌、前列腺癌等肿瘤治疗的药物。大多数PARPi通过细胞色素P450酶代谢，因此与肿瘤患者常用的其他药物之间存在广泛的相互作用。文章通过组建包括药学专家、临床专家、方法学专家等人员的共识工作组，按照确定临床问题、资料检索评价、德尔菲法形成共识意见，最终形成PARPi相互作用管理的指导性专家意见，为临床医务人员提供实践参考。.

Clinical practice guidelines (CPGs) are patient management tools that synthesize medical knowledge into an actionable format. CPGs are disease specific with limited applicability to the management of complex patients suffering from multimorbidity. For the management of these patients, CPGs need to be augmented with secondary medical knowledge coming from a variety of knowledge repositories. The operationalization of this knowledge is key to increasing CPGs\' uptake in clinical practice. In this work, we propose an approach to operationalizing secondary medical knowledge inspired by graph rewriting. We assume that the CPGs can be represented as task network models, and provide an approach for representing and applying codified medical knowledge to a specific patient encounter. We formally define revisions that model and mitigate adverse interactions between CPGs and we use a vocabulary of terms to instantiate these revisions. We demonstrate the application of our approach using synthetic and clinical examples. We conclude by identifying areas for future work with the vision of developing a theory of mitigation that will facilitate the development of comprehensive decision support for the management of multimorbid patients.

In agreement with the International Association for the Study of Pain, chronic pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage. To date, there are several types of pain: nociceptive, neuropathic, and nociplastic. In the present narrative review, we evaluated the characteristics of the drugs used for each type of pain, according to guidelines, and their effects in people with comorbidity to reduce the development of severe adverse events.

The Dutch Pharmacogenetics Working Group (DPWG) aims to facilitate pharmacogenetics implementation in clinical practice by developing evidence-based guidelines to optimize pharmacotherapy. A guideline describing the gene-drug interaction between the genes CYP2D6, CYP3A4 and CYP1A2 and antipsychotics is presented here. The DPWG identified gene-drug interactions that require therapy adjustments when respective genotype is known for CYP2D6 with aripiprazole, brexpiprazole, haloperidol, pimozide, risperidone and zuclopenthixol, and for CYP3A4 with quetiapine. Evidence-based dose recommendations were obtained based on a systematic review of published literature. Reduction of the normal dose is recommended for aripiprazole, brexpiprazole, haloperidol, pimozide, risperidone and zuclopenthixol for CYP2D6-predicted PMs, and for pimozide and zuclopenthixol also for CYP2D6 IMs. For CYP2D6 UMs, a dose increase or an alternative drug is recommended for haloperidol and an alternative drug or titration of the dose for risperidone. In addition, in case of no or limited clinical effect, a dose increase is recommended for zuclopenthixol for CYP2D6 UMs. Even though evidence is limited, the DPWG recommends choosing an alternative drug to treat symptoms of depression or a dose reduction for other indications for quetiapine and CYP3A4 PMs. No therapy adjustments are recommended for the other CYP2D6 and CYP3A4 predicted phenotypes. In addition, no action is required for the gene-drug combinations CYP2D6 and clozapine, flupentixol, olanzapine or quetiapine and also not for CYP1A2 and clozapine or olanzapine. For identified gene-drug interactions requiring therapy adjustments, genotyping of CYP2D6 or CYP3A4 prior to treatment should not be considered for all patients, but on an individual patient basis only.

Conventional synthetic (cs) and targeted synthetic (ts) disease-modifying antirheumatic drugs (DMARD) have potential interactions with a multitude of drugs. Furthermore, they sometimes have a lower therapeutic index, particularly in cases of limited organ functions. The aim of this work was to establish evidence-based recommendations on the therapeutic use of DMARDs in the context of drug interactions and dosage recommendations. A systematic literature search was carried out on the issue of drug interactions and dosages in cases of patients with limited kidney function and higher age and suffering from rheumatoid arthritis. A total of 2756 scientific publications were screened and 154 selected of which 68 were scrutinized in detail. Furthermore, the respective specialist subject information was also analyzed. A multitude of possible interactions of synthetic DMARDs with different drugs were detected, which were then assessed with respect to the clinical significance and consequences. A consensus process led to making recommendations with which the interactions were classified: A: dangerous combination, B: avoid combination (if possible, pausing DMARD treatment), C: possible combination requiring increased monitoring and potential adjustments in dosage and D: pharmacological interaction without relevance in DMARD standard doses. Apart from that dosage recommendations were established for each csDMARD and tsDMARD depending on kidney function and age. There are 3 primary recommendations and 11 core recommendations on interactions and dosages of csDMARDs and tsDMARDs meant as a practical help for therapeutic decision making and to improve safety in the treatment of rheumatoid arthritis.
UNASSIGNED: Konventionelle synthetische („conventional synthetic“ [cs]) und gezielte synthetische („targeted synthetic“ [ts]) DMARDs haben potenzielle Wechselwirkungen mit einer Vielzahl von Medikamenten. Darüber hinaus haben sie insbesondere bei eingeschränkten Organfunktionen teilweise eine geringe therapeutische Breite. Ziel der Arbeit war eine systematische Erarbeitung von evidenzbasierten Empfehlungen zur Therapie mit DMARDs im Kontext von Arzneimittelinteraktionen und Dosierungsempfehlungen. Es wurde eine systematische Literaturrecherche zur Frage nach Wechselwirkungen sowie Dosierungen bei eingeschränkter Nierenfunktion und höherem Lebensalter bei rheumatoider Arthritis durchgeführt. Insgesamt wurden 2756 wissenschaftliche Publikationen gescreent und 154 ausgewählt, wobei 68 Publikationen in eine detaillierte Analyse eingingen. Darüber hinaus wurden die Informationen der jeweiligen Fachinformationen analysiert. Es fand sich eine Vielzahl von möglichen Wechselwirkungen von synthetischen DMARDs mit verschiedenen Medikamenten, welche bezüglich klinischer Bedeutung und Konsequenz bewertet wurden. In einem Konsensprozess wurden Empfehlungen erarbeitet, wobei eine Graduierung der Wechselwirkungen erfolgte: A: gefährliche Kombination, B: Kombination meiden (wenn möglich DMARD-Pause), C: mögliche Kombination mit erhöhtem Überwachungsbedarf und evtl. Dosisanpassung, D: pharmakologische Interaktion ohne Relevanz in Standarddosierungen des DMARD. Es wurden darüber hinaus Dosierungsempfehlungen nach Nierenfunktion und Alter für jedes cs- und tsDMARD erarbeitet. Drei übergeordnete Empfehlungen und 11 Kernempfehlungen zu Wechselwirkungen und Dosierung von cs- und tsDMARDs sollen praktische Hilfestellung für therapeutische Entscheidungen geben und die Sicherheit der Therapie der rheumatoiden Arthritis verbessern.

Pharmacogenetics (PGx) studies the effect of heritable genetic variation on drug response. Clinical adoption of PGx has remained limited, despite progress in the field. To promote implementation, the Dutch Pharmacogenetics Working Group (DPWG) develops evidence-based guidelines on how to optimize pharmacotherapy based on PGx test results. This guideline describes optimization of atomoxetine therapy based on genetic variation in the CYP2D6 gene. The CYP2D6 enzyme is involved in conversion of atomoxetine into the metabolite 4-hydroxyatomoxetine. With decreasing CYP2D6 enzyme activity, the exposure to atomoxetine and the risk of atomoxetine induced side effects increases. So, for patients with genetically absent CYP2D6 enzyme activity (CYP2D6 poor metabolisers), the DPWG recommends to start with the normal initial dose, bearing in mind that increasing this dose probably will not be required. In case of side effects and/or a late response, the DPWG recommends to reduce the dose and check for sustained effectiveness for both poor metabolisers and patients with genetically reduced CYP2D6 enzyme activity (CYP2D6 intermediate metabolisers). Extra vigilance for ineffectiveness is required in patients with genetically increased CYP2D6 enzyme activity (CYP2D6 ultra-rapid metabolisers). No interaction was found between the CYP2D6 and COMT genes and methylphenidate. In addition, no interaction was found between CYP2D6 and clonidine, confirming the suitability of clonidine as a possible alternative for atomoxetine in variant CYP2D6 metabolisers. The DPWG classifies CYP2D6 genotyping as being \"potentially beneficial\" for atomoxetine. CYP2D6 testing prior to treatment can be considered on an individual patient basis.

BACKGROUND: Direct oral anticoagulants (DOACs) can be involved in clinical relevant drug-drug interactions (DDIs) which may compromise safe and effective use. However, assessing the clinical relevance of DDIs with DOACs and managing these interactions optimally, can be challenging in clinical practice.
OBJECTIVE: To develop a practice-oriented list of potentially clinically relevant DDIs with DOACs with corresponding management plans for which it is important to screen in ambulatory care.
METHODS: The RAND/UCLA appropriateness method was used to develop the DOACs DDI list. In a first step a preliminary list was compiled of potentially clinically relevant DDIs per DOAC (apixaban, dabigatran, edoxaban, rivaroxaban) using five reference sources. Subsequently, a two-step modified Delphi process involving a multidisciplinary panel (n = 10) including both pharmacists and physicians with expertise in all decision-making disciplines involved in care for patients using DOACs and with diversity of practice setting, was used to reach expert agreement on a final list of DDIs with corresponding management plans.
RESULTS: After a two-step consensus round, 71 DDIs for 20 different interacting drugs were included: five pharmacodynamic, nine pharmacokinetic inhibitor and six pharmacokinetic inducer interacting drugs. Considerations raised and discussed by the panellists were related to (1) the necessity of the interacting drug, (2) the manageability of the DDI (whether there are any alternatives), (3) the (clinical) evidence-base for the DDI and (4) the (potential) consequences of the DDI.
CONCLUSIONS: We developed a consensus list with specific and straightforward management plans on potentially clinically relevant DDIs with DOACs, for use in ambulatory care.