Visualizing classification of drugs used in psychotic disorders: A 'subway map' representing mechanisms, established classes and informal categories.

Drugs used to treat psychotic disorders ('antipsychotics') have been widely used in psychiatry since the introduction of chlorpromazine in the mid-1950s. The categorization of these drugs evolved in a piecemeal way, relying initially on grouping by chemical structure (e.g. phenothiazines, butyrophenones), then by epoch of introduction (e.g. first generation ('conventional') vs second generation ('atypical')). As psychopharmacological expertise has advanced, it has become possible to quantify affinities for each drug in this class for relevant receptors including dopamine D2, 5HT2A, 5HT2C, histamine H1 and others. However, until the recent emergence of a new generation of agents known collectively as dopamine D2 receptor partial agonists (e.g. aripiprazole, brexpiprazole and cariprazine), there had been little reference in drug classification to specific pharmacological properties. An overview of data on receptor affinities across multiple drugs and receptor types would permit categorization according to binding affinities and putative pharmacological mechanisms. In this paper, we have attempted to construct a 'subway map' of 32 drugs used for treatment of psychotic disorders. This design allows a visualization of both the historical classifications by structure and epoch of introduction, and of the binding affinities for key receptors based on appraisal of scientific literature. The map represents a step towards categorization by mechanism, allowing prescribers and patients to understand which drugs share common biological features and the extent to which drugs may have similarities and differences in their mechanisms. In addition, this approach may encourage more logical groupings of drugs to be used in systematic reviews and meta-analyses.

PI3Kδ Inhibition as a Potential Therapeutic Target in COVID-19.

The spread of the novel human respiratory coronavirus (SARS-CoV-2) is a global public health emergency. There is no known successful treatment as of this time, and there is a need for medical options to mitigate this current epidemic. SARS-CoV-2 uses the angiotensin-converting enzyme 2 (ACE2) receptor and is primarily trophic for the lower and upper respiratory tract. A number of current studies on COVID-19 have demonstrated the substantial increase in pro-inflammatory factors in the lungs during infection. The virus is also documented in the central nervous system and, particularly in the brainstem, which plays a key role in respiratory and cardiovascular function. Currently, there are few antiviral approaches, and several alternative drugs are under investigation. Two of these are Idelalisib and Ebastine, already proposed as preventive strategies in airways and allergic diseases. The interesting and evolving potential of phosphoinositide 3-kinase δ (PI3Kδ) inhibitors, together with Ebastine, lies in their ability to suppress the release of pro-inflammatory cytokines, such as IL-1ß, IL-8, IL-6, and TNF-α, by T cells. This may represent an optional therapeutic choice for COVID-19 to reduce inflammatory reactions and mortality, enabling patients to recover faster. This concise communication aims to provide new potential therapeutic targets capable of mitigating and alleviating SARS-CoV-2 pandemic infection.

Antihistamine Drug Ebastine Inhibits Cancer Growth by Targeting Polycomb Group Protein EZH2.

Enhancer of zester homolog 2 (EZH2), a histone lysine methyltransferase and the catalytic component of polycomb repressive complex 2, has been extensively investigated as a chromatin regulator and a transcriptional suppressor by methylating H3 at lysine 27 (H3K27). EZH2 is upregulated or mutated in most cancers, and its expression levels are negatively associated with clinical outcomes. However, the current developed small-molecule inhibitors targeting EZH2 enzymatic activities could not inhibit the growth and progression of solid tumors. Here, we discovered an antihistamine drug, ebastine, as a novel EZH2 inhibitor by targeting EZH2 transcription and subsequently downregulating EZH2 protein level and H3K27 trimethylation in multiple cancer cell lines at concentrations below 10 µmol/L. The inhibition of EZH2 by ebastine further impaired the progression, migration, and invasiveness of these cancer cells. Overexpression of Ezh2 wild-type and its mutant, H689A (lacking methyltransferase activity), rescued the neoplastic properties of these cancer cells after ebastine treatment, suggesting that EZH2 targeted by ebastine is independent of its enzymatic function. Next-generation RNA-sequencing analysis also revealed that C4-2 cells treated with 8 µmol/L ebastine showed a gene profiling pattern similar to EZH2-knockdown C4-2 cells, which was distinctively different from cells treated with GSK126, an EZH2 enzyme inhibitor. In addition, ebastine treatment effectively reduced tumor growth and progression, and enhanced progression-free survival in triple-negative breast cancer and drug-resistant castration-resistant prostate cancer patient-derived xenograft mice. Our data demonstrated that ebastine is a novel, safe, and potent anticancer agent for patients with advanced cancer by targeting the oncoprotein EZH2.

Ebastine in the Treatment of Allergic Rhinitis and Urticaria: 30 Years of Clinical Studies and Real-World Experience.

Histamine, acting predominantly via the H1-receptor, is an important mediator of the symptoms of allergy. H1-antihistamines, which stabilize the receptor in its inactive form, are the treatment of choice for some chronic allergic conditions. Ebastine is a well-established secondgeneration oral H1-antihistamine that is administered once daily at a dose of 10-20 mg and is available both as a standard tablet and as a fast-dissolving tablet that disintegrates in the mouth. Ebastine has been shown to relieve symptoms in patients with allergic rhinitis or urticaria in multiple clinical trials. In addition to its antihistamine effects, the drug has modulating effects on the allergic inflammatory process, thus potentially explaining its beneficial effect on nasal obstruction in some patients. Ebastine is generally well tolerated at recommended doses and is one of the lowest-risk antihistamines with respect to adverse cognitive/psychomotor effects, as confirmed by decades of pharmacovigilance. New long-term data confirm its efficacy and tolerability during up to 1 year of treatment in patients with chronic urticaria.

Emergency department pain management: beyond opioids.

Pain is a common factor in many emergency department visits. While opioids remain a mainstay of treatment for many patients, prescription-opioid overuse and misuse have become epidemic in the United States. A lack of clear understanding of the pain management options available contributes to this problem, resulting in opioid overuse and over-prescription. National guidelines and consensus statements emphasize the importance of knowing nonopioid pharmacological and nonpharmacological options for treating patients with acute pain. This evidence-based review summarizes the pathophysiology of pain and pain syndromes and provides recommendations for a variety of nonopioid treatment options.

Influence of Antipsychotics on Functional Prognosis after Geriatric Hip Fracture.

OBJECTIVE: To investigated the effects of antipsychotics on rehabilitation outcomes for geriatric hip fracture inpatients. DESIGN: Retrospective cohort study. SETTING: The registry data from the Japan Rehabilitation Nutrition Database for analysis. PARTICIPANTS: Of the 234 patients in the Japan Rehabilitation Nutrition Database admitted between November 2015 and March 2018, 214 met the eligibility criteria. MEASUREMENTS: The antipsychotics were phenothiazine, butyrophenone, benzamide, and atypical antipsychotics. For hip fracture patients, the following information was registered: (a) admission data: age, sex, Charlson Comorbidity Index, Functional Independence Measure (FIM) at admission, medications, height, body weight, and Mini Nutritional Assessment-Short Form score (MNA-SF) and (b) discharge data: discharge destination, FIM at discharge, MNA-SF, and total units of provided rehabilitation therapy (one unit = 20 minutes based on the national healthcare insurance policy). RESULTS: Thirteen patients (6.1%) were prescribed antipsychotics. According to the multiple linear regression analysis, antipsychotics negatively affected FIM efficiency (ß=-0.190, 95% confidence interval, -0.652 to -0.104, p=0.007). Furthermore, on logistic regression analysis, fall during hospitalization was correlated with the use of antipsychotics (odds ratio=4.376, 95% confidence interval: 1.153 to 16.612, p=0.030). CONCLUSION: The use of antipsychotics impaired the improvement of the activities of daily living (ADL) and increased the incidence of fall during hospitalization. Reviewing medication therapies at admission may further improve ADL.

Comparison of Outcomes of Allogeneic Hematopoietic Cell Transplantation for Multiple Myeloma Using Three Different Conditioning Regimens.

Allogeneic hematopoietic cell transplantation (allo-HCT) is a potentially curative therapy for patients with multiple myeloma, as it provides a graft-versus-myeloma effect alongside a myeloma-free graft. Although reduced-intensity conditioning regimens decrease nonrelapse mortality (NRM), there is a paucity of data with regard to the ideal conditioning regimen in myeloma. We conducted a retrospective comparison of 3 different preparative regimens used for allo-HCT for multiple myeloma at our institution in recent clinical trials: busulfan/fludarabine (BuFlu), fludarabine/melphalan 100 mg/m2 (FM100), and fludarabine/melphalan 140 mg/m2 (FM140). NRM, progression-free survival (PFS) at 3 years, and overall survival (OS) at 3 years were the primary endpoints. Secondary endpoints included time to engraftment, and the incidence of grades II through IV acute graft-versus-host disease and chronic graft-versus-host disease. A total of 73 patients received allo-HCT with these regimens. NRM at 3 years was seen in 3 (21%), 5 (28%), and 6 (24%) patients in the BuFlu, FM100, and FM140 groups, respectively. Three-year PFS in the BuFlu, FM100, and FM140 groups was 16% (hazard ratio [HR], 1.2; 95% confidence interval [CI], 0.6 to 2.1), 26% (HR, 0.6; 95% CI, 0.3 to 1.2), and 11% (reference), respectively. Three-year OS in the BuFlu, FM100, and FM140 groups was 39% (HR, 1.1; 95% CI, 0.5 to 2.2), 43% (HR, 0.7; 95% CI, 0.3 to 1.4), and 32% (reference), respectively. High-risk cytogenetics and relapsed disease prior to allo-HCT were found to be independent predictors of inferior OS on multivariate analysis, with a HR of 2.1 (P = .02) and 2.6 (P = .004), respectively. In contrast, the preparative regimen did not emerge as a predictor of PFS or OS. Durable clinical remission can be achieved in 11% to 25% of patients with multiple myeloma with the use of allo-HCT without any significant difference in the safety or efficacy of the conditioning regimen. High-risk cytogenetics and relapsed disease prior to transplant were associated with inferior PFS and OS.

[Effects of double-dose antihistamine or combined therapy in allergic rhinitis].

Objective:To compare the efficacy and side effects of combined therapy with single-dose oral antihistamine and intranasal corticosteroid to monotherapy with double-dose oral antihistamine in the treatment of seasonal allergic rhinitis. Method:Eighty-two patients with seasonal allergic rhinitis caused by cypress pollen were enrolled in a randomized, parallel-group studycomparing 2 weeks therapy of either 10mg oral ebastine plus 200 µg intranasal mometasone furoate once daily (combined group) or 20 mg oral ebastine once daily (double-dose group) during the pollen season. Daily rhinoconjunctivitis symptom score and rescue medication use were recorded in both groups. After the treatment period, questionnaires were used to survey the side effects of medicines and dosage form preference of the patients. The levels of IL-6, IL-8 and TNF-α in the peripheral blood were measured before and after the therapy. Result:During the cypress pollen season, the daily rhinoconjunctivitis symptom score of the combined group (n=42, 3.7±0.4) was significantly lower than that of double-dose group (n=40, 4.5±0.5), P<0.001. The daily rescue medication score of the combined group (1.3±0.6) was also significantly lower than double-dose group(1.7±0.7), P<0.001. The daily medication cost of combined group was 7.08±0.33 Yuan, which was less than that of double-dose group (7.28±0.51 Yuan, P=0.002). There was no statistical difference in the rate of adverse reactions between the two groups. The peripheral levels of IL-6, IL-8 and TNF-α in two groups did not show significant difference at the end of therapy . Conclusion:The combined therapy with single-dose oral antihistamine and intranasal corticosteroid was superior to the monotherapy with double-dose oral antihistamine in the treatment of seasonal allergic rhinitis in our study.

[Altered orientation and aggressiveness in an 89-year-old woman]. / Wechselnde Vigilanz und Fremdaggressivität bei einer 89­jährigen Patientin.

An 89-year-old woman with Alzheimer's dementia was admitted because of altered orientation, aggressiveness and inability to take care of herself at home. Her patient history indicated that 14 days ago the battery of the pacemaker had be renewed. During that time the patient suffered from psychomotor alterations. Therefore, melperone had been initiated. Inspection of the urine and laboratory findings pointed towards an acute exacerbation of acute intermittent porphyria as a possible cause of the delirium. After discontinuation of melperone with additional parenteral therapy with physiological fluids, the signs of delirium significantly improved.

In silico repurposing of antipsychotic drugs for Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD) is the most prevalent form of dementia and represents one of the highest unmet requirements in medicine today. There is shortage of novel molecules entering into market because of poor pharmacokinetic properties and safety issues. Drug repurposing offers an opportunity to reinvigorate the slowing drug discovery process by finding new uses for existing drugs. The major advantage of the drug repurposing approach is that the safety issues are already investigated in the clinical trials and the drugs are commercially available in the marketplace. As this approach provides an effective solution to hasten the process of providing new alternative drugs for AD, the current study shows the molecular interaction of already known antipsychotic drugs with the different protein targets implicated in AD using in silico studies. RESULT: A computational method based on ligand-protein interaction was adopted in present study to explore potential antipsychotic drugs for the treatment of AD. The screening of approximately 150 antipsychotic drugs was performed on five major protein targets (AChE, BuChE, BACE 1, MAO and NMDA) by molecular docking. In this study, for each protein target, the best drug was identified on the basis of dock score and glide energy. The top hits were then compared with the already known inhibitor of the respective proteins. Some of the drugs showed relatively better docking score and binding energies as compared to the already known inhibitors of the respective targets. Molecular descriptors like molecular weight, number of hydrogen bond donors, acceptors, predicted octanol/water partition coefficient and percentage human oral absorption were also analysed to determine the in silico ADME properties of these drugs and all were found in the acceptable range and follows Lipinski's rule. CONCLUSION: The present study have led to unravel the potential of leading antipsychotic drugs such as pimozide, bromperidol, melperone, anisoperidone, benperidol and anisopirol against multiple targets associated with AD. Benperidol was found to be the best candidate drug interacting with different target proteins involved in AD.

Prevención y tratamiento de pacientes con náuseas y vómitos postoperatorios / Prevention and treatment of patients with postoperative nausea and vomiting

Resumen Las náuseas y vómitos postoperatorios (NVPO) son un problema frecuente en los pacientes quirúrgicos. Cuando no son prevenidos adecuadamente pueden provocar mayor morbilidad, estadía prolongada en la unidad de recuperación postoperatoria y hospitalización no planificada. El objetivo del equipo quirúrgico debe ser la profilaxis de las NVPO más que su tratamiento, con el fin de disminuir significativamente su incidencia y complicaciones asociadas. Los principales factores de riesgo para NVPO son: sexo femenino, historia de NVPO en cirugías previas y/o cinetosis, no fumar, uso de opioides sistémicos en el postoperatorio, someterse a ciertos tipos de cirugía (como colecistectomía, cirugía laparoscópica y cirugía ginecológica), utilizar anestésicos volátiles y/u óxido nitroso intraoperatorios, y duración de la cirugía. Sugerimos objetivar el riesgo de NVPO utilizando las escalas de riesgo de NVPO de Apfel o Koivuranta. Los principales fármacos antieméticos usados como profilaxis y tratamiento en el período perioperatorio son dexametasona, ondansetrón y droperidol. Existen estrategias generales que se pueden utilizar para reducir el riesgo quirúrgico basal de NVPO como evitar la anestesia general, privilegiando la anestesia regional, utilizar propofol para la inducción y mantención de la anestesia, evitar el uso de óxido nitroso y/o anestésicos inhalatorios, minimizar el uso postoperatorio de opioides sistémicos y recibir una hidratación intravenosa abundante durante la cirugía. La etiología de las NVPO es multifactorial, por lo que la prevención y tratamiento deben incluir diferentes clases de antieméticos, que actúen sobre los diferentes receptores de náuseas y/o vómitos hasta el momento conocidos, junto con las estrategias generales antes mencionadas.

Abstract Postoperative nausea and vomiting (PONV) are a common problem in surgical patients. When not properly prevented, they can lead to increased morbidity, prolonged stay in the postoperative recovery unit and unplanned hospitalization. The objective of the surgical team should be the prophylaxis of PONV rather than its treatment, in order to significantly reduce its incidence and associated complications. The main risk factors for PONV are: female sex, history of PONV in prior surgeries and/or motion sickness, non-smoking, use of systemic opioids postoperatively, undergo certain types of surgery (such as cholecystectomy, laparoscopic surgery and gynecological surgery), use volatile anesthetics and/or intraoperative nitrous oxide, and duration of surgery. We suggest to objectify the risk of PONV using the Apfel or Koivuranta PONV risk scales. The main anti-emetic drugs used as prophylaxis and treatment in the perioperative period are dexamethasone, ondansetron and droperidol. There are general strategies that can be used to reduce the baseline surgical risk of PONV such as avoiding general anesthesia, favoring regional anesthesia, using propofol for induction and maintenance of general anesthesia, avoiding the use of nitrous oxide and/or inhalational anesthetics, minimizing the postoperative use of systemic opioids and to receive an abundant intravenous hydration during surgery. The etiology of PONV is multifactorial, so prevention and treatment should include different classes of antiemetics, acting on the different receptors of nausea and/or vomiting so far known, together with the general strategies mentioned above.

Pipamperone and delirium: a preliminary evaluation of its effectiveness in the management of delirium and its subtypes.

INTRODUCTION: Delirium has been recognised as an underdiagnosed and undermanaged syndrome with substantial prevalence rates and potentially deleterious consequences in the medically ill population. Despite its frequent administration in the management of delirium, the effectiveness of pipamperone has not yet been evaluated. METHODS: In this retrospective, descriptive cohort study of 192 patients, pipamperone as monotherapy and as an adjunct to haloperidol, haloperidol alone, or atypical antipsychotics were compared with respect to their effectiveness in the management of delirium and its subtypes over the course of 20 days. RESULTS: In this elderly patient population, pipamperone alone and as an adjunct to haloperidol was as effective as haloperidol or atypical antipsychotics in the management of delirium. Management with low-dose pipamperone monotherapy achieved delirium resolution in 70% of patients, over a mean of 6.4 (2-20) days. With pipamperone as an adjunct to haloperidol, delirium resolved in 59% of patients, over a mean of 7.4 (2-20) days. When haloperidol or atypical antipsychotics (risperidone, olanzapine or quetiapine) were used, the delirium resolution rates were 72 and 67%, over a mean of 5.2 (2-11) and 6.4 (2-20) days, respectively. The addition of pipamperone to haloperidol decreased the requirement for lorazepam. Pipamperone proved to be equally effective in all delirium subtypes - hypoactive, hyperactive and mixed. Nonetheless, potential bias could not be excluded in this observational design. CONCLUSION: From these initial results, low-dose pipamperone was as effective as haloperidol or atypical antipsychotics in the management of delirium and its subtypes, and was benzodiazepine-sparing when used as an adjunct to haloperidol.

Dietary and pharmacological treatment of abdominal pain in IBS.

This review introduces the principles of visceral sensation and appraises the current approaches to management of visceral pain in functional GI diseases, principally IBS. These approaches include dietary measures including fibre supplementation, low fermentable oligosaccharides, disaccharides, monosaccharides and polyols diet, and pharmacological approaches such as antispasmodics, peppermint oil, antidepressants (tricyclic agents, selective serotonin reuptake inhibitors), 5-HT3 receptor antagonists (alosetron, ondansetron, ramosetron), non-absorbed antibiotic (rifaximin), secretagogues (lubiprostone, linaclotide), µ-opioid receptor (OR) and κ-OR agonist, δ-OR antagonist (eluxadoline), histamine H1 receptor antagonist (ebastine), neurokinin-2 receptor antagonist (ibodutant) and GABAergic agents (gabapentin and pregabalin). Efficacy and safety are discussed based on pivotal trials or published systematic reviews and meta-analysis, expressing ORs or relative risks and their 95% CIs. Potential new approaches may be based on recent insights on mucosal expression of genes, and microRNA and epigenetic markers in human biopsies and in animal models of visceral hypersensitivity.The objectives of this review are to appraise the physiology and anatomy of gut sensation and the efficacy in the relief of visceral pain (typically in IBS) of several classes of therapies. These include fermentable oligosaccharides, disaccharides, monosaccharides and polyols (FODMAPs) and different classes of medications (box 1). Box 1Classes of pharmacological agents for visceral painAntidepressants (tricyclic agents, selective serotonin reuptake inhibitors)Peppermint oil5-HT3 receptor antagonists (alosetron, ondansetron, ramosetron)Non-absorbed antibiotic (rifaximin)Secretagogues (lubiprostone, linaclotide)µ-Opioid receptor (OR) and κ-OR agonist and δ-OR antagonist (eluxadoline)Histamine H1 receptor antagonist (ebastine)Neurokinin-2 receptor antagonist (ibodutant)GABAergic agents (gabapentin and pregabalin).

Histamine Receptor H1-Mediated Sensitization of TRPV1 Mediates Visceral Hypersensitivity and Symptoms in Patients With Irritable Bowel Syndrome.

BACKGROUND & AIMS: Histamine sensitizes the nociceptor transient reporter potential channel V1 (TRPV1) and has been shown to contribute to visceral hypersensitivity in animals. We investigated the role of TRPV1 in irritable bowel syndrome (IBS) and evaluated if an antagonist of histamine receptor H1 (HRH1) could reduce symptoms of patients in a randomized placebo-controlled trial. METHODS: By using live calcium imaging, we compared activation of submucosal neurons by the TRPV1 agonist capsaicin in rectal biopsy specimens collected from 9 patients with IBS (ROME 3 criteria) and 15 healthy subjects. The sensitization of TRPV1 by histamine, its metabolite imidazole acetaldehyde, and supernatants from biopsy specimens was assessed by calcium imaging of mouse dorsal root ganglion neurons. We then performed a double-blind trial of patients with IBS (mean age, 31 y; range, 18-65 y; 34 female). After a 2-week run-in period, subjects were assigned randomly to groups given either the HRH1 antagonist ebastine (20 mg/day; n = 28) or placebo (n = 27) for 12 weeks. Rectal biopsy specimens were collected, barostat studies were performed, and symptoms were assessed (using the validated gastrointestinal symptom rating scale) before and after the 12-week period. Patients were followed up for an additional 2 weeks. Abdominal pain, symptom relief, and health-related quality of life were assessed on a weekly basis. The primary end point of the study was the effect of ebastine on the symptom score evoked by rectal distension. RESULTS: TRPV1 responses of submucosal neurons from patients with IBS were potentiated compared with those of healthy volunteers. Moreover, TRPV1 responses of submucosal neurons from healthy volunteers could be potentiated by their pre-incubation with histamine; this effect was blocked by the HRH1 antagonist pyrilamine. Supernatants from rectal biopsy specimens from patients with IBS, but not from the healthy volunteers, sensitized TRPV1 in mouse nociceptive dorsal root ganglion neurons via HRH1; this effect could be reproduced by histamine and imidazole acetaldehyde. Compared with subjects given placebo, those given ebastine had reduced visceral hypersensitivity, increased symptom relief (ebastine 46% vs placebo 13%; P = .024), and reduced abdominal pain scores (ebastine 39 ± 23 vs placebo 62 ± 22; P = .0004). CONCLUSIONS: In studies of rectal biopsy specimens from patients, we found that HRH1-mediated sensitization of TRPV1 is involved in IBS. Ebastine, an antagonist of HRH1, reduced visceral hypersensitivity, symptoms, and abdominal pain in patients with IBS. Inhibitors of this pathway might be developed as a new treatment approach for IBS. ClinicalTrials.gov no: NCT01144832.

[Pain medication in nursing home residents with and without cancer. Most frequently with metamizole]. / Schmerzmittelversorgung von Pflegeheimbewohnern mit und ohne Krebserkrankung. Am häufigsten mit Metamizol.

BACKGROUND: Pain is a highly prevalent symptom in nursing home residents. The analgesic pharmacotherapy of older adults is associated with challenges; however, studies from Germany examining the prescription pattern of analgesics in nursing home residents are rare. OBJECTIVES: This study was carried out to examine the prescription of analgesics in nursing home residents with and without the diagnosis of cancer. MATERIAL AND METHODS: Using health insurance claims data persons aged ≥ 65 years who were newly admitted to a nursing home between 2004 and 2009 and who survived at least the first 90 days after admission were included in the study. Cancer was identified by outpatient diagnoses of malignant neoplasms (ICD-10: C00-C97). Prescription drugs within the first 90 days after admission to a nursing home were analyzed which means that aspirin and acetaminophen were not taken into account. RESULTS: A total of 5549 nursing home residents were included, who were on average 81.5 years old (56.8 % females). More than half (53.5 %) were assigned to care level I and 781 (14.1 %) were diagnosed with cancer. The study cohort received on average 7.8 different medications (with vs. without cancer: 8.6 vs. 7.6, respectively) and 43.8 % had prescriptions for analgesics (with vs. without cancer: 52.5 vs. 42.3 %, respectively). A total of 37.1 % were taking WHO step 1 analgesics (step 2: 11.4 % and step 3: 9.2 %). The proportion of persons receiving metamizole (dipyrone) was 28.3 % (with vs. without cancer: 35.6 vs. 27.1 %, respectively). Regarding all prescriptions, metamizole was by far the most frequently prescribed medication in nursing homes followed by melperone and omeprazole. CONCLUSION: Approximately one third of nursing home residents received metamizole and most were long-term prescriptions. Considering that metamizole is associated with potentially life-threatening adverse effects, caution is indicated particularly when prescribed over long periods.

Melperone but not bisoprolol or metoprolol is a clinically relevant inhibitor of CYP2D6: evidence from a therapeutic drug monitoring survey.

Cytochrome P450 enzymes (CYP) can be inhibited or induced by drugs, resulting in clinically significant drug-drug interactions that can cause unanticipated adverse reactions or therapeutic failures. The objective of the study was to analyze the in vivo inhibitory potential of the beta-blockers bisoprolol and metoprolol as well as the low-potency antipsychotic melperone on CYP2D6. By utilizing a large therapeutic drug monitoring database of 2874 samples, data from patients who had been treated with venlafaxine (VEN) either without (control group) or with a concomitant medication with bisoprolol, metoprolol or melperone were evaluated retrospectively to study the CYP2D6-catalyzed O-demethylation to O-desmethylvenlafaxine (ODVEN). Dose-adjusted serum levels (C/D) of VEN and ODVEN as well as the metabolic ratios (ODVEN/VEN) were computed for the four groups and compared using Kruskal-Wallis test. In total, 381 patients could be included for analysis. No significant difference was found in the median C/D (VEN), C/D (ODVEN) or C/D of the active moiety (VEN + ODVEN) in either the metoprolol (N = 103) or bisoprolol group (N = 101), compared to the control group (N = 108). In contrast, a significantly higher median C/D (VEN) (0.79 ng/ml/mg, range 0.13-5.73 ng/ml/mg) (P < 0.01) was found in the melperone group (N = 69), compared to the control group (0.46 ng/ml/mg, range 0.02-7.39 ng/ml/mg). A significant decrease (P < 0.01) was solely found in the median metabolic ratios of ODVEN/VEN between the melperone group (0.90, range 0.14-15.15), compared to the control group (2.39, range 0.06-15.31). The results of this study provided evidence that melperone but not bisoprolol or metoprolol has a clinically relevant inhibitory potential on CYP2D6.