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Background We report a case of sudden, lethal metabolic acidosis in a 70-year-old man on long-term nucleoside reverse transcriptase inhibitor (NRTI) -based antiretroviral therapy (ART) who had developed atypical necrotizing fasciitis 1 month after kidney transplantation. Case presentation The HIV infection of the patient was treated for the last four months with an integrase strand inhibitor (dolutegravir 50 mg/d) plus a NRTI backbone including lamivudine (150 mg/d) and abacavir (600 mg/d). In this renal transplant patient we hypothesize that the co-existence of sepsis, renal failure and an accumulation of lamivudine led to the development of fatal metabolic acidosis and hyperlactatemia. Although lamivudine is only rarely associated with hyperlactatemia, there is evidence that overdose may be a risk factor for developing it. In our patient the lamivudine concentration two days after stopping and during hemodiafiltration was more than 50 times higher than therapeutic target trough concentrations. Likely reasons for this were renal impairment and concurrent treatment with trimethoprim, known to inhibit the renal elimination of lamivudine. Conclusions NRTIs could trigger the development of hyperlactatemia in septic patients. The use of NRTI sparing regimens might be considered in the presence of this critical condition.

Abstract. This short review addresses disease-drug interactions requiring special attention, namely interactions between common conditions and over-the-counter medication and interactions between rare conditions and drugs that are absolutely contraindicated. We specifically examine over-the-counter analgesics, antiemetics and drugs used to treat allergy symptoms and underlying disease conditions they can exacerbate. Resources for avoiding disease-drug interactions in patients with rare conditions, such as myasthenia gravis, glucose-6-phosphate deficiency, mitochondriopathies and long QT-syndrome are given. We also discuss methods for avoiding disease-drug interactions in clinical practice. These include awareness, regular diagnosis- and drug-history taking, consulting the product information, good communication between healthcare providers and patient education. Furthermore, pharmacovigilance activities help in the early identification and characterization of adverse drug reactions resulting from disease-drug interactions.

Zusammenfassung. Zur Linderung einer Hustensymptomatik können diverse Arzneimittel mit verschiedenen protussiven oder antitussiven Wirkmechanismen eingesetzt werden. Für gewisse Indikationen spielen auch Phytopharmaka eine bedeutende Rolle. In der Ursachensuche eines persistierenden Hustens ist die Dauermedikation kritisch zu prüfen und bei Verdacht auf eine unerwünschte Arzneimittelwirkung gegebenenfalls anzupassen.

Background The introduction of new therapy modalities has significantly improved the outcome of aplastic anemia (AA) and paroxysmal nocturnal hemoglobinuria (PNH) patients. However, relatively little is known about the exact disease burden of AA/PNH since standardized assessments of symptoms including health-related quality of life (HRQoL) are frequently missing or inadequately designed for this rare patient group. We aimed to develop AA/PNH-specific questionnaires for self-reporting of symptoms, which could be included in electronic platforms for data collection and patient care. Methods By scoping review, we extracted any reported symptoms in AA/PNH and their prevalence from the literature (Phase I). Consensus rounds with patients and medical experts were conducted to identify core symptoms reported in the literature and to add missing items (Phase II). Ultimately, AA/PNH-specific patient-reported outcome (PRO) questionnaires including the selected measures were designed (Phase III). Results AA symptoms from 62 and PNH symptoms from 45 observational studies were extracted from the literature. Twenty-four patients and seven medical experts identified 11 core symptoms including HRQoL issues after three consensus rounds. Significant differences in the symptom ranking of patients versus medical experts could be observed. Therefore, patient- as well as expert-centered PRO questionnaires in AA and PNH were created following the concepts of validated instruments. Conclusion The development of symptom self-reporting questionnaires for AA and PNH was feasible and the disease-specific PRO questionnaires can now be validated within a web-based workflow in a subsequent feasibility study.

Aims To determine whether enzyme-inducing antiseizure drugs (ASDs) affect the risk of developing chronic obstructive pulmonary disease (COPD) or lung cancer in smokers. Methods Cases of COPD and lung cancer and matched controls without these conditions were identified from a population of smokers with ≥1 prescription for any type of ASD in the Clinical Practice Research Datalink UK database of patients managed in primary care (1995-2016). A matched case-control study was performed utilising multivariate logistic regression analyses of exposure to enzyme-inducing ASDs compared to non-enzyme-inducing ASDs. The duration of ASD exposure and level of tobacco exposure were also assessed. Results We identified 5952 incident COPD and 1373 incident lung cancer cases, and 59 328 and 13 681 matched controls, respectively. Compared with never use, ever use of enzyme-inducing ASDs was associated with slightly decreased risk estimates of COPD (adjusted odds ratio: 0.85, 95% confidence interval: 0.81-0.89) and lung cancer (adjusted odds ratio: 0.82, 95% confidence interval: 0.73-0.92). These risk estimates were attenuated in heavy smokers. Conclusion We found slightly decreased risk estimates of COPD and lung cancer among smokers taking enzyme-inducing ASDs and hypothesise that this may be related to induction of detoxification of tobacco-specific lung toxins.

Cardiovascular risk factors (CVRF) are frequent among long-term survivors after allogeneic hematopoietic cell transplantation (HCT) but prospective data on CVRF are sparse. We conducted a cross-sectional single center study including patients who underwent a first HCT mostly for hematologic malignancies at our center between 2000 and 2016, surviving at least 1 year. 260 patients (median age 54 years [range 19–78], 40% female) who were median 6 years (range 1–16) after transplantation were included. Most patients (232, 89%) had peripheral blood stem cell transplantation. cGVHD was present in 41% at the time of study inclusion. Prevalence of hypertension, dyslipidemia, and diabetes was 58%, 63% and 9%, respectively. Untreated hypertension, dyslipidemia and diabetes was found in 15%, 35% and 2%. Among patients with treated hypertension, 38% did not have blood pressure controlled to levels ≤140/90 mmHg. 36% patients under lipid-lowering therapy did not reach their LDL target. Multivariable logistic regression analyses showed that age and diabetes increased the likelihood for hypertension and dyslipidemia, whereas body mass index, cGVHD and male sex predicted hypertension only. In summary, CVRF in long-term survivors are frequent and persisting after cessation of immunosuppression. A large proportion of CVRF are either untreated or uncontrolled.

Zusammenfassung. Eine Nierenfunktionsstörung kann die Elimination von bestimmten Opioiden und ihren Metaboliten reduzieren. Es kann zu Akkumulation und Toxizität kommen. Aufgrund ihrer pharmakokinetischen Eigenschaften sind Fentanyl, Alfentanil und Buprenorphin bei Patienten mit Niereninsuffizienz gut einsetzbar. Codein und Pethidin sollten ganz vermieden werden. Morphin sollte bei einer Kreatinin-Clearance unter 30 ml / min ebenfalls vermieden werden. Hydromorphon in reduzierter Dosis ist hier eine Alternative. Methadon, Oxycodon und Tramadol sollten nur mit Vorsicht und in reduzierter Dosis verwendet werden. In diesem Artikel erläutern wir kurz die renalen Eliminationsprozesse, wesentliche pharmakokinetische Eigenschaften der verschiedenen Opioide und die Schlussfolgerung für die Klinik.

Background: Joint pain is frequently observed in patients on antituberculous treatment, and pyrazinamide is known to be associated with joint pain in patients receiving antituberculous treatment. Fluoroquinolone-associated joint pain and tendon injury have been reported in long-term corticosteroid and transplant recipients, but data are lacking in patients with tuberculosis. Objectives: The objective of this study was to examine the incidence of joint pain manifested during administration of antituberculous therapy and their association with fluoroquinolones. Methods: Patients diagnosed with tuberculosis attending the outpatient clinic over a period of 1 year were reviewed and divided into 3 groups: group A receiving pyrazinamide, group B receiving a fluoroquinolone, and group C receiving both pyrazinamide and a fluoroquinolone. Latency to onset of joint pain was noted in all 3 groups. Joint pain was initially managed with analgesics, and associated hyperuricemia was treated with allopurinol/febuxostat. Causative drugs were stopped in case of intolerable joint pain. Results: 260 patients (47% females, aged 38 ± 18 years; mean ± SD) were included [group A (n = 140), group B (n = 81), and group C (n = 39)]. Overall, 76/260 (29%) patients developed joint pain: group A – 24/140 patients (17%), group B – 32/81 patients (40%), and group C – 20/39 patients (51%). The median latency to the onset of joint pain was 83 days (interquartile range, IQR 40–167): 55 days (IQR 32–66) in group A, 138 days (IQR 74–278) in group B, and 88 days (IQR 34–183) in group C. Hyperuricemia was present in 12/24 (50%) patients in group A and 11/20 (55%) patients in group C. Pyrazinamide was stopped in 7/140 (5%) patients in group A, fluoroquinolones in 6/81 (7%) patients in group B, and both pyrazinamide and fluoroquinolones were stopped in 5/39 (13%) patients in group C because of intolerable joint pain. Major joints affected were knees and ankles. Conclusion: There is a high incidence of joint pain in patients receiving antituberculous treatment, which is higher when fluoroquinolones or the pyrazinamide-fluoroquinolone combination are administered as compared to pyrazinamide alone.

Amina El Saghir,1,* Georgios Dimitriou,2,* Miriam Scholer,3 Ioanna Istampoulouoglou,1 Patrick Heinrich,3 Klaus Baumgartl,3 René Schwendimann,4 Stefano Bassetti,2 Anne Leuppi-Taegtmeyer1 1Department of Clinical Pharmacology & Toxicology, University Hospital and University of Basel, Basel, Switzerland; 2Division of Internal Medicine, University Hospital and University of Basel, Basel, Switzerland; 3Department of Information Technology, University Hospital Basel, Basel, Switzerland; 4Patient Safety Office, University Hospital Basel, Basel, Switzerland*These authors contributed equally to this workCorrespondence: Anne Leuppi-TaegtmeyerDepartment of Clinical Pharmacology & Toxicology, University Hospital Basel, Schanzenstrasse 55, Basel, CH4031, SwitzerlandTel +41 61 328 68 48Fax +41 61 265 45 60Email anne.leuppi-taegtmeyer@usb.chPurpose: The purpose of the study was to develop and implement an institution-specific trigger tool based on the Institute for Healthcare Improvement medication module trigger tool (IHI MMTT) in order to detect and monitor ADEs.Methods: We performed an investigator-driven, single-center study using retrospective and prospective patient data to develop (“development phase”) and implement (“implementation phase”) an efficient, institution-specific trigger tool based on the IHI MMTT. Complete medical data from 1008 patients hospitalized in 2018 were used in the development phase. ADEs were identified by chart review. The performance of two versions of the tool was assessed by comparing their sensitivities and specificities. Tool A employed only digitally extracted triggers (“e-trigger-tool”) while Tool B employed an additional manually extracted trigger. The superior tool – taking efficiency into account – was applied prospectively to 19– 22 randomly chosen charts per month for 26 months during the implementation phase.Results: In the development phase, 189 (19%) patients had ≥ 1 ADE (total 277 ADEs). The time needed to identify these ADEs was 15 minutes/chart. A total of 203 patients had ≥ 1 trigger (total 273 triggers – Tool B). The sensitivities and specificities of Tools A and B were 0.41 and 0.86, and 0.43 and 0.86, respectively. Tool A was more time-efficient than Tool B (4 vs 9 minutes/chart) and was therefore used in the implementation phase. During the 26-month implementation phase, 22 patients experienced trigger-identified ADEs and 529 did not. The median number of ADEs per 1000 patient days was 6 (range 0– 13). Patients with at least one ADE had a mean hospital stay of 22.3 ± 19.7 days, compared to 8.0 ± 7.6 days for those without an ADE (p = 2.7× 10− 14).Conclusion: We developed and implemented an e-trigger tool that was specific and moderately sensitive, gave consistent results and required minimal resources.Keywords: electronic health record, medication module, drug safety, patient safety, digital health

The aims of the survey were to assess first experiences of Swiss COPD patients switching from the disposable to the new reusable Respimat inhaler, and to evaluate physicians´ and patients´ views of the new training material.Patients with a confirmed diagnosis of COPD using a disposable Respimat inhaler for at least three months were included. Patients´ demographics, COPD stage, current treatment, and comorbidities relevant for the handling of the device were assessed. Further, patients were trained on the reusable Respimat by placebo inhaler, patient brochure, video cards/demo films and SMS reminder service. After at least one cartridge change, patients gave comprehensive feedback on their satisfaction with the reusable Respimat and physicians evaluated the need for re-training.235 patients participated in the survey. Of these, 37% suffered from comorbidities restricting the handling of the Respimat. 216 (92%) patients had a better overall satisfaction with the reusable than with the disposable Respimat. Dose counter (86%), monthly preparation (81%) and daily handling (77%) were also assessed as better by most of the patients. In 80% of cases, the user ability was stated as better than for the disposable Respimat. Less than 15% of the patients required further training. Placebo inhaler was the mostly preferred training material by both, physicians (in 86% of the patients) and patients (75%). In patients with comorbidities affecting inhaler handling, overall satisfaction was also better in 86% of the patients.The majority of patients were satisfied with the new reusable Respimat device and proper handling could be attained using the provided training material, even in patients with restricting comorbidities.

BackgroundPoor medication-adherence is common in chronic lung patients, resulting in reduced health-outcomes and increased healthcare-costs. This study aimed to investigate the impact of an acoustic reminder and support calls on adherence to inhaled therapy in asthma and COPD patients and to determine their effect on exacerbations.MethodsThis single-blinded randomized controlled trial investigated asthma and COPD patients during 6 months in an ambulatory setting. The intervention consisted of daily alarm clock and support phone calls, whenever use of rescue medication doubled or inhaled medication was not taken as prescribed. Primary outcome was time to next exacerbation. Frequency of exacerbations, adherence to inhaled medication and quality of life scores were secondary outcomes. Cox and Poisson regression were used to determine intervention effect on time to exacerbation and frequency of exacerbations, respectively.ResultsSeventy-five participants were assigned to the intervention group and 74 to usual follow-up care. During a median follow-up of 6.2 months, 22 and 28% in the intervention and control groups respectively, experienced at least one exacerbation. Intervention had no effect on time to first exacerbation (HR 0.65, 95% CI 0.21 to 2.07,P = .24), but showed a trend toward a 39% decreased frequency of exacerbations (RR = 0.61, 95% CI 0.35 to 1.03,P = .070) for the adjusted models, respectively. The intervention group had significantly more days with 80–100% taking adherence regarding puff inhalers (82 ± 14% vs. 60 ± 30%,P P = .01). Timing adherence in participants using puff inhalers was higher in the intervention group (69 ± 25% vs. 51 ± 33%,P ConclusionParticipants assigned to the intervention group had significantly better taking and timing adherence of inhaled medication resulting in a trend towards a decreased frequency of exacerbations. However, no effect on time to next exacerbation was observed.Trial registrationClinicalTrials.gov:NCT02386722, Registered 14 February 2014.

Fatal Outcome of Agranulocytosis after Re-Exposure to Metamizole and Cefepime-Induced Encephalopathy Abstract. We present the case of an 83-year-old female patient who died as a result of likely drug-induced complications, namely agranulocytosis caused by metamizole and cefepime-induced encephalopathy. Agranulocytosis precipitated a cascade of events that eventually led to death. As prescription of metamizole has increased over the past decades, it is important to keep in mind its serious adverse drug reactions. Metamizole must be stopped immediately at the onset of symptoms such as fever, mucositis and sore throat, and re-exposure in patients who have previously developed leukopenia under metamizole must be avoided. This can be achieved by meticulous documentation in the medical records and the use of an emergency or allergy alert card which the patient carries at all times. When using cefepime, renal function should be closely monitored, especially in multimorbid geriatric patients, and the dose should be adjusted accordingly.

Background True hypersensitivity reactions to rifampicin are relatively rare, nonetheless severe manifestations mostly involving a single organ have been documented. We report a case of acute multi-organ failure occurring after a medication error with re-exposure to rifampicin. Case presentation A 68-year old patient developed acute hypersensitivity pneumonitis, acute renal failure, acute liver failure and haemolytic anemia within hours after a second re-exposure to Rifampicin for the treatment of a hip prosthesis infection with Staphylococcus epidermidis. A recent rifampicin exposure 1 week earlier had resulted in a massive rise of CRP levels without organ manifestations. Nine years previously, the patient had developed a multi-organ hypersensitivity reaction 8 days after commencing treatment with rifampicin for pulmonary tuberculosis; and 23 years previously he had received rifampicin without problems. The organ-specific hypersensitivity reactions were largely reversible after withdrawal of rifampicin and treatment with steroids. A review of the literature and summary of WHO spontaneous safety reports is also given. Conclusions Re-exposure to rifampicin in sensitised individuals may cause acute severe hypersensitivity reactions. Due to its indications in the management of mycobacterial and implant-associated infections, rifampicin is a drug which might be given decades apart, which poses a risk that information about previous intolerance is lost.

BackgroundThe Coronavirus disease 19 (Covid-19) pandemic has caused more than a million deaths and new treatments are urgently needed. Factors associated with a worse Covid-19 prognosis include old age (> 65 years), ethnicity, male sex, obesity and people with comorbidities such as hypertension, diabetes, cardiovascular disease, and respiratory diseases. Further, vitamin D deficiency has been reported to be a predictor of poor prognosis in patients with acute respiratory failure due to Covid-19. Vitamin D deficiency is a modifiable risk factor, which - according to a recent clinical case series – has the prospect of reducing hospital stay, intensive care and fatal outcomes. Vitamin D has potent immunomodulatory property sand its supplementation might improve important outcomes in critically ill and vitamin D deficient Covid-19 patients. Despite the evidence that supports an association between vitamin D deficiency and Covid-19 severity, there is uncertainty about the direct link. The aim of the trial is therefore to assess if high dose vitamin D supplementation has a therapeutic effect in vitamin D deficient patients with Covid-19.MethodsRandomized, placebo-controlled double blind, multi-centre study trial to compare a high single dose of vitamin D (140’000 IU) followed by treatment as usual (TAU) (VitD + TAU) with treatment as usual only (placebo + TAU) in patients with Covid-19 and vitamin D deficiency.DiscussionVitamin D substitution in patients with Covid-19 and vitamin D deficiency should be investigated for efficacy and safety. The objective of the study is to test the hypothesis that patients with vitamin D deficiency suffering from Covid-19 treated under standardized conditions in hospital will recover faster when additionally treated with high dose vitamin D supplementation. Latest studies suggest, that vitamin D supplementation in patients with Covid-19 is highly recommended to positively influence the course of the disease. With this randomised controlled trial, a contribution to new treatment guidelines shall be made.Trial registration: clinicaltrials.gov: NCT04525820 and SNCTP: 2020 − 01401

In this article we summarize the cardiovascular adverse events that were observed in three patients during their treatment for COVID-19 and discuss their association with lopinavir/ritonavir (LPV/r) and hydroxychloroquine (HCQ). The cases were reported to our regional pharmacovigilance centre in April 2020. All three patients were above 75 years in age, male and multimorbid, and had been hospitalized for treatment of COVID-19. As part of their treatment, all of them received a very strictly monitored off-label therapy with LPV/r and HCQ, for which they had given their prior, written, informed consent. In one patient, erythromycin was also administered. All three patients developed a significant QTc time prolongation during or shortly after therapy with the above drugs. On account of this, the treatment had to be discontinued early in each case and QTc time recovered in all three patients.

We present the case of a 34-year-old woman with recurrent depressive disorder who ingested purple foxglove with suicidal intent. She bought a foxglove plant (Digitalis purpurea) over the internet and used all of its leaves to make a tea that she then drank over a period of a few hours. Seventeen hours later, she developed abdominal pain, emesis and bradycardia and was admitted via the emergency department to the intensive care unit for further treatment and monitoring. The plasma digoxin concentration measured 3.53 nmol/l (therapeutic reference range 0.77-1.50 nmol/l) 21 hours after ingestion of the tea. She remained heamodynamically and neurologically stable, was treated with antiemetics and simple analgesia and did not require digoxin-specific antibodies. Despite normal renal function, her plasma digoxin half-life was prolonged (estimated 76 h), reflecting the long half-life of the parent compound digitoxin which is the main cardiac glycoside in Digitalis purpurea. She was transferred to psychiatric care 48 h after admission. In this report, we compare this case to other similar cases, which to date have only been rarely reported in the literature.

Cough from a pharmacological point of view

Opioids in patients with renal impairment

Background: The spectrum of inflammatory marker response in DRESS (drug reaction with eosinophilia and systemic symptoms) syndrome has not been systematically characterized. Methods: An epidemiological biomarker study of C-reactive protein (CRP) and procalcitonin (PCT) values in patients with DRESS syndrome reported at 2 regional pharmacovigilance centers in Switzerland or published in the medical literature 2008–2016 was performed. Results: Ninety-four DRESS cases were studied. All cases showed a CRP value > 10 mg/L (the upper limit of normal). The mean CRP value was 109.2 ± 79.4 mg/L. CRP values were significantly higher in 22 cases where a cause of inflammation besides DRESS could not be excluded (mean 162.1 vs. 92.9 mg/L; p = 0.003). Receiver operator characteristics curve analysis showed a moderate performance with a CRP cut-off value of 99.4 mg/L (AUC 0.717) to distinguish between patients with and without a possible additional cause of inflammation. The mean and median PCT values were 2.44 ± 5.94 and 0.69 ng/mL, respectively (n = 25 patients). Patients in whom an additional cause of inflammation besides DRESS could not be excluded showed a median PCT of 1.37 ng/mL (n = 9) versus 0.67 ng/mL (n = 16) in patients with DRESS only. PCT values were above the normal cut-off of 0.1 ng/mL, suggestive of bacterial infection in all but 1 case. Furthermore, there was a correlation between PCT values and hepatic enzyme measurements. Conclusions: Evaluating CRP and PCT values might be of use in helping physicians to distinguish between cases of DRESS syndrome with and without concurrent infection or other causes of inflammation. Further prospective investigation is required to define the use of these inflammatory markers in the management of DRESS.

We report the case of a 20-year-old male complaining of sudden-onset, severe headaches, fever, chills, and generalized arthralgia. He had no symptoms of a respiratory tract infection. Blood examination revealed severe leukopenia and mild to moderate thrombocytopenia. Onset of symptoms was rapid, intense, and occurred only a few hours after routine tick-borne encephalitis (TBE) booster vaccine. The question of a relationship between booster vaccine administration and the febrile illness with bicytopenia was raised. A broad range of diagnostics excluded infections and other causes for bicytopenia. Symptoms resolved within a few days, and blood counts normalized within two weeks. Due to the close temporal relationship, a transient benign bicytopenia and febrile illness as a systemic reaction to TBE vaccination was assumed. Review of the literature and adverse event reporting systems suggest that this is a very rare reaction.

Background:; Artemisia annua; is a Chinese medicinal herb. Artemisinin-derivatives are recommended as part of a combination treatment for uncomplicated malaria. Herbal and dietary supplements (HDS) are increasingly used worldwide and HDS-induced liver injury is becoming a growing concern.; Case Report:; We present the first case of severe acute cholestatic hepatitis due to the intake of; Artemisia annua; tea as chemoprophylaxis for malaria in a patient returning from Ethiopia. The patients presented with jaundice, elevated transaminases, and parameters of cholestasis (total bilirubin 186.6 μmol/L, conjugated bilirubin 168.5 μmol/L). A liver biopsy showed a portal hepatitis with lymphocytic infiltration of the bile ducts and diffuse intra-canalicular and intra-cytoplasmic bilirubinostasis. The toxicologic analysis of the Artemisia tea revealed the ingredients arteannuin b, deoxyartemisin, campher, and scopoletin. There were no other identifiable etiologies of liver disease. The Roussel Uclaf Causality Assessment Method (RUCAM) score assessed a "probably" causal relationship. Sequencing of genes encoding for hepatic transporters for bile acid homeostasis (BSEP, MDR3, and FIC1) found no genetic variants typically associated with hereditary cholestasis syndromes. Normalization of bilirubin occurred 3 months after the onset of disease.; Conclusion:; The use of artemisinin-derivatives for malaria prevention is ineffective and potentially harmful and should thus be discouraged. Moreover, the case demonstrates our as yet inadequate understanding of the pathophysiology and susceptibility to HDS induced liver injury.

Aim: To evaluate the feasibility of continuous non-invasive monitoring of ventilation using combined oximetry and transcutaneous carbon dioxide (TcCO2) measurement in the palliative care setting in patients receiving opioids. Methods: 15 patients with advanced cancer and chronic pain at a palliative care hospital were included prospectively. TcCO2 and oxygen saturation (SpO2) were monitored. Results: Mean and median McGill pain scores were 20.5 + 13 and 18 respectively. Mean and median duration of the measurements were 43 + 8.8 hours and 46 hours respectively. Buprenorphine patch was used in 10 patients, oral buprenorphine in 3 patients, morphine in 7 patients, pregabalin in 7 patients, lorazepam in 4 patients and midazolam and a fentanyl patch in 1 patient each. Mean and median baseline SpO2 before administration of the opioids were 94% + 4% and 95% (range 87 – 100%) respectively. SpO2 of less than 88% was recorded in 10 patients after administration of opioids. Mean and median baseline TcCO2 values were 37 + 8 mm Hg and 35 mm Hg (range 28 – 60 mm Hg) respectively. Mean and median highest TcCO2 values were 53 + 12 mm Hg and 47 mm Hg (range 43 – 85 mm Hg) respectively. Mean and median rise in TcCO2 from baseline was 16 + 9 mm Hg and 15 mm Hg (7 – 45 mm Hg) respectively. 5 patients showed significant rise in TcCO2 measurement as per the AASM criteria. Conclusion: It is feasible to continuously monitor ventilation noninvasively using combined SpO2 and TcCO2 to detect hypoventilation in the palliative care setting. Patients with advanced cancer administered opioids in palliative care are at risk of manifesting hypercapnia and hypoxemia.

Background: It was observed that not all patients having idiopathic pulmonary fibrosis (IPF) and were tolerating the full recommended dose of pirfenidone 2400 mg/day. Aims: Examine the best tolerated dose of pirfenidone administered to patients with IPF and the adverse effects leading to a dose reduction. Methods: 87 Patients (M:F, 51:36) were included. Pirfenidone was initiated at 600 mg per day, administered with food and escalated every 1 to 2 weeks with monitoring of liver function test and adverse events to target 2400 mg/day. If the escalated dose was not tolerated then the previous best tolerated dose was continued. Since the availability to Nintedanib, the switch option was given to patients not tolerating recommended dose of Pirfenidone. In our setting treatment cost is borne by patient. Pirfenidone is typically our first choice antifibrotic for IPF as it is generic and cheaper compared to nintedanib. Results: 74/87 (85%) patients had IPF–UIP, 4 CPFE and in 9 patients pirfenidone was administered off label for advanced fibrosing interstitial lung diseases (2 RA – UIP, 4 chronic hypersensitivity pneumonitis, 3 post H1N1 lung fibrosis). Mean duration of follow up was 515 + 588 days. 1 patient tolerated 600 mg/day, 39 (45%) patients 1200 mg/day, 29 (33%) patients 1800 mg/ day and 18 (21%) 2400 mg/day. Major adverse events limiting the dose of pirfenidone were gastoinstestinal side effects(33), deranged liver enzymes(7), weight loss(19), itching(7), dizziness(3). 6 patients switched to nintedanib. Conclusion: Most patients with IPF do not tolerate the full recommended dose of pirfenidone at 2400mg/day. Gastrointestinal side effects and weight loss are the most common cause of dose limitation.

Background: Poor medication-adherence is common in chronic lung patients, resulting in reduced health-outcomes and increased healthcare-costs. Objective: To investigate the impact of an acoustic reminder and support calls on adherence to inhaled therapy in asthma and COPD patients and to determine their effect on exacerbations. Methods: This single-blinded randomized trial investigated patients during 6 months. Exacerbations were recorded and adherence to inhaled medication was monitored using electronic data capture devices. Cox and Poisson regression were used to determine intervention effect on time to exacerbation and frequency of exacerbations, respectively. Results: Of 149 eligible patients, 75 participants were assigned to the intervention group and 74 to usual follow-up care. During follow-up, 22% and 28% in the intervention and control groups respectively, experienced at least one exacerbation. Intervention had no effect on time to first exacerbation (HR 0.62, 95% CI 0.20 to 1.91, p=.20), but showed a trend toward a 39% decreased frequency of exacerbations (RR=0.61, 95% CI 0.35 to 1.03, p=.070). The intervention group had significantly more days with 80-100% taking adherence regarding puff inhalers (82±14% vs. 60±30%, p Conclusion: Patients in the intervention group had significantly better taking and timing adherence of inhaled medication resulting in a trend towards a decreased frequency of exacerbations. However, no effect on time to next exacerbation was observed.

Drug-drug interaction (DDI) screening programmes aim to increase the safety of medication by issuing alerts based on the severity of DDIs, since an increased risk of adverse drug events has been reported for some DDIs (clinically relevant alerts). However, not all DDI alerts may be clinically relevant, depending on the clinical decision support system (CDSS) interaction tool used and the target population. There are few data about the frequency and relevance of DDIs in the paediatric population. The objective of this study was to evaluate the prevalence and appropriateness of high-risk DDI alerts (drug combinations that are rated asldquo;contraindicatedrdquo; orldquo;contraindicated by precautionrdquo; according to the Swiss CDSS interaction tool Pharmavistareg; (HCI Solutions AG, Bern, Switzerland)) in paediatric inpatients.We carried out a retrospective, single-centre study examining a cohort of paediatric cases hospitalised between January and May 2017 on the surgery/orthopaedic and oncology wards at the University of Basel Childrenrsquo;s Hospital (UKBB), Switzerland. Drugs administered to the patients concomitantly were obtained from the medical records. DDI screening was performed using Pharmavistareg;. All DDIs detected were documented with their severity grading for each hospital day per case. The clinical relevance of DDI alerts for drug combinations rated as contraindicated or contraindicated by precaution was critically evaluated by a literature review.A total of 300 patient cases were assessed forldquo;contraindicatedrdquo; orldquo;contraindicated by precautionrdquo; DDI alerts. Of these, none hadldquo;contraindicatedrdquo; and five had DDI alerts rated asldquo;contraindicated by precautionrdquo; (1.7%, 95% CI 0.6ndash;4.1%). The corresponding drug combinations were tramadol/fentanyl/morphine-nalbuphine (n = 3), droperidol-ondansetron (n = 1) and methotrexate-metamizole (n = 1), given for a duration of 1ndash;2 days. Adverse drug events (ADEs) due to these three combinations (QT prolongation with the combination droperidol-ondansetron, reduced effect of opioid agonists with nalbuphine and increased haematotoxicity with methotrexate-metamizole) were not documented in the patientsrsquo; medical records.The low prevalence of contraindicated DDIs suggests that Pharmavistareg; has a low risk of over-alerting when used in a Swiss paediatric hospital. However, the current literature suggests that the severity rating of established contraindicated DDIs could be partially downgraded, and that patient/population-specific evaluations of DDI alerts are needed.

Fatal Outcome of Agranulocytosis after Re-Exposure to Metamizole and Cefepime-Induced Encephalopathy

We will present a 42-year-old woman with acute myeloid leukemia and pulmonary aspergillosis. She was treated with several antifungal agents, including three triazoles. Voriconazole, posaconazole, and isavuconazole all led to hepatocellular liver injury. Voriconazole administration led to a peak alanine aminotransferase (ALT) value of 1,793 U/L (normal range, 9–59 U/L). After posaconazole and isavuconazole treatment, ALT rose over 500 U/L. The typical course of events, exclusion of differential diagnoses, and normalization of the liver function tests (LFTs) after stopping the triazoles were highly suspicious for a drug-induced liver injury (DILI). Interestingly, our patient carries a rare HLA B allele (HLA B*35:02), which occurs in less than 1% of the population and is known to be associated with minocycline-induced liver injury. Over the course of 4 months, the patient received two induction chemotherapies and afterward underwent a successful allogenic hematopoietic stem cell transplantation. Her liver function recovered rapidly and favorable clinical findings concerning the aspergillosis led to a de-escalation of the antifungal treatment to prophylactic dose fluconazole. Delayed hepatotoxicity suggested a dose dependency and a cumulative effect. The question of a common pathophysiology and a cross-toxicity was raised. At the present time, only a few case reports describe cross-toxicity or its absence after rechallenge with different azoles. The pathophysiology is not well understood. Ketoconazole was found to impair rat mitochondrial function in vitro. Further investigations showed cell membrane toxicity and ATP depletion in isolated human liver cancer cells. Our case report suggests a cross-toxicity, dose-dependency, and a possible genetic predisposition of triazole-induced liver injury.

Background The pharmacokinetics of oxycodone in patients with end-stage renal disease (ESRD) requiring haemodialysis are largely unknown. Therefore, we investigated the pharmacokinetics of oxycodone/naloxone prolonged release and their metabolites in patients with ESRD during and between haemodialysis sessions. Methods Single doses of oxycodone/naloxone (5/2.5 or 10/5 mg) were administered in nine patients with ESRD using a cross-over design on the day of dialysis and on a day between dialysis sessions. Plasma, dialysate and urine concentrations of oxycodone, naloxone and their metabolites were determined up to 48 h post-dosing using a liquid chromatography-tandem mass spectrometry system. Results Haemodialysis performed 6-10 h after dosing removed ∼10% of the administered dose of oxycodone predominantly as unconjugated oxycodone and noroxycodone or conjugated oxymorphone and noroxymorphone. The haemodialysis clearance of oxycodone based on its recovery in dialysate was (mean ± SD) 8.4 ± 2.1 L/h. The geometric mean (coefficient of variation) plasma elimination half-life of oxycodone during the 4-h haemodialysis period was 3.9 h (39%) which was significantly shorter than the 5.7 h (22%) without haemodialysis. Plasma levels of the active metabolite oxymorphone in its unconjugated form were very low. Conclusions Oxycodone is removed during haemodialysis. The pharmacokinetics including the relatively short half-life of oxycodone in patients with ESRD with or without haemodialysis and the absence of unconjugated active metabolites indicate that oxycodone can be used at usual doses in patients requiring dialysis.

Intravenous colistimethate sodium (CMS) is used to treat infections with multiresistant Gram-negative bacteria. Optimal dosing in patients undergoing continuous renal replacement therapy (CRRT) is unclear. In a prospective study, we determined CMS and colistin pharmacokinetics in 10 critically ill patients requiring CRRT (8 underwent continuous venovenous hemodialysis [CVVHD]; median blood flow, 100 ml/min). Intensive sampling was performed on treatment days 1, 3, and 5 after an intravenous CMS loading dose of 9 million international units (MU) (6 MU if body weight was

Background: Literature about torsade de pointes induced by azole antifungal agents is scarce, despite the well-known association. Furthermore, little is known about the latency time between commencing an azole antifungal agent and developing torsade de pointes. The objectives of the present study were therefore to identify all cases of torsade de pointes associated with systemic azole antifungal use reported to the WHO monitoring centre (Uppsala, Sweden) and to determine the latency times between commencing the azole and developing torsade de pointes. Methods: Investigator-driven, retrospective, descriptive analysis of post-marketing pharmacovigilance data regarding systemic azole antifungal agents and the development of torsade de pointes reported to the WHO monitoring centre 1995–2015. Results: 191 cases were reported as follows: fluconazole 130, itraconazole 22, ketoconazole 5, posaconazole 1, voriconazole 33. More than half of all cases involved concomitant suspected or interacting drugs. The median latency times between starting the azole and developing torsade de pointes ranged from 1 (posaconazole) – 9.5 days (itraconazole), range

Dyslipidemia is common after hematopoietic stem cell transplantation (HSCT). Few data regarding the time course of lipid profiles after HSCT, the effect of multiple transplantations, and efficacy and safety of lipid-lowering treatments are available.The objective of the study was to determine the prevalence and treatment of dyslipidemia over a 25-year period in a large, single-center cohort.One thousand one hundred ninety-six adult patients (≥16 years) who underwent HSCT during 1973 to 2013 and who survived ≥100 days were studied retrospectively.The prevalence of dyslipidemia before transplantation was 36% and 28% in the autologous and allogeneic groups, respectively (P .001). Three months after HSCT, the prevalence rose to 62% and 74% (P .001), and at 25 years, it was 67% and 89%. Lipid profiles were similar after first and subsequent transplants. Baseline dyslipidemia (odds ratio [OR] = 2.72), allogeneic transplant (OR = 2.44), and age ≥ 35 years (OR = 2.33) were independent risk factors for dyslipidemia at 1 year. Lipid-lowering treatment was given to 223 (19%) patients, primarily in the form of statins (86%) and was associated with a decrease in total cholesterol from 246 to 192 mg/dL (P .01) and from 244 to 195 mg/dL (P .001) in the autologous and allogeneic groups, respectively. There were 10 cases (4%) of muscle symptoms prompting cessation of lipid-lowering therapy, including 1 case of rhabdomyolysis. The OR for dyslipidemia among patients who suffered a cardiovascular event (conditional logistic regression) was 3.5 (95% confidence interval = 1.6-7.7, P = .002).This study confirms that dyslipidemia is a common and long-lasting phenomenon among both allogeneic and autologous HSCT patients. Statins are effective, generally well-tolerated and should be highly recommended for the management of post-HSCT dyslipidemia.