Antonios Douros

Drug-induced liver injury: results from the hospital-based Berlin Case–Control Surveillance Study

AIM Drug-induced liver injury (DILI) is often responsible for acute liver failure, drug withdrawal, boxed warnings or drug non-approval. Therefore, we conducted a case-control study to determine the hepatotoxic risk of a wide range of drugs. METHODS The Berlin Case-Control Surveillance Study FAKOS included all 51 Berlin hospitals in a hospital network. Between 2002 and 2011, 198 patients with acute idiopathic hepatitis, 377 inpatient controls and 708 outpatient controls were ascertained. Case patients were thoroughly validated using anamnestic, clinical, laboratory and histological data. Drug exposure was obtained in a face-to-face interview. A possible drug aetiology was assessed in individual patients by applying the updated Council for International Organizations of Medical Sciences (CIOMS) scale. Drug risks were further quantified [odds ratios (OR) with 95% confidence intervals (CI)] in a case-control design with unconditional logistic regression analysis. Drug intake in the last 28 days before index date was considered for the analysis. RESULTS The study corroborated hepatotoxic risks for a number of drugs, including phenprocoumon (OR 3.3, 95% CI 1.5, 6.7), amiodarone (OR 5.5, 95% CI 1.3, 21.2), clozapine (OR 34.6, 95% CI 2.8, 824.9) and flupirtine (OR 40.2, 95% CI 5.5, 856.9). Increased risks were also suggested for less commonly reported substances such as angiotensin II receptor blockers, atypical antipsychotics and for biperiden, a drug never before reported to be hepatotoxic. CONCLUSIONS Our study identified a large number of drugs as possible causes of hepatotoxicity. The observed risk for seldom reported substances highlights the need for further post-authorization safety studies not exclusively focusing on drugs already labelled as potentially hepatotoxic.

Drug–drug interactions and safety of linezolid, tedizolid, and other oxazolidinones

Introduction: Oxazolidinones are synthetic antimicrobials with strong bacteriostatic activity against Gram-positive organisms. Recently, tedizolid phosphate was approved for clinical use becoming the second agent of this class after linezolid available in clinical practice. Areas covered: Oxazolidinone pharmacology including structure-activity relationships, mode of action, pharmacokinetics, drug–drug interactions, and adverse drug reactions is reviewed. Furthermore, bacterial resistance, approved indications, use in paediatric populations, and tuberculosis treatment with oxazolidinones are discussed, and differences in indications and pharmacotoxicological properties between the two approved agents are elucidated. A MEDLINE PubMed search for articles published in English from January 1960 to June 2015 was completed using the terms: oxazolidinone, oxazolidinone-induced toxicity, oxazolidinone pharmacokinetics, serotonin syndrome, oxazolidinone drug–drug interactions, antituberculotic treatment. Expert opinion: Linezolid illustrates an important antimicrobial in several Gram-positive infections especially when methicillin-resistant Staphylococcus aureus strains are involved. Myelosuppression and neuropathy are toxicities of high relevance particularly in case of prolonged treatment periods. The significance of linezolid in the treatment of extensively drug-resistant tuberculosis has to be further investigated. Tedizolid phosphate represents a welcome addition in our anti-infective arsenal, and future research will clarify its role in indications other than the already approved acute bacterial skin infections.

Drug-induced acute pancreatitis: results from the hospital-based Berlin case–control surveillance study of 102 cases

Drug toxicity is a well‐known cause of acute pancreatitis (AP). Although many drugs have been associated with AP, the magnitude of the risk of most of them remains largely unknown.

Herb-Induced Liver Injury in the Berlin Case-Control Surveillance Study

Herb-induced liver injury (HILI) has recently attracted attention due to increasing reports of hepatotoxicity associated with use of phytotherapeutics. Here, we present data on HILI from the Berlin Case-Control Surveillance Study. The study was initiated in 2000 to investigate the serious toxicity of drugs including herbal medicines. Potential cases of liver injury were ascertained in more than 180 Departments of all 51 Berlin hospitals from October 2002 to December 2011. Drug or herb intake was assessed through a standardized face-to-face interview. Drug or herbal aetiology was assessed based on the updated Council for International Organizations of Medical Sciences scale. In ten of all 198 cases of hepatotoxicity included in the study, herbal aetiology was assessed as probable (once ayurvedic herb) or possible (Valeriana five times, Mentha piperita once, Pelargonium sidoides once, Hypericum perforatum once, Eucalyptus globulus once). Mean age was 56.4 ± 9.7 years, and the predominant pattern of liver injury was hepatocellular. No cases of acute liver failure or death were observed. This case series corroborates known risks for ayurvedic herbs, supports the suspected association between Valeriana use and liver injury, and indicates a hepatotoxic potential for herbs such as Pelargonium sidoides, Hypericum perforatum or Mentha piperita that were rarely associated with liver injury before. However, given that possible causality does not prove clinical significance, further studies in this field are needed.

Safety issues and drug–drug interactions with commonly used quinolones

Introduction: Quinolones are widely used antimicrobials with good efficacy and favourable safety. Recently, forms of quinolone toxicity such as peripheral neuropathy, retinal detachment or QTc-prolongation have attracted attention. Areas covered: Data on different aspects of direct quinolone toxicity are reviewed and consider risk factors and predisposing structural properties. Indirect forms of quinolone toxicity such as Clostridium difficile infections or adverse reactions associated with drug–drug interactions are also discussed. Finally, the role of transporters in the pharmacokinetics of these antimicrobials and their utilisation in critically ill patients are illustrated. A MEDLINE PubMed search for articles published in English from January 1960 to June 2014 was completed using the terms: quinolone, quinolone-induced toxicity, quinolone pharmacokinetics, quinolone and critically ill, drug–drug interactions. Expert opinion: Quinolones exhibit an important component of the antibiotic arsenal. Although several adverse events have been associated with their use, taking into consideration risk factors, contraindications and potential drug–drug interactions can drastically reduce the respective risks.

Estimating kidney function and use of oral antidiabetic drugs in elderly

The prevalence of diabetes mellitus (DM) and renal impairment rises with age making regular estimation of glomerular filtration rate (eGFR) in older diabetics necessary. This study investigated the differences among available estimating equations in assessing eGFR in older diabetics and examined the use of oral antidiabetic drugs (OADs) in relation to renal function. Patients with DM were participants of the Berlin Initiative Study (BIS), a population‐based cohort study initiated in 2009 in Berlin, Germany, to evaluate kidney function in people ≥70 years. GFR was estimated with the creatinine‐based CKD‐EPICREA (Chronic Kidney Disease Epidemiology Collaboration), the MDRD (Modification of Diet in Renal Diseases) and the BIS1 equation and was directly measured (mGFR) with iohexol clearance as a gold standard in a subgroup (n = 137). Creatinine clearance was estimated with the Cockcroft–Gault equation (CrCl). DM prevalence was 26% (539 of 2070 overall participants). The antidiabetic drugs most commonly used among OAD patients were metformin (67%), glimepiride (27%) and glibenclamide (14%). Three of ten metformin patients had a CrCl <60 mL/min. Compared to mGFR, the mean differences of filtration rates calculated by MDRD, CKD‐EPICREA and BIS1 were +8.9, +6.7 and −1.8 mL/min/1.73 m2, respectively. Summing up, many patients with a CrCl <60 mL/min received metformin, although this represents a contraindication in Germany. Glibenclamide was commonly used despite its classification as potentially inappropriate medication in older adults. Finally, BIS1 performed better in estimating GFR in older diabetics than MDRD or CKD‐EPICREA.

Ramipril-induced liver injury: case report and review of the literature.

BACKGROUND Ramipril, an inhibitor of the angiotensin-converting enzyme (ACEI), is a drug commonly used in the therapy of hypertension. ACEI-induced hepatotoxicity is rare, and most of the reported cases are associated with captopril. Here, we present the first case of ramipril-induced liver injury proven by positive rechallenge and a review of the literature including the data from the US Food and Drug Administration adverse event reporting system (FAERS). METHODS Patient data were collected in the Berlin Case-Control Surveillance Study for adverse drug reactions. PubMed research on ACEI-induced hepatotoxicity included all ACEIs except captopril; analysis of the FAERS database focused on ramipril-induced hepatotoxicity in the period 2009-2011. RESULTS A 40-year-old male patient presented with acute onset jaundice and highly (>20-fold increase of alanine aminotranferase (ALT)) elevated liver enzymes (LEs). Viral or autoimmune hepatitis and biliary etiology were ruled out. Withdrawal of several medications including ramipril resulted in an immediate decrease in LEs, whereas a subsequent re-exposure with ramipril resulted in a striking increase in LEs (>35-fold increase of ALT). After definitely discontinuing ramipril, a rapid decline in LEs was observed, suggesting a certain causal relationship between drug intake and hepatic damage. Analysis of the FAERS database retrieved 65 cases of ramipril-associated hepatotoxicity, with jaundice being the most frequent hepatic adverse event. PubMed research detected 23 relevant publications, with enalapril being the ACEI most commonly reported as being associated with liver injury. CONCLUSIONS ACEI-induced hepatotoxicity is rare. Our case confirms a hepatotoxic potential of ramipril, highlighting the need for alertness among physicians regarding this matter.

Tocilizumab-induced pancreatitis: case report and review of data from the FDA Adverse Event Reporting System

Tocilizumab (TCZ) is a humanized monoclonal antibody acting against the IL‐6 receptor. It is a drug used in the treatment of rheumatoid arthritis and can be either given intravenously every 4 weeks or subcutaneously once a week. Known adverse events (AE) associated with TCZ include: infections of the upper respiratory tract, arterial hypertension, hypercholesterolaemia and hypertriglyceridaemia. Here, we present the first well‐documented case of TCZ‐induced acute pancreatitis (AP) and a systematic review of the literature including data from the Food and Drug Administration Adverse Event Reporting System (FAERS) database.

Immobilization and high platelet count are associated with thromboembolic complications in heparin‐induced thrombocytopenia

Immune‐mediated heparin‐induced thrombocytopenia (HIT type II, HIT) is a potentially serious adverse drug reaction characterized by an increased risk of venous and arterial thrombosis. This study aimed to identify risk factors associated with the development of these complications.

Single-Pill Triple Fixed Dose Combination Therapy with Single Component Drug Monitoring in Treatment-Resistant Hypertension: A Pilot Study.

BACKGROUND Single-pill fixed dose combination (FDC) therapies are widely used in the treatment of arterial hypertension. OBJECTIVE This pilot study aimed to evaluate the effects of a FDC therapy combined with therapeutic drug monitoring (TDM) on blood pressure (BP) in patients with treatment resistant hypertension. METHOD The study population included patients with suspected treatment-resistant hypertension during treatment with at least 3 antihypertensive drugs. We evaluated the effect of switching all patients to a regime including a single-pill triple FDC containing olmesartan, amlodipine and hydrochlorothiazide. Adherence was evaluated by measuring serum concentrations of amlodipine in a single-blinded fashion. RESULTS We enrolled 13 patients (mean age 57.2±9.1 years, 8 males) with resistant hypertension (office systolic and diastolic BP 158.3±17.3 and 94.8±11.1 mmHg); mean use of antihypertensive drugs was 3.8±1.1. Medication intake of FDC was confirmed in all patients at 18 weeks. Systolic and diastolic office BP were significantly lower (-22.8 and -13.6 mmHg) after 18 weeks of treatment with triple FDC (135.5±20.1 and 81.2±6.3 mmHg, p<0.01, respectively); mean use of antihypertensive drugs was 3.8±0.9. In 9 patients with 24-h ambulatory BP monitoring (ABPM) both at baseline and after 18 weeks, 24-h mean arterial pressure decreased (-9.3 mmHg, p=0.055). Overall, 9 (69%) patients achieved BP control in office BP and 4 (31%) in 24-h ABPM. CONCLUSION Our results support the use of single-pill triple FDC therapy in combination with TDM for the management of patients with suspected treatment-resistant hypertension and further testing in clinical studies.