Stefan Russmann

Current concepts of mechanisms in drug-induced hepatotoxicity.

Drug-induced liver injury (DILI) has become a leading cause of severe liver disease in Western countries and therefore poses a major clinical and regulatory challenge. Whereas previously drug-specific pathways leading to initial injury of liver cells were the main focus of mechanistic research and classifications, current concepts see these as initial upstream events and appreciate that subsequent common downstream pathways and their attenuation by drugs and other environmental and genetic factors also have a profound impact on the risk of an individual patient to develop overt liver disease. This review summarizes current mechanistic concepts of DILI in a 3-step model that limits its principle mechanisms to three main ways of initial injury, i.e. direct cell stress, direct mitochondrial impairment, and specific immune reactions. Subsequently, initial injury initiates further downstream events, i.e. direct and death receptor-mediated pathways leading to mitochondrial permeability transition, which then results in apoptotic or necrotic cell death. For all mechanisms, mitochondria play a central role in events leading to apoptotic vs. necrotic cell death. New treatment targets consequently focus on interference with downstream pathways that mediate injury and therefore determine the ultimate outcome of DILI. Genome wide and targeted pharmacogenetic as well as metabonomic approaches are now used in order to reach the key goals of a better understanding of mechanisms in hepatotoxicity, and to develop new strategies for its prediction and treatment. However, the complexity of interactions between genetic and environmental risk factors is considerable, and DILI therefore currently remains unpredictable for most hepatotoxins.

Secreted Klotho and FGF23 in chronic kidney disease Stage 1 to 5: a sequence suggested from a cross-sectional study

BACKGROUND Klotho and fibroblast growth factor 23 (FGF23) are key regulators of mineral metabolism in renal insufficiency. FGF23 levels have been shown to increase early in chronic kidney disease (CKD); however, the corresponding soluble Klotho levels at the different CKD stages are not known. METHODS Soluble Klotho, FGF23, parathyroid hormone (PTH), 1,25-dihydroxy vitamin D(3) (1,25D) and other parameters of mineral metabolism were measured in an observational cross-sectional study in 87 patients. Locally weighted scatter plot smoothing function of these parameters were plotted versus estimated glomerular filtration rate (eGFR) to illustrate the pattern of the relationship. Linear and non-linear regression analyses were performed to estimate changes in mineral metabolism parameters per 1mL/min/1.73 m(2) decline. RESULTS In CKD 1-5, Klotho and 1,25D linearly decreased, whereas both FGF23 and PTH showed a baseline at early CKD stages and then a curvilinear increase. Crude mean Klotho level declined by 4.8 pg/mL (95% CI 3.5-6.2 pg/mL, P < 0.0001) and 1,25D levels by 0.30 ng/L (95% CI 0.18-0.41 ng/L, P < 0.0001) as GFR declined by 1 mL/min/1.73 m(2). After adjustment for age, gender, serum 25-hydroxyvitamin D levels and concomitant medications (calcium, supplemental vitamin D and calcitriol), we estimated that the mean Klotho change was 3.2 pg/mL (95% CI 1.2-5.2 pg/mL, P = 0.0019) for each 1 mL/min/1.73 m(2) GFR change. FGF23 departed from the baseline at an eGFR of 47 mL/min/1.73 m(2) (95% CI 39-56 mL/min/1.73 m(2)), whereas PTH departed at an eGFR of 34 mL/min/1.73 m(2) (95% CI 19-50 mL/min/1.73 m(2)). CONCLUSIONS Soluble Klotho and 1,25D levels decrease and FGF23 levels increase at early CKD stages, whereas PTH levels increase at more advanced CKD stages.

Mitochondria in chronic liver disease.

Mitochondria are the main energy source in hepatocytes and play a major role in extensive oxidative metabolism and normal function of the liver. This key role also assigns mitochondria a gateway function in the center of signaling pathways that mediate hepatocyte injury, because impaired mitochondrial functions affect cell survival and contribute to the onset and perpetuation of liver diseases. Altered mitochondrial functions have indeed been documented in a variety of chronic liver diseases including alcohol-induced liver disease, nonalcoholic fatty liver disease, viral hepatitis, primary and secondary cholestasis, hemochromatosis, and Wilsons disease. Major changes include impairment of the electron transport chain and/or oxidative phosphorylation leading to decreased oxidative metabolism of various substrates, decreased ATP synthesis, and reduced hepatocyte tolerance towards stressing insults. Functional impairment of mitochondria is often accompanied by structural changes, resulting in organelle swelling and formation of inclusion in the mitochondrial matrix. Adequate mitochondrial functions in hepatocytes are maintained by mitochondrial proliferation and/or increased activity of critical enzymes. The assessment of mitochondrial functions in vivo can be a useful tool in liver diseases for diagnostic and prognostic purposes, and also for the evaluation of (novel) therapeutic interventions.

Pharmacotherapeutic trends in 2231 psychiatric inpatients with bipolar depression from the International AMSP Project between 1994 and 2009.

BACKGROUND Pharmacological treatment of bipolar depression is a complex and controversial issue, and its real-world practice remains largely unknown. METHOD Observational analysis of the pharmacotherapy of 2231 psychiatric inpatients with a current episode of bipolar depression. The study was based on cross-sectional prescription data from European psychiatric hospitals that had been repeatedly collected between 1994 and 2009 through the collaborative Drug Safety in Psychiatry (AMSP) program. RESULTS Overall 81.3% of patients received antidepressants (AD) (7.8% monotherapy), 57.9% antipsychotics (AP), 50.1% anticonvulsants (AC), 47.5% tranquilizers, and 34.6% lithium (Li). Use over time was stable for AD, decreased for Li, and increased for AC, AP and tranquilizers. Pronounced increases were specifically observed for quetiapine, lamotrigine and valproate. Use of tricyclic AD decreased but its prevalence was still 11.8% in 2009. Venlafaxine was used by 19.5% in 2009. We also observed an increase of polypharmacy combining AD, AP, AC and Li. From 2006 to 2009 37.0% received concomitant treatment with three, and 6.4% even with all four of those drug classes. LIMITATIONS Observational cross-sectional study without follow-up or additional clinical information. CONCLUSIONS Monotherapy with antidepressants and any use of tricyclic AD and venlafaxine still has a considerable prevalence in bipolar depression, but this is controversial due to the reported risk of treatment emergent affective switches. Triple and quadruple therapy is not evidence-based but increasingly used in clinical practice. This may reflect an attempt to overcome treatment failure, and further studies should evaluate efficacy and safety of this common practice.

Impact of genetic SLC28 transporter and ITPA variants on ribavirin serum level, hemoglobin drop and therapeutic response in patients with HCV infection

BACKGROUND & AIMS In the last decade, pegylated interferon-α (PegIFN-α) plus ribavirin (RBV) was the standard treatment of chronic hepatitis C for genotype 1, and it remains the standard for genotypes 2 and 3. Recent studies reported associations between RBV-induced anemia and genetic polymorphisms of concentrative nucleoside transporters such as CNT3 (encoded by SLC28A3) and inosine triphosphatase (encoded by ITPA). We aimed at studying genetic determinants of RBV kinetics, efficacy and treatment-associated anemia. METHODS We included 216 patients from two Swiss study cohorts (61% HCV genotype 1, 39% genotypes 2 or 3). Patients were analyzed for SLC28A2 single nucleotide polymorphism (SNP) rs11854484, SLC28A3 rs56350726, and SLC28A3 rs10868138 as well as ITPA SNPs rs1127354 and rs7270101, and followed for treatment-associated hemoglobin changes and sustained virological response (SVR). In 67 patients, RBV serum levels were additionally measured during treatment. RESULTS Patients with SLC28A2 rs11854484 genotype TT had higher dosage- and body weight-adjusted RBV levels than those with genotypes TC or CC (p=0.02 and p=0.06 at weeks 4 and 8, respectively). ITPA SNP rs1127354 was associated with hemoglobin drop ≥3 g/dl during treatment, in genotype (relative risk (RR)=2.1, 95% CI 1.3-3.5) as well as allelic analyses (RR=2.0, 95%CI 1.2-3.4). SLC28A3 rs56350726 was associated with SVR in genotype (RR=2.2; 95% CI 1.1-4.3) as well as allelic analyses (RR=2.0, 95% CI 1.1-3.4). CONCLUSIONS The newly identified association between RBV serum levels and SLC28A2 rs11854484 genotype, as well as the replicated association of ITPA and SLC28A3 genetic polymorphisms with RBV-induced anemia and treatment response, may support individualized treatment of chronic hepatitis C and warrant further investigation in larger studies.

Mono- and combination drug therapies in hospitalized patients with bipolar depression. Data from the European drug surveillance program AMSP

BackgroundFor the pharmacological treatment of bipolar depression several guidelines exist. It is largely unknown, to what extent the prescriptions in daily clinical routine correspond to these evidence based recommendations and which combinations of psychotropic drugs are frequently used.MethodsThe prescriptions of psychotropic drugs were investigated of all in-patients with bipolar depression (n = 2246; time period 1994–2009) from hospitals participating in the drug surveillance program AMSP. For the drug use in 2010, 221 cases were analysed additionally.ResultsFrom 1994 to 2009, 85% of all patients received more than one class of psychotropic substances: 74% received antidepressants in combination therapy, 55% antipsychotics, 48% anticonvulsants and 33% lithium. When given in combination, lithium is the most often prescribed substance for bipolar depression (33%), followed by valproic acid (23%), mirtazapine and venlafaxine (16% each), quetiapine (15%), lamotrigine (14%) and olanzapine (13%). Both, lithium and valproic acid are often combined with selective serotonin reuptake inhibitors (SSRI), but also with mirtazapine und venlafaxine. Combinations of more than one antidepressant occur quite often, whereby combinations with bupropion, paroxetine, fluoxetine or fluvoxamine are very rare. In 2010, quetiapine (alone and combined) was the most frequently prescribed drug (39%); aripiprazole was administered in 10%.ConclusionCombinations of antidepressants (SSRI, mirtazapine, venlafaxine) with mood stabilizers (lithium, valproic acid, lamotrigine) and / or atypical antipsychotics (quetiapine, olanzapine) are common. Of most of those combinations the efficacy has not been studied. The use of aripiprazole and the concomitant use of two or three antidepressants contrast the guidelines.

Evaluation of Drug Interactions in a Large Sample of Psychiatric Inpatients: A Data Interface for Mass Analysis With Clinical Decision Support Software

In order to improve medication safety, more epidemiological data on the prevalence and clinical relevance of drug interactions are required. We developed an interface for mass analysis using the Clinical Decision Support Software (CDSS) MediQ and a multidimensional classification (Zurich Interaction System (ZHIAS)) incorporating the Operational Classification of Drug Interactions (ORCA). These were applied to 359,207 cross‐sectional prescriptions from 84,607 psychiatric inpatients collected through the international AMSP program. MediQ issued 2,308 “high” and 71,112 “average” danger interaction alerts. Among these, after ORCA reclassification, there were 151 contraindicated and 4,099 provisionally contraindicated prescriptions. The ZHIAS provided further detailed categorical information on recommended management and specific increased risks (QTc prolongation being the most frequent one) associated with interactions. We developed a highly efficient solution for the identification and classification of drug interactions in large prescription data sets; this solution may help to reduce the frequency of overalerting and improve acceptance of the efficacy of CDSS in reducing the occurrence of potentially harmful drug interactions.

Risk of Further Decline in Renal Function After the Use of Oral Sodium Phosphate or Polyethylene Glycol in Patients With a Preexisting Glomerular Filtration Rate Below 60 ml/min

OBJECTIVES: The aim of this study was to estimate the risk of further creatinine increase in patients with preexisting renal disease after the use of oral sodium phosphate (OSP) versus polyethylene glycol (PEG), and to study usage patterns of OSP in relation to renal function.METHODS: A cohort study was done using clinical records and electronic patient information from the Henry Ford Health System (HFHS) in patients who had used either OSP or PEG for colonoscopy between February 1999 and April 2006. Among patients with an estimated GFR <60 ml/min before colonoscopy, we identified cases with an unexplained creatinine increase of ≥0.5 mg/dl within 14 days after colonoscopy.RESULTS: We identified 7,971 OSP and 1,511 PEG users. Relative use of OSP versus PEG decreased from 88.0% before 2004 to 48.4% in 2006. 70.2% of OSP users had no recorded creatinine determination within 60 days before colonoscopy, and this proportion did not decrease over time. The study population included 317 patients with a baseline GFR <60 ml/min, and we identified one case with an unexplained creatinine increase ≥0.5 mg/dl among 191 PEG users (0.5%) versus eight cases among 126 OSP users (6.3%). Unadjusted and adjusted relative risk estimates on comparing OSP with PEG were 12.1 (95% CI, 1.5–95.8) and 12.6 (95% CI, 1.5–106.5), respectively.CONCLUSIONS: In patients with preexisting renal disease, OSP use was associated with an increased risk of aggravated renal dysfunction versus PEG. Creatinine measurement with GFR estimation should be done before OSP administration in order to avoid its use in patients with renal disease.

Comparative evaluation of three clinical decision support systems: prospective screening for medication errors in 100 medical inpatients

PurposeClinical decision support systems (CDSS) are promoted as powerful screening tools to improve pharmacotherapy. The aim of our study was to evaluate the potential contribution of CDSS to patient management in clinical practice.MethodsWe prospectively analyzed the pharmacotherapy of 100 medical inpatients through the parallel use of three CDSS, namely, Pharmavista, DrugReax, and TheraOpt. After expert discussion that also considered all patient-specific clinical information, we selected apparently relevant alerts, issued suitable recommendations to physicians, and recorded subsequent prescription changes.ResultsFor 100 patients with a median of eight concomitant drugs, Pharmavista, DrugReax, and TheraOpt generated a total of 53, 362, and 328 interaction alerts, respectively. Among those we identified and forwarded 33 clinically relevant alerts to the attending physician, resulting in 19 prescription changes. Four adverse drug events were associated with interactions. The proportion of clinically relevant alerts among all alerts (positive predictive value) was 5.7, 8.0, and 7.6%, and the sensitivity to detect all 33 relevant alerts was 9.1, 87.9, and 75.8% for Pharmavista, DrugReax and TheraOpt, respectively. TheraOpt recommended 31 dose adjustments, of which we considered 11 to be relevant; three of these were followed by dose reductions.ConclusionsCDSS are valuable screening tools for medication errors, but only a small fraction of their alerts appear relevant in individual patients. In order to avoid overalerting CDSS should use patient-specific information and management-oriented classifications. Comprehensive information should be displayed on-demand, whereas a limited number of computer-triggered alerts that have management implications in the majority of affected patients should be based on locally customized and supported algorithms.

Diagnosis of melanoma under concomitant natalizumab therapy.

Sir We have read with great interest the short report on natalizumab and melanoma from Bergamaschi and Montomoli published recently in this journal. Natalizumab (Tysabri, Biogen Idec and Elan Pharmaceuticals) is a humanized monoclonal antibody against a4 integrins used in the treatment of multiple sclerosis and Crohn’s disease. Mullen et al. reported on two cases of melanoma in patients with multiple sclerosis receiving natalizumab. Their letter was criticized since case reports in general show limited interpretability in establishing cause-and-effect relationships and since controlled clinical trials and postmarketing surveillance studies did not indicate an increased risk of melanoma in patients receiving natalizumab. However, melanoma is underreported to cancer registries as compared with other cancers due to its occurrence in the outpatient setting and, therefore, postmarketing surveillance studies might also underestimate the true incidence of melanomas as a side-effect of any drug therapy. We report here on a 41-year-old woman who had been treated with natalizumab (once per month i.v.) for 15 months for multiple sclerosis. The patient had no known history of melanoma but displayed many atypical moles for years that were regularly checked by a dermatologist. The family history was negative for melanomas and she did not expose herself to sunlight regularly. She noticed a rapidly growing mole on her upper arm. On evaluation it proved to be a superficial spreading melanoma in situ pTis (SSM-type) on the basis of a dysplastic nevus of a compound type. The lesion was excised in total. Other moles were also removed but did not show any histological signs of melanoma. An eye examination with a special focus on the retina revealed no signs of ocular melanoma. The patient is now on regular follow up with a dermatologist and showed no other transdifferentiation of the known nevi. She is still on natalizumab therapy. The occurrence of melanoma in our patient was in close temporal relation to the administration of natalizumab and an alteration in a long-standing nevus. It should be taken into account that anti-a4 -integrin antibodies suppress the immune system by inducing apoptosis in lymph node T cells in an in vitro model, which could explain the potential of melanoma cells to spread. The already published case reports together with the present case report should raise the awareness of this possible side effect of developing melanoma under natalizumab therapy. Medical doctors using natalizumab should consider regular dermatological checkups for their patients until further data are available.