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.     

Flupirtine-induced liver injury—Seven cases from the Berlin Case–control Surveillance Study and review of the German spontaneous adverse drug reaction reporting database

Purpose

The hepatotoxic potential of the analgesic flupirtine has attracted increased attention over the past years. Recently, risk minimisation measures such as maximum treatment duration of 2 weeks have been requested by the European Medicines Agency (EMA). This study was conducted to further elucidate the clinical pattern of flupirtine-induced liver injury (FILI).

Methods

Seven FILI patients were ascertained in all Berlin hospitals in the Berlin Case–control Surveillance Study (FAKOS) between 2002 and 2011. Furthermore, we reviewed the severe cases of flupirtine-associated hepatotoxicity included in the adverse drug reaction database of the Federal Institute for Drugs and Medical Devices (BfArM) in Germany from between 1991 and 2012.

Results

All seven FILI patients of FAKOS were hospitalised. Six of them were female, mean age was 55 years, and the most common symptoms were fatigue and jaundice. Three patients developed acute liver failure (ALF). Discontinuation of flupirtine invariably led to clinical and laboratory improvement. Review of the BfArM cases (n?=?248) showed female sex predominance and high prevalence of jaundice and ALF. Time to onset of symptoms was less than 2 weeks in 9 % of the patients with respective data.

Conclusions

Our results corroborate previous findings on FILI’s clinical pattern and on its potentially severe course. Although the hepatotoxic risk might be higher after the first 2 weeks of treatment, earlier onset of severe FILI cannot be ruled out. Postauthorisation safety studies are needed to evaluate EMA’s risk minimisation measures and to quantify flupirtine’s risk according to its duration of use.     

Drug-induced agranulocytosis in the Berlin case–control surveillance study

Purpose

Drug-induced agranulocytosis (DIAG) is a rare but serious adverse drug reaction. The Berlin Case–Control Surveillance Study (FAKOS) aimed to identify pharmaceuticals with an increased risk for this condition.

Methods

Adult patients with acute non-chemotherapy–induced agranulocytosis, developed in hospital or in the outpatient setting, were ascertained by active surveillance in all 51 Berlin hospitals between the years 2000 and 2010. Applying the criteria of the World Health Organization, a standardized drug causality assessment was conducted for each agranulocytosis patient to determine possible drug aetiology. Drug risks were quantified in a case–control design with unconditional logistic regression analysis.

Results

Sixty-three out of 88 validated cases of agranulocytosis were identified as being at least probably drug-related. Drug causality assessment resulted in 36 pharmaceuticals with a certain or probable relationship to agranulocytosis. Drugs involved in ≥ 3 cases with a probable or certain causality were metamizole (dipyrone) (N?=?10), clozapine (N?=?6), sulfasalazine (N?=?5), thiamazole (N?=?5), and carbamazepine (N?=?3). In case–control analysis, six drugs were identified with significant odds ratios for DIAG. The highest odds ratios were observed for clozapine, sulfasalazine, and thiamazole.

Conclusions

Our findings are generally in agreement with those of earlier case–control studies. The spectrum of drugs causing acute agranulocytosis has not changed considerably over recent years, despite many newly marketed drugs. Evidence for induction of agranulocytosis by some new pharmaceuticals is supported.     

β-Blockers and the Risk of Depression: A Matched Case–Control Study

Drug Safety - Depression is a commonly cited adverse effect of β-blockers but the evidence for a causal relationship is limited. We aimed to explore whether β-blockers are associated with...     

Study results from the Clinical Trials Network's first 10 years: Where do they lead?

The National Drug Abuse Treatment Clinical Trials Network (CTN) began in 2000 with the goal of “improv[ing] the quality of drug abuse treatment throughout the country using science as the vehicle.” Since then, 24 discrete clinical trials were launched, 20 are completed, and 15 have published main outcome papers. Of the latter, 4 tested pharmacological treatment, 8 psychosocial/behavioral treatment, 1 a combination of medication and counseling, and 2 targeted HIV/hepatitis C virus risk behavior. We review main study findings for these trials, including treatment retention, substance use or risk behavior outcomes, and secondary outcomes when analyzed. The purpose of this review is to identify the incremental progress toward improving drug treatment made by these trials and to propose next steps for the CTN and for the field arising from these studies. The CTN provides a unique opportunity to systematically design trials that incorporate treatment improvements from previous trials and to direct efforts toward innovations most likely to be incorporated into practice.     

Case–Control Genome-Wide Association Study of Persistent Attention-Deficit Hyperactivity Disorder Identifies FBXO33 as a Novel Susceptibility Gene for the Disorder

Attention-deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder with high heritability. At least 30% of patients diagnosed in childhood continue to suffer from ADHD during adulthood and genetic risk factors may play an essential role in the persistence of the disorder throughout lifespan. To date, genome-wide association studies (GWAS) of ADHD have been completed in seven independent datasets, six of which were pediatric samples and one on persistent ADHD using a DNA-pooling strategy, but none of them reported genome-wide significant associations. In an attempt to unravel novel genes for the persistence of ADHD into adulthood, we conducted the first two-stage GWAS in adults with ADHD. The discovery sample included 607 ADHD cases and 584 controls. Top signals were subsequently tested for replication in three independent follow-up samples of 2104 ADHD patients and 1901 controls. None of the findings exceeded the genome-wide threshold for significance (P_GC<5e−08), but we found evidence for the involvement of the FBXO33 (F-box only protein 33) gene in combined ADHD in the discovery sample (P=9.02e−07) and in the joint analysis of both stages (P=9.7e−03). Additional evidence for a FBXO33 role in ADHD was found through gene-wise and pathway enrichment analyses in our genomic study. Risk alleles were associated with lower FBXO33 expression in lymphoblastoid cell lines and with reduced frontal gray matter volume in a sample of 1300 adult subjects. Our findings point for the first time at the ubiquitination machinery as a new disease mechanism for adult ADHD and establish a rationale for searching for additional risk variants in ubiquitination-related genes.     

Plasma Vitamin K1 Levels in Italian Patients Receiving Oral Anticoagulant Therapy for Mechanical Heart Prosthesis: A Case–Control Study

Background

Oral anticoagulant therapy (OAT) with a vitamin K antagonist (VKA) is the choice of treatment for preventing thromboembolism in patients with mechanical heart valve prosthesis (MHP). The percentage of time in the therapeutic range (TTR%) expresses the OAT quality. We planned a case–control study in order to determine vitamin K1 plasmatic concentrations in MHP patients and to correlate these with TTR%.

Materials and Methods

Of 756 MHP patients receiving OAT, 125 patients (61 younger than 65 years, and 64 older than 65 years) and 120 healthy blood donors, matched for sex and age, were enrolled in the study. All subjects completed a living questionnaire regarding diet, and underwent blood collection. Vegetable and fruit intake was categorized as optimal or suboptimal, and the high-performance liquid chromatography method was used to determine vitamin K1 levels.

Results

Neither the patients nor controls had been taking vitamin supplements prior to the start of the study. The median vitamin K1 level was 290 pg/L in 72 controls with optimal intake, and 274 pg/L in 48 controls with suboptimal intake, while the median vitamin K1 level in MHP patients with optimal intake was 409 pg/L, significantly higher (p < 0.001) than the 133.5 pg/L in patients with suboptimal intake. Vitamin K1 concentration in MHP patients appears to be linked to an age-related threshold: in patients younger than 65 years of age, the median vitamin K1 level was 431 pg/L, significantly higher (p < 0.05) than the 290 pg/L in patients older than 65 years of age. No clear relation was found between vitamin K1 levels and TTR% (Pearson = 0.14). However, patients with vitamin K1 >160 pg/L showed a TTR% >60 %. Among patients younger than 65 years, subjects with vitamin K1 >160 pg/L showed a median TTR of 66 %, this being significantly higher (p < 0.001) than the 46 % level shown by patients with vitamin K1 <160 pg/L.

Conclusions

Vitamin K1 concentrations in MHP patients seem to be related to both diet and age.

     

Relating alcohol use and mood: results from the Tromsø study

OBJECTIVE: The interrelationships between alcohol consumption and depressed mood were studied in a population to determine if the relationships differed by sex and consumption. METHOD: Alcohol consumption and mood were surveyed at a 7-year interval by self-report (N = 8,260; 4,407 women). Frequency of intoxication was used to divide the sample into moderate and immoderate drinkers. Structural equations modeling was then applied to describe the interrelationships of drinking and mood both cross-sectionally and over time. RESULTS: Overall, self-reported drinking was stable over a 7-year period, although drinking patterns were less stable for immoderate drinkers. Drinking predicted higher levels of depressed mood among the immoderate drinkers of both sexes at follow-up. Drinking also weakly predicted depressed mood among moderately consuming men. However, among moderately consuming women dysphoric mood predicted less drinking. Depressed mood was related to higher levels of concurrent drinking among the immoderately drinking men. Among immoderately drinking women, however, concurrent depressed mood predicted more drinking. CONCLUSIONS: Generally, drinking predicted subsequent depressed mood although this pattern was reversed among moderately drinking women. Furthermore, a synchronous effects model indicated that some immoderately drinking women used alcohol as a response to emotional distress. It appears that gender and the level of consumption need to be taken into account in studies relating mood and drinking.     

Treatment of psoriasis with different dosage regimens of etanercept: preliminary results from the Tαranta Plastic Study Group

This pilot open-label study is aimed to assess clinical response in psoriasis patients receiving diverse dose regimens of etanercept, consisting of the same global cumulative dose of etanercept administered over different treatment periods. Eligible patients were assigned sequentially in a 1:1 ratio to receive: etanercept 50 mg once weekly (QW) or 50 mg twice weekly (BIW) for 12 weeks. The final analysis included a total of 72 patients. At week 12 the Psoriasis Area and Severity Index (PASI) and Skindex-29 scores notably improved in both treatment arms, without significant differences between the two groups. The rate of patients attaining a PASI improvement >or= 50% (PASI 50) at week 12 was 92% in the high-dose group. In these patients, etanercept dosage was decreased to 50 mg QW from week 13, with persistence of the PASI 50 response at week 24 in all cases. Thereafter, treatment was discontinued up to week 36 and almost 30 % of patients experienced a gradual relapse of their psoriasis within this period. In the low-dose group, the PASI 50 response was observed in 75% of patients. These responders continued to be treated with etanercept 50 mg QW up to week 36 with persistence of the PASI 50 in 100% of cases at week 24 and 93% at week 36. In the low-dose regimen, 8 patients who did not respond at week 12 underwent dose escalation to 50 mg BIW for a further 12 weeks. At week 24, six of these patients gained the PASI 50 response, 4 of whom maintained the response up to week 36, after treatment discontinuation from week 24. Our results confirm that etanercept is very effective and well-tolerated in psoriasis and that the drug dosages and treatment duration may be modulated and adapted to clinical needs in a flexible way.     

Ceftaroline activity tested against uncommonly isolated Gram-positive pathogens: report from the SENTRY Antimicrobial Surveillance Program (2008–2011)

Ceftaroline was tested against 1859 clinically significant Gram-positive organisms from uncommonly isolated species. The organisms (31 species/groups) were collected from 133 medical centres worldwide over a 4-year period (2008–2011). Coagulase-negative staphylococci were generally susceptible to ceftaroline, with MIC₅₀ values (minimum inhibitory concentration required to inhibit 50% of the isolates) of 0.06–0.5 mg/L. Ceftaroline was active against Micrococcus spp. [minimum inhibitory concentration required to inhibit 90% of the isolates (MIC₉₀) = 0.06 mg/L], but showed more limited potency versus some Corynebacterium spp. and Listeria monocytogenes isolates. Ceftaroline was active against all β-haemolytic streptococci and viridans group streptococcal species/groups listed, with MIC₅₀ and MIC₉₀ values ranging from ≤0.015 mg/L to 0.03 mg/L and from ≤0.015 mg/L to 0.5 mg/L, respectively. Based on these in vitro findings, ceftaroline may have a potential role in the treatment of infections caused by these rarer species as guided by reference MIC test results.     

New levothyroxine formulation meeting 95–105% specification over the whole shelf-life: results from two pharmacokinetic trials

Objective: Small levothyroxine (L-T4) dose changes can lead to significant clinical effects. To ensure thyroid hormone levels are safely maintained, authorities are increasingly adopting stricter potency specifications for L-T4, the most stringent of these being 95–105% of the labeled dose over the whole shelf-life. Levothyroxine sodium (Euthyrox, Eutirox, Lévothyrox) has been reformulated, and two studies performed, to ensure bioequivalence to the currently marketed formulation and dosage form proportionality of the new formulation.

Methods: The bioequivalence study was an open-label, randomized, single-dose, two-period, two-sequence crossover comparing the highest dosage strengths of the currently marketed and the new L-T4 formulation at a total dose of 600?μg. The dosage form proportionality study was an open-label, randomized, three-period, six-sequence crossover, comparing 50?μg, 100?μg, and 200?μg L-T4 tablets, at a total dose of 600?μg. Blood samples were taken at predefined time intervals. Primary outcomes were area under the curve (AUC) and maximum concentration (C_max) of thyroxine (T4) in plasma.

Results: In the bioequivalence study, comparing the T4 profiles for the new and current formulation of L-T4, the geometric least square mean ratio of the baseline-adjusted AUC_0–72,adj was 99.3% (90% confidence interval [CI]: 95.6–103.2) and the C_max,adj was 101.7% (90% CI: 98.8–104.6). Bioequivalence was established if the 90% CI lay within the predefined 0.9–1.11 limits. In the dosage form proportionality study, pairwise comparisons ranged from 99.3% to 104.8%, and all 95% CIs were within the predefined CI range (0.8–1.25): the three dose strengths were dosage form proportional.

Conclusions: The new formulation of L-T4 meets the most stringent potency specification guidelines, and has been demonstrated to be bioequivalent to the current formulation and to show dosage form proportionality. The new formulation will enable patients to receive a dose fine tuned to their medical needs, contributing to improved safety in the use of L-T4.     

Interaction of Polysorbate 80 with Erythropoietin: A Case Study in Protein–Surfactant Interactions

Purpose The cause of antibody positive pure red cell aplasia associated with the subcutaneous administration of EPREX® to patients with chronic kidney failure has been determined to be due to the leaching of weakly adjuvant compounds from the uncoated rubber stoppers that were formerly used in prefilled syringes. Other researchers have suggested that polysorbate 80 micelles containing erythropoietin may be a causative factor. The purpose of this work was to repeat previously published studies in a more controlled manner and to define the precise nature of the interactions between polysorbate 80 and erythropoietin.Methods The contents of EPREX® prefilled syringes and laboratory-prepared, well-characterized formulations of EPREX® were analyzed by size exclusion chromatography. Fractions were analyzed for the presence of erythropoietin by ELISA. EPREX® formulations prepared with increasing amounts of polysorbate 80 were analyzed by light scattering.Results Well-controlled chromatographic studies showed that when EPREX® formulations containing no aggregate were analyzed by high-performance liquid chromatography, erythropoietin monomer could not be detected under the polysorbate 80 peak. Dimer and oligomers of erythropoietin coeluted under the polysorbate 80 peak as the molecular weights overlapped on the size exclusion chromatogram. Solution light scattering indicated that polysorbate 80 associates with erythropoietin in a defined stoichiometric ratio of 1:12.Conclusions Based on controlled studies, previous results suggesting that EPREX® contains micelle-associated erythropoietin were incorrect. As with other surfactants and proteins, polysorbate 80 associates with erythropoietin in a defined stoichiometric ratio.     

Medicine-Induced Acute Kidney Injury Findings from Spontaneous Reporting Systems,Sequence Symmetry Analysis and a Case–Control Study with a Focus on Medicines Used in Primary Care

Drug Safety - Primary care provides an opportunity to prevent community acquired, medicine or drug-induced acute kidney injury. One of the barriers to proactive prevention of medicine-induced...     

Case reports of lead poisoning in dogs from the National Animal Poison Control Center and the Centre National D'Informations Toxicologiques, Veterinaires: anecdotes or reality?

This paper presents case reports of lead toxicoses from 2 major animal poison control centers in Europe and North America, gathered from 1985 through 1989. All results examined here involved cases assessed as "toxicosis" or "suspected toxicosis" by the National Animal Poison Control Center (NAPCC) or the Centre National d'Informations Toxicologiques Veterinaries (CNITV). 537 cases were reported to the NAPCC, most of them concerning dogs (59%). In France, most of the 362 cases involved cattle (57.2%). There was an increased number of cases reported during late summer and early fall, and a decreased number of cases in November and December, in both centers. Dogs intoxicated were predominantly young animals (60% were less than 2 years old). No sex difference was noted. Pure bred dogs appeared more often involved than mixed-breed ones, but the breed distribution closely resembles dog breed distribution in the US. The source of lead was usually unknown and, when information was available, paint seemed to be the most common cause of poisoning. Clinical signs reported to the animal poison control centers involved the CNS and GI tract. Results from the French and the American database showed similar trends. They are compared to data from veterinary clinics and veterinary colleges in the US and Australia. In each case, data are very similar to what was reported to the CNITV and the NAPCC. It is concluded that animal poison control centers databases can provide a useful tool for better knowledge of animal poisoning. They can also help identify unexpected toxicologic problems related to drug administration or pesticide use.     

Monitoring Ecstasy Content in France: Results From the National Surveillance System 1999–2004

The French National Identification System for Drugs and Other Substances (SINTES) is an original scheme gathering analytical information for synthetic drugs, both through police and customs' seizures in the entire country and collection of samples and questionnaires directly from the users by social field workers. Between July 1999 and June 2004, 9543 samples were included. Tablets (7004) were mainly containing MDMA (82%) and caffeine was the most frequent blended psychoactive substance. Mean MDMA dosage of tablets decreased from 1999 to 2003 and dosage for tablets bearing the same logo appeared to be highly variable. Notwithstanding the difficulties for data collection due to the illicit nature of these drugs, this surveillance and early warning system, which combines the cooperative efforts of law enforcement laboratories and social workers, provided relevant and timely information. It is accurate regarding the follow-up of trends in drugs' composition, and the identification of new or potentially dangerous substances, to the professionals, the public, and the European partners.     

Celecoxib to prevent restenosis – results from the COREA-TAXUS trial

Celecoxib inhibits Akt, which is stimulated during restenosis. Cell and animal studies showed that celecoxib inhibited Akt stimulation and restenosis. Recently, the COREA-TAXUS (Effect of Celecoxib on Restenosis after Coronary Angioplasty with Taxus stent) trial was performed in subjects with angina or a positive-stress test receiving paclitaxel-eluting stents. The primary end point at 6 months was the in-stent, late luminal loss, which was 0.49 mm in the celecoxib-treated group; less than the 0.75 mm in the group not treated with celecoxib. The rate of revascularisation of the target lesion was lower in celecoxib-treated subjects (5%) than in the untreated subjects (15%). In conclusion, this is an excellent demonstration of translating a mechanism of action of a drug into a clinical use.     

Tableting Lipid-Based Formulations for Oral Drug Delivery: A Case Study with Silica Nanoparticle–Lipid–Mannitol Hybrid Microparticles

Silica–lipid–mannitol hybrid (SLMH) microparticles have been developed that were compressible into high quality tablets suitable for oral dosing and delivery of poorly soluble drugs. SLMH tablets enable high lipid-loading levels (>40%) and retain the immediate release, enhanced lipase digestion and drug solubilisation performance. Specifically, we report formulation optimisation of SLMH microparticles and tablets using coumarin 102 (log P = 4.09) as a model Biopharmaceutics Classification System class II drug. SLMH tablets were acceptable according to standard British Pharmacopoeia friability, hardness and disintegration tests; this is not the case for conventional dry emulsions. Furthermore, in vitro dissolution and pancreatic-lipase-induced lipolysis studies under simulated intestinal conditions have demonstrated enzymatic-digestion-mediated drug solubilisation. SLMH microparticles and tablets are suitable as liquid lipid containing solid dosage forms for enhancing and controlling oral absorption of poorly soluble drugs. © 2012 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:684–693, 2013