Drug Safety Program Research Articles

Cross‐Species Genetic Toxicity Assessment Accomplished by Flow Cytometric Analysis of Blood

The formation of micronuclei in blood cells has been an established indicator of genotoxicity for decades. Standard microscopy methods are time-consuming and lack the objectivity that fully automated methods can provide. The ability of flow cytometric technology to rapidly and objectively survey thousands of cells for micronuclei can significantly improve the value of this endpoint. In addition, since many more cells can be scored, and specific populations can be targeted, species that historically have been difficult to obtain micronucleus data from, such as humans, can now be readily evaluated using this methodology. This unit describes a procedure for fixation, staining, and analysis of blood samples using materials supplied in MicroFlow kits (Litron Laboratories) and a single-laser flow cytometer. This methodology provides a reliable, robust assessment of chromosome damage that is used in basic science research as well as drug-safety screening programs at large pharmaceutical and chemical companies.

Polypharmacy in psychiatric inpatients: Data from AMSP, a European pharmacovigilance system

Material and methods The AMSP study is a drug safety program that ensures the continuous assessment of severe adverse drug reactions (ADR) in psychiatric inpatients under the natural conditions of routine clinical treatment. Furthermore on two reference days per hospital and per year, the following data are recorded for all patients on the wards under AMSP surveillance: all drugs applied on that day with the daily dosage for psychotropic drugs, ICD diagnosis, age, and sex. Data is stored at the study center in Munich. Due to the increasing number of participating clinics over the years only data of 33 hospitals (5 austrian, 22 german and 6 swiss institutions including university and non-university institutions) who participated since 2003 will be presented.

Pharmacological treatment of acute mania in psychiatric in-patients between 1994 and 2004

Background In a cross-section approach we investigated prescription practice in acute mania in 63 German, Swiss and Austrian hospitals between 1994 and 2004. Methods Our data were gathered from a large drug safety program (AMSP) within which on two reference days each year all administered drugs are recorded. For the present study, all cases with a primary diagnosis of acute euphoric mania ( n = 1291) or mixed-state mania ( n = 143) were identified. Prescription rates from two periods, 1994 to 1999 and 2000 to 2004, were compared. Results In euphoric mania, prescription of lithium decreased by about one-fifth (43.3% to 34.5%, p < 0.01), while prescription of anticonvulsants increased by one-half (from 40.0% to 60.7%, p < 0.001). Administration of atypical antipsychotics more than doubled (18.5% to 43.9%, p < 0.001), while use of typical antipsychotics decreased significantly (56.9% to 27.8%, p < 0.001). Overall prescription rates of antipsychotics (79.6% vs. 81.6%) and antidepressants (14.0% vs. 15.5%) remained stable, while administration of tranquilizers increased significantly (26.3% to 34.3%, p < 0.01). In mixed-state mania, similar trends over time to those seen in euphoric mania were observed for lithium (43.2% to 33.3%), anticonvulsants (50.0% to 69.7%, p < 0.05) and tranquilizers (22.7% to 40.4%). Prescription rates of antipsychotics slightly increased (63.6% to 72.7%), while prescription of antidepressants slightly decreased (54.5% to 46.5%). Polypharmacy was a common phenomenon: patients with euphoric mania were treated with a mean number of 2.9 ± 1.2 psychotropic agents, and patients with mixed-state mania with 3.3 ± 1.5 psychotropic agents. Both groups showed a significant increase over time. Second-generation atypical antipsychotics were adopted quite rapidly for the treatment of acute mania considering the availability of the scientific evidence at that time. Off-label use was a common phenomenon. Deviations from recommended guidelines were found mainly in the use of antidepressant and antipsychotic drugs both in mixed-state and euphoric mania. Conclusions Naturalistic prescription studies like this may encourage a critical scrutiny of clinical treatment habits and may also drive further research thus moderating potential differences between evidence-based knowledge and everyday clinical practice.

In vitro micronucleus scoring by flow cytometry: Differential staining of micronuclei versus apoptotic and necrotic chromatin enhances assay reliability

The in vitro micronucleus test has received considerable attention in recent years for its use in drug safety assessment and toxicological research. The less tedious nature of the assay relative to chromosome aberration analyses is a driving force, and explains why many chemical and drug safety programs have adopted the endpoint. Development of a high-throughput micronucleus scoring system would further enhance the utility of the assay for lead optimization and other early drug development work. Although several variations of a flow cytometric (FCM) method for scoring cell-culture-derived micronuclei (MN) have been described in the literature, they have been unable to distinguish true MN from apoptotic and necrotic chromatin (Nüsse M and Marx K 1997: Mutat Res 392: 109-115). Here, we report advances to this methodology whereby a sequential staining procedure is used to differentially label these types of sub-2n particles. With the use of ethidium monoazide (EMA), the chromatin of dead and dying cells is labeled. After a photoactivation step that covalently binds EMA to chromatin, cytoplasmic membranes are digested and resulting lysates are incubated with RNase plus a pan-nucleic acid dye (SYTOX Green). This process provides a suspension of free nuclei and sub-2n particles that are labeled with either SYTOX or SYTOX and EMA. Preliminary studies with heat-shocked L5178Y mouse cells demonstrated that EMA stains necrotic and mid- through late-stage apoptotic cells. Importantly, the sequential labeling procedure provided reliable micronucleus enumeration, even when cultures contained high percentages of dead cells. Subsequently, experiments with the following diverse genotoxicants were performed: hydroxyurea, methyl methanesulfonate, benzo[a]pyrene, etoposide, cyclophosphamide, and vinblastine. Additionally, the nongenotoxicants sucrose, tributyltin methoxide, and dexamethasone were tested up to 5 mg/ml, or to cytotoxic concentrations. FCM data were found to correspond closely with microscopy-based measurements. Collectively, these data suggest that this sequential EMA/SYTOX staining procedure provides reliable, high-throughput enumeration of in vitro MN.

Pharmacotherapy of Personality Disorders in German Speaking Countries: State and Changes in the Last Decade

In many cases, patients with personality disorders currently receive psychopharmacological treatment as well as psychotherapy. Empirically oriented studies of outcome and efficacy are still rare, and clinical practice is still dominated by a symptomatic and rather pragmatic approach. This study provides empirical insight into the reality of psychopharmacological practice in psychiatric institutions in German speaking countries. The use of psychotropic drugs in patients with personality disorders is demonstrated using the data base of the AMSP drug safety program. Recent changes are shown by comparing results from 1996 and 2003. Our data show a symptom-driven, polypragmatic, and often off-label use of psychotropic drugs in personality disorders.

HERG-Lite®: A novel comprehensive high-throughput screen for drug-induced hERG risk

Introduction Direct block of I Kr by non-antiarrhythmic drugs (NARDs) is a major cause of QT prolongation and torsades de pointes (TdP), and has made the hERG potassium channel a major target of drug safety programs in cardiotoxicity. Block of hERG currents is not the only way that drugs can adversely impact the repolarizing current I Kr, however. We have shown recently that two drugs in clinical use do not block hERG but produce long QT syndrome (LQTS) and TdP by inhibiting trafficking of hERG to the cell surface. To address the need for an inexpensive, rapid, and comprehensive assay to predict both types of hERG risk early in the drug development process, we have developed a novel antibody-based chemiluminescent assay called HERG-Lite®. Methods HERG-Lite® monitors the expression of hERG at the cell surface in two different stable mammalian cell lines. One cell line acts as a biosensor for drugs that inhibit hERG trafficking, while the other predicts hERG blockers based on their ability to act as pharmacological chaperones. In this study, we have validated the HERG-Lite® assay using a panel of 100 drugs: 50 hERG blockers and 50 nonblockers. Results HERG-Lite® correctly predicted hERG risk for all 100 test compounds with no false positives or negatives. All 50 hERG blockers were detected as drugs with hERG risk in the HERG-Lite® assay, and fell into two classes: B (for blocker) and C (for complex; block and trafficking inhibition). Discussion HERG-Lite® is the most comprehensive assay available for predicting drug-induced hERG risk. It accurately predicts both channel blockers and trafficking inhibitors in a rapid, cost-effective manner and is a valuable non-clinical assay for drug safety testing.

Galactorrhea and Antipsychotic Use: Data from the AMSP

Within the drug safety program in psychiatry AMSP (Arzneimittelsicherheit in der Psychiatrie) severe adverse drug reactions (ADR) are assessed. Currently 35 psychiatric hospitals and departments are participating in detecting severe ADR. This presentation focuses on the prolactin-dependent ADR galactorrhea due to antipsychotic medications. Related to the number of patients surveyed (122.562 from 1993–2000) these are rare events (0.03%). Women are the population mainly at risk concerning galactorrhea induced by antipsychotics. In the group of antipsychotics, relative frequencies of galactorrhea observed here correspond to the degree of D2-binding. Galactorrhea assessed as ‘severe’ was seriously incommodating patients or accompanied by distressing symptoms like pain, tension, enlargement of breasts, weight gain or soaked clothing. Galactorrhea appeared mostly in week one two after administration of a new drug and dosages were within normal range compared to patients without this ADR. Management of this ADR implied discontinuation or reduction of the drugs. The AMSP data contribute to the knowledge on endocrine ADR by the large number of patients examined and help clinicians select the appropriate drug if their patients have been sensitive for these ADR in the past.

FDA Plans to Strengthen Drug Safety Program

FDA Plans to Strengthen Drug Safety Program

FDA Plans to Strengthen Drug Safety Program

FDA Plans to Strengthen Drug Safety Program

FDA Vows to Improve Drug-Safety Assessments

FDA Vows to Improve Drug-Safety Assessments

Severe adverse drug reactions of typical and atypical neuroleptics in routine clinical treatment: results from the AMSP drug safety program

Most of the studies comparing adverse drug reactions (ADR) of the various ‘typical’ and newer ‘atypical’ neuroleptics represent an artificial setting of drug administration and do not easily relate to the ‘real life’ setting of psychiatric treatment. In contrast, the AMSP drug safety program allows the monitoring of ADR in the naturalistic setting of routine clinical practice. Between 1993 and 2000 86,439 patients treated with at least one neuroleptic agent were monitored. In 1.1% of the patients severe ADR occurred. In contrast to the results from controlled trials, ‘atypical’ neuroleptics caused more severe ADR than ‘typical’ neuroleptics. This result was mainly caused by the high amount of severe ADR in patients treated with clozapine. Excluding the data on clozapine, we found ‘typical’ and ‘atypical’ neuroleptics to be similar in the occurrence of severe ADR, although the profiles differ between these two groups as well as between the single substances.

Cardiac Adverse Effects Associated with Psychotropic Drugs

Within the drug safety program in psychiatry AMSP ( Arzneimittelsicherheit in der Psychiatrie), severe adverse drug reactions (ADRs) in psychiatric inpatients are assessed in the naturalistic setting of routine treatment. Currently, 35 psychiatric hospitals and departments are participating. This paper focuses on severe cardiovascular ADRs due to psychotropic medications. Related to the number of patients surveyed (122,562 from 1993 to 2000), these are rare events (68 cases or 0.055 %). Imputed drug classes for probable cases were antidepressants in 0.03 % and neuroleptics in 0.019 %, but other drugs were also involved. Within the group of antidepressants, the risk for a cardiac ADR depends much on the class: SSRIs were never imputed alone, but tricyclic antidepressants were imputed alone in 0.05 %. In the group of antipsychotics, the lowest rate of cardiac ADRs was found for the group of phenothiazines (0.003 %). Cardiovascular risk factors elevated the risk for a cardiac ADR from 0.04 % to 0.14 %. Age as an independent factor did not contribute substantially to the risk for a cardiac ADR. The data of the drug safety program in psychiatry allow some estimate of differential risk rates for cardiac ADRs with different psychotropic drug groups. The results of the project can help clinicians select the appropriate drug for patients at risk to develop cardiac ADRs.

The AMSP drug safety program: methods and global results.

The AMSP (Arzneimittelsicherheit in der Psychiatry) study is a drug safety program that ensures the continuous assessment of severe adverse drug reactions (ADR) in psychiatric inpatients under the natural conditions of routine clinical treatment. It developed out of the preceding drug surveillance study AMUP (Arzneimittelüberwachung in der Psychiatrie). Currently 35 hospitals participate in the study. This paper describes the methods of the AMSP, gives detailed definitions of ADRs assessed to be "severe," and discusses the implications of these definitions and the methodological approach for evaluating the AMSP data. In addition, some overall data compiled on ADR rates from 1993 to 2000 are given.

Assessment of sexual dysfunctions in schizophrenic inpatients with the AMSP drug safety program

Several studies have analyzed prescription patterns for bipolar disorder, but few have for acute mania. Treatment strategies in this complex domain change over time and do not always follow evidence-based guidelines.Prescription data of in-patients suffering from acute mania in the time period from 2005 to 2012 were obtained from the database of the Drug Safety Program in Psychiatry (Institut für Arzneimittelsicherheit in der Psychiatrie; AMSP). Data were collected on two index dates per year. Changes over time were analyzed comparing the time periods 2005/06 and 2011/12.Among 1650 patients (mean ±SD; age: 48.9±14.91 years; 53.1% females) 54.1% received anticonvulsants, 74.5% second-generation antipsychotics (SGAs), 17.8% first-generation antipsychotics (FGAs), 29.1% lithium, 44.1% benzodiazepines and 14.5% antidepressants. Prescription of SGAs increased from 70% to 79% (p=0.005), while prescription of FGAs and anticonvulsants decreased from 19% to 13% (p<0.05) and 59% to 46% (p<0.001), respectively. Only 30% of patients received monotherapy with one mood stabilizer. We observed an impact of gender, age and psychotic symptoms on treatment strategy. 36.8% of the women≤40 years received valproate.Follow-up data are missing and no differentiation between acute and maintenance treatments could be made due to the cross-sectional design. Additionally, our findings do not necessarily translate to outpatients or to other countries.Combination therapies represent standard clinical practice. Though many results reflect clinical necessity, the high number of antidepressant prescriptions or valproate use in women of child-bearing age should be judged critically. Further prospective studies should focus on real-world prescription practice in acute mania to evaluate efficacy and safety of common practice.This paper is dedicated to Prof. Dr. Hanns Hippius on the occasion of his 90th birthday.

Disinhibition of libido: an adverse effect of SSRI?

Background: The article focuses on adverse drug reactions (ADR) to selective serotonin reuptake inhibitors (SSRI) concerning libido and sexual behaviour: cases of disinhibition of libido observed at the Psychiatric Hospital of Kilchberg near Zurich are described. Method: Within the scope of a drug safety program, the physicians of the hospital are regularly asked about severe and unexpected events under drug treatment. Results: During remission of depression, five outpatients noticed an increase of libido experienced as strange to them, i.e. preoccupation with sexual thoughts, first appearance of promiscuity, of unsafe sexual intercourse, and of excessive pursuit of pornography, respectively, during administration, change in dose or discontinuation of SSRI. Discussion: The case studies suggest that SSRI treatment might be associated with increase and disinhibition of libido. The phenomena are discussed as a ‘selective switch’ into partly manic symptomatology or an induction of mixed states with prevailing sexual symptoms.