Development of a shared decision-making intervention to improve drug safety and to reduce polypharmacy in frail elderly patients living at home.

Objectives: For patients with geriatric frailty, reducing inappropriate medication is an important goal to improve patient safety in primary care. GP-side barriers include knowledge gaps, legal concerns, and lack of communication between the actors involved. The aim was to develop a multi-faceted intervention to facilitate deprescribing and shared prioritisation among frail elderlies with polypharmacy living at home. Methods: Mixed methods study including: 1) scoping review on family conferences, expert panels; 2) group discussions with GPs, mapping of needs and challenges in Primary Care; 3) workshops and expert interviews with GPs, patient advocates, researchers as a basis for a theoretical intervention model; 4) piloting. Results: A major challenge for GPs is to conduct a productive discussion with patients and family cares on deprescribing and drug safety. A guideline for a structured family conference with a medication check and geriatric assessment was developed and proved to be feasible in the pilot study. Conclusion: The intervention developed to facilitate deprescribing and shared prioritisation of drug therapy based on family conferences seems suitable to be tested in a subsequent cRCT. Innovation: Adapting family conferences to primary care for frail patients with polypharmacy.

A patient-centred web-based adverse drug reaction reporting system identifies not yet labelled potential safety issues.

PURPOSE: Reporting of adverse drug reactions (ADRs) by patients is essential for a comprehensive risk-benefit evaluation of drugs after marketing, but only few data are available regarding patient-centred web-based ADR reporting systems. Hence, we aimed to analyze ADRs reported by patients with a particular emphasis on novel drugs and serious ADRs not yet labelled in the respective summary of product characteristics (SPC). METHODS: All ADR reports received by a web-based, patient-centred platform ( www.nebenwirkungen.de ) between April 1, 2019, and September 1, 2020, were descriptively analyzed. ADRs and drugs were coded automatically according to MedDRA and ATC classification system. SPC labelling of reported ADRs for novel drugs marketed since 2015 was checked manually. RESULTS: In total, 13,515 patient reports including 29,529 ADRs were received during the study period (serious ADRs [SADRs] n = 1,318; 4.5%). Women were affected in more than two-thirds of ADR reports. The most common patient-reported ADRs were nausea, dizziness and headache, whereas arrhythmia, intestinal obstruction and erectile dysfunction were the most frequent SADRs. Ciprofloxacin, levothyroxine and venlafaxine were the compounds most frequently suspected for causing both ADRs and SADRs. Regarding novel compounds, 289 reports including 739 ADRs were received (mainly fatigue, headache and myalgia). Three hundred thirty-one (44.8%) out of those ADRs were not yet labelled in the respective SPC, whereof twelve were SADRs. CONCLUSION: The majority of patient-reported ADRs were non-serious. However, a relevant number of non-labelled even serious ADRs was reported for novel compounds by patients. Despite well-known limitations of patient-reported ADRs, this web-based ADR reporting system contributes to the identification of new ADRs and thus can help to improve patients' safety complementing other pharmacovigilance instruments.

[Influence of drugs on urological diseases]. / Einfluss von Medikamenten auf urologische Krankheiten.

A number of drugs prescribed for the treatment of various diseases can induce urological symptoms as side effects. Antihypertensive drugs (particularly alpha blockers) can result in stress incontinence, whereas selective serotonin reuptake inhibitors (SSRI) can cause urge incontinence and estrogen promotes both forms. A wide range of drugs with anticholinergic activity, among them neuroleptics, tricyclic antidepressants and certain drugs used in airway disorders are associated with urinary retention. Only very few drugs bear a relevant risk for urolithiasis, i. e. the diuretic triamterene and protease inhibitors, such as indinavir; however, the widely used combination of calcium and vitamin D supplementation for prevention of osteoporosis may be an underdiagnosed cause of renal calculi. Drug-induced sexual dysfunction is a frequent side effect of antihypertensive treatment, particularly with beta adrenoceptor blockers and diuretics. The SSRI and some neuroleptics can also impair sexual function.

Adverse drug reactions in a complementary medicine hospital: a prospective, intensified surveillance study.

Background. Anthroposophic medicine is one of the widely used approaches of complementary and alternative medicine. However, few prospective studies have generated safety data on its use. Objectives. We aimed to assess adverse drug reactions (ADRs) caused by anthroposophical medicines (AMEDs) in the anthroposophical Community Hospital Havelhoehe, GERMANY. Study Design and Methods. Between May and November 2007, patients of six medical wards were prospectively assessed for ADRs. Suspected ADRs occurring during hospitalization were documented and classified in terms of organ manifestation (WHO SOC-code), causality (according to the Uppsala Monitoring Centre WHO criteria), and severity. Only those ADRs with a severity of grade 2 and higher according to the CTCAE classification system are described here. Results. Of the 3,813 patients hospitalized, 174 patients (4.6%) experienced 211 ADRs (CTCAE grade 2/3 n = 191, 90.5%, CTCAE grade 4/5 n = 20, 9.5%) of which 57 ADRs (27.0%) were serious. The median age of patients with ADRs (62.1% females) was 72.0 (IQR: 61.0; 80.0). Six patients (0.2%) experienced six ADRs (2.8% of ADRs) caused by eight suspected AMEDs, all of which were mild reactions (grade 2). Conclusion. Our data show that ADRs caused by AMEDs occur rarely and are limited to mild symptoms.

[Drug treatment of elderly patients]. / Pharmakotherapie alter Patienten.

Drug therapy in seniors needs to be adapted to the capacity of the aged organism. The dosages of a high number of drugs from several classes (e.g., antibiotics, low molecular weight heparins) have to be modified according to age or reduced renal function, which is a common feature in old age. Moreover, elderly patients due to their physiological alterations exhibit an increased response to drugs having an influence on renal function: diuretics, nonsteroidal anti-inflammatory drugs, inhibitors of the renin-angiotensin-aldosterone system, and contrast media. The choice of drugs should consider their age-specific tolerability, i.e., fall-risk increasing drugs and those with strong anticholinergic side effects should be avoided. Analgesics, sedatives, and narcotics have to be selected according to the age of the patient and dosages should be adapted. Multimorbidity is often treated with polypharmacy, whereby it is not unusual that this is the cause for acute hospital admission. The necessity of all drugs prescribed has to be scrutinized and the drug burden should be reduced as clinically required.

Prerequisites for a new health care model for elderly people with multimorbidity: the PRISCUS research consortium.

BACKGROUND: Multimorbidity, the concurrent manifestation or presence of multiple chronic conditions, poses huge challenges to affected patients, their relatives, physicians, and practitioners alike. The growing number of affected persons and the complexity of their needs places just as much of a burden on the health care system as does the plethora of often poorly coordinated interventions. The Chronic Care Model developed for different chronic diseases is suited for improving medical care. The PRISCUS research consortium was established to create the prerequisites for a new care model for multimorbid, elderly patients oriented along those lines. METHODS: The research consortium utilizes data gathered in a large-scale epidemiological study on peripheral arterial disease (getABI study) and from the Dortmund and Münster stroke registries, by extracting epidemiologic and health economic data, quality-of-life parameters, and data on the extent and quality of medication. Additional projects evaluate the implementation of a multidimensional geriatric assessment in primary care, the functional consequences of multimorbidity in stroke patients along with options for prevention and therapy afforded by physical activity. Systematic reviews of the literature are used to describe quality of life and patient preferences. Experts will work on an initial draft treatment standard for patients with multimorbidity and a list of potentially inappropriate medication for the elderly in Germany. CONCLUSION: The results of the PRISCUS research consortium will enable an epidemiologic characterization and description of consequences of multimorbidity, while illustrating new approaches towards prevention, diagnosis, and management of multimorbid patients. With this, some prerequisites for a new health care model for patients with multimorbidity comparable to the Chronic Care Model will be fulfilled.

[Prerequisites for a new health care model for elderly people with multiple morbidities: results and conclusions from 3 years of research in the PRISCUS consortium]. / Voraussetzungen für ein neues Versorgungsmodell für ältere Menschen mit Multimorbidität: Ergebnisse und Schlussfolgerungen aus 3-jähriger Forschung im PRISCUS-Verbund.

BACKGROUND: The concurrent presence or manifestation of multiple chronic conditions, i.e. multimorbidity, poses a challenge to affected patients and their relatives, physicians, and practitioners, and to the health care system in general. Aiming to improve medical care for different chronic diseases, the Chronic Care Model also appears to be suited for multimorbidity. The established research consortium PRISCUS is trying to create some of the prerequisites for a new care model for multimorbid, elderly patients oriented along the lines of the Chronic Care Model. METHODS AND RESULTS: Four out of seven subprojects of the research consortium provide an overview of some of their findings. Topics in a sports medicine subproject were the assessment of physical activity by means of a newly developed questionnaire and the development and feasibility testing of an exercise program for elderly people with chronic conditions and mobility impairment. Partners from family medicine implemented geriatric assessment in a primary care setting and evaluated its consequences. In a pharmacological subproject, potentially inappropriate medication as well as drug-drug interactions and dosing errors were addressed. The health economic subproject investigated quality of life impairment due to multiple chronic diseases and the effects of multimorbidity on costs. CONCLUSIONS: The results of the PRISCUS research consortium allow a better description of consequences of multimorbidity and illustrate at least some new approaches towards prevention, diagnosis, and treatment of patients suffering from multimorbidity. Ongoing projects will test the efficacy of a physical activity program and a new complex intervention to reduce potentially inappropriate medication in the elderly. With this, the research consortium will create some prerequisites for a new health care model for patients with multimorbidity comparable to the Chronic Care Model.

[Antibiotic prophylaxis for patients with transurethral resection of the prostate (TUR-P)]. / Antibiotikaprophylaxe bei transurethraler Resektion der Prostata (TUR-P).

BACKGROUND: For patients undergoing urologic interventions, relevant aspects of antibiotic prophylaxis such as drug of choice and duration of prophylaxis are still discussed controversially. According to the current European and German guidelines, single-shot prophylaxis is recommended only in patients with risk factors. METHODS: Discussion of two published meta-analyses with regard to of recently published randomized controlled trials. RESULTS: Two comprehensive meta-analyses concordantly revealed a significant reduction in bacteriuria and fever incidence without stratification according to preexisting risk factors. A single antibiotic dose ("single shot") of, for example, a cephalosporin or chinolone reduced the bacteriuria rate significantly. However, for the cephalosporines, the most frequently studied drug class, repeated dosing seems to be more effective. CONCLUSION: Antibiotic prophylaxis reduces the rates of bacteriuria and fever in patients without existing risk factors undergoing transurethral resection of the prostate. The optimal duration of antibiotic prophylaxis and the drug of choice must be evaluated in further studies investigating clinically relevant endpoints.

[Chemotherapy in patients with colorectal carcinoma: applicability of data from clinical trials for the individual patient]. / Pharmakotherapie beim kolorektalen Karzinom: Ubertragbarkeit der Ergebnisse auf den individuellen Patienten.

Randomised, controlled clinical trials provide a valid foundation for evidence-based clinical guidelines. The representativeness of the patient population studied is one major aspect of external validity. With respect to the patient population enrolled in clinical trials studying the effects of chemotherapy in patients with colorectal cancer, older patients are significantly underrepresented, i. e., they represent between 14 and 40 % of the study population, but approximately 70 % of the population concerned. The major reasons for the exclusion of older patients are comorbidities and functional status. Moreover, gender differences in pharmacokinetics and therapeutic effects of 5-fluorouracil are usually not considered. Although individualisation of therapy by means of pharmacogenetics and pharmacogenomics may offer promising options, to date these methods are still not in routine use for colorectal cancer patients. Due to a lack of information about the relevant populations from randomised controlled trials, data from registries and observational trials are necessary to complement our knowledge.

[Adverse drugs reactions: diagnosis and assessment]. / Unerwünschte Arzneimittelwirkungen Diagnostik und Bewertung.

Adverse drug reactions (ADR) occur in about 5% of all pharmacologically treated patients. Between 2% and 20% of all hospital admissions are caused by ADR, and approximately 10% of all hospitalized patients experience ADR during their hospital stay. Several thousand patients die due to ADR in Germany each year. ADR-associated drugs come predominantly from the class of non-steroidal antiinflammatory drugs, anticoagulants, acetylsalicylic acid and cardiovascular drugs. Most ADR cases present as gastrointestinal bleeding and adverse cardiovascular effects. Apart from this, one or more drugs are withdrawn from the market each year because of unwanted but mostly rare side effects. In recent years the most prominent cases were rofecoxib, cisapride and cerivastatin. Physicians in Germany are obliged to report ADR. A substantial proportion of ADR, however, is not reported because it is deemed to be either too well known or the association between the drug and the adverse effect is too doubtful. In some cases, histopathological findings are needed to determine the diagnosis of ADR. Accordingly, physicians should inform the pathologist whether an ADR is suspected and which drugs may be responsible.

[Cardiorespiratory effects of heliox using a model of upper airway obstruction]. / Kardiorespiratorische Effekte von Heliox an einem Modell der oberen Atemwegsobstruktion.

Heliox is a mixture of Oxygen and Helium. The low density of Helium allows this mixture to flow in a laminar pattern where oxygen, nitrogen or air flow would be turbulent. Therefore the force necessary to move a volume of gas (e.g. Heliox) is greatly reduced in comparison to a turbulent gas flow. In a respiratory loading experiment we investigated the effects which Heliox exerts on hemodynamic as well respiratory variables. 10 volunteers were breathing spontaneously and through three different endotracheal (ET-) tubes (ID 4.0, 4.5, 5.0 mm). The subjects were switched from room air to Heliox and differences in the variables heart rate (HR), blood pressure (BP), stroke volume (SV), stroke index (SI), peripheral vascular resistance (TPRI) and left ventricular work index (LVWI) were measured. Furthermore the (PhAng) between abdomen and thorax was detected using respiratory inductance plethysmography (n=2) and the sense of dyspnoe under the different conditions was assessed by the use of a dyspnea score (DS). The means of BP, SV, SI, TPRI and LVWI did not significantly differ between the resting and the different loading conditions irrespective of the gas that was used. The variability of hemodynamic measures was significant larger during loaded vs. unloaded breathing. Heliox could significantly reduce this degree of variability. In two subjects Heliox could also significantly reduce the PhAng as well as DS. Heliox showed effects on hemodynamic as well as respiratory and subjective variables. These effects can be interpreted as a reduction of the extent of pressure variations in the intrapleural space leading to less impact on hemodynamic variables while breathing Heliox vs. room air in a resistive loading experiment. In the future the combined measurement of hemodynmic variables as well as non-invasive assessment of respiration might shed new light on cardio-respiratory interaction and effects of Heliox during airway obstruction.

[Gender-related differences in pharmacokinetics and pharmacodynamics]. / Geschlechtsspezifische Unterschiede in der Pharmakokinetik und -dynamik von Arzneimitteln.

Following the negative experience with thalidomide, women were excluded from participation in clinical trials with new pharmaceutical agents as far as possible, especially from phase I studies. However, in the early 1990s a body of evidence accumulated suggesting clinically relevant gender-related differences in the efficacy and safety of drugs. Gender-related differences have been shown for the metabolism and the effects of drugs. Gender differences have been described especially for the enzymes of the cytochrome P 450 family, but also for phase II reactions and most recently for P-glycoprotein. Most of these differences observed are only of minor clinical relevance, however may result in an increased rate of adverse drug reactions. Further differences may be based on different receptor/target sensitivities, e. g. the increased sensitivity for drug-induced torsade de pointes arrhythmia in women. In addition, in complex diseases such as heart failure, men and women may develop different mechanisms of counter- regulation requiring different therapeutic approaches. Population-based approaches demonstrate gender differences in the incidence of adverse drug reactions.

Interference of Uzara glycosides in assays of digitalis glycosides.

OBJECTIVE: Presentation of a case report and pharmacokinetic investigation in healthy volunteers on the potential interference between cardiac glycosides and glycosides of Uzara, a herbal antidiarrheal preparation. METHODS: Pharmacokinetic pilot investigation of apparent digitoxin and digoxin serum concentrations in 4 healthy volunteers after single-dose administration of 30 drops Uzara (approximately 1.5 ml approximately = 22 mg glycosides). RESULTS: Maximal apparent serum concentrations of digitoxin between 198.0 microg/l and 919.8 microg/l (therapeutic range: 10-25 microg/l) occurred at 4-8 hours after administration. The terminal half-life of the glycosides was 8.87 +/- 2.20 hours. For digoxin, maximal apparent serum concentrations ranged between 1.4 microg/l and 6.34 microg/l (therapeutic range: 0.9-2.0 microg/l) at 6 hours post dosing. CONCLUSIONS: Administration of a single dose of an Uzara preparation, an over-the-counter product, results in false high serum concentrations of digitoxin and digoxin. As described in the manufacturers Summary of Product Characteristics, this preparation should not be given to patients with cardiac failure or arrhythmia who require treatment with cardiac glycosides because of the demonstrated pharmacological actions of uzara glycosides.

Methods and systems to detect adverse drug reactions in hospitals.

Detection of adverse drug reactions (ADRs) in hospitals offers the chance to detect serious ADRs resulting in hospitalisation and ADRs occurring in hospitalised patients, i.e. patients with high comorbidity and receiving drugs that are administered only in hospitals. The most commonly applied methods involve stimulated spontaneous reporting of doctors and nurses, comprehensive collection by trained specialists and, more recently, computer-assisted approaches using routine data from hospital information systems. The different methods of ADR detection used result in different rates and types of ADRs and, consequently, in different drug classes being responsible for these ADRs. Another factor influencing the results of surveys is the interpretation of the term ADR, where some authors adhere to the strict definition of the World Health Organization and many others include intended and unintended poisoning as well as errors in prescribing and dispensing, thus referring to adverse drug events. Depending on the method used for screening of patients, a high number of possible ADRs and only few definite ADRs are found, or vice versa. These variations have to be taken into account when comparing the results of further analyses performed with these data. ADR rates and incidences in relation to the number of drugs prescribed or patients exposed have been calculated in only a few surveys and projects, and this interesting pharmacoepidemiological approach deserves further study. In addition, the pharmacoeconomic impact of ADRs, either resulting in hospitalisation or prolonging hospital stay, has been estimated using different approaches. However, a common standardised procedure for such calculations has not yet been defined. Although detection of ADRs in hospitals offers the opportunity to detect severe ADRs of newly approved drugs, these ADRs are still discovered by spontaneous reporting systems. The prospects offered by electronic hospital information systems as well as implementation of pharmacoepidemiological approaches increases the possibilities and the value of ADR detection in hospitals.

Pharmacokinetics of viral antibodies after administration of intravenous immunoglobulin in patients with chronic lymphocytic leukaemia or multiple myeloma.

OBJECTIVE: Intravenous immunoglobulin (IVIG) preparations are derived from human pooled plasma and should fulfil high standards of purity and viral safety. Introduction of additional purification steps, however, may result in modulation of the biological properties of immunoglobulins. Since cleavage of the Fab-fragment leads to a significant decrease in half-life, the latter provides information about the integrity of the immunoglobulin G (IgG) molecules. Therefore, a pharmacokinetic study of a novel preparation is required to determine safety and disposition in the target population. METHODS: Twenty-seven patients with chronic lymphocytic leukaemia (CLL) and 12 with multiple myeloma received intravenous infusions of IVIG containing antibodies against hepatitis B virus (anti-HBs; n= 15; 8960 IU), cytomegalovirus (anti-CMV; n = 9; 14,250 U) or varizella-zoster-virus (anti-VZV; n = 15; 6000 IU), respectively. Serum concentrations of viral antibodies were determined for 71 days during and after infusion. RESULTS: Maximum serum concentrations of anti-HBs, anti-CMV and anti-VZV were observed at about 4 h (median) after start of the infusion. Total body clearances came to 0.14 +/- 0.08 ml/min (anti-HBs), 0.10 +/- 0.02 ml/ min (anti-CMV) and 0.14 +/- 0.07 ml/min (anti-VZV). The terminal elimination half-lives were determined to be 25.34 +/- 8.34 days (anti-HBs), 24.66 7.28 days (anti-CMV) and 31.79 +/- 12.47 days (anti-VZV). Clinical chemistry parameters including C3- and C4-complement serum concentrations revealed no pathological changes, seroconversion for hepatitis B and C and HIV did not occur. CONCLUSIONS: The pharmacokinetic parameters of the IgG antibodies calculated after administration of the novel IVIG preparations to patients with CLL and multiple myeloma are in close agreement with data obtained from healthy volunteers and with values of native IgG, suggesting that the production process did not impair clinically relevant characteristics of the viral antibodies.

[Pharmacotherapy of hypertension]. / Pharmakotherapie der Hypertonie.

A large variety of drugs is available for treatment of hypertension. Moreover, many randomised controlled trials with clinically relevant endpoints (morbidity, mortality, quality of life) do exist in the cardiovascular field, providing for sufficient evidence to choose the appropriate agent in most circumstances. For diuretics and betablockers a large body of evidence in terms of beneficial effects on outcome does exist, for ACE-inhibitors in some special indications only. These drugs are therefore recommended as first-line treatments. For calcium-channel blockers (with the exception of isolated systolic hypertension in the elderly) and AT1-receptor-antagonists the results of endpoint-studies are still awaited. These results will have to be considered for revised versions of currently available guidelines.