[Immunosuppressive drugs - how they work, their side effects and interactions]

The central issue in organ transplantation remains suppression of allograft rejection. Immunosuppression can be achieved by depleting lymphocytes, diverting lymphocyte traffic, or blocking lymphocyte response pathways. Immunosuppressive drugs include small-molecule drugs, depleting and nondepleting protein drugs (polyclonal and monoclonal antibodies), fusion proteins, intravenous immune globulin, and glucocorticoids. Small-molecule immunosuppressive agents include calcineurin-inhibitors (cyclosporine, tacrolimus), Target-of-Rapamycin Inhibitors (Sirolimus, Everolimus), inhibitors of nucleotide synthesis and azathioprine. The review covers the mode of action of these drugs with a special focus on belatacept, a new promising fusion protein. Different immuo-suppressive strategies mean also different safety profiles. Common side effects include the consequences of diminished immuno- response, i.e. infections and cancer (mainly involving the skin). Toxic side effects of immunosuppressive drugs range in a wide spectrum that involves almost every organ. The major interest of this toxic effects is the cardiovascular tolerance (with large differences from drug to drug), that are discussed seperately. The calcineurin- and mTOR-inhibitors are both metabolized by the CYP450 3A4 enzyme, which is also involved in the metabolism of many other drugs. The review discusses the most important interactions that in- or decreases the through level of these drugs.

[Drug therapy of acute and chronic abdominal pain]

For drug therapy a differentiation of acute and chronic pain is essential. In emergency situations of acute abdominal pain a fast diagnosis is mandatory. Analgesia should be provided as soon as possible. The different groups of analgesics should be used according to their known effects, side effects and contraindications. Postoperative pain after abdominal surgery has to be considered as a special condition of acute abdominal pain. Main treatment options are non opioid analgesics and opioids. Opioids can be administered intravenously via patient controlled analgesia (PCA) devices. In major abdominal surgery neuroaxial analgesia, preferentially administered via an epidural catheter provides excellent pain relief with positive impact on gastrointestinal motility and patients' recovery. Because of difficulties to allocate chronic abdominal pain to a specific organ, causal treatment often turns out to be difficult. Peripheral and central sensitization, as well as an alteration of the endogenous pain modulation comes to the fore in these chronic pain conditions. Co-analgesics like anticonvulsants and antidepressants are utilized to reduce sensitization and improve the endogenous pain modulating system. Non drug approaches and alternative treatment options might be useful. In contrast, orally or transcutaneously administered opioids are the principal corner stone for the treatment of cancer pain.

[Cosmetic results after breast conserving carcinoma treatment in patients with intramammarian seromas]

INTRODUCTION: There were 373 patients irradiated after breast conserving carcinoma treatment. A planning computed tomography revealed in 97 of these patients seromas and tissue defects exceeding 2cm in diameter. The cosmetic results in those patients and the impact of seromas herein had to be evaluated. PATIENTS AND METHODS: Mean age was 59 years. A quadrant resection was performed in 17.5 percent of the patients, a segmental resection in 27.8 percent and a tumour excision in 54.6 percent. Radiation therapy was applied with the Linear accelerator and 6 MeV photons up to a total dose in the residual breast of 50 Gy followed by a boost dose to the former tumour bed of 10 Gy. A distinct evaluation and documentation of therapy related side effects and the resulting cosmesis was done in 51 patients. RESULTS: In all the examined seroma patients there were moderate acute skin reactions grade 1 to 3. As late effects in 82.3 percent scar indurations were noticed. At the skin 51 percent showed enhanced pigmentation, 68.6 percent atrophia and only 11 percent teleangiectasia. Subcutaneous fibrosis occurred in 56,9 percent of the patients, 78.4 percent of the women had breast asymmetries. In 41.2 percent there were a lymphedema subcutaneously, in 72.5 percent impaired sensibility. The overall cosmetic result documented with a 5 point score was "very good" (score 1) in 19.6 percent and "good" (score 2) in 33.3 percent, 37.3 percent were "satisfactory" (score 3) and 9.8 percent "bad" (score 4) respectively. No "very bad" results (score 5) were seen. CONCLUSIONS: The cosmetic results in the examined group of seroma and hematoma patients were inferior to those reported in the literature. We conclude that postoperative seroma and hematoma have an adverse effect on the resulting cosmesis and that their frequency and extent have to be reduced in future by the responsible surgeons.

Rapid induction of remission in large vessel vasculitis by IL-6 blockade. A case series

OBJECTIVE: To evaluate the effect of IL-6 blockade using tocilizumab in inducing remission of arterial large vessel vasculitides (LVV). METHODS: Five consecutive patients with giant-cell arteritis (GCA) and two with Takayasu’s arteritis (TA) were treated by tocilizumab infusions (8 mg/kg). Tocilizumab was given every other week for the first month and once monthly thereafter. Clinical symptoms of disease activity, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) level and glucocorticoid (GC) dosage necessary to maintain remission were prospectively assessed. MR angiography was performed to monitor local inflammation. RESULTS: Of the seven patients three were newly diagnosed and four showed GC resistance, i.e. GC could not be lowered to less than 7.5 mg/day. The mean follow-up time was 4.3 months (range 3–7 months). All patients achieved a rapid and complete clinical response and normalisation of the acute phase proteins. Remarkably, prednisone dosage could be reduced within 12 weeks to a mean of 2.5 mg/day (range 0–10 mg/day). No relapse and no drug-related side effects were noted. CONCLUSION: Collectively the data suggest that IL-6 blockade using tocilizumab qualifies as a therapeutic option to induce rapid remission in large vessel vasculitides.

Etomidate - a review of robust evidence for its use in various clinical scenarios

Etomidate is an intravenous hypnotic with a favourable clinical profile in haemodynamic high-risk scenarios. Currently, there is an active debate about the clinical significance of the drug's side effects and its overall risk-benefit ratio. Etomidate-induced transient adrenocortical suppression is well documented and has been associated with increased mortality in sepsis. In surgical patients at risk of hypotensive complications, however, a review of current literature provides no robust evidence to contraindicate a single-bolus etomidate induction. Large randomised controlled trials as well as additional observational data are required to compare safety of etomidate and its alternatives.

Adverse side-effects to biological agents

Biological agents-like cytokines, monoclonal antibodies and fusion proteins are widely used in anti-inflammatory and tumour therapy. They are highly efficient in certain diseases, but can cause a great variety of adverse side-effects. Based on the peculiar features of biological agents a new classification of these adverse side-effects of biological agents is proposed - related but clearly distinct from the classification of side-effects observed with chemicals and drugs. This classification differentiates five distinct types, namely clinical reactions because of high cytokine levels (type alpha), hypersensitivity because of an immune reaction against the biological agent (beta), immune or cytokine imbalance syndromes (gamma), symptoms because of cross-reactivity (delta) and symptoms not directly affecting the immune system (epsilon). This classification could help to better deal with the clinical features of these side-effects, to identify possible individual and general risk factors and to direct research in this novel area of medicine.

The complex clinical picture of side effects to biologicals

Biologicals are proteins used as drugs. Biologicals target clearly defined molecular structures, being part of established pathogenetic pathways. Therefore, their focused mode of action seems to render them superior to classic small molecular drugs regarding "off-target" adverse drug reactions (ADR). Nevertheless, the increasing use of biologicals for the treatment of different diseases has revealed partially unexpected adverse reactions. The often direct interaction of a biological with the immune system provides a clue to most side effects, which have consequently been subclassified, based on pathogenetic principles, into 5 subtypes named alpha, beta, gamma, delta, and epsilon, reflecting overstimulation (high cytokine values, type alpha), hypersensitivity (type beta), immune deviation (including immunodeficiency, type gamma), cross-reactivity (type delta), and nonimmune mediated side effects (type epsilon). This article presents typical clinical manifestations of these subtypes of ADR to biologicals, proposes general rules for treating them, and provides a scheme for a thorough allergological workup. This approach should help in future handling of these often very efficient drugs.

Potential drug-drug interactions and adverse drug reactions in patients with liver cirrhosis

Patients with liver cirrhosis may be at risk for potential drug-drug interactions (pDDIs) and/or adverse drug reactions (ADRs) due to the severity of their disease and comorbidities associated with polypharmacy.

Cyclophosphamide: As bad as its reputation? Long-term single centre experience of cyclophosphamide side effects in the treatment of systemic autoimmune diseases

OBJECTIVES Despite new treatment modalities, cyclophosphamide (CYC) remains a cornerstone in the treatment of organ or life-threatening vasculitides and connective tissue disorders. We aimed at analysing the short- and long-term side-effects of CYC treatment in patients with systemic autoimmune diseases. METHODS Chart review and phone interviews regarding side effects of CYC in patients with systemic autoimmune diseases treated between 1984 and 2011 in a single university centre. Adverse events were stratified according to the "Common Terminology Criteria for Adverse Events" version 4. RESULTS A total of 168 patients were included. Cumulative CYC dose was 7.45 g (range 0.5-205 g). Gastro-intestinal side effects were seen in 68 events, hair loss occurred in 38 events. A total of 58 infections were diagnosed in 44/168 patients (26.2%) with 9/44 suffering multiple infections. Severity grading of infections was low in 37/58 cases (63.8%). One CYC-related infection-induced death (0.6%) was registered. Amenorrhoea occurred in 7/92 females (7.6%) with 5/7 remaining irreversible. In females with reversible amenorrhoea, prophylaxis with nafarelin had been administered. Malignancy was registered in 19 patients after 4.7 years (median, range 0.25-22.25) presenting as 4 premalignancies and 18 malignancies, 3 patients suffered 2 premalignancies/malignancies each. Patients with malignancies were older with a higher cumulative CYC dose. Death was registered in 28 patients (16.6%) with 2/28 probably related to CYC. CONCLUSIONS Considering the organ or life-threatening conditions which indicate the use of CYC, severe drug-induced health problems were rare. Our data confirm the necessity to follow-up patients long-term for timely diagnosis of malignancies. CYC side-effects do not per se justify prescription of newer drugs or biologic agents in the treatment of autoimmune diseases.

The well-being model: a new drug interaction model for positive and negative effects

BACKGROUND: Drugs are routinely combined in anesthesia and pain management to obtain an enhancement of the desired effects. However, a parallel enhancement of the undesired effects might take place as well, resulting in a limited therapeutic usefulness. Therefore, when addressing the question of optimal drug combinations, side effects must be taken into account. METHODS: By extension of a previously published interaction model, the authors propose a method to study drug interactions considering also their side effects. A general outcome parameter identified as patient's well-being is defined by superposition of positive and negative effects. Well-being response surfaces are computed and analyzed for varying drugs pharmacodynamics and interaction types. In particular, the existence of multiple maxima and of optimal drug combinations is investigated for the combination of two drugs. RESULTS: Both drug pharmacodynamics and interaction type affect the well-being surface and the deriving optimal combinations. The effect of the interaction parameters can be explained in terms of synergy and antagonism and remains unchanged for varying pharmacodynamics. For all simulations performed for the combination of two drugs, the presence of more than one maximum was never observed. CONCLUSIONS: The model is consistent with clinical knowledge and supports previously published experimental results on optimal drug combinations. This new framework improves understanding of the characteristics of drug combinations used in clinical practice and can be used in clinical research to identify optimal drug dosing.

Effects of an educational patient safety campaign on patients' safety behaviours and adverse events

Rationale, aims and objectives  The study aims to investigate the effects of a patient safety advisory on patients' risk perceptions, perceived behavioural control, performance of safety behaviours and experience of adverse incidents. Method  Quasi-experimental intervention study with non-equivalent group comparison was used. Patients admitted to the surgical department of a Swiss large non-university hospital were included. Patients in the intervention group received a safety advisory at their first clinical encounter. Outcomes were assessed using a questionnaire at discharge. Odds ratios for control versus intervention group were calculated. Regression analysis was used to model the effects of the intervention and safety behaviours on the experience of safety incidents. Results  Two hundred eighteen patients in the control and 202 in the intervention group completed the survey (75 and 77% response rates, respectively). Patients in the intervention group were less likely to feel poorly informed about medical errors (OR = 0.55, P = 0.043). There were 73.1% in the intervention and 84.3% in the control group who underestimated the risk for infection (OR = 0.51, CI 0.31-0.84, P = 0.009). Perceived behavioural control was lower in the control group (meanCon  = 3.2, meanInt  = 3.5, P = 0.010). Performance of safety-related behaviours was unaffected by the intervention. Patients in the intervention group were less likely to experience any safety-related incident or unsafe situation (OR for intervention group = 0.57, CI 0.38-0.87, P = 0.009). There were no differences in concerns for errors during hospitalization. There were 96% of patients (intervention) who would recommend other patients to read the advisory. Conclusions  The results suggest that the safety advisory decreases experiences of adverse events and unsafe situations. It renders awareness and perceived behavioural control without increasing concerns for safety and can thus serve as a useful instrument for communication about safety between health care workers and patients.

Relaxing hydrotherapy WATSU (WaterShiatsu) and its effects in third trimester of pregnancy

Background WATSU (WaterShiatsu) is a bodywork-technique comprising buoyancy, passive stretches, massage, and acupressure that is administered in 35° C warm water. WATSU is believed to exert beneficial effects on pregnancy-related complaints. We conducted a pilot study to test the hypothesis that WATSU treatment during pregnancy can affect low back pain, everyday stress perception, quality of life, tonus of the uterus, amount of amniotic fluid, spontaneous course of breech presentations, and the success rate of external cephalic versions. Methods Healthy women with singleton pregnancies at gestational week 36 were included in our cohort control pilot trial. Participants in the treatment group (n = 8) received a standardized WATSU-treatment on their first and fourth day of study participation, while participants in the control group were in a waiting condition. Participants underwent ultrasound investigations and completed quantitative and qualitative questionnaires before and after intervention, as well as weekly until birth. Results In contrast to the control group, participants in the WATSU-treatment group reported significant relief of low back pain and stress. After WATSU treatment spontaneous version out of breech position occurred once in seven cases, and external cephalic version was successful in two out of three cases. As qualitative data indicate, WATSU was appreciated as a deep relaxing and enjoyable treatment method. No negative side-effects or adverse events were reported. Conclusion The findings from our pilot-study support the notion that WATSU might yield therapeutic benefits for pregnant women and warrant further research.

Patient information leaflets: informing or frightening? A focus group study exploring patients' emotional reactions and subsequent behavior towards package leaflets of commonly prescribed medications in family practices.

BACKGROUND The purpose of patient information leaflets (PILs) is to inform patients about the administration, precautions and potential side effects of their prescribed medication. Despite European Commission guidelines aiming at increasing readability and comprehension of PILs little is known about the potential risk information has on patients. This article explores patients' reactions and subsequent behavior towards risk information conveyed in PILs of commonly prescribed drugs by general practitioners (GPs) for the treatment of Type 2 diabetes, hypertension or hypercholesterolemia; the most frequent cause for consultations in family practices in Germany. METHODS We conducted six focus groups comprising 35 patients which were recruited in GP practices. Transcripts were read and coded for themes; categories were created by abstracting data and further refined into a coding framework. RESULTS Three interrelated categories are presented: (i) The vast amount of side effects and drug interactions commonly described in PILs provoke various emotional reactions in patients which (ii) lead to specific patient behavior of which (iii) consulting the GP for assistance is among the most common. Findings show that current description of potential risk information caused feelings of fear and anxiety in the reader resulting in undesirable behavioral reactions. CONCLUSIONS Future PILs need to convey potential risk information in a language that is less frightening while retaining the information content required to make informed decisions about the prescribed medication. Thus, during the production process greater emphasis needs to be placed on testing the degree of emotional arousal provoked in patients when reading risk information to allow them to undertake a benefit-risk-assessment of their medication that is based on rational rather than emotional (fearful) reactions.

Should the standard dimethyl sulfoxide concentration be reduced? Results of a European Group for Blood and Marrow Transplantation prospective noninterventional study on usage and side effects of dimethyl sulfoxide.

BACKGROUND Dimethyl sulfoxide (DMSO) is essential for the preservation of liquid nitrogen-frozen stem cells, but is associated with toxicity in the transplant recipient. STUDY DESIGN AND METHODS In this prospective noninterventional study, we describe the use of DMSO in 64 European Blood and Marrow Transplant Group centers undertaking autologous transplantation on patients with myeloma and lymphoma and analyze side effects after return of DMSO-preserved stem cells. RESULTS While the majority of centers continue to use 10% DMSO, a significant proportion either use lower concentrations, mostly 5 or 7.5%, or wash cells before infusion (some for selected patients only). In contrast, the median dose of DMSO given (20 mL) was much less than the upper limit set by the same institutions (70 mL). In an accompanying statistical analysis of side effects noted after return of DMSO-preserved stem cells, we show that patients in the highest quartile receiving DMSO (mL and mL/kg body weight) had significantly more side effects attributed to DMSO, although this effect was not observed if DMSO was calculated as mL/min. Dividing the myeloma and lymphoma patients each into two equal groups by age we were able to confirm this result in all but young myeloma patients in whom an inversion of the odds ratio was seen, possibly related to the higher dose of melphalan received by young myeloma patients. CONCLUSION We suggest better standardization of preservation method with reduced DMSO concentration and attention to the dose of DMSO received by patients could help reduce the toxicity and morbidity of the transplant procedure.

Older Breast Cancer Survivors: Geriatric Assessment Domains Are Associated With Poor Tolerance of Treatment Adverse Effects and Predict Mortality Over 7 Years of Follow-Up

Purpose To evaluate geriatric assessment (GA) domains in relation to clinically important outcomes in older breast cancer survivors. Methods Six hundred sixty women diagnosed with primary breast cancer in four US geographic regions (Los Angeles, CA; Minnesota; North Carolina; and Rhode Island) were selected with disease stage I to IIIA, age ≥ 65 years at date of diagnosis, and permission from attending physician to contact. Data were collected over 7 years of follow-up from consenting patients' medical records, telephone interviews, physician questionnaires, and the National Death Index. Outcomes included self-reported treatment tolerance and all-cause mortality. Four GA domains were described by six individual measures, as follows: sociodemographic by adequate finances; clinical by Charlson comorbidity index (CCI) and body mass index; function by number of physical function limitations; and psychosocial by the five-item Mental Health Index (MHI5) and Medical Outcomes Study Social Support Survey (MOS-SSS). Associations were evaluated using t tests, χ2 tests, and regression analyses. Results In multivariable regression including age and stage, three measures from two domains (clinical and psychosocial) were associated with poor treatment tolerance; these were CCI ≥ 1 (odds ratio [OR] = 2.49; 95% CI, 1.18 to 5.25), MHI5 score less than 80 (OR = 2.36; 95% CI, 1.15 to 4.86), and MOS-SSS score less than 80 (OR = 3.32; 95% CI, 1.44 to 7.66). Four measures representing all four GA domains predicted mortality; these were inadequate finances (hazard ratio [HR] = 1.89; 95% CI, 1.24 to 2.88; CCI ≥ 1 (HR = 1.38; 95% CI, 1.01 to 1.88), functional limitation (HR = 1.40; 95% CI, 1.01 to 1.93), and MHI5 score less than 80 (HR = 1.34; 95% CI, 1.01 to 1.85). In addition, the proportion of women with these outcomes incrementally increased as the number of GA deficits increased. Conclusion This study provides longitudinal evidence that GA domains are associated with poor treatment tolerance and predict mortality at 7 years of follow-up, independent of age and stage of disease.