Psychoneuroendocrinological effects of music therapy versus mindfulness in palliative care: results from the 'Song of Life' randomized controlled trial.

PURPOSE: Although research on psychosocial interventions in palliative care provided evidence for their effectiveness regarding patient-reported outcomes, few studies have examined their psychobiological effects yet. Therefore, the purpose of the present work as part of an overarching study was to investigate differential effects of music therapy versus mindfulness on subjective distress and both neuroendocrine and autonomic stress biomarkers. METHODS: A total of 104 patients from two palliative care units were randomly assigned to three sessions of either music therapy or mindfulness. Before and after the second session (completed by 89 patients), participants rated their momentary distress and provided three saliva samples for cortisol and α-amylase analysis. Furthermore, photoplethysmography recordings were continuously assessed to calculate mean heart rate and heart rate variability. Data were analyzed using multilevel modeling of all available data and sensitivity analysis with multiply imputed data. RESULTS: Between 67 and 75% of the maximally available data points were included in the primary analyses of psychobiological outcomes. Results showed a significant time*treatment effect on distress (b = - 0.83, p = .02) indicating a greater reduction in the music therapy group. No interaction effects were found in psychobiological outcomes (all p > .05), but multilevel models revealed a significant reduction in cortisol (b = - 0.06, p = .01) and mean heart rate (b = - 7.89, p = .05) over time following either intervention. CONCLUSION: Findings suggest a beneficial effect music therapy on distress while no differential psychobiological treatment effects were found. Future studies should continue to investigate optimal stress biomarkers for psychosocial palliative care research. TRIAL REGISTRATION: German Clinical Trials Register (DRKS)-DRKS00015308 (date of registration: September 7, 2018).

Characteristics of salivary cortisol and alpha-amylase as psychobiological study outcomes in palliative care research.

BACKGROUND: Psychosocial interventions are rapidly emerging in palliative care. However, randomized trials often fail to provide evidence for their effectiveness with regard to patient-reported outcomes. Stress biomarkers could complement self-report data, but little is known about their feasibility, acceptance, and interpretability. METHODS: Therefore, we designed a randomized crossover trial in which 42 patients in a palliative care unit participated in both a brief mindfulness intervention (MI) and a resting state control condition (CC) on two consecutive afternoons. On each day, we collected four saliva samples in 20-min intervals using Salivettes© to determine salivary cortisol (sCort) and alpha-amylase (sAA) concentration levels. At all measurement points, self-rated well-being and stress as well as cardiovascular markers were assessed. Baseline measurements further included self-rated quality of life and clinician-rated functional status. RESULTS: 78.6% of the patients provided the maximum number of 8 saliva samples and 62.2% reported no subjective difficulties with the sampling procedures. 66.6% (sCort) and 69.6% (sAA) of all possible samples were finally included in the analysis. Xerostomia and nausea were the main reasons for missing data. Higher sCort levels were associated with higher heart rate and lower quality of life, functional status, and heart rate variability. Corticosteroid and sedative medication as well as time since last meal were identified as potential confounders. Regarding reactivity to the MI, we found an overall decrease in sCort levels over time (b = -.03, p = .01), but this effect did not differ significantly between the study conditions (b = .03, p = .21). sAA levels were higher in men than in women. Trajectories over time did not significantly differ between the two conditions (b = -.02, p = .80) and associations with other stress and health-related constructs were weak. CONCLUSIONS: Findings indicate that sCort might serve as a psychobiological outcome in future palliative care trials. However, future research should refine the exact measurement and conceptualization strategies for sCort in palliative care research. High attrition rates should be expected in patients with xerostomia or nausea. TRIAL REGISTRATION: Registered at the German Clinical Trials Registry (DRKS00013135) at 04/12/2017.

"Song of Life": Results of a multicenter randomized trial on the effects of biographical music therapy in palliative care.

BACKGROUND: Awareness for the importance of psychological and spiritual needs in patients with terminal diseases has increased in recent years, but randomized trials on the effects of psychosocial interventions are still rare. AIM: To investigate the efficacy of the "Song of Life" music therapy intervention regarding the emotional and psycho-spiritual dimensions of quality of life. DESIGN: Patients were randomly assigned to either "Song of Life" or a relaxation intervention. "Song of Life" is a novel three-session music therapy intervention working with a biographically meaningful song. Primary outcome was the improvement in psychological quality of life. Secondary outcomes included spiritual well-being, ego-integrity, momentary distress, and global quality of life and the explorative assessment of treatment satisfaction (patient and family member version). Intention-to-treat analysis was conducted including adjustment for multiple testing in secondary outcomes. SETTING/PARTICIPANTS: Between December 2018 and August 2020, 104 patients receiving specialized palliative care were recruited from two palliative care wards. RESULTS: No significant differences were found regarding psychological and global quality of life, but "Song of Life" participants reported significantly higher spiritual well-being (p = 0.04) and ego-integrity (p < 0.01), as well as lower distress (p = 0.05) than patients in the control group. Both patients' and family members' treatment satisfaction was higher after "Song of Life" with large between-group effect sizes on items asking for meaningfulness (d = 0.96) and importance (d = 1.00). CONCLUSIONS: Our findings provide evidence that "Song of Life" is an effective and meaningful biographical music therapy intervention to facilitate psycho-spiritual integration in terminally ill patients. TRIAL REGISTRATION: German Clinical Trials Register (DRKS)-DRKS00015308 (date of registration: September 7th 2018).

Stress-reducing effects of a brief mindfulness intervention in palliative care: Results from a randomised, crossover study.

OBJECTIVE: Mindfulness-based interventions are a widely used and highly accepted adjunct treatment in oncology. Due to a paucity of research in advanced cancer and other terminal illnesses, we aimed to evaluate the stress-reducing effects of a brief, standardised mindfulness intervention for use in palliative care. METHODS: This study was a randomised, crossover trial where patients participated in both a single mindfulness intervention and a resting state control condition. The order of the conditions was randomised. Study outcomes encompassed self-report data on stress and well-being and measures of heart rate variability. All outcome data were measured at four times per day. RESULTS: Forty-two patients participated in this study. We found significantly stronger reductions in self-rated stress and mean heart rate as well as an increase in heart rate variability after the mindfulness intervention. Psychophysiological effects were strongest in the immediate pre- to post-intervention comparison, while the effect on subjective stress persisted after 20 to 40 min. No significant differences were found for self-rated well-being. CONCLUSIONS: Despite the rather small magnitude of effects, the brief mindfulness intervention showed to be effective and accepted by patients in very advanced stages of a disease and could be offered by trained healthcare professionals in palliative care.

Alteration of drug-metabolizing enzyme activity in palliative care patients: Microdosed assessment of cytochrome P450 3A.

BACKGROUND: Cytochrome P450 3A is the most relevant drug-metabolizing enzyme in humans as it is involved in the elimination of 50% of marketed drugs. Nothing is known about the activity of cytochrome P450 3A in palliative care patients who have complicated symptoms often associated with a terminal illness. AIM: In order to improve drug dosing in end-of-life care and to avoid drug interactions, cytochrome P450 3A activity was determined in patients of a palliative care unit under real-life clinical conditions. DESIGN: As midazolam is an established marker substance for cytochrome P450 3A activity, this single-arm prospective trial was designed to obtain a 4-h pharmacokinetic profile of midazolam after oral administration of a 10-µg dose from each enrolled patient. Plasma concentrations of midazolam and its primary metabolite 1'-hydroxy-midazolam were quantified by mass spectrometry techniques. Cytochrome P450 3A activity was calculated as partial metabolic clearance from a limited sampling area under the curve. All other drugs taken by the participating patients were considered, as well as recent blood test results and patients' diagnoses. The trial was registered at German Clinical Trials Register ( www.drks.de ): DRKS00011753. SETTING/PARTICIPANTS: The trial was carried out at a university palliative care unit under real-life clinical conditions. Every patient admitted to the ward was screened for possible participation, independent of the individual performance status. RESULTS: Partial metabolic clearance of midazolam in palliative care patients was 31.7 ± 32.1 L/h. This was a highly significant 40% reduction (p < 0.0001) in comparison with the cytochrome P450 3A activity of healthy subjects. CONCLUSION: Dosing of cytochrome P450 3A substrate drugs (e.g. macrolide antibiotics, benzodiazepines, calcium channel blockers) needs to be adjusted in palliative care patients; otherwise, escalation of debilitating symptoms due to drug interactions might occur.

"Song of Life (SOL)" study protocol: a multicenter, randomized trial on the emotional, spiritual, and psychobiological effects of music therapy in palliative care.

BACKGROUND: Although patients in palliative care commonly report high emotional and spiritual needs, effective psychosocial treatments based on high quality studies are rare. First research provides evidence for benefits of psychosocial interventions in advanced cancer care. To specifically address end-of-life care requirements, life review techniques and creative-arts based therapies offer a promising potential. Therefore, the present study protocol presents a randomized controlled trial on the effectiveness of a newly developed music therapy technique that is based on a biographically meaningful song ("Song of Life"; SOL). METHODS: In a design with two parallel arms, 104 patients at two palliative care units will be randomly assigned to three sessions of either SOL (experimental group) or relaxation exercises (control group). Improvements in the psychological domain of quality of life will be the primary endpoint, while secondary outcomes encompass spiritual well-being, ego-integrity, overall quality of life, and distress. Additionally, caregivers will be asked to provide feedback about the treatment. Assessment of biopsychological stress markers and qualitative analysis of perceived strengths and weaknesses will complement data collection. DISCUSSION: Based on the results of a previous pilot study, we dedicated considerable efforts to optimizing the intervention and selecting appropriate outcomes for the present trial. We are confident to have designed a methodologically rigorous study that will contribute to the evidence-base and help to develop the potential of psychosocial interventions in palliative care. TRIAL REGISTRATION: German Clinical Trials Register (DRKS) - DRKS00015308 (date of registration: September 07th 2018).

Chronic Hiccups: An Underestimated Problem.

Persistent singultus, hiccupping that lasts for longer than 48 hours, can have a tremendous impact on a patient's quality of life. Although involved neurologic structures have been identified, the function of hiccups remains unclear-they have been controversially interpreted as a primitive reflex preventing extent swallowing of amniotic fluid in utero, an archaic gill ventilation pattern, or a fetus' preparation for independent breathing. Persistent singultus often presents as a symptom for various diseases, most commonly illnesses of the central nervous system or gastrointestinal tract; they can also be evoked by a variety of pharmacological agents. It is often impossible to define a singular cause. A wide range of treatment attempts, pharmacological and nonpharmacological, have been concerted to this date; however, chlorpromazine remains the only Food and Drug Administration-approved drug in this context. Large-scale studies on efficacy and tolerance of other therapeutic strategies are lacking. Gabapentin, baclofen, and metoclopramide have been reported to accomplish promising results in reports on the therapy of persistent singultus; they may also be effective when given in combination with other drugs, eg, proton pump inhibitors, or as conjoined therapy. As another approach of note, acupuncture treatment was able to abolish hiccups in a number of studies. When managing hiccup patients within the clinical routine, it is of importance to conduct a comprehensive and effective diagnostic workup; a well-functioning interdisciplinary team is needed to address possible causes for the symptom. Persistent singultus is a medical problem not to be underestimated; more research on options for effective treatment would be greatly needed.

Bleeding Control in Palliative Care Patients With the Help of Tranexamic Acid.

BACKGROUND: Persistent bleeding is a common reason for admitting patients with advanced cancer to a palliative care unit. Several reports show a successful therapeutic use of the antifibrinolytic agent tranexamic acid in palliative care patients having hemorrhages. However, it is not administered routinely in severe bleeding situations in palliative care, and general dosing recommendations are unclear. CASE PRESENTATION: We report on 3 patients who were treated with tranexamic acid due to symptomatic hemorrhage complicating different malignant processes. Case Management and Outcome: A dosing regimen of 1000 mg intravenous tranexamic acid 3 times a day caused an arrest of bleeding in the reported patients within 2 to 3 days. Having controlled the acute bleeding, we continued with an oral administration of 3000 mg per day as maintenance dose. CONCLUSIONS: The described dosing regimen was effective in controlling the symptomatic bleeding of the reported patients. Further studies are needed to get evidence-based information on the optimal dosing regimen of tranexamic acid and to emphasize its significance in palliative medicine.

Education in End-of-Life Care: What Do Experienced Professionals Find Important?

End-of-life care is an essential element of quality cancer care. Nevertheless, a majority of physicians and nurses working at cancer centers feel unprepared for this task. As part of a larger survey study, we investigated what suggestions experienced physicians and nurses have to improve education/training on end-of-life care. In an open question, participants were requested to suggest changes to the end-of-life curriculum for physicians and nurses. Answers to this question were content analyzed using the qualitative data analysis software MAXQDA. Physicians and nurses at 10 cancer centers throughout Baden-Wuerttemberg were surveyed. From the total 1131 survey participants, 675 (483 nurses, 167 physicians, 25 unknown) responded to the open question regarding suggestions for education/training in end-of-life care. Two main categories were inductively developed: (1) format (i.e., structure and method of teaching) and (2) content (i.e., knowledge and know-how required for care of the dying). Regarding format, both professional groups most often wished for more practical experiences with dying patients (e.g., internships at hospices). Regarding content, physicians and nurses most frequently requested (1) more basic information on palliative care, (2) increased skills training in communication, and (3) knowledge of how to appropriately care for patients' caregivers. The results of our analysis reflect already trained physicians' and nurses' interest in furthering their knowledge and skills to care for dying patients. The suggestions of experienced physicians and nurses should be integrated into the further development of palliative care curricula.

Early Palliative Care-Health services research and implementation of sustainable changes: the study protocol of the EVI project.

BACKGROUND: International medical organizations such as the American Society of Medical Oncology recommend early palliative care as the "gold standard" for palliative care in patients with advanced cancer. Nevertheless, even in Comprehensive Cancer Centers, early palliative care is not yet routine practice. The main goal of the EVI project is to evaluate whether early palliative care can be implemented-in the sense of "putting evidence into practice"-into the everyday clinical practice of Comprehensive Cancer Centers. In addition, we are interested in (1) describing the type of support that patients would like from palliative care, (2) gaining information about the effect of palliative care on patients' quality of life, and (3) understanding the economic burden of palliative care on patients and their families. METHODS/DESIGN: The EVI project is a multi-center, prospective cohort study with a sequential control group design. The study is a project of the Palliative Care Center of Excellence (KOMPACT) in Baden-Württemberg, Germany, which was recently established to combine the expertise of five academic, specialist palliative care departments. The study is divided into two phases: preliminary phase (months 1-9) and main study phase (months 10-18). In each of all five participating academic Comprehensive Cancer Centers, an experienced palliative care physician will be hired for 18 months. During the preliminary phase, the physician will be allowed time to establish the necessary structures for early palliative care within the Comprehensive Cancer Center. In the main study phase, patients with metastatic cancer will be offered a consultation with the palliative care physician within eight weeks of diagnosis. After the initial consultation, follow-up consultations will be offered as needed. The study is built upon a convergent parallel design. In the quantitative arm, patients will be surveyed in both the preliminary and main study phase at three points in time (baseline, 12 weeks, 24 weeks). Standardized questionnaires will be used to measure patients' quality of life, symptom burden and mood. Using interviews with palliative care physicians, oncologists, department heads, patients and their caregivers, the qualitative arm will explore (1) what factors encourage and hinder the early integration of palliative care into standard oncology care, (2) what support patients and their caregivers would like from palliative care, and (3) what effect palliative care has on the economic disease burden of patients and their families. DISCUSSION: The study proposed is meant to serve as a catalyzer. Local palliative care teams should be put in position to routinely cooperate with the primary treating department at their respective cancer center. The long-term goal of this project is to create sustainable improvements in the care of patients with incurable cancer. TRIAL REGISTRATION: DRKS00006162 ; date of registration: 19/05/2014.

Effects of vibroacoustic stimulation in music therapy for palliative care patients: a feasibility study.

BACKGROUND: The present study aimed at examining whether methodological strategies from a previously implemented study design could be transferred to the evaluation of the psychological and physiological effects of a music therapy intervention working with vibroacoustic stimulation in palliative care. METHOD: Nine participants suffering from advanced cancer took part in single-sessions of music therapy, lasting for 30 min. The live music therapy intervention utilized singing chair sounds and vocal improvisation. Visual analogue scales (VAS) were used to assess self-ratings of pain, relaxation, and well-being before and after each session. During the intervention, we continuously recorded heart rate variability (HRV) as a measure of autonomic functioning. Data collection was complemented by a semi-structured interview to explore subjective experiences in more detail. Feasibility was defined as the ability to complete 80 % of the sessions in accordance with the study protocol. RESULTS: In 5 out of 9 sessions (55 %) it was possible to deliver the intervention and obtain all data as intended. VAS assessment was feasible, although graphical and statistical examination revealed only marginal mean changes between pre and post. HRV recordings were subject to artifacts. While HRV parameters differed between individuals, mean changes over time remained relatively constant. Interview data confirmed that the individual perception was very heterogeneous, ranging from "calming" to "overwhelming". CONCLUSION: The criterion of feasibility was not met in this study. Physiological data showed high attrition rates, most likely due to movement artifacts and reduced peripheral blood flow in some participants' extremities. Examination of individual-level trajectories revealed that vibroacoustic stimulation may have an impact on the autonomic response. However, the direction and mechanisms of effects needs to be further explored in future studies. TRIAL REGISTRATION: German Clinical Trials Register - DRKS00006137 (July 4(th), 2014).

Dying in cancer centers: do the circumstances allow for a dignified death?

BACKGROUND: Prior research has shown that hospitals are often ill-prepared to provide care for dying patients. This study assessed whether the circumstances for dying on cancer center wards allow for a dignified death. METHODS: In this cross-sectional study, the authors surveyed physicians and nurses in 16 hospitals belonging to 10 cancer centers in Baden-Wuerttemberg, Germany. A revised questionnaire from a previous study was used, addressing the following topics regarding end-of-life care: structural conditions (ie, rooms, staff), education/training, working environment, family/caregivers, medical treatment, communication with patients, and dignified death. RESULTS: In total, 1131 surveys (response rate = 50%) were returned. Half of the participants indicated that they rarely have enough time to care for dying patients, and 55% found the rooms available for dying patients unsatisfactory. Only 19% of respondents felt that they had been well-prepared to care for the dying (physicians = 6%). Palliative care staff reported much better conditions for the dying than staff from other wards (95% of palliative care staff indicated that patients die in dignity on their ward). Generally, physicians perceived the circumstances much more positively than nurses, especially regarding communication and life-prolonging measures. Overall, 57% of respondents believed that patients could die with dignity on their ward. CONCLUSIONS: Only about half of the respondents perceived that a dignified death is possible on their ward. We recommend that cancer centers invest more in staffing, adequate rooms for dying patients, training in end-of-life care, advance-care planning standards, and the early integration of specialist palliative care services.

Music therapy to promote psychological and physiological relaxation in palliative care patients: protocol of a randomized controlled trial.

BACKGROUND: Music therapy is one of the most frequently used complementary therapies in different palliative care settings. Despite its long tradition and high acceptance by other health-care professionals, evidence on the effectiveness of music therapy interventions for terminally ill patients is rare. Recent reviews and health-care reports consistently point out the need of music therapists to provide an evidence-based rationale for their clinical treatments in this field. Therefore, the present study evaluates the psychological and physiological response of palliative care patients to a standardized music therapy relaxation intervention in a randomized controlled trial. METHODS/DESIGN: A sample of 84 participants from a palliative care unit in Heidelberg is randomized to either two sessions of music therapy or two sessions of a verbal relaxation exercise, each lasting 30 minutes. The music therapy sessions consist of live played monochord music and a vocal improvisation, the control group uses a prerecorded excerpt from the mindfulness-based stress reduction program containing no musical elements. Outcome measures include self-report data on subjective relaxation, well-being, pain intensity, and quality of life, as well as continuous recording of heart rate variability and blood volume pulse as indicators of autonomous nervous system functioning. DISCUSSION: To our knowledge, this study is the first clinical trial in Europe and one of very few randomized controlled trials worldwide to systematically examine the effects of music therapy in palliative care. TRIAL REGISTRATION: German Clinical Trials Register - DRKS00006137.

Predictors of survival in sepsis: what is the best inflammatory marker to measure?

PURPOSE OF REVIEW: Sepsis is relevant due to its high morbidity and mortality. For both sepsis diagnosis and outcome prediction many biomarkers have been described in the literature. Most of these markers are objects of scientific interest rather than being introduced into daily clinical practice. However, due to their unspecific character and their insufficient predictive value for the individual person, research focus is still on new aspects in sepsis-related biomarkers. RECENT FINDINGS: Beyond the widely used acute-phase proteins C-reactive protein (CRP) and procalcitonin (PCT), many new molecules have been studied deriving from different organs or cells affected, due to the systemic nature of sepsis. Cytokines, coagulation factors/characteristics, vasoactive hormones, and several others have been recently proved to be relevant in sepsis syndrome and probably useful for outcome prediction. However, single time point measurements may be less predictive than consideration of the time-dependent course of parameters. Clinical decision just based on a biomarker is still not feasible because of the huge inter-individual differences in the inflammatory response. SUMMARY: Many biomarkers display relevant correlation with the clinical outcome of patients with severe sepsis and septic shock. Consideration of their time courses may be more reliable than absolute levels. Clinical decision should not be based only on biomarkers but organ dysfunctions, for example, should also be taken into account.

Lipid peroxidation in acute respiratory distress syndrome and liver failure.

BACKGROUND: Lipid peroxidation processes (LPO) are evident in many organ failures. Due to their toxic properties, they are causative for cellular dysfunction at the site of their origin and far beyond. This study was conducted to investigate differences in LPO pattern of patients with established acute respiratory distress syndrome (ARDS) and patients with end-stage liver failure undergoing liver transplantation (LTX) as two mayor prototypes of organ failure. METHODS: In this prospective, nonrandomized, controlled trial, we examined LPO by measuring malondialdehyde (MDA), and the volatile aldehydes hexanal and propanal as LPO-markers. Eighteen patients with ARDS, 16 subjects undergoing liver transplantation due to liver failure, and 8 healthy controls were included to the study. RESULTS: ARDS patients showed significantly higher levels in MDA concentrations than LTX and controls, respectively. However, MDA levels of patients with end-stage liver failure were equal to those of controls. Blood concentrations of hexanal and propanal, specific by-products of lipid peroxidation, were elevated in both patient groups, but significantly higher only in LTX. Unexpectedly, hexanal and propanal concentrations were significantly higher in LTX than in ARDS patients. In both patient groups, MDA showed no differences between arterial and mixed venous blood, whereas volatile aldehydes were higher in arterial than in mixed venous compartment. CONCLUSIONS: Both ARDS and LTX-patients showed significant evidence of enhanced LPO. However, proportions of MDA and volatile aldehydes differed substantially between the groups. Thus, for the interpretation of LPO markers, disease-specific factors have to be taken into account. Distinctions might be attributable to differences in the effected lipid components or variations in metabolism.

The effect of endothelin-1 on alveolar fluid clearance and pulmonary edema formation in the rat.

BACKGROUND: Endothelin-1 (ET-1) is thought to play a pivotal role in pulmonary edema formation. The underlying mechanisms remain uncertain but may include alterations in capillary pressure and vascular permeability. There are no studies investigating whether ET-1 also affects alveolar fluid clearance which is the primary mechanism for the resolution of pulmonary edema. Therefore, we performed this study to clarify effects of ET-1 on alveolar reabsorption and fluid balance in the rat lung. METHODS: Alveolar fluid clearance was measured in fluid instilled rat lungs using a 5% albumin solution with or without ET-1 (10(-7) M) and/or amiloride (100 microM). Net alveolar fluid balance, time course of edema formation, pulmonary capillary pressure, and alveolar permeability to albumin were measured in the isolated, ventilated, constant pressure perfused rat lung with or without ET-1 (0.8 nM) added to the perfusate. RESULTS: In the fluid-instilled lung, ET-1 reduced alveolar fluid clearance by about 65%, an effect that was related to a decrease in amiloride-sensitive transepithelial Na(+) transport (P < 0.001). The ET-1-induced inhibition was completely prevented by the endothelin B receptor antagonist BQ788 (P = 0.006), whereas the endothelin A receptor antagonist BQ123 had no effect (P = 0.663). In the isolated, ventilated, perfused rat lung ET-1 caused a net accumulation of alveolar fluid by about 20% (P = 0.011 vs control), whereas lungs of control rats cleared about 20% of the instilled fluid. ET-1 increased pulmonary capillary pressure (+9.4 cm H(2)O), decreased perfusate flow (-81%), accelerated lung weight gain and reduced lung survival time (P < 0.001). Permeability to albumin was not significantly affected by ET-1 (P = 0.24). CONCLUSION: ET-1 inhibits alveolar fluid clearance of anesthetized rats by inhibition of amiloride-sensitive epithelial Na(+) channels. The inhibitory effect of ET-1 results from activation of the endothelin B receptor. These findings suggest a mechanism by which ET-1, in addition to increasing capillary pressure, contributes to pulmonary edema formation.

Decreased Cytochrome P450 3A activity in palliative patients with haematological diseases: Potential impact on supportive drug therapies.

Cytochrome P450 3A (CYP3A) is the most relevant drug-metabolizing enzyme in human beings involved in the elimination of about 50% of the marketed drugs. Comprehensive in vivo data of CYP3A activity in palliative patients with haematological diseases are missing. Therefore, CYP3A activity was determined under real-life clinical conditions in patients to gain knowledge about dose adjustments for supportive therapies and symptom management in haematology. The single-arm, prospective trial obtained a 4-hours pharmacokinetic profile of midazolam after oral administration of a microdose as marker substance from each enrolled patient. Plasma concentrations of midazolam and its primary metabolite 1'-hydroxy-midazolam were quantified by mass spectrometry techniques. CYP3A activity was calculated as partial metabolic clearance from an established limited sampling area under the curve. All other drugs taken by the participating patients were considered as well as recent laboratory test results and the patients' diagnoses. Partial metabolic clearance of midazolam in patients with haematological diseases was highly variable (36.9 ± 52.7 L/h). In comparison with the CYP3A activity of healthy individuals, this was a highly significant 30% reduction of activity (P < 0.0001). Dosing of major CYP3A substrate drugs needs to be reduced in palliative patients with haematological diseases, otherwise escalation of debilitating symptoms due to drug interactions might occur.

Minor contribution of cytochrome P450 3A activity on fentanyl exposure in palliative care cancer patients.

Transdermal fentanyl is widely used to control pain in cancer patients. The high pharmacokinetic variability of fentanyl is assumed to be due to cytochrome P450 3A-mediated (CYP3A) N-dealkylation to norfentanyl in humans. However, recently published clinical studies question the importance of the described metabolic pathway. In this small study in palliative cancer patients under real-life clinical conditions, the influence of CYP3A on fentanyl variability was investigated. In addition to the determination of midazolam plasma concentration to reveal CYP3A activity, plasma concentrations of fentanyl and its metabolite, norfentanyl, were measured in identical blood samples of 20 patients who participated in an ongoing trial and had been on transdermal fentanyl. Fentanyl, norfentanyl, midazolam, and 1'-OH-midazolam were quantified by liquid chromatography/tandem mass spectrometry. Plasma concentrations of fentanyl and norfentanyl exhibited a large variability. Mean estimated total clearance of fentanyl and mean metabolic clearance of midazolam (as a marker of CYP3A activity) were 75.5 and 36.3 L/h. Both clearances showed a weak correlation and hence a minimal influence of CYP3A on fentanyl elimination.

The adenosine deaminase inhibitor erythro-9-[2-hydroxyl-3-nonyl]-adenine decreases intestinal permeability and protects against experimental sepsis: a prospective, randomised laboratory investigation.

INTRODUCTION: The treatment of septic conditions in critically ill patients is still one of medicine's major challenges. Cyclic nucleotides, adenosine and its receptors play a pivotal role in the regulation of inflammatory responses and in limiting inflammatory tissue destruction. The aim of this study was to verify the hypothesis that adenosine deaminase-1 and cyclic guanosine monophosphate-stimulated phosphodiesterase inhibition by erythro-9-[2-hydroxyl-3-nonyl]-adenine could be beneficial in experimental endotoxicosis/sepsis. METHOD: We used two established animal models for endotoxicosis and sepsis. Twenty-four male Wistar rats that had been given intravenous endotoxin (Escherichia coli lipopolysaccharide) were treated with either erythro-9-[2-hydroxyl-3-nonyl]-adenine infusion or 0.9% saline during a study length of 120 minutes. Sepsis in 84 female C57BL/6 mice was induced by caecal ligation and puncture. Animals were treated with repeated erythro-9-[2-hydroxyl-3-nonyl]-adenine injections after 0, 12 and 24 hours or 4, 12 and 24 hours for delayed treatment. RESULTS: In endotoxaemic rats, intestinal production of hypoxanthine increased from 9.8 +/- 90.2 micromol/l at baseline to 411.4 +/- 124.6 micromol/l and uric acid formation increased from 1.5 +/- 2.3 mmol/l to 13.1 +/- 2.7 mmol/l after 120 minutes. In endotoxaemic animals treated with erythro-9-[2-hydroxyl-3-nonyl]-adenine, we found no elevation of adenosine metabolites. The lactulose/L-rhamnose ratio (14.3 versus 4.2 in control animals; p = 2.5 x 10(-7)) reflects a highly permeable small intestine and through the application of erythro-9-[2-hydroxyl-3-nonyl]-adenine, intestinal permeability could be re-established. The lipopolysaccharide animals had decreased L-rhamnose/3-O-methyl-D-glucose urine excretion ratios. Erythro-9-[2-hydroxyl-3-nonyl]-adenine reduced this effect. The mucosa damage score of the septic animals was higher compared with control and therapy animals (p < 0.05). Septic shock induction by caecal ligation and puncture resulted in a 160-hour survival rate of about 25%. In contrast, direct adenosine deaminase-1 inhibition resulted in a survival rate of about 75% (p = 0.0018). A protective effect was still present when erythro-9-[2-hydroxyl-3-nonyl]-adenine treatment was delayed for four hours (55%, p = 0.029). CONCLUSIONS: We present further evidence of the beneficial effects achieved by administering erythro-9-[2-hydroxyl-3-nonyl]-adenine, an adenosine deaminase-1 and cyclic guanosine monophosphate-stimulated phosphodiesterase inhibitor, in an endotoxicosis and sepsis animal model. This suggests a potential therapeutic option in the treatment of septic conditions.