Harald Matthes

Clinical trial: probiotic treatment of acute distal ulcerative colitis with rectally administered Escherichia coli Nissle 1917 (EcN)

BackgroundProbiotics are effective in inflammatory bowel diseases. Clinical effectiveness and dose dependency of E. coli Nissle (EcN) enemas were investigated in ulcerative colitis (UC).MethodsIn a double-blind study, 90 patients with moderate distal activity in UC were randomly assigned to treatment with either 40, 20, or 10 ml enemas (N = 24, 23, 23) containing 10E8 EcN/ml or placebo (N = 20). The study medication was taken once daily for at least 2 weeks. After 2, 4 and/or 8 weeks the clinical DAI was assessed together with tolerance to treatment. Patients who reached clinical DAI ≤ 2 within that time were regarded as responders.ResultsAccording to ITT analysis the number of responders was not significantly higher in the EcN group than in the placebo group (p = 0.4430, 2-sided). However, the Jonckheere-Terpstra rank correlation for dose-dependent efficacy indicated a significant correlation of per-protocol responder rates (p = 0.0446, 2-sided). Time to remission was shortest with EcN 40 ml, followed by EcN 20 ml. The number of adverse events did not differ notably.ConclusionIn contrast to ITT analysis, efficacy of rectal EcN application was significant in PP and points to EcN as a well tolerated treatment alternative in moderate distal UC.Trial registrationGerman Clinical Trials Register DRK00000234.

Educational intervention to improve physician reporting of adverse drug reactions (ADRs) in a primary care setting in complementary and alternative medicine

BackgroundRecent studies have shown that adverse drug reactions (ADRs) are underreported. This may be particularly true of ADRs associated with complementary and alternative medicine (CAM). Data on CAM-related ADRs, however, are sparse.Objective was to evaluate the impact of an educational intervention and monitoring programme designed to improve physician reporting of ADRs in a primary care setting.MethodsA prospective multicentre study with 38 primary care practitioners specialized in CAM was conducted from January 2004 through June 2007. After 21 month all physicians received an educational intervention in terms of face-to-face training to assist them in classifying and reporting ADRs. The study centre monitored the quantity and quality of ADR reports and analysed the results.To measure changes in the ADR reporting rate, the median number of ADR reports and interquartile range (IQR) were calculated before and after the educational intervention. The pre-intervention and post-intervention quality of the reports was assessed in terms of changes in the completeness of data provided for obligatory items. Interrater reliability between the physicians and the study centre was calculated using Cohens kappa with a 95% confidence interval (CI). We used Mann Whitney U-test for testing continuous data and chi-square test was used for categorical data. The level of statistical significance was set at P < 0.05.ResultsA total of 404 ADRs were reported during the complete study period. An initial 148% increase (P = 0.001) in the number of ADR reports was observed after the educational intervention. Compared to baseline the postinterventional number of ADR reportings was statistically significant higher (P < 0.005) through the first 16 months after the intervention but not significant in the last 4-month period (median: 8.00 (IQR [2.75; 8.75]; P = 0.605). The completeness of the ADR reports increased from 80.3% before to 90.7% after the intervention. The completeness of the item for classifying ADRs as serious or non-serious increased significantly (P < 0.001) after the educational intervention. The quality of ADR reports increased from kappa 0.15 (95% CI: 0.08; 0.29) before to 0.43 (95% CI: 0.23; 0.63) after the intervention.ConclusionThe results of the present study demonstrate that an educational intervention can increase physician awareness of ADRs. Participating physicians were able to incorporate the knowledge they had gained from face-to-face training into their daily clinical practice. However, the effects of the intervention were temporary.

Remedies Containing Asteraceae Extracts: A Prospective Observational Study of Prescribing Patterns and Adverse Drug Reactions in German Primary Care

AbstractBackground: The use of complementary therapies by patients has increased over the past 20 years, both in terms of self-medication and physician prescriptions. Among herbal medicines, those containing extracts of Asteraceae (Compositae), such as Echinacea spp., Arnica montana, Matricaria recutita and Calendula officinalis, are especially popular in the primary-care setting. However, there remains a gap between the growing acceptance of these remedies and the lack of data on their safety. Objective: The aim of this study was to analyse prescribing patterns and adverse drug reactions (ADRs) for Asteraceae-containing remedies in Germany. Methods: Primary-care physicians, all of whom were members of the German National Association of Anthroposophic Physicians were invited to participate in this prospective, multicentre, observational study. During the study period (September 2004 to September 2006), all prescriptions and suspected ADRs for both conventional and complementary therapies were documented using a web-based system. The study centre monitored all ADR reports and conducted a causality assessment according to Uppsala Monitoring Centre guidelines. Relative risks (RRs) and proportional reporting ratios (PRRs) were calculated. Results: Thirty-eight physicians, 55% of whom were general practitioners and 45% were specialists, fulfilled the technical requirements and were included in the investigation. Because documenting all ADRs (i.e. serious and non-serious) was time consuming, only a subgroup consisting of seven physicians agreed to report nonserious in addition to serious ADRs. During the study period, a total of 50 115 patients were evaluated and 344 ADRs for conventional and complementary remedies were reported. Altogether, 18 830 patients (58.0% female, 60.3% children) received 42 378 Asteraceae-containing remedies. The most frequently prescribed Asteraceae was Matricaria recutita (23%), followed by Calendula officinalis (20%) and Arnica montana (20%). No serious ADRs for Asteraceae-containing remedies were reported. In the analysis of the subgroup of seven physicians who also documented nonserious ADRs, 11 nonserious ADRs for Asteraceae-containing remedies occurred in 6961 patients, resulting in an RR of 0.13 (95% CI 0.07, 0.23). The majority of reported ADRs for Asteraceae-containing remedies were classified as uncommon. A subgroup analysis comparing phytotherapeutic and homoeopathic preparations did not reveal any relevant differences. The PRR for Asteraceae-containing remedies with respect to all other prescriptions was 1.7 (95% CI 1.0, 2.0) for the system organ class ‘skin and subcutaneous tissue disorders’ (six ADRs) and 1.0 (95% CI 0.3, 3.6) for ‘gastrointestinal disorders’ (three ADRs). Neither result was significant according to the PRR criteria developed by Evans et al. Conclusion: This is the first study to provide a systematic overview of prescribing patterns and ADRs for Asteraceae-containing remedies in the German primary-care sector. Asteraceae-containing remedies were used frequently in this context, especially among children. Our results indicate that treatment with Asteraceae-containing remedies is not associated with a high risk of ADRs.

Validation of a questionnaire measuring the regulation of autonomic function

BackgroundTo broaden the range of outcomes that we can measure for patients undergoing treatment for oncological and other chronic conditions, we aimed to validate a questionnaire measuring self-reported autonomic regulation (aR), i.e. to characterise a subjects autonomic functioning by questions on sleeping and waking, vertigo, morningness-eveningness, thermoregulation, perspiration, bowel movements and digestion.MethodsWe administered the questionnaire to 440 participants (♀: N = 316, ♂: N = 124): 95 patients with breast cancer, 49 with colorectal cancer, 60 with diabetes mellitus, 39 with coronary heart disease, 28 with rheumatological conditions, 32 with Hashimotos disease, 22 with multiple morbidities and 115 healthy people. We administered the questionnaire a second time to 50.2% of the participants. External convergence criteria included the German version of the Hospital Anxiety and Depression Scale (HADS-D), a short questionnaire on morningness-eveningness, the Herdecke Quality of Life Questionnaire (HLQ) and a short version questionnaire on self-regulation.ResultsA principal component analysis yielded a three dimensional 18-item inventory of aR. The subscales orthostatic-circulatory, rest/activity and digestive regulation had internal consistency (Cronbach-α: rα = 0.65 – 0.75) and test-retest reliability (rrt = 0.70 – 85). AR was negatively associated with anxiety, depression, and dysmenorrhoea but positively correlated to HLQ, self-regulation and in part to morningness (except digestive aR) (0.49 – 0.13, all p < 0.05).ConclusionAn internal validation of the long-version scale of aR yielded consistent relationships with health versus illness, quality of life and personality. Further studies are required to clarify the issues of external validity, clinical and physiological relevance.

Adverse Drug Reactions and Expected Effects to Therapy with Subcutaneous Mistletoe Extracts (Viscum album L.) in Cancer Patients

Background. In Europe, mistletoe extracts are widely used as a complementary cancer therapy. We assessed the safety of subcutaneous mistletoe as a conjunctive therapy in cancer patients within an anthroposophic medicine setting in Germany. Methods. A multicentre, observational study was performed within the Network Oncology. Suspected mistletoe adverse drug reactions (ADRs) were described by frequency, causality, severity, and seriousness. Potential risk factors, dose relationships and drug-drug interactions were investigated. Results. Of 1923 cancer patients treated with subcutaneous mistletoe extracts, 283 patients (14.7%) reported 427 expected effects (local reactions <5 cm and increased body temperature <38°C). ADRs were documented in 162 (8.4%) patients who reported a total of 264 events. ADRs were mild (50.8%), moderate (45.1%), or severe (4.2%). All were nonserious. Logistic regression analysis revealed that expected effects were more common in females, while immunoreactivity decreased with increasing age and tumour stage. No risk factors were identified for ADRs. ADR frequency increased as mistletoe dose increased, while fewer ADRs occurred during mistletoe therapy received concurrent with conventional therapies. Conclusion. The results of this study indicate that mistletoe therapy is safe. ADRs were mostly mild to moderate in intensity and appear to be dose-related and explained by the immune-stimulating, pharmacological activity of mistletoe.

Prescribing patterns in dementia: a multicentre observational study in a German network of CAM physicians

BackgroundDementia is a major and increasing health problem worldwide. This study aims to investigate dementia treatment strategies among physicians specialised in complementary and alternative medicine (CAM) by analysing prescribing patterns and comparing them to current treatment guidelines in Germany.MethodsTwenty-two primary care physicians in Germany participated in this prospective, multicentre observational study. Prescriptions and diagnoses were reported for each consecutive patient. Data were included if patients had at least one diagnosis of dementia according to the 10th revision of the International Classification of Diseases during the study period. Multiple logistic regression was used to determine factors associated with a prescription of any anti-dementia drug including Ginkgo biloba.ResultsDuring the 5-year study period (2004-2008), 577 patients with dementia were included (median age: 81 years (IQR: 74-87); 69% female). Dementia was classified as unspecified dementia (57.2%), vascular dementia (25.1%), dementia in Alzheimers disease (10.4%), and dementia in Parkinsons disease (7.3%). The prevalence of anti-dementia drugs was 25.6%. The phytopharmaceutical Ginkgo biloba was the most frequently prescribed anti-dementia drug overall (67.6% of all) followed by cholinesterase inhibitors (17.6%). The adjusted odds ratio (AOR) for receiving any anti-dementia drug was greater than 1 for neurologists (AOR = 2.34; CI: 1.59-3.47), the diagnosis of Alzheimers disease (AOR = 3.28; CI: 1.96-5.50), neuroleptic therapy (AOR = 1.87; CI: 1.22-2.88), co-morbidities hypertension (AOR = 2.03; CI: 1.41-2.90), and heart failure (AOR = 4.85; CI: 3.42-6.88). The chance for a prescription of any anti-dementia drug decreased with the diagnosis of vascular dementia (AOR = 0.64; CI: 0.43-0.95) and diabetes mellitus (AOR = 0.55; CI: 0.36-0.86). The prescription of Ginkgo biloba was associated with sex (female: AOR = 0.41; CI: 0.19-0.89), patient age (AOR = 1.06; CI: 1.02-1.10), treatment by a neurologist (AOR = 0.09; CI: 0.03-0.23), and the diagnosis of Alzheimers disease (AOR = 0.07; CI: 0.04-0.16).ConclusionsThis study provides a comprehensive analysis of everyday practice for treatment of dementia in primary care in physicians with a focus on CAM. The prescribing frequency for anti-dementia drugs is equivalent to those found in other German studies, while the administration of Ginkgo biloba is significantly higher.

Verordnungsverhalten anthroposophisch orientierter Ärzte bei akuten Infektionen der oberen Atemwege

Hintergrund: Akute Atemwegsinfektionen gehören zu den häufigsten Ursachen für einen Arztbesuch. Die vorliegende Arbeit untersucht die Behandlung akuter Atemwegsinfekte durch anthroposophisch orientierte Ärzte unter besonderer Berücksichtigung von Antibiotikaverordnungen, Komplikations- und Rezidivraten sowie Rezeptkosten. Material und Methoden: In einem Netzwerk von 35 Hausärzten in Deutschland wurden alle Verordnungsdaten beginnend ab Mai 2004 über den Zeitraum eines Jahres erfasst. Dazu wurden regelmäßig ärztliche Routinedaten durch speziell entwickelte Schnittstellen aus Praxissystemen ausgelesen. In standardisierten Web-Interfaces nahmen die Ärzte ergänzend eine Verknüpfung von Medikamenten und Diagnosen vor. Ergebnisse: Es wurden 21 818 Verordnungen von 12 081 Patienten (73,7% Kinder) für 19 050 akute Infekte der oberen Atemwege ausgewertet. Die häufigsten Diagnosen waren grippale Infekte (63,3%) und akute Tonsillitiden (12,9%). 63,0% der Erkrankungen wurden rein komplementärmedizinisch behandelt. Antibiotika wurden in 6,3% der Fälle verordnet (Minimum: grippale Infekte: 1,9%, Maximum: Tonsillitis: 24,3%). Prädiktive Faktoren für den Antibiotikaeinsatz waren neben den Diagnosen Tonsillitis (Odds Ratio [OR]: 6,7; 95%-Konfidenzintervall [KI]: 4,5-9,9) und Sinusitis (OR: 1,9; 95%-KI: 1,1-3,1) Begleiterkrankungen (OR: 1,2; 95%-KI: 1,0-1,4), Komplikationen (OR: 7,2; 95%-KI: 5,5-9,4) und die Facharztausrichtung Pädiatrie (OR: 2,1; 95%-KI: 1,7-2,6). Die Nachverschreibungsrate von Antibiotika für zunächst rein komplementärmedizinisch behandelte Patienten war mit 0,7% gering, ebenso die Komplikationsrate (2,9%) und die Folgekonsultationsrate (6,3%). Durchschnittlich erkrankten die Patienten 2,4-mal pro Jahr an einer akuten Atemwegsinfektion (Erwachsene: 1,7; Kinder: 2,7). Die Medikamentenkosten von komplementärmedizinischen und Antibiotikarezepten unterschieden sich nicht. Schlussfolgerung: Durch Aufbereitung und Ergänzung ärztlicher Routinedaten konnte der Verschreibungsalltag anthroposophischer Hausärzte abgebildet werden. Bezüglich des Einsatzes von Antibiotika wurde eine spezifische leitlinienkonforme Therapie durchgeführt. Die Antibiotikaverschreibungsrate lag deutlich unter dem Bundesdurchschnitt.

Diagnostic profiles and prescribing patterns in everyday anthroposophic medical practice--a prospective multi-centre study.

Background: Although anthroposophic medicine has been used for more than 80 years and global interest in complementary treatments is increasing, a comprehensive and long-term description of everyday anthroposophic care is still lacking. Our study aims to evaluate how anthroposophic medicine is practised under everyday conditions. Methods: A total of 38 primary-care physicians in Germany participated in this prospective, multi-centre observational study. Prescriptions, diagnoses, and non-pharmacological therapies were reported for each consecutive patient. Results: In 2005, 95,116 prescriptions for 32,839 patients (56.2% children, 57.3% female) were recorded. The median duration of consultation depended on physician specialization (general practitioners: 9.5 min; paediatricians: 8.1 min). The most frequent single diagnoses were acute upper respiratory tract infections (URTI), otitis media, and bronchitis in children; hypertension, breast cancer, and depressive episodes in adult females; and hypertension, URTI, and asthma in adult males. Anthroposophic remedies accounted for 41.8% of all drugs prescribed. The odds ratio (OR) for receiving an anthroposophic remedy was very high for cancer (OR = 4.5; 95% CI: 4.2–4.8) and >1 for dorsopathies (OR = 1.5; CI: 1.3–1.6), otitis media (OR = 1.3; CI: 1.2–1.3), and URTI (OR = 1.1; CI: 1.1–1.2). Of the 5,289 therapeutic procedures prescribed, 27% were anthroposophic. Conclusion: A broad range of anthroposophic remedies and non-pharmacological therapies are prescribed for a specific set of diseases in everyday anthroposophic practice. Particularly, patients <60 years received anthroposophic care. Our findings will help in the planning and implementation of further studies.

Intratumoral Mistletoe (Viscum album L) Therapy in Patients With Unresectable Pancreas Carcinoma A Retrospective Analysis

Pancreatic carcinoma remains one of the main causes for cancer-related death. Intratumoral application of anticancer agents is discussed as a promising method for solid tumors such as pancreatic cancer. Endoscopic ultrasound provides a good tool to examine and treat the pancreas. European mistletoe (Viscum album L) is a phytotherapeutic commonly used in integrative oncology in Central Europe. Its complementary use seeks to induce immunostimulation and antitumoral effects as well as alleviate chemotherapeutic side effects. Intratumoral mistletoe application has induced local tumor response in various cancer entities. This off-label use needs to be validated carefully in terms of safety and benefits. Here we report on 39 patients with advanced, inoperable pancreatic cancer, who received in total 223 intratumoral applications of mistletoe, endoscopic ultrasound guided or under transabdominal ultrasound control. No severe procedure-related events were reported. Adverse drug reactions were mainly increased body temperature or fever in 14% and 11% of the applications, respectively. Other adverse drug reactions, such as pain or nausea, occurred in less than 7% of the procedures. No severe adverse drug reaction was recorded. Patients received standard first- and second-line chemotherapy and underwent adequate palliative surgical interventions as well as additive subcutaneous and partly intravenous mistletoe application. A median survival of 11 months was observed for all patients, or 11.8 and 8.3 months for stages III and IV, respectively. Due to the multimodal therapeutic setting and the lack of a control group, the effect of intratumoral mistletoe administration alone remains unclear. This retrospective analysis suggests that intratumoral-applicated mistletoe might contribute to improve survival of patients with pancreatic cancer. In conclusion, the application is feasible and safe, and its efficacy should be evaluated in a randomized controlled trial.

Safety of Intravenous Application of Mistletoe (Viscum album L.) Preparations in Oncology: An Observational Study

Background. Traditional mistletoe therapy in cancer patients involves subcutaneous applications of Viscum album L. preparations, with doses slowly increasing based on patient responses. Intravenous infusion of high doses may improve therapeutic outcomes and is becoming more common. Little is known about the safety of this “off-label” application of mistletoe. Methods. An observational study was performed within the Network Oncology. Treatment with intravenous mistletoe applications is described. The frequency of adverse drug reactions (ADRs) to intravenous mistletoe applications was calculated and compared to ADR data from a study on subcutaneous applications. Results. Of 475 cancer patients who received intravenous infusions of Helixor, Abnoba viscum, or Iscador mistletoe preparations, 22 patients (4.6%) reported 32 ADRs of mild (59.4%) or moderate severity (40.6%). No serious ADRs occurred. ADRs were more frequently reported to i.v. mistletoe administered alone (4.3%), versus prior to chemotherapy (1.6%). ADR frequency differed with respect to preparation type, with Iscador preparations showing a higher relative frequency, compared to Abnoba viscum and Helixor. Overall, patients were almost two times less likely to experience an ADR to intravenous compared to subcutaneous application of mistletoe. Conclusion. Intravenous mistletoe therapy was found to be safe and prospective studies for efficacy are recommended.