Berthold Schneider

Impact of complementary oral enzyme application on the postoperative treatment results of breast cancer patients--results of an epidemiological multicentre retrolective cohort study.

Purpose: To evaluate the impact of postoperative treatment with an oral enzyme (OE) preparation given complementary to an antineoplastic therapy in patients with breast cancer. Methods: The design of this epidemiological study was a retrolective cohort analysis with parallel groups. Design and conduct of the study were performed to current standards for prospective, controlled clinical trials. A cohort of 2339 breast cancer patients undergoing surgical intervention and radio-, chemo- or hormonal therapy were studied in 216 centres. Of the 2339 patients, 1283 received complementary treatment with OE and 1056 did not receive OE. Patients with other complementary medications were excluded and the final analysis was performed with the data from 649 patients, of whom 239 (37%) were additionally treated with OE (test group) and 410 (63%) without OE (control group). The median follow-up time for the test group was 485 days and for the control group 213 days. The primary endpoint of the study was to determine whether complementary treatment with OE can reduce typical disease- or therapy-associated signs and symptoms (gastrointestinal symptoms, mental symptoms, dyspnoea, headache, tumour pain, cachexia, skin disorders, infections, and side effects associated with the antineoplastic therapy) in patients with breast cancer. Imbalances for causal effects (covariates) were adjusted for by means of the propensity score. Outcome analysis was performed by estimating the linear regression between change in symptom score and propensity score with all data and using this regression line to calculate the change in symptom score which would be expected for each patient. Tumour-associated events (recurrence, metastasis, and death) were evaluated in terms of the number of events observed and time to event. The safety of treatment with OE was analysed in terms of the number and severity of adverse events, their duration, treatment and outcome. Results: For all symptoms except tumour pain, the adjusted mean improvement in symptom scores was larger in the test group than in the control group. The adjusted difference was statistically significant for all symptoms, except tumour pain and infections. The results show that the typical disease- and therapy-associated signs and symptoms in patients on complementary therapy with OE during postoperative treatment were significantly less. For 75% of the test group and 55% of the control group the physician recorded “no signs and symptoms”. A clear reduction in the side effects of radiotherapy and chemotherapy was documented in 74% of the test group and 55% of the control group. Analysis of survival, recurrence, and metastasis demonstrated a reduced number of events in the test group. There was evidence of a beneficial influence of OE on time to event, although the median observation time was too short in these breast cancer patients to draw definite conclusions. The safety component was judged in 98% of the test group and 76% of the control group as “very good” or “good”. In the total sample of 2339 patients, the rate of OE-associated adverse reactions was 3.2%. All side effects were mild to moderate gastrointestinal symptoms. Conclusion: Complementary treatment of breast cancer patients with OE improves the quality of life by reducing signs and symptoms of the disease and the side effects of adjuvant antineoplastic therapies. This epidemiological retrolective cohort analysis provides evidence that the patients may also gain benefit by a prolongation of the time to event for cancer recurrence, metastasis and survival. OE was generally well tolerated.

Cerebral autoregulation during whole-body hypothermia and hyperthermia stimulus

The purpose of the study contained herein was to investigate the effects of old traditional physiotherapeutic treatments on cerebral autoregulation. Treatment consisted of complete body immersion in cold or warm water baths. Fifteen volunteers were investigated by means of transcranial Doppler sonography and a servo-controlled noninvasive device for blood pressure measuring. One group of 8 volunteers (mean age, 27.2+/-3.5 yr; gender, 3 females/5 males) was subjected to cold baths of 22 degrees C for 20 min Another group of 7 volunteers (mean age, 52.1+/-8.5 yr; gender, 4 females/3 males) took hyperthermic baths at rising water temperatures from 36 degrees to 42 degrees C, increased by 1 degree C every 5 min. Each volunteer in both groups underwent autoregulation tests two to four times before, during, and after the thermic bath. Dynamic autoregulation was measured by the response of cerebral blood flow velocity to a transient decrease of the mean arterial blood pressure, induced by rapid deflation of thigh cuffs. The autoregulation index, i.e., a measure of the speed of change of cerebral autoregulation, was used to quantify the response. Further parameters were core temperature, blood pressure (mm Hg) and CO2et. During hypothermic baths, core temperature decreased by 0.3 degrees C (P = 0.001), measured between preliminary phase and the end of the bath; the autoregulation index decreased significantly (P < 0.05) from 5.3 before the bath to 4.25 during the bath. During hyperthermic baths, the autoregulation index increased from 6.0 to 7.5 and 8.9 (P < 0.001), with an increase of core temperature of 0.4 degrees C. The main cerebral autoregulation system is dependent on changes of core temperature, provoked by hypothermic or hyperthermic whole-body thermostimulus. Application of hyperthermic baths increased the autoregulation index, and hypothermic baths decreased the autoregulation index. Further studies are needed to prove the positive effects of thermo-stimulating water applications on cerebral hemodynamics in patients with cerebral diseases.

Retrolective, Comparative, Epidemiological Cohort Study with Parallel Groups Design for Evaluation of Efficacyand Safety of Drugs with ‘Well-Established Use’ Experience with the Long-Term Treatment Using the European Mistletoe Extract (Viscum album L.) in Addition to Conventional Oncological Therapy in Primary, Non-Metastatic Breast Carcinoma

The randomized controlled clinical trial (RCT) is accepted as the ‘golden standard’ for the evaluation of efficacy and safety of new drugs. In contrast, to demonstrate efficacy and safety of drugs with ‘well-established use’ that have been on the European Community market for long time, observational comparative epidemiological studies can be used according to the European drug regulation directive. However, because comparative epidemiological cohort studies can share some risk of bias with other nonrandomized observational study designs, there is a need for an approach that could effectively reduce the bias risk in this type of studies. Study Objectives: The purpose of the study was to evaluate the therapeutic efficacy and safety of a long-term complementary therapy of primary, non-metastatic breast carcinoma patients treated with standardized European mistletoe extract IscadorTM (‘mistletoe’) in addition to the conventional adjuvant oncologic therapy, and compared to the control group treated with the conventional therapy alone. Methods: The multicenter, comparative, retrolective, pharmaco-epidemiological cohort study with parallel groups design and randomly selected centers that routinely used both treatments was carried out according to Good Epidemiological Practice rules under a standard operating procedure control. The test group patients received the mistletoe extract treatment subcutaneously for at least 3 months, while the control group patients of the same cohort was exclusively treated with the conventional therapy. The patients were followed up for at least 3 years or until death. The primary endpoint of efficacy was the incidence of adverse reactions to the conventional oncologic therapy. Secondary endpoints were change from baseline of the symptoms associated with the disease and treatment as well as overall survival. All endpoints were adjusted to baseline imbalance and confounders. Safety was assessed descriptively by the number of patients with adverse drug reactions (ADRs) attributed to the test treatment. Results: 1442 patients (710 tests and 732 controls) were eligible for the ‘per protocol’ analysis of efficacy and safety. At baseline, the test group had a more advanced disease and worse prognostic factors profile. After a median follow-up of 66 vs. 60 months, and a median mistletoe therapy duration of 52 months, significantly fewer test group patients (16.2%) than control patients (54.0%) developed ADRs attributed to the conventional therapy [adjusted odds ratio, OR (95% confidence interval, CI), OR = 0.47 (0.32–0.67), < 0.001]. In the test group, the majority of the symptoms disappeared more frequently, and overall mortality hazard was significantly lower [adjusted hazard ratio, HR (95% CI), HR = 0.46 (0.22–0.96), p = 0.038] than in the control group. Systemic ADRs attributed to the test treatment developed in 0.8%, and local ADRs in 17.3% of the patients. ADR severity was mild to intermediate. Tumor enhancement was not observed. Conclusions: Complementary therapy of patients with primary, non-metastatic breast carcinoma with the mistletoe extract Iscador was safe and in comparison to the control group within the same study cohort showed con- siderably fewer ADRs attributed to concurrent conventional therapy, reduced disease symptoms, and suggested a significant improvement of survival. Despite some methodical limitations that require careful study planning and conduction as well as critical interpretation, the applied study design seems suitable to evaluate the efficacy and safety of drugs with ‘well-established use’, particularly in oncology.

A randomised, double-blind, placebo-controlled trial of a herbal medicinal product containing Tropaeoli majoris herba (Nasturtium) and Armoraciae rusticanae radix (Horseradish) for the prophylactic treatment of patients with chronically recurrent lower urinary tract infections

ABSTRACT Objectives: The aim of this study was to verify the efficacy and safety of a herbal medicinal product containing Tropaeoli majoris herba and Armoraciae rusticanae radix in the prophylactic treatment of chronically recurrent urinary tract infections (UTIs), and to test whether the medicinal product decreases the incidence of relapses over the study period. Methods: A total of 219 adults aged between 18 and 75 years were screened and 174 patients enrolled. Of these 174 patients, a group of 45 patients were screening failures. Patients were randomised to receive either the study drug or placebo twice daily for 90 days. A UTI is confirmed by defined symptoms together with a laboratory result. The diagnosis of a new episode of a recurrent UTI included urine analysis from a central laboratory. The primary efficacy criterion – the number of recurrent UTIs over the study period – was tested between the treatment groups. Results: For the per-protocol population, the mean number of recurrent UTIs in the study period was 0.43 versus 0.77 for the placebo group. This result is statistically significant ( p = 0.035). A total of 36 patients in the test group and 37 patients in the placebo group reported adverse events. Two serious adverse events were reported in the placebo group and one serious adverse event in the treatment group (not associated with the study medication). Conclusion: This randomised, double-blind, placebo-controlled trial demonstrates the efficacy and safety of the herbal medicinal product Angocin Anti-Infekt N* in the prophylactic treatment of chronically recurrent UTIs. * Angocin Anti-Infekt N is a registered trade name of Repha GmbH, Langenhagen, Germany

Quinidine-digoxin interaction: cardiac efficacy of elevated serum digoxin concentration.

Cardioactivity due to elevated serum digoxin concentration (SDC) after quinidine (Q) and digoxin (D) was evaluated in six healthy subjects by means of measurement of systolic time intervals (STIs). Each subject randomly received basic treatments with 0.2 mg D and placebo (PL1). Randomized coadministrations with Q (1 gm/day), sparteine (SP) (0.8 gm/day), and placebo (PL2) were given for 7‐day periods. A steady‐state dose of 0.4 mg D was added. Mean SDC increased from 0.48 nglml during 0.2 mg D + PL2 to 1.13 ng/ml on 0.2 mg D + Q (P < 0.05); it was unchanged by SP. On 0.4 mg D there were further shortenings of STIs compared to those on 0.2 mg D + PL2. Q markedly prolonged STIs; the SP effects were similar but less pronounced. When given with Q or SP, the effect of D was obscured by opposing inotropic properties; consequently, despite increasing SDC, measurable STIs were unchanged. The true glycoside effect was determined by comparing the effects of the pure antiarrhythmic to those of the antiarrhythmic with D. These calculations showed that the glycoside effect of the elevated SDC during Q + D dosing was much the same as the effect of 0.4 mg D.

Pharmacodynamics of a single dose of quinidine during chronic digoxin treatment

SummaryThe influence of single doses of quinidine sulphate (Q) 0.5 g, sparteine sulphate (SP) 0.2 g, and placebo (PL) on heart rate-corrected systolic time intervals (STI) (QS2c, PEPc, LVETc) and on QTc duration was studied 2 and 4 h after treatment of six healthy volunteers. All measurements were done twice in a double blind fashion, once under digoxin (D) steady state (β-methyl digoxin 0.3 mg daily) and once after an equally prolonged basic treatment period with PL. All basic treatment periods and single dose periods were randomized. Drug effects were estimated by comparison with the results obtained after administration of the corresponding placebo. The data were analyzed by two-factorial multivariate analysis of variance. Steady state digoxin serum concentrations averaged 1.3 µg/l and there was no significant change following antiarrhythmic drugs compared to PL. Single oral doses of Q and SP resulted in mean serum concentrations of about 1.8 mg/l and 0.25 mg/l, respectively. In non-digitalized subjects Q 0.5 g resulted in a lengthening of QS2c (+15 ms), LVETc (+13 ms) and QTc (+65 ms). With SP 0.2 g similar but smaller effects were seen. D alone resulted in shortening of QS2c (−21 ms), LVETc (−14 ms), and QTc (−32 ms). Pretreatment with D did not influence the effects of Q on the various parameters. However, corresponding to the D-induced changes in STI, a parallel shift of the curve was observed. The effects of sparteine were somewhat reduced by D. Most of the effects of Q compared to PL and SP were statistically significant (p<0.05) during both basic treatments, and the D basic treatment had a statistically significant effect for all treatment regimens, but there was no significant interaction between them. In contrast to others, the present results indicate that the positive inotropic effect of D persists in the presence of Q and SP, and that the antiarrhythmic drugs induce negative inotropic effects independent of basic treatment with D. Under the conditions of this experiment, each drug maintains its negative or positive effect on inotropy, thus resulting in an almost arithmetical superposition of the separate drug effects.

Interrelations between diabetes therapy, self-monitoring of blood glucose, blood glucose and non-fatal or fatal endpoints in patients with type 2 diabetes / results of a longitudinal cohort study (ROSSO 5).

The ROSSO study is a retrospective, longitudinal cohort study performed to obtain epidemiological data on self-monitoring of blood glucose (SMBG) in patients with type 2 diabetes and to investigate the impact of SMBG on disease-related morbidity and mortality. 3,268 patients from 192 doctors practices in Germany were included and their data from diabetes diagnosis (between 1995 and end of 1999) till drop-out (120 died, 17 drop-outs) or end of 2003 were collected from the medical records. The mean observational time was 6.5 years; total patient years of follow-up were 21.266 years. Based on these population data, questions about the motivation of patients with type 2 diabetes to start with SMBG, the changes in diabetes therapy and blood glucose associated with SMBG and the relationship of SMBG with non-fatal or fatal events during follow-up were evaluated. Use of SMBG is significantly associated with personal and baseline conditions. Patients using SMBG are more frequently treated by an internist, more often male, have more frequently a private health insurance, exhibit less frequently arterial hypertension, are younger, have lower systolic blood pressure and higher values of fasting blood glucose (FBG), HbA1c and triglycerides at diagnosis. The start of SMBG is preceded by a steady increase in blood glucose levels. It is accompanied by an intensification of diabetes therapy and followed by a significant reduction of blood glucose in the year after start of SMBG. 67% of the patients treated with diet only before SMBG began with antidiabetic medication concomitantly with SMBG (48% with oral antidiabetic agents (OAD), 9% with insulin and 10% with OAD and insulin) and 30% of the patients treated with OAD started on additional insulin treatment in parallel with SMBG. Switching from no antidiabetic medication to OAD reduced the mean FBG levels significantly from 9.31 to 8.70 mmol/l, from no medication to insulin from 10.05 to 6.93 mmol/l and from no medication to OAD and insulin from 10.85 to 8.92 mmol/l. Similar reductions of mean FBG levels were observed for switching from OAD to insulin therapy. Patients who stayed on OAD therapy also showed a significant reduction of FBG concentrations after the start of SMBG. The hazard for non-fatal events (particularly myocardial infarction and stroke) or overall mortality was significantly reduced for patients who performed SMBG during follow-up (p<0.001). SMBG-associated changes of antidiabetic therapy may contribute to the better clinical outcome of patients with SMBG.

Myocardial infarction and stroke in early years after diagnosis of type 2 diabetes: risk factors and relation to self-monitoring of blood glucose.

BACKGROUND The natural course of macrovascular events in patients with type 2 diabetes was analyzed: what are the risk factors, and what is the relationship to the use of self-monitoring of blood glucose (SMBG)? METHODS Data were retrieved from ROSSO-a German retrospective observational study-which followed 3,268 patients from diagnosis of type 2 diabetes for 6.5 +/- 1.6 years. We compared patients with or without a nonfatal macrovascular event (myocardial infarction or stroke) and patients using or not using SMBG. RESULTS At baseline, worse glycemic control and higher body mass index were not risk factors for macrovascular events. Moreover, there was no association with classic risk factors like blood pressure or total cholesterol. Overall, there was a higher incidence of stroke than of myocardial infarction (0.78% vs. 0.51%). Myocardial infarction was positively associated with male sex, and stroke with age (P < 0.001 for each). Patients using SMBG compared to patients not using SMBG had fewer myocardial infarctions (2.0% vs. 4.0%, P = 0.002) and strokes (3.6% vs. 5.7%, P = 0.005), experienced a stroke later after diagnosis of type 2 diabetes (5.1 +/- 1.9 vs. 3.8 +/- 2.1 years, P < 0.001), and had a higher mean hemoglobin A1c in the years before a myocardial infarction (7.8 +/- 1.8% vs. 6.8 +/- 1.1%, P = 0.003) or a stroke (8.0 +/- 1.8% vs. 7.1 +/- 1.2%, P = 0.003). However, classic cardiovascular risk factors did not differ between patients using or not using SMBG. CONCLUSIONS In patients with type 2 diabetes SMBG was associated with a lower event rate of myocardial infarction (-50%) and stroke (-37%), although at baseline the classic risk factors for macrovascular events were not different in both groups.

External stimuli in the form of vibratory massage after heart or lung transplantation.

Manual vibratory massage is part of the preventive physiotherapeutic activities performed in intensive care units. The vibratory massage can be performed manually or as electrovibratory massage. The manual massage is a fast rhythmical vibration performed by the arm and shoulder muscles of the masseur and transferred to the patients thorax by the hand. The hand of the masseur has to achieve a tremor with a frequency of 8 to 11 tremors/s. The aim of the pilot study was to examine the influence of manual vibratory massage on the pulmonary function of postoperative patients who were receiving mechanical ventilation, with special interest being focused on pulmonary ventilation and perfusion and cerebral blood flow velocity. Manual vibratory massage was performed postoperatively in the intensive care unit on eight patients: three patients had undergone heart transplantation, three had undergone lung transplantation, and two had undergone coronary artery bypass grafting (mean age, 53.6+/-8 yr). With the aid of continuous monitoring, we examined the changes of the respiration parameters and the cerebral blood flow velocity (measured by transcranial Doppler sonography). The vibratory massage was performed with a frequency of 8 to 10 vibrations/s for 15 min, 7.5 min on each side of the thorax, starting from the lower costal arch and progressing to the upper thoracic aperture. For 10 min before, during, and 10 min after the massage, the parameters of peripheral oxygen saturation, central venous pressure, mean arterial pressure, heart rate, lung resistance and compliance, tidal volume, respiration rate, and cerebral blood flow velocity were recorded at 2-min intervals. Moreover, before and after vibratory massage, arterial blood gases were determined. In four of the eight patients, it was possible to determine pulmonary arterial pressure, pulmonary capillary wedge pressure, as well as pulmonary vascular resistance. During the vibratory massage, we could prove a significant increase of the mean tidal volume by 30% (P = 0.008). The percutaneous oxygen saturation significantly increased also, from 92 to 93.6% (P = 0.002). Central venous pressure significantly decreased by 11% (P = 0.04), and pulmonary vessel resistance was reduced by 18.3% (P = 0.001). The pulmonary resistance decreased from 10.5 to 9.2 H2O/l/s (P < 0.05) by the end of the observation period. Cerebral blood flow velocity showed no significant change. Vibratory massage seems to improve pulmonary mechanism and perfusion, thus, reducing ventilation perfusion mismatch and increasing oxygen saturation.

Altered Disease Course after Initiation of Self-Monitoring of Blood Glucose in Noninsulin-Treated Type 2 Diabetes (ROSSO 3)

Background: Patients with noninsulin-treated type 2 diabetes were documented from diagnosis to determine whether patients taking up self-monitoring of blood glucose (SMBG) are distinct by baseline characteristics, exhibit a different natural disease course, and are treated differently. Methods: The German multicenter, retrospective cohort study (ROSSO) followed 3268 persons from diagnosis of type 2 diabetes for a mean of 6.5 years. During follow-up, 1912 persons received oral antidiabetic agents (OAD) for at least 1 year, but no insulin. Data were retrieved from patient files of randomly contacted primary care practices. Results: During follow-up, 742 patients (38.8%) began with SMBG prior to an end point. Initiation of SMBG was followed by improved glycemic control. Patients in the SMBG cohort were treated more often by an internist, younger by a mean of 3 years, and more often male (p < 0.001, each). A higher percentage of persons in the SMBG cohort were treated with metformin (74.7% vs 65.0%, p < 0.001) or changed OAD therapy (66.3% of patients vs 48.3% of patients, p < 0.001). SMBG was not accompanied by more comedication. In the SMBG cohort, 68 persons had a clinical end point (myocardial infarction, stroke, foot amputation, blindness, hemodialysis, or all-cause mortality) (9.2%) compared to 155 persons (13.2%) in the cohort without SMBG (p = 0.04 after multivariate adjustments). Conclusion: This first large documentation of OAD-treated persons from diagnosis for 6.5 years indicates that the use of SMBG is associated with younger age at diagnosis, a higher prescription rate of metformin, more frequent changes of oral therapy, and a lower risk of a clinical end point.