Course of mitogen-stimulated T lymphocytes in cancer patients treated with Viscum album extracts.

BACKGROUND: In a prospective observational study, the impact of two different dose regimes of a commercially available fermented Viscum album L. extract (VA-E, Iscador) on the function of T lymphocytes from cancer patients was investigated. PATIENTS AND METHODS: A total of 71 cancer patients were enrolled. These patients attended two different sections of a tumor outpatient clinic which are used to apply different VA-E escalation schemes. Our hypothesis was that a rapid dose escalation of subcutaneously applied VA-E may induce strong local reactions at the injection side (>3 cm diameter) and may have an effect on the functional competence of T lymphocytes (mitogen-activated interleukin-2 receptor alpha chain), which was recorded over an observation period of six month. RESULTS: Within this observation period, a decline of stimulated T cell function was observed, particularly in patients with colorectal or prostate cancer; this decline was not seen in patients with breast cancer (who received lower mean concentrations per month) nor in patients with dose adaptation in response to too strong local reactions. CONCLUSION: With respect to T-cell function, our results indicate that in patients without local reactions, a long lasting mistletoe extract application should be withheld periodically to allow T-cell reactivity to recover.

Characterisation of granulocyte stimulation by thionins from European mistletoe and from wheat.

Thionins are small basic peptides found in different plant species, which are known to exert cytotoxic properties. In addition, previous data indicated an activation of human granulocytes by thionins from European mistletoe (viscotoxins, VT). To extend these latter findings, we investigated the influence of VT and from thionins from wheat flour (purothionin) on human granulocytes by flow cytometry and tried to characterise the involved molecular structures and mechanisms. Phagocytosis was determined by incorporation of FITC-labelled Escherichia coli and respiratory burst by oxidation of dihydrorhodamine 123 to rhodamine 123. VT and purothionin significantly enhanced E. coli-stimulated phagocytosis and respiratory burst at 25 and 250 microgram/ml. Phagocytosis of damaged lymphocytes by granulocytes was detected by electron microscopy in the VT-stimulated (100 microgram/ml) but not in the control cultures. The poly-cationic structure of the intact molecule seems to be crucial, as evidenced by comparison of the burst and phagocytosis-enhancing effects induced by other poly-cationic (protamine sulphate, histone, poly-l-arginine, poly-l-lysine) and poly-anionic (poly-l-glutamic acid) peptides, while pore forming due to amphipathic properties seems to be less important. Ca2+ and Mg2+ could not inhibit VT-enhanced phagocytosis and, thus, could not inhibit binding of VT to granulocytes. In addition, verapamil at low concentrations inhibited VT activity, suggesting the involvement of Ca2+ channels for granulocyte activation by the VT. Similarly, thionins and histones in contrast to protamine sulphate induced cell death of granulocytes at 250 microgram/ml as demonstrated by an enhanced release of reactive oxygen intermediates in unstimulated granulocytes. From these data one may suggest that activity of VT is induced by strong unspecific ionic binding, probably followed by specific receptor binding, and thionins exhibit stimulatory and cytotoxic effects on immune cells, which have to be further characterised.

Induction of apoptosis by the N-acetyl-galactosamine-specific toxic lectin from Viscum album L. is associated with a decrease of nuclear p53 and Bcl-2 proteins and induction of telomeric associations.

The ribosome-inhibiting proteins from Viscum album L., i.e. the mistletoe lectins (ML), were recognized to induce apoptosis in various tumour cell lines and human lymphocytes. However, several aspects of ML-induced cell death are unclear. We report that the galNAc-binding ML III incubated with human lymphocytes mediates a very effective death signal resulting in the binding of Annexin-V and expression of mitochondrial membrane proteins Apo2.7, but also in an influx of the DNA intercalating dye propidium iodide. The addition of the ribosome-inhibiting protein Volkensin also induced Apo2.7 molecules, while Momordin, lacking a carbohydrate-binding chain, did not enter the cell membrane and thus did not affect the cells. However, we observed ML III to preferentially affect CD8+ cells with a memory phenotype (CD62L(lo)) as compared to their CD8+ CD62L(hi) counterparts, CD4+ T cells and CD19+ B cells. Furthermore, ML III did not induce sister chromatid exchange-inducing DNA lesions but reduced the intensity of telomeric signals, increased the frequencies of telomeric associations and C-anaphases and reduced nuclear Bcl-2 and p53 proteins. Whatever the exact mechanisms are, our results provide strong evidence that the ML III-mediated cytotoxicity involves distinct killing pathways, i.e. (1) primary cell death via an induction of apoptosis which may not be dependent on protein and/or RNA synthesis and may not involve p53 and Bcl-2 proteins and (2) a loss of telomeres resulting in chromosomal instability in the surviving cells which is incompatible with life. However, we cannot exclude the possibility that this effect is due to a decrease in nuclear p53 proteins.

Induction of mitochondrial Apo2.7 molecules and generation of reactive oxygen-intermediates in cultured lymphocytes by the toxic proteins from Viscum album L.

We analysed mitochondrial alterations in human lymphocytes incubated with toxins exerting RNA and/or protein synthesis/transport inhibitory activity. We found that all toxins known to affect macromolecule synthesis, such as ricin from Ricinus communis, mistletoe lectin I (ML I) from Viscum album, cycloheximide, actinomycin D, and brefeldin A but also the thionins from Viscum album (viscotoxins; VT) generated reactive oxygen intermediates (ROI) and induced expression of newly described mitochondrial membrane proteins Apo2.7, however, with different kinetics. Apart from a rapid permeabilisation of cell membranes by the VT with swelling of mitochondria, loss of their cristae and ROI generation within 2-4 h, the majority of the cells may have received a distinct 'death signal' resulting in an induction of Apo2.7 molecules within 24 h. In contrast, protein synthesis/transport inhibition may signal for apoptosis within 24 h by decreasing distinct 'survival promotors' which remain to be characterised.

Induction of apoptosis in human lymphocytes treated with Viscum album L. is mediated by the mistletoe lectins.

Viscum album L. (VAL) is a phytopreparation used in adjuvant cancer therapy with both immunostimulatory and DNA stabilizing properties at low drug concentrations and cytostatic/cytotoxic properties at higher concentrations. The present work examines the cytotoxic effects of VAL extracts produced from mistletoes grown on different host trees and of purified toxic proteins from VAL, such as the D-galactose-specific lectin I (ML I), the N-acetyl-D-galactosamine-specific ML II and ML III, and crude viscotoxins towards cultured human lymphocytes. The decrease in the number of cultured lymphocytes and blast cells treated with whole plant extracts from VAL was host tree-specific. Nevertheless, there was no close correlation to the content of MLs or viscotoxins. Using the purified proteins, it became obvious that the cell killing was mediated by the induction of apoptosis, as measured by the appearance of a hypodiploid DNA peak using flow cytometry. ML III was the most effective to induce apoptosis, followed by ML II and ML I, while the viscotoxins and oligosaccharides from VAL did not. By measuring the surface expression of IL-2R alpha chains, transferrin receptors and APO-1/Fas molecules on non-apoptotic T cells, no significant changes were observed at low ML concentrations (1 ng/ml), but their decrease at higher ones. Our findings suggest that there might be at least two different ways of cell killing operative in VAL-mediated cytotoxicity: (a) the typical apoptotic cell death with the appearance of hypo-diploid nuclei, and (b) a direct or indirect killing by damaging the cell membrane with subsequent influx of Ca2+ and of the DNA intercalating dye propidium iodide and cell shrinkage. These effects might not be exclusive, as they probably occur simultaneously.

Apoptosis-inducing properties of Viscum album L. extracts from different host trees, correlate with their content of toxic mistletoe lectins.

BACKGROUND: Extracts from Viscum album L. (VAL), which are one of the most widely used alternative cancer therapies in Europe, have been recognised to induce apoptosis. A clinically relevant direct anti-tumour effect might be induced only by their intratumoural or intrapleural injection, and thus effectiveness is highly dependent on the apoptosis-inducing potencies of the extracts used. MATERIALS AND METHODS: To characterise these properties, human lymphocytes were incubated for 72 hours with VAL extracts from different host trees and harvest times. Cell death-associated changes such as an apoptotic sub-G1 peak, binding of Annexin-V, generation of reactive oxygen intermediates (ROI), expression of mitochondrial Apo2.7 molecules, and uptake of the DNA-intercalating dye propidium iodide were measured by flow cytometry. RESULTS AND CONCLUSIONS: Biologically active VAL compounds, and thus cytotoxicity, are dependent on the manufacturing process, host tree, and time of harvest. Although the mistletoe lectin (ML) content of VAL extracts strongly correlated with their apoptosis-inducing properties, the presence of these proteins will not guarantee its biological activity, indicating the involvement of other components which may modulate ML cytotoxicity.

Mistletoe in immunology and the clinic (short review).

The recent meeting of the AGMIF (Working Group for Mistletoe Therapy and Immunological Research) held in Herdecke, Germany, on October, 3rd, 1997, covered recent developments in the field of immunological and biological properties of Viscum album L., the European mistletoe, which is used for adjuvant cancer treatment. So far, one extract component, the mistletoe lectin (ML)-1, was propagated by some researchers to be the only relevant substance within the extracts. However, immunological activities of other extract components such as polysaccharides, vesicles, chitin-binding lectin and their interactions discussed in the first part, underline the significance of the other components as well. In the second part, clinical evidence for the beneficial effects of subcutaneous and intratumoral application of mistletoe therapy was presented by different working groups. However, further research is of great importance to carefully analyse and characterize the involved molecules and exact mechanisms underlying the beneficial effects reported in this meeting.

Viscotoxin-free aqueous extracts from European mistletoe (Viscum album L.) stimulate activity of human granulocytes.

BACKGROUND: Extracts from European mistletoe (Viscum album L., VAL) are used for complementary cancer treatment. Viscotoxins (VT) and whole plant extracts with high amounts of the VT have been shown to stimulate functional activity of granulocytes. MATERIALS AND METHODS: We stimulated neutrophils from healthy donors in vitro with aqueous VT-free VAL extracts and mistletoe lectins (ML) in the presence of E.coli and studied phagocytosis (via incorporation of FITC-labelled E.coli) and respiratory burst (via oxidation of dihydrorhodamine 123 to rhodamine 123) by flow cytometry. RESULTS: The VT-free VAL extract significantly stimulated granulocyte activity, and this effect correlated with the content of the ML, although the ML exerted no influence at relevant concentrations. Co-incubation of the cells with VAL in the presence of VT further increased granulocyte response. CONCLUSIONS: From these data it is suggested that (1) a non-VT non-ML component of the VAL extracts activated granulocytes and (2) different activation pathways may be involved in the stimulation by the whole plant extract and the VT.

Thionins from Viscum album L: influence of the viscotoxins on the activation of granulocytes.

BACKGROUND: Extracts from European mistletoe (Viscum album L.) are applied in adjuvant cancer treatment, and some components, especially the mistletoe lectins (ML) have been immunologically characterised, but not the thionins, termed viscotoxins (VT). MATERIALS AND METHODS: The influence of the VT on human granulocytes was studied by flow cytometry: E.coli co-stimulated respiratory burst by oxidation of dihydrorhodamine 123 to rhodamine 123 and phagocytosis by ingestion of FITC-labelled E.coli. RESULTS: VT (25 and 250 micrograms/ml), in contrast to ML, significantly enhanced phagocytosis and burst activity. VT-rich mistletoe extracts also exerted significant effects. In addition, E.coli-activated granulocytes positively stain with Annexin-V and propidium iodide only due to 250 micrograms/ml VT incubation, suggesting that at this concentration burst activity was induced by the physiological activity of granulocytes after microbial ingestion and also by cytotoxic effects. CONCLUSION: Viscotoxins exert yet unknown strong immunomodulatory effects on human granulocytes, which might be of benefit for tumour patients, in addition to their cytotoxic properties.

Induction of Fas ligand (CD95L) by the toxic mistletoe lectins in human lymphocytes.

BACKGROUND: Fas ligand (FasL, CD95L) predominantly expressed on activated cytotoxic T cells and NK cells triggers apoptosis in Fas receptor (Apo-1, CD95) positive target cells. We investigated the expression of FasL, Fas and tumor necrosis factor (TNF) receptor 1 (TNF-R1, CD120a) on cultured human lymphocytes and leukemic T and B cells. MATERIALS AND METHODS: Lymphocytes from six healthy individuals, from four patients with chronic lymphocytic T or B cell leukaemia, and leukemic Molt-4 cells were incubated with the apoptosis- inducing mistletoe lectins (ML I and ML III). RESULTS: Incubation of differentiated lymphocytes with the ML resulted in a significant upregulation of FasL in the surviving CD4+ T helper cells, CD8+ cells and CD19+ B cells. Similarly, the TNF receptor expression increased, while the Fas molecule decreased. In contrast, FasL was not induced in leukemic cells. CONCLUSIONS: Apart from a direct induction of apoptosis in response to an inhibition of protein synthesis by the enzymic ML A chain, ML treatment may indirectly induce apoptosis in Fas+ tumour cells through activated FasL+ lymphocytes.

Influence of polysaccharides from Viscum album L. on human lymphocytes, monocytes and granulocytes in vitro.

BACKGROUND: An acidic arabinogalactan from European mistletoe (Viscum album L, VAL; 1.34 x 10(6) Dalton) was studied in detail because its immunological properties are poorly characterised. MATERIALS AND METHODS: Flow cytometric studies focussed on PS-activated proliferation of human lymphocytes measured via incorporation of bromo-deoxyuridine (BrdU), granulocyte phagocytosis via ingestion of FITC-labelled E.coli, and respiratory burst via oxidation of dihydrorhodamine 123 to rhodamine 123. Cytokines were detected in the cell culture supernatants by ELISA. RESULTS: PS, in contrast to mistletoe lectins (ML), significantly stimulated proliferation of CD4+ T-cells but not CD8+ and CD19+ cells. However, ML influenced PS-mediated stimulation, with a synergistic effect in one and an inhibitory effect in another individual. Furthermore, IFN-gamma release was significantly enhanced by PS, favouring a T-helper cell type-1 cytokine pattern, further IL-6 was significantly stimulated, while granulocyte activity was not affected. CONCLUSIONS: VAL-PS exert yet unknown stimulatory activities, especially on specific CD4+ T-cells which may be influenced by other extract components like the ML. These components may contribute to the anti-tumour effect of VAL.

Release of interleukin-6 in cultured B-chronic lymphocytic leukaemia cells is associated with both activation and cell death via apoptosis.

BACKGROUND: There is growing evidence that some cytokines promote B cell survival, while others enhance cell death. Interleukin-6 was reported to induce proliferation of chronic lymphocytic leukaemia (B-CLL) cells, and to enhance survival of these cells through inhibition of spontaneous apoptosis. MATERIALS AND METHODS: To more clearly define the effects of an in vitro stimulation of B-CLL cells, lymphocytes from 13 patients with B-CLL and from 6 healthy individuals were incubated for 7 d with immunomodulators such as interleukin-6 (IL-6), pokeweed mitogen (PWM), lipopolysaccharides (LPS), and extracts from Viscum album L. (VAL; Helixor), which were recognised to induce apoptosis but also to induce a release of pro-inflammatory cytokines such as IL-1, IL-6, and tumour necrosis factor-alpha. RESULTS: Although both, IL-6 and PWM induced a release of IL-6 and expression of the activation markers CD25 and CD71 on the surface of B-CLL cells, IL-6 did not increase or accelerate the proliferation of these cells. In contrast, VAL extracts did not result in an upregulation of activation markers or proliferation of B-CLL cells but induced both, cell death via apoptosis and IL-6 release. In response to PWM, only few clones of leukemic B cells incorporated the thymidine-analogue 5-bromo-2'-deoxyuridine. Moreover, a remarkable response of B-CLL cells towards the immunomodulators was observed only in one patient with an advanced stage. CONCLUSIONS: These preliminary results do not support theoretical objections of a B-CLL stimulation via induction of IL-6 in vitro.

Differential binding of toxic lectins from Viscum album L., ML I and ML III, to human lymphocytes.

The killing capacity of extracts from Viscum album L., widely used as an adjuvant in complementary cancer therapy, is dependent on the content of toxic proteins, especially the mistletoe lectins (ML). Although one may expect a homogeneous distribution of 'receptors' for these proteins on the cell surface, the sensitivity of cells to the ML-mediated cytotoxicity obviously differs, as the galNAc-binding ML III in contrast to the gal-binding ML I selectively killed CD8+ lymphocytes with a 'memory' phenotype (CD62Llo), while CD19+ B cells remained almost unaffected. B cells hardly bind ML III but did bind the gal-specific ML I. In accordance with these observations, in leukaemic B cells from patients with B chronic lymphocytic leukaemia and the human IgE-secreting myeloma cell line U-266 a strong induction of apoptosis-associated mitochondrial Apo2.7 molecules was observed after treatment with ML I and less effectively by ML III, while in the leukaemic T cell line Molt-4 both ML were strong inductors of apoptosis. In the light of these findings, the possible impact of ML I- and ML III-rich mistletoe extracts in the treatment of B cell neoplasia has to be carefully investigated.

Intracellular expression of IL-4 and inhibition of IFN-gamma by extracts from European mistletoe is related to induction of apoptosis.

BACKGROUND: Extracts from European mistletoe are used for adjuvant cancer treatment. Their influence on the intracellular expression of cytokines of the T-helper cells type-1 (Th1; IFN-gamma) or type-2 (Th2; IL-4) is still unknown. MATERIALS AND METHODS: Lymphocytes from controls were incubated with mistletoe extracts (ME) and mistletoe lectins (ML) for 24 hours and co-stimulated with PMA/Ca-ionophore/monensin during the last 6 hours. Apoptosis and intracellular cytokine expression were detected by flow cytometry, the cytokine release into the supernatants by ELISA. RESULTS: ME and ML significantly inhibited intracellular expression of IFN-gamma but stimulated IL-4. Thereby, IL-4 was mainly expressed in apoptotic (Apo2.7+) cells. However, IFN-gamma secretion into the supernatants of the cells was dose-dependently inhibited by ME and ML, while IL-4 was not detected at all. CONCLUSION: The intracellular expression of the 'Th2-cytokine' IL-4 in ME- and ML-exposed cells may not be related to a typical Th2-response but rather to cell death. This effect might be of great relevance e.g. after intratumoural injection of the mistletoe extracts and, in general, for the inhibition of an inflammatory response during apoptosis.

Toxic proteins from European mistletoe (Viscum album L.): increase of intracellular IL-4 but decrease of IFN-gamma in apoptotic cells.

BACKGROUND: Mistletoe lectins (ML), the major biologically active components of mistletoe extracts, which are used for adjuvant cancer therapy, induce apoptosis in lymphocytes and tumor cells. In addition, ML at toxic concentrations induce the release of cytokines, but it remains unclear as to whether dying or activated cells are responsible. MATERIALS AND METHODS: By flow cytometry, expression of IFN-gamma, IL-4, apoptosis marker Apo2.7 and anti-apoptotic Bcl-2 proteins were analyzed in response to ML or viscotoxins (VT) in PBMC from controls and plasmocytoma cells (U-266). RESULTS: While ML inhibited PMA/Ca-ionophore/monensin co-stimulated IFN-gamma production, they increased IL-4 expression in CD8+ and CD4+ T-cells. Thereby, IL-4 was mainly expressed in apoptotic cells with a low level of Bcl-2 proteins. In contrast, the cell membrane permeabilising VT induced complete loss of Bcl-2 proteins but did not stimulate IL-4 production within 24 hours, indicating that IL-4 expression is related to apoptosis but not to necrosis. CONCLUSION: Despite the role of IL-4 during activation of type2 T-helper cells, IL-4 expression may play an important yet undefined role during apoptosis of normal and tumor cells.

[Vascularization of breast tumors: use of ultrasound contrast medium in evaluating tumor entity. Preliminary results]. / Vaskularisation von Mammatumoren: Einsatz des Ultraschallkontrastmittels in der Dignitätsbeurteilung. Vorläufige Ergebnisse.

PURPOSE: The objectives of the present study were to investigate the utility of an ultrasound echo enhancer in the evaluation of the dignity of breast tumors and to identify the best examination parameters. PATIENTS AND METHODS: 68 breast tumors in 61 female patients who were referred for operative tumor removal were examined by color-coded duplex sonography before and after administration of Levovist. The investigated parameters were: a) the degree of enhancement, b) the number of tumor vessels, c) the time to maximum enhancement, and d) the morphological pattern and course of vessels. RESULTS: With regard to parameters A, B, and C there were in part pronounced overlaps between malignant (n = 44) and benign (n = 24) lesions. The best differentiation was found for parameter D with a sensitivity of 95% and a specificity of 83%. In all previously operated patients a distinction between a postoperative scar (n = 8) and a tumor recurrence (n = 13) was possible. CONCLUSIONS: The use of Levovist leads to a clear improvement in the evaluation of dignity by duplex sonography. On the basis of our preliminary results, the characteristic pattern of vascular morphology and course is the best examination parameter. In particular, the otherwise difficult distinction between scar and recurrence appears to be an interesting application.

[Mistletoe extracts in the therapy of malignant, hematological and lymphatic diseases--a monocentric, retrospective analysis over 16 years]. / Therapie mit Mistelextrakten bei malignen hämatologischen und lymphatischen Erkrankungen--eine monozentrische retrospektive Analyse über 16 Jahre.

OBJECTIVE: The aim of the present investigation was to investigate potentials risks of treatment with mistletoe extracts in patients with malignant haematological and lymphatic diseases consulting the Tumour Ambulance of the Community Hospital Herdecke and to evaluate the therapeutic experiences with this treatment. PATIENTS AND METHODS: All 700 patients with these diseases who had been counselled at the Tumour Ambulance of Community Hospital Herdecke since the foundation of the unit were included in a retrospective questionnaire study to collect information on the course of the disease and the survival time. Therapy with mistletoe extracts had been recommended to all patients. The treatment was carried out by the patient's physician outside the hospital. For inclusion into further analysis, information on survival time and mistletoe treatment had to be available. Survival times of patients who had actually received the recommended mistletoe treatment and of patients who had not received the recommended mistletoe treatment were compared (internal comparison). Furthermore, the results were compared to those of conventionally treated patients obtained from the literature (literature comparison). RESULTS: Of 237 patients for whom sufficient data was available, 14 had not been treated with a mistletoe extract. The median survival time was 9.18 years among patients who had received mistletoe compared to 7.54 years among those without. Before a statistical test was carried out, the equivalent distribution of diagnosis in the 2 groups was tested. Regarding this criterion, only 205 patients treated with mistletoe extract and 9 patients not treated with mistletoe extract could be included into the statistical tests of the median survival time. The median survival time was 11.4 years (mistletoe patients) and 8.6 years (patients without mistletoe therapy). The difference was not significant. There were no cases in which mistletoe treatment was associated with deterioration. The comparison with data from the literature yielded very similar survival times among patients not treated with mistletoe extract and those included in our study. CONCLUSION: No indications to risks of a mistletoe therapy on progress of the disease and the survival time could be found. Therefore, no ethical reservations should be opposed to future prospective investigations of mistletoe therapy in patients with malignant haematological diseases.

[Retrospective study of malignant melanoma patients treated with mistletoe extracts]. / Retrospektive Untersuchung von Patienten mit malignem Melanom unter einer Misteltherapie.

OBJECTIVE: The aim of the present investigation was to analyze survival time and survival rate of all patients with malignant melanoma who had been counseled at the Tumorambulanz Herdecke of the Community Hospital Herdecke. PATIENTS AND METHODS: 284 melanoma patients were included in a retrospective questionnaire study. Only those patients were considered for analysis in whom the prognostic factors histology, tumor localization, and Clark level were known. The data of the study population were compared with patient data obtained from the literature. RESULTS: 94 patients were included in the analysis. 66 of whom had received and 7 had not received mistletoe treatment, in the remaining 21 patients there was no information whether or not mistletoe treatment had been given. Thus, we did our study without a clearly defined internal control group. The median survival time among patients treated with mistletoe had been 14.1 years. The 5- and 10-year survival rates were 80 and 68% for the mistletoe-treated patients, respectively. DISCUSSION: The 5-year survival rate of the mistletoe-treated patients is comparable to that of patients without mistletoe therapy while the 10-year survival rate is a little bit lower. This may be due to the fact that, in contrast to the patients from the relevant literature, 33.3% of the patients suffered from lymph node and/or distant metastases already before counseling the Tumorambulanz Herdecke. Moreover, 50% of our patients had melanoma of Clark level IV in contrast to 22.2% or 31% in the relevant literature. CONCLUSIONS: In spite of the theoretical reservations against mistletoe treatment in melanoma patients, our retrospective analysis did not show any clues about disadvantages of mistletoe treatment in melanoma patients. A controlled prospective study therefore should prove the efficacy of a mistletoe therapy in patients with malignant melanoma.

[Analgesia with mild side effects]. / Analgesie mit geringen Nebenwirkungen.

The efficacy of nefopam, a novel analgesic agent, was compared to pentazocine in a double blind study in 40 cancer patients with chronic pain. Both drugs were administered orally for 10 days. Pain relief after nefopam was at least as good as after pentazocine. Side efftects after nefopam were different in nature and less frequent than after pentazocine; respiratory depression or sedation were no observed.