[Multimorbidity and multi-target-therapy with herbal drugs]. / Multimorbidität und Multi-Target-Therapie in der Phytotherapie.

The active components of herbal drugs and substances are pleiotropic multi-ingredient compounds with multitarget properties including antiinflammatory effects. A pleiotropic inhibition of inflammation could play an important role in mutlimorbide patients as an attempt of prevention or retardation of metastasis. A large number of experimental data for European and non-European herbal drugs as well as various herbal drug combinations suggest such a possibility. Despite the so far small number of clinical studies, such an experimental herbal treatment could appear to be reasonable and acceptable, provided that there are data available on quality and safety of these herbal drugs by treatments of patients with various diseases. Besides, herbal drugs and substances play a growing role the treatment of patients with multimorbidity. Many of these herbal drugs have antiinflammatory effects beside their proved symptomatic efficacy in a lot of other diseases. The specific selection of herbal drugs that are efficacious in specific indications and additionally showed antiinflammatory effects offers the possibility of simultaneous antiinflammatory and specific efficacy. St. John's Wort and milk thistle belong to the oldest and to the best experimentally and clinically examined herbal remedies. The spectrum of internal and external uses of Hypercum perforatum as a multicompound herbal drug includes functional gastro-intestinal complaint and illness, skin disease, mucosal lesion, superficial injury, depressive upset and depression, somatoform disorders, restlessness, nervosity, convalescence, exhaustion and sleep disturbances respectively. The plurivalent character of the multicompound even enables a broad spectrum of activity. This might justify to prefer St. John's Wort to other drugs in a wide range of treatments: In multimorbide patients with depression or in depressive patients with coronary heart disease the anti-inflammatory effects could mean an additional advantage. However, at present there is still a great need and demand for therapy-oriented clinical research.

Peritoneal cancer treatment with CYP2B1 transfected, microencapsulated cells and ifosfamide.

The prognosis of peritoneal spread from gastrointestinal cancer and subsequent malignant ascites is poor, and current medical treatments available are mostly ineffective. Targeted chemotherapy with intraperitoneal prodrug activation may be a beneficial new approach. L293 cells were genetically modified to express the cytochrome P450 enzyme 2B1 under the control of a cytomegalovirus immediate early promoter. This CYP2B1 enzyme converts ifosfamide to its active cytotoxic compounds. The cells are encapsulated in a cellulose sulfate formulation (Capcell). Adult Balb/c mice were inoculated intraperitoneally with 1 x 10(6) colon 26 cancer cells, previously transfected with GFP to emit a stable green fluorescence, by injection into the left lower abdominal quadrant. Two or five day's later animals were randomly subjected to either i.p. treatment with ifosfamide alone or ifosfamide combined with microencapsulated CYP2B1-expressing cells. Peritoneal tumor volume and tumor viability were assessed 10 days after tumor inoculation by means of fluorescence microscopy, spectroscopy and histology. Early i.p. treatment with ifosfamide and CYP2B1 cells resulted in a complete response. Treatment starting on day 5 and single-drug treatment with ifosfamide resulted in a partial response. These results suggest that targeted i.p. chemotherapy using a combination of a prodrug and its converting enzyme may be a successful treatment strategy for peritoneal spread from colorectal cancer.

Topical tea tree oil effective in canine localised pruritic dermatitis--a multi-centre randomised double-blind controlled clinical trial in the veterinary practice.

Tea tree oil, a volatile oil, is well known for its broad antibacterial and antifungal activity. A standardised and stabilised 10% tea tree oil cream was tested against a commercial skin care cream (control cream) in the management of canine localised acute and chronic dermatitis. Fifty-seven dogs with clinical manifestations of mostly pruritic skin lesions or alterations, skin fold pyodermas and other forms of dermatitis, corroborated by predominantly positive fungal and bacterial skin isolates, were enrolled by seven practising veterinarians and randomly allocated to two study groups (28:29) and were treated twice daily with a blinded topical preparation. After 10 days of treatment, success rates of 71% for the tea tree oil cream and 41% for the control cream (over-all efficacy documented by the veterinary investigator) differed significantly (p = 0.04), favouring tea tree oil cream treatment. Accordingly on day 10, the tea tree oil cream caused significantly faster relief than the control cream (p = 0.04) for two common clinical dermatitis signs, pruritus (occurring in 84 % of dogs) and alopecia. Only one adverse event was reported in the tea tree oil group (suspected not to be causally related to the study drug) and none in the control cream group. The tested herbal cream appears to be a fast-acting safe alternative to conventional therapy for symptomatic treatment of canine localised dermatitis with pruritus.

[Complementary medicine: phytotherapy and soyaisoflavones as phytoestrogens]. / Komplementärmedizin, Phytotherapie und Sojaisoflavone als Phytoöstrogene.

After a introduction concerning complementary medicine, naturopathy and phytotherapy a general view of soy isoflavones as phytoestrogens will be given. In german speaking countries the term and topic naturopathy has a tradition of 150 years regarding theoretical development and practical use among lay people and health professionals in European culture. In contrary the term complementary medicine has been used for approximately 15 years in englisch speaking countries as a kind of collective name for European and Non-European medical cultures and traditions. Complementay medicine summarizes a huge variety of cultural, medical and qualitywise different medical methods and treatments which can be a contribution to conventional medicine. One of the oldest and intensly researched fields in European and Non-European complementary medicine is the use of herbal drugs (phytotherapy). Soy isoflavones serve as an example to show the differences between phytotherapy based on multicompounds and dietary supplements (neutraceuticals) based on monosubstances. The differing preparations of soy isoflavones are not phytotherapeutic medicine. A review of the experimental and clinical data concerning soy isoflavones as phytoestrogens for the prevention of cancer, menopausal complaints, osteoporosis or cardiovascular diseases indicates that the consumption of food containing phytoestrogens seems to be health protective. Yet, the relevance of supplementation of single phytoestrogens for an additional health effect is not sufficiently proven.

[Fennel tea: risk assessment of the phytogenic monosubstance estragole in comparison to the natural multicomponent mixture]. / Fencheltee: Risikoabschätzung der phytogenen Monosubstanz Estragol im Vergleich zum natürlichen Vielstoffgemisch.

For centuries, fennel fruits have been used as traditional herbal medicine in Europe and China. For the treatment of infants and sucklings suffering from dyspeptic disorders, fennel tea is the drug of first choice. Its administration as a carminativum is practiced in infant care in private homes and in maternity clinics as well where it is highly appreciated for its mild flavor and good tolerance. The long standing positive experience is astonishingly contrasted by a recent statement of the German 'Bundesinstitut für gesundheitlichen Verbraucherschutz und Veterinärmedizin' (BgVV, May 11, 2001), where consumers are advised to reduce their intake of foods containing estragole and methyleugenol, e.g. tarragon, basil, anis, star anis, jamaica pepper, nutmeg, lemon grass as well as bitter and sweet fennel fruits for reasons of health. These warnings are based on experiments with rats and mice where estragole, a natural ingredient of fennel fruits, proved to be carcinogenic. Meanwhile, criticism arose amongst experts concerning the interpretation of these studies. The crucial points of criticism concern the transfer of data obtained in animal models to the human situation as well as the high doses of the applied monosubstance, which do not at all represent the amounts humans are exposed to as consumers of estragole-containing foods and phytopharmaceuticals. Furthermore, studies on estragole metabolism revealed at least quantitative differences between the estragole metabolism of mice and men. In addition, it has been shown that an agent when administered in its isolated form may have significantly different effects and side effects than the same agent applied as a constituent in naturally occurring multicomponent mixtures. Thus, a multicomponent mixture such as fennel tea contains various antioxidants known to be protective against cancer. These differences were not considered in the risk assessment. A well done risk assessment should be based on appropriate data collected in humans. Considering the long traditional use of fennel tea and the total lack of epidemiological and clinical studies indicating a well founded cancerogenic potential, the probability of a serious risk connected with the consumption of fennel tea seems to be negligibly small.

Cimicifuga racemosa extract inhibits proliferation of estrogen receptor-positive and negative human breast carcinoma cell lines by induction of apoptosis.

Hormone replacement therapy is contraindicated in women with breast cancer. Extracts from the rhizomes of Cimicifuga racemosa, have gained acceptance as a natural alternative for the treatment of menopausal symptoms. In the present study we investigated the antiproliferative activity of C. racemosa extracts (isopropanolic and ethanolic) on the estrogen receptor positive MCF-7 and estrogen receptor negative MDA-MB231 breast cancer cells by WST-1 assay. Down regulation of the proliferative activity and cell killing by isopropanolic and ethanolic extracts occurred in a clear dose-dependent response with a 50% growth inhibitory concentration of 54.1 +/- 11.4 and 80.6 +/- 17.7 micro g/ml in MCF-7 cells and of 29.5 +/- 3.0 and 58.6 +/- 12.6 microg/ml in MDA-MB231 cells, respectively. Further, the mode of cell death was identified as apoptosis by microscopic inspection and confirmed by light scatter characteristics and by detection of Annexin V adherence to phosphatidylserine by flow cytometry. In addition, the involvement of activated caspases was supported by the cleavage of cytokeratin 18 detected with M30 antibody. Increases in the level of M30-antigen of about 4-fold and 2-fold over untreated controls were observed in C. racemosa -treated MCF-7 and MDA-MB231 cells. These results indicate that C. racemosa extract exerts no proliferative activity, but kills the estrogen receptor positive MCF-7 as well as estrogen receptor negative MDA-MB231 cells by activation of caspases and induction of apoptosis.

[St. John' Wort (Hypericum perforatum L.)--multicompound preparations versus single substances]. / Johanniskraut (Hypericum perforatum L.)--Vielstoffgemische kontra phytogene Einzelstoffe.

Aqueous alcoholic extracts of St. John s wort are used for the treatment of mild to moderate depression. Recently, Hypericum extracts were also shown to inhibit the growth of various human malignant cells. We promote the hypothesis that the various biological activities of aqueous Hypericum extracts are based on synergistic interactions of all compounds present therein and not on the pharmacological activities of single compounds.

[St. John's Wort (Hypericum perforatum): a plurivalent raw material for traditional and modern therapies]. / Johanniskraut (Hypericum perforatum): Ein plurivalenter Rohstoff für traditionelle und moderne Therapien.

St. John's Wort is one of the oldest and one of the best experimentally and clinically examined herbal remedies. In various medical cultures and medical systems--that is to say the regions of origin of Hypericum perforatum, like Europe, West Asia and North Africa--St. John's Wort has been used as a remedy for centuries. Preparations from St. John's Wort not only represent medical traditions but also ways of thinking, ideas and experiences from naturopathic healers (non-physicians) as well as patients. The complex multicompound with its evolutionary and coevolutionary developed composition and structure acts as a varied raw material for the production of quantitative and qualitative dissimilar remedies, which are multicompounds themselves. They differ not only analytically but also quite often in their effects. The certain and potential spectrum of internal and external uses includes gastrointestinal complaint and illness, skin disease, mucosal lesion, superficial injury, depressive upset and depression, somatoform disorders, restlessness, nervosity, convalescence, exhaustion, sleep disturbance and nursing treatment. The plurivalent character of the multicompound even enables a broad spectrum of activity. This might justify to prefer St. John's Wort to other drugs in a wide range of treatments: In tumor patients with depression the antioxidative effect and the experimentally documented induction of apoptosis could mean an additional advantage, and in depressive patients with coronary heart disease the same applies to the anti-inflammatory and antioxidative effects.

Recombinant mistletoe lectin induces p53-independent apoptosis in tumour cells and cooperates with ionising radiation.

Mistletoe extracts are used as alternative cancer treatment in addition to standard chemotherapy and radiation treatment and have an immunostimulatory and pain-relieving effect. A direct antitumour effect of mistletoe extracts against tumour cells of lymphoid origin has been linked to the D-galactoside-specific mistletoe lectin I. In this study, we investigated the cellular effect of bacterially expressed, recombinant mistletoe lectin alone or in combination with ionising radiation in a genetically defined p53-wild-type and p53-deficient E1A/ras-transformed murine tumour cells system. Downregulation of the proliferative activity and cell killing by recombinant mistletoe lectin occurred in a clear dose response (0.1-1 ng ml(-1)). Induction of apoptosis was p53-independent, but apoptosis-associated factor-1-dependent. Cellular treatment with lectin in combination with ionising radiation resulted in both p53-wild-type and p53-deficient tumour cells in an at least additive, antiproliferative effect and enhanced activation of caspase-3. Combined treatment with ionising radiation and lectin revealed a similar cytotoxic effect in human, p53-mutated adenocarcinoma cells. Thus, recombinant mistletoe lectin alone and in combination with ionising radiation bypasses often prevalent apoptotic deficiencies in treatment-resistant tumour cells.

[Adverse effects and interactions of phytotherapeutic drugs]. / Unerwünschte Wirkungen und Wechselwirkungen von Phytotherapeutika.

The significantly increased sales figures many phytopharmaceuticals have achieved during the last years prove the confidence that a great part of the population has in herbal remedies. This is primarily due to the wide-spread opinion that herbal remedies are free from side-effects. The long tradition and presumed 'natural' origin are no guarantee for safety in the treatment with herbal remedies. Even if a large proportion of the undesirable events is traceable to falsifications, impurities and lacking quality controls, herbal drugs with controlled quality should not be generally classified as harmless. In the meantime it has been possible to prove the presence of active substances with toxic and cancerogenic properties in various phytopharmaceuticals. Interactions with other drugs have been documented in a number of notes, where phytopharmaceuticals could influence the blood plasma level of various drugs, presumably by activating or inhibiting the cytochrom-P450-system. At present, especially data about adverse effects during long-term administration of herbal remedies are under-represented. Particularly because of their presumed harmlessness they often are prescribed in the case of chronic diseases and then taken over a longer period of time. The frequency of undesirable effects of phytopharmaceuticals is remarkably low, even if the present lack of data about side-effects is considered.

Aqueous ethanolic extract of St. John's wort (Hypericum perforatum L.) induces growth inhibition and apoptosis in human malignant cells in vitro.

Extracts of Hypericum perforatum (St. John's wort) are widely and effectively used in the treatment of mild to moderate depression. In addition, hypericin, a component of Hypericum p. extracts, exhibits light-dependent phototoxic properties and can be used in phototherapy. We therefore investigated the cytotoxic activity of two total Hypericum p. extracts, namely from fresh and dried plants in the dark and after exposure to 7.5 J/cm2 white light illumination and compared it with the effect of hypericin on K562, U937, LN229 glioblastoma cell lines and normal human astrocytes. The chemical toxicity of non-illuminated Hypericum p. extracts in the cells tested is low as expressed by a LC50 between 1.9-4.1 mg/ml, which corresponds to 10.3-17.3 microM hypericin and 114.4-190.7 microM hyperforin after 48 h treatment. Hypericum p. extracts induced dose-dependent growth arrest of human malignant cells in the absence of illumination with GI50 values between 0.43-1.77 mg/ml (2.3-9.7 microM hypericin, 26.1-106.7 microM hyperforin) for the fresh plant extract and 0.59-3.03 mg/ml (2.5-12.8 microM hypericin, 24.2-124.7 microM hyperforin) for the dried extract. The growth inhibitory effect of fresh Hypericum p. extract was more pronounced in leukemia cell lines K562 and U937, the GI50 concentrations being about 7-fold lower than the corresponding LC50 for the cell lines K562 and U937, but almost the same as the LC50 for LN229 and NHA cells. GI50 (microgram/ml) for tumor cell lines K562 and U937 (432 and 799) established after 48 h differed significantly (p < 0.05) from those of LN229 and normal human astrocytes (1767 and 2900). The light-exposed extracts were more toxic, their LC50 and GI50 values were reduced to values corresponding to LC50 concentration of 3.7-7.4 microM and a GI50 of 1.3-3.5 microM for phototoxic hypericin. After exposure to light, there was a significant difference (p = 0.006) between the GI50 of glioblastoma LN229 cells (582 micrograms/ml) and normal human astrocytes (1050 micrograms/ml). Morphological examination by light microscopy and phosphaditylserine exposure on the outer plasma membrane investigated by Annexin V-binding with flow cytometry after 24 h confirmed that Hypericum p. extracts caused apoptosis of treated cells without exposure to light. Hypericum p. extracts derived from fresh herbs and from dried herbs which differ in their levels of phloroglucinols (hyperforin and adhyperforin) were compared. The hyperforin content of fresh St. John's wort extract exceeded that of dried plant extract by 47% and the GI50 values of fresh plant extract were 73%, 77% and 58% of those established for dried extract in the three malignant cell lines K562, U937 and LN229 in the dark (p < 0.05). Under white light (7.5 J/cm2), both extracts exerted comparable growth inhibitory and apoptosis inducing effects due to the phototoxicity of hypericin, the corresponding concentrations of which were in the range of 1.3-3.5 microM. The data reported in this study suggest that illumination is not essential for the growth inhibitory and apoptotic effects of Hypericum p. extracts, but light activation potentiates them. Furthermore, the constituent hyperforin is at least partly responsible for these effects in the dark.

Phytotherapy of chronic dermatitis and pruritus of dogs with a topical preparation containing tea tree oil (Bogaskin).

Localised dermatitis, for example unspecific eczema or skinfold pyoderma, is a very common diagnosis in dogs. Typical and impressive complaints are pruritus, erythema, erosion and oozing surface. With respect to the underlying disease dermatological treatment is indicated, usually based on antimicrobial and antipruriginous active substances, it can include transient glucocorticoids. An effective and safe alternative might be a phytotherapeutic topical preparation containing tea tree oil. Tea tree oil exerts both antimicrobial and antipruriginous effects. In an open multicenter study efficacy and safety of a standardized 10% tea tree oil cream applied thinly and twice daily for 4 weeks was tested in 53 dogs with chronic dermatitis, particularly non-specific eczema, allergic dermatitis, interdigital pyoderma, acral lick dermatitis and skinfold pyoderma. Analysis of efficacy assessed by investigating veterinarians showed a good or very good response to treatment for 82% of the dogs, significant at a 5% level (p = 0.05). At the end of the study a strong and significant reduction (p = 0.001) as well as disappearance of major symptoms were observed. Only two adverse events (local reactions) possibly related to tea tree oil occurred during therapy. Consequently the tested study medication (Bogaskin) can be considered an alternative for uncomplicated and localised dermatitis in dogs. Bogaskin might allow reduction of other pharmaceutical products, perhaps even replace standard therapy.

Antifungal effect of Australian tea tree oil on Malassezia pachydermatis isolated from canines suffering from cutaneous skin disease.

The lipophilic yeast Malassezia pachydermatis is part of the normal skin flora of most warm-blooded organisms. In a number of surveys it could be demonstrated that this yeast species might be involved in different skin diseases like seborrhoeic dermatitis, especially in dogs and cats. In order to look for an alternative therapeutic agent to the commonly used antimycotic and antiseptic synthetic substances the in vitro activity of Australian tea tree oil, the essential oil of Melaleuca alternifolia, against several strains of Malassezia pachydermatis was examined. All tested strains showed remarkably high susceptibility to tea tree oil. With these results the excellent antibacterial activity of tea tree oil is extended to a new group of fungal pathogens colonizing mainly mammals' skin. During the last ten years there was an increasing popularity of tea tree oil containing human health care products. The presented data open up new horizons for this essential oil as a promising alternative agent for topical use in veterinary medicine as well.

Modulation of interleukin-15-induced human neutrophil responses by the plant lectin Viscum album agglutinin-I.

The plant lectin Viscum album agglutinin-I (VAA-I) and the interleukin-15 (IL-15) cytokine are two molecules with potential therapeutic properties known to modulate neutrophil functions when used separately. This study was conducted in order to better understand the mode of action of VAA-I and to elucidate how VAA-I could modulate IL-15-induced neutrophil responses. We found that VAA-I cannot induce phosphorylation events in human neutrophils. However, it enhances phagocytosis by itself without altering IL-15-induced phagocytosis. VAA-I was found to reverse the ability of IL-15 to delay neutrophil apoptosis and this was correlated with an inhibition of IL-15-induced de novo protein synthesis. In addition, we also found that IL-15 cannot reverse or attenuate the caspase-induced gelsolin fragmentation observed during apoptosis as assessed by immunoblotting. We conclude that VAA-I can be used to modulate some, but not all, IL-15-induced neutrophil responses and that it acts independent of phosphorylation events.

Immuno-isolation in oncology--a mini-review.

Immuno-isolation provides a potentially safe and effective method of delivering recombinant therapeutic molecules. Its application as a drug-delivery platform for the treatment of cancer has shown promising developments recently. This review will summarize the principle and current progress of this novel therapy paradigm in oncology. In this approach, a non-autologous cell line is genetically modified to secrete a recombinant product with potential for tumor suppression. Such a cell line may be implanted without graft rejection into all patients with similar neoplastic disease. The immune protection is conferred by enclosure within immuno-isolating devices such as microcapsules whose permeability would allow passage of smaller molecules such as oxygen, nutrients and waste products as well as the desired therapeutic transgene product. However, large immune mediators such as complement, macrophages and lymphocytes responsible for graft rejection would be excluded. In this review, we will consider how this technology may be applied as a novel genetic tool for cancer treatment to deliver antibodies, cytokines, enzymes and growth factors for treatment of various types of cancer. These molecules can be delivered at low constitutive levels, thereby permitting long-term systemic delivery, maintaining biological activity over extended periods, and eliminating the costs of product purification. The current success of this strategy in cancer treatment will be reviewed in in vitro systems, in animal models of cancer, and in human clinical trials.

In vivo perivascular implantation of encapsulated packaging cells for prolonged retroviral gene transfer.

Long-term benefits of coronary angioplasty remain limited by the treatment-induced renarrowing of arteries, termed restenosis. One of the mechanisms leading to restenosis is the proliferation of smooth muscle cells. Therefore, proliferating cells of the injured arterial wall, which can be selectively transduced by retroviruses, are potential targets for gene therapy strategies. A direct single-dose therapeutic application of retroviral vectors for inhibition of cell proliferation is normally limited by too low transduction efficiencies. Encapsulated retrovirus-producing cells release viral vectors from microcapsules, and may enhance the transduction efficiency by prolonged infection. Primary and immortal murine and porcine cells and murine retrovirus-producing cells were encapsulated in cellulose sulphate. Cell viability was monitored by analysing cell metabolism. Safety, stability, transfer efficiency and extent of restenosis using capsules were determined in a porcine restenosis model for local gene therapy using morphometry, histology, in situ beta-galactosidase assay and PCR. Encapsulation of cells did not impair cell viability. Capsules containing retrovirus-producing cells expressing the beta-galactosidase reporter gene were implanted into periarterial tissue or a pig model of restenosis. Three weeks following implantation, beta-galactosidase activity was detected in the pericapsular tissue with a transduction efficiency of approximately 1 in 500 cells. Adventitial implantation of vector-producing encapsulated cells for gene therapy may, therefore, facilitate successful targeting of proliferating vascular smooth muscle cells, and allow stable integration of therapeutic genes into surrounding cells. The encapsulation of vector-producing cells could represent a novel and feasible way to optimize local retroviral gene therapy.

Microencapsulated cell-mediated treatment of inoperable pancreatic carcinoma.

Pancreatic cancer can seldom be resected, and chemotherapy has only a limited effect on survival or tumour load. We did a phase I/II trial in 14 patients with pancreatic cancer to assess the safety of local activation of low-dose ifosfamide. We encapsulated genetically modified allogeneic cells, which expressed a cytochrome P450 enzyme, in cellulose sulphate and delivered them by supraselective angiography to the tumour vasculature. These cells locally activated systemically administered ifosfamide. The tumours of four patients regressed after treatment, and those of the other ten individuals who completed the study remained stable. Median survival was doubled in the treatment group by comparison with historic controls, and 1-year survival rate was three times better. Further studies of this cell-therapy-based treatment combined with chemotherapy for inoperable pancreatic cancer are warranted.

Analgesic efficacy of the serial application of a sulfurated mud bath at home.

The purpose of this randomized controlled trial was to evaluate the analgesic efficacy of a series of applications of sulfurated mud baths in outpatients suffering from back pain. Within 2 weeks 13 patients took 6 sulfurated mud baths (group A) and 12 patients 6 tap water baths (group B) at home. Before the bath and over 48 h after starting the 1st and the 6th bath, pain intensity was evaluated by the patients according to a visual analogue scale (VAS). The main outcome parameter was the weighted (for time of observation) sum of pain intensity (SPI) after the 6th bath. The mean SPI in group A was 741 mm x h (95% CI 594-864 mm x h) and in group B 1,112 mm x h (95% CI 929-1,252 mm x h) (p = 0.009), suggesting a significantly stronger analgesic effect of a series of sulfurated mud baths than of a series of tap water baths.

[Comparative epidemiological study in patients with rheumatic diseases illustrated in a example of a treatment with non-steroidal anti- inflammatory drugs versus an oral enzyme combination preparation]. / Vergleichende epidemiologische Studie bei Erkrankungen des rheumatischen Formenkreises am Beispiel der Therapie mit nichtsteroidalen Antiphlogistika versus einem oralen Enzymkombinationspräparat.

To establish the safety and efficacy of an oral enzyme-combination product (OE; Phlogenzym, containing trypsin, bromelain and rutin) in the treatment of rheumatic diseases a retrolective cohort study with parallel groups was undertaken as an epidemiological study, in which the enzyme combination was compared with non steroidal anti-inflammatory drugs (NSAID). Data of 3326 patients treated for rheumatic diseases between January 1993 and the end of March 1995 were registered by 380 physicians. From the patient file age, gender, indication for treatment (diagnostic group), anamnestic data (especially pre-treatment), complaints at the beginning and end of treatment, treatment duration, prescribed drugs (OE, NSAID), additional treatment and adverse events were transferred into case report forms (CRFs). The quality of the data was monitored and additionally checked by internal and external quality audits. Included in the efficacy analysis were 2139 patients which were treated either only with OE or only with NSAID and could be classified unambiguously into one of the following diagnostic groups: joint diseases, spinal diseases, rheumatic soft tissue diseases. As clinically relevant and reliably evaluable criterion freedom from rheumatic complaints at the end of treatment was considered. For evaluation of safety the documented adverse events of all patients were considered. Two thirds of the OE patients received the recommended dose of 6 tablets/day, taken for 23 to 35 days. The respective mean values for NSAID patients were 16 to 25 days, and the patients were treated with the recommended symptomatically effective doses of NSAID. As the allocation of the compared treatment options (OE or NSAID) to the patients was not randomized, a mixing of treatment effects with other factors cannot be excluded. For adjustment of these confounding factors two methods were applied: a) logistic regression of the relative ratio of the main criterion and all confounding factors and b) stratification of data according to the propensity score i.e. the probability of a treatment with OE. Both methods yielded similar results: A 50% higher success rate can be expected in total for OE than for NSAID at comparable initial and treatment situations (95% confidence interval with logistic regression = 1.218-1.96, with stratification according to propensity score = 1.16-1.84). As significant negative indicators for response age over 50 years, pre-treatment with antirheumatic or analgetic drugs, treatment duration more than 30 days and joint diseases or fibromyalgias could be revealed. Since there was no interaction between these indicators and the type of treatment also in patients presenting with these indicators a treatment success (freedom from symptoms) with OE can be expected with a higher probability than with NSAID. OE were well tolerated showing much less adverse events when compared with conventional doses of NSAID.

Immunotherapy of a viral disease by in vivo production of therapeutic monoclonal antibodies.

Continuous and sustained in vivo production of monoclonal antibodies by engineered cells might render long-term antibody-based treatments cost-effective, avoid side effects associated with infusion of massive doses of antibody, and circumvent possible antiidiotypic responses against the therapeutic agent. The FrCasE retrovirus induces a lethal neurodegeneration on infection of newborn mice. We report here that implantation of cellulose sulfate capsules containing cells secreting an ectopic monoclonal antibody neutralizing FrCasE can prevent animals from developing the disease. All treated mice showed reduced or undetectable viremia in addition to a lack of the histopathological lesions characteristic of FrCasE infection. This work paves the way for a novel gene/cell antibody-based immunotherapy of a variety of severe viral and nonviral diseases.