Drug safety aspects of herbal medicinal products.

There are numerous statements in the literature suggesting that the safety of herbal products or herbal medicinal products is inadequately considered. Despite the presence of risk, the potential is commonly underestimated as herbals are considered to be natural substances. It is necessary to consider the different categories of herbal products in the market. On one hand there are authorised herbal medicinal products (HMPs) which have adhered to the requirements to present data on quality, efficacy and safety. On the other hand there are products falling outside the use of marketing authorisations as for remedies. In the European Union (EU), HMPs are subject to an ambitious and comprehensive risk management system as for chemically defined drugs, which react effectively to risk concerns with scientific methods, as has been shown in the past. The established methods of pharmacovigilance and risk management favour the authorisation of herbal preparations for medicinal purposes as proprietary medicinal drugs.

[Topical gel formulation of ibuprofen in the treatment of acute and chronic joint and soft tissue pain. Results of a non-interventional observational trial]. / Topisches Ibuprofen bei akuten und chronischen Gelenk- und Weichteilschmerzen. Ergebnisse einer nicht-interventionellen Studie.

BACKGROUND: Pain, inflammation or swelling of soft tissues orjoints is often treated with oral or topical formulation of lbuprofen. METHOD: Thetherapeutic effect of a topical gel formulation of Ibuprofen (doc Ibuprofen Schmerzgel) was investigated in an observational trial. A total of 170 patients suffering either from pain, inflammation or swelling of soft tissues or joints or having experienced a blunt trauma were enrolled into this study. Physicians and patients evaluated typical symptoms at study entry and after 1 week at the final visit. Further, the patients were asked and instructed to monitor their symptoms in a daily diary over this week. RESULTS: Patientssufferingfromacute trauma (group A (symptoms existent up to 48 hours) as well as patients with chronic symptoms (group B) experienced a fast and prominent improvement of symptoms. In group A total reduction of all symptoms after one week was recorded to amount to considerably more than 80%, in group B a reduction of more than 50% compared to the initial scores could be seen. Evaluation done by physicians and patients were extremely concordant with regard to timecourse and final outcome of the treatment. After first use on day one group A noted a reduction of pain symptoms after approximately 25 minutes, while in group B a considerable relief of pain was reported after approximately 37 minutes. During this one-week treatment period no adverse-effects were reported.Tolerability and applicability were classified as good to excellent. CONCLUSIONS: The results of this study confirm findings from existing clinical trials data. In acute traumata a faster symptom relief is found, in chronic conditions the product leads to symptom reduction in case seven where pretreatment has shown insufficient results. Thus this topical treatment provides a treatment option either alone or in combination with orally taken NSAIDS.

Process optimization and biocompatibility of cell carriers suitable for automated magnetic manipulation.

There is increasing demand for automated cell reprogramming in the fields of cell biology, biotechnology and the biomedical sciences. Microfluidic-based platforms that provide unattended manipulation of adherent cells promise to be an appropriate basis for cell manipulation. In this study we developed a magnetically driven cell carrier to serve as a vehicle within an in vitro environment. To elucidate the impact of the carrier on cells, biocompatibility was estimated using the human adenocarcinoma cell line Caco-2. Besides evaluation of the quality of the magnetic carriers by field emission scanning electron microscopy, the rate of adherence, proliferation and differentiation of Caco-2 cells grown on the carriers was quantified. Moreover, the morphology of the cells was monitored by immunofluorescent staining. Early generations of the cell carrier suffered from release of cytotoxic nickel from the magnetic cushion. Biocompatibility was achieved by complete encapsulation of the nickel bulk within galvanic gold. The insulation process had to be developed stepwise and was controlled by parallel monitoring of the cell viability. The final carrier generation proved to be a proper support for cell manipulation, allowing proliferation of Caco-2 cells equal to that on glass or polystyrene as a reference for up to 10 days. Functional differentiation was enhanced by more than 30% compared with the reference. A flat, ferromagnetic and fully biocompatible carrier for cell manipulation was developed for application in microfluidic systems. Beyond that, this study offers advice for the development of magnetic cell carriers and the estimation of their biocompatibility.

[Vitamin E for gonarthrosis and coxarthrosis--results of a postmarketing surveillance study]. / Vitamin E bei Gon- und Coxarthrose. Ergebnisse einer Anwendungsbeobachtung.

BACKGROUND: Inflammatory processes release reactive oxygen species, destroying cartilage tissue. Vitamin E is an antioxidant and protects cartilage tissue. Dietary intake of vitamin E is often low in patients with osteoarthrosis, and short term clinical studies have shown symptomatic relief in pain. Therefore, efficacy and tolerability of vitamin E are investigated in routine use of medical practitioners. PATIENTS AND METHODS: Open, multicentric observational study including 151 patients with osteoarthritis (knee, hip): 85 patients were treated with 333,5 mg RRR-alpha-tocopherol (monotherapy), 61 patients with 333,5 mg RRR-alpha-tocopherol and a further analgesic (combination therapy). 5 patients (2 monotherapy, 3 combination) failed to turn up for follow-up (dropout). According to the study design, the physician was free in his treatment (assignment to treatment, choice of analgesic). After 4, 8, and 12 weeks the efficacy and tolerability were determined by physicians and by patients. RESULTS: Demographic data were comparable in both groups, however clinical condition was slightly worse in the combination group. In the course of the treatment, all parameters improved in both groups. Monotherapy was somewhat less effective and set on later. There were two adverse events in the monotherapy group (total endoprosthesis, itching). Tolerability of monotherapy was rated slightly better than combination therapy by physicians and by patients. CONCLUSIONS: For patients with gonarthrosis or coxarthrosis the supplementation of Vitamin E to an analgetic medication is reasonable and well tolerated.

Willow bark extract (Salicis cortex) for gonarthrosis and coxarthrosis--results of a cohort study with a control group.

STUDY OBJECTIVE: The examination of the effectiveness and tolerance of willow bark extract in patients with gonarthrosis and coxarthrosis compared to conventional therapies. METHODS: In an open, multicentric observational study with reference treatment, 90 patients were treated with a standardised willow bark extract preparation, 41 patients with a standard therapy prescribed by a doctor and 8 patients with a combination of the two. After 3 and finally 6 weeks the effectiveness and tolerance were determined by the doctor (clinical findings, recording of adverse events, global tolerance) and by the patients (WOMAC questions concerning pain and stiffness, questions on general state of health). RESULTS: A total of 88 patients in the willow bark group and 40 patients in the reference group completed the study. The doctors and patients judged the effectiveness in both groups to be comparable. After 6 weeks the effectiveness of the willow bark extract tended to be assessed as better than in the group undergoing conventional therapy. Also in the subgroup of chronically sick patients (>3 months), after 6 weeks the effectiveness of both forms of treatment was comparable; however, the effect was slower to set in the willow bark group than in the reference group. Doctors and patients assessed the tolerance of the willow bark extract to be better than the conventional therapy. Adverse effects of the drugs did not occur in the willow bark group; one case each of reflux symptoms occurred in the reference group and the CONCLUSIONS: For treating mild or fairly severe cases of gonarthrosis and coxarthrosis the effect of willow bark extract is comparable to that of standard therapies, without the corresponding side effects having to be accepted.

The active components and the pharmacological multi-target principle of STW 5 (Iberogast).

The therapeutic equivalence of the multi-herbal drug combination STW 5 (Iberogast) with two synthetic standard drugs can be explained by an additive or overadditive pharmacological synergism. A review of the different chemical constituents contained in this fixed combination of nine herbal drug extracts and their dominant mechanisms of action shows that they correlate very well with the clinically relevant overall pharmacological profile of the multi-herbal drug combination. This comprises modulatory effects on gastro-intestinal motility, anti-inflammatory action, inhibitory effects on gastric acid production and anti-oxidative and radical-inhibiting properties. As a multi-drug preparation with a multitude of therapeutic targets relevant in functional gastrointestinal diseases, its pharmacological profile of action in accordance with the multi-target principle.

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.

Proposals to enhance the quality of observational cohort studies.

For herbal medicinal products the methodology of observational cohort studies (observational studies, drug monitoring studies, Anwendungsbeobachtung) represents a useful addition to clinical trials. The key objectives are the documentation of efficacy in particular under conditions of everyday medical practice in authentic patients and the documentation of the safety profile. Supplementary to earlier activities, members of the "Clinical Trials of Herbal Medicinal Products" Working Party of the German Society for Phytotherapy have therefore again addressed the issue of observational cohort studies for to enhance the informative value and importance of this clinical research methodology. Recommendations were developed on quality aspects, methodological approaches of observation parameters, and for the reporting of the study's results. Properly planned and conducted observational cohort studies may contribute to the documentation and proof of well-established medicinal use according the EU Directive 2001/83/EC.

[Degenerative diseases of the musculoskeletal system--overview of current clinical studies of Devil's Claw (Harpagophyti radix)]. / Degenerative Erkrankungen des Bewegungsapparates--Ubersicht zu aktuellen klinischen Studien mit Extrakten aus der Teufelskralle (Harpagophyti radix).

Herbal medicinal products with secondary tubers of Devil's Claw (Harpagophyti radix) are successfully used in degenerative rheumatism. The interest in this herbal drug is documented by many controlled and uncontrolled clinical studies in the last few years. Efficacy was tested in patients with degenerative rheumatism or low back pain. There was shown an improvement of motility and a reduction of pain sensation and a good tolerability following an administration even for only few weeks.

[The status of herbal antilipemic agents]. / Zum Stellenwert phytotherapeutischer Lipidsenker.

A favourable effect on serum lipids may be achieved with herbal medicinal products, if they are administered at sufficient high dosages and sufficient long term use. Their efficacy is not so strong than that documented for chemically defined products, however their tolerability is superior. Maximal effects are more than that of a strong lipid lowering diet, however, lipid lowering herbal drugs are Allium sativum L., Cynara scolymus L., Curcumae longa L. All of them exert some more beneficial effects, which suggest to be an advantageous alternative for patients. This contribution gives a brief review and an assessment of the suitability of herbal medicinal preparations for the prophylactic or therapeutic treatment of hyperlipidemia and atherosclerosis.

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.

Extended NO analysis applied to patients with COPD, allergic asthma and allergic rhinitis.

The recommended method to measure exhaled nitric oxide (NO) cannot reveal the source of NO production. We applied a model based on the classical Fick's first law of diffusion to partition NO in the lungs. The aim was to develop a simple and robust solution algorithm with a data quality control feature, and apply it to patients with known alterations in exhaled NO. Subjects with allergic rhinitis, allergic asthma, chronic obstructive pulmonary disease (COPD) smokers and controls were investigated. NO was measured at three expiratory flow rates. An iteration method was developed to partition NO. The airway tissue content of NO was increased in asthma, 144 +/- 80 ppb (P = 0.04) and decreased in smokers, 56 +/- 36 ppb (P = 0.02). There was no difference between subjects with rhinitis, 98 +/- 40 ppb and controls, 98 +/- 44 ppb. The airway transfer rate was increased in allergic asthma and allergic rhinitis, 12 +/- 4 vs. 12 +/- 5 ml sec(-1), compared to controls, 8 +/- 2 ml sec(-1) (P < 0.001). The alveolar levels were no different from controls, 2 +/- 1 ppb. In COPD the alveolar levels were increased, 4 +/- 2 ppb (P < 0.001). Extended NO analysis reveals from where in the respiratory system NO is generated. Hence, this new test can be added to the tools the physician has for the diagnosis and treatment of patients with respiratory disorders.

Dose-ranging study of mometasone furoate dry powder inhaler in the treatment of moderate persistent asthma using fluticasone propionate as an active comparator.

BACKGROUND: Mometasone furoate (MF; Schering-Plough, Madison, NJ), is a glucocorticoid with high local potency and low potential systemic availability. OBJECTIVES: To compare the relative efficacy and safety of a new formulation of MF, coupled with a recently designed dry powder inhaler (DPI), in the treatment of patients with moderate persistent asthma. Fluticasone propionate administered by Diskhaler (FP Diskhaler, 250 microg twice a day; Glaxo Wellcome, Research Triangle Park, NC) was used as an active control. DESIGN: A randomized, parallel group, double-blind (for MF-DPI dosage), evaluator-blind (for MF-DPI vs FP) trial. SETTING: Sixty centers in 20 countries. PATIENTS: Seven hundred thirty-three patients with moderate persistent asthma on inhaled corticosteroid treatment. INTERVENTIONS: Discontinuation of previous inhaled corticosteroid and initiation of one of four study treatments: three doses of MF-DPI (100, 200, and 400 microg twice daily) and one of FP (250 microg twice daily >12 weeks). RESULTS: FEV1 (primary efficacy variable) was evaluated as the mean change from baseline to endpoint (last evaluable visit). All dosage groups showed improvement at endpoint. Only 400 microg twice daily of MF-DPI (+0.19 L) was statistically different from 100 microg twice daily of MF-DPI (+0.07 L; P = 0.02). MF-DPI (200 microg twice daily) and FP Diskhaler groups showed similar improvement (+0.16 L). Greater improvement in most secondary variables (forced expiratory flow between 25% and 75% of vital capacity, and morning and evening peak expiratory flows) also resulted from treatment with 200 or 400 microg twice daily of MF-DPI or with FP Diskhaler, compared with 100 microg twice daily of MF-DPI. Overall, a total daily 800-microg dose of MF-DPI conferred no significant additional benefit >400 microg of MF-DPI. The incidence of oral candidiasis was 1%, 7%, 10%, and 10% in the 100, 200, and 400 microg twice daily of MF-DPI and FP groups, respectively. CONCLUSIONS: A total daily dose of 400 microg of MF-DPI provides clinical benefit comparable to that observed with a total daily dose of 500 microg of FP Diskhaler.

[Serious effects of chloroquine overdose. Prescribe the smallest possible dosage-packages and inform about the risks]. / Allvarliga skador vid överdos av klorokin. Skriv ut minsta möjliga förpackning och informera om riskerna.

An increasing number of acute overdoses with chloroquine has been reported in Sweden--some with fatal outcome. This substance is clearly one of the most toxic pharmaceuticals on the Swedish market. Four cases are described. Travelling to the tropics has become very popular, and chloroquine is often given as a prophylactic antimalarial. This inexpensive drug is often prescribed in 100-tablet packages, and any surplus is often stored in the home. Awareness of toxicity is low among users and doctors in this country. Preventive measures are suggested.

[Plantain (Plantago lanceolata L.): anti-inflammatory action in upper respiratory tract infections]. / Der Spitzwegerich (Plantago lanceolata L.): Reizlinderung bei Infektionen der oberen Atemwege.

Plantain (Plantago lanceolata L.) is used for the therapy of infections of the upper respiratory airways. While only few clinical data are available, results of experimental research confirm e.g. antiinflammatory, spasmolytic and immunostimulatory actions. A positive benefit-risk-ratio allows the recommendation of plantain in moderate chronic irritative cough, also especially for children.

[Pharmacological properties and therapeutic profile of artichoke (Cynara scolymus L.)]. / Pharmakologische Eigenschaften und therapeutisches Profil der Artischocke (Cynara scolymus L.).

The results of several clinical investigations showed the efficacy and safety of artichoke extracts (Cynara scolymus L.) in the treatment of hepato-biliary dysfunction and digestive complaints, such as sensation of fullness, loss of appetite, nausea and abdominal pain. Moreover earlier findings on a lipidlowering and hepatoprotective effect may be confirmed. In-vitro and in-vivo it has been possible to evaluate the underlying pharmacological mechanisms. Flavonoids and caffeoylquinic acids are mainly responsible for the observed actions.

[Therapy of degenerative diseases of the musculoskeletal system with South African devil's claw (Harpagophytum procumbens DC)]. / Therapie degenerativer Erkrankungen des Bewegungsapparates mit südafrikanischer Teufelskralle (Harpagophytum procumbens DC).

Extracts of the secondary tubers of Devil's Claw (Harpagophytum procumbens) are recommended for the supportive treatment of degenerative painful rheumatism. There was observed an improvement of motility and a reduction of pain sensation in several clinical studies. Pharmacological experiments have shown analgesic, antiphlogistic and antiinflammatory actions. Most important constituents are iridoid glycosides, which are supposed to contribute mainly to the observed effects. However, the entire extract has to be considered as active ingredient.

The kinetic of the oxidation of InSn48.

The oxidation of InSn48 has been investigated at partial pressures between 10(-8) Pa and 10(+4) Pa over a temperature range from 22 ( degrees )C to 250 ( degrees )C with different analytical methods. The oxide film contains a mixture of several oxides, although indium oxide forms preferentially. Below the melting point a logarithmic growth, and above this, a parabolic growth of the oxide film has been observed. The oxide film formed in air at 250 ( degrees )C does not become thicker than 50 nm in the first 5 min of oxidation.

Inhaled formoterol dry powder in the treatment of patients with reversible obstructive airway disease. A 3-month, placebo-controlled comparison of the efficacy and safety of formoterol and salbutamol, followed by a 12-month trial with formoterol.

Inhaled formoterol is a potent selective beta 2-agonist with rapid onset and at least 12-h duration of bronchodilation. The aim of the study was to compare the bronchodilating effect of inhaled formoterol dry powder (dp) 12 micrograms b.i.d. with salbutamol dp 400 micrograms q.i.d. and placebo in patients with reversible obstructive airway disease (ROAD). The study design consisted of a closed 12-week double-blind, placebo-controlled, multicenter trial followed by an open noncomparative, multicenter, 12-month follow-up trial, in which the tolerability of formoterol dp was assessed. A total of 304 patients (146 men, 158 women) aged 18-79 years, ill during 0.1-64 years, were randomized. No demographic or baseline differences were found among the different treatment groups. The bronchodilating effect of formoterol, assessed by morning premedication PEFR, was significantly superior to placebo (P < 0.0001) and salbutamol (P < 0.0001). Efficacy was maintained during the open follow-up study with 12 micrograms b.i.d. in most of the patients. A few patients, however, needed 24 micrograms b.i.d. to control their ROAD. Formoterol 12 micrograms b.i.d. significantly reduced morning and evening asthma symptoms and sleep disturbances, and reduced significantly the need for rescue medication. The tolerability of the three treatment groups was comparable. In conclusion, formoterol 12 micrograms dp b.i.d. was significantly superior to both salbutamol 400 micrograms dp q.i.d. and placebo, and reduced asthma symptoms significantly. Overall, formoterol showed a tolerability profile comparable to that of salbutamol, and no tachyphylaxis was observed during 1 year of treatment.