Exploring the integration of the biomedical research component in undergraduate medical education.

BACKGROUND: A task force of MEDINE (Thematic Network on Medical Education in Europe) organized a survey of European Medical Schools. AIM: To investigate the link between education and biomedical research in the medical curriculum questioning university staff responsible for the curriculum. METHOD: The survey was online between 10/2006 and 3/2007. Answers pertained to the situation in the academic year 2005/06. RESULTS: Ninety-one medical schools/faculties in 26 countries participated, but response rates to some questions were lower due to incomplete responses. In undergraduate programs, 3/4 of the schools offer research courses and in 2/3 students can do research themselves. However, in most schools, fewer than 10% students choose this option. In about half the medical schools writing a thesis is a requirement for graduation, although the term "thesis" is interpreted broadly. Color map analysis revealed the link between medical education and biomedical research: about 25% of the medical schools had little emphasis on research in their undergraduate curriculum. CONCLUSIONS: We identified the curriculum elements most suitable to improve the link between medical education and research for the initial stage (years 1-3) as literature search techniques, statistics and epidemiology, while for the advanced stage (years 4-6), writing a thesis was most relevant.

[Willow bark extract--effects and effectiveness. Status of current knowledge regarding pharmacology, toxicology and clinical aspects]. / Weidenrindenextrakt--Wirkungen und Wirksamkeit. Erkenntnisstand zu Pharmakologie, Toxikologie und Klinik.

New pharmacological and clinical studies show that standardized willow bark extracts (WRE) is not only the natural form of salicylic acid. Willow bark extract has comparable antiinflammatory activities as higher doses of acetylsalicylic acid (ASS), and it shows antinociceptive and antipyretic activities. Under the pharmacologically active doses, no adverse effects regarding the stomach mucosa was observed, in contrast to acetylsalicylic acid. A daily dose of 1572 mg willow bark extract of a proprietary preparation (Assalix; standardised to 15.2% salicin, i.e. 240 mg salicin per day) was significantly superior to placebo in patients with osteoarthritis of the hip and the knee and in patients with exacerbations of chronic low back pain. In 2 open studies against active treatments as controls, willow bark extract exhibited advantages against a routinely prescribed treatment scheme of orthopedic specialists based on nonsteroidal antirheumatic drugs and rather similar efficacy as the COX-2-inhibitor refecoxib. Willow bark extract also displays an activity regarding the thrombocyte function, but the activity is clearly weaker.

[Effectiveness of Vitex agnus-castus preparations]. / Zur Wirksamkeit von Vitex agnus castus-Präparaten.

The prolactin-inhibiting effect of ACF-preparations, which is due to dopaminergic activities, has been shown in humans too and gives a pharmacological rationale for the clinical effects observed in the different indications (2, 11, 25, 26, 35, 41). Confirmation of efficacy in the treatment of mastalgia has been best endorsed by two recently published double-blind studies conducted according to the principles of GCP (14, 41). One double-blind study, several open and postmarketing surveillance studies have shown that the premenstrual syndrome, or individual symptoms, can be influenced positively (3, 6, 7, 9, 19, 21, 37). Design shortcomings in a second double-blind study should be eliminated in future studies in this indication to improve the body of evidence (18). Hither to there has been one controlled double-blind study of cycle disorders in the case of corpus luteum insufficiency with significant results and a number of non-controlled open studies (1, 4, 15, 16, 20, 24, 26, 27, 32, 35, 36). The high success rates in the open studies indicate therapeutic effects, and it should be possible to reproduce these results under double-blind conditions. The success rates on fertility disorders should be confirmed in controlled double-blind studies (10, 33, 34).

Enhanced resistance to Sendai virus infection in DBA/2J mice with a botanical drug combination (Sinupret).

It was investigated whether the botanical drug combination Sinupret is able to modulate the resistance of mice to a respiratory tract infection with Sendai virus (Parainfluenza viridae) if given prophylactically to the animals. Three doses of Sinupret drops (SD) and Sinupret tablets (ST, p.o.), and two active controls, the chemical secretolytic ambroxol (p.o.) and the immunomodulator Muramyldipeptide (MDP, i.v.) were used. Test and reference substances were applied at days - 3 and -1 before infection, except MDP, which was given once on day--before infection. CD4+ and CD8 + lymphocyte subpopulations were measured after infection as indicators of immunological treatment response. Groups of 20 mice each were infected by intranasal application of Sendai virus under anaesthesia. We found that the 1 x and 5 x human doses of Sinupret drops significantly prolonged the survival times (p < 0.05) compared to placebo. Additionally, ambroxol and MDP were comparably less effective. In all groups, changes in CD4 + and CD8 + T-lymphocyte subpopulations of the peripheral blood were observed, but no clear relationship to the treatment results was seen. It was concluded that Sinupret increases the resistance to an experimentally induced respiratory tract infection in mice. Moreover, the effect of Sinupret was superior to that of an immunostimulant (MDP) and of a synthetic secretagogue (ambroxolhydrochloride).

Bioavailability and pharmacokinetics of natural volatile terpenes in animals and humans.

Herbal medicinal products containing natural volatiles are used in the treatment of gastrointestinal diseases, pain, colds and bronchitis. Many pharmacological studies report a wide variety of in vitro effects, with anti-inflammatory and antimicrobial activities investigated most frequently. In comparison, relatively few studies on the bioavailability and pharmacokinetics have been carried out. Thus, the relevance of the in vitro activity to the therapeutic effects found in individual studies or documented in textbooks of phytotherapy is still not established. Further studies with essential oils and their single compounds providing supporting evidence of efficacy and demonstrating systemic availability are necessary. Such data could also be important in the context of safety.

The process of defining a profile of student competencies at the University of Vienna Medical School.

CONTEXT: A new law enabling curriculum reform led a small circle of interested faculty members at the University of Vienna medical school to launch the Medizin Curriculum Wien project (MCW) to plan a new curriculum under the supervision of the Committee on Educational Affairs (Studienkommission). OBJECTIVE: The first stage of the project dealt with the definition of a profile of competencies (Qualifikationsprofil), which describes all the competencies we want our students to possess upon graduation. METHOD: This paper presents the approach to and process of defining this profile at one of Europe's largest medical schools, currently enrolling over 1500 new students per year. The procedure involved: preparing materials; communication with stakeholders; information dissemination; feedback gathering; information structuring, and formulating the profile of competencies. RESULTS: Application of the outlined steps in two rounds proved successful for the development of a profile of student competencies for Vienna. General acceptance and awareness of the new profile as well as commitment for a further reform process was engendered. The distinct characteristics of the profile are discussed. CONCLUSION AND UTILIZATION: A profile of student competencies must balance the demanding objectives of curriculum planners and the actual challenges presented by many local parameters; this can be done by employing the process outlined in this paper. The defined profile serves as an accepted reference point in the further development of the medical curriculum.

Measurement of the bioavailability of aescin-containing extracts.

OBJECTIVE: In horse chestnut seed extracts (HCSE), the triterpene saponin mixture aescin is considered the active principle. The bioavailability and pharmacokinetics of different HCSE preparations have been studied under single and repeated applications using a radioimmunological method (RIA) developed to identify beta-aescin, one of the pharmacologically active fractions of the saponin mixture. In this paper, the available pharmacokinetic data are reviewed and the observed heterogenicity between comparable studies is discussed. DATA SOURCES: Pharmacokinetic data from 5 single- and 4 multiple-dose bioequivalence studies with HCSE-containing products, were measured by the same analytical laboratory using the same RIA. EVALUATION: In studies where procedures were identical the pharmacokinetic data of beta-aescin show high variations. Even under steady-state conditions a considerable variability for the same HCSE product is obtained. CONCLUSION: Formal reasons like study design and medications can be ruled out as a source of pharmacokinetic variation. In extracts of herbal drugs like HCS, the relative concentration of the individual saponin fractions can considerably differ from batch to batch. For immunological methods, identification of such antigens with intermolecular variability, e.g., the structural aescin analogs, is of unknown validity. Therefore the shape of the concentration-time curve would only show an approximation of the time course but not for the absolute concentrations. A specific validation procedure for the RIA must be developed, otherwise a LC-MS/MS-method of sufficient sensitivity should be elaborated.

[Profile and effectiveness of a phytogenic combination preparation for treatment of sinusitis]. / Wirkprofil und Wirksamkeit eines pflanzlichen Kombinationspräparates zur Behandlung der Sinusitis.

Complex combinations of botanical drugs are usually regarded as non-rational medicines. In the case of Sinupret, a combination of 5 botanical drugs, the pharmacological profile was investigated thoroughly with respect to activities on secretion of the respiratory epithelium, with respect to anti-inflammatory activities and to effects against a murine Sendai-virus infection model (including in-vitro antiviral activities), after a randomised, placebo-controlled study of the ENT-clinic of the University of Freiburg had shown superiority of the verum in patients with chronic sinusitis. For patients with acute sinusitis, the additional treatment with Sinupret improved the response rate of the patients, who were basically treated with antibiotics and nasal decongestants, significantly compared to placebo. In a series of randomised trials of the combination versus active controls, the botanical combination was shown to be at least as effective and to have a low prevalence of adverse side effects. The individual ingredients contribute to the overall pharmacological profile of the combination with secretolytic, anti-inflammatory, immunomodulating and anti-viral effects.

A controlled multi-centre study of herbal versus synthetic secretolytic drugs for acute bronchitis.

Herbal expectorants and secretolytic drugs hold a sizeable share of the European market. Therefore it is essential to test their clinical effectiveness and safety. The aim of the present study was to compare the herbal medication Bronchipret(®) with various other pharmacotherapeutical options for acute bronchitis. The study was designed as a matched-pair comparison of 7783 patients. Clinical outcomes of bronchitis and adverse reactions were documented. The data were evaluated by comparing the treatment success of the test medication and 3 control groups using ordinal regression. The results suggest that clinical effectiveness of Bronchipret(®) was not less than with synthetic drugs. There was a tendency for better results with Bronchipret(®), particularly in the treatment of adults. Similar results were obtained with respect to adverse reactions. Particularly in the adult sub-group, these were markedly less with herbals as compared to synthetic drugs. These findings imply that a risk/benefit evaluation would favour Bronchipret(®) over synthetic drugs for acute bronchitis. Their interpretation is limited through the fact that this study could not be randomised nor blinded. The results therefore require confirmation through randomised, double-blind trials.

Effects of prenatal treatment with betamethasone, L-carnitine, or betamethasone-L-carnitine combinations on the phosphatidylcholine content and composition of the foetal and maternal rat lung.

Pregnant rats received 0.10 or 0.20 mg/kg body weight betamethasone, or 100 mg/kg body weight L-carnitine, or L-carnitine 100 mg/kg plus betamethasone 0.05 or 0.10 mg/kg body weight, or saline (controls) for three days before delivery of foetuses at day 19 of gestation. Dose-related effects on the dipalmitoyl phosphatidylcholine content and the phosphatidylcholine species composition of foetal and maternal lungs were determined. Betamethasone (0.10 and 0.20 mg/kg) or L-carnitine (100 mg/kg) significantly increased (p < 0.05) the dipalmitoyl phosphatidylcholine content in the foetal lungs, while only small changes were found in relative terms. Combinations of betamethasone (0.05 or 0.10 mg/kg) with L-carnitine (100 mg/kg) also significantly increased the dipalmitoyl phosphatidylcholine content of the foetal lungs above control values (p < 0.01) and above the values achieved with betamethasone alone (p < 0.05). In the maternal lungs a significant increase of the dipalmitoyl phosphatidylcholine content above the control values was only found after treatment with betamethasone-carnitine combinations, whereas compared with the foetal lung the relative increase of dipalmitoyl phosphatidylcholine as a fraction of total phosphatidylcholine was more pronounced after betamethasone treatment. The gas chromatographic method used separates two monoenoic phosphatidylcholine species with 32 carbon atoms in the acyl residues. These two phosphatidylcholine species showed striking differences between adult and foetal lungs. Palmitoleyl palmitoyl phosphatidylcholine predominates in the maternal lung, whereas palmitoyl palmitoleyl phosphatidylcholine is the major monoenoic phosphatidylcholine species with 32 carbon atoms in the foetal lung. These two species were not affected in maternal or foetal lung by betamethasone or L-carnitine treatment. In contrast, after treatment with betamethasone-carnitine combinations, a significant increase of the fraction of palmitoyl palmitoleyl phosphatidylcholine was found in foetal but not in the maternal lung. The results of the present study demonstrate that maternal glucocorticoid and carnitine treatment affects the maternal as well as the foetal lung but with different effects on the dipalmitoyl phosphatidylcholine content and phosphatidylcholine species composition.

Membrane transport of nucleobases: interaction with inhibitors.

1. The kinetic properties and the mechanism of nucleobase transport and transport inhibition are briefly reviewed. 2. Many purine derivatives even when bearing large substituents on N9 and C6 are inhibitors of nucleobase transport, some are also substrates. 3. Papaverine and other benzyl-isoquinolines are efficient inhibitors of facilitated transport of nucleobases. 4. Papaverine is a noncompetitive inhibitor of nucleobase transport in human erythrocytes. 5. Reduction of the aromatic isoquinoline to the tetrahydro form causes loss of inhibitory activity whereas replacement of methoxy groups by ethoxy groups leads to increased activity. 6. Papaverine also inhibits sodium dependent active nucleobase transport in pig kidney cells. 7. The nucleoside transport inhibitors dipyridamole and dilazep have no effect on facilitated diffusion transport of nucleobases, but inhibit in micromolar concentrations active sodium dependent nucleobase transport in pig kidney cells.

Nucleobase and nucleoside transport in mammalian cells.

Membrane transport of nucleobases and nucleosides has been an actively pursued research field for the past 25 years. Not only are these substances of physiological interest; derivatives are in clinical use or under investigation for their pharmacological activity against viral and neoplastic disease. An understanding of the molecular pharmacology of these substances includes a detailed knowledge of how they reach their intracellular targets. Membrane transport systems which have so far been found in all cells examined play an important role in this process. Since the transporters are minor membrane components, little is known about them on a molecular basis. This review discusses methodological approaches used to measure initial rates of membrane transport and summarizes current knowledge of the various transport systems which have been characterized with these kinetic methods.

Pregnancy-related changes of carnitine and acylcarnitine concentrations of plasma and erythrocytes.

Total-, free-, and acylcarnitine concentrations were determined in whole blood, plasma, and red blood cells of 88 women during pregnancy. Already in the 12th week of gestation the mean whole blood carnitine level was significantly (p < 0.01) lower than those of the controls. From the 12th gestational week up to parturition there was a further significant (p < 0.01) decrease. This reduction of total carnitine in whole bloods was mainly caused by a significant (p < 0.01) decrease of free carnitine levels, since no marked changes of short chain acylcarnitine values were found throughout pregnancy. The contribution of red blood cell L-carnitine to whole blood carnitine increased significantly (p < 0.05) to 61% at delivery versus 39% (controls). In umbilical cord blood free and total carnitine levels were significantly (p < 0.05) higher than the corresponding maternal levels. The contribution of red blood cell L-carnitine to whole blood carnitine was higher in cord blood than in maternal blood. The results of the present study demonstrate that during pregnancy whole blood and plasma carnitine levels decrease to those levels found in patients with carnitine deficiency. Also the percentage of acylcarnitine on total carnitine, found in the present study, is characteristic for a secondary carnitine deficiency. Thus L-carnitine substitution in pregnant women, especially in risk pregnancies, may be advantageous.

Adverse drug reactions to herbal and synthetic expectorants.

Our knowledge relating to adverse drug reactions (ADRs) of phytomedicines is highly fragmentary. The aim of this study was to define the prevalence of ADRs following medication with herbal or synthetic expectorants. In a multicentre, comparative post-marketing surveillance study of more than 3000 patients with acute bronchitis, about half were treated with a herbal remedy (SinupretR) and the other half with various other expectorants. In ascending order of incidence, ADRs were noted during mono-medication of SinupretR (0.8%), Ambroxol (1.0%) and acetylcysteine (4.3%). When concomitant drugs were used, this rank order was unchanged but incidence rates were markedly increased (3.4, 6.5 and 8.2%, respectively). The most frequent ADRs were gastrointestinal symptoms. It is concluded that expectorants are associated with ADRs in roughly 1-5% of cases undergoing single drug treatment and in 3-10% when more than one medication is being used. Amongst the expectorants used in this study, the herbal preparation SinupretR is associated with the lowest incidence of ADRs.

Inhibition of purine nucleobase transport in human erythrocytes and cell lines by papaverine. Investigation of structure-activity relationship.

Papaverine was found to be an effective inhibitor of hypoxanthine transport not only in human erythrocytes, but also in the human cell lines HL60 (myeloic) and U937 (monocytic). IC50 values for inhibition of hypoxanthine influx ranged from 6 to 20 microM. In erythrocytes papaverine was found to be a non-competitive inhibitor of hypoxanthine equilibrium-exchange transport with a Ki value of approximately 13 microM, which is in close agreement with the respective IC50 values estimated for zero-trans influx of hypoxanthine. In addition papaverine also had a slight inhibitory effect on unmediated nucleobase transport, most likely due to a perturbation of the membrane lipid environment. Several papaverine analogs were tested for their inhibitory effect on nucleobase transport. Only ethaverine was as effective as papaverine. Drotaverine and berberine were moderately inhibitory while laudanosine had no inhibitory effect at all. Isoquinoline acted as a very weak inhibitor.

Effects of hypolipidaemics cetaben and clofibrate on mitochondrial and peroxisomal enzymes of rat liver.

Clofibrate or cetaben was administered to male rats for 10 days. Peroxisomal and mitochondrial enzymes were assayed in liver subcellular fractions. Clofibrate affected the specific activities of both mitochondrial enzymes (glycerol-3-phosphate dehydrogenase and nicotinamide-linked isocitrate dehydrogenase) and peroxisomal enzymes (fatty acyl-CoA oxidase, glycerone phosphate acyltransferase, urate oxidase, and D-amino-acid oxidase). In contrast, cetaben raised only the peroxisomal enzymes, acyl-CoA oxidase, glycerone-phosphate acyltransferase, D-amino-acid oxidase, catalase, and urate oxidase. Thus, the hypolipidaemic activity of these drugs may be exclusively related to stimulated peroxisomal functioning, while mitochondria play only a minor role.

Placebo-controlled, randomized double-blind clinical trial with Sinupret® sugar coated tablets on the basis of a therapy with antibiotics and decongestant nasal drops in acute sinusitis.

On the basis of therapy with antibiotics and nasal decongestants the efficacy of an additional treatment with the herbal combination Sinupret containing gentian root, cowslip flowers, sour dock herbs, elder flowers and shop vervain wort herbs was assessed in a randomized, placebo-controlled double-blind clinical trial involving 160 patients with acute bacterial sinusitis. Primary outcome criteria were radiographic findings and patient assessment. Secondary variables were several clinical symptoms of sinusitis which served as indicators of the pharmacological profile. The results showed that, according to the radiographic findings and the patient assessments, therapy with antibiotic and decongestants achieved a significant improvement in the treatment group; changes in clinical signs showed good correlation with the radiographic findings and the patient assessments. Conventional therapy for acute bacterial sinusitis can be improved markedly by including Sinupret in the therapeutic regimen.

Allopurinol transport in human erythrocytes.

The mechanism of allopurinol [4-hydroxypyrazolo(3,4-d)pyrimidine] transport into human erythrocytes was investigated with an inhibitor stop assay. Allopurinol transport could be resolved into two components: (1) a saturable system and (2) a non-saturable process, which most likely represents non-facilitated diffusion. Allopurinol transport had a Km of 268 mumol/L and a Vmax of 28 pmol/microL intracellular volume/sec; the non-saturable component was 0.0195/sec. Mutual inhibition studies showed that the competitive Ki values of hypoxanthine and adenine on allopurinol transport were 120 and 3 mumol/L, respectively. These Ki values as well as the IC50 values of 100-150 mumol/L for hypoxanthine and 3-10 mumol/L for adenine were similar to the corresponding transport Km values of these bases, which are 128 and 8 mumol/L, respectively. The Ki of allopurinol on hypoxanthine transport was 274 mumol/L and thus nearly identical to its Km. Thus in erythrocytes the uricostatic agent allopurinol is an alternative substrate for the purine transport system, but lacks the exceptional high affinity it has for xanthine oxidase. This could explain the paradoxical clinical side effect of allopurinol, namely that it can provoke an attack of gout. Theophylline, a methylated purine, inhibited allopurinol transport with an IC50 of 200-400 mumol/L. Oxypurinol [4,6-dihydroxypyrazolo(3,4-d)pyrimidine], the main metabolite of allopurinol, also inhibited allopurinol transport with an IC50 of 20-40 mumol/L. This is noteworthy, since allopurinol and oxypurinol do not share the same transport system in the kidney.