[Literature review on pharmacovigilance of medicines derived from traditional pharmacopoeias. Part I: Risks identification]. / Revue de la littérature sur la pharmacovigilance des médicaments issus des pharmacopées traditionnelles. Partie I : identification des risques.

Globally, the use of drugs from traditional pharmacopoeias is a major subject. The confidence of the populations in these drugs is linked to their presumption of safety and also to the fact that geographically and financially they are more accessible than synthetic drugs. In view of the high exposure of the world population to traditional medicines, they are subject to pharmacovigilance guaranteeing their safety in use. Thus, this review aims to take stock of the risks identified by the national pharmacovigilance systems. It is based on research referenced in PubMed, Embase, ScienceDirect and GoogleScholar. These studies indicate that the use of traditional drugs can involve risks including adverse effects, interactions with synthetic drugs, adulteration and contamination. The spontaneous notification system was the basis for their identification. Strengthening this system and making populations aware of these risks constitute the key levers for traditional medicines pharmacovigilance progress.

[Literature review on pharmacovigilance of medicines derived from traditional pharmacopoeias. Part II: Risks assessment and prevention]. / Revue de la littérature sur la pharmacovigilance des médicaments issus des pharmacopées traditionnelles. Partie II : évaluation et prévention des risques.

After the initial stage of the pharmacovigilance process for medicines from traditional pharmacopoeias - which concerns the identification of the risks associated with their use - the risk assessment should now be approached. The latter makes it possible to detect potential signals early and to take preventive measures. We sought to understand, from a review of the literature, the steps and methods of risk assessment relating to traditional medicines, as well as the prevention strategies applied to them. All of the work carried out on the subject has shown that the steps and methods for assessing and preventing drug risks are the same for both conventional and traditional medicines. Risk assessment includes analysis of the quality of individual notifications, assessment of causality, detection and evaluation of signals. The World Health Organization method is the most widely used for causality assessment internationally, while disproportionality measures are the most applied for signal detection. Regarding prevention, risk communication is the main strategy for the risks associated with traditional medicines. This review suggests the involvement of traditional medicine practitioners both in the notification system and in the communication strategy on the risks associated with their products.

[Phytovigilance: A medical requirement and a legal obligation]. / La phytovigilance: impératif médical et obligation légale.

Phytovigilance consists in supervision of side effects and drug interactions consequential to use of herbal medicinal products, herbal food supplements, herbal cosmetics and/or medicinal plants. It includes thus pharmacovigilance applied to phytotherapy, nutrivigilance and cosmetovigilance but also addictovigilance in case of plants, which lead to drug addiction, and toxicovigilance in case of toxic plants. Becoming necessary owing to (acute or chronic) toxicity risks or to drug interactions risks (of pharmacocinetical or pharmacodynamical kind)--as far as it concerns interactions between several associated plants or between a plant and a chemical or biotechnological allopathic medicine--phytovigilance represents moreover a legal obligation. Pharmacovigilance--in case of herbal medicinal products--is indeed becoming mandatory according to title IX of the European directive 2001/83/EC, whereas nutrivigilance is imposed by the European Food Safety Agency (EFSA).

[A new breath actuated dry powder inhaler (Auto-Jethaler)]. / Ein neuer atemzuggesteuerter Pulverinhalator (Auto-Jethaler).

BACKGROUND: The aim was to examine the handling of the recently developed breath actuated dry powder inhaler Auto-Jethaler (PulmoTec GmbH/Höchstädt, launch by Ratiopharm and CT Berlin). METHOD: 75 patients suffering from asthma, cystic fibrosis or primary ciliary dysfunction (age: 3 to 34 years; 29 female, 46 male) with mild or moderate bronchial obstruction took part in the study. Lung function testing including body plethysmography was performed to measure bronchial obstruction independent of effort. Peak Inspiratory Flow (PIF) was measured using a Fleisch pneumotachograph equipped with or without a Auto-Jethaler. Instead of the commercially available drug tablet a stainless steal ring device of equivalent resistance, easy to disinfect, was used. Actuation of the rotation mechanism which was triggered by inspiration at an inspiratory flow of about 40 L/min was accompanied by a rattling noise. Aims of the study were to examine, whether the subjects were able to handle the new device, and to measure PIF without and via Auto-Jethaler. RESULTS: Handling of the Auto-Jethaler was found to be easy. All patients managed to reach or surpass the critical value of 40 L/min, even those with mild to moderate bronchial obstruction. PIF without Jethaler was 85 to 599 L/min, via Auto-Jethaler 40 to 215 L/min. PIF was significantly age dependent (p<0.001). CONCLUSIONS: These findings suggest that the Auto-Jethaler will be an appropriate device for drug administration in children older than 3 years provided that they understand the inspiratory breathing manoeuvre.

Lung deposition of salbutamol in healthy human subjects from the MAGhaler dry powder inhaler.

The MAGhaler (Mundipharma GmbH) is a multidose dry powder inhaler (DPI) containing a novel formulation of drug and lactose compacted by an isostatic pressing technique (GGU GmbH). On actuation, a precise dose is metered from a compacted ring-shaped drug tablet. In this study, the lung deposition of salbutamol from this device has been assessed. Ten healthy non-smoking subjects completed a two-way cross-over study assessing the pulmonary deposition of salbutamol (200 microg) from the MAGhaler at high (60 l/min) and low (30 l/min) peak inhaled flow rates (PIFRs), representing maximal and sub-maximal inspiratory efforts. The formulation was radiolabelled with 99mTc, and lung and oropharyngeal depositions were quantified by gamma scintigraphyThe mean (SD)% ofthe delivered dose deposited in the lungs was 26.4 (4.3)% at 60 l/min and 21.1 (5.1)% at 30 l/min (P < 0.05), corresponding to mean lung depositions of 52.8 and 42.2 microg salbutamol, respectively. The distribution of drug within different lung regions did not vary significantly with inhaled flow rate. The data provided proof of concept for the novel inhaler device and the innovative drug formulation. In comparison with previous deposition data obtained with other DPIs, the lung deposition was relatively high, relatively reproducible (coefficient of variation 16% at 60 l/min) and relatively insensitive to the change in peak inhaled flow rate.

[Orphan drugs: some legal, ethical and economics aspects]. / Médicaments orphelins: quelques aspects juridiques, éthiques et économiques.

Besides well-known diseases, about 5,000 identified are classed as "orphan" because of the lack of any response in terms of diagnosis, prevention and treatment. The development of drugs for these diseases, intended for a limited number of patients, often requires considerable research, and subsequently, cost. The aim of the present article is to discuss the ethical, political and economic problems relevant to the development and disposal of drugs specifically designed for these diseases, now commonly called "orphan" drugs. These questions have been raised at discussions and dialogues at the European Parliament where European regulations on orphan drugs were adopted on December 15, 1999. These regulations (141/2000/EEC) came into effect in the European Union on January 22, 2000, and are widely inspired from the American model. The regulations stipulate that the criterion for designation of the drug is based on a disease prevalence of 5/10000). Advantages commonly recognized for the orphan drug status concern: community registration (centralized marketing approval), eligibility for grants and national or community fiscal support, lower or canceled registration fees, technical contribution via the European drug agency (EMEA), and exclusive rights for a 10-year period. On May 12, 2000, the European Commission completed the status by adopting rules establishing the criteria used for designating a drug as an orphan drug. This document implements the dispositions available to pharmaceutical firms inciting them to invest in the development of orphan drugs.

Enantiomeric determination of tramadol and its main metabolite O-desmethyltramadol in human plasma by liquid chromatography-tandem mass spectrometry.

Pharmacokinetic studies require sensitive analytical methods to allow the determination of low concentrations of drugs and metabolites. When drugs present an asymmetric center, the enantiomeric determination of the compounds of interest should be performed. The method developed is based on on-line LC-MS-MS using atmospheric pressure chemical ionization as an interface determination of enantiomers of tramadol (T) and its active metabolite O-desmethyltramadol (ODT) in human plasma. This determination is preceded by an off-line solid-phase extraction (SPE) on disposable extraction cartridges (DECs), performed automatically by means of a sample processor equipped with a robotic arm (ASPEC system). The DEC filled with ethyl silica (50 mg) was first conditioned with methanol and water. The washing step was performed with water and the analytes were finally eluted by dispensing methanol. The collected eluate was then evaporated to dryness before being dissolved in the LC mobile phase and injected into the LC system. The enantiomeric separation of tramadol and ODT was achieved on a Chiralpak AD column containing amylose tris-(3,5-dimethylphenylcarbamate) as chiral selector. The mobile phase was isohexane-ethanol-diethylamine (97:3:0.1, v/v). The LC system was then coupled to a tandem mass spectrometry system with an APCI interface in the positive ion mode. The chromatographed analytes were detected in the selected reaction monitoring mode. The MS-MS ion transitions monitored were 264-->58 for tramadol, 250-->58 for ODT, and 278-->58 for ethyltramadol, used as internal standard. The method was validated. The recoveries were around 90% for both T and ODT. The method was found to be linear for each enantiomer of both compounds (r2>0.999). The mean RSD values for repeatability and intermediate precision were 3.5 and 6.4% for T enantiomers and 5.0 and 5.6% for ODT enantiomers, respectively. Moreover, the method was found to be selective towards other metabolites, N-desmethyltramadol and N,O-desmethyltramadol (NODT). The method developed was successfully used to investigate plasma concentration of enantiomers of T and ODT in a pharmacokinetic study.

Alanine-ESR in vivo dosimetry: a feasibility study and possible applications.

A new alanine-ESR dosimeter has been developed at AERIAL in order to study its potential use in radiotherapy. Alanine-ESR results are compared with ion chamber for depth-dose measurements. A good concordance has been found between provisional dosimetry and absorbed dose during high dose rate and intra operative treatments. The results of the experiments indicate that alanine-ESR dosimetry is suited to check dose optimisation routines and seems to be a promising in vivo dosimetry technique.

[Serological studies of the recent infections of Austrian horses with the equine arteritis virus]. / Serologische Untersuchungen zur aktuellen Verseuchung österreichischer Pferde mit dem Virus der Equinen Arteritis.

944 serum samples of horses, collected in 1988 and 1989, were examined for the occurrence of antibodies against equine arteritis virus by a microneutralizations test. In 10.9% of all sera reactors could be found. The distribution of seropositive horses varied from 4.6% (Salzburg) to 15.7% (Lower Austria). From Tyrol and Vorarlberg no samples could be obtained. It was not possible, to correlate clinical symptoms (infertility, respiratory symptoms, fever and edema) with the infection. It is assumed, that the disease appears in Austria only in a clinical inapparent form.

Digitoxin in patients with hepatorenal insufficiency after repeated oral administration.

Following chronic oral administration of digitoxin 0.1 mg day-1 the pharmacokinetics of this glycoside were studied in seven patients with hepatorenal insufficiency and were compared with those of seven healthy volunteers. Liver cirrhosis of the patients was confirmed by liver biopsy. Mean creatinine clearance of the healthy subjects was 129.7 +/- 3.3 ml min-1 (mean +/- SEM), that of the patients was 25.6 +/- 20.4 ml min-1. Mean antipyrine clearance (parameter of oxidative liver function) was 49.7 +/- 6.0 ml min-1 in the volunteers and 22.0 +/- 2.9 ml min-1 in the patients. Plasma protein binding of digitoxin (PPB) was 95.0 +/- 1.1% in the patients and 96.7 +/- 0.6% in the healthy subjects (n.s.). Total body clearance of digitoxin (Cltot) was 0.0728 +/- 0.0120 ml min-1 kg-1 in the patients and 0.0615 +/- 0.0027 ml min-1 kg-1 in normals (n.s.]. Mean steady state plasma levels (Css) of the patients were 18.3 +/- 4.7 ng ml-1 and 15.8 +/- 1.3 ng ml-1 in the normals (n.s.). Our data obtained from chronic oral administration do not indicate a reduced total body clearance of digitoxin in patients with hepatorenal insufficiency.

Pharmacokinetics of bisoprolol during repeated oral administration to healthy volunteers and patients with kidney or liver disease.

The pharmacokinetics of bisoprolol were investigated following oral administration of 10mg once daily for 7 days in 8 healthy subjects, in 14 patients with different degrees of renal impairment and in 18 patients with liver disease. In healthy subjects peak and trough steady-state concentrations of 52 micrograms/L and 11 micrograms/L, respectively, an elimination half-life of 10.0 hours and total body clearance of 14.2 L/h were observed. 5.21 mg/24 hours of unchanged bisoprolol were recovered following urinary excretion during the dosage interval. In 11 patients with renal impairment (mean CLCR = 28 +/- 5 ml/min/1.72m2) half-life was prolonged to 18.5 hours, and peak and trough concentrations were 74 and 32 micrograms/L, respectively. Correspondingly, urinary excretion decreased to 3.35 mg/24 hours and total body clearance to 7.8 L/h. In uraemic patients (CLCR less than 5 ml/min/1.73m2) the total clearance of bisoprolol was 5.0 L/h and the elimination half-life was 24.2 hours. In patients with liver cirrhosis half-life increased to 13.5 hours, steady-state peak and trough concentrations increased to 62 and 22 micrograms/L, respectively, and total body clearance decreased to 10.8 L/h. The present study indicates that in patients with impairment of kidney or liver function accumulation of bisoprolol above a factor of 2 did not occur. However, in the terminal stages of insufficiency of kidney or liver function bisoprolol dosage should not exceed 10mg.

Basic pharmacokinetics of bisoprolol, a new highly beta 1-selective adrenoceptor antagonist.

The basic pharmacokinetics of bisoprolol were investigated in three independent studies involving 23 healthy volunteers. After administering 20 mg of 14C-bisoprolol orally, mean elimination half-lives of 11 hours for the unchanged drug and 12 hours for total radioactivity were observed. The enteral absorption of bisoprolol was nearly complete. Fifty percent of the dose was eliminated renally as unchanged bisoprolol and the other 50% metabolically, with subsequent renal excretion of the metabolites. Less than 2% of the dose was recovered from the feces. Intraindividual comparison of the pharmacokinetic data measured after oral and intravenous administration of 10 mg bisoprolol to 12 subjects yielded an absolute bioavailability of 90%. Total and renal clearance were calculated as 15.6 L/hr and 9.6 L/hr, respectively. The volume of distribution was 226 L. Concomitant food intake did not influence the bioavailability of bisoprolol.

Pharmacodynamic profile of bisoprolol, a new beta 1-selective adrenoceptor antagonist.

The pharmacodynamic profile of bisoprolol, a new beta 1-selective adrenoceptor antagonist, was investigated in four independent studies including 36 healthy male volunteers. Using the model of exercise-induced tachycardia (ET) the beta-adrenoceptor blocking properties of bisoprolol (2.5-40 mg) were examined in comparison to metoprolol (50 and 100 mg), propranolol (40 and 80 mg) and atenolol (50 and 100 mg). The maximal reduction of ET was achieved between 1 and 4 h following single oral administration. The dose-response relationship using individual maximal reduction of ET showed, on a molar basis, that bisoprolol is about 5, 7 and 10 times more effective than propranolol, atenolol and metoprolol, respectively. In the model of insulin-induced hypoglycaemia bisoprolol behaved as a beta 1-selective adrenoceptor antagonist. There was a good correlation (r = 0.94) between the log bisoprolol concentration and the reduction in exercise-induced tachycardia. Bisoprolol is a potent new cardioselective beta-adrenoceptor antagonist with a competitive action at beta 1-adrenoceptors.

Bioavailability and elimination of digitoxin in patients with hepatorenal insufficiency.

Following administration of digitoxin, 1 mg intravenously, the pharmacokinetics of this glycoside were studied in eight healthy volunteers and in eight patients with hepatorenal insufficiency (mean creatinine clearance 19.6 +/- 2.9 ml/min; antipyrine clearance 25.6 +/- 3.2 ml/min; means +/- SEM). Liver cirrhosis of the patients was confirmed by liver biopsy. Plasma protein binding of digitoxin (means +/- SEM) was 95.1 +/- 0.7% in the patients and 95.6 +/- 1.2% in the volunteers (NS). Total body clearance of digitoxin was 0.0530 +/- 0.0040 ml/min/kg of body weight in the patients and 0.0547 +/- 0.0043 ml/min/kg of body weight in the healthy subjects (NS). When elimination half-lives of the patients and the volunteers were compared, there was also no significant difference (7.0 +/- 0.77 days in the patient group and 7.8 +/- 0.8 days in the volunteers). Our data concerning digitoxin kinetics in patients with hepatorenal insufficiency do not indicate an accumulation of the drug in these patients.

Pharmacokinetics of bisoprolol and influence on serum thyroid hormones in hyperthyroid patients.

Nine hyperthyroid patients (FT4 greater than or equal to 20 ng/L; FT3 greater than or equal to 6 ng/L) were given 1 X 10 mg bisoprolol/day p.o. for a period of 7 days. Pharmacokinetic data were derived from measurements of plasma bisoprolol concentrations after the first dose and at steady state after 7 days treatment. The thyroid hormones FT4, FT3, and rT3 were determined in the serum before and after bisoprolol treatment. In addition, subjective and objective parameters of thyroid function were recorded during the course of the therapy. The maximum bisoprolol concentrations measured after the first dose and after 7 days were 54.3 +/- 2.1 and 70.3 +/- 3.8 ng/ml, respectively, the minimum concentrations being 9.6 +/- 1.0 ng/ml and 11.9 +/- 1.7 ng/ml, respectively. This yields an accumulation factor of 1.2. At steady state, the plasma elimination half-life of bisoprolol was 9.8 +/- 0.9 h. No significant changes in serum thyroid hormones were observed during bisoprolol treatment. There was, however, an improvement in the subjective and objective clinical symptoms of hyperthyroidism. In comparison with the findings in healthy volunteers, the pharmacokinetics of bisoprolol remained unaltered in mild to moderate hyperthyroid patients. After oral application of bisoprolol, only small variations in the plasma concentration were observed inter- and also intraindividually in the course of treatment. This finding reflects the high absolute bioavailability of bisoprolol.

Pharmacokinetics and metabolism of bisoprolol-14C in three animal species and in humans.

The pharmacokinetic properties of bisoprolol-14C were studied in Wistar rats, beagle dogs, and Cynomolgus monkeys. Bisoprolol is well absorbed in these species; independent of the route of administration (i.v. or p.o.), 70-90% of the 14C-dose was recovered in urine. Faecal excretion was approximately 20% in rats and less than 10% in dogs and monkeys. Rats excreted approximately 10% of the dose in bile after i.v. as well as after oral administration. The plasma half-life of the unchanged drug was approximately 1 h in rats, 3 h in monkeys, and 5 h in dogs. The bioavailability was 40-50% in monkeys, approximately 80% in dogs, and 10% in rats. Studies in rats have shown that the drug is rapidly taken up by the tissues. After i.v. administration, high levels of radioactivity were found in lung, kidneys, liver, adrenals, spleen, pancreas, and salivary glands. After oral administration, the highest concentration occurred in the liver and kidneys. With the exception of plasma and liver, unchanged bisoprolol was the major radioactive constituent in all tissues studied. Both the blood-brain and placental barriers were penetrated, but only to a small degree. No accumulation of radioactivity in tissues was observed after repeated dosing (1 mg/kg/day). The metabolism of bisoprolol was studied in the same three animal species and in humans. The major metabolites are the products of O-dealkylation and subsequent oxidation to the corresponding carboxylic acids. The amount of bisoprolol excreted unchanged in the urine is 50-60% of the dose in humans, 30-40% in dogs, and approximately 10% in rats and monkeys.

Concentration kinetics of propranolol, bisoprolol, and atenolol in humans assessed with chemical detection and a subtype-selective beta-adrenoceptor assay.

After oral administration of single doses of 240 mg of (+/-)propranolol (prop), 200 mg of (+/-)-atenolol (aten), and 100 mg of (+/-)-bisoprolol (biso) to six healthy male volunteers, the plasma concentration time profile was investigated. To measure total plasma concentrations of the parent racemic mixture of drug administered, a HPLC-assay of drug concentrations was used. To detect active metabolites and stereoselective pharmacokinetics of the racemates, plasma concentrations were also monitored by means of a subtype-selective receptor assay, using a beta 1-adrenoceptor preparation from rat salivary glands. It is shown that relevant amounts of active metabolites do not become apparent for either of the three drugs investigated. Furthermore, for neither of them can significant stereoselective elimination characteristics be seen. Monophasic elimination characteristics with t1/2 of 4.8 +/- 0.42 (prop), 6.87 +/- 0.46 (aten), and 9.19 +/- 0.38 h (biso) become apparent. The maximum concentrations observed after administration of the doses mentioned previously were 220 +/- 71 (prop), 904 +/- 104 (aten), and 445 +/- 32 (biso) (ng/ml plasma). One can conclude from comparison with the results from receptor-binding studies that the 100 mg dose of biso is five- to seven-fold more potent than the 200 mg dose of aten, with respect to antagonism versus beta 1-adrenoceptor-mediated effects.

Interaction of bisoprolol with cimetidine and rifampicin.

In 6 healthy volunteers the pharmacokinetics of bisoprolol under steady-state conditions was investigated over three consecutive phases: over 7 days of 10 mg of bisoprolol once daily per os, 7 days of 10 mg of bisoprolol once daily plus 400 mg of cimetidine t.i.d. and 14 days of 10 mg of bisoprolol and 600 mg of rifampicin once daily with adequate intervals free of medication. After therapy with bisoprolol alone peak plasma levels (Cssmax) of the beta-blocker were 55.5 +/- 6.4 ng/ml (means +/- SEM), area under the plasma level-time curve (AUC tau) was 597 +/- 70 ng/ml.h, total body clearance (CL) 15.8 +/- 1.8 l/h and elimination half-lives (t1/2 beta) 10.1 +/- 1.2 h. Cimetidine did not cause any significant changes in the pharmacokinetics of bisoprolol. Co-administration of rifampicin resulted in a decrease in Cssmax (43.0 +/- 6.9 ng/ml), AUC tau (397 +/- 54 ng/ml X h) and t1/2 beta (6.2 +/- 0.4 h). Accordingly, total body clearance increased to 23.8 +/- 2.5 l/h (p less than 0.05). In conclusion bisoprolol showed a statistically significant but probably clinically not important interaction with the enzyme-inducing drug rifampicin, but not with the enzyme inhibitor cimetidine.