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The aim of this study was to describe identified risk areas related to the medication administration process in acute care in order to develop a three-dimensional-game intervention. A secondary analysis was conducted using (1) observed medication administrations (n = 1058) and identified medication errors in 2012 (n = 235), (2) a systematic review including a meta-analysis of previous medication administration educational interventions (n = 14) from 2000 to 2015, (3) incident reports of medication administration errors (n = 1012) from 2013 to 2014, and (4) focus group interviews with RNs' (n = 20) views in 2015. A qualitative content analysis was used to identify risk areas, and the data were organized according to the following main themes: (1) factors related to patients (patient identification, patients' characteristics or symptoms, and patients' allergies and interactions); (2) factors related to medications (medication information, changes in medications, generic substitutes, new drugs, look-alike/sound-alike drugs, demanding drug treatments, medication preparation, and administration techniques); (3) factors related to staffing (workload, skills, interruptions and distractions, division of work, responsibility, attitudes, and guidelines); and (4) factors related to communication (flow of information, communication with the patients, and marking of medication information). Identified risk areas could be used to develop interventions with the aim of increasing the safety of medication administration and nurses' skills.

Aims and objectives To describe ways of preventing medication administration errors based on reporters' views expressed in medication administration incident reports. Background Medication administration errors are very common, and nurses play important roles in committing and in preventing such errors. Thus far, incident reporters’ perceptions of how to prevent medication administration errors have rarely been analysed. Design and Methods This is a qualitative, descriptive study using an inductive content analysis of the incident reports related to medication administration errors (n = 1012). These free-text descriptions include reporters’ views on preventing the reoccurrence of medication administration errors. The data were collected from two hospitals in Finland and pertain to incidents that were reported between 1 January 2013 and 31 December 2014. Results Reporters’ views on preventing medication administration errors were divided into three main categories related to individuals (health professionals), teams and organisations. The following categories related to individuals in preventing medication administration errors were identified: (1) accuracy and preciseness; (2) verification; and (3) following the guidelines, responsibility and attitude towards work. The team categories were as follows: (1) distribution of work; (2) flow of information and cooperation; and (3) documenting and marking the drug information. The categories related to organisation were as follows: (1) work environment; (2) resources; (3) training; (4) guidelines; and (5) development of the work. Conclusions Health professionals should administer medication with a high moral awareness and an attempt to concentrate on the task. Nonetheless, the system should support health professionals by providing a reasonable work environment and encouraging collaboration among the providers to facilitate the safe administration of medication. Relevance to clinical practice Although there are numerous approaches to supporting medication safety, approaches that support the ability of individual health professionals to manage daily medications should be prioritised.

Aims The aim of this review was to identify methods for measuring Registered Nurses' medication administration skills and to describe these skills. Design A systematic literature review. Data sources The CINAHL, PubMed, Scopus, Cochrane, PsycInfo and Medic databases were searched for articles from the period 2007-2018. Review methods Two researchers independently selected the articles and evaluated their quality using the National Heart, Lung and Blood Institute study quality assessment tools. The data were analysed using content analysis. Results A total of 727 studies were identified of which 22 studies were included in this review. A total of six different measurement methods were identified: questionnaire or survey, observation, knowledge test or exam, focus group interviews, chart reviews and voluntarily reported errors. Different methods provided different information on medication administration skills. Medication administration skills were classified under nine areas: (1) safe ordering, handling, storing and discarding of medications, (2) preparing of medications, (3) the administration of medications to patients, (4) documentation, (5) evaluation and assessment of medication-related issues, (6) drug calculation skills, (7) cooperation with other professionals and (8) with the patients and (9) reporting of medication information. The results demonstrated that there are many areas that need to be improved to increase medication safety. Conclusions Medication administration includes many different phases, as a result of which nurses need to have many various skills to cope with medication administration as required by their profession. This review shows that nurses' medication administration skills need to be developed, and special attention should be paid to the preparation and administration phases. It is important to regularly utilise different teaching strategies and verify nurses' medication competence. As each research method has different limitations, it is vital that further studies combine different methods to form a comprehensive picture of nurses' medication administration skills.

Plasma levels of diazepam and its metabolites were compared after a controlled release formulation and a regular tablet. Both gas chromatographic analysis of plasma diazepam and desmethyldiazepam and radioreceptor assay of total benzodiazepine activity were used. Also the concentrations of benzodiazepine in saliva samples were analyzed by radioreceptor assay. A typical initial plasma peak was seen after the regular tablet but not after the controlled release capsule. Hence the excessive initial sedation can be avoided and the risk of abuse reduced. Desmethyldiazepam increased for about two days after a single dose of diazepam. The receptor assay correlated in general with the sum of diazepam and its desmethyl derivative. The saliva assay gave about 2.5% of the plasma total benzodiazepine which correlates well with the expected free benzodiazepine. It seems that both the plasma radioreceptor assay and the saliva assay can be used to monitor the total benzodiazepine concentration.

The structure and function of ciliated epithelium were studied in 44 human nasal mucosa samples using a photoelectric method and scanning electron microscopy (SEM). The ciliary beat frequency (CBF) of cases with recurrent or chronic sinusitis was 9.1 +/- 5.4 Hz. In eight of the samples (18.2%) no ciliary activity was detected. The amount of ciliated cells, the orientation of cilia, epithelial metaplasia, and secretion were found to be explanatory factors accounting for the decreased ciliary activity. Ciliary disorientation and a lack of ciliated cells in SEM correlated with low ciliary activity. In cases where sinusitis secretion was not seen, the CBF was slower than in cases with mucus or mucopurulent secretion. Sinusitis with disoriented cilia, a loss of ciliated cells, and a lack of mucosal secretion is associated with a decreased CBF. This may lead to impaired mucociliary clearance and increase the risk of recurrent and chronic sinusitis.

The aim of this paper is to analyse how medication incidents are detected in different phases of the medication process. The study design is a retrospective register study. The material was collected from one university hospital's web-based incident reporting database in Finland. In 2010, 1617 incident reports were made, 671 of those were medication incidents and analysed in this study. Statistical methods were used to analyse the material. Results were reported using frequencies and percentages. Twenty-one percent of all medication incidents were detected during documenting or reading the documents. One-sixth of medication incidents were detected during medicating the patients, and approximately one-tenth were detected during verifying of the medicines. It is important to learn how to break the chain of medication errors as early as possible. Findings showed that for nurses, the ability to concentrate on documenting and medicating the patient is essential.

Nurses are generally responsible for administering medication to patients and are, therefore, able to monitor or report medication errors. However, nurses can sometimes be responsible for causing errors, so it is important that they understand the consequences of these mistakes and how to prevent them. This article reports the results of a study that analysed the views of nurses, pharmacists and physicians at a Finnish university hospital on the prevention of medication errors. The findings suggest errors can be prevented by improving work environments and allowing healthcare staff, particularly nurses, to concentrate on the task at hand when dealing with medicines.

Leukotriene D4 (LTD4) is a potent bronchoconstrictor and inflammatory mediator in asthma. Data concerning the effects of LTD4 on ciliary function in the respiratory tract are sparse and contradictory. The purpose of the present study was to clarify the effects of LTD4 on mucociliary activity using the tracheal mucosa of two laboratory animal species, guinea-pig and rat, as well as human nasal mucosa. The ciliary beat frequency (CBF) was measured photoelectrically and determined by Fast Fourier Transform computer analysis. Additionally the structure of ciliated epithelia of guinea-pig trachea after LTD4-immersion was investigated using a scanning electron microscope (SEM). In all tissues, LTD4 increased CBF showing a bell-shaped dose-response curve. The maximum effect was 75 +/- 30% in guinea-pig at 10(-9) mol/l, 119 +/- 49% in rat at 10(-7) mol/l, and 86 +/- 28% at 10(-6) mol/l in human tissue. In guinea-pig tracheal mucosa, there was an indication of an increase in the amount of mucus and disorientation of cilia were seen by SEM after immersion in LTD4. These findings suggest that LTD4 stimulates ciliary activity, but impairs the orientation of cilia.

In 2000, regulation on orphan medicinal products was adopted in the European Union with the aim of benefiting patients who suffer from serious, rare conditions for which there is currently no satisfactory treatment. Since then, more than 850 orphan drug designations have been granted by the European Commission based on a positive opinion from the Committee for Orphan Medicinal Products (COMP), and more than 60 orphan drugs have received marketing authorization in Europe. Here, stimulated by the tenth anniversary of the COMP, we reflect on the outcomes and experience gained in the past decade, and contemplate issues for the future, such as catalysing drug development for the large number of rare diseases that still lack effective treatments.

Diseases and medications associated with the occurrence of falls leading to medical treatment in elderly Finns (65 yrs or older) during a one-year period are presented. The design was that of a case-control study involving 380 fallers seeking medical treatment and 342 unmatched controls selected randomly from the population register. The occurrence of a fall was shown by logistic regression analysis to be related to advanced age, presence of benzodiazepine in the serum, hypertrophy of the prostate, poor mental capacity, presence of chronic lung disease and asthma, use of analgesies and use of digitalis in the men, and to advanced age, poor mental capacity, presence of benzodiazepine in the serum, use of analgesies and non-occurrence of lower limb arthrosis in the women. The corresponding log-linear models showed advanced age and the presence of benzodiazepine in the serum to be independent risk factors for falling both in the men and women. Furthermore, the use of analgesies was related to falling in the women with normal mental capacities. No disease was independently associated with falls. The results suggest caution in the use of benzodiazepines among the elderly.

Chinoin-170 (Ch-170; 3,7-dihydro-1,3-dimethyl-7-[(5-methyl-1,2,4-oxadiazol-3-yl)methyl]1H-purine-2,6-dione) is a new antitussive with bronchodilating activity. Its effects on the ciliary beating frequency (CBF) and mucociliary clearance were studied. In tracheal explants of rats, Ch-170 dose-dependently at concentrations 2 and 5 mg mL−1 depressed CBF by 24 and 33%, respectively. In human mucosal explants, however, no effects were seen at concentrations up to 5 mg mL−1. In anaesthetized guinea-pigs, an intravenous 50 mg kg−1 dose of Ch-170 caused no changes, and 100 mg kg−1 increased the CBF by 15%. Intravenous Ch-170 dose-dependently increased by 93 (50 mg kg−1), 179 (70 mg kg−1) and 253% (100 mg kg−1) the tracheobronchial mucociliary clearance in rabbits. The effect, studied using 99mTc-labelled red blood cells as a marker, was of similar quantity to that brought about by administering 16, 25 and 40 mg kg−1 doses of bromhexine. It is concluded that unlike many older antitussives, Ch-170 in-vitro only slightly decreases the CBF in rats and has no adverse effects on the CBF in human mucosal explants at concentrations up to 5 mg mL−1. In-vivo, Ch-170 does not significantly alter the CBF in guinea-pigs, but dose-dependently increases the mucociliary clearance in rabbits. The increase is most probably a result of changes in the production and the properties of respiratory mucus.

1. Human calcitonin was administered into the distal colon and by intravenous infusion in eight healthy subjects in an open, fixed sequence, cross-over bioavailability study. 2. Intravenously infused human calcitonin elicited a standard pharmacokinetic profile in eight healthy subjects with a biphasic elimination with half-lives of 10.2 ± 0.7 min and 37.8 ± 2.5 min. 3. Colonoscopically administered human calcitonin was absorbed across the distal colonic mucosa in low amounts with a bioavailability of 0.00–0.22%. 4. Absorption from the distal colon was impeded by the presence of faecal material in three of the eight subjects. 5. We conclude that human calcitonin crosses the gastrointestinal epithelium of man. This may demonstrate the feasibility of an oral form for clinical use.

The effect of oxcarbazepine (OCBZ) on the kinetics of an oral contraceptive containing ethinyloestradiol (EE) and levonorgestrel (LNG) was investigated in 13 healthy female volunteers who had previously received the contraceptive for at least 3 months. After 15 days of the first study cycle, each subject received, in addition to the oral contraceptive, 300 mg OCBZ on day 16, 300 mg twice daily on day 17, and 300 mg three times daily from day 18 of the first cycle to day 18 of the next menstrual cycle. The area under the curve values for both EE and LNG decreased when OCBZ was given with the oral contraceptive (p = 0.006, analysis of variance). The results indicate that OCBZ, like most antiepileptic drugs (AEDs), decreases the bioavailability of EE and LNG, perhaps by affecting metabolism or protein binding.

Summary Objectives: In paediatric pharmacotherapy, many drugs are prescribed to be given in ways and for conditions not approved in the marketing authorization (MA). Thus, off-label prescribing of drugs with no MA is widespread in paediatric wards. However, drug MA status and clinical practices differ across countries. In this prospective study, we studied the prescribing of off-label and unlicensed drugs in three paediatric wards in a tertiary hospital in Finland. Furthermore, we reviewed previous published studies to provide an up-to-date international perspective on prescribing of off-label and unlicensed drugs for hospitalized children. Methods: During a 2-week period, prescriptions for patients under 18 years of age (median age 1·6 years) in three wards; neonatal intensive care unit (NICU), general paediatric ward and paediatric surgical ward were recorded daily and drug-licensing status of all prescriptions was determined according to the approved summary of product characteristics. Published studies were retrieved through electronic searches, including MEDLINE (PubMed). Results: Of the 141 children, 108 received 629 prescriptions. Of the 108 children with a prescription, 82 (76%) had at least one off-label or unlicensed drug prescribed; 79% in the NICU, 63% in the general ward and 91% in the surgical ward (P = 0·014). Of the 108 children with a prescription, 26 (24%) received prescriptions for licensed drugs, 71 (66%) received prescriptions off-label and 36 (33%) for unlicensed drugs. Of all 629 prescriptions, 321 (51%) were for licensed drugs, 226 (36%) for off-label and 82 (13%) for unlicensed drugs. International studies showed similar extents of off-label and unlicensed-drug prescribing. Conclusion: This study indicates that the use of off-label and unlicensed drugs is widespread in all the different paediatric wards surveyed and was as extensive as those reported for other countries.

Objective: To explore investigator barriers, preferences, and attitudes towards conducting clinical trials in Finland. Method: In‐depth, semi‐structured interviews with 20 clinicians working in the field of cardiovascular medicine were performed. The interviews were audiotaped, transcribed verbatim and analysed qualitatively. Twenty clinicians from all (five) university hospitals in Finland and from three subgroups: 1) with long experience, 2) with limited experience and 3) reluctant to carry out clinical trials, were sampled purposefully. Main outcome measures: Barriers and (de)motivating factors in carrying out clinical trials and need for training in Good Clinical Practice (GCP).Results: Overall, the investigators had a positive attitude towards conducting clinical trials. The major barriers seemed to occur at the beginning of the trial: bureaucracy, lack of time and laboriousness. The informants hoped for more specific in‐house rules and flexibility in hospitals. The greatest investigator barriers were insufficient financial incentives, trial‐related reasons and administrative affairs/bureaucracy. The smallest barriers were reported in subject recruitment, clinical work, documentation, investigational product logistics and communication with ethics committees. Financial incentives, a possibility to incorporate a personal sub‐study or other benefits for personal research and scientific and clinical interest in the trial were reported as the most motivating factors. Carrying out studies in practice and an opportunity to participate in a trial during one's postgraduate specialist education were considered beneficial. Training in GCP, mainly in the course of postgraduate education, and a certificate or equivalent were generally considered necessary, although a voluntary system was preferred.Conclusion: The interviews of clinicians provide valuable information about the barriers and preferences related to the practical implementation of clinical trials. If the trial is scientifically/clinically interesting and involves a small administrative burden and sufficient financial compensation, investigators are motivated to participate. The barriers and preferences should be considered in decision‐making, to meet the various needs of all parties involved and to produce high‐quality GCP‐compliant clinical drug research. This would ensure the availability of sufficient conditions to carry out clinical trials also in the future.

The feasibility of the water-activated, pH-controlled silicone reservoir devices for transdermal administration was investigated using timolol maleate as a model drug. Timolol patches were applied to the arm of 12 volunteers for 81 h, two patches per subject. Timolol absorption from patches was compared to that from a peroral timolol tablet formulation (Blocanol((R)) 10 mg). Furthermore, in vivo plasma levels of timolol were compared with those predicted by kinetic simulations. Skin irritation induced by timolol patches was assessed by visual scoring and color reflectance measurements. With water-activated, pH-controlled patches both steady-state concentrations of timolol in plasma and its duration could be controlled. However, a considerable, inter-individual variability in the transdermal absorption of timolol was observed. This is due to the high fractional skin control in timolol delivery. Timolol patches were well tolerated by subjects. Skin irritation induced by the combination of timolol with long-term occlusion was mild, and after removal of the patches, skin changes were practically reversed in 24 h. Simulation model was useful in prediction of timolol levels in plasma after transdermal administration.

The effects of felbamate on the pharmacokinetics of a low-dose combination oral contraceptive containing 30 micrograms ethinyl estradiol and 75 micrograms gestodene were assessed in a randomized, double-blind, placebo-controlled parallel-group study in healthy premenopausal female volunteers established in a regimen of oral contraceptive use. They received either placebo or 2400 mg/day felbamate from midcycle (day 15) to midcycle (day 14) of two consecutive oral contraceptive cycles (months 1 and 2). Pharmacokinetic assessments of ethinyl estradiol and gestodene were performed on day 14 of both cycles. To determine whether ovulation occurred, plasma progesterone and urinary luteinizing hormone levels were measured, and diaries recording vaginal bleeding were kept. Felbamate treatment resulted in a significant 42% decrease in gestodene area under the plasma concentration-time curve (0 to 24 hours) (p = 0.018) compared with baseline, whereas a minor but not clinically relevant effect was observed on the pharmacokinetic parameters of ethinyl estradiol. There were no changes in the pharmacokinetics of ethinyl estradiol or gestodene after placebo treatment. No volunteer showed hormonal evidence of ovulation; however, one volunteer reported the onset of intermenstrual bleeding during felbamate treatment. Because of the effect of felbamate on the pharmacokinetics of gestodene and the report of intermenstrual bleeding, it is possible that the contraceptive efficacy of low-dose combination oral contraceptives may be adversely affected during felbamate treatment.

Timolol eyedrops may cause systemic side-effects in glaucoma patients due to absorption of the drug into systemic circulation. In a previous study, timolol concentrations in plasma were reduced if timolol was administered in ocular inserts instead of eyedrops. We compared the intraocular pressure lowering effect and systemic absorption of timolol inserts to those of 0.5% timolol eyedrops in humans. Inserts of silicone tubing released 90.3 +/- 13.9 micrograms of timolol in 24 hours in vivo. Timolol inserts afforded similar decreases in intraocular pressure in open-angle glaucoma patients as did b.i.d. eyedrops, but produced lower peak timolol concentrations in plasma, 0.70 +/- 0.10 ng/ml and 0.24 +/- 0.05 ng/ml, respectively. After eyedrops, peak concentrations were achieved at 15.0 +/- 2.2 min, while application of an insert resulted in a delayed peak (tmax = 623 +/- 195 min). The insert resulted in a higher systemically absorbed fraction of the timolol dose than the eyedrop, but the peak timolol concentration and daily absorbed amount of timolol were decreased. The release rate of timolol from the inserts in vivo was only slightly less than that in vitro. Silicone devices are useful for clinical testing of controlled delivery properties of ocular drugs.

Ciliary beating frequency, one component of mucociliary function, was measured outside of the sinus in vitro with a photoelectric method in 150 patients with chronic sinusitis and in 26 control subjects. In the mucosal samples of 35 patients (23%), no ciliary activity was seen. Ciliary beating frequency in maxillary sinus mucosa of the rest of the 115 patients (77%) was, as an average, 16.6 +/- 3.0 Hz (range, 10.9 to 23.3 Hz) and it was 15.9 +/- 2.6 Hz (range, 13.2 to 22.8 Hz) for the control patients. No differences in ciliary beating frequency were found according to quality of sinus secretion, prevalent respiratory allergy, or mucosal thickness. However, in sinuses with purulent secretion, ciliary beating frequency was slightly better (P.05) than in "empty" sinuses. The study suggests that in many cases of chronic sinusitis, the sinus mucosa still has a capacity to recure.

A randomised, placebo-controlled, double blind single-dose cross-over study was arranged to investigate possible interactions between zopiclone (7.5 mg) and two widely used benzodiazepine (BZD) anxiolytics diazepam (5 mg) and lorazepam (1 mg) during the elimination phase of drugs. Psychomotor performance was tested before and 1, 6, 8, 12 and 24 hr after the drug administration. Simultaneously, blood samples were drawn for determination of plasma drug concentrations. The elimination of each compound was not altered by coadministration of other drugs. As expected, one hour after drug ingestion, psychomotor performance was impaired. The coadministration of drugs increased the effect. During the elimination phase, 6 and 8 hr after the drug intake, only zopiclone and lorazepam in combination slightly impaired performance as compared with the pretreatment levels, but there was no difference as compared with placebo. Adverse events after active treatments were not significantly different from those after placebo. At the recommended dose of 7.5 mg, zopiclone does not alter the elimination pharmacokinetics of the BZD anxiolytics diazepam (5mg) and lorazepam (1 mg), and neither is the elimination of zopiclone affected by these BZDs. Due to the rapid elimination of zopiclone, the increase in sedation seen after concurrent administration with BZDs is of short duration.

The effect of azelastine and some selected compounds on ciliary beating frequency (CBF) was investigated in vitro using human mucosal samples and in vivo using anesthetized guinea pigs. Further influence of azelastine on mucus secretion was evaluated in mice and on mucociliary clearance in anesthetized rabbits. Azelastine influenced the ciliary beating frequency neither in vitro nor in vivo. Azelastine, similarly to salbutamol, ambroxol, and bromhexine, increased mucus secretion measured by the tracheal output of phenol red. Azelastine dose-dependently enhanced mucociliary clearance measured by elimination of 99mTc-labeled erythrocytes in rabbits. The activity of azelastine proved to be about 10 times stronger than that of bromhexine. Since the ciliary activity remained unchanged under the influence of azelastine, it is likely that azelastine increases the mucociliary clearance by enhancing bronchial secretion. It is possible that the observed increase in mucociliary clearance may contribute to the beneficial effect of azelastine in the treatment of respiratory diseases.

The pharmacokinetic properties of two solid form, 400 mg ibuprofen (IP) preparations, a soft gelatin capsule and a film-coated tablet, were compared to those obtained after the administration of liquid prepared from effervescent IP tablets. IP was absorbed rapidly (tmax 0.6-1.9 h). The fastest absorption was observed after the ingestion of the soft gelatin capsule; liquid and film-coated tablet produced 12.2-7.8 times longer absorption half-lives, 50-39% lower peak concentrations of IP in serum and 3.5-3.2 times higher tmax values. Bioavailabilities were close to similar after all products. All products were tolerated without side effects in this single-dose, crossover study on 14 healthy volunteers. The results of this study support the earlier findings that after oral administration, IP is absorbed equally well from solid formulations as from liquid form. Liquid formulations of IP often deliver slower absorption than expected probably due to incomplete dissolution of the active principle. This may have therapeutic significance, and it should be taken into account when studies on the relative bioavailability of IP from pharmaceutical drug products are planned.

The effect of adenosine triphosphate (ATP) on the airway ciliary beating frequency (CBF) of mucosal explants excised from human maxillary sinuses was studied by measuring CBF photoelectrically before and after immersion of the explants in a solution containing ATP. In samples from 64 patients with chronic sinusitis the CBF was not significantly different from the CBF in mucosal specimens from healthy tissue of 22 patients without infection. During 15 min immersion, ATP (1 mg/ml) slightly (by 5%, p less than 0.05 in healthy tissue; by 2.7%, p less than 0.01, in tissue from sinusitis patients) increased the CBF. The effect of 10 mg/ml concentration was more pronounced (19.6%). It is concluded that the impairment in ciliary function caused by chronic sinusitis is reversible when the mucosal endothelium is cleansed of the infected mucus, and that the ciliostimulatory action of ATP seen in animals is also present in human respiratory mucosa.

Doxycycline (DC) is used either as solid form hydrochloride capsules, or as monohydrate tablets, which may be taken either as solid form tablets or dissolved in water. In this single dose (150 mg), crossover study on 15 healthy volunteers, the pharmacokinetic properties of DC from hydrochloride tablets taken either in dissolved or in solid form were compared with those observed after taking dissolved DC as a monohydrate tablet. The results of this study show that DC is absorbed rapidly (tmax 3.3-3.8 h) and with equal bioavailability (AUC values 52.9-58.5 mg/l x h) from both hydrochloride and monohydrate tablets. It can be concluded that taking the DC hydrochloride tablets in dissolved form does not affect the pharmacokinetics of DC, moreover the bioavailability of DC is comparable to that achieved after taking DC monohydrate tablets in dissolved form.

The pharmacokinetic properties of two 200 mg, over-the-counter (OTC) ibuprofen preparations were compared in a randomized crossover study on ten healthy volunteers. After 2 times 200 mg single dose, one preparation produced peak plasma ibuprofen concentration 30.0 +/- 2.1 micrograms/ml at 1.6 h and the other preparation 23.2 +/- 1.9 micrograms/ml at 2.3 h (p less than 0.05). There was no statistically significant difference between the preparations in the bioavailability of ibuprofen. OTC ibuprofen preparations are mainly used for acute indications, such as fever or headache. In these cases, rapid absorption and high concentrations of active ingredient are desirable properties, especially when the amount of drug is relatively low. Therefore, the pharmacokinetic differences between these preparations may be therapeutically significant.

There is scarce information in literature about the decisions made by ethics committees concerning the clinical studies they have reviewed. A retrospective, detailed review of 666 applications, their amendments and the ethics committees' statements was undertaken. All protrocols of clinical studies on medicinal products submitted to and reviewed by the ethics committees of two university hospitals during the years 1992, 1994, 1996 and 1998 were investigated. Most of the studies were international (50%), multicenter (71%), phase III trials (41%) on a new clinical entity, (38%). Validity of the clinical drug study applications was acceptable in more than half of the cases (364; 55%), while 91 (14%) were approved with advisory comments, 153 (23%) had to be amended, 35 (5%) were left pending and 23 (3%) were rejected. Most of the questions pertained to informed consent and the study protcol. In accordance with precious results, our findings support the opinion that the submitted documents need to be improved, especially with regard to informed consent and study protocols, in order to gain better Good Clinical Practice (GCP) compliance. Well-defined, documented operating procedures of the ethics committees would have facilitated the practical issues in the review process.

Article de synthese sur les sites de fixation peripheriques des benzodiazepines: distribution, fixation biologique, action au niveau du systeme nerveux central, regulation par le GABA et le stress, regulation endocrine, relation avec les canaux calcium, autres ligands, role physiologique

We have carried out a steady state pharmacokinetic comparison of three different theophylline preparations in nine healthy volunteers using a once a day dosage schedule of 600 mg theophylline given before bedtime for four days. The preparations tested were Retafyllin 200 mg depot tablet (R), Theo-Dur 200 mg depot tablet (T) and Uniphyllin 200 mg tablet (U). All preparations in steady state reached the serum level of 8.9-10.2 microg/ml after a single evening dose of theophylline 600 mg. The pharmacokinetic profile of these slow release theophylline preparations was such that there is no risk of exceeding the therapeutic range even after a rather high evening dose. Individual variation was also observed in the present study but nobody exceeded the therapeutic range. The pharmacokinetic profiles of R and U were quite similar and they seemed to have suitable pharmacokinetic properties for once a day dosage, and they showed a more sustained action than T. Only minimal gastrointestinal side effects were reported during this study.

The pharmacokinetics and acute adverse effects of nifedipine were studied in a cross-over, single dose (20 mg) study on ten healthy young volunteers. From the liquid-filled capsules, nifedipine was absorbed rapidly (tmax at 30-40 min). From tablets, the peak concentration was 79-88% lower and occurred 74-133 min after ingestion; also the bioavailability was lower, as indicated by on average 39% lower area under curve values after tablets. All the volunteers experienced side-effects: the most common (nine out of the ten) and the most intense was headache. One volunteer withdrew because of unbearable vomiting and headache. Also others felt nauseous (six out of nine who continued) and four of them vomited. After tablets, the dizziness was markedly less than after capsules, but the more slowly-appearing symptoms such as headache and nausea were similar after both types of drug products. By using slow-release tablets instead of capsules it seems possible to avoid some side-effects of nifedipine, but this benefit is gained at the expense of bioavailability.

The benzodiazepines had already been in wide use as anxiolytics and anticonvulsants for more than ten years before their site of action in the central nervous system, the benzodiazepine receptor, was discovered. Simultaneously, a binding site in the peripheral organs, e.g. heart, lungs and kidneys, was found. Although some benzodiazepines, such as diazepam, bind to both central and peripheral benzodiazepine receptors with a high affinity, these two binding sites exhibit quite different properties. It is already clear that the central benzodiazepine receptors are in many regions of the brain coupled with the receptors for gamma-amino butyric acid, and they mediate the acute actions of benzodiazepines in the central nervous system. Through them opposite effects, such as anxiety and convulsions, can also be evoked by using inverse agonists, e.g. some beta-carbolines. All these effects can be blocked with benzodiazepine receptor antagonists, some of which are already used as specific antidotes against benzodiazepine overdose. The multitude of pharmacological effects that can be produced through central benzodiazepine receptors provides a good opportunity for the development of new drugs. The role of the peripheral-type receptors is less clear, but it seems that they are connected with more slowly-appearing drug actions, such as modulation of cell proliferation. Now that endogenous ligands for both the central-type (a peptide called diazepam binding inhibitor; DBI) and for the peripheral-type (porphyrins) benzodiazepine receptors have been discovered, even more productive research can be expected.