Hospitalisations caused by adverse drug reactions (ADR): a meta-analysis of observational studies.

AIM: To establish the percentage hospital admission related to adverse drug reactions (ADRs) from the data available in the literature. METHOD: Literature search in the Medline database, meta-analysis. RESULTS: From the literature it is revealed that a considerable part of all hospital admissions are related to adverse drug reactions. However, these data are not homogenous, i.e. larger studies display a lower percentage of ADR related hospital admission, while smaller studies display a higher percentage. Subgroup analysis showed that for elderly people the odds of being hospitalised by ADR related problems is 4 times higher than for younger ones (16.6% vs. 4.1%). A considerable part of these hospitalisations can be prevented. Subgroup analysis revealed that in the elderly up to 88% of the ADR related hospitalisations are preventable; for the non-elderly this is only 24%. Comparatively more elderly people are hospitalised than younger ones. Combining these findings, twice as much elderly people are hospitalised by ADR related problems than non-elderly, while preventability of ADR related hospitalisation might yield 7 times more people in the elderly than in the non-elderly. The estimation of the costs of ADR related hospitalisations in the Health Care system in The Netherlands is discussed. CONCLUSION: Many elderly people are hospitalised by ADR related problems; an important part of these hospitalisations can be avoided.

Hospital prescribing errors: epidemiological assessment of predictors.

AIMS: To demonstrate an epidemiological method to assess predictors of prescribing errors. METHODS: A retrospective case-control study, comparing prescriptions with and without errors. RESULTS: Only prescriber and drug characteristics were associated with errors. Prescriber characteristics were medical specialty (e.g. orthopaedics: OR: 3.4, 95% CI 2.1, 5.4) and prescriber status (e.g. verbal orders transcribed by nursing staff: OR: 2.5, 95% CI 1.8, 3.6). Drug characteristics were dosage form (e.g. inhalation devices: OR: 4.1, 95% CI 2.6, 6.6), therapeutic area (e.g. gastrointestinal tract: OR: 1.7, 95% CI 1.2, 2.4) and continuation of preadmission treatment (Yes: OR: 1.7, 95% CI 1.3, 2.3). CONCLUSIONS: Other hospitals could use our epidemiological framework to identify their own error predictors. Our findings suggest a focus on specific prescribers, dosage forms and therapeutic areas. We also found that prescriptions originating from general practitioners involved errors and therefore, these should be checked when patients are hospitalized.

The quality of Dutch hospital drug formularies: evaluation of technical features and organisational information.

INTRODUCTION: Hospital drug formularies (HDFs) are widely used tools to help influence clinicians' prescribing behaviour. Besides the therapeutic quality of HDFs, the available information and the way in which this is presented are key factors in HDFs' success or failure to influence prescribing behaviour and enhance prescribing quality. This research evaluates the technical features and organisational information of Dutch HDFs. METHODS: Seventy-two (75%) of all Dutch HDFs were evaluated based on criteria retrieved from international literature and additional criteria drafted by occupational groups working with HDFs. Aspects that were studied were physical appearance and layout, practicability with respect to the available information and how easily this could be retrieved from the HDFs, information regarding drug choice policies such as seamless care, and the available type of therapeutic and pharmaceutical information. RESULTS: Thirty-three (46%) of the HDFs were less than 3 years old. Physical appearance of all HDFs was very well looked after. Two (3%) HDFs were disease-oriented rather than drug-oriented. Changes from pre-admission therapy were addressed in 30 (42%) of the HDFs, but other seamless care policies were addressed in less than 20% of the HDFs. Finally, less than 50% provided therapeutic information that clinicians indicated as important. DISCUSSION: Although Dutch HDFs are technically practicable with respect to user-convenience, practice-oriented features are capable of improvements. Furthermore, Dutch HDFs lack important clinical information for daily practice. To enhance seamless care across healthcare, generic prescribing and prescribing on admission from and discharge to any other sectors should be addressed more specifically.

Drug release from suppositories.

Many studies have been carried out over the past decades on suppositories and their drug release properties. The present state of knowledge is reviewed with the conclusion that our current understanding of the in vivo performance of suppositories is deficient. It is therefore not possible to rely on in vitro data to predict in vivo performance. Suggestions are presented for future studies that are required to enhance our knowledge of suppositiories as drug delivery systems.

Absorption of Etoposide (VP-16-213) from the Small Intestine of the Rat. The Potential Role of Mucus as an Absorption Rate Limiting Barrier.

The absorption of etoposide (VP-16-213) was investigated in a perfused intestinal loop. The absorbed amount of drug was determined by collecting the blood draining the loop via cannulation of the efferent jejunal vein. The absorption rate of VP-16-213 strongly depended on the composition of the perfusion medium. The addition of taurocholate to an aqueous etoposide solution enhanced the absorption rate. When N-acetylcysteine was added to an aqueous solution, the absorption rate dropped significantly.

Dissolution at porous interfaces VI: Multiple pore systems.

With the aid of rapidly dissolving sodium chloride particles, cubic pores were made in the surface of a theophylline tablet. The influence of the pores on the dissolution rate of the surface was investigated in a rotating disk apparatus. Like the drilled pores used in earlier studies, downstream on the surface they caused a turbulent flow regimen with the development of a trough due to enhanced erosion. The phenomenon of a critical pore diameter, discovered with single, drilled pores, seems to be applicable to the cubic pores investigated in this study, although a higher degree of surface coverage with pores caused complications, probably due to particles bordering one another and forming larger pores. The behavior of the porous surfaces at different rotation speeds was studied. Due to the presence of pores the laminar character of the boundary layer flow changes to turbulent, which induces locally an increased dissolution flux in the wake of a pore.

Pulsed proton NMR and solid-liquid fat ratio determinations in suppository vehicles and aminophylline suppositories.

The physical state, melting behaviour and release rate of aminophylline suppositories were studied during storage. The fraction of non-crystallized fat, assessed by pulse NMR, varies between different vehicles. At room temperature several vehicles do not seem to be completely crystalline. Aging, as observed in prolonged melting time and a reduced release rate, is not expressed in a drastic reduction of the fraction of non-crystallized fat, as observed by NMR. On the contrary the mobility of the protons in the non-crystallized state is likely to offer a more promising tool to monitor aging.

Prolonged storage of aminophylline suppositories. The impact on physical parameters and bioavailability.

Prolonged storage of aminophylline/cocoa butter suppositories at 30 degrees resulted in a marked decrease in bioavailability, after administration to a panel of human volunteers. Not more than 20% of the drug content was absorbed during the first 8 hours and the maximum plasma level was obtained 5-7 hours after administration. It was concluded that storage conditions should be considered well and storage instructions should be given to the patient.

A new approach of ordered mixing applied to digitoxin tablets.

In ordered mixing it is assumed that mixing very different amounts of two materials is improved by adsorption of small particles onto large carrier particles. This hypothesis could be confirmed with tablets of 120 mg containing 0.1 mg digitoxin, prepared by dry coating of particles.

Non-enhancement of sodium cromoglycate intestinal absorption by quaternary ammonium ions. An effect of salt on ion-pair formation?

Studies on the nature of rat small intestine perfusates indicate that this environment is thermodynamically unfavourable for the production of ion pairs between cromoglycate and alkylbenzyldimethylammonium ions. This is suggested as being the reason why, unlike previously found for ocular absorption of cromoglycate, these quaternary ammonium ions do not alter cromoglycate intestinal absorption.

Influence of bloodflow on the absorption of theophylline from the jejunum of the rat.

The influence of the jejunal bloodflow on the absorption of theophylline was investigated. The bloodflow through a segment under investigation was varied by changing the systemic blood pressure by means of a donor blood infusion into the jugular vein or by an infusion of isoprenaline or levarterenol into a femoral vein, and was measured by collecting the venous outflow from the intestinal segment. Above a bloodflow of approximately 0.40 µl/min/cm the flux/ flow ratio is reduced, and it is proposed that above this flow the intestinal epithelium provides the rate limiting step in the absorption of theophylline. When the bloodflow was held low for a prolonged time, the flux of theophylline decreased. The absorptive site bloodflow was calculated to be 18 % of the total bloodflow through the segment under investigation.

Rectal motility and bioavailability.

The contractile activity of the canine rectal wall exhibits a positive influence on the behaviour of fatty suppositories in vivo with respect to both spreading abilities and rate and extent of release of the readily water-soluble compound phenazone. This influence on bio-availability was marked when the drug was suspended in a large particle size (100-125 µm). When used in small particles (< 35µm), far less influence of contractile activity was found. Small particles were equivalent to coarse particles with respect to the bioavailability. The addition of colloidal silicium oxide has a marked influence on spreading and bioavailability. Enhanced rectal motility exhibits an influence on the absorption only when a coarse fraction of the drug is suspended. It was concluded that rectal motility might be a cause of variation in bioavailability of drugs from rectal suppositories. For this reason only well-trained animals should be used when bioavailability of drugs from suppositories is tested in an animal model.

Dissolution at porous interfaces. IV. Pore effects in natural convection flow.

The dissolution rate of a nicotinic acid tablet surface was measured in a dissolution system where mass transport in the solvent is governed by a combination of natural and forced convection. While such experimental conditions were chosen that natural convection outweighted forced convection, the dissolution rate increasing effect of large pores in the tablet surface was studied. To that end cylindrical pores were drilled into the tablet. The increase in dissolution rate was measured as a function of the number of pores, their depth and diameter and their position with respect to each other and to the centre of the dissolving surface. The results are discussed with regard to the hydrodynamic conditions near the pores. In addition to the regularly arranged cylindrical pores a more irregular configuration of cubic pores was investigated. These pores were created by embedding cubic sodium chloride crystals in the tablet surface during the compression procedure. After the sodium chloride particles had dissolved rapidly a porous surface of much slower dissolving nicotinic acid remained. The dissolution rate of the porous surface was determined and a comparison was made between surfaces with and without pores of several sizes.

In vitro testing of controlled release theophylline preparations: Theolair, Theograd and Theolin.

Three dissolution methods, i.e. a paddle type, the USP disintegration and a column method, were used to characterize the release from three controlled release theophylline preparations, i.e. Theolair Retard 250, Theolin Retard 300 and Theograd 350. The release profiles proved to be dependent upon agitation intensity and pH or a combination of both, but the sensitivity towards these variables differed markedly between the products tested.

Drug release from non-aqueous suspensions. I. Release of phenobarbital and phenobarbital sodium from paraffin suspensions.

The rate at which phenobarbital and phenobarbital sodium, suspended in liquid paraffin, are released to buffers pH = 3.0, 7.4 and 10.0 has been studied. The release rate of phenobarbital depends on its solubility and hence on the pH, whereas the initial release rate of phenobarbital sodium is governed by sedimentation and hence is independent of the pH. However, when phenobarbital sodium is released to buffer pH = 3.0, it crystallizes in the interfacial layer after an initial release time. The release process in the release apparatus used cannot be described by a theory based on forced convection [i.e. the (E)SCRD-theory], but has to be regarded as a natural convection process.

Dissolution kinetics of soluble nondisintegrating disks.

An equation describing the isotropical dissolution of soluble nondisintegrating disks was developed. It was equivalent to the cube root law only if the height and diameter of the disk were equal. The dissolution kinetics of sodium chloride disks were examined, using a beaker equipped with a centrifugal stirrer as the dissolution chamber. The fit of the experimental data to the cube root law had a coefficient of variation of about 4-5%. It was demonstrated statistically that a fit to a square root of mass versus time relation was significantly better. With increasing porosity, the dissolution process proceeded faster than predicted on the basis of the diffusion-convection model. An explanation is proposed by assuming an increased effective dissolution surface.