Mechanism-Based QSAR Modeling of Skin Sensitization.

Many chemicals can induce skin sensitization, and there is a pressing need for non-animal methods to give a quantitative indication of potency. Using two large published data sets of skin sensitizers, we have allocated each sensitizing chemical to one of 10 mechanistic categories and then developed good QSAR models for the seven categories that have a sufficient number of chemicals to allow modeling. Both internal and external validation checks showed that each model had good predictivity.

QSAR study of some anti-hyperglycaemic sulphonylurea drugs.

Sulphonylureas are widely used anti-hyperglycaemic drugs for the treatment of type 2 diabetes. The only published quantitative structure-activity relationship (QSAR) models for sulphonylurea drugs have been found to be questionable, for a number of reasons. We have re-analysed the human anti-hyperglycaemic potencies, acute mouse intraperitoneal toxicities (LD50) and plasma protein-binding abilities of the 15 drugs using multiple linear regression and obtained good QSAR models for each endpoint. The obtained QSARs all comply well with the Organisation for Economic Co-operation and Development (OECD) Guidelines for the Validation of (Q)SARs. We could not carry out external validation of our models for acute toxicity and plasma protein-binding because of the very small datasets available.

Prediction of immobilised artificial membrane chromatography retention factors using theoretical molecular fragments and structural features.

Many in silico alternatives to aquatic toxicity tests rely on hydrophobicity-based quantitative structure-activity relationships (QSARs). Hydrophobicity is often estimated as log P, where P is the octanol-water partition coefficient. Immobilised artificial membrane (IAM) high performance liquid chromatography (HPLC) may be a more biologically relevant alternative to log P. The aim of this study was to investigate the applicability of a theoretical structural fragment and feature-based method to predict log k IAM (the logarithm of the retention index determined by IAM-HPLC) values. This will allow the prediction of log k IAM based on chemical structure alone. The use of structural fragment values to predict log P was first proposed in the 1970s. The application of a similar method using fragment values to predict log k IAM is a novel approach. Values of log k IAM were determined for 22 aliphatic and 42 aromatic compounds using an optimised and robust IAM-HPLC assay. The method developed shows good predictive performance using leave-one-out cross validation and application to an external validation set not seen a priori by the training set also generated good predictive values. The ability to predict log k IAM without the need for practical measurement will allow for the increased use of QSARs based on this descriptor.

Repeatability analysis of the Tetrahymena pyriformis population growth impairment assay.

Assessments necessary to ensure the safety of both humans and the environment are challenged by the sheer number of chemicals in use today. Chemical legislation, such as REACH, aims to use alternative methods to reduce the reliance on in vivo animal testing. Consequently, databases such as the TETRATOX database, containing data from the Tetrahymena pyriformis population growth impairment assay, have been used extensively to develop computational models which aid in priority setting and initial hazard assessments. To use any toxicological data, an assessment of quality is required. One important aspect of quality is the repeatability of the assay. This study considered TETRATOX assay data for 85 structurally and mechanistically diverse compounds. The repeatability of replicate determinations was assessed and factors relating to repeatability are discussed. Despite the majority of compounds demonstrating excellent repeatability, it was found that the mechanism of action is likely to be a modulating factor, with compounds acting via electrophilic mechanisms being more likely to exhibit reduced repeatability than those acting via narcotic mechanisms. It is evident from this study that the TETRATOX assay is a robust and highly repeatable assay, suitable for use in toxicological modelling studies and priority setting.

Structure-based modelling in reproductive toxicology: (Q)SARs for the placental barrier.

The replacement of animal testing for endpoints such as reproductive toxicity is a long-term goal. This study describes the possibilities of using simple (quantitative) structure-activity relationships ((Q)SARs) to predict whether a molecule may cross the placental membrane. The concept is straightforward, if a molecule is not able to cross the placental barrier, then it will not be a reproductive toxicant. Such a model could be placed at the start of any integrated testing strategy. To develop these models the literature was reviewed to obtain data relating to the transfer of molecules across the placenta. A reasonable number of data were obtained and are suitable for the modelling of the ability of a molecule to cross the placenta. Clearance or transfer indices data were sought due to their ability to eliminate inter-placental variation by standardising drug clearance to the reference compound antipyrine. Modelling of the permeability data indicates that (Q)SARs with reasonable statistical fit can be developed for the ability of molecules to cross the placental barrier membrane. Analysis of the models indicates that molecular size, hydrophobicity and hydrogen-bonding ability are molecular properties that may govern the ability of a molecule to cross the placental barrier.

Structure-based methods for the prediction of the dominant P450 enzyme in human drug biotransformation: consideration of CYP3A4, CYP2C9, CYP2D6.

Metabolic drug-drug interactions are receiving more and more attention from the in silico community. Early prediction of such interactions would not only improve drug safety but also contribute to make drug design more predictable and rational. The aim of this study was to build a simple and interpretable model for the determination of the P450 enzyme predominantly responsible for a drug's metabolism. The P450 enzymes taken into consideration were CYP3A4, CYP2D6 and CYP2C9. Physico-chemical descriptors and structural descriptors for 96 currently marketed drugs were submitted to statistical analysis using the formal inference-based recursive modelling (FIRM) method, a form of recursive partitioning. Generally accepted knowledge on metabolism by these enzymes was also used to construct a hierarchical decision tree. Robust methods of variable selection using recursive partitioning were utilised. The descriptive ability of the resulting hierarchical model is very satisfactory, with 94% of the compounds correctly classified.

An assessment of dose-uniformity of samples delivered from paediatric oral droppers.

BACKGROUND AND OBJECTIVES: To assess the accuracy and precision of delivery from containers containing oral drops, both under optimal laboratory conditions and during use by volunteers using a variety of real pharmaceutical products and specially prepared fluids. METHODS: The effects of the physical properties (viscosity, surface tension, fluid density) of fluids and the angle of a dropper upon the accuracy and precision of dispensing were investigated under standard laboratory conditions. Dose delivery was then assessed using a number of volunteers who were either given no instructions on the use of containers or were instructed to hold the droppers vertically. RESULTS: Viscosity, surface tension, fluid density and residual volume had little or no effect upon the volume of liquid delivered by a dropper clamped in the vertical position. However, when the angle of the dropper was moved towards 45 degrees from the vertical, the volume dispensed declined and became more variable to a point where the requirements of the European Pharmacopoeia were no longer fulfilled. This finding applied to a variety of products. When volunteers used the same droppers manually, the mean volumes dispensed were lower than when the droppers were vertically clamped and the variability was greater. It appeared that these problems were associated with volunteers failing to hold the dropper vertically and the precision and accuracy were indeed increased if the volunteers were instructed as to how the dropper should be held. The results from volunteers were more precise and accurate with the most viscous of the fluids tested and it was speculated that this may have been because the volunteers could more easily use the droppers vertically as there was less fear of dispensing too many drops. CONCLUSIONS: The key factor in achieving satisfactory dispensing from droppers is to ensure that the dropper is held vertically and this should form the basis of instructions to patients. Formulators should consider increasing the viscosity of prepared dropper solutions to reduce further errors in dose.

Use of the Bard Memotherm self-expanding metal stent in the palliation of colonic obstruction.

BACKGROUND: Self-expanding metal stents (SEMS) are a recognized means of palliating large bowel obstruction due to colonic neoplasia. The literature mainly relates to the use of modified esophageal stents (expanded diameter, 18-22 mm) in the colorectum. Stent migration has been a common complication and may be related to expanded stent diameter. This series reports our experience with the Memotherm Colorectal SEMS (expanded diameter, 25-30 mm). METHODS: Prospective data were collected from February 1999 to September 2000. Sixteen patients (age range = 61-99 years) were considered for the Memotherm Colorectal SEMS. Stents were inserted radiologically under fluoroscopic control. Outcome was classified as a technical success (stent in correct position and expanded) and a clinical success (colon decompressed, symptoms relieved, and bowels working). RESULTS: Thirteen cases (81%) underwent successful SEMS placement. These were technically and clinically successful. Two cases required insertion of two overlapping stents to traverse long strictures. Three unsuccessful cases were emergency presentations in which a guidewire could not be passed across the lesion. Two of these were due to benign strictures and the third to extrinsic compression by ovarian carcinoma. CONCLUSION: In our experience, the Memotherm Colorectal SEMS was easy to use, was effective in the palliation of obstructing colorectal carcinoma, and appeared to reduce the risk of stent migration.

Attitudes and knowledge of hospital pharmacists to adverse drug reaction reporting.

AIMS: To investigate the attitudes of UK hospital pharmacists towards, and their understanding, of adverse drug reaction (ADR) reporting. METHODS: A postal questionnaire survey of 600 randomly selected hospital pharmacists was conducted. RESULTS: The response rate was 53.7% (n = 322). A total of 217 Yellow Cards had been submitted to the CSM/MCA by 78 (25.6%) of those responding. Half of those responding felt that ADR reporting should be compulsory and over three-quarters felt it was a professional obligation. However, almost half were unclear as to what should be reported, while the time available in clinical practice and time taken to complete forms were deemed to be major deterrents to reporting. Pharmacists were not dissuaded from reporting by the need to consult a medical colleague or by the absence of a fee. Education and training had a significant influence on pharmacists' participation in the Yellow Card Scheme. CONCLUSIONS: Pharmacists have a reasonable knowledge and are supportive of the Yellow Card spontaneous ADR reporting scheme. However, education and training will be important in maintaining and increasing ADR reports from pharmacists.

Analysis of intracytoplasmic sperm injection procedures related to delayed insemination and ejaculated, epididymal and testicular spermatozoa.

In all, 1210 treatment cycles were divided into three categories for retrospective analysis according to the period of delay between oocyte retrieval (occurring at a fixed time after human chorionic gonadotrophin) and intracytoplasmic sperm injection (ICSI) of <3 h, 3-5 h, >5 h (referred to as 'delayed ICSI'). Three stages from oocyte to the birth of a live baby were identified for statistical analysis, (i) fertilization (2PN zygotes), (ii) cleavage of 2PN zygotes, (iii) transferred embryo to live birth. Stages 1, 2 and 3 were analysed statistically for the three time periods. Chi-square analysis showed no significant effect of delayed ICSI on fertilization (chi(2) = 3.615, P = 0.65), and embryo transfer to birth (chi(2) = 1.840, P = 0.399). The effect on cleavage was significant (chi(2) = 9.625, P = 0.008). However, shorter incubation times produced results which were better than the traditional longer ones. The success rate at the cleavage stage was so high that the marginal advantage had very little effect on the overall process. This study of a substantial patient sample establishes that ICSI on a peri-ovulatory oocyte (<3 h after oocyte retrieval) does not compromise outcome parameters, and that longer periods of incubation (>5 h) do not offer a statistically significant advantage.

Adverse drug reactions as a cause of admission to an acute medical assessment unit: a pilot study.

BACKGROUND: In this pilot study, we have investigated the frequency of adverse drug reaction (ADR)-related admissions to an acute medical assessment unit. Although ADRs are thought to be responsible for 5% of hospital admissions, there have been no recent studies in the U.K. OBJECTIVE: To pilot such a study for estimating the incidence of ADR-related admissions to an acute medical assessment unit. METHOD: Data were collected for 200 patients including details of concurrent illness, drug usage and reasons for admission. ADRs were assessed for causality using two previously published classification systems. RESULTS: ADRs were responsible for admission in 15 (7.5%) patients, were present in an additional three (1.5%) patients and may have contributed to the deaths of two (1%) patients. Of the 15 ADRs suspected of causing an admission, three were considered to be 'possible' or 'unlikely', with the remaining 12 considered to be 'probable' or 'certain'. The proportion of patients identified in this study with ADR-related admissions is either similar to or larger than that found in comparable studies carried out in other hospitals. Nearly all ADRs were Type A reactions in that they were predictable and therefore potentially preventable. CONCLUSION: This study suggests that the proportion of ADR-related admissions has not decreased in the last decade and, given the increasing numbers of acute medical admissions, the absolute numbers may have actually increased. Furthermore, the nature of drugs causing admissions has not changed substantially over the last 20 years. Strategies to reduce the burden of ADR-related admissions are urgently needed.

Communication regarding adverse drug reactions between secondary and primary care: a postal questionnaire survey of general practitioners.

GPs are not always informed that their patient suffered an adverse drug reaction (ADR) while in hospital. We have conducted a postal questionnaire survey of 270 GPs in order to elicit their views regarding provision of information from secondary care regarding ADRs. Of the 141 (52.2%) GPs that replied, 127 (90.1%) saw patients that had experienced an ADR in hospital. Of these GPs, 113 (89%) stated that they encountered instances where no record of the ADR existed in patients' discharge documentation. Where written information was absent, GPs are reliant on information given to them by patients. Of those responding, none were 'very confident' of this information, while 92 (78.6%) were 'uncertain' or 'very uncertain' of this information. A sample notification form was developed. GPs were generally satisfied with its content and 110 (82.7%) thought that patients should receive a copy. Almost all GPs (135 (97.8%)) felt that it would be appropriate to provide patients with ADR warning cards. Ensuring that patients and their carers are aware of drugs to which they may be allergic or intolerant through verbal and written methods should minimize the unnecessary risks of inadvertent re-exposure.

The effects of lag-time and dwell-time on the compaction properties of 1:1 paracetamol/microcrystalline cellulose tablets prepared by pre-compression and main compression.

The effects of lag-time and dwell-time on the compaction properties of tablets compressed from a 1:1 blend of paracetamol and microcrystalline cellulose have been examined using a compaction simulator. Increases in lag-times (from 0.06 to 0.53 s) resulted in small increases in the tensile strengths of the tablets when combinations of 80 and 160 MPa were used as the compression pressures. Further increases in lag-time did not alter the tablet strengths. When combinations of 240 and 320 MPa were used for pre-compression and main compression, the effects on the tensile strengths were more complex, partly because the high elastic recoveries of the tablets resulted in greater variability in the data. Increases in lag-times from 0.06 to 0.97 s resulted in an increase of between 12 and 28% in tensile strength. Longer lag-times (1.24 or 1.52 s) did not result in further increases in tensile strength. The application of a dwell-time of 0.26 s during pre-compression or main compression pressures of 80 and 160 MPa generally led to a decrease (14-22%) in tensile strength compared with tablets where no dwell-time was used. This was because of increases in both the elastic recoveries and elastic energies. Subsequent increases in dwell-time from 0.26 to 0.9 s resulted in increases in tablet strength compared with that obtained when no dwell-time was applied. The tensile strengths of tablets made with a pre-compression of 160 MPa then a main compression of 80 MPa were 11-33% higher than those of tablets made with a pre-compression of 80 MPa then a main compression of 160 MPa. This was because higher plastic energies and more plastic deformation occurred at the higher pre-compression. Generally, the application of dwell-time resulted in greater increases in tensile strengths than lag-time, which had less effect on the compaction properties.

Restenting malignant oesophageal strictures.

BACKGROUND: Self-expanding metal stents are used to palliate malignant strictures of the oesophagus. This study was designed to identify the characteristics of patients requiring restenting of malignant oesophageal strictures. METHODS: Fifty-three stents were inserted in 42 patients. Thirty-two patients did not require further stenting (once-stented group). Ten patients received second stents for recurrent oesophageal obstruction (restented group), with one patient requiring restenting a second time. Comparisons were drawn between the once-stented and restented groups with regard to survival, patient, tumour and procedural characteristics. RESULTS: There were no significant differences with regard to tumour grade, tumour type, involvement of the cardia, procedural difficulties or the need for postprocedural oesophageal dilatation between the two groups. Survival from initial stenting was significantly greater in the restented group (median 24 (range 4-43) weeks) than in the once-stented group (median 9.5 (range 1-84) weeks) (P < 0.05). The mean length of stents used in the once-stented group was significantly greater than that of the initial stents used in the restented group (12 versus 10 cm, P = 0.032). CONCLUSION: Inserting a covered stent through a previously inserted uncovered stent is an uncomplicated and well tolerated technique which maintains palliation from obstructing oesophageal carcinoma. The need for restenting cannot be predicted on the basis of tumour characteristics alone.

The influence of moisture content on the consolidation properties of hydroxypropylmethylcellulose K4M (HPMC 2208).

The effect of moisture content, compression speed and compression force on the compaction properties of HPMC K4M has been evaluated. As the moisture content increased from 0 to 14.9% w/w, the thickness of HPMC K4M compacts increased at constant compression force and speed. This increase in moisture content also resulted in a marked increase in the tensile strength of the tablets. At a speed of 15 mm s-1 and force of 10 kN, as the moisture content increased from 0 to 14.9% w/w, the tensile strengths increased from 1.34 to 8.54 Mpa. Equivalent tensile strengths could be obtained with less compression force as the moisture content in the polymer was increased. Increasing the compression speed generally decreased the tensile strength of HPMC K4M tablets. The dependence of tablet porosity and tensile strength on compression speeds showed that HPMC K4M is consolidated by plastic deformation. At all compression speeds, an increase in moisture content reduced the percentage elastic recovery of HPMC compacts due to greater tablet consolidation. The lowest elastic recovery (1.18%) was found for tablets made at 15 mm s-1 and 5 kN, containing 14.9% w/w moisture content.

The effect of moisture on the heckel and energy analysis of hydroxypropylmethylcellulose 2208 (HPMC K4M).

The influence of moisture content on the Heckel analysis, energy analysis and strain-rate sensitivity of hydroxyproplymethylcellulose 2208 (HPMC K4M) has been evaluated. An increase in moisture content from 0 to 14.9% w/w decreased the mean yield pressure, probably due to a plasticizing effect of moisture which reduced the resistance of particles to deformation. For each moisture content (0, 2.2, 3.8, 5.9, 9.6 and 14.9% w/w), the initial relative density and the extrapolated density from the linear portion of the Heckel plot, tended to decrease with increasing compression speed. Minor changes were observed in the initial relative density due to changes in the moisture content. The strain-rate sensitivity increased from 21.6 to 50.7% as the moisture content increased from 0 to 14.9% w/w, indicating that the plasticity of HPMC increased with increase in moisture content, whereas increase in moisture content from 0 to 14.9% w/w decreased the plastic energy. Increase in compression force or speed of compaction increased both the plastic and elastic energies. An increase in moisture content from 0 to 5.9% w/w slightly reduced the elastic energy but above 5.9% moisture content the elastic energy was unaffected by the moisture content.

Transcatheter embolisation of a suprarenal aortic aneurysm persisting after bypass graft surgery.

We present a case of a large suprarenal aneurysm which recurred following aorto-biliac bypass grafting and ligation of the aneurysm. Successful thrombosis was achieved with selective embolisation.

Recurrent phaeochromocytoma.

The recurrence of symptoms and hypertension in a patient who has previously undergone an operation for phaeochromocytoma should alert the physician to the need to investigate for recurrent tumour. Failure to perform complete excision of the adrenal gland containing the tumour may lead to disseminated recurrence.

Splenic artery aneurysm embolisation--the preferred technique to surgery.

A case of embolisation of a splenic artery aneurysm is presented. The aneurysm and proximal splenic artery were successfully occluded with steel coils and there were no associated complications. Transcatheter embolisation-should be the treatment of choice for splenic artery aneurysms. The procedure carries less morbidity than surgery and more importantly allows preservation of the spleen and its function.