The safety of quetiapine: results of a post-marketing surveillance study on 1728 patients in England.

The safety of the atypical antipsychotic quetiapine as used in general practice in England was examined by prescription-event monitoring (PEM). Patients were identified from dispensed National Health Service (NHS) prescriptions issued by general practitioners (GPs) for quetiapine between October 1997 and July 1999. The outcome data were event reports obtained by sending questionnaires ('green forms') to the prescribing doctor at Least 6 months after the first prescription for an individual patient. Green forms with clinically useful information on 1728 patients (median age 39 years (IQR 30-56); 53% female) were received. The most frequently reported event during the first month of treatment was 'drowsiness/sedation' (47; 3% cohort). This was also the most frequently reported specified adverse drug reaction (ADR) to quetiapine (7; 11% of 65 reported ADRs) and the highest reported clinical reason for stopping quetiapine (51; 6% of the 734 reported reasons for stopping). There was a low incidence of extrapyramidal disease (21 during treatment, 1% of cohort) and hyperprolactinaemia (three during treatment, 0.2%) in this study. Three cases of diabetes mellitus in this cohort were reported to be a new diagnosis. Six pregnancies were reported during treatment with quetiapine, five of which were exposed during the first trimester only. There were four Live births with no reported congenital abnormaLities. Fifty-six deaths were reported during this study (3% cohort). The most frequently reported causes of death reLated to the cardiovascular (18) and respiratory (15) systems. The results of this post-marketing surveillance study demonstrated that quetiapine is generally well-tolerated when used in general practice.

Safety of zafirlukast: results of a postmarketing surveillance study on 7976 patients in England.

OBJECTIVES: A prescription event monitoring (PEM) postmarketing surveillance study was carried out to examine the safety of zafirlukast as used in general practice in England. METHODS: Exposure data were obtained from the first National Health Service (NHS) prescription dispensed for patients whose prescription details were processed by the Prescription Pricing Authority between August 1998 and December 2000. Outcome data were obtained from 'green form' questionnaires sent to general practitioners (GPs) at least 6 months following the first prescription issued. Incidence densities (IDs) were calculated for events reported per 1000 months of patient exposure and ID differences between the first month of treatment and months 2-6 combined were analysed. Events of medical interest were followed up by postal questionnaire sent to GPs. RESULTS: 21 557 green forms were sent to 8051 doctors, of which 9124 (42.3%) were returned. Useful clinical data was obtained for 7976 patients of which 4664 (58.5%) were female and 3265 (40.9%) were male. The patient's sex was not specified in 47 (0.6%) forms. The median age of the cohort was 53 years (interquartile range 38-66 years). The most frequently reported primary indication was the licensed indication of asthma, but for a small proportion of the cohort it was prescribed 'off label'.A total of 152 events in 120 (1.5%) patients were reported as adverse drug reactions (ADRs) by GPs on the green forms. ADRs with the highest reported frequency were headache and nausea. There were 3514 reasons for stopping zafirlukast in 3148 (39.5%) patients, the most frequently reported of which was that the drug was 'ineffective' (2008 patients; 25.2%). The most frequently reported specified clinical reason for stopping was headache (82 patients; 1.0%). There were 28 pregnancies reported in this cohort, 20 of which were reported to have exposure to zafirlukast during the first trimester. Nine live births with no recorded congenital abnormalities were reported for pregnancies with exposure in the first trimester. There were 151 deaths reported during the study period (1.9%). The most frequently reported causes of death were related to the respiratory system (57; 37.7%), including chronic obstructive pulmonary disease, asthma and bronchopneumonia. CONCLUSION: This study showed that zafirlukast, as used in general practice in England, is a generally well tolerated drug with few associated adverse events.

Thermoresponsive polymers as gene delivery vectors: cell viability, DNA transport and transfection studies.

A range of gene delivery vectors containing the thermoresponsive polymer, poly(N-isopropylacrylamide) (PNIPAm) was evaluated for effects on cell viability, intracellular trafficking and transgene expression in C2C12 mouse muscle cells. Polymers were complexed with plasmid DNA at pH 7.4 and the ability of the resulting particles to transfect cells was assessed via confocal microscopy and protein expression studies in tissue culture. Cell viability assays indicated that these polymers were toxic at high concentrations when not complexed to DNA or at certain polymer:DNA ratios. Poly(ethyleneimine) co-polymers with side-chain grafted PNIPAm were shown to be less toxic than poly(ethyleneimine) alone or PNIPAm-co-(N,N'-dimethylaminoethylmethacrylate) linear co-polymers and the effects were concentration dependent. Confocal micrographs of labeled polymers and DNA indicated rapid cellular entry for all the complexes but expression of Green Fluorescent Protein was achieved only when the branched PEI-PNIPAm co-polymers were used as vectors. The results indicate that design of appropriate co-polymer components and overall polymer architecture can be used to mediate, and perhaps ultimately control, DNA transport and transgene expression.

Thermo and pH responsive polymers as gene delivery vectors: effect of polymer architecture on DNA complexation in vitro.

Poly(N-isopropylacrylamide) (PNIPAm) co-polymers responsive to temperature and pH were prepared with side chain chemistries in order to exhibit phase transitions under physiologically relevant conditions. Fluorescence spectroscopy, gel retardation assays, dynamic light scattering and atomic force microscopy were used to characterize the binding of plasmid DNA to these materials and to control polymers poly(ethyleneimine) (PEI) and poly(ethyleneimine)-octanamide. Complexes of plasmid DNA with thermoresponsive cationic polymers containing PNIPAm displayed variations in gel retardation behaviour above and below polymer phase transition temperatures, with a high molecular weight linear cationic PNIPAm co-polymer forming complexes with reduced affinity above LCST whereas a branched PEI-PNIPAm co-polymer bound with higher affinity above the PNIPAm phase transition. The thermoresponsive polymers also exhibited changes in particle morphology across the same temperature ranges with polymer DNA complexes prepared at N/P ratios of 2:1 generating spherical particles varying in radius between 30-70 nm at 25 degrees C and 60-100 nm at 40-45 degrees C. The transport of DNA within these complexes to cell nuclei was demonstrated to occur within 24 h in tissue culture via confocal microscopy, and low level transfection of mouse muscle cells by a reporter gene encoding green fluorescent protein was achieved with the branched thermoresponsive PEI-PNIPAm conjugate.