The pharmacological disruption of memory by various protein synthesis inhibitory drugs (PSIs) has implicated protein synthesis as a requirement for long term learning but not for short. However, evidence derived from PSI research remains equivocal, with the apparent amnesic effects of PSIs being attributed to drug side-effects and general behavioural debilitations. Research reported in this thesis investigates the behavioural effects on short and long term habituation of the dorsal antennae withdrawal reflex in the snail (Helix aspersa) of three antibiotic drugs known to reversibly inhibit protein synthesis; anisomycin, actinomycin D, and puromycin. Initially, habituation was established as true learning in the snail and was demonstrated to be capable of retention for over 24 hours from one training session and over 6 months from a series of training sessions. The parametric characteristics of both short and long term habituation in the snail was established and found to be identical to those demonstrated in vertebrate habituation. Such characteristics were found to be different for short and long term habituation. Injection of PSIs showed no effect on short term habituation but disrupted long term habituation if PSI was active within a 'critical time window' during or for approximately 40 minutes after training. Later injections had no amnesic effect, and neither did injections 2 hours prior to training. The amnesic effects were demonstrated not to be attributable to drug side-effects by the development and application of a 'behavioural test battery' to screen general snail behaviour for drug induced debilitations at a variety of doses. Dose/amnesic effect relationships are also reported. Potentially confounding effects, such as, state dependent learning, and drug performance effects, were controlled out. The effects of the PSIs on short and long term habituation are then reported in terms of their effects on the established short and long term parametric characteristics of the learning. Drug injected snails showed normal short term parametric characteristics in training. However, in a long term retest drug treated snails also showed the parametric characteristics of short term habituation which demonstrated the degree of induced amnesia. The results are discussed in terms of a gene expression model of long term habituation and suggest that short and long term habituation are mediated by different processes. Short term habituation is protein synthesis independent and long term habituation is protein synthesis dependent.

No description available.

Surface properties affect pharmaceuticals by influencing physical behaviour, which can cause problems for both formulation and medication. Poorly water soluble compounds are often modified with polymer surfactants. The presence of amorphous material, due to its effect on dissolution rate, can modify the bioavailability of a compound. This thesis reports the novel application of X-ray Absorption Spectroscopy (XAS) and X- ray Photoelectron Spectroscopy (XPS) to surface related pharmaceutical problems. XAS is sensitive to bond angles, local symmetry and oxidation states and XPS provides information on local chemical environment. Both have a probing depth <10 nm in the soft X-ray range. It is shown that XAS and XPS are capable of determining the physicalcoverage of ultra-thin polymer coatings. In situ XAS confirmed they formraft-like structures on the drug surface. Adsorbed water could also be de-tected on the surface and this corresponds to improvement in dissolutionrate, which implies an improvement in bioavailability. XAS was capableof distinguishing between amorphous and crystalline batches of two drugsat the surface. It was also able to detect a nanoscale amorphous overlayerin predominantly crystalline micronised batches of the drug. High relativehumidity was shown to recrystallise both the amorphous and micronisedbatches. X-ray PhotoElectron Emission Microscopy (XPEEM) of pharma-ceutical compounds was attempted but, due to the higher beamflux required,sample damage and charging effects were too great to draw any meaningfulconclusions at this time.

The aim of this research was to assess the pharmaceutical and therapeutic merit of ancient Egyptian remedies, employing analytical and historical methods, to demonstrate that the Egyptians were practising a credible and reproducible form of pharmacy as early as the 16th century BCE, 1800 years before Galen, the acknowledged 'father of pharmacy'. The 1000 prescriptions in the medical papyri, which provide the literary research source, are renowned for their uncertainty in interpretation and translation of drugs. Consequently, although much has been published, the materia medica of ancient Egypt is questionable and the efficacy of prescriptions, uncertain. Verification of the drug substances was sought in archaeobotanical evidence to determine availability, dynastic prevalence and predominance at the time of the papyri. Attestation was sought in contemporary pharmacognosy of plants and their clinical application, to measure the medicinal uses in ancient Egypt. Efficacy was established by comparing the ancient remedies against modem pharmaceutical protocols including drug source, extraction, pharmacognosy, phytochemistry, pharmacology, formulation, preparation, dosing regime, administration and therapeutic activity. Most drug sources have been verified, some 25% were determined to be of improbable use, alternative drugs being proposed. Significantly, 50% of the drug sources used by the ancient Egyptians, remain in use today, albeit that many are now synthesised. The first scientific estimate of pharmaceutical merit demonstrates 64% of remedies in the medical papyri have therapeutic value in physiological or physical action, 3% are toxic, 1.5% subtherapeutic, 20% undetermined and the remainder, have no known therapeutic activity. It is concluded that the application of archaeobotany and pharmacognosy may assist the identification of plants once available to ancient Egyptian medicine and consequently to endorse the ancient texts. Furthermore, the efficacy, reproducibility and protocols used in the prescriptions, qualify the ancient Egyptians to be recognised as the progenitors of pharmacy practise.

This thesis investigates the novel use of paper and Tyvek sterilisation pouches as containment systems to perform various applications of freeze-drying. Their effect on the freeze-drying of a pharmaceutical protein, mass and heat transfer, sterile freeze-drying and containment of microorganisms were examined. Ovine derived Immunoglobulin G (IgG) specific for fluorescein was used as a model biopharmaceutical protein and a range of assays developed to quantify its biological activity, aggregation, turbidity, residual moisture and reconstitution time. IgG was formulated using different carbohydrates and analysed using freeze-drying microscopy to allow precise development of optimum freeze-drying cycles. The IgG was freeze-dried using these cycles and the function and structure of the IgG was shown to be unaffected. Freeze-drying cycles were modified to investigate the effect paper and Tyvek pouches had on the IgG which showed no change in activity or structure. However, pouches decreased sublimation rates and increased process time. Resistance to water vapour, and the subsequent effect on mass and heat transfer during the freeze-drying process, imposed by paper and Tyvek sterilisation pouches, Gore Lyoguard, product dry layer and freeze-drying stoppers were investigated. Pouches presented greater resistance to water vapour movement than the dry product layer, Lyoguard and stoppers. Increasing resistance decreases mass transfer, increases pressure inside the pouches thereby increasing the heat transfer coefficient. A process simulation using nutrient rich media was performed where vials were packaged aseptically and transported to a freeze-drier in a normal laboratory environment. The vials showed no growth of contaminating microorganisms after incubation. In addition, pouches containing nutrient rich media were challenged with aerosolised Saccharomyces cerevisiae and also showed no growth of contaminating microorganisms after incubation. Finally, pouches were demonstrated to be able to contain Escherichia coli during freeze-drying thus preventing contamination of the freeze-drier and the environment.

Dispensing medication is inherently risky and errors are inevitable occurrences. Pharmacists are encouraged to monitor dispensing errors so that risk reduction strategies can be implemented. Automated dispensing systems (ADS) are advocated as a key error reduction strategy. However, little research has investigated the incidence, type and causes of dispensing errors in hospitals with ADS and manual dispensing systems. Analysis of dispensing error data, self-reported by hospitals using standardised definitions and a validated methodology, was undertaken. Prevented dispensing incidents (detected during dispensing) occurred more frequently than unprevented dispensing incidents (detected after issue of medication). However, automation had no significant effect on the unprevented dispensing incident rate. The most common dispensing error types reported were supply of the wrong drug, strength, form and printing the wrong directions/warnings on the label. The critical incident technique, employing self-reported incident forms, was used to investigate the causes of specific prevented dispensing incidents occurring at hospital pharmacies. These incidents were attributed to active failures (interchanging different formulations, computer and stock selection errors), error-producing conditions (high workload, complex prescriptions and interruptions) and latent conditions (inadequate staffing/skill mix, unclear drug computer selection lists and drug storage on dispensary shelves). Socio-technical theory was used to investigate the effect of dispensary workload and occupational stressors on prevented dispensing incidents in hospitals utilising ADS and manual dispensing. A strong positive relationship was identified between dispensary workload and prevented dispensing incidents. Workforce planning models were developed enabling determination of staffing levels required to maintain a safe permissible workload. Automation was associated with a higher workload, lower prevented dispensing incident rate and less job stress and overload. However, automation reduced staff autonomy, organisational commitment and job satisfaction. Improved workforce planning, staff training and design of pharmacy computer software are needed to reduce dispensing errors. Automation improves dispensing efficiency and safety. However, care must be taken to avoid an imbalance between technology and employee needs.

The bioactive peptides are the one of the most important components of skin secretions. They are classified into two major groups: antimicrobial peptides and pharmacological peptides that include anticancer peptides, neuropeptides, and vasoactive peptides. Tachykinins, bradykinins and bombesins from amphibian skin secretions belong to both neuropeptide and vasoactive peptide groupings and some of their homologues have been identified from mammals. For this reason, they interact with specific receptors in mammals causing pharmacological effects. This thesis was concerned with functional genomic studies on the skin secretions of four different frog species from southern China. Four bioactive peptides are described from these frog skin secretions. G-21-C-HG and Ranakinestatin-PPF were initially identified via a "shotgun" cloning approach which identified their respective precursor-encoding cDNAs. The predicted structures of pep tides were confirmed by RP-HPLC, MALDI-TOF mass spectrometry and LCQ-Fleet electrospray ion-trap mass spectrometry. Finally, synthetic replicates of both peptides were evaluated for their bioactivities. G-21-C-HG, from Hylarana guentheri skin secretion was found to be a broad-spectrum antimicrobial peptide. It also had anticancer activity against human H23 and LNCaP cancer cells. Ranakinestatin-PPF from the skin secretion of the Fukien goldstriped pond frog, Pelophylax plancyi fukienensi, represented a prototype of a novel class of bradykinin B2 receptor antagonist peptide. Due to their pharmacological effects on rat smooth muscle preparations, TK-OL and QUB 1940 were defined as myotropic peptides and were from the skin of Odorrana livida and Amolops wuyiensis, respectively. All of the pep tides described had conserved structures within their biological cores. TK-OL, a novel tachykinin peptide, contracted the smooth muscle ofrat urinary bladder. QUB 1940, a novel bombesin-like peptide, not only contracted the smooth muscle of rat urinary bladder, but also increased the contractile frequency of rat uterus.

The work in this thesis was centred on developing an alternative method for therapeutic drug monitoring based on using microneedle arrays to sample interstitial fluid combined with a SERS active layer for analysis of the sampled fluid. Simple aqueous colloids are too unstable to use in this application so here the colloid was aggregated and then preserved within hydroxyethylcellulose (HEC) films. The films were then tested alongside microneedle arrays, which were prepared and developed by Salvador and Donnelly in the School of Pharmacy, Queen's University Belfast. The principle was that the microneedle arrays would puncture the skin to take up the interstitial fluid containing therapeutic drugs and deliver it to the base plate where the SERS sensing HEC film would be located. The SERS films themselves were found to be effective for the analysis of the target thetapeutic drugs, theophylline and phenytoin. However, when the drugs were taken up by microneedle arrays they were largely trapped within them. The SERS films were found to have a much broader range of potential applications than therapeutic drug monitoring. They were shown not simply to be able to detect conventional aqueous solutions of drugs but they were used as the basis for a novel trace drug detection method. In this method the area to be tested was wiped with a moistened swab which was then contacted with the SERS active film. With mephedrone as a test analyte, drug deposits on surfaces in the Ilg range could be collected and detected. Alternatively, for seized bulk methiopropamine drug samples which had high fluorescence, the films provided a convenient method of quenching the fluorescence and enhancing spectra simultaneously. Finally, the films were also tested for use in analysis of ink samples and proved to be highly effective, providing spectra that allowed various inks to be discriminated.

Epilepsy is a neurological disorder characterized by abnormal neuronal excitability which has been suggested to result from altered ion channel activity. Of particular interest are the hyperpolarization-activated cation (HCN) channels which have recently been shown to play an important role in temporal lobe epilepsy (TLE) development. To evaluate how HCN channels are modulated during TLE development, I obtained acute hippocampal slices from appropriate control and “epileptic” rats and recorded the hyperpolarization-activated cation current (Ih) from CA1 pyramidal neurons. My results showed that Ih was enhanced 24 hours after seizure-induction compared to controls but this effect was diminished 1week later. However, in chronically epileptic rats that had started to experience spontaneous seizures Ih was significantly reduced compared to controls, and the excitability of CA1 pyramidal neurons was profoundly increased. To elucidate whether Ih modulation per se affects CA1 pyramidal neuron excitability, I used a recently published conductance-based model of a reconstructed CA1 pyramidal neuron which I adapted to match my experimental conditions. My simulations showed that modifications in Ih influences CA1 pyramidal neuron excitability consistent with that observed in “epileptic” neurons. The simulations also suggested that alteration in other currents, such as the persistent sodium current, together with the reduction of Ih, is required to determine the hyperexcitability of CA1 pyramidal neurons from chronically epileptic rats. In conclusion, Ih can be differentially modulated in CA1 pyramidal neurons during TLE development. These changes are likely to significantly affect CA1 pyramidal cell excitability and may contribute to the process of epileptogenesis.

Medication discrepancies occurring at the interfaces of care between hospital and home may cause patient harm. Medication reconciliation (also known as medicines reconciliation) has been suggested as an intervention that may reduce discrepancies. National guidance has made it mandatory for hospitals in the UK to have Medication Reconciliation policies in place for adult patients admitted to hospital. This policy excluded children aged less than 16 years. This thesis aimed to investigate the incidence and potential clinical outcome of medication discrepancies occurring across the interface of care for hospitalized children from admission, discharge and post-discharge. At hospital admission across four UK paediatric settings it was observed that 32% (95% CI = 26.1 – 37.8%) of 244 paediatric patients had at least one potentially clinically significant unintended discrepancy between their pre-admission medication and initial admission medication order in the absence of pharmacist-led medication reconciliation. At discharge, approximately one third of 142 discharge letters reviewed for accuracy over 5 weeks had at least one discrepancy which were detected and corrected by a pharmacist. Post-discharge follow up of patients revealed that 7.7% (95% CI 1.1 – 16%) of patients experienced at least one discrepancy between what was prescribed by the hospital at discharge in comparison to what was prescribed by the GP. Qualitative observations revealed that more than one source of information were required to reconcile medication at admission and GP records did not provide a complete medication history. Post discharge observations highlighted that hospital discharge letters were not always clear resulting in discrepancies between the intended discharge medication list and GP record. This work provides evidence that children aged less than 18 years of age require medication reconciliation when transferring between primary and secondary care. Preventable interventions are required across the care settings to ensure patient safety and to reduce chances of preventable adverse events.