Since their inception the B-Iactam antibiotics have become one of the most important classes of phannaceutical agents, both therapeutically and economically, in modern day usage for the treatment of a wide spectrum of bacterial infections. However, due to the versatility of bacteria many previously treatable species are developing resistance to the antibiotics currently available and so there is ever a need to develop more ~-lactam antibiotics, which are effective and yet safe. A major drawback to the ~-lactams is the degree of immunologically adverse reactions they induce. It was the aim of this study to develop both mechanistic and immunological methods to enable the prediction of a B-lactam's potential to induce an allergic response and to determine if a relationship between these responses and the molecular properties of the ~-lactams was present. In this study a database pertaining to frequency by which 70 p-lactams induce adverse reactions has been compiled and used to produce 27 QSAR models. A highly sensitive assay for the quantitation of cross-reactivity between B-lactams and serum anti-benzylpenicillin antibodies has been developed and used to determine the cross-reactivity potential of 31 ~-lactams and to develop 18 QSAR models. All of the QSARs developed suggest that the shape and electron separation of the ~-lactams are crucial to the development and extent of adverse response or crossreactivity induced by a specific p-lactam antibiotic, new or old. The QSARs developed will enable the design and development of new ~-lactam antibiotics which present a significantly lower risk of inducing immunologically mediated adverse responses when used therapeutically. Two sensitive assays for the quantitative detennination of the cytokines IL2 and IL4 in lymphocyte culture supernatants have been developed, and have been shown to have a potential use in the prediction of the type of immunological response initiated following p-Iactam stimulation of a sensitised individual.

Most methods used for the extraction of quaternary amines in biological fluids have been based on ion-pair extraction techniques. In this study, a sensitive and selective chromatographic procedure is described to measure the concentration of pyridostigmine, neostigmine and their major metabolites in the plasma and urine. The methods involve a preliminary selective ion-pair extraction of the unchanged drugs and their metabolites into dichloromethane and dichloromethane-acetone mixture respectively. Quantitation is possible down to 3 ng/ml for parent drugs and 50 ng/ml for the metabolites. The present work also described a modified procedure to measure neostigmine and pyridostigmine in plasma simultaneously, using a specially synthesized pyridostigmine analogue as a common internal marker. The plasma concentration of pyridostigmine was measured after three different doses of the quaternary amine (36.2 Ng/kg, 72.4 pg/kg and 144.8 )tg/kg) were given intravenously to twenty five surgical patients during anaesthesia. The relation between the plasma concentration of pyridostigmine and time was invariably expressed as a bi-exponential equation, and the data was interpreted in terms of a two compartment model. The slow disposition halflife of the drug was progressively prolonged as the dose of the drug was raised from 36.2 Ng/kg to 144.8 jig/kg. A similar increase in the half-life was observed in cross-over studies. The clearance of the quaternary amine was enhanced at intermediate dose (72.4 )xg/kg) but significantly reduced after high dose (144.8 pg/kg). It was suggested that these results may partially account for the observed differences in the duration of action of neostigmine and pyridostigmine in man. The dose of pyridostigmine used to reverse non-depolarizing neuromuscular block is 4-5 times greater than neostigmine. After intramuscular administration of neostigmine to five myasthenic patients, the plasma concentration of the drug declined monoexponentially from 21 ±2 no/ml to 9t1 ng/ml between 30 and 120 minutes and data was interpreted in terms of a one-compartment model. Estimates of the plasma half-life varied from 56.9 - 100.1 minutes. The oral administration of pyridostigmine alone and of both neostigmine and pyridostigmine in two different groups of myasthenic patients, were also studied. There was a direct linear relation between area, under the plasma concentration - time curve and total daily dose of pyridostigmine in the first group of patients (r = 0.95), but no such observation was noticed in either all patients (two groups; r=0.15) or in the second group who were treated with both drugs (r =-0.08). It was suggested that there might be a drug-drug interaction between pyridostigmine and neostigmine during oral absorption. The relation between plasma levels of pyridostigmine to clinical evaluation of muscle power was examined in nine myasthenic patients during treatment with pyridostigmine in doses of 60 to 1080 mg per day. Five of the nine subjects demonstrated a trend towards a positive correlation and in two of them was this significant at pt0.05. In addition, the presence or absence of a possible correlation between muscle power and plasma concentration was not related to the duration of disease, additional prednisolone therapy or thymectomy.

No description available.

No description available.

Community pharmacists are increasingly providing public health services in response to government policies. Published literature regarding the views of the general public related to pharmacy public health services, although important in ensuring uptake of these services, was limited. This study series aim to explore the general public's perspective on how to maximise the appropriate utilisation of community pharmacy services for improving public health. A large study comprising four sequential phases was designed and conducted in Sefton borough. Initially, to gather background information, focus group discussions (FGDs) and semi-structured interviews were undertaken with the general public and key stakeholders. The second phase involved the development and testing of a questionnaire extracted from the qualitative findings and a literature review. The questionnaire focused upon seven pharmacy public health services related to cardiovascular risks as well as views on factors influencing pharmacy use and advertising/promotion techniques. Geodemographic concepts, widely recognised in public health, were also included to identify potential benefits to pharmacy practice research. Next, a large scale survey was administered among the general public using eight survey modes, to additionally evaluate the range of methods available/for gathering public views. Finally, survey findings were evaluated by representatives of survey respondents using a FGD. Results indicated that, although stakeholders considered that community pharmacy can make an extensive contribution in supporting public health, pharmacy public health services are used at a relatively low level by the general public and awareness of services is also low. Survey respondents indicated a willingness to use services in the future. Important factors influencing pharmacy use include loyalty, location and convenient accessibility. Appropriate promotional campaigns are a key facilitator to help raise the public's awareness. The findings will help the profession to increase uptake of pharmacy public health services. The variety of survey modes used proved beneficial in obtaining diverse population demographics, with street survey being the optimal technique, however, the potential for social desirability bias must be considered with this and other interviewer-assisted approaches. MOSAIC™ as a geodemographic tool is potentially useful in helping to target services for specific groups and is recommended for use in further research.

Oxidation of fluphenazine decanoate, a member of the neuroleptic phenothiazine drugs, is believed to occur in oily solution via the hydroperoxides formed as a result of autoxidation of the oil. Synthesis and characterisation of the expected oxidation products of the drug was undertaken so that the formation of these degradation products in oily solution, could be accurately determined. By this means the rate of oxidation of fluphenazine decanoate by various hydroperoxides was determined. Only in the case of the C-IB unsaturated fatty esters did the overall oxidation process obey simple kinetics (2nd order) enabling values for the respective rate-constants to be calculated. The presence of acid was clearly demonstrated to catalyse oxidation of the tertiary amine centres in the molecule, a finding contrary to reports in the literature. In addition, the catalytic effect was shown to be related to the pKa value of the acid. Benzyl alcohol is commonly added as a preservative to oily formulations and thus the effect of this material on the rate of fluphenazine decanoate oxidation was investigated. Evidence for the enhanced oxidation of the drug in the presence of benzyl alcohol in a naturally ageing formulation was obtained and a plausible mechanism for this phenomenon was sought. Autoxidation of the benzyl alcohol was deemed a likely explanation and since little information on this aspect of benzyl alcohol chemistry could be found in the literature an extensive study of benzyl alcohol autoxidation was conducted. It was finally concluded that autoxidation of benzyl alcohol leads directly to hydrogen peroxide offering one viable explanation of the enhanced degradation of the drug observed in the presence of the preservative.

No description available.

No description available.

Whereas health care resources are limited, demands upon them are insatiable. Drug expenditure has received particular attention in attempts to regulate increasing costs. For hospitals, contract purchasing is designed to regulate drug expense. This thesis examines the contract mechanisms. Information was collected from pharmacists and supplies officers in all English health regions and pharmaceutical companies supplying the bulk of hospital drug requirements. The main findings of the research are:- 1 There is a large, unexplainable difference in price charged to various health regions for an identical drug. Price charged is independent of all obvious correlates. 2 Despite the oligopgonistic power of the National Health Service there is no centralised interchange of price or purchasing information between health regions. 3 Pharmaceutical suppliers view hospital drug purchasing as fertile for opportunistic pricing within the context of total profit regulation. 4 There is an ill-defined working relationship between pharmacists and supplies officers in the implementation of drug contracts, often amicable locally but tense and competitive nationally. The overall impression is of a purchasing mechanism which, due to its political sensitivity, has, by default, become increasingly outmoded and represents a triumph of public accountability over individual negotiating skill. The overall regulation of pricing is in substantive conflict with the hospital contract system. One encourages UK research, the other not, while the savings in hospital purchase are redundant in the context of both overall corporate and Governmental financing. Cost savings are unknown. Other methods of acquisition such as prime vendor buying should be considered, as a means of improving purchase efficiency for both supplier and purchaser.

Sulphathiazole is a highly polymorphic model system exhibiting at least five polymorphic forms: I, II, III, IV, and V. Polymorph stability is known to be susceptible to solvent environment, and it is established that 1-propanol stabilizes the most metastable form I. This study examines the effect of a range of alcohols on polymorph selection and attempts to elucidate the mechanism. The role of the alcohol functional group in the polymorph selection process is thus investigated and evaluated. Crystals were characterized using optical microscopy, SEM, PXRD, DSC, IR, and single-crystal X-ray diffraction for their polymorphic identity. The role of solvent in the stabilization of polymorphs was investigated by visualizing and calculating energy requirements for the interaction of each solvent molecule with α- and β-dimers of sulphathiazole, using Cerius2 modeling software and GRID based systematic search simulation. These studies showed that solvent had a significant impact on polymorph selection. In common with 1-propanol, 1-butanol was found to stabilize form I by inhibiting the formation of the β-dimer, which is necessary for nucleation of and transformation to forms II-IV. Shorter chain alcohols and branched chain alcohols such as methanol, 2-propanol, and ethanol did not stabilize form I but stabilized forms II, III, and IV, respectively, showing that it is not only the alcohol functionality but also the steric effects of the alkyl chain that contributed to the effect. Sulphathiazole form I normally has a needlelike morphology. Form I with a modified rodlike morphology was produced by crystallization from 1-propanol with the addition of methanol in low concentration, showing that it is possible to control the morphology and selectively isolate polymorphs. Indomethacin is known to exhibit at least five polymorphs but only the stable γ Form and metastable α Form are reported to be reliably produced by standard methods. The metastable α Form has an undesirable fibrous needle-like morphology. The current study focused on producing crystals of α Indomethacin with a well-defined morphology using additives. Adipic acid, myristic acid, oleic acid and structurally related 3-indoleacetic acid were selected as additives and their impact on the morphology and polymorphism of indomethacin were investigated in this study. Additives did not change the needle-like morphology of α-indomethacin but less fibrous and less aggregated well defined needles were observed in presence of adipic acid, oleic acid and 3-indole-3-acetic acid.