Understanding migraine

Better characterisation of migraine is critical to enhancing its diagnosis, assessment and, ultimately, effective treatments. The aim of this thesis was to better characterise migraine through more detailed investigation of selected headache-related factors and to compare these factors with those seen in other commonly occurring recurrent headaches. The factors investigated in this thesis were neurochemical profile, cervical musculoskeletal impairments, and patient experience, represented by pain and disability characteristics, emotional state and other personal factors. This thesis provides deeper information regarding the nature and characteristics of migraine compared with non-migraine headaches (tension-type and cervicogenic headaches). This thesis has established the potential of GABA as a biomarker for migraine and implies the possible role of GABA in the disease process. This thesis has also characterised migraine according to cervical musculoskeletal impairments and patient experience embodying disability, pain, central sensitisation, and other personal factors. The implications for clinical practice are to assess cervical musculoskeletal impairments and patient experience to facilitate differential diagnosis and prognostication, and to educate patients on the nature of their headaches. Findings from the thesis may also be used by guideline developers, providing stimulus for further discussions on the definition of migraine and reporting of participant selection criteria, with reference to this definition, in clinical trials. Future research directions are identified in validating GABA as a migraine biomarker and elucidating its pathophysiology. By characterising migraine more fully, findings from this thesis will inform the development of effective treatments that could possibly target GABA or clinical characteristics found to be present in migraine. Ultimately this should achieve better health outcomes for people with migraine

PKPD relationships and dose rationale in analgesic drug development : towards the prediction of target engagement

Chronic pain is a significant health problem that greatly impacts the quality of life of individual patients and imparts high costs to society. Despite intense research effort and progress in our understanding of the mechanistic and molecular basis of pain, chronic pain remains a significant clinical problem that has few effective therapies Throughout the various chapters we have highlighted some important conceptual and experimental flaws in the way that pain signalling and pharmacological activity are characterised and translated across species and disease conditions. The common denominator of the work presented here is the requirement for accurate characterisation of exposure-response relationships, without which the dose rationale for the progression of a molecule cannot justified, whether drugs are aimed at symptomatic relief, disease modification or prophylaxis. In addition to a comprehensive review of the mechanisms underlying pain signalling and symptoms, the work developed here focuses on three different aspects of research underpinning the use of pharmacokinetic-pharmacodynamic relationships. First, we have explored the requirements for the characterisation of behavioural measures of pain during the early screening of candidate molecules, shedding light onto the shortcomings of experimental protocols commonly used in preclinical research. Then we introduced the prerequisites for the parameterisation of pain behaviour to ensure accurate translation of the pharmacological properties across species as well as for bridging across different phases of development. Lastly, an attempt was made to model clinical response in chronic inflammatory pain and to establish correlations between symptom improvement and the underlying pharmacological effects using biomarkers. In addition our work showed how clinical trial simulations can be used as a design tool, enabling the evaluation of a variety of scenarios that disentangle the contribution of pharmacology from the confounding effects of placebo and disease dynamics.UBL - phd migration 201

Optimising antibiotic therapy for inpatient and outpatient settings

Background: Not only have antibiotics saved countless patients’ lives but they have also played a crucial role in supporting major advances in modern medicine. However, precipitously emerging resistant bacterial strains jeopardise the remarkable advances achieved with antibiotics. In the past, the development of new antibiotics was an effective strategy to combat resistant bacteria. However, with the discovery of new antibiotics diminishing, optimising the administration of currently available antibiotics has become a necessity. A strategy of particular interest involves applying pharmacokinetic and pharmacodynamic concepts to optimise time-dependant antibiotics dosing regimens. The latter is a growing area of interest for reducing the development of antibiotic resistance, and it involves differential dosing regimens such as prolonged or continuous infusions of beta-lactam antibiotics. Aim: The overarching aim of this research is to optimise antibiotic therapy for inpatient and outpatient use. This thesis consists of literature-based, practice-based, and laboratory-based research. Literature-based: The aim of the literature-based research category was to review existing literature to compare the clinical outcomes of continuous vs intermittent infusion beta-lactam antibiotics and appraise the strengths and the weaknesses of current evidence. Overall, literature-based research demonstrated a wealth of studies in terms of systematic reviews, meta-analysis as well as primary studies. Despite the literature exhibiting favourable outcomes towards prolonged/continuous infusions, the literature review and systematic reviews conducted support the need for better conducted, definitive trials and systematic reviews given the variability in scope of the available studies. Practice-based: The aim of the practice-based research category was to provide a snapshot of beta-lactam antibiotic use in clinical practice. The first study was single-centre retrospective cohort practice review conducted to Investigate the prescribing patterns of beta-lactam antibiotics in critical care wards. The second study was a cross sectional survey investigating nurse’s knowledge, perceptions, and experiences regarding differential antibiotic dosing. Findings show that prolonged/continuous infusions as dosing strategies are implemented in practice to improve patient outcomes, however, healthcare XI professionals implementing this practice have not received sufficient training to support the administration of differential antibiotic dosing. This was evident from both practice based studies that disclose beta-lactam antibiotics are not used to their full potential or are inaccurately used. There is a need for tailored education and training to improve health care professional’s knowledge of prolonged/continuous infusions. Laboratory-based: Despite the advantages that prolonged/continuous infusions beta-lactam antibiotics offer, in order to use these dosing regimens efficiently, infusion solutions should remain stable for the preparation, storage and infusion time. Concerns regarding stability present a challenge in practice as most stability information is based on administration via bolus injection or an intermittent infusion. Therefore, the aim of the laboratory-based research category was to determine the feasibility of prolonged/continuous infusion beta-lactam antibiotics for hospital and outpatient settings. Findings from the conducted studies aid in ameliorating current dosing regimens to optimise antibiotic efficacy. Results obtained from stability studies assist in resolving challenges experienced in practice in terms of preparation, storage, and administration as they indicate the effects of temperature, diluent, and pre-preparation of infusion solutions. Studies demonstrated that stability data generated in all studies are an improvement to the stability data presented in the British, American, and European pharmacopoeias. Conclusion: Findings of this PhD research are supportive of the beneficial role of differential antibiotic dosing. Overall, the gathered data indicate that prolonged/continuous infusions are feasible, advantageous and could potentially improve patient clinical outcomes