Magister Public Health - MPH / Background: Adverse Drug Reactions (ADRs) contribute to potentially expensive hospital admissions and are regarded as a major public health priority. ADRs in South Africa are mainly detected by a spontaneous reporting system but it is plagued by under-reporting. Previous records indicated under-reporting of ADRs in the Cape Winelands District amongst healthcare workers. Pharmacists, in particular, did not report ADRs compared to other healthcare cadres whilst they are generally considered to be the custodians of medicines. Study Aim: This study aimed to explore and describe the perceptions and experiences of rural public sector pharmacists’ reporting of ADRs and to understand why pharmacists in this rural health district under-reported ADRs. Study Design: A qualitative study design was appropriate for this research question as the researcher wanted to gain an in-depth understanding of human behavior related to the phenomena of under-reporting. Study Population and Sampling: The primary study population consisted of 24 public sector pharmacists in the Cape Winelands District. A purposive sampling strategy enabled the selection of 16 pharmacists ranging in gender, age, experience and rank. Eight pharmacists were supervisor pharmacists while the rest were production pharmacists, including a community service pharmacist and an intern pharmacist. Supervisor pharmacists are more involved with managerial tasks and the attendance of meetings compared to production pharmacists that focus on patient care and dispensing of medication. Two key informants involved in the Western Cape Pharmacovigilance System were included in the study. One key stakeholder was a policy specialist pharmacist working at Directorate: Pharmacy Services and primarily involved with the Provincial Pharmacy and Therapeutics Committee. The other key policy stakeholder, at the time of the study, was the manager of the Medicines Information Centre which forms part of the University of Cape Town’s (UCT) Pharmacology Division. Both were highly experienced pharmacists familiar with the pharmacovigilance system. Data Collection: In-depth interviews were conducted using a semi-structured interview guide consisting of open- ended questions. The semi-structured interview guide was tested on a participant outside the primary study population. Interviews were conducted in English and Afrikaans. Interviews were tape-recorded and the interviewers made field notes to supplement the data recorded. Two researchers with experience in qualitative data collection, briefed by the investigator, interviewed the pharmacists who worked in the district and the investigator interviewed the two key stakeholders. Data Analysis: The tape recordings were translated, where applicable, and all were transcribed verbatim by the investigator. The transcribed recordings were analyzed by the investigator by assigning codes to material on an Excel spreadsheet. This approach enabled the identification of themes which aided the understanding of the research phenomena. Ethics: Ethical approval was obtained from the University of the Western Cape Senate Research Committee and permission from the Western Cape Department of Health Research Committee. Written informed consent (See Appendix 1, page 73) was obtained from each participant prior to conducting the interviews and interviewees were assured of confidentiality throughout the research. Key Results and Discussion: Pharmacists in the study strongly acknowledged the importance of ADR reporting which is linked with pharmacists seeing themselves as the custodians of medication. Pharmacists in the study associated the reporting of ADRs with medication safety and felt responsible for ensuring it. In spite of this acknowledgement of the importance of ADR reporting, pharmacists rarely reported an ADR themselves. This finding was in line with previous research conducted and linked with barriers pharmacists faced in practice. The study revealed that pharmacists identified ADR reporting opportunities during their normal clinical work and enabled other health care professionals (HCPs) to confirm the occurrence of an ADR and report it. Pharmacists primarily identified ADRs when they scanned patient folders for clues that could indicate that an ADR had occurred. Other research conducted confirmed that the use of patient records could be used in the identification of ADRs. This finding was important to inform future training workshops to promote reporting of ADRs. Some pharmacists in the study associated an ADR with a therapeutic or clinical intervention. In general, therapeutic interventions usually involved a clinical action more closely associated with medical officers and were viewed by pharmacists in the study as being outside their legal and clinical scope of practice. A clinical intervention could include a change of medication, change of dose, and other prescription changes or might involve the medical officer referring the patient to a higher level of care depending on the severity of the suspected ADR experienced. A clinical intervention could include performing complex diagnostic tests, observations and laboratory investigations. Pharmacists’ association of an ADR experience with a clinical intervention was an important factor limiting their reporting of ADRs. The implication of this belief is that patients were referred from the pharmacy back to medical officers for the clinical intervention. In this way, although pharmacists do not directly report an ADR, their referral to medical officers would help improve reporting of ADRs. An unexpected and contrasting finding compared to previous research was the strong belief of some pharmacists in this study that common ADRs should be reported. Pharmacists believed that by reporting common ADRs en masse, authorities might decide to remove the problematic medication from the approved public sector formulary. This was in contrast to previous research where pharmacists either acknowledged that authorities only want novel or serious ADRs from newly marketed medication or believed that reporting well-known ADRs was a waste of time. Pharmacists reported that they faced several barriers in reporting ADRs. The main barriers that were mentioned were a lack of adequate feedback, heavy workload and time constraints, uncertainty in identifying the cause of an ADR and issues pharmacists had with the reporting process. These barriers were consistent with previous research conducted. Finally, pharmacists suggested various means of facilitating ADR reporting including use of electronic reporting aids, creating increased awareness amongst healthcare professionals, conducting continuous training and making amendments to the reporting form, some of which were in line with previous research conducted. Conclusion: Exploring the perceptions and experiences of pharmacists with respect to the under-reporting of ADRs revealed key knowledge about the spontaneous reporting system that could be applied to strengthen the current reporting system and enable more reporting. Whilst it was clear that pharmacists play an important role as the gatekeepers and drivers of the reporting process enabling other HCPs to report ADRs, more should be done to empower pharmacists in managing ADR reporting opportunities. This could benefit the healthcare system in ensuring that more ADRs are reported, as well as decrease the waiting time of patients and the workload of medical officers. In addition, engaging with pharmacists and HCPs to overcome barriers to reporting would facilitate increased ADR reporting. Recommendations: Several recommendations emerged from the study. Future circulars, training workshops and awareness posters about the ADR reporting process should inform all HCPs to report any medication suspected of being the cause of an ADR and not waste time in trying to identify the medication that caused it. A training workshop should be conducted with pharmacists to improve their skills in terms of identifying ADRs, how and what to report and of the appropriate referral of patients to the medical officers. An annual assessment on the availability of reporting forms in all health facilities should be conducted. In addition, the MIC should conduct a survey on the user-friendliness of the reporting form and enable HCPs to provide recommendations to help improve the reporting form template. Pharmacovigilance should be a standing item on the agendas of sub-district PTC meetings at which supervisor pharmacists should give quarterly updates to sub-district management on ADRs reported. As this study focused primarily on the experiences and perceptions of pharmacists in a rural health district, a follow-up study should explore perceptions and knowledge of medical officers and nurses of ADR reporting, specifically on the availability and complexity of the reporting form. Finally, the MIC should explore the development of a basic ADR causality assessment tool that could assist pharmacists and other HCPs in identifying a possible ADR and improve confidence amongst pharmacists and HCPs in reporting ADRs.

Yes / Patients' pharmacogenetic data could be used to improve adherence to antipsychotic medication by increasing the likelihood of therapeutic response and reducing the prevalence of adverse drug reactions.

Os medicamentos antidepressivos, especialmente os tricíclicos são indicados no tratamento farmacológico da depressão ou manejo de mialgias. Estes medicamentos têm sido utilizados em larga escala na rede sanitária pública do município de Ribeirão Preto, SP, Brasil. Os objetivos desta tese foram determinar o consumo dos psicotrópicos na rede pública de saúde de Ribeirão Preto, identificar os problemas relacionados com o medicamento amitriptilina (AMT), elaborar estratégias específicas de educação continuada para os médicos e verificar a resposta desta intervenção farmacêutica. Os dados de consumo foram obtidos das planilhas mensais das unidades de farmácia, arquivados na Divisão de Farmácia da Secretaria Municipal de Saúde de Ribeirão Preto. Para atingir os outros objetivos, esta pesquisa obteve os dados por meio de anamnese farmacêutica com os pacientes de oito unidades de saúde. Resultou na verificação da impressão dos pacientes sobre a assistência à saúde, dos fatores determinantes da prescrição de AMT, dos conhecimentos médicos sobre os problemas relacionados com este medicamento, seu comportamento quanto à assistência ao paciente e na resposta à intervenção farmacêutica, que mostrou impacto positivo. Este trabalho ainda reafirma a atenção farmacêutica como prática profissional de grande utilidade e necessidade para a melhor assistência ao paciente e como agente no uso racional do medicamento e da farmacovigilância / The antidepressants, specially the tricyclic ones, are indicated for the pharmacological treatment of depression and pain. This drugs have been used extensively by the public heath care of Ribeirão Preto, SP, Brazil. The purposes of this thesis were: to determine the psychotropic consumption at the Heath System of Ribeirão Preto, to identify the amitriptyline (AMT) adverse reactions and other related problems, to elaborate specific strategies of pharmaceutical continuing education to the physicians and to verify the response of this pharmaceutical intervention. Consumption data were obtained from monthly charts of the pharmacy sets, archived at the Pharmacy Division. To achieve the other purposes of this research, data were obtained from pharmaceutical anamnesis with patients from the health unities chosen. It resulted in verification of patients impression about health care received, AMT prescription determinant factors, medical knowledge about problems related to this drug and their behavior and also resulted in the pharmaceutical intervention response, which showed positive impact. This research affirms the pharmaceutical care as professional practice of great utility and necessity for better patient assistance and as agent at the rational drug use and pharmacovigilance.

This study examined the potential significant differences in the distribution of adverse drug reactions (ADRs) by reporter (consumer versus physician) and patient outcome at case and event level. This study also contains exploratory questions to evaluate reporting of ADRs by consumers versus physician by system organ class (SOC) and reporter demographics within the United States Food & Drug Administration Adverse Event Reporting System (FAERS). The theoretical foundation applied in this quantitative study was the social amplification of risk framework. Data from the second quarter of 2016 were obtained from FAERS, and a total of 87,807 ADR reports corresponding to 143,399 ADRs were analyzed by utilizing the chi-square test, the odds ratio, and logistic regression. Cross-sectional design was employed to compare reporting of ADRs at the case and event level (case-based and event-based analyses, respectively) between reporters (consumer versus physician), specifically, for patient outcome, as well as SOC and reporter demographics. For both the case-based and event-based analyses, findings revealed that consumers reported more serious ADRs in comparison to physicians. Furthermore, findings confirmed a difference in ADR reporting between consumers and physicians depending on SOC groups. Additionally, consumers reported more nonserious ADRs in comparison to physicians. The results from this study may have implications for positive social change by augmenting pharmacovigilance systems at a national and international level to identify risks and risk factors spontaneously reported after drugs have been on the market.

<p>The WHO database contains more than 2.8 million case reports of suspected adverse drug reactions reported from 70 countries worldwide since 1968. The Uppsala Monitoring Centre maintains and analyses this database for new signals on behalf of the WHO Programme for International Drug Monitoring. A goal of the Programme is to detect signals, where a signal is defined as "Reported information on a possible causal relationship between an adverse event and a drug, the relationship being unknown or incompletely documented previously."</p><p>The analysis of such a large amount of data on a case by case basis is impossible with the resources available. Therefore a quantitative, data mining procedure has been developed to improve the focus of the clinical signal detection process. The method used, is referred to as the BCPNN (Bayesian Confidence Propagation Neural Network). This not only assists in the early detection of adverse drug reactions (ADRs) but also further analysis of such signals. The method uses Bayesian statistical principles to quantify apparent dependencies in the data set. This quantifies the degree to which a specific drug- ADR combination is different from a background (in this case the WHO database). The measure of disproportionality used, is referred to as the Information Component (IC) because of its' origins in Information Theory. A confidence interval is calculated for the IC of each combination. A neural network approach allows all drug-ADR combinations in the database to be analysed in an automated manner. Evaluations of the effectiveness of the BCPNN in signal detection are described.</p><p>To compare how a drug association compares in unexpectedness to related drugs, which might be used for the same clinical indication, the method is extended to consideration of groups of drugs. The benefits and limitations of this approach are discussed with examples of known group effects (ACE inhibitors - coughing and antihistamines - heart rate and rhythm disorders.) An example of a clinically important, novel signal found using the BCPNN approach is also presented. The signal of antipsychotics linked with heart muscle disorder was detected using the BCPNN and reported.</p><p>The BCPNN is now routinely used in signal detection to search single drug - single ADR combinations. The extension of the BCPNN to discover 'unexpected' complex dependencies between groups of drugs and adverse reactions is described. A recurrent neural network method has been developed for finding complex patterns in incomplete and noisy data sets. The method is demonstrated on an artificial test set. Implementation on real data is demonstrated by examining the pattern of adverse reactions highlighted for the drug haloperidol. Clinically important, complex relationships in this kind of data are previously unexplored.</p><p>The BCPNN method has been shown and tested for use in routine signal detection, refining signals and in finding complex patterns. The usefulness of the output is influenced by the quality of the data in the database. Therefore, this method should be used to detect, rather than evaluate signals. The need for clinical analyses of case series remains crucial.</p>

<p>Spontaneous reporting systems (SRSs) for adverse drug reactions (ADRs) have been developed as a result of the thalidomide disaster, whereby thousands of children world-wide were born with birth defects. The Swedish Adverse Drug Reactions Advisory Committee was established in 1965. Since 1975, reporting has been compulsory for all suspected serious or new ADRs. International collaboration started in 1968 with countries contributing their ADR reports to an international database set up by the World Health Organization. </p><p>ADRs represent the negative side of the benefit-to-risk balance that in theory needs to be counteracted by perceived or established positive drug effects. All drugs are subject to preclinical and clinical testing prior to marketing authorization. However, these studies are insufficient to detect rare ADRs, ADRs that occur after long-term administration or with latency, ADRs that occur in special patient groups such as children, the elderly, patients with renal or hepatic insufficiency or patients on concomitant drug treatment, and ADRs that represent a modest increase in the risk of diseases (including mortality) that are prevalent in the study population. Postmarketing surveillance of drugs is therefore essential, and regulatory action may be needed on the basis of new ADR information. </p><p>SRSs are important sources of ADR information as exemplified here by the evaluation of peripheral sensory disturbances with fluoroquinolones, hyponatremia with antidepressants, blood dyscrasias with dipyrone, glucose intolerance with atypical antipsychotics, pulmonary embolism with combined oral contraceptives and extrapyramidal symptoms with selective serotonin reuptake inhibitors. SRSs can be used to study clinical manifestations of ADRs (that can give insights into potential ADR mechanisms), risk factors for the ADR or for specific outcomes of the ADR, and ADR reporting incidences when combined with sales data. Signals from SRSs may need to be studied further e.g., by use of large-scale epidemiologic studies based on record linkage between drug prescription databases and health databases. Owing to the rapid availability of information, however, SRSs are likely to remain of major importance for the post-marketing surveillance of drugs.</p>

The WHO database contains more than 2.8 million case reports of suspected adverse drug reactions reported from 70 countries worldwide since 1968. The Uppsala Monitoring Centre maintains and analyses this database for new signals on behalf of the WHO Programme for International Drug Monitoring. A goal of the Programme is to detect signals, where a signal is defined as "Reported information on a possible causal relationship between an adverse event and a drug, the relationship being unknown or incompletely documented previously." The analysis of such a large amount of data on a case by case basis is impossible with the resources available. Therefore a quantitative, data mining procedure has been developed to improve the focus of the clinical signal detection process. The method used, is referred to as the BCPNN (Bayesian Confidence Propagation Neural Network). This not only assists in the early detection of adverse drug reactions (ADRs) but also further analysis of such signals. The method uses Bayesian statistical principles to quantify apparent dependencies in the data set. This quantifies the degree to which a specific drug- ADR combination is different from a background (in this case the WHO database). The measure of disproportionality used, is referred to as the Information Component (IC) because of its' origins in Information Theory. A confidence interval is calculated for the IC of each combination. A neural network approach allows all drug-ADR combinations in the database to be analysed in an automated manner. Evaluations of the effectiveness of the BCPNN in signal detection are described. To compare how a drug association compares in unexpectedness to related drugs, which might be used for the same clinical indication, the method is extended to consideration of groups of drugs. The benefits and limitations of this approach are discussed with examples of known group effects (ACE inhibitors - coughing and antihistamines - heart rate and rhythm disorders.) An example of a clinically important, novel signal found using the BCPNN approach is also presented. The signal of antipsychotics linked with heart muscle disorder was detected using the BCPNN and reported. The BCPNN is now routinely used in signal detection to search single drug - single ADR combinations. The extension of the BCPNN to discover 'unexpected' complex dependencies between groups of drugs and adverse reactions is described. A recurrent neural network method has been developed for finding complex patterns in incomplete and noisy data sets. The method is demonstrated on an artificial test set. Implementation on real data is demonstrated by examining the pattern of adverse reactions highlighted for the drug haloperidol. Clinically important, complex relationships in this kind of data are previously unexplored. The BCPNN method has been shown and tested for use in routine signal detection, refining signals and in finding complex patterns. The usefulness of the output is influenced by the quality of the data in the database. Therefore, this method should be used to detect, rather than evaluate signals. The need for clinical analyses of case series remains crucial.

Spontaneous reporting systems (SRSs) for adverse drug reactions (ADRs) have been developed as a result of the thalidomide disaster, whereby thousands of children world-wide were born with birth defects. The Swedish Adverse Drug Reactions Advisory Committee was established in 1965. Since 1975, reporting has been compulsory for all suspected serious or new ADRs. International collaboration started in 1968 with countries contributing their ADR reports to an international database set up by the World Health Organization. ADRs represent the negative side of the benefit-to-risk balance that in theory needs to be counteracted by perceived or established positive drug effects. All drugs are subject to preclinical and clinical testing prior to marketing authorization. However, these studies are insufficient to detect rare ADRs, ADRs that occur after long-term administration or with latency, ADRs that occur in special patient groups such as children, the elderly, patients with renal or hepatic insufficiency or patients on concomitant drug treatment, and ADRs that represent a modest increase in the risk of diseases (including mortality) that are prevalent in the study population. Postmarketing surveillance of drugs is therefore essential, and regulatory action may be needed on the basis of new ADR information. SRSs are important sources of ADR information as exemplified here by the evaluation of peripheral sensory disturbances with fluoroquinolones, hyponatremia with antidepressants, blood dyscrasias with dipyrone, glucose intolerance with atypical antipsychotics, pulmonary embolism with combined oral contraceptives and extrapyramidal symptoms with selective serotonin reuptake inhibitors. SRSs can be used to study clinical manifestations of ADRs (that can give insights into potential ADR mechanisms), risk factors for the ADR or for specific outcomes of the ADR, and ADR reporting incidences when combined with sales data. Signals from SRSs may need to be studied further e.g., by use of large-scale epidemiologic studies based on record linkage between drug prescription databases and health databases. Owing to the rapid availability of information, however, SRSs are likely to remain of major importance for the post-marketing surveillance of drugs.

Idiosyncratic drug reactions (IDRs) represent a significant medical problem and pose a great challenge to drug development. Circumstantial evidence suggests that, in most cases, reactive metabolites of the drug are responsible. The major focus of this thesis is the identification of reactive metabolites and the synthesis of analogs required to test several hypotheses related to involvement of metabolism and covalent binding in the mechanisms of IDRs. Minocycline is unique among tetracyclines in causing a significant incidence of a lupus-like syndrome and autoimmune hepatitis. In this study, we demonstrated that minocycline is oxidized to reactive intermediates by myeloperoxidase/H2O2/Cl-, HOCl, horseradish peroxidase/H2O2, or hepatic microsomes. When trapped with N-acetylcysteine (NAC), two adducts with protonated molecular ions at m/z 619 were isolated and analyzed by NMR. One represents attack of the aromatic D ring by NAC meta to the N, N-dimethylamino group, implying that the reactive intermediate was a quinone iminium ion. The other adduct, which was not observed when minocycline was oxidized by hepatic microsomes, indicates that the NAC is attached at the junction of the B and C rings, suggesting that the HOCl added across the double bond of the B ring leading to a reactive molecule, and then NAC displaced the chloride ion. Nevirapine, an anti-HIV drug, is associated with idiosyncratic skin rashes in humans. The goal of this project was to investigate whether the 12-hydroxylation pathway is responsible for the skin rash. To test a part of this hypothesis, 12-trideuteronevirapine, 12-OH-NVP sulfate, and several other analogs of nevirapine were synthesized. D-penicillamine is known to cause idiosyncratic autoimmune reactions in humans. The goal of this project was to test whether D-penicillamine covalently binds to macrophages and triggers downstream events leading to autoimmunity. To test a part of this hypothesis, D-penicillamine conjugated to biotin was synthesized. In summary, reactive metabolites of minocycline were found that likely explain why minocycline has an IDR profile unique among the tetracyclines. In addition, analogs of nevirapine and D-penicillamine required for mechanistic studies of nevirapine and D-penicillamine-induced IDRs were synthesized. These studies provide additional support for the involvement of reactive metabolites in the mechanisms of IDRs.

Idiosyncratic drug reactions (IDRs) represent a significant medical problem and pose a great challenge to drug development. Circumstantial evidence suggests that, in most cases, reactive metabolites of the drug are responsible. The major focus of this thesis is the identification of reactive metabolites and the synthesis of analogs required to test several hypotheses related to involvement of metabolism and covalent binding in the mechanisms of IDRs. Minocycline is unique among tetracyclines in causing a significant incidence of a lupus-like syndrome and autoimmune hepatitis. In this study, we demonstrated that minocycline is oxidized to reactive intermediates by myeloperoxidase/H2O2/Cl-, HOCl, horseradish peroxidase/H2O2, or hepatic microsomes. When trapped with N-acetylcysteine (NAC), two adducts with protonated molecular ions at m/z 619 were isolated and analyzed by NMR. One represents attack of the aromatic D ring by NAC meta to the N, N-dimethylamino group, implying that the reactive intermediate was a quinone iminium ion. The other adduct, which was not observed when minocycline was oxidized by hepatic microsomes, indicates that the NAC is attached at the junction of the B and C rings, suggesting that the HOCl added across the double bond of the B ring leading to a reactive molecule, and then NAC displaced the chloride ion. Nevirapine, an anti-HIV drug, is associated with idiosyncratic skin rashes in humans. The goal of this project was to investigate whether the 12-hydroxylation pathway is responsible for the skin rash. To test a part of this hypothesis, 12-trideuteronevirapine, 12-OH-NVP sulfate, and several other analogs of nevirapine were synthesized. D-penicillamine is known to cause idiosyncratic autoimmune reactions in humans. The goal of this project was to test whether D-penicillamine covalently binds to macrophages and triggers downstream events leading to autoimmunity. To test a part of this hypothesis, D-penicillamine conjugated to biotin was synthesized. In summary, reactive metabolites of minocycline were found that likely explain why minocycline has an IDR profile unique among the tetracyclines. In addition, analogs of nevirapine and D-penicillamine required for mechanistic studies of nevirapine and D-penicillamine-induced IDRs were synthesized. These studies provide additional support for the involvement of reactive metabolites in the mechanisms of IDRs.