Epidemiology of Cytochrome P450-mediated Drug-Drug Interactions

Drug-drug interactions (DDIs) comprise an important cause of adverse drug reactions leading to excess hospitalizations. Drug metabolism is catalyzed by 75% by cytochrome P450 (CYP) enzymes and thus they are often involved in pharmacokinetic DDIs. In general, DDIs are studied in randomized controlled clinical trials in selected study populations. The overall aim of the present studies was to perform observational pharmacoepidemiological surveys on CYP-mediated DDIs in diseases important at the population level. The prevalence of co-administrations of four prodrugs (losartan, codeine, tramadol, and clopidogrel), three sulphonylureas (glibenclamide, glimepiride, and glipizide), or two statins (lovastatin and simvastatin) with well established agents altering CYP activity, as well as of statins with fibrates, was studied in Finland utilizing data from a university hospital medication database (inpatients) and the National Prescription Register of the Social Insurance Institution of Finland, Kela (outpatients). Clinical consequences of potential DDIs were estimated by reviewing laboratory data, and information from hospital care and cause-of-death registers. Concomitant use of study substrates with interacting medication was detected in up to one fifth of patients in both hospital and community settings. Potential CYP3A4 interactions in statin users did not manifest in clear adverse laboratory values but pharmacodynamic DDIs between statins and fibrates predisposed patients to muscular toxicity. Sulphonylurea DDIs with CYP2C9 inhibitors increased the risk of hypoglycaemia. CYP3A4 inhibitor use with clopidogrel was not associated with significant changes in mortality but non-fatal thrombosis and haemorrhage complications were seen less often in this group. Concomitant administration of atorvastatin with clopidogrel moderately attenuated the antithrombotic effect by clopidogrel. The overall mortality was increased in CYP3A4 inducer and clopidogrel co-users. Atorvastatin used concomitantly with prodrug clopidogrel seems to be beneficial in terms of total and LDL cholesterol concentrations, and overall mortality compared with clopidogrel use without interacting medication. In conclusion, CYP-mediated DDIs are a common and often unrecognized consequence of irrational drug prescribing.

Burden of Influenza in Children

Background: Most children with influenza are treated as outpatients but, especially among young children, influenza-attributable illnesses often result in hospitalization. However, relatively scarce data exist on the clinical picture and the full disease burden of pediatric influenza. Prompt diagnosis of influenza could enable the institution of antiviral therapy and adequate cohorting of patients. Data are needed to help clinicians correctly suspect influenza at the time of hospital admission. Aims and methods: We conducted a prospective 2-year cohort study of respiratory infections in children aged ≤13 years to determine the incidence of influenza in outpatient children and to assess the clinical presentation of influenza in various age groups seen in primary care. We also determined the rates of different complications attributable to influenza and the absenteeism of the children and their parents due to the child’s influenza infection. We then conducted a further 16-year retrospective study of children ≤16 years of age, hospitalized with virologically confirmed influenza. We estimated the population-based rates of hospitalizations and determined the primary admission diagnoses of the hospitalized children in different age groups. Results: The average annual rate of influenza was highest (179 / 1000) among children <3 years old. In this age group, acute otitis media was diagnosed as a complication of influenza in 40% of children. High fever was the most prominent sign of influenza, and 20% of children <3 years of age had a fever ≥40oC. Most children had rhinitis already during the first days of the illness. The average annual incidence of influenzarelated hospitalization was highest (276 / 100,000) among infants <6 months of age, of whom 52% were primarily admitted due to sepsis-like illnesses. Respiratory symptoms accounted for 38% of the hospitalizations. Conclusions: Influenza causes a substantial burden of illness on outpatient children and their families. The clinical presentation of influenza is most severe in children <3 years of age. The high incidence of influenza-associated hospitalizations among infants aged <6 months calls for more effective ways to prevent influenza in this age group. The clinical manifestations of influenza vary widely in different age groups of children at the time of hospital admission. Awareness of this phenomenon is important for the early recognition of the illness and the potential initiation of effective antiviral treatment of these patients.

Kallet til livets embete : mødre i helse og lidelse

Mothers represent the natural caring. Natural caring is the object of caring science and of research interest because it establishes the central core of professional caring. In this study, we encounter patients who are mothers in need of care in a psychiatric context. Motherhood involves taking responsibility that extends beyond one's own life, because the child represents possibilities in a yet unknown future. Understanding and knowledge about the mothers' struggle in health and suffering are of crucial importance to enable clinical practice to make provisions for and adapt to the individual patient. The overall purpose of this dissertation is to illuminate how the innermost essence of caring emerges in health and suffering in patients who are mothers in psychiatric care. The purpose of the study in a clinical sense is to seek to understand and illuminate the patient's inner world in health and suffering in terms of contextual, existential, ontological and ethical dimensions. The dissertation is exploratory and descriptive in nature and encompasses induction, deduction and abduction as logics tools of reasoning. A theoretical model of natural caring and a universal theoretical model of the innermost essence of caring is developed as seen from the patient's world in a psychiatric context. The dissertation is anchored in human science's view of the human being and the world and in caring science's perspective. Caring science's view of the human being as a unity comprising body, soul and spirit is central in the study's concept of the patient. This multi-dimensional conception of the human being encompasses the dissertation's basic values and is decisive for choice of methodology. Hermeneutic epistemology guided the interpretation of the empirical data, the paradigmatic theses and assumptions. The dialectical movement in interpretation moves back and forth between empirical data, caring science theory and philosophical theory and reveals deeper insight into meaningful content in the clinical context. The interpretation process comprises four levels of abstraction: rational, contextual, existential and ontological. Hermeneutic philosophy guides the inductive and deductive approach to interpretation, as well as the movement between the clinical context and the caring science paradigm. In this encounter between the visible and invisible reality, the image of natural caring – motherliness emerged. The dissertation consists of four studies. The first study is a systematic review of nineteen research articles. The three other studies are hermeneutical interpretations based on text materials from open interviews. Fifteen participants were interviewed, all of whom are mothers of children between 0 and 18 years of age. All were outpatients in the psychiatric specialist health service. In the interpretation process, the mothers' struggle in health and suffering emerges as a struggle between the inner and outer world. Being a mother and patient in health and suffering in a psychiatric context means to struggle to be oneself, to create oneself, to live and realize one's good deeds as a mother and human being. To be oneself, to possess oneself as a mother is not only a question of tending, playing and learning in order to master a practical situation or to survive. It involves constituting a deep, inner desire to courageously create oneself so that the child is able to realize his or her potential in health and suffering. Motherliness manifests itself in caring as a call to ministering humanity and life. The voice of motherliness is understood as the voice of life—the eternal, inner call of love and freedom. The inner call craves fulfilment. Motherliness in natural caring does not retreat. Motherliness defines the Other as freedom and proceeds without regard for all other exterior requirements to realizing wellbeing. The inner essence of caring is attentive, aware and heeds the call of the heart. The innermost essence of caring is to be and to make oneself responsible for the Other. Responsibility cannot be relinquished; free choice consists in whether or not to follow the call. To renounce the inner call to responsibility is to deny oneself and one's dignity as a human being. The theoretical models provide clinical and systematic caring science with knowledge and understanding based on the natural caring spirit inherent in the human being. The study elucidates and strengthens the ontological basic assumptions about the human being as a unity of body, soul and spirit, the sanctity of the human being and the core of caring, ethos. The results of the dissertation will provide clinical practice with knowledge about the inner movements of the mothers' souls in relation to their responsibility as mothers and human beings. Being able to understand the basic conditions for responsibility is crucial for developing care that encompasses mother and child and the mutual relationship between them. This is basic knowledge for developing attitudes and actions that meet and provide for the needs of the patient as mother and as a whole, suffering human being.

Tympanometry and Spectral Gradient Acoustic Reflectometry in the Diagnosis of Otitis Media in Young Children

Acute otitis media (AOM) is the most prevalent bacterial infection among children. Tympanometry and spectral gradient acoustic reflectometry (SG-AR) are adjunctive diagnostic tools to pneumatic otoscopy. The aim was to investigate the diagnostic accuracy and success rates of tympanometry and SG-AR performed by physicians and nurses. The study populations comprised 515 (I-II), 281 (III), and 156 (IV) outpatients (6-35 months). Physicians performed 4246 tympanometric (I) and SG-AR (II) examinations. Nurses performed 1782 (III) and 753 (IV) examinations at symptomatic and asymptomatic visits, respectively. Pneumatic otoscopy by the physician was the diagnostic standard. The accuracy of test results by physicians or nurses (I-IV) and the proportion of visits with accurate exclusive test results from both ears (III-IV) were analyzed. Type B tympanogram and SG-AR level 5 (<49˚) predicted middle ear effusion (MEE). At asymptomatic visits, type A and C1 tympanograms (peak pressure > -200 daPa) and SG-AR level 1 (>95˚) indicated healthy middle ear. Negative predictive values of type A and C1 tympanograms by nurses in excluding AOM at symptomatic and MEE at asymptomatic visits were 94% and 95%, respectively. Nurses obtained type A or C1 tympanogram from both ears at 94/459 (20%) and 81/196 (41%) of symptomatic and asymptomatic visits, respectively. SG-AR level 1 was rarely obtained from both ears. Type A and C1 tympanograms were accurate in excluding AOM at symptomatic and MEE at asymptomatic visits. However, nurses obtained these tympanograms from both ears only at one fifth of symptomatic visits and less than half of asymptomatic visits.