PURPOSE:

Important drugs in the treatment of childhood acute lymphoblastic leukaemia (ALL) are 6-mercaptopurine (6-MP) and methotrexate (MTX). Thiopurine methyltransferase (TPMT) is a polymorphic enzyme causing variability in 6-MP response and toxicity. The aim of this study was to investigate the fluctuation in TPMT enzyme activity over time and the effect of high-dose MTX infusions on TPMT enzyme activity and 6-MP metabolites in paediatric ALL patients.

METHODS:

Fifty-three children with ALL treated according to the NOPHO-ALL 2000 protocol were included in the study. TPMT enzyme activity was measured at six different times starting from diagnosis until after the end of maintenance treatment. TPMT and 6-MP metabolites were measured before the initiation of high-dose MTX (HD-MTX) infusions and at 66 h post-infusion. The interaction between MTX and TPMT was investigated in vitro using recombinant TPMT protein and a leukaemic cell line.

RESULTS:

Forty percent of TPMT wild-type individuals had deceptively low TPMT enzyme activity according to genotype at the time of diagnosis. TPMT activity had decreased significantly 66 h after the start of HD-MTX infusions (-9.2 %; p = 0.013). MTX bound to recombinant TPMT protein severely inhibiting TPMT enzyme activity (remaining activity 16 %).

CONCLUSIONS:

Our results show that TPMT genotyping should be performed in children with ALL, since 40 % of the children in our study who carried the wild-type TPMT gene were at risk of initial underdosing of 6-MP in cases where only TPMT enzyme activity was determined. MTX inhibits the TPMT enzyme activity after HD-MTX infusions due to protein binding.

PURPOSE:

To determine whether treatment with nitrofurantoin in women with urinary tract infection (UTI) and renal impairment in primary care is associated with a higher risk of ineffectiveness and/or serious adverse events than in women without renal impairment.

METHODS:

A cohort of 21,317 women treated with nitrofurantoin and a cohort of 7,926 women treated with trimethoprim, identified from the Pharmo Record Linkage System, were analysed. The primary outcome was ineffectiveness of treatment of nitrofurantoin defined as the start of a second antibacterial within 1 month after the start of nitrofurantoin. The secondary outcome was the occurrence of serious adverse events of nitrofurantoin leading to hospitalization within 90 days. A cohort of trimethoprim users was used to determine if the associations found for nitrofurantoin were mainly related to nitrofurantoin itself. The association between renal impairment and the risk of these outcomes was determined with Cox regression and expressed as hazard ratios (HRs).

RESULTS:

Overall, the incidence density for ineffectiveness was 5.4 per 1,000 person-days, and moderate renal impairment was not associated with ineffective treatment [HR 1.1, 95 % confidence interval (CI) 0.74-1.51]. The overall incidence density for adverse events was 0.02 per 1,000 person-days. In patients with renal impairment (<50 ml/min/1.73 m(2)) the risk of pulmonary adverse events leading to hospitalization was significantly increased (HR 4.1, 95 % CI 1.31-13.09)

CONCLUSIONS:

Nitrofurantoin treatment was not associated with a higher risk of ineffectiveness in women with UTI and moderate renal impairment (30-50 ml/min/1.73m(2)). However, we did find a significant association between renal impairment (<50 ml/min/1.73 m(2)) and pulmonary adverse events leading to hospitalization.

INTRODUCTION:

In order to discover how well the discipline of clinical pharmacology (CP) has developed in Europe, a questionnaire survey was undertaken in 31 countries.

METHODS:

The senior delegate of each of the 31 countries on the Council of the European Association for Clinical Pharmacology and Therapeutics (EACPT) was approached personally. This study was not an official EACPT survey.

RESULTS:

Based on the results of the completed survey forms, CP is recognized as an academic discipline in teaching and research fields in 28 of the 31 participating countries, but as a medical specialty in only 22 of these 31 countries. Surprisingly, France and Italy were two of the nine countries where CP was not recognized as a medical specialty. In 50 % of the countries where CP was recognized as a medical specialty, this recognition had occurred more than 30 years ago. The training of clinical pharmacologists in terms of years after internship varied between the countries. In eight countries the training was predominantly in internal medicine with shorter periods in pharmacology. In 11 countries the training was predominantly in CP, and in six countries there was dual training in pharmacology and clinical medicine. The training played a decisive role in terms of the clinical functions undertaken in health care. There was considerable variation in the numbers of clinical pharmacologists in each country, with the total figure varying between ≤10 to 600. In terms of the number of clinical pharmacologists per million inhabitants, nine countries have ≤1 (Belgium, Bulgaria, France, Greece, Italy, Lithuania, Poland, Turkey and UK) while four have ≥10 (Hungary, Norway, Slovakia and Sweden). Stumbling blocks which inhibit the development of CP as a discipline in health care are the lack of defined functions and consultant posts for clinical pharmacologists in health care in many countries and the underrepresentation of CP in pre- and postgraduate curricula.

CONCLUSION:

The majority of the responding countries suggested that EACPT should prioritize that CP becomes recognized and accredited as a European medical specialty.

To describe the discipline clinical pharmacology of today in the Swedish healthcare system from the performers' point of view.A questionnaire was administered in December 2012 to physicians working within the specialty clinical pharmacology in the Swedish healthcare system (7 sites; 1-26 physicians per site). The questionnaire included questions pertaining to the characteristics of the responder and statements to which the responder indicated his/her level of agreement using a score ranging from 1 (total disagreement) to 5 (total agreement).A total of 61 completed questionnaires were returned (response rate: 97 %; 55 % male; 74 % specialists and/or consultants). In the preceding month, 79 % of the responders had performed educational activities, 74 % had functioned as an "expert", and 75 % had performed research. The academic merits of the responders were high, with 72 % having at least a PhD degree and 23 % being professors. Among those performing research, the focus of 83 % was related to the field of clinical pharmacology, with the main sub-areas being pharmacoepidemiology (59 %) and/or pharmacogenetics (41 %). Regarding the apprehension questions, the responders strongly agreed that the specialty clinical pharmacology meets a need in the healthcare system (4.5 ± 0.7), that they wanted to continue to work within the specialty (4.5 ± 0.7), that their personal professional prospects were good (3.9 ± 1.0), and that they would recommend a colleague to specialize within the field (3.9 ± 1.1). The responders from the largest and first established site (Karolinska University Hospital) agreed with these points to a significantly greater extent than responders from other sites.The majority of the performers of clinical pharmacology in Swedish healthcare consider this specialty to be important to the medical community. By carrying out educational activities, providing expertise, and performing research, the performers seem to be content with their work and future prospects. Performers within the largest and oldest site in Sweden, generally held the most positive view of the specialty.

Since direct patient care is only one of the many fields of clinical pharmacologists world wide, the contribution of the discipline to the provision of healthcare is frequently underestimated. Besides therapeutic monitoring and pharmacogenetic services, particularly drug information services run by clinical pharmacology departments have been established in many countries. Despite the fact that electronic prescribing support may prevent physicians from major medication errors due to drug-drug interactions and inadequate dosages, a substantial number of questions addressed to drug information services include clinical expertise and judgement. Furthermore, a high number of requests deal with adverse drug interactions and involve requests for alternative drugs in the individual clinical context. Using information technology, an international web-based clinical pharmacology service using existing knowledge databases seems to be a promising option to demonstrate the excellence of the discipline.

During the last five decades drug and therapeutics committees (DTCs), have evolved from mainly hospital-based groups of experts in pharmacotherapy and drug logistics into an arena for healthcare professionals employing evidence-based methods of promoting rational drug use. The purpose of this study was to suggest a framework for analysing the structure and activities of DTCs.A literature search was carried out in the Medline, Cinahl and Web of Sciences databases for the period 1993-2012.A total of 207 articles were included. Based on these articles a framework for the analysis of the DTCs based on the role of the DTC, target groups, budget perspective and type of economic decisions could be suggested.In order to respond to future demands the DTCs will have to develop their skill in pharmacoeconomics. Their processes will have to be standardised and made more transparent in order to be better adapted to evidence-based decision-making. They will also have to embrace the possibilities created by electronic health records in both influencing the decisions of physicians, and in improving quality assurance programmes and longitudinal follow-up of drug therapy and outcomes. They will have to find new ways of interacting with the public and policy makers in order to get the resources needed for their work. Finally, they will have to handle the conflict among national, regional and local decision-making processes and the relationship between formularies and therapeutic guidelines.

In September 2012 an interactive course on the "Interface Management of Pharmacotherapy" was organized by the Stockholm Drug and Therapeutics Committee in cooperation with Department of Clinical Pharmacology at Karolinska Institutet and at Karolinska University Hospital in Stockholm, Sweden, in collaboration with the WHO. The basis for the course was the "Stockholm model" for the rational use of medicines but also contained presentations about successful models in interface management of pharmacotherapy in other European countries.The "Stockholm model" consists of 8 components: 1) Independent Drug and Therapeutics Committee with key role for respected drug experts with policy for "interest of conflicts", 2) The "Wise List", recommendations of medicines jointly for primary and hospital care, 3) Communication strategy with continuous medical education, 4) Systematic introduction of new expensive medicines, 5) E-pharmacological support at "point of care", 6) Methods and tools for follow-up of medicines use, 7) Medicines policy strategy and 8) Operative resources.The course highlighted the importance of efficient and targeted communication of drug recommendations building on trust among prescribers and patients for the guidelines to achieve high adherence. Trust is achieved by independent Drug and Therapeutics Committees with a key role for respected experts and a strict policy for "conflicts of interest". Representations of GPs are also crucial for successful implementation, being the link between evidence based medicine and practice.The successful models in Scotland and in Stockholm as well as the ongoing work in Catalonia were considered as examples of multifaceted approaches to improve the quality of medicine use across primary and hospital care.

Information must be collected, evaluated and utilized to support every qualified activity. Medicine, with a written scientific tradition stretching back more than 2,000 years, is no exception. Here, we discuss a number of important items associated with the establishment of a drug information centre run by clinical pharmacologists and information pharmacists, serving a broad demand, mainly among clinical specialists. The working methods include a professional literature search, critical evaluation of the material, writing a structured answer, quality control, feedback to the inquirer and storage in a database which is publicly available. One can foresee even more complex systems wherein a number of active and specialized databases communicate to provide relevant advice and support at the point of care, supplying information on drug recommendations, reimbursement, environmental aspects, antimicrobial resistance, pharmacogenetics and adverse effects, and linked to a list of prescribed drugs for the individual patient. This will be possible in both rich and poor countries through the application of modern and developing information technology. However, research on the best and safest methods of such decision support systems will be needed to ensure that they really do improve the quality of drug prescribing and use.

Access to medicines filling children's therapeutic needs is a long-standing global problem. The problem has been recognised and initiatives for correction were adopted in the USA in the late 1990s, and in the European Union in the first decade of this century. Paediatric medicines are particularly problematic in middle- and low-income countries, where most of the children of the world live.A paediatric medicines initiative involving the WHO in parallel with the US and EU initiatives was seen as important by the global paediatric and paediatric clinical pharmacology community, but the WHO was resistant to getting involved.Advocacy, networking, cooperation, persistence, hard work and some luck were needed to get the "Better medicines for children" resolution 60.20 adopted by the World Health Assembly in May 2007.Science has been a key enabler of the developments leading to and following the adoption of the paediatric initiatives, but as the example of the WHO shows, science alone was not enough to make the change.