Pharmacogenetic Aspects and Drug Interactions in Anticoagulation Therapy with Coumarins

The mysterious ability of blood to clot has fascinated people over millennia. In the beginning of the 20th century, the mechanisms became better understood. In 1922, the development of hemorrhagic disease in cattle caused by mouldy sweet clover was described by Schofield. The absence or delay of blood clotting was correlated to a greatly diminished quantity of prothrombin. This discovery remained unnoticed until twenty years later the ‘hemorrhagic agent’ was identified as dicoumarol, 3,3-methylene-bis. It was promptly made available for clinical studies and already one year later first experiences on the effectiveness in deep vein thrombosis as well as its hemorrhagic complications were published. From the coumarin derivates synthesized, the most potent one was warfarin, an acronym for the Wisconsin Alumni Research Foundation (WARF). As it was used successfully to fight rats, its name may also contribute to that ‘warfare’. It was patented in 1948 and is since then the most frequently used coumarin worldwide. In 1929, Dam observed haemorrhage and markedly prolonged coagulation times in chickens fed with diets from which fat was completely extracted. He concluded that the substance whose absence in the diet was responsible for the coagulation and bone growth pathologies should be a new fat-soluble vitamin which he named vitamin K (“Koagulation”). For the discovery of vitamin K and the purification, characterization and synthesis of the vitamin, Dam and Doisy were awarded the Nobel Prize in Medicine in 1943. It was known then empirically that vitamin K reversed the bleeding problem of mouldy sweet clover poisoning. However, it took three more decades until the vitamin K cycle was proposed in 1974. After another three decades, in 2004, the complex biochemical relationship between vitamin K, its epoxide, and coumarins was enlightened by identifying the VKORC1 gene. This gene encodes the protein which is the target of the coumarins. Genetically mutated variants of the gene have been shown to cause warfarin-resistance phenotypes as well as pathogenic deficiency of all vitamin K-dependent coagulation factors

Filled prescriptions of age-related contraindicated drugs in children: a one-year nationwide cohort study in the Netherlands

Background Children are still prescribed age contraindicated drugs, but information about the number and type of these drugs dispensed for children in the Netherlands is limited. Objective To determine the incidence and prevalence of contraindicated drugs that were dispensed for the use by children. Setting The study was conducted in the Netherlands with routinely collected data from 95% of all community pharmacies. Method We performed a one-year nationwide observational study where all patients aged 17 years or younger who have received at least one prescription in 2016 were included. Contraindicated drugs were selected, according to the 5th level of ATC code, using different information sources. Main outcome measure The proportion of (newly) contraindicated drugs that were dispensed to children. Results In total, 3.9% of all children received at least one drug that was contraindicated for their age. The highest percentage of contraindicated drugs that was dispensed, was observed in patients aged 1–2 years and 13–17 years (7.0 and 5.7%, respectively) and the percentage of contraindicated drugs that were dispensed was higher in female than in male patients (4.3 and 3.6%, respectively; p value < 0.001). Conclusion The results of this study show that a substantial percentage of children received a drug that was conta-indicated for their age, and it happes more in female than in male patients. Furthermore, the information about this type of contraindications is limited and inconsistent

SERIES:eHealth in primary care. Part 2: Exploring the ethical implications of its application in primary care practice

Background: eHealth promises to increase self-management and personalised medicine and improve cost-effectiveness in primary care. Paired with these promises are ethical implications, as eHealth will affect patients' and primary care professionals' (PCPs) experiences, values, norms, and relationships.Objectives: We argue what ethical implications related to the impact of eHealth on four vital aspects of primary care could (and should) be anticipated.Discussion: (1) EHealth influences dealing with predictive and diagnostic uncertainty. Machine-learning based clinical decision support systems offer (seemingly) objective, quantified, and personalised outcomes. However, they also introduce new loci of uncertainty and subjectivity. The decision-making process becomes opaque, and algorithms can be invalid, biased, or even discriminatory. This has implications for professional responsibilities and judgments, justice, autonomy, and trust. (2) EHealth affects the roles and responsibilities of patients because it can stimulate self-management and autonomy. However, autonomy can also be compromised, e.g. in cases of persuasive technologies and eHealth can increase existing health disparities. (3) The delegation of tasks to a network of technologies and stakeholders requires attention for responsibility gaps and new responsibilities. (4) The triangulate relationship: patient-eHealth-PCP requires a reconsideration of the role of human interaction and 'humanness' in primary care as well as of shaping Shared Decision Making.Conclusion: Our analysis is an essential first step towards setting up a dedicated ethics research agenda that should be examined in parallel to the development and implementation of eHealth. The ultimate goal is to inspire the development of practice-specific ethical recommendations

Contraindicated use of 5-alpha-reductase inhibitors in women

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Self-Management Maintenance Inhalation Therapy With eHealth (SELFIE): Observational Study on the Use of an Electronic Monitoring Device in Respiratory Patient Care and Research

Contains fulltext : 204620.pdf (publisher's version ) (Open Access

Adherence to guideline recommendations for asthma care in community pharmacies: actual and needed performance

Contains fulltext : 206032.pdf (publisher's version ) (Open Access

Isotretinoin Use and Compliance with the Dutch Pregnancy Prevention Programme A Retrospective Cohort Study in Females of Reproductive Age Using Pharmacy Dispensing Data

Background: Isotretinoin is very effective in the treatment of severe acne. However, because of the teratogenic properties of this agent an isotretinoin Pregnancy Prevention Programme (PPP) was implemented in the Netherlands to guarantee that treatment is contraindicated in women of reproductive age unless at least one effective method of contraception is used. Furthermore, the PPP stipulates that isotretinoin treatment should be managed by physicians or specialists experienced in treatment with this drug and that only monthly prescriptions are issued. Objective: To assess compliance with the Dutch isotretinoin PPP in women of reproductive age during the study period of 1 January 2005 to 31 December 2008. Methods: Detailed information on dispensed medication and co-medication was available from the Dutch Foundation of Pharmaceutical Statistics. Four types of outcome were studied: concomitant dispensing of hormonal contraceptive with isotretinoin; the proportion of specialist prescribing of isotretinoin; prescribing of conventional acne therapy prior to isotretinoin initiation; and isotretinoin dispensing exceeding the maximum amount. The use of contraceptives in women aged between 15 and 45 years was defined as concomitant if the period of systemic contraceptive use overlapped the period of isotretinoin dispensing for at least 10 days, or if any dispensing of an intrauterine or intravaginal contraceptive was recorded since the year 2000. Dispensings were separated into those prescribed by either specialists or general practitioners (GPs). The use of antibacterials, anti-androgens or topical agents against acne was checked 4 months prior to an isotretinoin dispensing, and a possible excess of the maximum amount of isotretinoin was defined as prescriptions of more than 100 defined daily doses. Results: During the study period, data were available for 442 Dutch pharmacies encompassing 4881 women of reproductive age using isotretinoin at least once during study period. Among women of reproductive age, the use of isotretinoin increased during the study period. The proportion of isotretinoin initiation with concomitant oral hormonal or intrauterine contraceptives was low (59.3% [95% CI 57.6, 61.0]). Initiation of isotretinoin by a specialist increased the chance for concomitant contraception by 26% (95% CI 6.0, 49.0); in 78.2% (95% CI 76.8, 79.6) of women, isotretinoin was initiated by a specialist. Conventional acne therapy up to 16 months prior to isotretinoin initiation was found in 70% of the women (70.3% [95% CI 66.0, 74.6]). In 1.4% (95% CI 1.0, 1.8) of cases of treatment initiation, the amount of isotretinoin dispensed on one prescription seemed too high. Conclusion: Attention should be paid to improving the implementation of the isotretinoin PPP. Despite clear guidelines and warnings in the product information, our study strongly suggests that concomitant use of isotretinoin and contraceptives is too low. Even though we will have missed non-pharmacological forms of contraception, these results raise doubts about the safe use of isotretinoin in women of reproductive age in the Netherlands. Furthermore, isotretinoin does not seem to be used in cases of severe acne only. Reserving isotretinoin prescribing to specialists may improve adherence to the PPP