Abstract:The aim was to present and evaluate the impact of a comprehensive strategy over 10 years to select, communicate and achieve adherence to essential drug recommendations (EDR) in ambulatory care in a metropolitan healthcare region. EDRs were issued and launched as a 'Wise List' by the regional Drug and Therapeutics Committee in Stockholm. This study presents the concept by: (i) documenting the process for selecting, communicating and monitoring the impact of the 'Wise List'; (ii) analysing the variation in the number of drug substances recommended between 2000 and 2010; (iii) assessing the attitudes to the 'Wise List' among prescribers and the public; (iv) evaluating the adherence to recommendations between 2003 and 2009. The 'Wise List' consistently contained 200 drug substances for treating common diseases. The drugs were selected based on their efficacy, safety, suitability and cost-effectiveness. The 'Wise List' was known among one-third of a surveyed sample of the public in 2002 after initial marketing campaigns. All surveyed prescribers knew about the concept and 81% found the recommendations trustworthy in 2005. Adherence to recommendations increased from 69% in 1999 to 77% in 2009. In primary care, adherence increased from 83% to 87% from 2003 to 2009. The coefficient of variation (CV%) decreased from 6.1% to 3.8% for 156 healthcare centres between these years. The acceptance of the 'Wise List' in terms of trust among physicians and among the public and increased adherence may be explained by clear criteria for drug recommendations, a comprehensive communication strategy, electronic access to recommendations, continuous medical education and involvement of professional networks and patients.

Deficient hydroxylation of debrlsoquine Is an autosomal recessive trait that affects =7% of the Caucasian population. These individuals (poor metabolizers) carry deficient CYP2D6 gene variants and have an impaired metabolsm of several commonly used drugs. The opposite phenomenon also exists, and certain individuals metabolize the drugs very rapidly, resulting in subtherapeutic plasma concentrations at normal doses. In the present study, we have investigated the molecular genetic basis for ultrarapid metabolism of debrisoquine. Restriction fragment length polymorphism analysis of the CYP2D locus in two families with very rapid metabolism of debrisoquine [metabolic ratio (MR) for debrisoquine = 0.01-0.11 revealed the variant CYP2D6 gene CYP2D6L. EcoRI RFLP and Xba I pulsed-field gel electrophoresis analyses showed that this gene had been amplifled 12-fold in three members (father and his two children) of one ofthe families, and two copies were present among members of the other family. The CYP2D6L gene had an open reading frame and carried two mutations causing amino acid substitutions: one in exon 6, yielding an Arg-296 --Cys exchange and one in exon 9 causing Ser-486 --Thr. The MR of subjects carrying one copy of the CYP2D6L gene did not signicantiy differ from that of those with the wild-ype gene, indicating that the structural alterations were not of importance for the catalytic properties of the gene product. Examination of the MR among subjects carrying wild-type CYP2D6, CYP2D6L, or deficient alleles revealed a relationship between the number of active genes and MR. The data show the principle of inherited amplification of an active gene. Furthermore, the finding of a specific haplotype with two or more active CYP2D6 genes allows genotyping for ultrarapid drug metabolizers. This genotyping could be of predictive value for individualized and more efficient drug therapy.

We have provided preliminary average dose suggestions based on the phenotype or genotype. This is a first attempt to apply the new pharmacogenetics to suggest dose-regimens that take the differences in drug metabolic capacity into account.

The frequency of poor metabolizers of debrisoquin was low and similar in four different native Chinese nationalities. In a total sample of 695 Chinese subjects, only seven (1.01%) had a urinary ratio between debrisoquin and 4-hydroxydebrisoquin greater than 12.6, which is the antimode between poor metabolizers and extensive metabolizers in white populations. This is significantly lower than the 6.82% found in 1011 white Swedish healthy subjects (p less than 0.0001). Admixture analysis indicated the occurrence of two distributions within extensive metabolizers among both Chinese and white subjects. The mean of the distribution of metabolic ratios among Chinese extensive metabolizers was shifted toward higher values compared with Swedish extensive metabolizers (p less than 0.01). The frequency of poor metabolizers of S-mephenytoin was higher in 137 Chinese (14.6%) than in 488 Swedish (3.3%) subjects (p less than 0.0001). Our findings imply that drugs metabolized by these two polymorphic hydroxylases should be prescribed in different dosages to Chinese and white subjects.