The 'wise list'- a comprehensive concept to select, communicate and achieve adherence to recommendations of essential drugs in ambulatory care in Stockholm.

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.

Nationwide drug-dispensing data reveal important differences in adherence to drug label recommendations on CYP2D6-dependent drug interactions.

AIMS: The study aimed to investigate the clinical adherence to drug label recommendations on important drug-drug interactions (DDIs). Dispensing data on drug combinations involving selective serotonin reuptake inhibitor (SSRI) antidepressants could help to identify areas for intensified medical education. METHODS: This was a retrospective, cross-sectional analysis of individual dispensing data regarding all individuals > or =15 years old in Sweden. The study analysed the prescribing and dispensing of CYP2D6 drugs (metoprolol, donepezil, galantamine, codeine, tamoxifen) together with CYP2D6-blocking SSRIs (paroxetine/fluoxetine) or SSRIs without significant CYP2D6 inhibition (citalopram/escitalopram/sertraline), and the related prescribing of CYP2D6-independent comparator drugs (atenolol, rivastigmine, propoxyphene, anastrozole). Odds were calculated between each CYP2D6 drug and the corresponding comparator drug in patients on fluoxetine/paroxetine and citalopram/escitalopram/sertraline, respectively. The odds ratio (OR) was calculated by dividing the obtained odds in patients on fluoxetine/paroxetine by the corresponding odds in patients on citalopram/escitalopram/sertraline. RESULTS: Compared with patients that were dispensed citalopram/escitalopram/sertraline, patients dispensed fluoxetine/paroxetine had lower prescribing rates of metoprolol (adjusted OR 0.80; 95% confidence interval 0.76, 0.85), donepezil (0.65; 0.49, 0.86) and galantamine (0.58; 0.41, 0.81). In contrast, the use of prodrugs codeine (compared woth propoxyphene) or tamoxifen (compared with anastrozole) was similar among patients on fluoxetine/paroxetine and citalopram/escitalopram/sertraline (adjusted OR 1.03; 0.94, 1.12 and 1.29; 0.96, 1.73, respectively). CONCLUSIONS: Clinically important DDIs that are associated with impaired bioactivation of prodrugs might be more easily neglected in clinical practice compared with DDIs that cause drug accumulation and symptomatic adverse drug reactions.

Impact of multiple inhibitors or substrates of cytochrome P450 2D6 on plasma risperidone levels in patients on polypharmacy.

Studies that focus on multidrug interactions in natural settings are sparse. In this investigation, data from therapeutic drug monitoring (TDM) were used to study the impact of multiple cytochrome P450 enzyme (CYP) 2D6 substrates and inhibitors on plasma risperidone levels. CYP2D6 catalyzes the conversion of risperidone to the active metabolite 9-OH-risperidone. The question whether CYP2D6 activity is important for the level of the "active moiety" (ie, the sum of risperidone and 9-OH-risperidone) is controversial. Concentration-to-dose (C:D) ratios of risperidone and 9-OH-risperidone in 218 patients were associated with the number of concomitantly used substrates or inhibitors of CYP2D6. The C:D ratios of risperidone in patients with 0, 1, and >1 numbers of CYP2D6 inhibitors were 2.6, 8.5, and 17 nmol L mg, respectively. Differences between the groups were highly significant (P < 0.001). All patients with >1 CYP2D6 inhibitors were administered at least 1 potent CYP2D6 inhibitor, that is fluoxetine, paroxetine, thioridazine, and/or levomepromazine. The C:D ratios of the active moiety (risperidone + 9-OH-risperidone) in patients with 0, 1, and >1 numbers of concomitant CYP2D6 inhibitors were 17, 24, and 30 nmol L mg, respectively (P = 0.001), which was explained by higher levels of risperidone without any change in the levels of 9-OH-risperidone. Concomitant use of 1 or several drugs recognized as substrates for CYP2D6, without any proven inhibitory effect, had no apparent influence on the levels of risperidone or 9-OH-risperidone, suggesting that the risk of drug-drug interactions between different substrates of CYP2D6 is low when used in therapeutic doses. In conclusion, the results suggest that an increase in the number of concomitant inhibitors may be associated with a lower CYP2D6 activity, although the type of inhibitor is probably more important. Drug-dependent inhibition of CYP2D6 increases the active moiety of risperidone. An indication for risperidone TDM should therefore include concomitant medication with established CYP inhibitors.

A clinical evaluation of the Janus Web Application, a software screening tool for drug-drug interactions.

PURPOSE: To evaluate the clinical relevance of the Janus Web Application (JWA) in screening for potential drug-drug interactions (DDIs). METHODS: One hundred and fifty patients taking two drugs or more were studied. Potential DDIs were identified by the JWA. Interviewing the patient and looking into his/her medical records provided complementing information. A clinical pharmacologist judged which potential DDIs were clinically relevant. Potentially relevant DDIs identified by the JWA were then correlated with clinically relevant DDIs. RESULTS: A total of 150 significant potential DDIs were found. Sixteen percent (24/150) were judged to be clinically relevant. CONCLUSIONS: A very small proportion of DDIs was considered clinically relevant in the specific clinical context. To optimise the software's user-friendliness, the following points need to be considered: the possibility of eliminating trivial potential DDIs, individualising drug alerts, and providing written information, accessible via a hyperlink.

Adherence to drug treatment in association with how the patient perceives care and information on drugs.

AIM: This study was to explore concordance with drugs prescribed and the patient's self-reported drug consumption, in relation to the older patient's perceived care and information given. BACKGROUND: Lack of adherence to prescriptions may lead to therapeutic failure with risks for relapse, unnecessary suffering and increased costs. DESIGN: A cross-sectional study with structured interviews of 200 patients who had recently been treated in a medical ward. METHODS: Patients' medical records were studied to obtain information on their current use of drugs. The data were analyzed by logistic regression, adherence being the dependent response variable. RESULTS: The mean age of the study group was 79 years. The number of drugs reported in the medical chart ranged from one to 17 with a mean of 6.9. The patients reported a drug consumption ranging from 0 to 24 with a mean of 7.3. When comparing the interview results with the information in the medical charts, 30% of the patients showed adherence. An association was found between adherence and self-reported health status. Patients in the non-adherent group reported a higher consumption of drugs. Patients felt that the opportunity to ask questions of either the responsible physicians or of the nurses was influential in decreasing risk. CONCLUSION: In this study, the patient's total drug consumption was considered. The study showed a large discrepancy between the drugs stated in the medical chart and patient's self-reported drug consumption. The study failed to show that perceived information or educational level had an impact on the results but implicate that the quality of information influences adherence. RELEVANCE TO CLINICAL PRACTICE: It is of importance to recognize patients at risk for non-adherence. Decreased health status and many drugs are the main risk factors for patients being non-adherent, and should be recognized as such.

Drug-related problems and pharmacotherapeutic advisory intervention at a medicine clinic.

OBJECTIVE: To describe the scenario and frequency of drug-related problems (DRPs) in in-patients and to determine whether a pharmacotherapeutic advisory intervention aiming at reducing DRPs could affect rates of re-hospitalisation and/or death within 6 months. METHODS: This prospective, randomised, controlled advisory intervention study was carried out at the Clinic of Internal Medicine at Stockholm Söder Hospital. Three hundred patients from four wards took part in the study. Patients taking two drugs or more were included. In the intervention arm, potential drug interactions were found using a computer system. Medical symptoms were estimated by a nurse together with the patient. Creatinine clearance was calculated. Thereafter a clinical pharmacologist scrutinised the patient s medical record for DRPs together with the nurse. DRPs judged to be clinically relevant resulted in written advice to the physician in charge of the patient. The control group received usual care. RESULTS: In the intervention group, a total of 299 DRPs were found among 71% of the patients (106/150). The number of written letters of advice to the physicians in charge was 106. Of these, 63% were accepted. After 6 months, the proportion of re-hospitalisations or death in the intervention group was 49% (73/150) compared to 46% (69/150) in the control group. The difference was not significant. CONCLUSIONS: DRPs were common. Potential drug interactions and adverse drug reactions dominated. Hospital-based medication review by a clinical pharmacologist was not associated with reduced rates of re-hospitalisation and/or death. The clinical relevancy of DRPs might be overestimated as a risk for re-hospitalisation or death. It is of great importance to clarify if and how drug-related problems can be prevented. In designing such studies, one should consider choosing inclusion criteria that accumulate risk.

Drug use and perceived health in recently hospitalized older people.

Older patients often have multiple diseases, resulting in treatment with many drugs. This may increase the risk for drug-related problems. This study aimed to analyse the congruence between the patient's self-reported drug use and the medical record, and the relationship to perceived health among older patients recently discharged from hospital. A total of 200 patients over 65 years of age who were admitted to a medical ward and were treated with at least one drug participated in an interview study one week after discharge from the hospital. The patients provided information on their current drug therapy. This information was compared to the prescriptions documented in the medical record. Thirty per cent of the study population reported a drug use which was in congruence with the medical record, 28% used less drugs than prescribed, and 42% more. Statistical analysis showed a high probability of non-congruence with prescriptions among patients who reported poor health.

Influence of cigarette smoking on melatonin levels in man.

OBJECTIVE: Polycyclic aromatic hydrocarbons in cigarette smoke induce cytochrome P450(CYP)1A2, which is involved in the hepatic metabolism of melatonin (MT). This suggests that habitual smokers may have low serum MT levels during smoking compared with a non-smoking period. We decided to investigate whether this suggestion is correct. METHODS: Eight habitual smokers were tested on two occasions. They had smoked prior to the first occasion but had not smoked for 7 days prior to the second. Each test was divided into two parts. The first part spanned the night between 2000 hours and 0800 hours. Venous blood samples were collected every second hour during this period for analysis of endogenous serum MT. The second part was performed the subsequent day. At 0930 hours, 25 mg MT was ingested orally, and blood samples for exogenous serum MT analysis were collected every hour between 1000 hours and 1600 hours. Endogenous and exogenous areas under the serum MT-time curve (MT-AUCs) were calculated. RESULTS: Endogenous serum MT-AUCs were similar during the two periods. Oral administration of MT induced supraphysiological levels of serum MT. Moreover, exogenous serum MT-AUCs were significantly smaller before than after smoking abstinence (7.34+/-1.85 versus 21.07+/-7.28 nmol/lxh; P<0.02; means+/-SEM). CONCLUSION: This investigation shows that exogenous, but not endogenous (at night), serum MT levels are influenced by cigarette smoking. When the MT levels are low, the influence of CYP1A2 levels appears to be less pronounced than when they are high, and the enzyme capacity hugely utilized. These findings implicate that interactions between exogenous MT, and substrates metabolized by CYP1A2, may differ in individuals before and after smoking abstinence.

[Combination of serotonergic agents resulted in severe adverse effects]. / Kombination av serotonerga läkemedel gav kraftiga biverkningar.

A 52 year old woman on buspirone was prescribed paroxetine for depressive symptoms. She also got papaverine. Within a month she experienced high fever, shivering, tremor, hyper-reflexia, tachycardia (120 bpm), and tracheal cramps, symptoms of the serotonin syndrome. Since both paroxetine and buspirone have serotonergic effects it is probable that the symptoms were caused by the drug combination. She also had ecchymoses on her thighs, probably due to serotonergic effects. The symptoms rapidly decreased after withdrawing paroxetine. Paroxetine, papaverine, and possibly also buspirone interact with cytochrome P450 CYP2D6. They can probably inhibit the metabolism of each other. We recommend observance of serotonergic syndrome symptoms and restricted combination of serotoninergic drugs.

Controlled withdrawal of selective serotonin reuptake inhibitor drugs in elderly patients in nursing homes with no indication of depression.

OBJECTIVE: The aim of the investigation was to study the effects of withdrawing selective serotonin reuptake inhibitor (SSRI) drugs in nursing home patients, who had no documented diagnosis or symptoms of depression. SETTING: The setting of the study was in 11 nursing homes in the county of Stockholm, Sweden. PARTICIPANTS: Participants were patients without dementia or history of depression who had received treatment with SSRI drugs for more than 6 months and who had no indications of anxiety disorder or major depression DESIGN: The included patients ( n=70) were randomized to either the intervention group (withdrawal of SSRI) or the control group (no change in treatment), 35 patients to each group. MAIN OUTCOME MEASURES: The patients were subjected to assessment using the following instruments: Montgomery-Asberg depression rating scale, global assessment for functioning, health index and a symptom assessment form. Assessment was made at the start of the study and at the 3-month and 6-month follow-ups. RESULTS: We found no significant difference between the intervention and control groups in any outcome measure. CONCLUSION: Treatment with SSRI drugs in patients without clinical major depression or anxiety disorder is often unjustified and should be discontinued.

Randomized controlled intervention in cardiovascular drug treatment in nursing homes.

OBJECTIVE: To study drug treatment of patients with cardiovascular diseases (heart failure, post-myocardial infarction, angina pectoris, hypertonia or cardiac valvular disease) in nursing homes and assess effect of medication advice. INTERVENTION: The patients were randomized to an intervention or control group. Medication reviews were made by one specialist in clinical pharmacology and one in cardiology. Symptoms related to heart failure or adverse reactions to cardiovascular drugs were recorded using a questionnaire. Quality of life and activities of daily living (ADL) were assessed and follow-ups performed after 2 weeks and 3 months. Outcome measures were changes of drug therapy and the global scores computed from symptoms scales. RESULTS: Eighty patients were randomized. They had a mean age of 87 years and their average number of drugs was 9.6. Changed drug therapy was suggested in 40 patients and the advice was followed by the responsible physicians in 19 patients. The physicians mostly followed advice for changed furosemide therapy but not for introducing an ACE-inhibitor, probably due to uncertain diagnosis and need for follow-up after initiation of such therapy. No significant changes from baseline to later follow-up were found in the mean total scores of any questionnaire. CONCLUSION: Intervention did not affect cardiovascular symptoms. Drug revisions should involve more than one class of drugs in order to be cost-effective.

[Metabolic interaction between psychopharmaceuticals. Probable cause of exacerbation of hypothyroidism according to a case report]. / Metabol interaktion mellan psykofarmaka. Trolig orsak till aggraverad hypotyreoidism enligt fallbeskrivning.

Little is known about how psychotropic drugs influence thyroid function in man, but it has been reported that sertraline decreases the efficacy of levothyroxine in patients treated for hypothyroidism. Most psychotropic drugs are metabolized in the liver by cytochrome P450. Sertraline is metabolized by cytochrome P450 CYP 2D6, CYP 3A4, and CYP 2C19. Mianserin is metabolized by CYP 2D6, and to some extent also by CYP 3A4. Since both substances, at least in part, are metabolized by the same liver enzymes, drug interactions can be expected. In this article we describe such a possible interaction between sertraline and mianserin in a patient treated with levothyroxine for hypothyroidism (Hashimoto's thyroiditis). She displayed both clinical symptoms and laboratory data typical of hypothyroidism when long-term antidepressive sertraline therapy (100 mg/day) was transiently supplemented with mianserin (30 mg/day). All symptoms and signs of hypothyroidism disappeared completely when the mianserin treatment was discontinued. These findings imply that unexpected drug effects may occur in depressed patients with primary hypothyroidism if they are treated with both sertraline and mianserin. In such situations thyroid function should be checked carefully.