Drug-drug interactions with direct oral anticoagulants: development of a consensus list for ambulatory care.

BACKGROUND: Direct oral anticoagulants (DOACs) can be involved in clinical relevant drug-drug interactions (DDIs) which may compromise safe and effective use. However, assessing the clinical relevance of DDIs with DOACs and managing these interactions optimally, can be challenging in clinical practice. AIM: To develop a practice-oriented list of potentially clinically relevant DDIs with DOACs with corresponding management plans for which it is important to screen in ambulatory care. METHOD: The RAND/UCLA appropriateness method was used to develop the DOACs DDI list. In a first step a preliminary list was compiled of potentially clinically relevant DDIs per DOAC (apixaban, dabigatran, edoxaban, rivaroxaban) using five reference sources. Subsequently, a two-step modified Delphi process involving a multidisciplinary panel (n = 10) including both pharmacists and physicians with expertise in all decision-making disciplines involved in care for patients using DOACs and with diversity of practice setting, was used to reach expert agreement on a final list of DDIs with corresponding management plans. RESULTS: After a two-step consensus round, 71 DDIs for 20 different interacting drugs were included: five pharmacodynamic, nine pharmacokinetic inhibitor and six pharmacokinetic inducer interacting drugs. Considerations raised and discussed by the panellists were related to (1) the necessity of the interacting drug, (2) the manageability of the DDI (whether there are any alternatives), (3) the (clinical) evidence-base for the DDI and (4) the (potential) consequences of the DDI. CONCLUSION: We developed a consensus list with specific and straightforward management plans on potentially clinically relevant DDIs with DOACs, for use in ambulatory care.

Prevalence of alcohol-drug interactions in community-dwelling older patients with polypharmacy.

OBJECTIVES: Alcohol and medication use are increasingly prevalent in the older population. Concurrent use of alcohol and alcohol-interactive (AI) medication can lead to significant adverse consequences. METHODS: Three reference works were used to create an explicit list of drug substances for which information about the interaction with alcohol was available in at least one of them. Additional information was extracted from the Summary of Product Characteristics (SPC). The first aim was to generate a list of 256 substances with standardized advice regarding the concurrent use of each drug with alcohol. The second aim was to observe the prevalence of potential drug-alcohol-interactions. The list was applied to a database containing information about alcohol and medication use of 1,016 community-dwelling older patients (≥70 years) with polypharmacy. RESULTS: About half of the sample population reported to consume alcohol at least once a week. Around 22% were classified as frequent drinkers (5-7 days/week) and 11% as heavier drinkers (>7 units/week). Ninety-three percent alcohol consumers in our sample took at least one chronic drug that potentially interacts with alcohol and 42% used at least one chronic drug for which alcohol use is considered contraindicated. CONCLUSIONS: We developed an explicit list of potentially drug-alcohol-interactions in older adults, with standardized handling advice. We observed that prevalence of potential drug-alcohol-interactions is substantial in community-dwelling older patients with polypharmacy.

Prevalence of alcohol-drug interactions in community-dwelling older patients with polypharmacy.

OBJECTIVES: Alcohol and medication use are increasingly prevalent in the older population. Concurrent use of alcohol and alcohol-interactive (AI) medication can lead to significant adverse consequences. METHODS: Three reference works were used to create an explicit list of drug substances for which information about the interaction with alcohol was available in at least one of them. Additional information was extracted from the Summary of Product Characteristics (SPC). The first aim was to generate a list of 256 substances with standardized advice regarding the concurrent use of each drug with alcohol. The second aim was to observe the prevalence of potential drug-alcohol-interactions. The list was applied to a database containing information about alcohol and medication use of 1,016 community-dwelling older patients (≥70 years) with polypharmacy. RESULTS: About half of the sample population reported to consume alcohol at least once a week. Around 22% were classified as frequent drinkers (5-7 days/week) and 11% as heavier drinkers (>7 units/week). Ninety-three percent alcohol consumers in our sample took at least one chronic drug that potentially interacts with alcohol and 42% used at least one chronic drug for which alcohol use is considered contraindicated. CONCLUSIONS: We developed an explicit list of potentially drug-alcohol-interactions in older adults, with standardized handling advice. We observed that prevalence of potential drug-alcohol-interactions is substantial in community-dwelling older patients with polypharmacy.

Ghent Older People's Prescriptions Community Pharmacy Screening (GheOP3S)-Tool Version 2: Update of a Tool to Detect Drug-Related Problems in Older People in Primary Care.

BACKGROUND: The Ghent Older People's Prescriptions community Pharmacy Screening (GheOP3S)-tool was developed in 2016 as a screening tool to detect drug-related problems (DRPs) and to help in performing medication reviews in older people (≥ 65 years). OBJECTIVE: This study aimed to revise and update the GheOP3S-tool. METHODS: Users' comments were collected to improve the usability and appropriateness of the original GheOP3S-tool, followed by a two-round modified Delphi process according to the RAND/UCLA appropriateness method. This included a literature review, a round zero meeting, a first written round (with 15 international and multidisciplinary experts) and a second face-to-face round (with 11 experts) to change, delete or add GheOP3S-criteria. An additional third round with 14 community pharmacists was organised to preserve criteria applicable in the current community pharmacy practice. RESULTS: The updated GheOP3S-tool consists of five lists of DRPs and a new addendum containing medications that should be avoided or used with caution in older people with reduced renal function. During the first two rounds, related criteria were grouped, 14 criteria were added and 17 criteria were deleted from the original tool. All criteria were deemed applicable in round 3. This led to a final tool (version 2) with 64 GheOP3S-criteria. CONCLUSION: GheOP3S-criteria were revised and updated according to experts' agreement on their clinical relevance and recent scientific evidence. Future studies should investigate the impact of pharmacist-led medication reviews with GheOP3S-tool version 2 on clinical, humanistic and economic outcomes in primary care.

COPD management in primary care: an observational, community pharmacy-based study.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a prevalent disease that is frequently treated in primary care. However, data regarding the primary care management of COPD are scarce. Such observational data are necessary to detect problem areas and to develop targeted interventions for improvement of COPD management. OBJECTIVE: To provide a detailed description of (1) drug therapy, (2) drug adherence, (3) inhalation technique, and (4) health status of patients with COPD recruited via community pharmacies. METHODS: A cross-sectional, observational study was conducted in 93 pharmacies in Belgium. Participants (N = 555) completed a questionnaire collecting information on personal characteristics, smoking history, influenza vaccination, COPD medication, and adverse effects. Adherence to COPD maintenance medication was analyzed 1 year retrospectively through prescription refill rates. Inhalation technique was scored using a checklist. Health status was evaluated with the St. George's Respiratory Questionnaire, the Clinical COPD Questionnaire, and the Modified Medical Research Council dyspnea scale. RESULTS: The mean age of the patients was 68.6 years; 73.7% were men and 37.2% were current smokers. The influenza vaccination status was significantly lower in patients aged less than 65 years (65.7%) than in patients aged 65 years or more (86.2%) (p < 0.001). Fixed combinations of inhaled corticosteroids and long-acting beta(2)-agonists were the most frequently used COPD medications (75.4%). About 48% of patients were underadherent (<80% adherence), 47% were adherent (80-120% adherence) and 5% were overadherent (>120% adherence). Predictors for underadherence were age and number of drugs. Twenty-one percent of patients made major inhalation technique errors with rescue medication; these were all errors in handling pressurized metered-dose inhalers (pMDIs). CONCLUSIONS: This observational study on COPD management in primary care highlights 4 main aspects that could be improved: (1) drug adherence, (2) inhalation technique with pMDIs, (3) influenza vaccination in COPD patients younger than 65 years, and (4) smoking cessation.

Self-medication of upper gastrointestinal symptoms: a community pharmacy study.

BACKGROUND: Upper gastrointestinal (GI) symptoms are a common reason for self-treatment with over-the-counter (OTC) medication. However, data are scarce on the typology of GI complaints for which individuals seek self-medication and, more importantly, on the prevalence of alarm symptoms in this population. OBJECTIVE: To investigate: (1) the nature of GI symptoms that people intend to self-medicate, (2) prevalence of alarm symptoms, (3) adherence to referral advice given by the pharmacist, and (4) self-reported efficacy and frequency of use of OTC medication for minor complaints. METHODS: This descriptive study was performed in 63 community pharmacies. Participants (N = 592, aged 18-82 y) completed a questionnaire to assess symptom characteristics and previous medical consulting. Based on this information, the pharmacist referred subjects to a physician or advised self-treatment. Four weeks later, participants were presented a follow-up questionnaire evaluating their adherence to referral advice or efficacy of self-treatment. RESULTS: The most frequently reported GI symptoms were burning retrosternal discomfort (49.2%), acid regurgitation (53.2%), and bothersome postprandial fullness (51.2%). At least one alarm symptom was present in 22.4% of the individuals, with difficulty in swallowing being the most prevalent (15.4%). Although 21% of the customers were referred, only 51.7% of these contacted a physician. Almost all (95.1%) of the remaining customers who were advised self-treatment reported symptom relief with the OTC drug obtained. CONCLUSIONS: Mild GI symptoms will mostly resolve with self-treatment. Yet, the value of pharmacist counseling on OTC treatment should be recognized, as community pharmacists can play an important role in distinguishing symptoms that warrant further medical examination.

Home medication cabinets and self-medication: a source of potential health threats?

BACKGROUND: Data regarding the contents of home medication cabinets (HMCs), the management of leftover medications, and the inclination of patients toward self-initiated treatment using nonprescription drugs are scarce. OBJECTIVE: To evaluate the nature and safety of medication storage and intended self-medication in a general population. METHODS: A cross-sectional study was conducted in 72 Belgian community pharmacies. Pharmacy customers (N = 288, aged 18-80 y) were visited in their homes by pharmacy students. The HMCs were inventoried and the participants were interviewed. RESULTS: A mean of 31 +/- 17 (range 6-136) drug packages were identified per household; in one-third of the cases, the packages were not stored safely. Prescription drugs accounted for 34% of the total. The most frequently encountered categories of registered medicines were nonopioid analgesics (7.2%), nonsteroidal antiinflammatory drugs (NSAIDs) (6.9%), nasal decongestants (3.5%) and antinausea agents (3.2%). Despite their high prevalence, NSAIDs and non-opioid analgesics did not predominate among the most frequently used drugs, whereas food supplements were used daily in 23.3% of households. Twenty-one percent of the drugs were expired, 9% were not stored in the original container, and the package insert was missing for 18%. Self-initiated treatment was considered for 56% of all drugs (over-the-counter drugs, 74%; prescription drugs, 21%). Indication, dosage, or treatment duration was misjudged by only 5.2% of the participants, but consulting the package insert was allowed. The tendency toward self-treatment decreased with age and with increasing number of medications taken daily (p = 0.002). CONCLUSIONS: We found large amounts of drugs per household, with a high prevalence of analgesics and NSAIDs. Self-medication, although generally acceptable in terms of indication and dosage, was commonly practiced, also with prescription drugs. Taking into account that younger people showed a significantly higher intention of self-medication, a sustained awareness of the risks of self-medication is warranted for the future.

Antiviral properties of new arylsulfone derivatives with activity against human betaherpesviruses.

Based on our previous experience with arylsulfone derivatives displaying antiherpetic activity, we synthesized several analogues in which the sulfonyl group is part of a bicyclic structure. The benzene-fused derivative 2H-3-(4-chlorophenyl)-3,4-dihydro-1,4-benzo-thiazine-2-carbonitrile 1,1-dioxide and its thiophene-fused analogue were shown to have favorable activity and selectivity against the betaherpesviruses human cytomegalovirus (HCMV) and human herpesvirus 6 (HHV-6) and 7 (HHV-7). The benzene-fused derivative retained its anti-HCMV activity when evaluated against virus strains resistant to foscarnet, ganciclovir, and/or cidofovir. The compound conferred >or=95% inhibition of viral DNA synthesis in HHV-6-infected cells. RT-PCR analysis of immediate-early, early and late gene products revealed that this arylsulfone compound acts at a step preceding late gene expression, and coinciding with the inhibition exerted by foscarnet. No inhibitory effect was seen in an enzyme assay for DNA elongation catalyzed by the HCMV or HHV-6 DNA polymerase catalytic subunit. The arylsulfone derivatives had no effect on the functional interaction between the catalytic subunit of HCMV DNA polymerase and its accessory protein, nor did they disrupt the physical interaction between the two proteins. We conclude that these arylsulfone derivatives represent new betaherpesvirus inhibitors with a novel mode of action that results in indirect inhibition of viral DNA synthesis.

Modulation of the cytokine network in human adult astrocytes by human herpesvirus-6A.

Human herpesvirus-6A (HHV-6A) is a common pathogen whose role in CNS disorders including multiple sclerosis remains controversial. To understand how HHV-6A could influence inflammatory pathways in the CNS, we infected cultured human adult astrocytes and examined the expression of 268 cytokines, chemokines, growth factors and their receptors by gene profiling. HHV-6 infection alone had little effect on the astrocyte gene profile but strongly altered the astrocyte response to proinflammatory cytokines. Under those conditions astrocytes express higher levels of anti-inflammatory mediators including IL-10 and IL-11, chemotactic factors, growth factors and factors controlling type I interferon production. Our data suggest that HHV-6 itself does not evoke a pro-inflammatory response in astrocytes but rather triggers immune modulatory factors in the face of inflammation.

Characterisation of patient encounters in community pharmacies (with special focus on self-medication).

OBJECTIVES: To characterise patient encounters during routine drug dispensing in community pharmacies. METHODS: Cross-sectional survey in community pharmacies (Belgium). KEY FINDINGS: Fifty-four per cent of all encounters (N = 1650) concerned patients carrying a prescription, of which 39% were prescriptions for new medication and 61% were repeat prescriptions. In 62% of all encounters, patients asked for non-prescribed medication. Almost one-third of self-medication requests related to special patient populations (mainly children and elderly). CONCLUSIONS : Many encounters related to self-medication, and a substantial number of these self-medication requests concerned vulnerable patient populations.

Human herpesvirus 6 infection arrests cord blood mononuclear cells in G(2) phase of the cell cycle.

We here report that after infection with human herpesvirus 6A, human cord blood mononuclear cells accumulate in G(2)/M phase of the cell cycle. Experiments with foscarnet or ultraviolet (UV)-irradiated virus stocks pointed at an (immediate-)early, newly formed viral protein to be responsible for the arrest. At the molecular level, p53, cyclin B(1), cyclin A and tyrosine(15)-phosphorylated cdk1 accumulated after HHV-6A infection, indicating an arrest in G(2). However, no change was observed in the levels of downstream effectors of p53 in establishing a G(2) arrest, i.e. p21 and 14-3-3sigma. We thus conclude that the HHV-6A-induced G(2) arrest occurs independently of p53 accumulation.

Potent, selective and cell-mediated inhibition of human herpesvirus 6 at an early stage of viral replication by the non-nucleoside compound CMV423.

CMV423 (2-chloro-3-pyridin-3-yl-5,6,7,8-tetrahydroindolizine-1-carboxamide) is a new antiviral agent with potent and selective in vitro activity against the beta-herpesvirus human cytomegalovirus (HCMV), but not against alpha- or gamma-herpesviruses. Here we report that its activity also extends to human herpesvirus 6 (HHV-6) and 7 (HHV-7). When compared in vitro to ganciclovir and foscarnet (the standard drugs recommended for treatment of HHV-6 infections), CMV423 showed a superior selectivity, due to its high activity (antiviral IC(50): 53nM) and low cytotoxicity (CC(50): 144microM), both in continuous cell lines and in CBLCs infected with HHV-6. From mechanistic experiments at the level of viral mRNA and protein expression, we learned that CMV423 targets an event following viral entry but preceding viral DNA replication. Its antiviral action was dependent on the cell line used, implying involvement of a cellular component. When compared to a panel of known protein kinase inhibitors, CMV423 was found to share anti-HHV-6 characteristics with herbimycin A, which affects tyrosine kinase activity through heat shock protein 90 (Hsp90) inhibition. We demonstrated that high concentrations of CMV423 have an inhibitory effect on the total cellular protein tyrosine kinase activity, and that CMV423 and herbimycin A, when combined, act synergistically against HHV-6. The activities of cyclin-dependent kinases, protein kinases A and C, and the HHV-6-encoded pU69 kinase were not affected. We, therefore, conclude that CMV423 exerts its activity against HHV-6 through inhibition of a cellular process that is critical at early stages of viral replication and that may affect protein tyrosine kinase activity.

Human herpesvirus 6 DNA polymerase: enzymatic parameters, sensitivity to ganciclovir and determination of the role of the A961V mutation in HHV-6 ganciclovir resistance.

Human herpesvirus 6 (HHV-6) is latent in the majority of the adult population. Due to its ability of causing opportunistic infections, alone or in concert with the other beta-herpesviruses human cytomegalovirus (HCMV) and HHV-7, its importance as a pathogen in immunocompromised patients has increasingly been recognized. We here report the characterization of the main antiviral target, the HHV-6 DNA polymerase, expressed in a eukaryotic in vitro transcription/translation assay. This technique represents a fast and straightforward approach for the study of existing and new inhibitors of HHV-6 DNA polymerase. The present study shows that ganciclovir is less active against HHV-6, as compared to its activity against HCMV, both in cell culture and at the enzymatic (i.e. DNA polymerase) level. Recently, a mutant HHV-6 strain carrying an amino acid substitution in the ganciclovir phosphorylating pU69 kinase has been isolated both from patients and in cell culture. The strain isolated in vitro, however, carried an additional mutation in the viral DNA polymerase. From our experiments presented here, we conclude that the pU69 M(318)V amino acid substitution rather than the A(961)V substitution in HHV-6 DNA polymerase, is responsible for the ganciclovir-resistant phenotype.

Medication use and disease management of type 2 diabetes in Belgium.

OBJECTIVE: The aim of this study was (International Diabetes Federation. Diabetes Atlas Second Edition Executive Summary. Brussels: International Diabetes Federation; 2003) to describe the current status of medication use and disease management of type 2 diabetic patients in Flanders (Belgium), (World Health Organization. Prevention of diabetes mellitus. Technical report series no. 844. Geneva: World Health Organization; 1994) to identify the aspects of type 2 diabetes care a community pharmacist could provide additional educational services for, and (American Diabetes Association. Diabetes Care 2006;29:S4-42) to propose these services as a pharmacist intervention. METHOD: We recruited 338 patients in 77 community pharmacies in Flanders (Belgium). Each patient completed a questionnaire collecting personal data, information on duration of diabetes, medication, diabetes symptoms and self-management. At inclusion, patients measured their fasting plasma glucose (FPG) on three consecutive days. Prescription drugs (antidiabetic and other) purchased by each patient during the 12 months prior to inclusion in the study were reviewed from anonymized computerized pharmacy records. MAIN OUTCOME MEASURES: Degree of self-management, glycaemic control and medication use. RESULTS: The mean FPG of the sample was 150.7+/-43.0 mg/dl. Controlled glycaemia (FPG between 90 and 130 mg/dl (5.0-7.2 mmol/l)) was achieved in only 34.9% of the patients. Mainstay of hypoglycemic treatment consisted of metformin monotherapy (29.6%) and metformin combined with sulfonylurea (29.0%). Regarding co-medication, 76.9% of the patients used antihypertensive drugs whereas only 33.1% and 39.9% were on aspirin and statin therapy, respectively. ADA recommendations for annual eye and foot examination were not followed in 38.8% (eye) and 39.2% (feet) of the patients. CONCLUSION: The current management of type 2 diabetic Flemish patients falls short of recommended treatment goals. Community pharmacists may play a role in enhancing the awareness of glycaemic control and in stimulating self-management in diabetic patients by motivating patients towards correct medication use, better medication adherence, healthy lifestyle and smoking cessation.

Update on human herpesvirus 6 biology, clinical features, and therapy.

Human herpesvirus 6 (HHV-6) is a betaherpesvirus that is closely related to human cytomegalovirus. It was discovered in 1986, and HHV-6 literature has expanded considerably in the past 10 years. We here present an up-to-date and complete overview of the recent developments concerning HHV-6 biological features, clinical associations, and therapeutic approaches. HHV-6 gene expression regulation and gene products have been systematically characterized, and the multiple interactions between HHV-6 and the host immune system have been explored. Moreover, the discovery of the cellular receptor for HHV-6, CD46, has shed a new light on HHV-6 cell tropism. Furthermore, the in vitro interactions between HHV-6 and other viruses, particularly human immunodeficiency virus, and their relevance for the in vivo situation are discussed, as well as the transactivating capacities of several HHV-6 proteins. The insight into the clinical spectrum of HHV-6 is still evolving and, apart from being recognized as a major pathogen in transplant recipients (as exemplified by the rising number of prospective clinical studies), its role in central nervous system disease has become increasingly apparent. Finally, we present an overview of therapeutic options for HHV-6 therapy (including modes of action and resistance mechanisms).

Role of the human herpesvirus 6 u69-encoded kinase in the phosphorylation of ganciclovir.

The human herpesvirus 6 (HHV-6) U69 gene product (pU69) is the presumed functional homolog of the human cytomegalovirus (HCMV) UL97-encoded kinase (pUL97), which converts ganciclovir to its monophosphate metabolite in HCMV-infected cells. It has been reported that insertion of U69 into baculovirus confers sensitivity to ganciclovir in insect cells (J Virol 73:3284-3291, 1999). Our metabolic studies in HHV-6-infected human T-lymphoblast cells indicated that the efficiency of ganciclovir phosphorylation induced by HHV-6 was relatively poor. Recombinant vaccinia viruses (rVVs), expressing high levels of pU69 from two HHV-6 strains (representing the A and B variant), were constructed and used to compare the ganciclovir-phosphorylating capacity of pU69 and pUL97 in human cells. Metabolic studies with [8-(3)H]ganciclovir showed that ganciclovir was phosphorylated in human cells infected with pU69-expressing rVVs, although the levels of phosphorylated ganciclovir metabolites were approximately 10-fold lower than those observed with pUL97. We also demonstrated that pU69, like pUL97, is expressed as a nuclear protein. Our results indicate that the limited phosphorylation of ganciclovir by pU69 may contribute to its modest antiviral activity against HHV-6 in certain cell systems.