Community Pharmacists' Contribution to Medication Reviews for Older Adults: A Systematic Review.

OBJECTIVES: To identify medication review interventions for older adults that involve community pharmacists and evidence of outcomes of these interventions. DESIGN: Systematic review. MEASUREMENTS: Cinahl, MEDLINE (Ovid), Scopus, International Pharmaceutical Abstracts, and Cochrane Library were searched for articles published between January 2000 and February 2016. Articles involving community pharmacists in medication reviews for outpatients aged 65 and older were included. Evidence of economic, clinical, and humanistic outcomes of interventions was summarized. RESULTS: Sixteen articles were found that described 12 medication review interventions, of which 6 were compliance and concordance reviews, 4 were clinical medication reviews, and 2 were prescription reviews according to a previously developed typology. Community pharmacists' contributions to reviewing medications varied from sending the dispensing history to other healthcare providers to comprehensive involvement in medication management. The most commonly assessed outcomes of the interventions were medication changes leading to reduction in actual or potential drug-related problems (n=12) and improved adherence (n=5). CONCLUSION: Regardless of community pharmacists' contributions to interventions, medication review interventions seem to reduce drug-related problems and increase medication adherence. More well-designed, rigorous studies with more sensitive and specific outcomes measures need to be conducted to assess the effect of community pharmacists' contributions to reviewing medications and improving the health of older adults.

Towards interprofessional networking in medication management of the aged: current challenges and potential solutions in Finland.

OBJECTIVE: The Finnish Medicines Agency (Fimea) initiated a programme in 2012 for enhancing interprofessional networking in the medication management of the aged. The goal is to develop national guidelines for interprofessional collaboration with respect to medication management. This study aims to explore the challenges and potential solutions experienced by existing health care teams in managing medication of the aged: (1) at the individual and team level (micro level), (2) organisational level (meso level) and (3) structural level (macro level). DESIGN: Group discussions (n = 10), pair (n = 3) and individual interviews (n = 2). Abductive content analysis combining data and theory was applied. Networking was used as a theoretical framework. SETTING: Meetings (n = 15) organised by Fimea in the formation phase of the interprofessional network in 2012. SUBJECTS: Health care professionals (n = 55). MAIN OUTCOME MEASURES: Challenges and solutions in the medication management of the aged at the micro, meso and macro levels. RESULTS: Challenges in interprofessional collaboration, problems with patient record systems, and the organisation of work and lack of resources were present at all the levels contributing to patients' medication problems. Participants suggested multiple potential solutions to improve interprofessional collaboration, sharing of tasks and responsibilities, better exploitation of pharmaceutical knowledge and developing tools as being the most commonly mentioned. CONCLUSIONS: Optimising medication use of the aged requires new systemic solutions within and between different system levels. The main challenges can be solved by clarifying responsibilities, enhancing communication and applying operational models that involve pharmacists and the use of information technology in medication management. KEY POINTS An interprofessional team approach has been suggested as a solution to promote rational medicine use among the aged. Fragmented health care system and lack of coordinated patient care are reasons for medication related problems of the aged. Challenges in the implementation of interprofessional collaboration in medication management appear in legislation, information systems, operational models and individuals' attitudes. Optimising medications requires better interprofessional networking and new systemic solutions within and between macro, meso and micro levels.

Automated dose dispensing service for primary healthcare patients: a systematic review.

BACKGROUND: An automated dose dispensing (ADD) service has been implemented in primary healthcare in some European countries. In this service, regularly used medicines are machine-packed into unit-dose bags for each time of administration. The aim of this study is to review the evidence for ADD's influence on the appropriateness of medication use, medication safety, and costs in primary healthcare. METHODS: A literature search was performed in April 2012 in the most relevant databases (n = 10), including the Medline, Embase, and Cochrane Library. The reference lists of the studies selected were manually searched. A study was included in the review if the study was conducted in primary healthcare or nursing home settings and medicines were dispensed in unit-dose bags. RESULTS: Out of 328 abstracts, seven studies met the inclusion and reporting quality criteria, but none applied a randomized controlled study design. Of the four controlled studies, one was a national register-based study. It showed that the patient group in the ADD scheme more often used three or more psychotropic drugs and anticholinergics than patients using the standard dispensing procedure, while women in the ADD group used less long-acting benzodiazepines and both genders had fewer drug-drug interactions. In another, regional controlled study, the ADD group consisted of patients with higher risk of inappropriate drug use, according to all indicators applied. The third controlled study indicated that ADD user drug treatments were more likely to remain unchanged than in patients using a standard dispensing procedure. A controlled study from Norway showed that ADD reduced discrepancies in the documentation of patient medication records. Costs were not investigated in any of the studies. CONCLUSIONS: A very limited number of controlled studies have explored ADD in primary healthcare. Consequently, the evidence for ADD's influence on appropriateness and safety of medication use is limited and lacking in information on costs. The findings of this review suggest that patients using the ADD have more inappropriate drugs in their regimens, and that ADD may improve medication safety in terms of reducing the discrepancies in medication records. Further evidence is needed to draw sound conclusions on ADD's outcomes.

Synthesis, in vitro and in vivo characterization of novel ethyl dioxy phosphate prodrug of propofol.

A novel ethyl dioxy phosphate prodrug of propofol (3) was synthesized and characterized in vitro and in vivo as safer alternative for phosphonooxymethyl prodrugs. The synthesis of 3 was achieved via vinyl and 1-chloroethyl ether intermediates, followed by addition of phosphate group. Aqueous solubility and chemical stability of 3 was determined in buffer solutions and the bioconversion of 3 to propofol was determined in vitro and in vivo. The results show that 3 greatly enhanced the aqueous solubility of propofol (solubility over 10 mg/mL) and the stability in buffer solution (t1/2=5.2+/-0.2 days at pH 7.4, r.t.) was sufficient for i.v. administration. The enzymatic hydrolysis of 3 to propofol was extremely rapid in vitro (t1/2=21+/-3s) and 3 was readily converted to propofol in vivo in rats. During bioconversion, 3 releases acetaldehyde, a less toxic compound than the formaldehyde released from the phosphonooxymethyl prodrug of propofol (Aquavan), currently undergoing clinical trials. The maximum plasma concentration of propofol, 3.0+/-0.2 microg/mL, was reached within 2.1+/-0.8 min after the i.v. administration of 3. The present study indicates that ethyl dioxy phosphate represents a potentially useful water-soluble prodrug structure suitable for i.v. administration.

In vivo studies on the antileishmanial activity of buparvaquone and its prodrugs.

OBJECTIVES: The efficacy of different formulations of the naphthoquinone buparvaquone and two phosphate prodrugs in in vivo models of both visceral and cutaneous leishmaniasis is described. METHODS: Several topical formulations of buparvaquone containing acceptable excipients were tested in vivo against Leishmania major cutaneous lesions in BALB/c mice. In vivo studies against Leishmania donovani investigated whether the prodrugs had improved efficacy when compared with buparvaquone. RESULTS: Both a hydrous gel and water-in-oil emulsion of buparvaquone significantly reduced cutaneous parasite burden (P < 0.05, 22 days post-infection) and lesion size, compared with the untreated control (P < 0.0001, 16 days post-infection). The prodrug 3-phosphonooxymethyl-buparvaquone was formulated into an anhydrous gel and this also significantly reduced parasite burden and lesion size (P < 0.0001, 16 days post-infection). Histology confirmed this efficacy. In the visceral model, both prodrugs were significantly more effective at reducing liver parasite burden than the parent drug, buparvaquone. Buparvaquone-3-phosphate was shown to be the most effective antileishmanial (P = 0.0003, 50 mg buparvaquone molar equivalent/kg/day five times), reducing the liver parasite burden by approximately 34% when compared with the untreated control. CONCLUSIONS: The introduction of a topical formulation, such as buparvaquone (or its prodrug), would be a significant advance for the treatment of simple cutaneous lesions. In particular, the avoidance of the parenteral antimonials would greatly increase patient compliance and reduce treatment costs.

Topical buparvaquone formulations for the treatment of cutaneous leishmaniasis.

As the part of a study to develop buparvaquone (BPQ) formulations for the treatment of cutaneous leishmaniasis, the topical delivery of BPQ and one of its prodrugs from a range of formulations was evaluated. In previous studies, BPQ and its prodrugs were shown to be potent antileishmanials in-vitro, with ED50 values in the nanomolar range. 3-Phosphono-oxymethyl-buparvaquone (3-POM-BPQ) was the most potent antileishmanial and was chosen, together with the parent drug, for further investigation. The ability of the parent and prodrug formulations to cross human and murine skin was tested in-vitro using the Franz diffusion cells. Formulations intended for topical application containing either BPQ or 3-POM-BPQ were developed using excipients that were either acceptable for topical use (GRAS or FDA inactive ingredients) or currently going through the regulatory process. BPQ was shown to penetrate both human epidermal membranes and full thickness BALB/c skin from a range of formulations (gels, emulsions). Similarly, 3-POM-BPQ penetrated full-thickness BALB/c skin from several gel formulations. In-vitro binding studies showed that BPQ bound melanin in a dose-dependent manner and preferably bound to delipidized skin over untreated BALB/c skin (on a weight to weight basis). The results confirm that BPQ and its prodrug 3-POM-BPQ can penetrate the skin from several formulations, making them potentially interesting candidates for further investigation of topical formulations using in-vivo models of cutaneous leishmaniasis.

Fadolmidine-induced ocular hypotension in normotensive rabbits.

Fadolmidine, a novel selective alpha2-adrenoceptor agonist, was evaluated for its efficacy to lower intraocular pressure in normotensive rabbits (n=5-6). The dose-response profile between 0.004 microg and 12.5 microg of fadolmidine was determined. The effect of pH on the partition of fadolmidine was studied in order to select an optimal pH for topical fadolmidine administration. After topical administration, fadolmidine significantly lowered the intraocular pressure in normotensive rabbits. The onset of action was immediate, with no initial increase in intraocular pressure. A significant decrease in intraocular pressure was already observed at 1 h after dosing. The maximum decrease in intraocular pressure was observed after a 2.5 microg dose of fadolmidine in both eyes at 2 h after dosing. The mean maximum decrease in the treated and untreated eye was 6.4 mmHg and 3.9 mmHg, respectively. In conclusion, fadolmidine is a potent intraocular pressure lowering agent. In addition, fadolmidine does not cause a significant initial increase in intraocular pressure. Because of the strong dependence of the distribution coefficient on pH, the pH of the administered solution is important, with physiological pH being optimal in this respect.

Design, synthesis and in vitro evaluation of novel water-soluble prodrugs of buparvaquone.

Novel water-soluble phosphate prodrugs (2b-5b) of buparvaquone-oxime (1a) and buparvaquone-O-methyloxime (1b) were synthesized and evaluated in vitro as potential oral prodrugs against leishmaniasis. Buparvaquone-oxime (1a), and most probably also buparvaquone-O-methyloxime (1b), released the parent buparvaquone via a cytochrome P450-catalysed reaction. The prodrugs 2b-5b showed significantly higher aqueous solubilities (>4 mg/ml) than buparvaquone (< or = 0.03 microg/ml) over a pH range of 3.0-7.4. The prodrugs 2b, 3b and 5b rapidly released (t1/2 = 7 min) the corresponding oximes of buparvaquone (1a and 1b), and prodrug 4b at a moderate rate (t1/2 = 22.5 min) in alkaline phosphatase solution in vitro. Prodrug 3b was the most chemically stable in the aqueous solutions over a pH range of 3.0-7.4 (t1/2 > 8 days). Although buparvaquone-oxime (1a) has been shown to undergo a cytochrome P450-catalysed oxidation in liver microsomes to the parent buparvaquone and behave as a novel bioreversible prodrug, its usefulness is limited in oral drug delivery due to its poor aqueous solubility, like buparvaquone itself. Further phosphorylation of an oxime form of buparvaquone significantly increased water solubility, and this novel approach is therefore useful to improve physicochemical properties of drugs containing a ketone functional group.

Synthesis and antileishmanial activity of novel buparvaquone oxime derivatives.

Novel oxime derivatives (2, 3 and 5) of buparvaquone (1) and O-methyl-buparvaquone (4) were synthesized and their in vitro activities against Leishmania donovani, the causative agent of visceral leishmaniasis (VL), were determined. Buparvaquone-oxime (2) was also studied as a bioreversible prodrug structure of buparvaquone (1). Buparvaquone-oxime (2) released buparvaquone (1) in vitro when it was incubated with induced rat liver microsomes, which suggests that the oxime-structure is a useful prodrug template for developing novel prodrugs of buparvaquone and other hydroxynaphthoquinones. Moreover, the formation of NO(2)(-) , formed via oxidation of NO, was confirmed during the bioconversion. The release of NO from buparvaquone-oxime (2) may provide an additional therapeutic effect in the treatment of leishmaniasis. Buparvaquone-oxime (2) and buparvaquone-O-methyloxime (3) demonstrated moderate activity against amastigotes of the Leishmania species that causes VL. However, the studied oximes (2, 3) most probably did not release buparvaquone (1) and NO during the present in vitro experiment. Further in vivo studies are needed to verify the biological activity of buparvaquone-oximes in the treatment of leishmaniasis.

Synthesis, in vitro evaluation, and antileishmanial activity of water-soluble prodrugs of buparvaquone.

Water-soluble phosphate prodrugs of buparvaquone (1), containing a hydroxynaphthoquinone structure, were synthesized and evaluated in vitro for improved topical and oral drug delivery against cutaneous and visceral leishmaniasis. The successful prodrug synthesis involved a strong base; e.g., sodium hydride. Buparvaquone-3-phosphate (4a) and 3-phosphonooxymethyl-buparvaquone (4b) prodrugs possessed significantly higher aqueous solubilities (>3.5 mg/mL) than the parent drug (