Pharmaceutical care in community pharmacies: practice and research in Sweden.

OBJECTIVE: To describe the organization and delivery of community pharmacy and medical care, as well as pharmaceutical care practice and research, in Sweden. FINDINGS: The Swedish retail pharmacy system of 800 community pharmacies and nearly 80 hospital pharmacies is unique in that it is organized into one single, government-owned chain, known as Apoteket AB. The pharmacy staff consists of pharmacists, prescriptionists, and pharmacy technicians. Some activities related to pharmaceutical care have been directed toward specific patient groups during annual theme campaigns. In the past few years, there has been a growing emphasis on the identification, resolution, and documentation of drug-related problems (DRPs) in Swedish pharmacy practice. A classification system for documenting DRPs and pharmacy interventions was developed in 1995 and incorporated into the software of all community pharmacies in 2001. A national DRP database (SWE-DRP) was established in 2004 to collect and analyze DRPs and interventions on a nationwide basis. Recently, a new counseling technique composed of key questions to facilitate the detection of DRPs has been tested successfully. Patient medication profiles are kept in 160 pharmacies, and a new national register of drugs dispensed to patients became available in 2006. Most pharmaceutical care studies in Sweden have focused on DRPs and resulting pharmacy interventions. DISCUSSION: Swedish community pharmacy DRP work is in the international forefront but there is a potential for further developing cognitive services, given the beneficial organization of the country's pharmacies into one single pharmacy chain. The introduction of patient medication profiles has been both late and slow and has only had a marginal effect on pharmaceutical care practice so far. The universities do not appear to have any desire to influence the practice of pharmacy and could potentially take on a more active role in preparing pharmacy students for patient-oriented services. Current threats to pharmaceutical care practice and research include organizational changes, budget cuts, and reduced manpower of Apoteket AB. CONCLUSIONS: The identification, resolution, and documentation of DRPs are central to community pharmacy practice in Sweden, resulting in a number of research studies. A national DRP database, patient medication profiles, and a new national register of drugs dispensed to patients provide opportunities for growth in pharmaceutical care practice and research in the country.

Superlattice formation in the lithiated vanadium oxide phases Li(0.67)V(6)O(13) and LiV(6)O(13).

Two new lithiated phases of V(6)O(13) were formed by carefully tuning the temperature of electrochemical lithiation in a "coffee-bag" type Li-ion battery at 2.78 V versus Li/Li(+). These were studied by single-crystal X-ray diffraction. A phase with the composition Li(2/3)V(6)O(13) was obtained at 308 K with a unit cell three times the volume of the original V(6)O(13) cell. A single crystal discharged at ambient temperature was shown to be LiV(6)O(13) and twice the unit-cell volume of the original V(6)O(13) cell. On lithiation, the structures retain their basic V(6)O(13) structure of alternating single and double layers of VO(6) octahedra. The lithium ions occupy chemically equivalent sites, where they coordinate fivefold to O atoms, and associate with the single layers of VO(6) octahedra. The insertion of lithium causes a significant elongation of one of the V-O bonds in each structure, which expands from 1.65 to 1.89 A; this is due to the charge reduction of a specific V atom.

(Li0.91Mn0.09)Mn2O4.

Lithium manganese oxide crystals with composition (Li(0.91)Mn(0.09))Mn(2)O(4) were synthesized by a flux method. The crystals have a structure closely related to that of the cubic spinel LiMn(2)O(4), but 9% of the lithium ions in the tetrahedral 4a site are substituted by Mn(2+) ions. This substitution lowers the average Mn oxidation state below 3.5+, resulting in a Jahn-Teller distortion of the MnO(6) octahedron.

The identification of dilignols from dehydrogenation mixtures of coniferyl alcohol and apocynol [4-(1-Hydroxyethyl)-2-methoxyphenol] by LC-ES-MS/MS.

A LC-ES-MS/MS method for the identification of dilignols formed by the oxidative cross-coupling of coniferyl alcohol and apocynol has been developed. The identification is based on the generation of ammonium adduct ions [M + NH(4)](+) by electrospray ionization and thereafter the following fragmentation patterns for the selected precursor ions. Fragmentation of several arylglycerol-beta-aryl ether (beta-O-4) and phenyl coumarane (beta-5) model compounds were studied as a reference.

Two-dimensional TLC separation and mass spectrometric identification of anthraquinones isolated from the fungus Dermocybe sanguinea.

A new two-dimensional TLC technique was developed to separate substituted anthraquinones on silica plates using n-pentanol-pyridine-methanol (6:4:3, v/v/v) and toluene-ethyl acetate-ethanol-formic acid (10:8:1:2, v/v/v/v) as eluents. The good separation power of the new technique was demonstrated by applying it to the analysis of complex anthraquinone mixtures isolated from the Scandinavian Dermocybe sanguinea. Emodin, physcion, endocrocin, dermolutein, dermorubin, 5-chlorodermorubin, emodin-1-beta-D-glucopyranoside, dermocybin-1-beta-D-glucopyranoside and dermocybin, and five new, earlier in D. sanguinea unidentified compounds, 7-chloroemodin, 5,7-dichloroemodin, 5,7-dichloroendocrocin, 4-hydroxyaustrocorticone and austrocorticone, were separated and identified on the basis of Rf-values, UV/Vis spectra and mass spectra.

Brain monoamine output alterations after a single venlafaxine challenge in experimental hepatic encephalopathy.

Venlafaxine (VEN) pharmacokinetics and effects on the brain monoamine output were investigated in the context of experimental hepatic encephalopathy (HE). Systemic VEN (10 mg/kg; subcutaneous) was administered to chronic portacaval shunted (PCS) and sham-operated rats. Their neocortical extracellular levels of 5-HT, 5-HIAA, NA, and DA were then assessed using microdialysis. Serum, brain extracellular, and brain tissue levels of racemic VEN and its main metabolites were also investigated. In a dose-equipotent manner, the VEN challenge increased the 5-HT levels in PCS rats compared with VEN-treated controls, whereas the 5-HIAA levels decreased similarly with time after the challenge in PCS and controls. Brain extracellular NA levels increased similarly in PCS and controls after VEN, but DA increased predominantly in controls. A similar single dose challenge resulted in clearly higher VEN levels in serum, brain extracellular fluid, and brain tissue in the PCS rats compared with controls. However, the VEN brain tissue/serum ratios were in the same order of magnitude for the two groups. Of the main VEN metabolites, only O-desmethylvenlafaxine (ODV) could be detected in pharmacologically significant amounts. The ODV concentration was also elevated in all three investigated biomatrices of the PCS rats versus control rats. The authors concluded that a typical novel brain monoamine-acting drug, such as VEN, exhibits both pharmacokinetic and pharmacodynamic alterations in experimental HE. Accordingly, the results of this study suggest that this frequently used type of drug should be further studied for its potential combined kinetic/dynamic actions in compromised patients with liver impairment.

Intravesical oxybutynin for neurogenic bladder dysfunction: less systemic side effects due to reduced first pass metabolism.

PURPOSE: To unravel why intravesical oxybutynin is more effective and causes significantly fewer systemic side effects than oral oxybutynin in the treatment of neurogenic bladder dysfunction, we tested the hypothesis that the absorption and metabolism of oxybutynin are changed after intravesical instillation. MATERIALS AND METHODS: A high-performance liquid chromatography assay was developed for both oxybutynin and its active metabolite, N-desethyl-oxybutynin. Plasma concentrations were quantified after intravesical (n = 11) and oral (n = 5) administration of oxybutynin in children under steady-state conditions. Pharmacokinetic parameters were calculated. RESULTS: Oral administration of oxybutynin (0.2 mg./kg./dose) resulted in peak plasma concentrations for N-desethyl-oxybutynin which were 7.4 +/- 1.3 times higher than corresponding values for oxybutynin (n = 5). Also the AUC (area under the plasma concentration time curve) values were higher for N-desethyl-oxybutynin compared with those of oxybutynin, the ratio being 10.8 +/- 1.0 (n = 5). Intravesical instillation (0.2 mg./kg./dose), on the other hand, resulted in reduced metabolite generation and peak plasma concentrations for N-desethyl-oxybutynin which were in the same range as those for oxybutynin, the ratio being 1.2 +/- 0.1 (n = 11). The ratio for the AUC values for N-desethyl-oxybutynin and oxybutynin was 2.1 +/- 0.2 (n = 11). CONCLUSIONS: The significantly lower AUC ratio of the N-desethyl metabolite over the mother compound, due to a reduced first pass metabolism, may explain the clinically relevant reduction of side effects that characterizes intravesical compared with oral oxybutynin therapy.

Sample handling for determination of free platinum in blood after cisplatin exposure.

Cisplatin is a commonly used cytostatic drug that can be pharmacokinetically monitored by measurement of non-protein-bound platinum (Pt) in plasma. The present report elucidates some practical aspects on blood sample preparation with the purpose of identifying methodological error sources and simplifying sample handling. Human blood was incubated in vitro with clinically relevant doses of cisplatin and then stored at different temperatures for various periods prior to deproteinization. Pt concentrations were analyzed by inductively coupled plasma mass spectrometry, which is a very sensitive technique that is well suited for determination of free Pt in biological samples. Free Pt concentration is usually determined after ultrafiltration of plasma. An alternative approach used to study the protein-free fraction is to precipitate the proteins with ice-cold ethanol and then analyze the aliquot. We compared the Pt concentrations in protein-free plasma obtained by these two methods and the levels were very similar. Thus, ethanol deproteinization may be an attractive alternative to ultrafiltration, since it is both simple to perform and very cost-effective. Storage of nondeproteinized whole blood or plasma at 4 degrees C or 20 degrees C did not affect the free Pt fraction significantly for the first 2 h, after which a gradual decrease was noted. This suggests that saving the blood sample for approximately 1 h before processing should not have any major impact on the result. On long-term storage of frozen blood samples prior to deproteinization the freezing temperature proved to be of critical importance. At -20 degrees C there was a gradual decrease in the free Pt fraction during the study period of 14 days, whereas the free Pt concentration remained unchanged at -70 degrees C for at least 3 months. Thus, samples may be stored unprocessed at -70 degrees C for several months, whereas -20 degrees C is not sufficiently cold.

Hydroxylated metabolites of thalidomide: formation in-vitro and in-vivo in man.

There is renewed interest in the clinical use of thalidomide, because of its unique immunomodulating action. Because data on the metabolism of thalidomide in man are very sparse, the aim of this study was to develop HPLC assays for the 5-hydroxy, 5,6-dihydroxy, 4,5-dihydroxy and 5'-hydroxy metabolites of thalidomide and to investigate their possible formation in man-in-vitro in liver homogenates and in-vivo in healthy volunteers. Reversed-phase HPLC assays with UV detection were developed for quantification of the metabolites in the low ng mL(-1) range in plasma and incubate samples. The stability of the metabolites was investigated and degradation was avoided by rapid chilling and acidification of the samples. After incubation of thalidomide with fraction S9 from human liver, formation of the 5-hydroxy and 5'-hydroxy metabolites could be demonstrated. The 5'-hydroxy metabolite was found, in low concentrations, in plasma samples from eight healthy male volunteers who had received thalidomide orally. The other three metabolites could not be found by HPLC with detection limits of 1-2 ng mL(-1). Thus the formation of two hydroxylated metabolites of thalidomide in the liver in man was demonstrated, but only one of these could be detected in the circulation.

Fragmentation of protonated O,O-diethyl O-aryl phosphorothionates in tandem mass spectral analysis.

The gas-phase ion chemistry of protonated O,O-diethyl O-aryl phosphorothionates was studied with tandem mass spectrometric and ab initio theoretical methods. Collision-activated dissociation (CAD) experiments were performed for the [M+H](+) ions on a triple quadrupole mass spectrometer. Various amounts of internal energy were deposited into the ions upon CAD by variation of the collision energy and collision gas pressure. In addition to isobutane, deuterated isobutane C4D10 also was used as reagent gas in chemical ionization. The daughter ions [M+H-C2H4](+) and [M+H-2C2H4](+) dominate the CAD spectra. These fragments arise via various pathways, each of which involves γ-proton migration. Formation of the terminal ions [M+H-2C2H4-H2O](+), [M+H-2C2H4-H2S](+), [ZPhOH2](+), [ZPhSH2](+), and [ZPhS](+) [Z = substituent(s) on the benzene ring] suggests that (1) the fragmenting [M+H](+) ions of O,O-diethyl O-aryl phosphorothionates have protons attached on the oxygen of an ethoxy group and on the oxygen of the phenoxy group; (2) thiono-thiolo rearrangement by aryl migration to sulfur occurs; (3) the fragmenting rear-ranged [M+H](+) ions have protons attached on the oxygen of an ethoxy group and on the sulfur of the thiophenoxy group. To get additional support for our interpretation of the mass spectrometric results, some characteristics of three protomers of O,O-diethyl O-phenyl phosphorothionate were investigated by carrying out ab initio molecular orbital calculations at the RHF/3-21G* level of theory.

Fragmentation of protonated O,O-dimethyl O-aryl phosphorothionates in tandem mass spectral analysis.

A study was carried out on the fragmentation of 12 protonated O,O-dimethyl O-aryl phosphorothionates by tandem quadrupole mass spectrometry. Some of the studied compounds are used in agriculture as pesticides. Energy-resolved and pressure-resolved experiments were performed on the [M + H](+) ions to investigate the dissociation behavior of the ions with various amounts of internal energy. On collisionally activated dissociation, the [M + H](+) ions decompose to yield the [M + H - CH3OH](+), (CH3O)2PS(+) (m/z 125), and (CH3O)2PO(+) (m/z 109) ions as major fragments. The ions [M + H - CH3OH](+) and (CH3O)2PS(+) probably arise from the [M + H](+) ions of the O,O-dimethyl O-aryl phosphorothionates with the proton on the sulfur or on the oxygen of the phenoxy group. The origin of the hydroxy proton of the methanol fragment was in many cases, surprisingly, the phenyl group and not the reagent gas. This was confirmed by using deuterated isobutane, C4D10, as reagent gas in Cl. The fragment ions (CH3O)2PO(+) and [ZPhS](+) are the results of thiono-thiolo rearrangement reaction. The precursor ion for the ion (CH3O)2PO(+) arises from most compounds upon chemical ionization, whereas the precursor ion for the ion [ZPhS](+) arises only from a few compounds upon chemical ionization. The observed fragments imply that several sites carry the extra proton and that these sites get the proton usually upon ionization. The stability order and some characteristics of three protomers of O,O-dimethyl O-phenyl phosphorothionate were investigated by ab initio calculations at the RHF/3-21G* level of theory.

Inhibition of platelet accumulation by beta 1-adrenoceptor blockade in the thoracic aorta of rabbits subjected to experimental sympathetic activation.

Arterial platelet adhesion is an initiating event in the thrombo-embolic complications of atherosclerosis and may also accelerate the development rate of atherosclerotic lesions. Psychosocial stress has been shown to accelerate atherogenesis in animals, an effect probably mediated via beta-adrenoceptor activation. In view of the postulated roles of platelets and beta-adrenoceptor activation in atherosclerosis development, we decided to test whether beta blockade affects arterial platelet accumulation. We studied the accumulation of radioactivity from 111In-labelled platelets on the wall of the thoracic aorta of rabbits as a measure of platelet accumulation. During the exposure to the labelled platelets, the animals were also exposed to 3 hours of chloralose anesthesia. This is a reproducible model of experimental sympathetic activation, including beta-adrenoceptor activation, which we used to amplify possible effects of beta-blockade on platelet-vessel wall interaction. The effectiveness of the anesthesia in increasing sympathetic activity was verified by significant rises in mean arterial blood pressure (from 77 to 88 mmHg), heart rate (190 to 290 bpm), and plasma levels of norepinephrine (1.0 to 3.3 nM) and epinephrine (0.13 to 0.83 nM). In chloralose anesthetized rabbits, approximately 30 x 10(-9)% of the injected 111In accumulated in each square millimeter of intima at unbranched thoracic aorta. Platelet accumulation was significantly higher at arterial branching points, 70% higher at intercostal artery bifurcations, and 150% higher at coronary artery bifurcations than in unbranched aortic intima. Pretreatment with metoprolol in a dose resulting in "therapeutic" plasma levels significantly reduced platelet accumulation by 48% in unbranched aorta, 65% at intercostal, and 53% at coronary artery bifurcations.(ABSTRACT TRUNCATED AT 250 WORDS)

Experimental sympathetic activation causes endothelial injury in the rabbit thoracic aorta via beta 1-adrenoceptor activation.

Sympathetic activation appears to accelerate the development of atherosclerosis, an effect that may be inhibited by beta-receptor blockade. It is unclear, however, which mechanisms mediate this effect. In view of the significance attached to endothelial injury in the initial phases of atherogenesis, we decided to test whether sympathetic activation might lead to an increase in endothelial injury. Chloralose anesthesia was used to induce sympathetic activation and the presence of intracellular IgG as a criterion of endothelial cell injury. The beta 1-selective beta-blocker metoprolol was used to evaluate if the effect(s) of sympathetic activation might be mediated by beta 1-adrenoceptors. In normal rabbits, the frequency of injured endothelial cells in unbranched areas of the thoracic aorta was 0.23%, compared with 1.93% in circumostial areas. Chloralose anesthesia caused significant increases in blood pressure, heart rate, and plasma norepinephrine, that is, caused sympathetic activation, and led to an approximately fivefold increase in the number of injured cells both in unbranched and in circumostial areas. This increase was totally inhibited by metoprolol pretreatment, indicating that it was mediated by beta 1-receptors. These observations suggest one possible mechanism that may connect sympathetic activation with atherogenesis and explain why beta-blockade protects against atherosclerosis.