Selective serotonin reuptake inhibitors during pregnancy and risk of persistent pulmonary hypertension in the newborn: population based cohort study from the five Nordic countries.

OBJECTIVE: To assess whether maternal use of selective serotonin reuptake inhibitors (SSRIs) increases the risk of persistent pulmonary hypertension in the newborn, and whether such an effect might differ between specific SSRIs. DESIGN: Population based cohort study using data from the national health registers. SETTING: Denmark, Finland, Iceland, Norway, and Sweden, 1996-2007. PARTICIPANTS: More than 1.6 million infants born after gestational week 33. MAIN OUTCOME MEASURES: Risks of persistent pulmonary hypertension of the newborn associated with early and late exposure to SSRIs during pregnancy and adjusted for important maternal and pregnancy characteristics. Comparisons were made between infants exposed and not exposed to SSRIs. RESULTS: Around 30 000 women had used SSRIs during pregnancy and 11 014 had been dispensed an SSRI later than gestational week 20. Exposure to SSRIs in late pregnancy was associated with an increased risk of persistent pulmonary hypertension in the newborn: 33 of 11 014 exposed infants (absolute risk 3 per 1000 liveborn infants compared with the background incidence of 1.2 per 1000); adjusted odds ratio 2.1 (95% confidence interval 1.5 to 3.0). The increased risks of persistent pulmonary hypertension in the newborn for each of the specific SSRIs (sertraline, citalopram, paroxetine, and fluoxetine) were of similar magnitude. Filling a prescription with SSRIs before gestational week 8 yielded slightly increased risks: adjusted odds ratio 1.4 (95% confidence interval 1.0 to 2.0). CONCLUSIONS: The risk of persistent pulmonary hypertension of the newborn is low, but use of SSRIs in late pregnancy increases that risk more than twofold. The increased risk seems to be a class effect.

Pharmacy care perspectives on problems with HIV antiretroviral therapy in Sweden.

OBJECTIVE: This study has three main objectives (1) to identify the major problems or difficulties pharmacy staff in Sweden experience regarding pharmacy care of patients receiving antiretroviral therapy, (2) to identify the perceptions of pharmacy staff regarding what are patient-related concerns with antiretroviral therapy and (3) to compare the extent to which pharmacy staff awareness matches patient perceptions regarding what are the major problems or difficulties associated with antiretroviral therapy. METHODS: A problem detection study (PDS) containing two questionnaires was conducted: one to be completed by pharmacy staff and another to be completed by both pharmacy staff and patients. In the latter survey, staff were asked about what they thought that patients would have responded. Staff and patient responses were then matched and compared with one another. RESULTS: The pharmacy staff expressed their need for continuous education so as to assist the patients with their complex regimens. The staff were aware that patients were worried about therapy failure and viral resistance, medication-related problems and negative attitudes from the public. The staff however were less aware of the extent to which patients worried about not having their HIV infection under control. The staff also valued written patient information to a much higher extent than the patients. CONCLUSIONS: The pharmacy staff' awareness of the major problems HIV patients are experiencing seems incomplete and may lead to lack of concordance between the patients and pharmacy staff. This in turn may lead to non-adherence and poor therapy outcomes. Pharmacy staff should be encouraged to improve and systematically assess patient issues regarding antiretroviral therapy. Through assessing patient needs and concerns, the pharmacists can better identify patient needs and thus better tailor their educational and behavioural interventions to improve therapy outcomes.

Common problems with antiretroviral therapy among three Swedish groups of HIV infected individuals.

OBJECTIVE: The main objective of this study was to identify and compare the common problems and difficulties associated with combination antiretroviral therapy (CART) as experienced by three major groups of HIV infected individuals (homo- or bisexuals, former injecting drug users and origins of Sub-Saharan Africa) in Sweden. METHODS: Based on the results from in-depth interviews with 15 representatives from the three major groups, a questionnaire was designed for use in a problem detection study (PDS). The study was conducted with 195 HIV-positive patients residing in the major cities of Sweden. RESULTS: The overall response rate was 79%. The problems identified in all three groups were negative attitudes from the public, worries about disease progression or therapy failure, medication or drug-related problems and problems in connection to pharmacy visits. A specific problem in the homo- or bisexual group was drug-related problems such as adverse effects, drug interactions and pill burden. For former injecting drug users, the specific problem was disease-related conflicts with relatives and the problem of coping with the social and psychological burden caused by the HIV infection. The African group termed the risk of exposing their medication at the pharmacy as a specific problem, as this could reveal their HIV status. CONCLUSIONS: Our findings regarding problems with CART in three patient groups in Sweden may be of use to tailor pharmacy care to HIV infected individuals. General strategies to improve adherence need to be complemented with approaches that will address the specific needs for the different patient groups affected by HIV. Further studies on group-specific interventions that promote concordance and adherence to CART will be necessary to minimize therapy failure and viral resistance.

Existence of antimalarial formulations with low bioavailability in Tanzania.

The main objective of this work was to assess the relative bioavailability of two tablet formulations containing sulfadoxine/pyrimethamine (SP) and marketed in Tanzania. Twelve healthy volunteers were randomized to receive a single oral dose of three SP tablets each containing 500 mg sulfadoxine (SDX) and 25 mg pyrimethamine (PYR) in a form of either A (a locally manufactured SP tablet formulation, manufactured by a local pharmaceutical industry in Tanzania) or B (Fansidar), Hoffmann La Roche, Basel, Switzerland, an innovator's SP) after an overnight fasting. Serial blood samples (100 microL) were collected from a finger prick in duplicate up to 10 days and dried on Whatman filter paper. The samples were assayed for SDX and PYR using high-performance liquid chromatographic methods. Pharmacokinetic parameters of SDX and PYR were estimated by single compartment method. The pharmacokinetics of formulation A--maximum plasma concentration, the areas under the plasma concentration--time curve and the relative bioavailability (A versus B) were significantly lower than those of formulation B (P < 0.1). These observed differences indicate bioinequivalence between the two products.

Use of antibiotics at hospitals in Stockholm: a benchmarking project using internet.

PURPOSE: To evaluate the internet way of feedback to prescribing physicians, providing data on antimicrobial use and to assess the applicability of the DU90% (i.e. Drug Utilisation 90%--the number of drugs accounting for 90% of the volume of usage in defined daily doses, (DDDs)) methodology in the hospital setting. METHODS: Antimicrobial drug use was evaluated in all major departments in seven hospitals in Stockholm in the year 2000. All data were presented anonymously on www.janusinfo.org. Aggregate data on antimicrobial drug use were expressed as the number of DDDs and costs per 100 bed-days. We focused on the number of drugs accounting for 90% of the volume (DDD), including the level of adherence to guidelines. The chief physicians assessed this feedback by a questionnaire. RESULTS: The number of DDDs/100 bed-days varied among different clinics and ranged from 39 to 57 (internal medicine) to 102 to 161 (infectious disease). The cost per 100 bed-days varied more than two-fold. The number of different antibiotics within the DU90% segment ranged from 9 to 13 (orthopaedic clinics) to 16 to 23 (infectious disease). According to the questionnaire, data were considered to be clearly presented and physicians would like to receive this kind of reports in the future, not only for antibiotics but also for other drugs. CONCLUSION: Presenting physicians with aggregate data on drug use via internet could provide a stimulus for prescribing improvement.

Metabolism and elimination of quinine in healthy volunteers.

OBJECTIVES: The aims were to investigate: (1) The renal elimination of quinine and its metabolites 3-hydoxyquinine, 2'-quininone, (10R) and (10S)-11-dihydroxydihydroquinine and (2) the relative importance of CYP3A4, CYP1A2 and CYP2C19 for the formation of 2'-quininone, (10R) and (10S)-11-dihydroxydihydroquinine in vivo. METHODS: In a randomised three-way crossover study, nine healthy Swedish subjects received a single oral dose of quinine hydrochloride (500 mg), on three different occasions: (A) alone, (B) concomitantly with ketoconazole (100 mg twice daily for 3 days) and (C) concomitantly with fluvoxamine (25 mg twice daily for 2 days). Blood and urine samples were collected before quinine intake and up to 96 h thereafter. All samples were analysed by means of high-performance liquid chromatography. RESULTS: Co-administration with ketoconazole significantly increased the area under the plasma concentration versus time curve (AUC) of 2'-quininone, (10S)-11-dihydroxydihydroquinine, and (10R)-11-dihydroxydihydroquinine, the geometric mean ratios (90% CI) of the AUC were 1.9 (1.8, 2.0), 1.3 (1.1, 1.7) and 1.6 (1.4, 1.8), respectively. Co-administration with fluvoxamine had no significant effect on the mean AUC of any of the metabolites. A mean of 56% of the administered oral quinine dose was recovered in urine after hydrolysis with beta-glucuronidase relative to the 40% recovered before hydrolysis. CONCLUSION: Quinine is eliminated in urine mainly as unchanged drug and as 3-hydroxyquinine. The major metabolite of quinine is 3-hydroxyquinine formed by CYP3A4. There is no evidence for the involvement of CYP3A4, 1A2 or 2C19 in the formation of 2'-quininone, (10S)-11-dihydroxydihydroquinine and (10R)-11-dihydroxydihydroquinine in vivo. Glucuronidation is an important pathway for the renal elimination of quinine, mainly as direct conjugation of the drug.

Quinine 3-hydroxylation as a biomarker reaction for the activity of CYP3A4 in man.

OBJECTIVE: To investigate the usefulness of the 3-hydroxylation of quinine as a biomarker reaction for the activity of CYP3A4 in man and to study the interindividual variation in the metabolic ratio (MR), i.e. quinine/3-hydroxyquinine. METHODS: Data from a previous study (A) was used for determination of the MR of quinine in plasma and urine at different time points. In study B, 24 healthy Swedish subjects received 250 mg quinine hydrochloride first alone and later together with four other CYP probe drugs [losartan (CYP2C9), omeprazole (CYP2C19), debrisoquine (CYP2D6) and caffeine (CYP1A2)] administered on the same day. Plasma and urine samples were collected before quinine intake and 16 h thereafter and analysed for quinine and 3-hydroxyquinine using high-performance liquid chromatography. Plasma and/or urine were collected for the other probes at different time points. MRs of all the probes were determined and correlations to quinine MR were studied. RESULTS: In study A, the MR in plasma was stable over 96 h. The ratio increased from 5.8 to 12.2 (P=0.006) during co-administration with ketoconazole, whereas no significant difference (P=0.76) was observed during co-administration with fluvoxamine (from 5.8 to 6.0). In study B, there was no significant difference (P=0.36) between the mean MRs when quinine was given alone (4.7) or together with the four other drugs (4.5). There was a significant correlation between the MR of quinine and omeprazole sulphone formation (r=0.52, P<0.01), but not to the MRs of the other probes. There was a fivefold interindividual variability in the MR. CONCLUSIONS: The MR of quinine in plasma or urine may serve as a stable measure of the activity of CYP3A4 in man. These results together with in vitro data show that quinine is also a specific CYP3A4 probe.

Determination of pyronaridine in whole blood by automated solid phase extraction and high-performance liquid chromatography.

A new extraction procedure for the analysis of pyronaridine in whole blood is presented. A weak cation exchanger with a carboxylic acid (CBA) sorbent was found to be a suitable solid phase sorbent for the extraction of pyronaridine. High-performance liquid chromatography with UV detection at 278 nm and an electrochemical detector at +0.75 V is used. The electrochemical detector gives higher selectivity than the UV detector. The separation was performed using a C18 reversed phase column with mobile phase of acetonitrile-phosphate buffer (0.01 mol/L, pH 2.5)- sodium perchlorate (1.0 mol/L; 22:77:1, v/v/v). The within-day RSDs were below 5% at all concentration levels between 75 nmol/L and 1500 nmol/L, and the between-day RSDs were below 14% at all concentration levels. The limit of quantification was about 50 nmol/L in 1000 microL whole blood with an RSD of 20% or less on a day-to-day basis. The stability of pyronaridine is increased if the pH is less than 3 in water solutions. In whole blood, the concentration decreases by about 10% for each freeze-thaw cycle performed. At room temperature (about 22 degrees C), pyronaridine concentration in whole blood decreases by about 10% within 12 to 24 hours.

Enzyme kinetics for the formation of 3-hydroxyquinine and three new metabolites of quinine in vitro; 3-hydroxylation by CYP3A4 is indeed the major metabolic pathway.

The formation kinetics of 3-hydroxyquinine, 2'-quininone, (10S)-11-dihydroxydihydroquinine, and (10R)-11-dihydroxydihydroquinine were investigated in human liver microsomes and in human recombinant-expressed CYP3A4. The inhibition profile was studied by the use of different concentrations of ketoconazole, troleandomycin, and fluvoxamine. In addition, formation rates of the metabolites were correlated to different enzyme probe activities of CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 in microsomes from 20 human livers. Formation of 3-hydroxyquinine had the highest intrinsic clearance in human liver microsomes (mean +/- S.D.) of 11.0 +/- 4.6 micro l/min/mg. A markedly lower intrinsic clearance, 1.4 +/- 0.7, 0.5 +/- 0.1, and 1.1 +/- 0.2 micro l/min/mg was measured for 2'-quininone, (10R)-11-dihydroxydihydroquinine and (10S)-11-dihydroxydihydroquinine, respectively. Incubation with human recombinant CYP3A4 resulted in a 20-fold higher intrinsic clearance for 3-hydroxyquinine compared with 2'-quininone formation whereas no other metabolites were detected. The formation rate of 3-hydroxyquinine was completely inhibited by ketoconazole (1 micro M) and troleandomycin (80 micro M). Strong inhibition was observed on the formation of 2'-quininone whereas the formation of (10S)-11-dihydroxydihydroquinine was partly inhibited by these two inhibitors. No inhibition on the formation of (10R)-11-dihydroxydihydroquinine was observed. There was a significant correlation between the formation rates of quinine metabolites and activities of the CYP3A4 selected marker probes. This in vitro study demonstrates that 3-hydroxyquinine is the principal metabolite of quinine and CYP3A4 is the major enzyme involved in this metabolic pathway.