Medication use in pregnancy: a cross-sectional, multinational web-based study.

OBJECTIVES: Intercountry comparability between studies on medication use in pregnancy is difficult due to dissimilarities in study design and methodology. This study aimed to examine patterns and factors associated with medications use in pregnancy from a multinational perspective, with emphasis on type of medication utilised and indication for use. DESIGN: Cross-sectional, web-based study performed within the period from 1 October 2011 to 29 February 2012. Uniform collection of drug utilisation data was performed via an anonymous online questionnaire. SETTING: Multinational study in Europe (Western, Northern and Eastern), North and South America and Australia. PARTICIPANTS: Pregnant women and new mothers with children less than 1 year of age. PRIMARY AND SECONDARY OUTCOME MEASURES: Prevalence of and factors associated with medication use for acute/short-term illnesses, chronic/long-term disorders and over-the-counter (OTC) medication use. RESULTS: The study population included 9459 women, of which 81.2% reported use of at least one medication (prescribed or OTC) during pregnancy. Overall, OTC medication use occurred in 66.9% of the pregnancies, whereas 68.4% and 17% of women reported use of at least one medication for treatment of acute/short-term illnesses and chronic/long-term disorders, respectively. The extent of self-reported medicated illnesses and types of medication used by indication varied across regions, especially in relation to urinary tract infections, depression or OTC nasal sprays. Women with higher age or lower educational level, housewives or women with an unplanned pregnancy were those most often reporting use of medication for chronic/long-term disorders. Immigrant women in Western (adjusted OR (aOR): 0.55, 95% CI 0.34 to 0.87) and Northern Europe (aOR: 0.50, 95% CI 0.31 to 0.83) were less likely to report use of medication for chronic/long-term disorders during pregnancy than non-immigrants. CONCLUSIONS: In this study, the majority of women in Europe, North America, South America and Australia used at least one medication during pregnancy. There was a substantial inter-region variability in the types of medication used.

Identification of coenzyme A-related tolmetin metabolites in rats: relationship with reactive drug metabolites.

1. It has recently been proposed that acyl coenzyme A thioesters (acyl-CoAs) of xenobiotic carboxylic acids are electrophilic, reactive metabolites that may react with proteins. 2. The primary objective was to investigate the reactivity of the tolmetin acyl coenzyme A thioester (Tol-CoA). The second objective was to identify and quantify tolmetin (Tol) metabolites in vivo that were formed via Tol-CoA, e.g. the glycine (Tol-Gly) and taurine (Tol-Tau) conjugates. This finding would be indicative of Tol-CoA formation and thus of other acyl-CoA-related reactions that might occur, e.g. covalent binding to proteins. 3. In order to study the chemical reactivity, Tol-CoA (0.5 mM) was incubated with glutathione (5 mM) in a 0.1 M phosphate buffer (pH 7.4) at 37 degrees C. Tol-CoA reacted rapidly with glutathione in vitro to form the S-acyl glutathione conjugate at a rate of 14.9 +/- 0.7 micro M min(-1) (mean +/- SD, n = 3) from 0 to 10 min. Compared with acyl-CoAs of other xenobiotic carboxylic acids, naproxen and clofibric acid, the rate by which Tol-CoA reacted with glutathione was high. 4. Following administration of (3)H-Tol (100 mg kg(-1), 200 micro Ci kg(-1), p.o.) to male Sprague-Dawley rats, Tol-Tau and Tol-Gly were identified in urine by electrospray ionization MS-MS in both positive- and negative-ion modes. The conjugates were only formed at trace levels (< 0.5%). However, the presence of Tol-Tau and Tol-Gly showed the reactive Tol-CoA was formed in vivo.

Ethical dilemmas in antibiotic prescribing: analysis of everyday practice.

OBJECTIVE: To explore general practitioners' (GP's) views on their obligations with respect to diagnosing infections and prescribing antibiotics. METHODS: The GP's reflections and prioritization were studied by means of interviews and observations. We analysed how their prioritization complied with an ethical guidance that ranked patient autonomy and welfare highest, then competence obligations and obligations to society, followed by fraternal obligations. RESULTS: Balancing of pros and cons was prominent in our informants' decision making but often resulted in decisions that deviated from the ethical guidance. The ranking varied much between the GPs. The highest priorities in the GPs' practice were related to the patient's everyday life (sometimes autonomy, sometimes beneficence in a broad sense), doctor-patient relationship (communication competence), the patient's perceived importance on the job market (society) and relationship with colleagues (fraternal). Perceived lack of resources and uncertainty with respect to both diagnostic and treatment decisions frequently influenced decision making.

Telephone prescribing of antibiotics. General practitioners' views and reflections.

BACKGROUND: In this era of increasing problems with resistance, rational prescribing of antibiotics is extremely important. Therefore, rationales for prescribing require analyses. The objective of this study was to explore general practitioners' (GPs') reasons for prescribing antibiotics by telephone. METHODS: Qualitative analysis of semistructured interviews with and observations of GPs in Iceland enquiring about the rationale for prescribing antibiotics was used. Ten GPs were interviewed for 45 min to 2 h each including three who were observed between 3 and 10 h. RESULTS: The GPs generally indicated a restrictive attitude to telephone prescribing, although they all gave examples of their prescribing by telephone. The prescribing was mostly but not always based on some kind of diagnosis. The factors influencing diagnosis and prescribing were largely non-clinical: knowledge of the patients as persons, including their complaint threshold, confidence in their descriptions, the GPs' communication strategies and the travelling distance between patients and GPs. The clinical factors were the patients' description of signs and symptoms and knowledge of their history. Prescriptions not based on diagnosis were 'therapeutic trial' or GP-approved self-medication. Sometimes, the GPs requested to see a patient even though the diagnosis was based on history, signs and symptoms. CONCLUSIONS: Multiple factors affected the decision-making process when antibiotics were prescribed by telephone, most of which were non-clinical. The diagnosis, if there was one, was generally presumptive. GPs' general attitudes correlated well with current knowledge but were contrasted by the reality of their daily work conditions.

Evidence based information on drug use during pregnancy: a survey of community pharmacists in three countries.

OBJECTIVE: To evaluate whether community pharmacists provide evidence-based information to women inquiring about specific drug use during pregnancy. DESIGN: A trained female student posing as a surrogate shopper requested information about the relative safety/risks of medications during pregnancy in two scenarios. Forty randomly selected pharmacies were surveyed in the Netherlands, Canada and Iceland, and pharmacists' recommendations were noted. Main outcome measures included the type of information that was provided, its presentation, and the source of information used. RESULTS: A relatively small proportion of pharmacists surveyed, provided evidence-based information regarding the drugs in question. Only 14% referred to current medical literature, while 60% consulted the product monograph. Over 90% of pharmacists referred the client to a physician. CONCLUSIONS: Community pharmacists do not disseminate evidence-based recommendations when counseling women on drug use in pregnancy, and need further education on resources concerning drugs in pregnancy that are currently available.

The analgesic effect of codeine as compared to imipramine in different human experimental pain models.

The hypoalgesic effect of single oral doses of 100 mg imipramine and 125 mg codeine was evaluated in a randomised, placebo-controlled, double-blind, 3-way cross-over experiment including 18 healthy volunteers. Pain tests were performed before and 90, 180, 270, 360 and 450 min after medication. The tests included determination of pain tolerance thresholds to pressure, pain detection/tolerance thresholds to single electrical sural nerve stimulation and pain summation at tolerance threshold to repetitive electrical sural nerve stimulation (temporal summation) and pain experienced during the cold pressor test, rated as peak pain intensity, pain average intensity and discomfort. Compared to placebo, imipramine significantly increased pressure pain tolerance threshold (P = 0.03) and increased pain tolerance threshold (P = 0.05) and pain summation threshold (P = 0.03), but not pain detection threshold to electrical stimulation. Imipramine did not cause significant changes in pain perception during the cold pressor test. Codeine significantly increased pressure pain tolerance threshold (P = 0.02), pain detection (P = 0.04) and pain tolerance threshold (P = 0.01) and pain summation threshold (P = 0.02) to electrical stimulation. In addition, codeine reduced the pain experienced during the cold pressor test (P = 0.04-0.003). It is concluded that both imipramine and codeine inhibit temporal pain summation, whereas only codeine reduces cold pressor pain. Pain summation may be a key mechanism in neuropathic pain. Imipramine has a documented effect on such pain conditions on temporal summation. The present study showed that codeine also inhibits temporal summation, which is in line with the clinical observations indicating that opioids relieve neuropathic pain.

Application of directly coupled HPLC NMR to separation and characterization of lipoproteins from human serum.

Disorders in lipoprotein metabolism are critical in the etiology of several disease states such as coronary heart disease and atherosclerosis. Thus, there is considerable interest in the development of novel methods for the analysis of lipoprotein complexes. We report here a simple chromatographic method for the separation of high-density lipoprotein, low-density lipoprotein, and very low-density lipoprotein from intact serum or plasma. The separation was achieved using a hydroxyapatite column and elution with pH 7.4 phosphate buffer with 100-microL injections of whole plasma. Coelution of HDL with plasma proteins such as albumin occurred, and this clearly limits quantitation of that species by HPLC peak integration. We also show, for the first time, the application of directly coupled HPLC 1H NMR spectroscopy to confirm the identification of the three major lipoproteins. The full chromatographic run time was 90 min with stopped-flow 600-MHz NMR spectra of each lipoprotein being collected using 128 scans, in 7 min. The 1H NMR chemical shifts of lipid signals were identical to conventional NMR spectra of freshly prepared lipoprotein standards, confirming that the lipoproteins were not degraded by the HPLC separation and that their gross supramolecular organization was intact.

Directly coupled HPLC-NMR and HPLC-MS approaches for the rapid characterisation of drug metabolites in urine: application to the human metabolism of naproxen.

High resolution nuclear magnetic resonance (NMR) spectroscopy is a very powerful tool for the structural identification of xenobiotic metabolites in complex biological matrices such as plasma, urine and bile. However, these fluids are dominated by thousands of signals resulting from endogenous metabolites and it is advantageous when investigating drug metabolites in such matrices to simplify the spectra by including a separation step in the experiment by directly-coupling HPLC and NMR. Naproxen (6-methoxy-alpha-methyl-2-naphthyl acetic acid) is administered as the S-enantiomer and is metabolised in vivo to form its demethylated metabolite which is subsequently conjugated with beta-D-glucuronic acid as well as with sulfate. Naproxen is also metabolised by phase II metabolism directly to form a glycine conjugate as well as a glucuronic acid conjugate at the carboxyl group. In the present investigation, the metabolism of naproxen was investigated in urine samples with a very simple sample preparation using a combination of directly-coupled HPLC-1H NMR spectroscopy and HPLC-mass spectrometry (MS). A buffer system was developed which allows the same chromatographic method to be used for the HPLC-NMR as well as the HPLC-MS analysis. The combination of these methods is complementary in information content since the NMR spectra provide evidence to distinguish isomers such as the type of glucuronides formed, and the HPLC-MS data allow identification of molecules containing NMR-silent fragments such as occur in the sulfate ester.

A question of emphasis: efficiency or equality in the provision of pharmaceuticals.

The reported results are part of the overall evaluation of the new drug distribution legislation that went into effect in March 1996, liberalising ownership of community pharmacies in Iceland. We addressed the following question: What impact did the legislation have on users' access to and costs of pharmaceuticals? Seven focus group discussions were conducted with pharmacy customers in different locations in May, August and October 1997. Widespread ignorance about the legislation was observed. Pharmacy customers preferred to discuss the role of physicians in 'irrational drug use' to discussing community pharmacies. A definite split was observed between urban and rural pharmacy customers; whereas definite changes were reported in the urban setting (lower prices and increased access), the rural population's perception is that it is being left out. Although the study design is not generalisable, it is clear that the equilibrium between equality and efficiency in pharmaceutical distribution in Iceland has shifted. The introduction of the free market system has increased inequality between rural and urban residents in exchange for increased efficiency.

Solid phase synthesis and biological evaluation of enantiomerically pure wasp toxin analogues PhTX-343 and PhTX-12.

PhTX-343 and PhTX-12, analogues of the natural polyamine wasp toxin PhTX-433, were synthesised in 40-60% yields as pure enantiomers using solid phase synthesis techniques. Capillary electrophoresis procedures were developed for chiral separation and determination of enantiomeric purity (ee) of the enantiomers of PhTX-343 and PhTX-12. The methods were optimised with respect to chiral selector, buffer pH, and temperature around the capillary. Thus, rac-PhTX-343 was resolved using a separation buffer containing 30 mM heptakis-(2, 6-di-O-methyl)-beta-cyclodextrin in 50 mM 6-aminocarproic acid (pH 4. 0) at 15 degrees C. rac-PhTX-12 was not resolvable in this system, but could be resolved using a separation buffer containing 10% w/v of dextrin 10, a linear maltodextrin, in 50 mM 6-aminocaproic acid (pH 4.0) at 15 degrees C. Using these methods, the optical purity of the synthetic enantiomers was determined to be ee > 99%. The enantiomers were also characterised by chiroptical methods. The antagonist potency of the enantiomers was tested on nicotinic acetylcholine receptors (human muscle-type nAChR) expressed in TE671 cells, ionotropic glutamate receptors in Xenopus laevis oocytes (expressing recombinant GluR1flop receptors), and locust muscle ionotropic glutamate receptors sensitive to quisqualate (qGluR). The potencies of each pair of enantiomers were similar (eudismic ratio close to 1).

Quality assessment of drug sales data: the case of antibacterials in Iceland.

BACKGROUND: Two sets of drug sales data, published by the Icelandic Ministry of Health, did not match for antibacterials in 1989. The search for causes turned out to be a project in itself. OBJECTIVE: To analyze quality problems in the sales data on antibacterials and describe a method for systematic quality assessment of drug sales data. METHODS: Documentary analysis based on the following sources: 1) Nordic Statistics on Medicines, 1975-95; 2) Drug Use (Notkun Iyfja), 1975-93; 3) Icelandic Drug Market, 1975-94; 4) Unpublished data from the Icelandic Ministry of Health. The following framework was developed to evaluate the quality of drug sales data: 1. Completeness of registration; 2. Accuracy and degree of completeness of data; 3. Size and coverage of the data source; 4. Data format; 5. Data accessibility, availability and cost. RESULTS: Four discrepancies were found, two due to changes in DDD, and two larger ones stemming from errors in calculating DDD, resulting in an overestimation of the contribution of the respective products to the total DDD/1000 inhabitants/day. Errors were detected in available sales data at least back to 1980, resulting in sales being overestimated by up to 13%. The reasons for the discrepancies were found mostly under point 2 in the framework. CONCLUSION: The errors uncovered by this study indicate a possible low quality of drug statistics which might lead to wrong conclusions about the level and development of sales of drugs. As a tool, the framework might be used for quality assessment of drug sales data.

Electrospray ionization mass spectrometric method for the determination of cannabinoid precursors: N-acylethanolamine phospholipids (NAPEs).

N-Acylethanolamine phospholipids (NAPEs) serve as endogenous precursors of N-acylethanolamines (NAEs), e.g. N-arachidonoylethanolamine (anandamide) and N-palmitoylethanolamine that are endogenous ligands of cannabinoid receptors. Under physiological conditions, NAPE is found in very low concentrations in mammalian tissue (3-12 nmol g(-1)). However, pathophysiological conditions may increase the endogenous NAPE levels, which again may cause an increase in endocannabinoid concentrations. This paper presents a simple and selective method for the determination of NAPE standards using negative electrospray ionization mass spectrometry (ESI-MS). The procedure provides complete positioning of all acyl and alkenyl groups contained in each NAPE species. The calibration curve for standard NAPE was linear over the range 100 fmol-50 pmol (0.1-50 ng) per injection. The lower limit of detection (signal-to-noise ratio of 3) was 100 fmol, implying that this method is superior to previous methods for the determination of NAPE. These results suggest that this ESI-MS method can be used to identify and quantify NAPE species in mammalian tissues and provide information on the corresponding NAEs to be released from the endogenous NAPE pool.

Fast separation of 16 seizure drug substances using non-aqueous capillary electrophoresis.

A fast and simple method for separation of 16 seizure drug substances using capillary electrophoresis in a non-aqueous separation medium is described. The separation medium consists of a mixture of acetonitrile, methanol and glycerol with ammonium acetate/acetic acid as the electrolyte. The analytes are detected by UV detection at 214 nm. Injection from the detection end (8.5 cm to detector) combined with the usage of a short capillary (32.5 cm total length) makes it possible to separate all 16 amines within 2 min. The choice of solvents, electrolytes and viscosity increasing additives are discussed with special emphasis to their influence on the separation selectivity.

Detection of metallothionein isoforms from three different species using on-line capillary electrophoresis-mass spectrometry.

An on-line capillary electrophoresis-mass spectrometry method (CE-MS) for the detection of metallothionein (MT) isoforms is described. The detected masses were usually within 1-1.5 mass units of the expected molecular weights. MT-containing samples from rabbit, sheep, and yeast (Saccharomyces cerevisiae) were subjected to CE-MS analysis. The analysis of rabbit liver MT revealed the masses of 10 proteins/peptides. Five of the detected masses corresponded well with the expected masses calculated from the amino acid sequence of previously described MT isoforms, one was suspected to be a deacetylated form of MT-2A, one was presumed to be a yet unknown isoform, and three masses were classified as non-MT compounds. From the analysis of a fetal sheep liver extract six proteins were detected of which three masses corresponded to previously described MT isoforms. Two purified MT subforms from S. cerivisiae (encoded by the CUP1 locus) were analyzed for their copper content and both forms were found to contain eight copper atoms per molecule.

Nonaqueous capillary electrophoresis--its applicability in the analysis of food, pharmaceuticals and biological fluids.

The use of nonaqueous electrophoresis media for the application of capillary electrophoresis in the analysis of food, pharmaceuticals and biological fluids is reviewed. Some of the applications are discussed in detail and the benefits of using nonaqueous media in these cases are outlined. Three new applications within pharmaceutical analyses are presented. In these methods either a simple sample pretreatment by dilution with methanol (determination of chlorhexidine in a cream) or selective on-line capillary electrophoresis mass spectrometry (methods for identification of seizure drugs or opium alkaloids) are used. The choice of organic solvents and electrolytes for nonaqueous capillary electrophoresis are discussed. Furthermore, validation data obtained using capillary electrophoresis based on the nonaqueous principle are listed and discussed.

Separation of the enantiomers of ibuprofen and its major phase I metabolites in urine using capillary electrophoresis.

A capillary electrophoresis method for determination of the enantiomers of ibuprofen and its major phase I metabolites: 2'-hydroxyibuprofen and 2'-carboxyibuprofen in urine samples have been developed. Cyclodextrins and linear dextrins have been investigated as chiral selectors. Simultaneous chiral separation of the enantiomers of ibuprofen, 2'-hydroxyibuprofen and 2'-carboxyibuprofen was obtained using a mixture of dextrin 10 and heptakis (2,3,6-tri-O-methyl)-beta-cyclodextrin in a 2-[N-morpholino]ethanesulphonic acid buffer, pH 5.26. The electroosmotic flow was reversed using hexadimethrine bromide as a buffer additive. The method can be used for the determination of the free enantiomers of ibuprofen, 2'-hydroxyibuprofen and 2'-carboxyibuprofen as well as for the indirect determination of their glucuronic acid conjugates in urine samples.

Inherited BRCA2 mutation associated with high grade breast cancer.

Inheritance is believed to play a major role in 5-10% of breast cancer. The breast cancer susceptibility genes BRCA1 and BRCA2 are estimated to account for more than half of these cases. Recent studies have suggested that breast cancers associated with BRCA1 germline mutations are of higher grade than sporadic cases. The purpose of this investigation was to determine if there are significant pathologic and biologic differences between hereditary BRCA2 related breast carcinomas and non-hereditary breast cancers. Forty cases of hereditary breast cancer from families associated with a specific 999del5 BRCA2 mutation were compared with regard to histologic and biologic factors to an age matched control group. Thirty-four patients (85%) had ductal carcinoma, two had lobular carcinoma, and one patient had medullary carcinoma. Compared to the control group, the BRCA2 tumors had less tubule formation (p = 0.02), more nuclear pleomorphism (p = 0.02), and higher mitotic rates (p = 0.002), and were thus of higher histologic grade (p = 0.003). By flow cytometry the BRCA2 tumors also had significantly higher S-phase fractions than the control tumors (p = 0.02). Significant differences in axillary lymph-node involvement or ploidy status were not detected. According to the results of this study, hereditary breast cancers associated with the 999del5 BRCA2 mutation are high grade tumors with a rapid proliferation rate. Other or additional factors than the defining BRCA2 mutation are involved in determining the tumor type.

Assay of acetylsalicylic acid and three of its metabolites in human plasma and urine using non-aqueous capillary electrophoresis with reversed electroosmotic flow.

The separation of acetylsalicylic acid and three of its metabolites--salicylic acid, salicyluric acid and gentisic acid--is demonstrated in a non-aqueous capillary electrophoresis system with reversed electroosmotic flow. Solvent mixtures of methanol and acetonitrile are used for the electrophoresis media and different electrolytes have been investigated. The flow is reversed by the addition of the polycation hexadimethrine bromide and thus a negative voltage is used. This system provides a fast and effective separation of the four analytes. The separation method was applied to the assay of acetylsalicylic acid and its major metabolites in plasma and urine and the limits of quantification for all of these compounds are about 5 microg ml(-1) in plasma and 25 microg ml(-1) in urine.

Mapping loss of heterozygosity at chromosome 13q: loss at 13q12-q13 is associated with breast tumour progression and poor prognosis.

Several chromosome regions exhibit loss of heterozygosity (LOH) in human breast carcinoma and are thought to harbour tumour suppressor genes (TSG). At chromosome 13q, two TSGs have been identified, RB1 at 13q14 and BRCA2 at 13q12-q13. In this study, 139 sporadic breast tumours were analysed with 18 polymorphic microsatellite markers for detailed mapping of LOH at chromosome 13q and evaluation of an association with known progression factors. LOH with at least one marker was observed in 71 (51%) of the tumours analysed. The deletion mapping indicated three LOH target regions, 13q12-q13, 13q14 and 13q31-q34. LOH at chromosome 13q12-q13 was associated with low progesterone receptor content, a high S phase fraction and aneuploidy. Multivariate analysis adjusting for lymph node involvement and S phase fraction showed that patients with tumours exhibiting LOH at 13q12-q13 have a 3-4-fold increased risk of recurrence and death compared with other patients. Our results suggest there are at least three separate LOH target regions at chromosome 13q and inactivation of one or more genes at chromosome 13q12-q13 results in poor prognosis for breast cancer patients.

Comparison of aqueous and non-aqueous capillary electrophoresis for quantitative determination of morphine in pharmaceuticals.

Two capillary electrophoresis methods involving aqueous and non-aqueous electrophoresis media, respectively, have been compared for the quantitative determination of morphine in pharmaceutical preparations. In the aqueous system the separation from other opium alkaloids was achieved using 2,6-di-O-methyl-beta-cyclodextrin as an additive to the electrophoresis buffer. In the non-aqueous system no other additives than the electrolytes were necessary in order to achieve separation of the opium alkaloids. The two methods have been partially validated and compared with a currently used high-performance liquid chromatography method. From the overall point of view the validations show that the three methods are equivalent in performance and that they are appropriate for the purposes they are intended for.