Optimisation of pharmacotherapy in psychiatry through therapeutic drug monitoring, molecular brain imaging and pharmacogenetic tests: focus on antipsychotics.

BACKGROUND: For psychotic disorders (i.e. schizophrenia), pharmacotherapy plays a key role in controlling acute and long-term symptoms. To find the optimal individual dose and dosage strategy, specialized tools are used. Three tools have been proven useful to personalize drug treatments: therapeutic drug monitoring (TDM) of drug levels, pharmacogenetic testing (PG), and molecular neuroimaging. METHODS: In these Guidelines, we provide an in-depth review of pharmacokinetics, pharmacodynamics, and pharmacogenetics for 50 antipsychotics. Over 30 international experts in psychiatry selected studies that have measured drug concentrations in the blood (TDM), gene polymorphisms of enzymes involved in drug metabolism, or receptor/transporter occupancies in the brain (positron emission tomography (PET)). RESULTS: Study results strongly support the use of TDM and the cytochrome P450 (CYP) genotyping and/or phenotyping to guide drug therapies. Evidence-based target ranges are available for titrating drug doses that are often supported by PET findings. CONCLUSION: All three tools discussed in these Guidelines are essential for drug treatment. TDM goes well beyond typical indications such as unclear compliance and polypharmacy. Despite its enormous potential to optimize treatment effects, minimize side effects and ultimately reduce the global burden of diseases, personalized drug treatment has not yet become the standard of care in psychiatry.

Neonatal withdrawal syndrome following in utero exposure to antidepressants: a disproportionality analysis of VigiBase, the WHO spontaneous reporting database.

BACKGROUND: Evidence on neonatal withdrawal syndrome following antidepressant intrauterine exposure is limited, particularly for antidepressants other than selective serotonin reuptake inhibitor (SSRIs). METHODS: In our case/non-case pharmacovigilance study, based on VigiBase®, the WHO database of suspected adverse drug reactions, we estimated reporting odds ratio (ROR) and the Bayesian information component (IC) with 95% confidence/credibility intervals (CI) as measures of disproportionate reporting of antidepressant-related neonatal withdrawal syndrome. Antidepressants were first compared to all other medications, then to methadone, and finally within each class of antidepressants: SSRIs, tricyclics (TCA) and other antidepressants. Antidepressants were ranked in terms of clinical priority, based on semiquantitative score ratings. Serious v. non-serious reports were compared. RESULTS: A total of 406 reports of neonatal withdrawal syndrome in 379 neonates related to 15 antidepressants were included. Disproportionate reporting was detected for antidepressants as a group as compared to all other drugs (ROR: 6.18, 95% CI 5.45-7.01, IC: 2.07, 95% CI 1.92-2.21). Signals were found for TCAs (10.55, 95% CI 8.02-13.88), followed by other antidepressants (ROR: 5.90, 95% CI 4.74-7.36) and SSRIs (ROR: 4.68, 95% CI 4.04-5.42). Significant disproportionality emerged for all individual antidepressants except for bupropion, whereas no disproportionality for any antidepressant was detected v. methadone. Eleven antidepressants had a moderate clinical priority score and four had a weak one. Most frequent symptoms included respiratory symptoms (n = 106), irritability/agitation (n = 75), tremor (n = 52) and feeding problems (n = 40). CONCLUSIONS: Most antidepressants are associated with moderate signals of disproportionate reporting for neonatal withdrawal syndrome, which should be considered when prescribing an antidepressant during pregnancy, irrespective of class.

Tools for optimising pharmacotherapy in psychiatry (therapeutic drug monitoring, molecular brain imaging and pharmacogenetic tests): focus on antidepressants.

Objectives: More than 40 drugs are available to treat affective disorders. Individual selection of the optimal drug and dose is required to attain the highest possible efficacy and acceptable tolerability for every patient.Methods: This review, which includes more than 500 articles selected by 30 experts, combines relevant knowledge on studies investigating the pharmacokinetics, pharmacodynamics and pharmacogenetics of 33 antidepressant drugs and of 4 drugs approved for augmentation in cases of insufficient response to antidepressant monotherapy. Such studies typically measure drug concentrations in blood (i.e. therapeutic drug monitoring) and genotype relevant genetic polymorphisms of enzymes, transporters or receptors involved in drug metabolism or mechanism of action. Imaging studies, primarily positron emission tomography that relates drug concentrations in blood and radioligand binding, are considered to quantify target structure occupancy by the antidepressant drugs in vivo. Results: Evidence is given that in vivo imaging, therapeutic drug monitoring and genotyping and/or phenotyping of drug metabolising enzymes should be an integral part in the development of any new antidepressant drug.Conclusions: To guide antidepressant drug therapy in everyday practice, there are multiple indications such as uncertain adherence, polypharmacy, nonresponse and/or adverse reactions under therapeutically recommended doses, where therapeutic drug monitoring and cytochrome P450 genotyping and/or phenotyping should be applied as valid tools of precision medicine.

Vascular risk factor control and adherence to secondary preventive medication after ischaemic stroke.

BACKGROUND: Studies regarding adequacy of secondary stroke prevention are limited. We report medication adherence, risk factor control and factors influencing vascular risk profile following ischaemic stroke. METHODS: A total of 664 home-dwelling participants in the Norwegian Cognitive Impairment After Stroke study, a multicenter observational study, were evaluated 3 and 18 months poststroke. We assessed medication adherence by self-reporting (4-item Morisky Medication Adherence Scale) and medication persistence (defined as continuation of medication(s) prescribed at discharge), achievement of guideline-defined targets of blood pressure (BP) (<140/90 mmHg), low-density lipoprotein cholesterol (LDL-C) (<2.0 mmol L-1 ) and haemoglobin A1c (HbA1c) (≤53 mmol mol-1 ) and determinants of risk factor control. RESULTS: At discharge, 97% were prescribed antithrombotics, 88% lipid-lowering drugs, 68% antihypertensives and 12% antidiabetic drugs. Persistence of users declined to 99%, 88%, 93% and 95%, respectively, at 18 months. After 3 and 18 months, 80% and 73% reported high adherence. After 3 and 18 months, 40.7% and 47.0% gained BP control, 48.4% and 44.6% achieved LDL-C control, and 69.2% and 69.5% of diabetic patients achieved HbA1c control. Advanced age was associated with increased LDL-C control (OR 1.03, 95% CI 1.01 to 1.06) and reduced BP control (OR 0.98, 0.96 to 0.99). Women had poorer LDL-C control (OR 0.60, 0.37 to 0.98). Polypharmacy was associated with increased LDL-C control (OR 1.29, 1.18 to 1.41) and reduced HbA1c control (OR 0.76, 0.60 to 0.98). CONCLUSION: Risk factor control is suboptimal despite high medication persistence and adherence. Improved understanding of this complex clinical setting is needed for optimization of secondary preventive strategies.

Topical moistening of mastectomy wounds with diluted tranexamic acid to reduce bleeding: randomized clinical trial.

BACKGROUND: Topical administration of tranexamic acid (TXA) may be an alternative to intravenous administration to reduce bleeding with a lower risk of systemic adverse events. The aim of this study was to investigate whether moistening a surgical wound with TXA before closure, leaving a thin film of drug only, would reduce postoperative bleeding. METHODS: This was a two-centre, stratified, parallel-group, placebo-controlled, double-blind RCT. Patients undergoing mastectomy with or without axillary lymph node clearance were randomized 1 : 1 to moistening of wound surface before closure with either 25 mg/ml TXA or 0·9 per cent sodium chloride (placebo). The primary endpoint was postoperative bleeding as measured by drain production in the first 24 h. Secondary endpoints were early haematoma, total drain production, postoperative complications and late aspirations of seroma within 3 months. RESULTS: Between 1 January 2016 and 31 August 2018, 208 patients were randomized. Two patients were converted to a different surgical procedure at surgery, and four did not receive the intervention owing to technical error. Thus, 202 patients were included in the study (101 in the TXA and 101 in the placebo group). TXA reduced mean drain production at 24 h (110 versus 144 ml; mean difference 34 (95 per cent c.i. 8 to 60) ml, P = 0·011). One patient in the TXA group had early haematoma compared with seven in the placebo group (odds ratio (OR) 0·13 (95 per cent c.i. 0·02 to 1·07); P = 0·057). There was no significant difference in postoperative complications between TXA and placebo (13 versus 10; OR 1·11 (0·45 to 2·73), P = 0·824) or need for late seroma aspirations (79 versus 67 per cent; OR 1·83 (0·91 to 3·68), P = 0·089). CONCLUSION: Moistening the wound with TXA 25 mg/ml before closure reduces postoperative bleeding within the first 24 h in patients undergoing mastectomy. Registration number: NCT02627560 (https://clinicaltrials.gov).

ANTECEDENTES: La administración tópica de ácido tranexámico (tranexamic acid, TXA) puede ser una alternativa a la administración por vía intravenosa para reducir la hemorragia, con menor riesgo de eventos sistémicos adversos. El objetivo de este estudio fue investigar si humedecer la herida quirúrgica con TXA 25 mg/ml antes del cierre de la incisión dejando solo una fina película de fármaco, reducía la hemorragia postoperatoria. MÉTODOS: Se trata de un ensayo clínico aleatorizado, a doble ciego, controlado con placebo, de grupos paralelos, estratificado por dos centros. Las pacientes sometidas a mastectomía con/sin resección de los ganglios linfáticos axilares se asignaron al azar 1:1 para la humidificación de la superficie de la herida antes del cierre con TXA 25 mg/ml o con NaCl al 0,9% (placebo). El objetivo primario fue la hemorragia postoperatoria medida por el débito del drenaje durante las primeras 24 horas. Los objetivos secundarios fueron el desarrollo de hematoma precoz, el débito total del drenaje, las complicaciones postoperatorias y la necesidad de aspiración de un seroma tardío durante los primeros 3 meses tras la cirugía. RESULTADOS: Entre el 1 de enero de 2016 y el 31 de agosto de 2018, 208 pacientes fueron asignadas al azar. En dos pacientes tuvo que realizarse un procedimiento quirúrgico diferente durante el periodo perioperatorio y cuatro pacientes no recibieron la intervención por errores técnicos. Por lo tanto, se incluyeron 202 pacientes en el estudio (101 fueron tratadas con TXA y 101 con placebo). El TXA redujo el débito medio del drenaje a las 24 horas (110 versus 144 ml, diferencia media 34 ml, i.c. del 95%: 8 a 60 ml, P = 0,010). Se presentó un hematoma precoz en una paciente del grupo del TXA versus siete pacientes tratadas con placebo (razón de oportunidades, odds ratio, OR 0,13, i.c. del 95% 0,02-1,07, P = 0,057). No hubo diferencias significativas en las complicaciones postoperatorias entre TXA y placebo (13 versus 10, OR 1,11, i.c. del 95% 0,45-2,73, P = 0,824) o la necesidad de aspiración tardía de seromas (79,3 versus 66,6%, OR 1,83, i.c. del 95% 0,91-3,68, P = 0,089). CONCLUSIÓN: Humedecer la herida antes del cierre con TXA 25 mg/ml reduce la hemorragia postoperatoria durante las primeras 24 horas en pacientes sometidas a mastectomía.

Language impairment in children aged 5 and 8 years after antiepileptic drug exposure in utero - the Norwegian Mother and Child Cohort Study.

BACKGROUND AND PURPOSE: The purpose was to examine the consequences of antiepileptic drug (AED) exposure during pregnancy on language abilities in children aged 5 and 8 years of mothers with epilepsy. METHODS: The study population included children of mothers with and without epilepsy enrolled in the Norwegian Mother and Child Cohort Study 1999-2008. Mothers prospectively provided information on epilepsy diagnosis, AED use during pregnancy and the child's language abilities at age 5 and 8 years, in questionnaires with validated language screening tools. AED concentrations in gestation week 17-19 and in the umbilical cord were measured. RESULTS: The study population included 346 AED-exposed and 388 AED-unexposed children of mothers with epilepsy, and 113 674 children of mothers without epilepsy. Mothers of 117 and 121 AED-exposed children responded to the questionnaires at age 5 and 8 years, respectively. For AED-exposed children, the adjusted odds ratio for language impairment was 1.6 [confidence interval (CI) 1.1-2.5, P = 0.03] at age 5 years and 2.0 (CI 1.4-3.0, P < 0.001) at age 8 years, compared to children of mothers without epilepsy. Children exposed to carbamazepine monotherapy had a significantly increased risk of language impairment compared to control children at age 8 years (adjusted odds ratio 3.8, CI 1.6-9.0, P = 0.002). Higher maternal valproate concentrations correlated with language impairment at age 5 years. Periconceptional folic acid supplement use protected against AED-associated language impairment. CONCLUSION: Foetal AED exposure in utero is associated with an increased risk of language impairment in children aged 5 and 8 years of mothers with epilepsy. Periconceptional folic acid use had a protective effect on AED-associated language impairment.

Cytotoxicity and effect on wound re-epithelialization after topical administration of tranexamic acid.

Background: Topical administration of tranexamic acid (TXA) reduces bleeding from surgical wounds similarly to intravenous use, but with negligible risk of adverse systemic events. Topical use is expanding, but is off-label. Surgeons lack guidelines regarding safe topical dosages and modes of administration. The effects of topical TXA on skin cells and wound healing are unknown. This study investigated whether topical TXA might be cytotoxic or affect wound re-epithelialization. Methods: Human keratinocytes and fibroblast cell cultures and an ex vivo human skin wound model were subjected to both short (limited) and long (chronic) exposure to various clinically relevant concentrations of TXA to mimic different modalities of topical administration. Cytotoxicity and effects on wound re-epithelialization were evaluated. Results: In cell culture, toxicity from chronic exposure was associated with increasing concentration and exposure time. Limited exposure to TXA did not cause significant cytotoxicity even at high concentrations. Re-epithelialization was completely absent in wounds chronically exposed to TXA concentrations of 25 mg/ml or above, and 50-100 mg/ml induced epidermolysis of normal epithelium, possibly by a non-toxic mechanism. Wound re-epithelialization was slightly delayed, but not impaired, by limited exposure to 100 mg/ml or chronic exposure to 6·25 mg/ml. Conclusion: Although short exposure to even high concentrations of topical TXA seems well tolerated in vitro, prolonged exposure can be cytotoxic and may affect wound re-epithelialization. Surgeons should adjust the TXA concentration to the planned mode of topical administration in clinical practice.

Antecedentes: La administración tópica de ácido tranexámico (tranexamic acid, TXA) reduce la hemorragia de las heridas quirúrgicas de forma equivalente a su uso endovenoso, pero con un riesgo insignificante de eventos adversos sistémicos. El uso tópico se está expandiendo, pero se realiza fuera de indicación. Los cirujanos no disponen de directrices sobre las dosis para uso tópico seguras y las formas de administración. Se desconocen los efectos del TXA tópico sobre las células de la piel y sobre la curación de las heridas. Nos propusimos investigar si el TXA tópico puede ser citotóxico o afectar la reepitelización de la herida. Métodos: Los cultivos de queratinocitos humanos y fibroblastos y un modelo ex vivo humano de herida en la piel se sometieron a una exposición corta (limitada) y larga (crónica) de varias concentraciones clínicamente relevantes de TXA para simular diferentes modalidades de administración tópica. Se evaluaron la citotoxicidad y los efectos sobre la reepitelización de la herida. Resultados: En los cultivos celulares, la toxicidad de la exposición crónica se correlacionó con el incremento de la concentración y el tiempo de exposición. La exposición limitada al TXA no causó toxicidad significativa incluso a elevadas concentraciones. No se observó reepitelización en heridas expuestas de forma crónica a concentraciones de TXA de 25 mg/ml o superiores, y 50­100 mg/ml provocó epidermólisis del epitelio normal, posiblemente por un mecanismo no tóxico. La reepitelización de la herida se retrasó ligeramente, pero no se deterioró por una exposición limitada de 100 mg/ml o exposición crónica de 6,25 mg/ml. Conclusión: Mientras que la exposición corta, incluso hasta concentraciones elevadas, de TXA tópico parecen ser bien toleradas in vitro, la exposición prolongada al TXA tópico puede ser citotóxica y afectar la reepitelización de la herida. Los cirujanos deben ajustar la concentración de TXA al modo previsto de administración tópica en la práctica clínica.

Effects of Adrenaline on maternal and fetal fentanyl absorption in epidural analgesia: A randomized trial.

BACKGROUND: The combination of low-dose local anesthesia and lipophilic opioids such as fentanyl is established as a standard solution for labor epidural analgesia. Fentanyl increases efficacy, but may have negative effects on the neonate in terms of reduced neonatal neurologic and adaptive capacity scores and breast feeding. We hypothesized that addition of adrenaline 2 µg/mL to a solution of bupivacaine 1 mg/mL and fentanyl 2 µg/mL would reduce the systemic uptake of fentanyl, resulting in reduced serum fentanyl in the fetus at birth. METHODS: Forty-one nulliparous women requesting epidural analgesia were randomized to epidural analgesia with or without adrenaline. Blood samples were drawn from the mother with regular intervals, and at delivery. An umbilical vein blood sample (used as a proxy for fetal exposure) was drawn after clamping. RESULTS: There were no significant differences between the groups in fentanyl concentrations in the umbilical vein and maternal serum at birth. There was a significantly lower mean area under the maternal serum-concentration curve for the first 2 hours of treatment in the adrenaline group (mean difference 0.161 nmol h/L [0.034; 0.289], P = .015), implying slower systemic uptake in the adrenaline group initially. There were no significant differences in treatment duration, motor block, Apgar scores, umbilical pH and base excess, or mode of delivery. CONCLUSIONS: The addition of adrenaline to an epidural solution containing fentanyl lowered maternal systemic serum fentanyl concentration during the first 2 hours, but did not lower serum fentanyl concentration in the umbilical vein and mother at delivery.

Enantiomeric separation and quantification of R/S-amphetamine in urine by ultra-high performance supercritical fluid chromatography tandem mass spectrometry.

To distinguish between legal and illegal consumption of amphetamine reliable analytical methods for chiral separation of the R- and S-enantiomers of amphetamine in biological specimens are required. In this regard, supercritical fluid chromatography (SFC) has several potential advantages over liquid chromatography, including rapid separation of enantiomers due to low viscosity and high diffusivity of supercritical carbon dioxide, the main component in the SFC mobile phase. A method for enantiomeric separation and quantification of R- and S-amphetamine in urine was developed and validated using ultra-high performance supercritical fluid chromatography-tandem mass spectrometry (UHPSFC-MS/MS). Sample preparation prior to UHPSFC-MS/MS analysis was a semi-automatic solid phase extraction method. The UHPSFC-MS/MS method used a Chiralpak AD-3 column with a mobile phase consisting of CO2 and 0.2% cyclohexylamine in 2-propanol. The injection volume was 2 µL and run-time was 6 min. MS/MS detection was performed with positive electrospray ionization and two multiple reaction monitoring transitions (m/z 136.1 > 119.0 and m/z 136.1 > 91.0). The calibration range was 50-10,000 ng/mL for each enantiomer. The between-assay relative standard deviations were in the range of 3.7-7.6%. Recovery was 92-93% and matrix effects ranged from 100 to 104% corrected with internal standard. After development and validation, the method has been successfully implemented in routine use at our laboratory for both separation and quantification of R/S-amphetamine, and has proved to be a reliable and useful tool for distinguishing intake of R- and S-amphetamine in authentic patient samples.

Metabolic risk factors in schizophrenia and bipolar disorder: The effect of comedication with selective serotonin reuptake inhibitors and antipsychotics.

BACKGROUND: The aim of this observational study was to investigate the relationship between metabolic factors and use of selective serotonin reuptake inhibitors (SSRIs) combined with olanzapine, quetiapine or risperidone. METHODS: Data from the Norwegian Thematically Organized Psychosis study, a cross-sectional study on 1301 patients with schizophrenia (n=868) or bipolar disorder (n=433), were analyzed. As exposure variables in the linear regression model were included the dose or serum concentration of SSRIs (n=280) and of olanzapine (n=398), quetiapine (n=234) or risperidone (n=128). The main outcome variables were levels of total cholesterol, low and high density lipoprotein (LDL and HDL) cholesterol, triglycerides and glucose. RESULTS: One defined daily dose (DDD) per day of an SSRI in addition to olanzapine was associated with an increase in total cholesterol of 0.16 (CI 0.01 to 0.32) mmol/L (P=0.042) and an increase in LDL-cholesterol of 0.17 (CI 0.02 to 0.31) mmol/L (P=0.022). An SSRI serum concentration in the middle of the reference interval in addition to quetiapine was associated with an increase in total cholesterol of 0.39 (CI 0.10 to 0.68) mmol/L (P=0.011) and an increase in LDL-cholesterol of 0.29 (0.02 to 0.56) mmol/L (P=0.037). There were no such effects when combined with risperidone. CONCLUSIONS: The findings indicate only minor deteriorations of metabolic variables associated with treatment with an SSRI in addition to olanzapine and quetiapine, and none when combined with risperidone. These results suggest that SSRIs can be used in combination with antipsychotics, and that the possible increase in cardiovascular risk is negligible.

Effects of age and gender on the serum levels of clozapine, olanzapine, risperidone, and quetiapine.

OBJECTIVE: To investigate serum concentrations of second-generation antipsychotics in relation to age and gender in a population ranging from 18 to 100 years. METHOD: Results from a routine therapeutic drug monitoring database were retrieved, and 43 079 samples from 11 968 patients were included (17 249 samples for clozapine, 16 171 samples for olanzapine, 5343 samples for risperidone, and 4316 samples for quetiapine). The dose-adjusted concentration was used as the primary target variable. A linear mixed model was used to allow the inclusion of multiple samples from each patient. RESULTS: Age had a significant impact on the concentrations of all four drugs. At the age of 80, the dose-adjusted concentrations were up to twice those of the age of 40. At the age of 90, dose-adjusted concentrations were two- to three-fold higher. Age-related increases were largest for clozapine (+108% at 80 years; +197% at 90 years) and smallest for olanzapine (+28% at 80 years; +106% at 90 years). Females generally had dose-adjusted concentrations 20-30% higher than males. CONCLUSION: The effect of age on the serum concentrations of the antipsychotics studied becomes pronounced with advanced age. The patient population aged above 70 should be subdivided according to exact age, and considerable dose reductions are recommended.

Randomized clinical trial of topical tranexamic acid after reduction mammoplasty.

BACKGROUND: The antifibrinolytic drug tranexamic acid is currently being rediscovered for both trauma and major surgery. Intravenous administration reduces the need for blood transfusion and blood loss by about one-third, but routine administration in surgery is not yet advocated owing to concerns regarding thromboembolic events. The aim of this study was to investigate whether topical application of tranexamic acid to a wound surface reduces postoperative bleeding. METHODS: This was a randomized double-blind placebo-controlled trial on 30 consecutive women undergoing bilateral reduction mammoplasty. On one side the wound surfaces were moistened with 25 mg/ml tranexamic acid before closure, and placebo (saline) was used on the other side. Drain fluid production was measured for 24 h after surgery, and pain was measured after 3 and 24 h. Postoperative complications including infection, seroma, rebleeding and suture reactions were recorded. RESULTS: Topical application of tranexamic acid to the wound surface after reduction mammoplasty reduced drain fluid production by 39 per cent (median 12·5 (range 0-44) versus 20·5 (0-100) ml; P = 0·038). Adverse effects were not observed. There were no significant differences in postoperative pain scores or complications. CONCLUSION: Topical application of dilute tranexamic acid reduced bleeding in this model. The study adds to the evidence that this simple procedure may reduce wound bleeding after surgery. REGISTRATION NUMBER: NCT01964781 ( http://www.clinicaltrials.gov).

Alfentanil during rapid sequence induction with thiopental 4 mg/kg and rocuronium 0.6 mg/kg: tracheal intubation conditions.

BACKGROUND: Opioids have become an integral part of anaesthesia induction. We aimed to determine the dose of alfentanil needed to obtain perfect tracheal intubation conditions during rapid sequence induction with standard doses of thiopental and rocuronium, where laryngoscopy was initiated 55 s after commencement of drug administration. The influence of covariates (sex, body weight, age, alfentanil plasma concentration at laryngoscopy) was tested. METHODS: Eighty-four healthy individuals were randomly assigned to receive one of the seven assessor-blinded alfentanil doses (0, 10, 20, 30, 40, 50 and 60 µg/kg) in conjunction with thiopental 4 mg/kg and rocuronium 0.6 mg/kg. For drug administration, 15 s was allowed. Laryngoscopy was initiated 40 s after rocuronium and tracheal intubation concluded within 70 s after commencement of drug administration. Alfentanil doses associated with 50%, 90% and 95% probability of perfect intubation conditions were determined with logistic regression. Multiple logistic regressions were used to test the influence of covariates. The relationship between alfentanil dose and concentration at laryngoscopy was analysed with linear regression. The effects of covariates on plasma concentrations of alfentanil were tested with multiple linear regressions. RESULTS: Perfect intubation conditions of 95% probability was obtained with 56 µg/kg (confidence intervals 44-68). None of the covariates were significant predictors of perfect intubation conditions. Alfentanil plasma concentration correlated with dose and increased with increasing body weight (1.7 ng/ml/kg). CONCLUSION: Perfect intubation conditions during rapid sequence induction can be obtained with clinically relevant doses of alfentanil in most healthy patients anaesthetized with thiopental 4 mg/kg and rocuronium 0.6 mg/kg.

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.

Effects of ibuprofen, diclofenac, naproxen, and piroxicam on the course of pregnancy and pregnancy outcome: a prospective cohort study.

OBJECTIVE: To investigate the individual effects of ibuprofen, diclofenac, naproxen, and piroxicam on pregnancy outcome. DESIGN: Cohort study. SETTING: Norwegian population. POPULATION: A total of 90 417 women and singleton child pairs. METHODS: The Norwegian Mother and Child Cohort Study and Medical Birth Registry of Norway data sets were used. MAIN OUTCOME MEASURES: Infant survival, congenital malformations, structural heart defects, neonatal complications, haemorrhage during pregnancy and postpartum, asthma at age of 18 months. RESULTS: One or more of the four nonsteroidal anti-inflammatory drugs (NSAIDs) were used by 6511 pregnant women (7.2%). No effect on rates of infant survival, congenital malformation, or structural heart defects was found. The use of ibuprofen in the second trimester was significantly associated with low birthweight (adjusted OR 1.7, 95% CI 1.3-2.3), and ibuprofen use in the second and third trimesters was significantly associated with asthma in 18-month-old children (adjusted OR 1.5, 95% CI 1.2-1.9; adjusted OR 1.5, 95% CI 1.1-2.1). The use of diclofenac in the second trimester was significantly associated with low birthweight (adjusted OR 3.1, 95% CI 1.1-9.0), whereas diclofenac use in the third trimester was significantly associated with maternal vaginal bleeding (adjusted OR 1.8, 95% CI 1.1-3.0). No associations with other neonatal complications were found. CONCLUSIONS: The lack of associations with congenital malformations is reassuring. The significant association between diclofenac and ibuprofen use late in pregnancy, and maternal bleeding and asthma in the child, respectively, is consistent with their pharmacological effects. The increased risk of low birthweight may partly have been caused by underlying inflammatory conditions, and was reassuringly similar to the expected baseline risk of low birthweight.

Characterisation of zuclopenthixol metabolism by in vitro and therapeutic drug monitoring studies.

OBJECTIVE: Zuclopenthixol pharmacokinetics is incompletely characterised. We investigated potential interactions mediated through cytochrome P450 enzymes. METHOD: In vitro, we examined the impact of CYP2D6 and CYP3A4 inhibitors on zuclopenthixol metabolism in microsomes from six human livers. Subsequently, we compared dose-corrected serum zuclopenthixol concentrations in 923 samples from a therapeutic drug monitoring database from patients prescribed oral (n = 490) or injected (n = 423) zuclopenthixol alone or with fluoxetine, paroxetine, levomepromazine or carbamazepine. RESULTS: In vitro fluoxetine, paroxetine, ketoconazole and quinidine all significantly inhibited zuclopenthixol metabolism. Ketoconazole and quinidine together abolished zuclopenthixol disappearance. Clinically, dose-corrected oral zuclopenthixol serum concentrations increased significantly, after adjustment, by 93%, 78% and 46% during co-treatment with fluoxetine, paroxetine and levomepromazine and decreased 67% with carbamazepine. Carbamazepine caused dose-dependent reductions in the oral zuclopenthixol concentration-dose ratio (P < 0.001), fluoxetine (P < 0.001) and paroxetine (P = 0.011) dose-dependent increases and levomepromazine an increase related to its serum concentration (P < 0.001). Results for injected zuclopenthixol were similar but not all reached statistical significance. CONCLUSION: The In vitro study suggests zuclopenthixol is metabolised primarily by CYP2D6 and CYP3A4. The clinical study supports this, demonstrating the impact of co-prescribed inhibitors or inducers. Guidelines should incorporate these interactions noting the potential for zuclopenthixol-related toxicity or treatment failure.

Maternal characteristics and migraine pharmacotherapy during pregnancy: cross-sectional analysis of data from a large cohort study.

Little is known about factors associated with migraine pharmacotherapy during pregnancy. Of 60 435 pregnant women in a population-based cohort, 3480 (5.8%) reported having migraine during the first 5 months of pregnancy. Of these, 2525 (72.6%) reported using migraine pharmacotherapy, mostly non-narcotic analgesics (54.1%) and triptans (25.4%). After adjustment for sociodemographic factors and comorbidities in logistic regression analysis, high pregestational body mass index [odds ratio (OR) 1.3, 95% confidence interval (CI) 1.2, 1.4], sleep < 5 h (OR 1.6, 95% CI 1.3, 1.9), being on sick-leave (OR 1.3, 95% CI 1.2, 1.5) and acute back/shoulder/neck pain (OR 0.6, 95% CI 0.6, 0.7) were associated with migraine pharmacotherapy during pregnancy. Many women need drug treatment for migraine during pregnancy, and the choice of pharmacotherapy during this period may be influenced by maternal sociodemographic factors and comorbidities.

Pharmacokinetics of intraperitoneally instilled aminophylline, terbutaline and tobramycin in pigs.

INTRODUCTION: Venous catheters are sometimes difficult or even impossible to insert and may also be associated with serious complications. This study was carried out to investigate whether intraperitoneal administration of drugs may be an alternative to the intravenous route in patients with limited vascular access. MATERIALS AND METHODS: Three drugs commonly in use in clinical practise, aminophylline, terbutaline and tobramycin, were administered to pigs intravenously and intraperitoneally in small volumes. Serum concentrations were analysed over a period of 6 h and pharmacokinetic key variables for each drug were calculated. RESULTS: Aminophylline (theophylline), terbutaline and tobramycin were absorbed from the peritoneal space and into systemic circulation. For theophylline, the concentration/time profiles after intraperitoneal and after intravenous administration were almost identical, and the intraperitoneal bioavailability was calculated to 0.94. For terbutaline and tobramycin, the intraperitoneal absorption was delayed without any initial peak. Moreover, the intraperitoneal bioavailability was lower than for theophylline (0.71 and 0.65, respectively). CONCLUSION: The pharmacokinetic properties after intraperitoneal administration differed among the three drugs, but the results are encouraging and provide a basis for further investigation in humans.