Risk of preterm birth in relation to history of preterm birth: a population-based registry study of 213 335 women in Norway.

OBJECTIVE: To assess the association between preterm first birth and preterm second birth according to gestational age and to determine the role of placental disorder in recurrent preterm birth. DESIGN: Population-based registry study. SETTING: Medical Birth Registry of Norway and Statistics Norway. POPULATION: Women (n = 213 335) who gave birth to their first and second singleton child during 1999-2014 (total n = 426 670 births). METHODS: Multivariate logistic regression analyses, adjusted for placental disorders, maternal, obstetric and socio-economic factors. MAIN OUTCOME MEASURES: Extremely preterm (<28+0 weeks), very preterm (28+0 -33+6 weeks) and late preterm (34+0 -36+6 weeks) second birth. RESULTS: Preterm birth (<37 weeks) rates were 5.6% for first births and 3.7% for second births. Extremely preterm second births (0.2%) occurred most frequently among women with an extremely preterm first birth (aOR 12.90, 95% CI 7.47-22.29). Very preterm second births (0.7%) occurred most frequently after an extremely preterm birth (aOR 12.98, 95% CI 9.59-17.58). Late preterm second births (2.8%) occurred most frequently after a previous very preterm birth (aOR 6.86, 95% CI 6.11-7.70). Placental disorders contributed 30-40% of recurrent extremely and very preterm births and 10-20% of recurrent late preterm birth. CONCLUSION: A previous preterm first birth was a major risk factor for a preterm second birth. The contribution of placental disorders was more pronounced for recurrent extremely and very preterm birth than for recurrent late preterm birth. Among women with any category of preterm first birth, more than one in six also had a preterm second birth (17.4%). TWEETABLE ABSTRACT: Preterm first birth is a major risk factor for subsequent preterm birth, regardless of maternal, obstetric or fetal risk factors.

Country of birth and county of residence and association with overweight and obesity-a population-based study of 219 555 pregnancies in Norway.

BACKGROUND: The aim was to study the effect of country of birth, educational level and county of residence on overweight and obesity among pregnant women in Norway. METHODS: Observational study based on Medical Birth Registry Norway and Statistics Norway. The study population consisted of 219 555 deliveries in 2006-2014. Body mass index (BMI) was registered at the first antenatal care visit. Multivariate regression analysis was used to explore the study aims. RESULTS: Overweight (BMI 25-29.9) was recorded in 22.3% of the women, obesity (BMI ≥30) in 12.2%. Highest rates of overweight (30.8%) and obesity (13.5%) was recorded among women from the Middle East and North Africa or with no education (30.7% and 17.2%). The prevalence of overweight and obesity was 39.5% in sparsely populated counties and 26.4% for women living in Oslo. Adjusted for country of birth, education level, age, parity, smoking and marital status, the relative odds of overweight and obesity were 65% (95% CI 59-72%) higher in sparsely populated counties compared to Oslo. CONCLUSIONS: The prevalence of overweight (BMI ≥25) was 34.5%. The factors associated with overweight were living in rural districts in Norway, lower education and being born in countries in the Middle East or Africa.

Hypertension after kidney donation: Incidence, predictors, and correlates.

Incidence of postdonation hypertension, risk factors associated with its development, and impact of type of treatment received on renal outcomes were determined in 3700 kidney donors. Using Cox proportional hazard model, adjusted hazard ratios (HRs) for cardiovascular disease (CVD); estimated glomerular filtration rate (eGFR) <60, <45, <30 mL/min/1.73m2 ; end stage renal disease (ESRD); and death in hypertensive donors were determined. After a mean (standard deviation [SD]) of 16.6 (11.9) years of follow-up, 1126 (26.8%) donors developed hypertension and 894 with known antihypertensive medications. Hypertension developed in 4%, 10%, and 51% at 5, 10, and 40 years, respectively, and was associated with proteinuria, eGFR < 30, 45, and 60 mL/min/1.73m2 , CVD, and death. Blood pressure was <140/90 mm Hg at last follow-up in 75% of hypertensive donors. Use of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (compared to other antihypertensive agents) was associated with a lower risk for eGFR <45 mL/min/1.73m², HR 0.64 (95% confidence interval [CI] 0.45-0.9), P = .01, and also less ESRD; HR 0.03 (95% CI 0.001-0.20), P = .004. In this predominantly Caucasian cohort, hypertension is common after donation, well controlled in most donors, and factors associated with its development are similar to those in the general population.

Differences in physical activity at recess and school-related social factors in four Finnish lower secondary schools.

This study investigated the differences in physical activity (PA) at recess and school-related social factors, and described school PA promotion processes and staff experiences at four lower secondary schools from the Finnish Schools on the Move programme. Recess PA, peer relationships at school, relatedness to school, and school climate were assessed via surveys with eighth-grade students in spring 2011 (n = 385) and spring 2013 (n = 373). Local contact people in the school projects (n = 6), school staff (n = 83) and principals (n = 3) provided information on the PA promotion process via telephone interviews and surveys. Differences in student-level data in years 2011 and 2013 were analysed by gender using two-way ANOVA. Data on school processes were analysed using a combination of classification, narrative approach and content analysis.In two of the four schools, male students reported higher levels of recess PA in 2013 compared to 2011. In three schools, school-related social factors did not differ between 2011 and 2013. School cultures and routes towards a more physically active school day differed; the project was highly visible in all schools, but staff participation varied. More research is needed to determine the effective physically active strategies to promote positive social well-being and to enhance staff engagement.

High completeness of the brest stroke registry evidenced by analysis of sources and capture-recapture method.

BACKGROUND: Population-based stroke registries are necessary to evaluate the precise burden of stroke. The methodology used in the Brest Stroke Registry and an estimation of its completeness are described. METHODS: 'Hot pursuit' as well as 'cold pursuit' were used, and five sources of identification were included: emergency wards, brain imaging, practitioners, death certificates and hospital-based electronic research. Ascertainment for each case was certified by a neurologist. Inclusion criteria were: (1) age >15 years; (2) a stroke defined by WHO criteria or all neurological deficits lasting at least 1 h. Completeness was estimated using capture-recapture method. RESULTS: For 2008, 2009 and 2010, 851, 898, 823 patients were collected, respectively. The number of sources of identification per patient was as follows: one source: 30.8, 24.1 and 18.7%; two sources: 54.5, 42.9 and 31.0%; three sources: 13.4, 30.1 and 46%; four sources: 1.3, 3.0 and 3.8%. Capture-recapture analysis showed data completeness over 90%. Standardized cumulative first-ever stroke incidence using a world standard population was 87 in 2008, 87 in 2009 and 84 in 2010. CONCLUSIONS: Case ascertainment by a neurologist, numerous sources, as well as 'hot' and 'cold' pursuit can provide a reliably large data set suitable for further epidemiological studies.

Adolescents' physical activity at recess and actions to promote a physically active school day in four Finnish schools.

The national Finnish Schools on the Move programme support schools with their individual plans to promote school-based physical activity (PA). We examined the changes in adolescents' recess and overall PA in four lower secondary schools and described the school actions to promote students' PA and the local contact persons' perceptions of the effects. Recess and overall PA were assessed four times by anonymous questionnaires from students in grades 7-9 (n = 789) in 2010-12, and local contact persons (n = 7) provided information on school actions with diaries, interviews and surveys. Student data were analysed with descriptive statistics and chi-square tests, and school actions data were analysed with quantitative content analysis. The proportion of students who participated in physical activities at recess at least sometimes increased from 30% to 49% in physically active play and from 33% to 42% in ball games, mostly due to improvements in males' participation. Females' participation in recess activities increased in two schools with gender-specific physical activities or facilities. Overall PA levels declined slightly. Organized recess activities, student recess activators and equipment provision and sports facilities development were considered to have affected students' PA positively. Solutions for getting females more physically active in the school setting are needed.

Classification of episiotomy: towards a standardisation of terminology.

Seven episiotomy incisions are described in the literature, although only midline, mediolateral or lateral episiotomies are commonly used. Recent research has demonstrated variations in both site and direction of the incision, and differences between the angle of incision at the time of crowning of the fetal head and the angle of the scar once the wound has been repaired. We review this evidence and suggest that this variation may undermine the reliability of much published work. We suggest a standardised definition of each type of episiotomy to establish uniformity going forward, so that future studies are amenable to comparison and meta-analysis.

Potential CYP2C9-mediated drug-drug interactions in hospitalized type 2 diabetes mellitus patients treated with the sulphonylureas glibenclamide, glimepiride or glipizide.

OBJECTIVES: Sulphonylureas are widely used in the treatment of type 2 diabetes mellitus (T2DM). Based on laboratory findings, we determined the clinical significance of potential CYP2C9-mediated drug-drug interactions in hospitalized patients receiving glibenclamide, glimepiride or glipizide, all of which are metabolized by CYP2C9, together with a CYP2C9 inhibitor. DESIGN, SETTING AND SUBJECTS: An observational pharmaco-epidemiological database study was performed in a university hospital setting with 3884 patients with T2DM. MAIN OUTCOME MEASURES: Efficacy and safety of sulphonylurea therapy during the potential interaction (sulphonylurea treatment with a CYP2C9 inhibitor) vs. control periods (sulphonylurea treatment without a CYP2C9 inhibitor) were estimated using laboratory parameters. RESULTS: Almost 20% of patients were exposed to a potential drug-drug interaction with a CYP2C9 inhibitor during sulphonylurea treatment. More than 75% of the potential interactions occurred with trimethoprim, metronidazole and fluconazole. When all sulphonylureas were pooled and adjusted for age, gender, ward and sulphonylurea dose, mean and maximum fasting plasma glucose concentrations as well as maximum values of glycosylated haemoglobin were significantly lower during the interaction periods compared with control periods, whereas mean and minimum activities of alanine amino transferase and gamma-glutamyl transferase were higher. The minimum fasting plasma glucose values were more often below the target range in patients with potential interactions. The sulphonylurea dose did not differ significantly between patients who were or were not concomitantly treated with a potentially interacting drug. CONCLUSIONS: Concomitant use of a CYP2C9 inhibitor results in exaggerated pharmacodynamic effects of sulphonylureas and increases the risk of hypoglycaemia in T2DM patients receiving glibenclamide, glimepiride or glipizide.

Voriconazole increases while itraconazole decreases plasma meloxicam concentrations.

This study investigated the effect of voriconazole, an inhibitor of cytochrome P450 2C9 (CYP2C9) and CYP3A4, and itraconazole, an inhibitor of CYP3A4, on the pharmacokinetics and pharmacodynamics of meloxicam. Twelve healthy volunteers in a crossover study ingested 15 mg of meloxicam without pretreatment (control), after voriconazole pretreatment, and after itraconazole pretreatment. The plasma concentrations of meloxicam, voriconazole, itraconazole, and thromboxane B(2) (TxB(2)) generation were monitored. Compared to the control phase, voriconazole increased the mean area under the plasma concentration-time curve from 0 to 72 h (AUC(0-72)) of meloxicam by 47% (P < 0.001) and prolonged its mean half-life (t(1/2)) by 51% (P < 0.01), without affecting its mean peak concentration (C(max)). In contrast, itraconazole decreased the mean AUC(0-72) and C(max) of meloxicam by 37% (P < 0.001) and by 64% (P < 0.001), respectively, and prolonged its t(1/2) and time to C(max). The plasma protein unbound fraction of meloxicam was unchanged by voriconazole and itraconazole. Lowered plasma meloxicam concentrations during the itraconazole phase were associated with decreased pharmacodymic effects of meloxicam, as observed by weaker inhibition of TxB(2) synthesis compared to the control and voriconazole phases. Voriconazole increases plasma concentrations of meloxicam, whereas itraconazole, unexpectedly, decreases plasma meloxicam concentrations, possibly by impairing its absorption.

The role of mediolateral episiotomy during operative vaginal delivery.

The role of episiotomy with regard to prevention of anal sphincter injuries (OASIS) is under discussion. The recently published guideline of the WHO "Intrapartum care for a positive childbirth experience" states that the role of episiotomy during operative vaginal deliveries remains to be established. This guideline is based on the evidence coming from randomised clinical trials. However, since the turn of the century large observational studies have pointed out that adequately performed mediolateral episiotomies may play an important role in the prevention of OASIS during operative vaginal deliveries. In this paper we present this evidence and plead for a broader vision on, and use of other evidence than randomised clinical trials solely, the preventive role of mediolateral episiotomy with regard to the occurrence of OASIS.

Influence of adenosine triphosphate and ABCB1 (MDR1) genotype on the P-glycoprotein-dependent transfer of saquinavir in the dually perfused human placenta.

BACKGROUND: The ATP-dependent drug-efflux pump, P-glycoprotein (P-gp) encoded by ABCB1 (MDR1), plays a crucial role in several tissues forming blood-tissue barriers. Absence of a normally functioning P-gp can lead to a highly increased tissue penetration of a number of clinically important drugs. METHODS: We have studied the dose-response effect of exogenous ATP on the placental transfer of the well-established P-gp substrate saquinavir in 17 dually perfused human term placentas. We have also studied the influence of the ABCB1 polymorphisms 2677G>T/A and 3435C>T on placental P-gp expression (n = 44) and the transfer (n = 16) of saquinavir. RESULTS: The present results indicate that the addition of exogenous ATP to the perfusion medium does not affect the function of P-gp as measured by saquinavir transfer across the human placenta. The variant allele 3435T was associated with significantly higher placental P-gp expression than the wild-type alleles. However, neither polymorphism affected placental transfer of saquinavir nor there was any correlation between P-gp expression and saquinavir transfer. CONCLUSIONS: Our results indicate that addition of exogenous ATP is not required for ATP-dependent transporter function in a dually perfused human placenta. Although the ABCB1 polymorphism 3435C>T altered the expression levels of P-gp in the human placenta, this did not have any consequences on P-gp-mediated placental transfer of saquinavir.

[Smoking among hospital staff and the impact of the November, No Smoking Month campaign on this population]. / Tabagisme chez les agents d'un hôpital et impact de la campagne Novembre, mois sans tabac sur cette population.

INTRODUCTION: Smoking cessation is a public health priority. Several prevention campaigns exist, including this one of the "month without tobacco", made in November in France. Healthcare workers have an important role to play in stopping smoking, while many of the healthcare workers are themselves smokers. The purpose of this article is to study the prevalence of tobacco consumption among hospital staff and to evaluate its effects. MATERIAL AND METHOD: It is a transversal study, carried out among the 734 agents of a French hospital, between December 2016 and January 2017, by anonymous self-questionnaires. The study included all hospital employees, whether they were caregivers or not. RESULTS: The participation rate was 35%, of whom 193 (75.7%) were health care workers, 46 (17.6%) were administrative and 17 (6.7%) were working in technical services. There were 31% smokers and 26% forming smokers. There were no significant differences in smoking by age, or socio-occupational category. During this campaign, 66.7% of smokers had plans to quit, and 29% tried to quit. CONCLUSION: The prevalence of smoking in this hospital was comparable to that of the general population, and among the highest in hospital in the literature. The campaign of the month without tobacco has influenced the consumption of smokers. Other studies need to analyze how to handle this population.

Phylogenetic background of Orange lily (Lilium bulbiferum s.l.) cultivars from a genetically isolated environment.

Domesticated Orange lily ( LILIUM BULBIFERUM s.l.) cultivars do not typically produce seeds, and Orange lily is not native to Finland. Therefore, back crossing of the cultivars with wild species has not been possible. Genetic variability and genuineness of eight Finnish traditionally-grown Orange lily cultivars was studied. RAPD patterns were compared between the cultivars and genuine Orange lily ( LILIUM BULBIFERUM L.), and a related Dauricum group. The results showed partition of tested genotypes into four groups, L. CANADENSE as the outgroup. The cultivars were divided into two subgroups where the trait to form bulbils was characteristic to subgroup I. The cultivated strains differed from each other as much as from the seedling strains, but were genetically closer to genuine Orange lily than the Dauricum group. This indicates that the cultivars are genuine forms of Orange lily species. The special morphological features of the cultivars have likely been formed during centuries-long genetic isolation from natural populations.

Identifying high risk medications causing potential drug-drug interactions in outpatients: A prescription database study based on an online surveillance system.

BACKGROUND: Drug-drug interactions (DDIs) are a significant cause for adverse drug events (ADEs). DDIs are often predictable and preventable, but their prevention and management require systematic service development. Most DDI studies focus on interaction rates in hospitalized patients. Less is known of DDIs in outpatients, particularly how community pharmacists could contribute to DDI management by applying their surveillance systems for identifying high-risk medications. OBJECTIVES: The study was related to the implementation of the first online DDI surveillance system in Finnish community pharmacies. The goal was to demonstrate how community pharmacies can utilize their prospective surveillance system 1) for identifying high risk medications causing potential DDIs in outpatients, 2) for collaborative service development with local physicians, and 3) for academic risk management research purposes. METHODS: All DDI alerts given by the online surveillance system were collected during a one-month period in 16 out of 17 University Pharmacy outlets in Finland, covering approximately 10% of the national outpatient prescription volume. The surveillance system was based on the FASS database, which categorizes DDIs into four classes (A-D) according to their clinical significance. RESULTS: Potential drug-drug DDIs were analyzed for 276,891 dispensed community pharmacy prescriptions. Potential DDIs were associated with 10.8%, or 31,110 of these prescriptions. Clinically significant interaction alerts categorized as FASS classes D (most severe, should be avoided) and C (clinically significant but controllable) were associated with 0.5% and 7.0% of the prescriptions, respectively. Methotrexate and warfarin had the highest risk of causing potentially serious (class D) interactions. These interaction alerts were most frequently between methotrexate and NSAIDs and warfarin and NSAIDs. In general, NSAIDs were the most commonly interacting drugs in this study. CONCLUSIONS: This study demonstrates that community pharmacies can actively contribute to DDI risk management and systematically use their surveillance systems for identifying patients having clinically significant DDIs. The findings also indicate that the majority of potentially serious interactions in outpatients involve a limited number of drugs, particularly NSAIDs, warfarin and methotrexate. Further research should focus on community pharmacists' involvement in DDI risk management in collaboration with local health care providers.

Normal laser-evoked cortical responses in patients with chronic hemibody pain.

BACKGROUND: Patients with widespread unilateral chronic pain associated with recurrent herpes simplex virus (HSV) infections show functional and/or structural changes in the insula, anterior cingulate cortex, frontal and prefrontal cortices, as well as the thalamus, suggesting central dysfunction of the pain system in these patients. Central pain has been associated with attenuated laser-evoked cortical responses. We aimed to clarify whether the observed deficient activation of these areas to acute nociceptive stimuli is due to a lesion at a lower level of pain processing pathways. METHODS: We explored the functional integrity of the ascending nociceptive pathways by recording the cortical-evoked responses to noxious laser stimulation using magnetoencephalography and electroencephalography in eight patients (age 41-51 years, mean 46) with recurrent HSV infections and a history of chronic, spontaneous, widespread unilateral pain, and in nine age-matched healthy control subjects. RESULTS: The cortical-evoked fields of the HSV patients originating from the secondary somatosensory and posterior parietal cortices, as well as the evoked potentials recorded from the midline, did not differ from those of the control subjects, indicating functionally intact ascending nociceptive pathways. CONCLUSIONS: The present results show that our patients with chronic hemibody pain do not show signs of spinothalamic tract lesion. This indicates normal processing of sensory aspects of painful stimuli, while higher pain processing areas show altered activation. We conclude that normal laser-evoked magnetic fields (LEF) or laser-evoked potentials (LEP) may not exclude central pain condition.

No sex-related differences but significant inhibition by oral contraceptives of CYP2C19 activity as measured by the probe drugs mephenytoin and omeprazole in healthy Swedish white subjects.

BACKGROUND: Although it is known that the use of oral contraceptives inhibits oxidative drug metabolism, there is little information regarding their effect on CYP2C19 activity. Moreover, earlier reports suggest that there may be differences in CYP2C19 activity between men and women. OBJECTIVE: We sought to assess the effect of sex and intake of oral contraceptives on CYP2C19 activity as measured by the probe drugs mephenytoin and omeprazole. METHODS: To determine CYP2C19 activity in white Swedish subjects, 644 subjects previously phenotyped with mephenytoin and 175 subjects phenotyped with omeprazole were investigated. The 8-hour urinary mephenytoin S/R ratio after ingestion of 100 mg mephenytoin and the plasma concentration ratio of omeprazole/hydroxyomeprazole at 3 hours after ingestion of 20 mg omeprazole were used as measures of CYP2C19 activity. Differences in these ratios and in their frequency distributions were then examined among women with and without oral contraceptives and men. In addition, nearly all subjects in the omeprazole group had been genotyped with regard to the CYP2C19*2 (ml) allele. Subjects homozygous for the CYP2C19*2 allele were excluded from the study. RESULTS: The median mephenytoin S/R ratio was 2.5-fold higher in the subgroup of women taking oral contraceptives compared with either women not taking oral contraceptives (P < .001) or men (P < .001). Similarly, the mean omeprazole/hydroxyomeprazole ratio was twice as high in the oral contraceptive group compared with women not taking oral contraceptives (P < .001) or men (P < .001). However, no differences were evident between women not taking oral contraceptives and men in either the mephenytoin group (P = .48) or the omeprazole group (P = .77). The oral contraceptive-induced inhibitory effect on CYP2C19 activity was similar between the CYP2C19*1/*1 and *1/*2 genotypes, and they were independent of age. CONCLUSIONS: Intake of oral contraceptives significantly inhibits CYP2C19 activity, but there is no true sex-related difference in CYP2C19 activity in healthy, white, Swedish subjects.

Plasma tacrine concentrations are significantly increased by concomitant hormone replacement therapy.

BACKGROUND: In vitro results suggest that the synthetic hormones used in postmenopausal hormone replacement therapy (HRT) may be significant inhibitors of oxidative drug metabolism. Moreover, HRT has been reported to enhance response to tacrine in postmenopausal patients with Alzheimer's disease, but the mechanism of this interaction remains unclear. OBJECTIVE: To examine the effect of HRT with 2 mg estradiol valerate and 0.25 mg levonorgestrel once daily on the pharmacokinetics of tacrine. METHODS: Ten healthy female volunteers received treatment for 10 days with once-daily HRT or placebo in a randomized, double-blind crossover study. One hour after the last HRT or placebo capsule on day 10, the subjects received a single 40-mg dose of tacrine. Plasma samples were collected for 30 hours and urine samples were collected for 24 hours after tacrine intake for the measurement of tacrine and 1-hydroxytacrine concentrations. RESULTS: HRT increased the mean plasma concentration-time curve calculated from zero to infinity (AUC) of tacrine by 60% (P = .009); the greatest individual increase in the AUC was about threefold. Similarly, the mean peak concentration in plasma of tacrine was 46% (P = .031) higher in the HRT phase compared with the placebo phase. HRT reduced the mean apparent oral clearance of tacrine by 31% (P = .014), but no significant difference was found in the elimination half-life or the renal clearance of tacrine between the HRT phase and the placebo phase. The metabolic ratio (1-hydroxytacrine AUC/tacrine AUC) was significantly (mean, 26%; P < .001) reduced in all 10 subjects. CONCLUSIONS: HRT with estradiol and levonorgestrel significantly increased plasma tacrine concentrations. This interaction between tacrine and HRT involves reduced metabolic conversion of tacrine to its main metabolite 1-hydroxytacrine by CYP1A2 during the first-pass phase. The interaction may be clinically important with regard to both enhanced efficacy and increased likelihood of concentration-dependent adverse effects of tacrine in the long-term treatment of patients with Alzheimer's disease. Accordingly, smaller doses of tacrine may be appropriate when coadministered with HRT.

Inhibition of cytochrome P4502D6 activity with paroxetine normalizes the ultrarapid metabolizer phenotype as measured by nortriptyline pharmacokinetics and the debrisoquin test.

BACKGROUND: The ultrarapid metabolizer phenotype of the cytochrome P4502D6 (CYP2D6) enzyme has been considered a relevant cause of nonresponse to antidepressant drug therapy. Prescribing high doses of antidepressants to such patients leads to high concentrations of potentially toxic metabolites and an increased risk for adverse reactions. Normalization of the metabolic status of ultrarapid metabolizers by inhibition of CYP2D6 activity could offer a clinically acceptable method to successfully treat such patients with antidepressants. METHODS: Five ultrarapid metabolizers with a CYP2D6 gene duplication or triplication were treated with 25 mg nortriptyline twice a day for 3 consecutive weeks, alone during the first week and concomitantly with the CYP2D6 inhibitor paroxetine 10 mg or 20 mg twice a day, respectively, during the second and third weeks. After the third week, nortriptyline was discontinued and the subjects were treated with paroxetine 20 mg twice a day during the fourth study week. At the end of each study week, the steady-state pharmacokinetic parameters of nortriptyline or paroxetine were determined within the dose interval. In addition, the CYP2D6 phenotype was determined by debrisoquin (INN, debrisoquine) test at baseline and at the end of each study phase. Treatment-related adverse events were recorded during drug administration and for 1 week thereafter. RESULTS: All 5 subjects had very low (subtherapeutic) nortriptyline concentrations after 7 days' treatment with nortriptyline only. Addition of paroxetine 10 mg twice a day to the nortriptyline regimen resulted in a change in all individuals to the "normal" extensive debrisoquine metabolizer phenotype, and therapeutic plasma nortriptyline concentrations were achieved in 4 of 5 subjects after a 3 times mean increase in nortriptyline trough concentration (P =.0011). Doubling the paroxetine dose caused a 15 times mean increase in paroxetine trough concentration (P <.001), indicating strong inhibition by paroxetine of its own metabolism. The high paroxetine concentrations in 2 subjects caused them to have the poor debrisoquine metabolizer phenotype and resulted in a further increase in plasma nortriptyline trough concentration (P =.0099). A strong correlation (rank correlation coefficient [r(s)] = 0.89; P <.0001) was observed between paroxetine and nortriptyline trough concentrations. Paroxetine also significantly decreased the fluctuation of nortriptyline concentrations within the dose interval. One subject discontinued the study after the second study week because of adverse effects; otherwise, the study drugs were well tolerated. CONCLUSIONS: Paroxetine, with a daily dosage from 20 to 40 mg, is an effective tool in normalizing the metabolic status of CYP2D6 ultrarapid metabolizers.

Synthesis and in vitro evaluation of novel morpholinyl- and methylpiperazinylacyloxyalkyl prodrugs of 2-(6-methoxy-2-naphthyl)propionic acid (Naproxen) for topical drug delivery.

Various novel morpholinyl- (3a,b) and methylpiperazinylacyloxyalkyl (3c-f) esters of 2-(6-methoxy-2-naphthyl)propionic acid were synthesized and evaluated in vitro for topical drug delivery as potential prodrugs of naproxen (1). Compounds 3a-f were prepared by coupling the corresponding naproxen hydroxyalkyl ester with the morpholinyl- or (4-methyl-1-piperazinyl)acyl acid in the presence of dicyclohexylcarbodiimide (DCC) and 4-(dimethylamino)pyridine (DMAP) and quantitatively hydrolyzed (t(1/2) = 1-26 min) to naproxen in human serum. Compounds 3c-f showed higher aqueous solubility and similar lipophilicity, determined by their octanol-buffer partition coefficients (log P(app)), at pH 5.0 when compared to naproxen. At pH 7.4 they were significantly more lipophilic than naproxen. The best prodrug 3c led to a 4- and 1.5-fold enhancement of skin permeation when compared to naproxen at pH 7.4 and 5.0, respectively. The present study indicates using a methylpiperazinyl group yields prodrugs that are partially un-ionized under neutral and slightly acidic conditions, and thus, a desirable combination is achieved in terms of aqueous solubility and lipophilicity. Moreover, the resulting combination of biphasic solubility and fast enzymatic hydrolysis of the methylpiperazinylacyloxyalkyl derivatives gave improved topical delivery of naproxen.