Pharmacology Portal: An Open Database for Clinical Pharmacologic Laboratory Services.

PURPOSE: More than 50 Norwegian public and private laboratories provide one or more analyses for therapeutic drug monitoring or testing for drugs of abuse. Practices differ among laboratories, and analytical repertoires can change rapidly as new substances become available for analysis. METHODS: The Pharmacology Portal was developed to provide an overview of these activities and to standardize the practices and terminology among laboratories. The Pharmacology Portal is a modern dynamic web database comprising all available analyses within therapeutic drug monitoring and testing for drugs of abuse in Norway. Content can be retrieved by using the search engine or by scrolling through substance lists. The core content is a substance registry updated by a national editorial board of experts within the field of clinical pharmacology. This ensures quality and consistency regarding substance terminologies and classification. FINDINGS: All laboratories publish their own repertoires in a user-friendly workflow, adding laboratory-specific details to the core information in the substance registry. The user management system ensures that laboratories are restricted from editing content in the database core or in repertoires within other laboratory subpages. The portal is for nonprofit use, and has been fully funded by the Norwegian Medical Association, the Norwegian Society of Clinical Pharmacology, and the 8 largest pharmacologic institutions in Norway. IMPLICATIONS: The database server runs an open-source content management system that ensures flexibility with respect to further development projects, including the potential expansion of the Pharmacology Portal to other countries.

Modulation of high affinity ATP-dependent cyclic nucleotide transporters by specific and non-specific cyclic nucleotide phosphodiesterase inhibitors.

Intracellular cyclic nucleotides are eliminated by phosphodiesterases (PDEs) and by ATP Binding cassette transporters such as ABCC4 and ABCC5. PDE5 and ABCC5 have similar affinity for cGMP whereas ABCC5 has much higher affinity for cGMP compared with cAMP. Since the substrate (cGMP) is identical for these two eliminatory processes it is conceivable that various PDE inhibitors also modulate ABCC5-transport. Cyclic GMP is also transported by ABBC4 but the affinity is much lower with a Km 50-100 times higher than for that of ABBCC5. The present study aimed to determine Ki-values for specific or relative specific PDE5 inhibitors (vardenafil, tadalafil, zaprinast and dipyridamole) and the non-specific PDE inhibitors (IBMX, caffeine and theophylline) for ABCC5 and ABCC4 transport. The transport of [(3)H]-cGMP (2 µM) was concentration-dependently inhibited with the following Ki-values: vardenafil (0.62 µM), tadalafil (14.1 µM), zaprinast (0.68 µM) and dipyridamole (1.2 µM), IBMX (10 µM), caffeine (48 µM) and theophylline (69 µM). The Ki-values for the inhibition of the [(3)H]-cAMP (2 µM) transport were: vardenafil (3.4 µM), tadalafil (194 µM), zaprinast (2.8 µM), dipyridamole (5.5 µM), IBMX (16 µM), caffeine (41 µM) and theophylline (85 µM). The specificity for ABCC5 we defined as ratio between Ki-values for inhibition of [(3)H]-cGMP and [(3)H]-cAMP transport. Tadalafil showed the highest specificity (Ki-ratio: 0.073) and caffeine the lowest (Ki-ratio: 1.2).

Urinary concentrations of gamma-hydroxybutyric acid and related compounds in pregnancy.

Endogenous production complicates the interpretation when gamma-hydroxybutyric acid (GHB) is measured in urine for forensic purposes. We performed a cross-sectional study to test the hypothesis that pregnant women have higher levels of urinary GHB than non-pregnant controls, and thus increased risk of false-positive GHB tests. GHB, gamma-butyrolactone (GBL) and beta-hydroxybutyric acid (BHB) concentrations in urine from 66 pregnant women and 69 non-pregnant controls were analyzed by liquid chromatography-tandem mass spectrometry (LC-MS-MS). The mean GHB, GBL, and BHB concentrations were 0.36, 0.34 and 1.92 mg/L in the pregnant women, and 0.24, 0.08 and 0.40 mg/L in the control group. The pregnant women had significantly higher levels of GHB (1.5-fold), GBL (4.3-fold), and BHB (4.8-fold). Creatinine-adjusted GHB concentrations were similar in both groups. Pregnant women have higher urinary levels of GHB, GBL, and BHB. In LC-MS-MS assays not distinguishing between GHB and BHB, there is a significantly increased risk of false-positive GHB tests in pregnant women. This false-positive rate can be reduced by correcting for creatinine concentration, by using GHB-specific assays or by introducing higher interpretative cut-off levels for pregnant women in assays that do not discriminate between GHB and GBL or BHB.

Severe apnea in an infant exposed to lamotrigine in breast milk.

OBJECTIVE: To report a case of severe apnea in an infant exposed to lamotrigine through breast-feeding. CASE SUMMARY: A 16-day-old infant developed several mild episodes of apnea that culminated in a severe cyanotic episode requiring resuscitation. A thorough examination at the hospital gave no evidence of underlying diseases that could explain the reaction. The mother had used lamotrigine in increasing doses throughout pregnancy, and at the time of the apneic episodes, she used 850 mg/day. The infant was fully breast-fed, and the neonatal lamotrigine serum concentration was 4.87 microg/mL at the time of admission. Breast-feeding was terminated, and the infant fully recovered. DISCUSSION: Although there are several reports on extensive passage of lamotrigine into breast milk, this is the first published report of a serious adverse reaction in a breast-fed infant. Lamotrigine clearance increases throughout pregnancy, and maternal dose increases are often necessary to maintain therapeutic effect. After delivery, clearance rapidly returns to preconception levels, enhancing the risk of adverse reactions in both mothers and breast-fed infants if the dose is not sufficiently reduced. In this case, the dose was slowly reduced after delivery, and the maternal lamotrigine serum concentration more than doubled in the week before the neonatal apneic episodes. A high lamotrigine concentration was detected in the breast milk, and the neonatal lamotrigine serum concentration was in the upper therapeutic range. The neonatal lamotrigine elimination half-life was approximately twice that seen in adults. The Naranjo probability scale indicated a probable relationship between apnea and exposure to lamotrigine through breast-feeding in this infant. CONCLUSIONS: Infants can be exposed to clinically relevant doses of lamotrigine through breast-feeding. Individual risk/benefit assessment is important, and close monitoring of both mother and child is advisable, especially during the first 3 weeks postpartum.

[The endocannabinoid system and treatment of obesity]. / Det endocannabinoide system og fedmebehandling.

Rimonabant is a novel drug for treatment of obesity. Four randomised studies have shown a significant effect of 20 mg rimonabant on bodyweight and other cardiovascular risk factors. The weight loss is modest, approximately 5 %, and the patients regain their baseline weight within 9 months after withdrawal. There is no evidence that rimonabant reduces morbidity or mortality, and no comparative studies with orlistat or sibutramine have been performed. Long-term effects of blocking the endocannabinoid system are not known. Side effects are nausea, depressive symptoms, anxiety and dizziness. There are reports on increased suicidality, and rimonabant is contraindicated in depressed patients.

[Smoking is associated with increased risk of ectopic pregnancy--a population based study]. / Røyking er assosiert med økt risiko for ekstrauterine svangerskap.

BACKGROUND: There has been a world-wide increase in the incidence of ectopic pregnancies over the last decades. In Norway about 1,500 women are hospitalized every year because of this potentially lethal condition. Several studies have shown that smoking is one of several risk factors for ectopic pregnancies. We wanted to examine whether such an association could be established in a large Norwegian material. MATERIAL AND METHODS: We analysed data from a cross-sectional questionnaire-based study of 9,237 Norwegian women aged 35-49 years. 61.6% responded. RESULTS: 67.4% of the women were present or previous smokers. 301 (3.3%) had experienced an ectopic pregnancy. We found that smokers had a relative risk of 1.5 (95% CI 1.1-1.9) for ectopic pregnancy compared to non-smokers. INTERPRETATION: Our results support other studies. Identification of risk factors is important in the prevention of ectopic pregnancies. Smoking is a risk factor for ectopic pregnancy that can be reduced through counselling.