Diagnostic error as a result of drug-laboratory test interactions.

Background Knowledge of possible drug-laboratory test interactions (DLTIs) is important for the interpretation of laboratory test results. Test results may be affected by physiological or analytical drug effects. Failure to recognize these interactions may lead to misinterpretation of test results, a delayed or erroneous diagnosis or unnecessary extra tests or therapy, which may harm patients. Content Thousands of interactions have been reported in the literature, but are often fragmentarily described and some papers even reported contradictory findings. How can healthcare professionals become aware of all these possible interactions in their individual patients? DLTI decision support applications could be a good solution. In a literature search, only four relevant studies have been found on DLTI decision support applications in clinical practice. These studies show a potential benefit of automated DLTI messages to physicians for the interpretation of laboratory test results. All physicians reported that part of the DLTI messages were useful. In one study, 74% of physicians even sometimes refrained from further additional examination. Summary and outlook Unrecognized DLTIs potentially cause diagnostic errors in a large number of patients. Therefore, efforts to avoid these errors, for example with a DLTI decision support application, could tremendously improve patient outcome.

Impact of interactions between drugs and laboratory test results on diagnostic test interpretation - a systematic review.

Intake of drugs may influence the interpretation of laboratory test results. Knowledge and correct interpretation of possible drug-laboratory test interactions (DLTIs) is important for physicians, pharmacists and laboratory specialists. Laboratory results may be affected by analytical or physiological effects of medication. Failure to take into account the possible unintended influence of drug use on a laboratory test result may lead to incorrect diagnosis, incorrect treatment and unnecessary follow-up. The aim of this review is to give an overview of the literature investigating the clinical impact and use of DLTI decision support systems on laboratory test interpretation. Particular interactions were reported in a large number of articles, but they were fragmentarily described and some papers even reported contradictory findings. To provide an overview of information that clinicians and laboratory staff need to interpret test results, DLTI databases have been made by several groups. In a literature search, only four relevant studies have been found on DLTI decision support applications for laboratory test interpretation in clinical practice. These studies show a potential benefit of automated DLTI messages to physicians for the correct interpretation of laboratory test results. Physicians reported 30-100% usefulness of DLTI messages. In one study 74% of physicians sometimes even refrained from further additional examination. The benefit of decision support increases when a refined set of clinical rules is determined in cooperation with health care professionals. The prevalence of DLTIs is high in a broad range of combinations of laboratory tests and drugs and these frequently remain unrecognized.

AT2 receptor-mediated vasodilation in the mouse heart depends on AT1A receptor activation.

Angiotensin (Ang) II type 2 (AT(2)) receptors are believed to counteract Ang II type 1 (AT(1)) receptor-mediated effects. Here, we investigated AT(2) receptor-mediated effects on coronary and cardiac contractility in C57BL/6 mice. Hearts were perfused according to Langendorff. Baseline coronary flow (CF) and left ventricular systolic pressure (LVSP) were 2.7 +/- 0.1 ml min(-1) and 111 +/- 3 mmHg (n = 50), respectively. Ang II (n = 14) concentration dependently decreased CF and LVSP, by maximally 41 +/- 4 and 25 +/- 3%, respectively (pEC(50)s 7.41 +/- 0.12 and 7.65 +/- 0.12). The AT(1) receptor antagonist irbesartan (n = 4) abolished all Ang II-induced changes, whereas the AT(2) receptor antagonist PD123319 (n = 6) enhanced (P < 0.05) the effect of Ang II on CF (to 59 +/- 1%) and LVSP (to 44 +/- 2%), without altering its potency. A similar enhancement was observed in the presence of nitric oxide (NO) synthase inhibitor N(omega)-nitro-L-arginine methyl ester HCl (L-NAME; n = 4). On top of L-NAME, PD123319 no longer affected the response to Ang II (n = 4). The AT(2) receptor agonist CGP42112A (n = 4) did not affect CF or LVSP, nor did CGP42112A (n = 4) alter the constrictor response to the alpha(1)-adrenoceptor agonist phenylephrine. Furthermore, Ang II exerted no effects in hearts of AT(1A)(-/-) mice (n = 5), whereas its effects in hearts of AT(1A)(+/+) wild-type control mice (n = 7) were indistinguishable from those in hearts of C57BL/6 mice. In conclusion, Ang II exerts opposite effects on coronary and cardiac contractility in the mouse heart via activation of AT(1A) and AT(2) receptors. AT(2) receptor-mediated effects depend on NO and occur only in conjunction with AT(1A) receptor activation.

Angiotensin II type 2 receptor-mediated vasodilation. Focus on bradykinin, NO and endothelium-derived hyperpolarizing factor(s).

Angiotensin (Ang) II type 1 (AT(1)) receptors account for the majority of the cardiovascular effects Ang II, including vasoconstriction and growth stimulation. Recent evidence, mainly obtained in animals, suggests that Ang II type 2 (AT(2)) receptors counteract some or all of these effects. This review summarizes the current knowledge on the vasodilator effects induced by AT(2) receptors in humans and animals, focussing not only on the mediators of this effect, but also on the modulatory role of age, gender, and endothelial function. It is concluded that AT(2) receptor-mediated vasodilation most likely depends on the bradykinin-bradykinin type 2 (B(2)) receptor-NO-cGMP pathway, although evidence for a direct link between AT(2) and B(2) receptors is currently lacking. If indeed B(2) receptors are involved, this would imply that, in addition to NO, also the wide range of non-NO 'endothelium-derived hyperpolarizing factors' (EDHFs) that is released following B(2) receptor activation (e.g., K(+), cytochrome P450 products from arachidonic acid, H(2)O(2) and S-nitrososothiols), could contribute to AT(2) receptor-induced vasodilation.

Effects of the calcitonin gene-related peptide (CGRP) receptor antagonist BIBN4096BS on alpha-CGRP-induced regional haemodynamic changes in anaesthetised rats.

Several studies suggest that a calcitonin gene-related peptide (CGRP) receptor antagonist may have antimigraine properties, most probably via the inhibition of CGRP-induced cranial vasodilatation. We recently showed that the novel selective CGRP receptor antagonist, BIBN4096BS (1-piperidinecarboxamide, -N-[2-[[5-amino-1-[[4-(4-pyridinyl)-1-piperazinyl] carbonyl] pentyl]amino]-1-[(3,5-dibromo-4-hydroxyphenyl) methyl]-2-oxoethyl]-4-(1,4-dihydro-2-oxo-3(2H)-quinazolinyl)-, [[R-(R,(R*,S*)]), attenuated the CGRP-induced porcine carotid vasodilatation in a model predictive of antimigraine activity. In order to evaluate the potential safety of BIBN4096BS in migraine therapy, this study was designed to investigate the effects of intravenous BIBN4096BS on alpha-CGRP-induced systemic and regional haemodynamic changes in anaesthetised rats, using radioactive microspheres. In vehicle-pretreated animals, consecutive intravenous infusions of alpha-CGRP (0.25, 0.5 and 1 microg kg(-1) min.(-1)) dose-dependently decreased mean arterial blood pressure with an accompanying increase in heart rate and systemic vascular conductance whereas cardiac output remained unchanged. Alpha-CGRP also increased the vascular conductance to the heart, brain, gastrointestinal tract, adrenals, skeletal muscles and skin, whilst that to the kidneys, spleen, mesentery/pancreas and liver remained unaltered. The above systemic and regional haemodynamic responses to alpha-CGRP were clearly attenuated in BIBN4096BS (3 mg kg(-1) intravenously)-pretreated animals. These results indicate that exogenously administered alpha-CGRP dilates regional vascular beds via CGRP receptors on the basis of the antagonism produced by BIBN4096BS. Moreover, the fact that BIBN4096BS did not alter baseline haemodynamics suggests that endogenously produced CGRP does not play an important role in regulating the systemic and regional haemodynamics under resting conditions.

Superoxide does not mediate the acute vasoconstrictor effects of angiotensin II: a study in human and porcine arteries.

OBJECTIVE: To investigate whether superoxide mediates angiotensin (Ang) II-induced vasoconstriction. METHODS: Human coronary arteries (HCAs), porcine femoral arteries (PFA) and porcine coronary arteries (PCAs) were mounted in organ baths and concentration-response curves to Ang II, the nitric oxide (NO) donor S-nitroso-N-acetylpenicillamine (SNAP) and the NAD(P)H oxidase substrate NADH were constructed in the absence and presence of superoxide inhibiting and activating drugs. Extracellular superoxide was measured using cytochrome c reduction. RESULTS: Ang II constricted both HCAs and PFAs. In HCAs, the NAD(P)H inhibitors diphenyleneiodonium (DPI) and apocynin, and the xanthine oxidase (XO) inhibitor allopurinol, but not the superoxide dismutase (SOD) mimetic tempol or the SOD inhibitor diethyldithiocarbamate (DETCA), reduced this constriction. Catalase potentiated Ang II in HCAs, indicating a vasodilator role for H2O2. DPI, tempol and SOD did not affect Ang II in PFAs. DPI, apocynin and allopurinol relaxed preconstricted HCAs. Although the relaxant effects of the NO donor SNAP in PCAs was reduced by DETCA, indicating that superoxide-induced constrictions depend on NO inactivation, the apocynin-induced relaxations were NO independent. Moreover, NADH relaxed all vessels, and this effect was blocked by KCl but not DPI or NO removal. Xanthine plus XO also relaxed HCAs and PCAs. Incubation of human or porcine arteries with Ang II or NADH did not result in detectable increases of extracellular superoxide within 1 h. CONCLUSIONS: Acute vasoconstriction by Ang II is not mediated via superoxide generated through NAD(P)H oxidase and/or XO activation. Such activation, if occurring, rather results in the generation of the vasodilator H2O2.

Cardiac angiotensin II: an intracrine hormone?

The beneficial effects of renin-angiotensin system blockers on cardiac structure and function are usually explained based on the capacity of these drugs to interfere with angiotensin II at cardiac tissue sites. This review addresses to what degree cardiac angiotensin II generation occurs independently of the circulating renin-angiotensin system, and in particular tries to unravel where such generation might take place, taking into consideration that many reports suggest that angiotensin II is an intracrine hormone (ie, a hormone that is synthesized and acts intracellularly). It concludes that angiotensin II generation in the heart depends on circulating (ie, kidney-derived) renin, and occurs in interstitial fluid and possibly, in view of the recent discovery of renin-binding sites, on the cell surface of cardiac cells. Intracellular angiotensin II generation is unlikely to occur, in particular because angiotensinogen is not available in the cytosol.

The role of locally expressed angiotensin converting enzyme in cardiac remodeling after myocardial infarction in mice.

OBJECTIVE: Angiotensin II, generated from angiotensin I by angiotensin converting enzyme (ACE), induces multiple effects including vasoconstriction, positive cardiac inotropy, hypertrophy of cardiomyocytes and proliferation of fibroblasts. ACE exists both in a tissue-bound (t-ACE) and a soluble form. The functional importance of locally produced angiotensin II is still unclear. In the present study, mice lacking tissue-bound angiotensin converting enzyme (t-ACE -/-) were used to investigate the importance of t-ACE during cardiac remodeling after myocardial infarction. METHODS: Mice were subjected to coronary artery occlusion or sham surgery. At 14 days after MI, stroke volume (SV) was determined with an electromagnetic flow probe around the ascending aorta. Mean arterial pressure (MAP) was measured through a cannula in the abdominal aorta. Both parameters were determined at rest and after a volume loading of 2.5 ml warm (37 degrees C) Ringer's solution in 60 s. Hearts were dissected and formalin-fixed to measure infarct size, cardiac dimensions and collagen concentration. Tissue levels of angiotensin I and II were determined in hearts and kidneys. RESULTS: At rest, under pentobarbital anaesthesia, t-ACE -/- mice (n=12) exhibited a significantly lower MAP (26+/-3 vs. 45+/-3 mmHg) than t-ACE +/+ (n=11). SV was similar in both strains. Maximal SV was significantly reduced after MI. Furthermore, infarcted t-ACE -/- (n=6) exhibited a significantly lower maximal SV compared to infarcted t-ACE +/+ mice (n=5; 20.4+/-1.5 vs. 29.6+/-2.3 microl). Structural cardiac parameters as well as cardiac and renal angiotensin II levels in t-ACE -/- and t-ACE +/+ were comparable. CONCLUSIONS: These results suggest that the structural adaptations of the heart that follow MI are independent of t-ACE. However, the presence of t-ACE is necessary for maintenance of cardiac function.

Vasoconstriction is determined by interstitial rather than circulating angiotensin II.

1. We investigated why angiotensin (Ang) I and II induce vasoconstriction with similar potencies, although Ang I-II conversion is limited. 2. Construction of concentration-response curves to Ang I and II in porcine femoral arteries, in the absence or presence of the AT(1) or AT(2) receptor antagonists irbesartan and PD123319, revealed that the approximately 2 fold difference in potency between Ang I and II was not due to stimulation of different AT receptor populations by exogenous and locally generated Ang II. 3. Measurement of Ang I and II and their metabolites at the time of vasoconstriction confirmed that, at equimolar application of Ang I and II, bath fluid Ang II during Ang I was approximately 18 times lower than during Ang II and that Ang II was by far the most important metabolite of Ang I. Tissue Ang II was 2.9+/-1.5% and 12.2+/-2.4% of the corresponding Ang I and II bath fluid levels, and was not affected by irbesartan or PD123319, suggesting that it was located extracellularly. 4. Since approximately 15% of tissue weight consists of interstitial fluid, it can be calculated that interstitial Ang II levels during Ang II resemble bath fluid Ang II levels, whereas during Ang I they are 8.8 - 27 fold higher. Consequently at equimolar application of Ang I and II, the interstitial Ang II levels differ only 2 - 4 fold. 5. Interstitial, rather than circulating Ang II determines vasoconstriction. Arterial Ang I, resulting in high interstitial Ang II levels via its local conversion by ACE, may be of greater physiological importance than arterial Ang II.