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Hereditary angioedema (HAE) is becoming much more genetically complex than was initially considered. Thus, the role of HAE genetics is expanding beyond research laboratories, and the genotyping of subjects suffering from HAE has become diagnostically indispensable in clinical practice. The synthesis and interpretation of the clinical and biochemical analyses to facilitate appropriate genetic test selection has thus also become significantly more complex. With this in mind, an international multidisciplinary group of 14 experts in HAE genetics and disease management was convened in October 2018. The objective was to develop clear, actionable, evidence- and consensus-based statements aiming to facilitate the communication between physicians treating patients with HAE and clinical geneticists, and thus promote the effective use of genetics in the management of the disease. Eleven consensus statements were generated, encompassing considerations regarding the clinical indications for genotyping patients with angioedema, the methods of detection of HAE-causative variants, the variant pathogenicity curation, the genotyping of patients with HAE in the clinic, and genetic counseling. These statements are intended both to guide clinicians and to serve as a framework for future educational and further genetic testing developments as the field continues to evolve rapidly.

International audience; Bradykinin mediated angioedema (BK-AE) can be associated either with C1Inhibitor deficiency (hereditary and acquired forms), either with normal C1Inh (hereditary form and drug induced AE as angiotensin converting enzyme inhibitors…). In case of high clinical suspicion of BK-AE, C1Inh exploration must be done at first: C1Inh function and antigenemy as well as C4 concentration. C1Inh deficiency is significant if the tests are below 50 % of the normal values and controlled a second time. In case of C1Inh deficiency, you have to identify hereditary from acquired forms. C1q and anti-C1Inh antibody tests are useful for acquired BK-AE. SERPING1 gene screening must be done if a hereditary angioedema is suspected, even if there is no family context (de novo mutation 15 %). If a hereditary BK-AE with normal C1Inh is suspected, F12 and PLG gene screening is suitable.

Introduction Les angioedemes hereditaires par mutation du facteur XII representent, selon les series, 20 a 25 % des angiœdemes hereditaires bradykiniques a C1 inhibiteur normal. Ils surviennent preferentiellement chez les femmes apres la puberte, sous contraception contenant des œstrogenes ou pendant la grossesse. Cependant les hormones ne semblent pas etre le seul facteur declenchant ce type d’angiœdeme, en effet certaines patientes developpent des angiœdemes en dehors des grossesses et de la prise de contraception oestroprogestative et quelques series rapportent des cas de sujets de sexe masculin symptomatiques. L’objectif principal de notre etude est d’etudier la prevalence des symptomes d’angioedeme chez les sujets de sexe masculin et de les caracteriser en decrivant leur localisation, leur frequence, leur duree et leur reponse aux traitements eventuellement administres. Materiels et methodes Nous avons realise une etude observationnelle retrospective des manifestations d’angiœdeme chez les sujets de sexe masculin porteurs de la mutation du FXII au sein du centre de reference des angiœdemes de l’hopital Saint Antoine a Paris, et chez ceux depistes par le laboratoire de genetique de Grenoble entre juin 2006 et mai 2020. Resultats 168 sujets de sexe masculin ont ete recenses au sein du centre de reference de l’hopital Saint Antoine, 21 sont porteurs de la mutation du FXII. Nous avons pu obtenir les informations concernant 22 autres sujets masculins porteur de la mutation suivis dans d’autres centres de reference des angiœdemes bradykiniques. Parmi ces sujets, 19 % (8/43) sont symptomatiques. L’âge moyen des premiers symptomes est de 29,5 ans (6 a 68 ans). Les localisations principales sont des œdemes de la face (50 %) et des douleurs abdominales (50 %), moins frequemment les œdemes siegent au niveau des extremites (12 %), du larynx (12 %) et de la langue (12 %). La duree des crises est de 48 a 72 heures, avec une frequence moyenne de 2,25 crises par an. La reponse au traitement n’a pu etre evaluee chez tous les patients ; la moitie des patients ont repondu a l’icatibant ou aux concentres de C1 Inhibiteur Conclusion Notre travail a permis de recenser les sujets masculins symptomatiques porteurs de la mutation du facteur XII depistes en France entre 2006 et 2021. Les manifestations cliniques sont rares ; la localisation et la duree des crises sont similaires a celles observees chez les femmes, mais leurs crises semblent moins frequentes chez ces derniers. Le mecanisme bradykinique n’a cependant pas pu etre confirme chez tous les sujets. Le suivi de ces patients est donc necessaire ainsi que leur information sur la maladie, le mode de transmission genetique et sa prise en charge.

International audience; Acquired angioedema with C1-inhibitor deficiency is a rare and peculiar entity belonging to the spectrum of bradykinin angioedemas. It usually occurs in subjects over 60 years old, and is mostly associated with a B-cell lymphoid hemopathy or a monoclonal gammopathy.The diagnosis relies on at least one angioedema episode, lasting more than 24 h, and on the decrease of functional C1-inhibitor. Low C1q is observed in 90% of patients, and an anti C1-inhibitor antibody is found in 50% of patients.The treatment of severe attacks relies on icatibant or C1-inhibitor perfusions. Long term prophylaxis in patients with frequent attacks requires treatment of the associated hemopathy if so. In case of idiopathic angioedema, tranexamic acid and danazol may be used, provided that there is-no thrombophilia; as well as rituximab as second-line treatment. Inhibitors of kallikrein still need to be evaluated in this therapeutic indication.; Les angiœdèmes par déficit acquis en C1-inhibiteur représentent une entité rare au sein des angiœdèmes bradykiniques. Ils diffèrent des formes héréditaires essentiellement par le terrain, car ils surviennent chez des sujets âgés de 60 ans en moyenne, et sont, le plus souvent, associés à une hémopathie lymphoïde B de bas grade ou à une gammapathie monoclonale.Leur diagnostic repose sur la survenue d'au moins un épisode d'angiœdème durant plus de 24 heures et sur la diminution de C1-inhibiteur fonctionnel. Une baisse du C1q est présente dans 90 % des cas et un anticorps anti C1-inhibiteur chez 50 % des patients.Le traitement des crises sévères repose sur l'icatibant ou l'administration de C1-inhibiteur. Le traitement préventif, indiqué en cas de crises fréquentes, nécessite le traitement de l'hémopathie identifiée. En l'absence de pathologie associée, l'acide tranexamique ou le danazol sont des options à envisager en l'absence de facteur de risque de thrombose, et le rituximab peut être proposé en cas d'échec. La place des inhibiteurs de la kallicréine sera à définir dans cette indication.

Introduction Les angiœdemes bradykiniques par deficit acquis en C1 inhibiteur (C1-INH) peuvent etre la consequence de la consommation excessive de C1 inhibiteur (type 1) ou lies a la presence d’un anticorps anti-C1-INH (type 2). Ils sont associes, le plus souvent, a des syndromes lymphoproliferatifs ou a des gammapathies monoclonales. Un traitement par rituximab semble efficace pour prevenir les crises, mais merite d’etre mieux evalue. Patients et methodes Une etude descriptive, multicentrique, retrospective a ete realisee en France, grâce a l’aide du CREAK, incluant tous les patients ayant un angiœdeme par deficit acquis en C1-INH et traites par rituximab entre avril 2005 et juillet 2019. Resultats Cinquante-cinq patients ont ete inclus dans l’etude dont 25 avec un anticorps anti-C1-INH. Quarante (72 %) patients presentaient une hemopathie lymphoide (23 lymphomes de la zone marginale dont deux secondairement transformes, 4 maladies de Waldenstrom, 3 leucemies lymphoides chroniques, un lymphome folliculaire et 2 lymphomes lymphocytiques, 4 lymphomes B de bas grade non classes et 3 lymphomes agressifs) ; 7 (13 %) patients une gammapathie monoclonale de signification indeterminee (3 Ig G,3 IgM et une IgA) et 1 (2 %) myelome indolent (Ig A). Aucune pathologie associee n’etait retrouvee dans 7 (13 %) cas : tous ceux-ci avaient un anticorps anti-C1-INH. Vingt-huit (51 %) patients ont recu un traitement par rituximab seul (8 a la dose de 1 gramme j1–j15, 20 a 375 mg/m2/semaine ×4) ; l’indication etait l’angiœdeme chez 19 patients, l’hemopathie chez 5 patients, et les deux chez 4 patients. Vingt-sept (49 %) patients ont recu une chimiotherapie associee au rituximab. Quatorze (25 %) patients ont eu un nouveau traitement par rituximab pour rechute de l’angiœdeme, 7 d’entre eux avaient alors une rechute de l’hemopathie sous-jacente associee. Apres une mediane de suivi de 6,1 annees, 41 (75 %) patients n’avaient plus de crise d’angiœdeme (70 % % des type 1, 30 % des type 2), dont 11 en remission clinique et biologique, 6 (11 %) patients avaient un angiœdeme toujours actif malgre une reponse initiale et 3 (5 %) patients etaient en cours de traitement. Cinq (9 %) patients sont decedes : un des suites de l’hemopathie, deux d’une autre cause avec angiœdeme en remission aux dernieres nouvelles et deux de cause inconnue. Chez 30 patients, le lymphome etait alors en remission. Pour 10 patients, l’hemopathie sous-jacente etait stable (5 lymphomes et 5 gammapathies monoclonales). Trois patients etaient en cours de traitement du lymphome. Il semblerait que la remission clinique de l’angiœdeme soit liee a la remission de l’hemopathie lymphoide sous-jacente : ceci est observe chez 29 patients sur 41, et a l’absence d’anticorps anti-C1-INH puisqu’elle est observee chez 76 % des patients sans anticorps et seulement 24 % des patients avec anticorps. Les patients avec gammapathie monoclonale et sans pathologie associee repondent moins bien au rituximab : 3 patients sans pathologie associee et 3 patients avec gammapathie monoclonale (2 Ig G et 1IgM) sont en echec du traitement par rituximab ; ces 6 patients avaient un anticorps anti-C1-INH. Une hypogammaglobulinemie secondaire ( Conclusion Le traitement par rituximab parait etre une option therapeutique interessante et bien toleree dans l’angiœdeme par deficit acquis en C1-INH surtout si celui-ci est associe a une hemopathie lymphoide et en l’absence d’anticorps anti-C1-INH.

International audience

International audience; BACKGROUND: Mitochondrial DNA (mtDNA) diseases are rare disorders whose prevalence is estimated around 1 in 5000. Patients are usually tested only for deletions and for common mutations of mtDNA which account for 5-40% of cases, depending on the study. However, the prevalence of rare mtDNA mutations is not known. METHODS: We analysed the whole mtDNA in a cohort of 743 patients suspected of manifesting a mitochondrial disease, after excluding deletions and common mutations. Both heteroplasmic and homoplasmic variants were identified using two complementary strategies (Surveyor and MitoChip). Multiple correspondence analyses followed by hierarchical ascendant cluster process were used to explore relationships between clinical spectrum, age at onset and localisation of mutations. RESULTS: 7.4% of deleterious mutations and 22.4% of novel putative mutations were identified. Pathogenic heteroplasmic mutations were more frequent than homoplasmic mutations (4.6% vs 2.8%). Patients carrying deleterious mutations showed symptoms before 16 years of age in 67% of cases. Early onset disease (16 years) were associated with mutations in tRNA genes. MTND5 and MTND6 genes were identified as 'hotspots' of mutations, with Leigh syndrome accounting for the large majority of associated phenotypes. CONCLUSIONS: Rare mitochondrial DNA mutations probably account for more than 7.4% of patients with respiratory chain deficiency. This study shows that a comprehensive analysis of mtDNA is essential, and should include young children, for an accurate diagnosis that is now accessible with the development of next generation sequencing technology.

Objective Diabetes mellitus is associated with inflammatory state and increased cardiovascular mortality. Leukotrienes are arachidonic acid metabolites derived from the 5-lipoxygenase pathway that possess vasoactive, chemotactic and proinflammatory properties. The aim of this study was to evaluate (1) the urinary excretion of leukotriene E4 (LTE4) in type 1 diabetic subjects and healthy volunteers and (2) the influence of glycemic control attested by HbA1C on LTE4 excretion. Methods and results Urinary excretion of LTE4, measured by liquid chromatography–tandem mass spectrometry, was significantly (P = 0.033) increased in diabetic patients (median [10th–90th percentiles]: 42.1 pg/mg creatinine [16.7–71.4], n = 34), compared to healthy subjects (25.5 pg/mg creatinine [13.9–54.1], n = 28). Subgroup analysis indicated a trend towards increased LTE4 excretion in patients with poor glycemic control [(HbA1C ≥ 9% or plasma glucose >18 mmol/L): 43.3 pg/mg creatinine [21.6–70.5], n = 14], whereas no difference was observed between patients with good metabolic control [(HbA1C ≤ 7.5%): 36.4 pg/mg creatinine [15.8–83.4], n = 20] and healthy subjects. Conclusions This study suggested that increased LTE4 excretion in type 1 diabetic state might reflect systemic activation of the 5-lipoxygenase pathway. It could be a determinant of underlying inflammatory state and vascular disease.

Objectives: Endocannabinoids have been shown to play a role in the regulation of vascular tone. The effects of 2-arachidonoyl glycerol (2-AG) on induced-tone were examined in rat aortic rings in vitro. Methods: Aortic rings from Wistar Kyoto (WKY) rats were suspended in organ chambers for recording isometric tension development in response to 2-AG. The production of TXA2 in response to 2-AG was also assessed by enzyme immunoassay. Results: In endothelium-intact rings pre-contracted to PGF2α, 2-AG (10 nM–30 μM) induced a biphasic effect: a weak relaxation from 10 nM to 0.1 μM, which turned into a concentration-dependent contraction from 3 to 30 μM. Endothelium-denudation did not change 2-AG-mediated vascular effects. 2-AG-induced contraction was unaffected by both the cannabinoid CB1 receptor antagonist SR141716A (3 μM) and the CB2 receptor antagonist SR144528 (1 μM). In contrast, the anandamine transport inhibitor (AM404, 100 μM) and the amino hydrolase inhibitor (PMSF, 30 μM) attenuated ( P

L'azathioprine est un medicament largement utilise dans la prevention et le traitement des maladies inflammatoires cryptogenetiques de l'intestin. Sa biotransformation est soumise a un polymorphisme genetique qui impose un suivi pharmacotherapeutique du traitement. La meconnaissance de ces elements peut se traduire par la survenue d'accidents hematologiques severes mais reversibles en l'absence de complications infectieuses. Ce polymorphisme pourrait expliquer la survenue de cytolyses hepatiques. Les modalites de prise en compte de ce polymorphisme dans la conduite du traitement sont controversees et font l'objet de recommandations divergentes. Une analyse des bases pharmacologiques sur lesquelles reposent les recommandations proposees dans la litterature est presentee.

Long-term treatment of rats with Nω-nitro-L-arginine methyl ester (L-NAME) induces hypertension associated with inflammatory and vascular changes. Leukotrienes are proinflammatory vasoactive products that are suspected to be involved in the pathogenesis of hypertension. We investigated, in rats chronically treated with L-NAME, the involvement of leukotrienes in the in vivo regulation of blood pressure and the in vitro contraction elicited by noradrenaline in isolated aorta. Rats were randomly assigned to four groups and orally treated for 3 weeks with L-NAME (1 mg ml−1), L-NAME (1 mg ml−1) plus the leukotriene biosynthesis inhibitor MK-886 (0.1 mg ml−1), MK-886 (0.1 mg ml−1) alone or vehicle (Methocel, 0.1%). All the drugs were added to the drinking fluid. The mean arterial blood pressure (MABP) increased significantly in L-NAME-treated rats (173.3±9.4 mmHg (n=25)) vs Methocel-treated rats (110.7±4.8 mmHg (n=11), P

OBJECTIVES We have previously reported that 5-lipoxygenase-derived products, and particularly the cysteinyl leukotrienes (CysLTs), were involved in angiotensin II (Ang II)-induced contractions in isolated aortas from spontaneously hypertensive rats. DESIGN The aim of this study was to assess the role of CysLTs in the vascular response to Ang II in an Ang II-dependent model of hypertension, the (mRen-2)27 transgenic rats (TGs). METHODS Intact aortic rings from TG and normotensive Sprague-Dawley rats (SDs) were suspended in organ chambers for isometric tension development in response to Ang II. In addition, the release of CysLTs in response to Ang II (0.3 micromol/l) was measured by enzyme immunoassay. RESULTS In isolated aortas from TG rats, pretreatment with the 5-lipoxygenase inhibitor (AA861, 10 micromol/l) or the CysLT1 receptor antagonist (MK571, 1 micromol/l) significantly (P < 0.05) reduced Ang II-induced contractions by 52 and 42%, respectively. In addition, Ang II induced a 2.6-fold increase in CysLT release (pg/mg dry weight tissue: 58.3 +/- 17.9 (Ang II, n = 7) versus 22.5 +/- 5.9 (basal, n = 7) P < 0.05), which was inhibited by the AT1 receptor antagonist losartan (1 micromol/l). In contrast, in aortas from SD rats, pretreatment with AA861 or MK571 did not alter Ang II-induced contraction and CysLT production remained unchanged after exposure to Ang II. CONCLUSION These data suggest that CysLTs are involved in the contractile responses to Ang II in isolated aortas from TG but not from SD rats.

Angiotensin II (Ang II) is a vasopressor peptide involved in the pathogenesis of cardiovascular diseases associated with diabetes mellitus. We have previously reported that the 5-lipoxygenase-derived products, particularly the cysteinyl leukotrienes (CysLTs), are involved in Ang II-induced contraction. In this study, we demonstrated that CysLTs contribute to the contraction elicited by Ang II in isolated aortas from streptozotocin-induced diabetic (SS) rats but not from insulin-treated diabetic rats, fructose-fed rats, or control rats. In an organ bath, pretreatment with the 5-lipoxygenase inhibitor (AA861, 10 μmol/L) reduced by 37.6±8.2% and 30.1±10.9% the Ang II-induced contractions in intact and endothelium-denuded aortic rings, respectively, from SS rats. In contrast, the CysLT 1 receptor antagonist (MK571, 1 μmol/L) or the dual CysLT 1 /CysLT 2 receptor antagonist (BAY-u9773, 0.1 μmol/L) did not affect Ang II-induced contraction. In addition, Ang II induced a 6.2±1.5-fold increase in CysLT release through the stimulation of the Ang II type 1 receptor. Furthermore, the urinary excretion of leukotriene E 4 was increased in SS rats (leukotriene E 4 , 13.7±2.9 ng/24 h [SS rats, n=10] versus 1.5±0.5 ng/24 h [control rats, n=6]; P 1 or CysLT 2 receptor.

Chronic treatment with Sandimmune (cyclosporine A [CsA] dissolved in Cremophor EL [CrEL]) is often associated with hypertension and nephrotoxicity. The aims of the present study were to assess the effect of Sandimmune and its two main components (CsA and CrEL) on human saphenous veins and to study the underlying mechanism of their contractile responses. In organ bath, concentration-response curves for Sandimmune (36 ng/ml-120 microg/ml of CsA). CsA (36 ng/ml-120 microg/ml), or CrEL (2.4 microg/ml-8 mg/ml) were elicited in the presence of a thromboxane A2 (TXA2) receptor antagonist (GR32191, 0.3 microM), a cyclooxygenase inhibitor (indomethacin, 1 microM), a 5-lipoxygenase inhibitor (AA861, 10 microM), or their respective vehicles. In addition, the production of TXA2 after CsA challenge was assessed by enzyme immunoassay. Sandimmune, CsA, and CrEL induced concentration-dependent contractions on human saphenous veins. In terms of potency, CsA was a more potent vasoconstrictor agent than CrEL (EC50 values: 11.9+/-3.7 microg/ml (CsA, n = 12) vs. 1.2+/-0.4 mg/ml (CrEL, n = 16), p < 0.05). In contrast, in terms of efficacy, CrEL induced greater contractions than CsA (Emax (% of KCl 90 mM-induced contraction): 98.1+/-16.1% (CrEL, n = 16) vs. 17.0+/-4.3% (CsA, n = 12) p < 0.05). Pretreatment with GR32191 significantly reduced by 85% and 56% the contractions elicited by CsA and CrEL, respectively, whereas indomethacin had no effect. Finally, CsA (12 and 120 microg/ml) failed to stimulate TXA2 production. These in vitro data suggest that Sandimmune-induced contractions on human vascular smooth muscle appear to be mediated by CsA in the therapeutic ranges of doses and by both CsA and CrEL, which, in supratherapeutic doses, acted through a TXA2 receptor-dependent pathway.

Diabetes mellitus is associated with inflammatory state and increased cardiovascular mortality. Leukotrienes are arachidonic acid metabolites derived from the 5-lipoxygenase pathway that possess vasoactive, chemotactic and proinflammatory properties. The aim of this study was to evaluate (1) the urinary excretion of leukotriene E4 (LTE4) in type 1 diabetic subjects and healthy volunteers and (2) the influence of glycemic control attested by HbA(1C) on LTE4 excretion.Urinary excretion of LTE(4), measured by liquid chromatography-tandem mass spectrometry, was significantly (P=0.033) increased in diabetic patients (median [10th-90th percentiles]: 42.1 pg/mg creatinine [16.7-71.4], n=34), compared to healthy subjects (25.5 pg/mg creatinine [13.9-54.1], n=28). Subgroup analysis indicated a trend towards increased LTE4 excretion in patients with poor glycemic control [(HbA(1C)or =9% or plasma glucose18 mmol/L): 43.3 pg/mg creatinine [21.6-70.5], n=14], whereas no difference was observed between patients with good metabolic control [(HbA(1C)or =7.5%): 36.4 pg/mg creatinine [15.8-83.4], n=20] and healthy subjects.This study suggested that increased LTE4 excretion in type 1 diabetic state might reflect systemic activation of the 5-lipoxygenase pathway. It could be a determinant of underlying inflammatory state and vascular disease.

International audience; BACKGROUND: 6-Thioguanine (6-tioguanine) nucleotides are the active metabolites of azathioprine. AIM: The aim of the study was to evaluate the rate of clinical remission without steroids in steroid-dependent Crohn's disease and ulcerative colitis patients receiving azathioprine, the medium- and long-term efficacy and the predictive factors of clinical response when monitoring 6-tioguanine. METHODS: Steroid-dependent Crohn's disease and ulcerative colitis patients receiving either azathioprine or not (treated later with a daily dose of 2.5 mg/kg) were prospectively included. 6-tioguanine was monitored at 1 and 2 months and every 3 months thereafter for 1 year. The azathioprine dose was adapted to reach a 6-tioguanine level of >250 pmol/8 x 10(8) red blood cells. Thiopurine methyltransferase genotype/phenotype was evaluated in some patients. RESULTS: A total of 106 patients were prospectively included (70 Crohn's disease, 36 ulcerative colitis). The clinical remission rate without steroids in patients receiving azathioprine, in intention-to-treat analysis, was 72% and 59% at 6 and 12 months, respectively. The remission rate was significantly higher in patients with 6-tioguanine >250 pmol/8 x 10(8) RBC (86% and 69% at 6 and 12 months, respectively; P < 0.01). No significant difference was observed between Crohn's disease and ulcerative colitis patients whether treated by azathioprine or not on inclusion. In the univariate analysis, the absence of Crohn's disease stenosis, a 6-tioguanine level >250 pmol/8 x 10(8) RBC, and an increase of erythrocyte mean corpuscular volume were the factors predictive of a favourable clinical response. In the multivariate analysis, only a 6-tioguanine level of >250 pmol/8 x 10(8) red blood cells was a predictive factor of favourable clinical remission. CONCLUSIONS: Clinical remission without steroids is significantly more likely when monitoring 6-tioguanine so as to reach a level of >250 pmol/8 x 10(8) red blood cells in steroid-dependent Crohn's disease and ulcerative colitis patients receiving azathioprine (86% and 69% at 6 and 12 months, respectively).

International audience; We previously reported an activation of the 5-lipoxygenase pathway in aorta from streptozotocin-induced diabetic rats. The aim of this study was to investigate whether this activation was associated with an increased expression of 5-lipoxygenase, an increased cysteinyl leukotriene (CysLT) production in response to arachidonic acid or calcium ionophore A23187 and/or a hypersensitivity of the aorta to CysLTs in streptozotocin-induced diabetic rats. In aorta from diabetic and control rats, reverse transcriptase-PCR and western blot analysis with a specific 5-lipoxygenase antibody provided evidence for the presence of 5-lipoxygenase in aorta. However, the expression of 5-lipoxygenase was not significantly different between diabetic and control rats. Challenge by A23187 (10 microM) and arachidonic acid (10 microM and 0.1 mM) with or without A23187 (10 micromol/l) induced a significant increase of CysLT release (measured by enzyme immunoassay) that was in the same range in aorta from control and diabetic rats. In contrast, aortas from diabetic rats showed a greater sensitivity to LTC4 and LTD4 contractile effects. These data suggested that the activation of the 5-lipoxygenase pathway previously reported in streptozotocin-induced diabetic rats could be explained by an augmented sensitivity to CysLTs of the diabetic aorta.

Azathioprine is an immunosuppressive drug used in the treatment of inflammatory bowel disease. It is a prodrug that is hydrolysed to 6-mercaptopurine, which represents the active form. Azathioprine is also used in the treatment of leukaemia in children and in organ transplantation. Azathioprine treatment is associated with adverse effects such as leukopenia and aplasia. These adverse effects are related to a single nucleotide polymorphism, including the inability of cells to synthesize thiopurine methyltransferase (TPMT). TPMT is a detoxification enzyme that limits 6-thioguanine nucleotide production and thereby interferes with normal DNA and RNA synthesis. This review presents the different approaches used for azathioprine therapeutic monitoring in IBD treatment and discusses the discrepancies in recent clinical trials.

Tacrolimus is a potent calcineurin inhibitor currently used for prophylaxis and treatment of allograft rejection. As tacrolimus metabolism occurs for the most part via the cytochrome P450-3A4 (CYP3A4) enzyme system, co-administration of drugs activating or inhibiting this metabolic pathway may affect tacrolimus pharmacokinetics. We report a case of dramatic increase in tacrolimus blood concentration that could be attributed, at least in part, to enzymatic inhibition by protease inhibitors and diltiazem.

SUMMARY This study was undertaken to investigate the vascular actions (contraction and relaxation) of the F(2)-isoprostane metabolites 15-keto-15-F(2t)-IsoP, 2,3-dinor-15-F(2t)-IsoP, and 2,3-dinor-5,6-dihydro -15-F(2t)-IsoP in comparison with 15-F(2t)-IsoP on the rat thoracic aorta. 15-keto-15-F(2t)-IsoP induced a vasoconstriction in a concentration-dependent manner with a pD(2) value of 5.80 +/- 0.05, whereas 2,3-dinor-15-F(2t)-IsoP and 2,3-dinor-5,6-dihydro-15-F(2t)-IsoP had no effect. The parent compound 15-F(2t)-IsoP was more potent (pD(2) value: 6.46 +/- 0.1). Endothelium removal had no influence on the contraction to 15-keto-15-F(2t)-IsoP. GR32191 (a TP-receptor antagonist) concentration-dependently inhibited the contraction induced by 15-keto-15-F(2t)-IsoP, with a significant decrease in the E(max) values for GR32191 10(-7) M. Pretreatment with 2,3-dinor-15-F(2t)-IsoP and 2,3-dinor-5,6-dihydro-15-F(2t)-IsoP induced no alteration of 15-F(2t)-IsoP concentration-response curves. In contrast, 15-keto-15-F(2t)-IsoP pretreatment competitively inhibited the response to 15-F(2t)-IsoP. When concentration ratios of EC(50) values were used, a Schild regression of this data was linear with a slope of 0.974 and a pA(2) value of 6.13. 15-keto-15-F(2t)-IsoP at high concentrations caused a weak concentration-dependent relaxation of rat aorta rings contracted with U46619 (3.10(-8) M) that was not modified in the absence of endothelium. In contrast, 2,3-dinor-15-F(2t)-IsoP and 2,3-dinor-5,6-dihydro-15-F(2t)-IsoP induced no vasodilation. In conclusion, among the F(2)-isoprostane metabolites, 2,3-dinor-15-F(2t)-IsoP and 2,3-dinor-5,6-dihydro-15-F(2t)-IsoP did not cause vasorelaxation or vasoconstriction on the rat thoracic aorta. In contrast, 15-keto-15-F(2t)-IsoP mediates contraction through activation of TP-receptors, probably as a partial agonist, and induces a weak endothelium-independent relaxation at high concentrations.