Lorenz Sellin

Eosinophilic gastroenteritis in a young girl – long term remission under Montelukast

BackgroundEosinophilic gastrointestinal disorders are an emerging disease entity characterized by eosinophilic infiltration of the intestinal wall. Oral steroids can be still considered as first line treatment. Unfortunately relapses are quite common. Usually long term low-dose prednisone or immunosuppressive therapy is required, which is especially problematic in young patients. Thus a reliable steroid sparing agent with low side effects suitable for long term use is needed. There are strong hints to a similar pathophysiology of eosinophilic gastrointestinal disorders to that of asthma. Indeed leukotriene D4 plays an important role in the recruitment of eosinophils into the intestinal tissue causing damage. This patho-mechanism provides the rationale for the treatment with a leukotriene D4 receptor antagonist. Recently there have been first reports about successful short term use of Montelukast in eosinophilic gastrointestinal disorders.Case presentationWe report the case of a 17 year old girl with a long history of severe abdominal complaints leading to several hospitalizations in the past. Mimicking the picture of an intestinal tuberculosis she received an anti mycobacterial treatment without any success. Marked eosinophilia in blood, ascites and tissue samples of the intestinal tract finally lead to the diagnosis eosinophilic gastroenteritis. Tapering off prednisone caused another severe episode of abdominal pain. At that point leukotriene antagonist Montelukast was started at a dose of 10 mg once daily. Steroids could be tapered off completely within six weeks. The patient has been free of symptoms for over two years by now. Routine examinations, blood tests and endoscopy have rendered regular results. So far no side effects were noted.ConclusionHere report about successful long term remission of eosinophilic gastroenteritis under Montelukast. Further randomized control trials are required to asses the full benefits of Montelukast therapy in the whole spectrum of eosinophilic gastrointestinal disorders.

Adding hydrochlorothiazide to olmesartan dose dependently improves 24-h blood pressure and response rates in mild-to-moderate hypertension.

Objective To test whether adding hydrochlorothiazide (HCTZ) (12.5 or 25 mg) to olmesartan 20 mg improves 24-h blood pressure in patients whose conventional diastolic blood pressure is inadequately controlled by olmesartan monotherapy. Patients Male and female patients ≥ 18 years with mean sitting diastolic blood pressure (DBP) of 100–115 mmHg, mean sitting systolic blood pressure (SBP) greater than 150 mmHg, mean 24-h DBP of at least 84 mmHg, and at least 30% of DBP daytime readings > 90 mmHg. Interventions Four weeks of single-blind treatment with olmesartan 20 mg once daily, followed in non-responders by 8 weeks of randomized double-blind treatment with placebo or HCTZ (12.5 or 25 mg) once-daily, added to olmesartan. Results HCTZ 25 mg added to olmesartan 20 mg decreased mean daytime DBP significantly more (P = 0.0012) than placebo added to olmesartan 20 mg. Compared to olmesartan monotherapy, mean 24-h DBP and SBP were significantly reduced by combination therapy with olmesartan/HCTZ 20/12.5 mg (−1.9 mmHg, P = 0.0167 and −3.9 mmHg, P = 0.0018, respectively) and 20/25 mg (−3.7 and −7.4 mmHg respectively, P < 0.0001 for both). Mean 24-h DBP and SBP and mean night-time SBP reductions were significantly greater for HCTZ 25 mg than for HCTZ 12.5 mg. Response rates (mean daytime DBP assessed by ambulatory blood pressure measurement ≤ 85 mmHg) approximately doubled following the addition of HCTZ (12.5 mg = 57.6% and 25 mg = 69.5%). Conclusion Combination of olmesartan 20 mg with HCTZ provides significantly better 24-h blood pressure reduction than olmesartan monotherapy in patients with mild-to-moderate hypertension. Moreover, increasing the dose of HCTZ from 12.5 to 25 mg is a reasonable step to reach better daytime and night-time blood pressure control.

Angiotensin II Receptor Modulation of Renal Vascular Resistance and Neurotransmission in Young and Adult Spontaneously Hypertensive Rats

Background/Aims: Angiotensin (Ang) II modulates vascular resistance and sympathetic neurotransmission through Ang II type 1 (AT1) receptors. Recent studies reported an involvement of AT2 receptors. We investigated whether AT2 receptors participate in modulation of vascular resistance and sympathetic neurotransmission in spontaneously hypertensive rats (SHR). Methods: Kidneys of 6- and 16-week-old normotensive (WKY) and SHR were isolated and perfused. Results: Noradrenaline release induced by renal nerve stimulation (RNS) was increased in SHR (WKY: 1,837 ± 128, SHR: 2,310 ± 192 pg/g). Ang I- and II-induced pressor responses and enhancement of noradrenaline release were greater in SHR than in WKY. Pressor responses to Ang I and II were greater in adult compared with young SHR. The AT1 receptor antagonist EXP3174 (0.1 µM) blocked Ang I- and II-induced renal vasoconstriction and noradrenaline release to RNS in both strains. In contrast, the selective AT2 receptor antagonist PD 123319 (1 µM) had no influence in young and adult WKY and SHR. Conclusion: Ang I and II had a greater impact on renal vascular resistance and neurotransmission in SHR, which was more pronounced in adult SHR. All effects are mediated by the AT1 receptor and no modulatory influence of the AT2 receptor could be found.

ANGIOTENSIN II MODULATES THE INTERACTION OF NEPHRIN WITH PODOCIN AND BETA-ARRESTIN2: PP.24.460

Introduction: Microalbuminuria is a marker for glomerular impairment and is regarded to be the strongest predictor for cardiovascular disease. In a mouse model for hypertensive nephrophathy, Angiotensin II (Ang II) leads to proteinuria. The underlying, molecular biological mechanisms of Ang II mediated proteinuria have not yet been determined. Recently, we were able to show that Ang II increases tyrosine phosphorylation of the nephrin C-terminus. Purpose: We postulate that Ang II stimulation modulates the integrity of the glomerular slit diaphragm. On a molecular level the integrity of the slit diaphargm is mediated by the interaction between nephrin and podocin as well as beta-arrestin2. Methods: We examined HEK293T cells expressing AT1-receptor, the nephrin C-terminus and podocin or beta-arrestin2. We stimulated the cells with Ang II. Co-immunoprecipitation of the nephrin C-terminus with subsequent westernblot analysis was performed. We tested different inhibitors in this context. For binding domain studies, different truncations of the nephrin C-terminus were transfected with podocin. Results: In HEK293T cells, Ang II enhances the interaction of the nephrin C-terminus with podocin and beta-arrestin2. This effect is dosage dependent and increases with time. Bapta-AM, a calcium-chelator, does not influence the Ang II mediated modulation of the protein interaction of nephrin and podocin or beta-arrestin2. However, genistein, an unspecific tyrosine kinase inhibitor, blocks the Ang II mediated modulation of the nephrin-podocin interaction but fails to block the effect on nephrin-beta-arrestin2. Candesartan, a specific AT1-receptor antagonist, inhibits the Ang II modulation of nephrin with both podocin and beta-arrestin2. The Ang II mediated enhancement of the interaction between nephrin and podocin is not mediated through an additional binding domain at the nephrin C-terminus. Conclusion: Ang II enhances the nephrin-podocin and nephrin-beta-arrestin2 interaction. The effect is Ang II specific. Ang II enhancement of nephrin-podocin interaction is likely to be mediated through tyrosine kinases. The modulation of the nephrin-podocin and nephrin-beta-arrestin2 interaction by Ang II might help to understand the underlying mechanisms of the Ang II-mediated microalbuminuria in diabetic and hypertensive nephropathy.