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Analysis of the nitric oxide-cyclic guanosine monophosphate pathway in experimental liver cirrhosis suggests phosphodiesterase-5 as potential target to treat portal hypertension

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World Journal of Gastroenterology 2018年第38期24卷 4356-4368页

作者： Denise Schaffner Adhara Lazaro Peter Deibert Peter Hasselblatt Patrick Stoll Lisa Fauth Manfred W Baumstark Irmgard Merfort Annette Schmitt-Graeff Wolfgang Kreisel Institute for Exercise-und Occupational Medicine Faculty of MedicineUniversity of FreiburgFreiburg 79106Germany Department of Medicine II GastroenterologyHepatologyEndocrinologyand Infectious DiseasesFaculty of MedicineUniversity of FreiburgFreiburg 79106Germany Anaesthesiological Practice Freiburg 79104Germany Institute of Clinical Pathology Faculty of MedicineUniversity of FreiburgFreiburg 79106Germany Department of Pharmaceutical Biology and Biotechnology University of FreiburgFreiburg 79104Germany

AIM To investigate the potential effect of inhibitors of phosphodiesterase-5(PDE-5) for therapy of portal hypertension in liver *** In the rat model of thioacetamide-induced liver fibrosis/cirrhosis the nitric oxide-cyclic guanosine monophosphate(NO-cGMP) pathway was investigated. Expression and localization of PDE-5, the enzyme that converts vasodilating cGMP into inactive 5'-GMP, was in the focus of the study. Hepatic gene expression of key components of the NO-cGMP pathway was determined by qRT-PCR: Endothelial NO synthase(eNOS), inducible NO synthase(iNOS), soluble guanylate cyclase subunits α1 and β1(sGCa1, sGCb1), and PDE-5. Hepatic PDE-5 protein expression and localization were detected by immunohistochemistry. Serum cGMP concentrations were measured using ELISA. Acute effects of the PDE-5 inhibitor Sildenafil(0.1 mg/kg or 1.0 mg/kg) on portal and systemic hemodynamics were investigated using pressure *** Hepatic gene expression of eNOS(2.2-fold; P = 0.003), sGCa1(1.7-fold; P = 0.003), sGCb1(3.0-fold; P = 0.003), and PDE-5(11-fold; P = 0.003) was increased in cirrhotic livers compared to healthy livers. Overexpression of PDE-5(7.7-fold; P = 0.006) was less pronounced in fibrotic livers. iNOS expression was only detected in fibrotic and cirrhotic livers. In healthy liver, PDE-5 protein was localized primarily in zone 3 hepatocytes and to a lesser extent in perisinusoidal cells. This zonation was disturbed in cirrhosis: PDE-5 protein expression in perisinusoidal cells was induced approximately 8-fold. In addition, PDE-5-expressing cells were also found in fibrous septa. Serum cGMP concentrations were reduced in rats with cirrhotic livers by approximately 40%. Inhibition of PDE-5 by Sildenafil caused a significant increase in serum cGMP concentrations [+ 64% in healthy rats(P = 0.024), + 85% in cirrhotic rats(P = 0.018)]. Concomitantly, the portal venous pressure was reduced by 19% in rats with liver cirrhosis. CONCLUSION Overexpres

关键词： Portal hypertension Thioacetamide Nitric oxide Liver cirrhosis Cyclic guanosine monophosphate phosphodiesterase-5 Sildenafil Hepatic stellate cells Metabolic zonation

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Beneficial long term effect of a phosphodiesterase-5-inhibitor in cirrhotic portal hypertension:A case report with 8 years follow-up

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World Journal of Gastroenterology 2018年第3期24卷 438-444页

作者： Peter Deibert Adhara Lazaro Zoran Stankovic Denise Schaffner Martin Rossle Wolfgang Kreisel Faculty of Medicine Institute for Exercise and Occupational MedicineDepartment of MedicineUniversity HospitalFreiburg 79106Germany Inselspital Interventional and Pediatric RadiologyInstitute of DiagnosticUniversity of BernBern 3010Switzerland Department of Pharmaceutical Biology and Biotechnology University of FreiburgFreiburg 79106Germany Private Praxis PraxiszentrumFreiburg 79104Germany Faculty of Medicine Endocrinology and Infectious DiseasesDepartment of GastroenterologyHepatologyUniversity HospitalFreiburg 79106Germany

Non-selective beta-blockers are the mainstay of medical therapy for portal hypertension in liver cirrhosis. Inhibitors of phosphodiesterase-5(PDE-5-inhibitors) reduce portal pressure in the acute setting by > 10% which may suggest a long-term beneficial effect. Currently, there is no available data on long-term treatment of portal hypertension with PDE-5-inhibitors. This case of a patient with liver cirrhosis secondary to autoimmune liver disease with episodes of bleeding from esophageal varices is the first documented case in which a treatment with a PDE-5-inhibitor for eight years was monitored. In the acute setting, the PDE-5-inhibitor Vardenafil lowered portal pressure by 13%. The portal blood flow increased by 28% based onDoppler sonography and by 16% using MRI technique. As maintenance medication the PDE-5-inhibitor Tadalafil was used for eight consecutive years with comparable effects on portal pressure and portal blood flow. There were no recurrence of bleeding and no formation of new varices. Influencing the NO-pathway by the use of PDE-5 inhibitors may have long-term beneficial effects in compensated cirrhosis.

关键词： Portal hypertension phosphodiesterase-5 Liver hemodynamics Doppler sonography Magnetic resonance imaging Liver cirrhosis

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Bioenhanced advanced third generation solid dispersion of tadalafil: Repurposing with improved therapy in pyelonephritis

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Asian Journal of Pharmaceutical Sciences 2017年第6期12卷 569-579页

作者： Prashant P. Mande Sagar S. Bachhav Padma V. Devarajan Department of Pharmaceutical Sciences and Technology Institute of Chemical Technology N. P. Marg

Tadalafil (TDL) a BCS-II drug is recently reported for repurposing nephroprotective effect in Pyelonephritis (PN). However, poor water solubility and dissolution rate limited oral bioavailability pose serious challenges in its therapeutic applications. We present an advanced third generation Solid Dispersion (SD) of TDL comprising a polymer in combination with a Self Micro-emulsifying Composition (SMEC) to achieve high drug loading, improved stability and rapid dissolution of TDL for enhancing bioavailability and efficacy in PN. TDLSMEC-SD was coated onto rapidly disintegrating inert tablet cores which disintegrated rapidly in water to release SD as a film. TDL-SMEC-SD was evaluated for in-vivo oral bioavailability and in-vivo efficacy in lipopolysaccharide-induced PN in rats. TDL exhibited high solubility (45.6 mg/ml) in the SMEC. TDL-SMEC-SD exhibited remarkably high TDL loading (45%w/w),exceptionally low contact angle (9°), rapid in-vitro release (t50 7.3 min), microemulsion formation(globule size ~100 nm) in aqueous dispersion, and stability as per ICH ***, DSC, and XRD confirmed high physical stability. A relative bioavailability of 350% and 150% compared to TDL and TDL-SD without SMEC respectively, established the superiority of TDL-SMEC-SD. A significant reduction in serum creatinine, blood urea nitrogen and nitric oxide levels in the lipopolysaccharide-induced PN confirmed the benefit of the TDL-SMECSD. The advanced third generation SMEC SDs presents the possibility of platform technology for bioenhancement of poorly water soluble drugs.

关键词： phosphodiesterase-5 Lipopolysaccharide Kidney infection Eudragit EPO Kidney failure

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Haemodynamic and renal effects of tadalafil in patients with cirrhosis

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World Journal of Gastroenterology 2010年第39期16卷 5009-5010页

作者： Georgios N Kalambokis Paraskevi Kosta Konstantinos Pappas Epameinondas V Tsianos 1st Division of Internal Medicine and Hepato-Gastroenterology Unit University HospitalMedical School of Ioannina Department of Radiology University Hospital Department of Cardiology University Hospital

A recent report introduced the phosphodiesterase-5 inhibition by vardenafil as a novel treatment of portal hypertension in patients with *** the herein presented"letter to the editor",the administration of tadalafil did not influence portal haemodynamics but impaired systemic haemodynamics in patients with *** observations concur with the results of a report in a previous issue of World Journal of Gastroenterology(October 2008).Moreover,tadalafil adversely affected renal function in patients with decompensated liver disease.

关键词： Tadalafil Portal hypertension Cirrhosis Ascites phosphodiesterase-5 inhibition

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Update summarising the conclusions of the international consultation on male lower urinary tract symptoms

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World Journal of Clinical Urology 2015年第2期4卷 83-91页

作者： Altaf Mangera Christopher Chapple Department of Urology Research Royal Hallamshire Hospital

The International Consultation on Urological Disease have recently published comprehensive conclusions, based on evidence reviewed by eight committees, on aspects of male lower urinary tract symptoms(LUTS). In this review, we summarise the conclusions from fourof the committees, namely, the evidence regarding the epidemiology of male LUTS, patient assessment, nocturia and medical management. It is indisputable that with an expanding and ageing global population the prevalence of male LUTS is likely to increase. Therefore symptom prevention and preservation of quality of life(Qo L) feature highly in the guidelines. There are now a number of different medical options, proven to lead to significant improvements in symptom scores, flow rate and Qo L available to men with LUTS. Metaanalyses have shown the benefits for alpha blockers, antimuscarinics, 5-α reductase and phosphodiesterase-5 inhibitors. High level evidence also exists for combinations of all of the above with alpha blockers and so men with concomitant storage symptoms, prostate volume > 30 mL, PSA > 1.4 or erectile dysfunction may be considered for combination treatment of an alpha blocker with an antimuscarinic, 5-α reductase inhibitor or phosphodiesterase-5 inhibitor respectively. In an era of personalised medicine, appropriate patient selection is likely to provide the key to the most effective clinical management strategy.

关键词： International consultation Antimuscarinic Male lower urinary tract symptoms Guidelines Nocturia Epidemiology 5-αreductase phosphodiesterase-5 inhibitors Alpha antagonist

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