Broad-Spectrum Matrix Metalloproteinase Inhibition Curbs Inflammation and Liver Injury but Aggravates Experimental Liver Fibrosis in Mice

Background Liver fibrosis is characterized by excessive synthesis of extracellular matrix proteins, which prevails over their enzymatic degradation, primarily by matrix metalloproteinases (MMPs). The effect of pharmacological MMP inhibition on fibrogenesis, however, is largely unexplored. Inflammation is considered a prerequisite and important co-contributor to fibrosis and is, in part, mediated by tumor necrosis factor (TNF)-α-converting enzyme (TACE). We hypothesized that treatment with a broad-spectrum MMP and TACE-inhibitor (Marimastat) would ameliorate injury and inflammation, leading to decreased fibrogenesis during repeated hepatotoxin-induced liver injury.Methodology/Principal Findings Liver fibrosis was induced in mice by repeated carbon tetrachloride (CCl4) administration, during which the mice received either Marimastat or vehicle twice daily. A single dose of CCl4was administered to investigate acute liver injury in mice pretreated with Marimastat, mice deficient in Mmp9, or mice deficient in both TNF-α receptors. Liver injury was quantified by alanine aminotransferase (ALT) levels and confirmed by histology. Hepatic collagen was determined as hydroxyproline, and expression of fibrogenesis and fibrolysis-related transcripts was determined by quantitative reverse-transcription polymerase chain reaction. Marimastat-treated animals demonstrated significantly attenuated liver injury and inflammation but a 25% increase in collagen deposition. Transcripts related to fibrogenesis were significantly less upregulated compared to vehicle-treated animals, while MMP expression and activity analysis revealed efficient pharmacologic MMP-inhibition and decreased fibrolysis following Marimastat treatment. Marimastat pre-treatment significantly attenuated liver injury following acute CCl4-administration, whereas Mmp9 deficient animals demonstrated no protection. Mice deficient in both TNF-α receptors exhibited an 80% reduction of serum ALT, confirming the hepatoprotective effects of Marimastat via the TNF-signaling pathway.Conclusions/Significance Inhibition of MMP and TACE activity with Marimastat during chronic CCl4administration counterbalanced any beneficial anti-inflammatory effect, resulting in a positive balance of collagen deposition. Since effective inhibition of MMPs accelerates fibrosis progression, MMP inhibitors should be used with caution in patients with chronic liver diseases

Diagnostic value of biochemical markers (NashTest) for the prediction of non alcoholo steato hepatitis in patients with non-alcoholic fatty liver disease

BACKGROUND: Liver biopsy is considered the gold standard for assessing histologic lesions of non-alcoholic fatty liver disease (NAFLD). The aim was to develop and validate a new biomarker of non alcoholic steato hepatitis (NASH) the NashTest (NT) in patients with NAFLD. METHODS: 160 patients with NAFLD were prospectively included in a training group, 97 were included in a multicenter validation group and 383 controls. Histological diagnoses used Kleiner et al's scoring system, with 3 classes for NASH: "Not NASH", "Borderline", "NASH"). The area under the ROC curves (AUROC), sensitivity (Se), specificity (Sp), and positive and negative predictive values (PPV, NPV) were assessed. RESULTS: NT was developed using patented algorithms combining 13 parameters: age, sex, height, weight, and serum levels of triglycerides, cholesterol, alpha2macroglobulin, apolipoprotein A1, haptoglobin, gamma-glutamyl-transpeptidase, transaminases ALT, AST, and total bilirubin. AUROCs of NT for the diagnosis of NASH in the training and validation groups were, respectively, 0.79 (95%CI 0.69–0.86) and 0.79 (95%CI 0.67–0.87; P = 0.94); for the diagnosis of borderline NASH they were: 0.69 (95%CI 0.60–0.77) and 0.69 (95%CI 0.57–0.78; P = 0.98) and for the diagnosis of no NASH, 0.77 (95%CI 0.68–0.84) and 0.83 (95%CI 0.67–0.90; P = 0.34). When the two groups were pooled together the NashTest Sp for NASH = 94% (PPV = 66%), and Se = 33% (NPV = 81%); for borderline NASH or NASH Sp = 50% (PPV = 74%) and Se = 88% (NPV = 72%). CONCLUSION: In patients with non-alcoholic fatty liver disease, NashTest, a simple and non-invasive biomarker reliably predicts the presence or absence of NASH

The effect of intravitreal bevacizumab (avastin) administration on systemic hypertension

WOS: 000268915900016PubMed ID: 19079149Aims To determine the short-term effect of intravitreal bevacizumab administration on systemic blood pressure levels of patients and to evaluate the safety of the drug in these patients. Methods Study population was divided into two groups: group A comprised patients who had hypertension and were under medication with antihypertensive drugs; group B comprised patients with normal blood pressure and were not under medication with antihypertensive drugs. All patients were graded according to their blood pressure levels before single dose of bevacizumab (0.05 ml; 1.25 mg) injection, and at day 1 and weeks 1, 3, and 6 thereafter. The blood pressure levels were analysed using repeated measures of analysis of variance (ANOVA). A P-value of <0.05 was considered significant. Results The study population included 82 patients with a mean age of 67.2 +/- 5.2 years. In group A, the systolic blood pressure levels showed significant increases at weeks 1, 3, and 6 (P = 0.001, P < 0.001, and P = 0.003, respectively) compared with baseline. Similarly, diastolic blood pressure levels were significantly higher at weeks 3 (P < 0.001) and 6 (P = 0.016). In group B, the mean systolic and diastolic blood pressure levels showed significant elevations only at week 3 (P = 0.004 and P < 0.001, respectively). The percentages of both group A and B patients with normal blood pressure decreased at week 3 compared with baseline (P < 0.001 and P = 0.012 for groups A and B, respectively). Conclusions The findings of this study show that there is a risk of disregulation of blood pressure levels or persistence of hypertension in hypertensive patients after intravitreal bevacizumab injections. Eye (2009) 23, 1714-1718; doi: 10.1038/eye.2008.360; published online 12 December 200

Intravitreal bevacizumab injection in patients with choroidal neovascularization due to choroid rupture after blunt-head trauma

PubMed ID: 18825317Purpose: To describe and report the effect of intravitreal bevacizumab (Avastin) as primary treatment for secondary choroidal neovascularization (CNV) after choroidal rupture due to blunt-head trauma. Design: Interventional case report. Methods: The study was ofthe left eye of a patient who presented with choroidal neovascularization secondary to choroidal rupture due to blunt-head trauma. The patient received single intravitreal injection of 1.25 mg (0.05 ml) bevacizumab as treatment for CNV after informed consent was signed. The patient underwent fundus fluorescein angiography (FA) and optic coherence tomography (OCT) before the bevacizumab injection and then again three months after. Visual acuity was also measured before and after treatment. The patient was re-examined on the first day, and monthly thereafter. After intravitreal injection of bevacizumab the visual and anatomic responses were observed. Results: The patient showed regression of the neovascularization three months after injection of bevacizumab. There was no loss of vision in the immediate postoperative period and at the 3rd month vision improved from 20/60 to 20/20. Central retinal thickness decreased. No cataract progression, endophthalmitis, or injection-related complications were observed. Conclusions: Our study shows that intravitreal 1.25 mg bevacizumab can be an effective alternative treatment for choroidal neovascularization (CNV) due to choroidal rupture. © Springer Science+Business Media B.V. 2008

Ocular Penetration of Cefepime Following Systemic Administration in Humans

OBJECTIVE: To investigate the penetration of cefepime (a fourth generation cephalosporin) into the aqueous humor after single-dose intravenous administration in humans

Short-term effects of intravitreal ranibizumab and bevacizumab administration on 24-h ambulatory blood pressure monitoring recordings in normotensive patients with age-related macular degeneration

WOS: 000401036900003PubMed ID: 28060360Purpose To evaluate effects of intravitreal ranibizumab and bevacizumab administration on ambulatory blood pressure monitoring (ABPM) recordings in normotensive patients with age-related macular degeneration (AMD). Patients and methods A total of 72 patients (mean age: 61.8(6.2) years, 52.8% were females) diagnosed with AMD were included in this study as divided into ranibizumab (n = 34) and bevacizumab (n = 38) treatment groups. Twenty-four hour, nighttime, and daytime ABMP values for systolic and diastolic BP were recorded in study groups before and after the third intravitreal injection of ranibizumab or bevacizumab. Results Ranibizumab injection had no impact on ABPM recordings and dipping status. In the bevacizumab group, increased daytime (129.0(6.6) vs 127.7(6.6) mm Hg, P = 0.002) and nighttime systolic (116.9(7.5) vs 112.6(7.1) mmHg, p<0.001) BP and decreased daytime diastolic (80.1(6.5) vs 82.4(6.1) mm Hg, P = 0.001) BP were noted in the post-injection period. Also, percentage of non-dippers was significantly increased from 5.3% at pre-injection to 28.9% (P = 0.004) at the post-injection period. Conclusion In conclusion, given that it has no significant impact on ABPM recordings and dipping status, in our study, intravitreal ranibizumab injection may be the better choice in the management of AMD

Hepatitis B virus genotype D prevails in patients with persistently elevated or normal ALT levels in Turkey

Background: The clinical relevance of hepatits B virus (HBV) genotypes are poorly understood and it is unclear if the prevalence of HBV genotypes differs with the various clinical features of HBV carriers. The aim of our study was to examine the prevalence of the HBV genotype in a group of patients with chronic hepatitis B, compared to a group with chronic inactive hepatits B surface antigen (HbsAg) carriers