Biomedical subjects

S Zeuzem

Publications and source records attributed to S Zeuzem.

At least 73 records · Page 4Linked to original sources

PubMed2001

[Retrospective cohort study of lamivudine therapy in patients with chronic hepatitis B].

BACKGROUND AND AIMS: Lamivudine, a nucleoside analogue with specific antiviral activity against the hepatitis B virus, is now available as an alternative therapeutic option to standard interferon-alpha treatment in chronic hepatitis B. Larger studies with lamivudine treatment in chronic hepatitis B were mainly performed in North America and Asia. Data on treatment responses in European patients are sparse. Therefore, we evaluated the efficacy and safety of lamivudine therapy in Central European patients and compared the data with the results from international trials. PATIENTS AND METHODS: In this retrospective, multicenter, cohort study, 95 patients with chronic hepatitis B (median age: 40.4 years, male: 87 patients, female: 8 patients, HBeAg positive: 47 patients, anti-HBe positive: 48 patients), who were treated with lamivudine (100-300 mg/d per os) between 1997 to 1999, were enrolled. RESULTS: During lamivudine treatment a virologic response with HBeAg to anti-HBe seroconversion was achieved in 22/47 (47%) of the HBeAg positive patients. Pretreatment ALT levels (> threefold the upper limit of normal; p = 0.03) and HBV-DNA serum concentration (< or = 100 pg/ml; p = 0.08) were identified as positive predictors for virologic responses. The virologic response was sustained in six of nine patients who had a follow-up period (median 26 weeks). In anti-HBe positive patients a virologic response with undectable HBV-DNA levels was achieved in 35/48 (73%) patients during lamivudine treatment. Side effects during lamivudine therapy were generally mild and reversible. CONCLUSIONS: In this retrospective cohort study virologic end-of-treatment responses to lamivudine monotherapy in patients with chronic hepatitis B were comparable with yet reported international trials. Thus, lamivudine represents a cost-effective and well tolerable option in addition to IFN-alpha in the treatment of chronic hepatitis B.

Adult↗

PubMed2001

[Clinical aspects of liver cirrhoses and its complications and diagnostic problems].

Liver cirrhosis is the end-stage of chronic liver disease with a prevalence of 0.5-0.8 percent in the German population. The main causes are chronic viral hepatitis B and C and alcohol abuse. Liver cirrhosis is often oligosymptomatic and frequently only diagnosed when complications occur (laboratory tests, ultrasound, computertomography or nuclear resonance imaging and histology). Complications include portal hypertension, gastrointestinal bleeding, ascites, spontaneous bacterial peritonitis, hepatorenal syndrome, hepatopulmonary syndrome, hepatic encephalopathy and hepatocellular carcinoma. Therapeutic management should mainly focus on the treatment of the underlying chronic liver disease in a precirrhotic stage. In the case of cirrhosis, prevention and treatment of complications are clinically most important.

Diagnosis, Differential↗

PubMed2001

[Diagnostic imaging in liver cirrhosis].

For the diagnosis of liver cirrhosis ultrasound, computed tomography, magnetic resonance imaging, and angiography are recommended as imaging modalities. Ultrasound of the liver is used as a screening imaging tool in cases of patients suspicious for diffuse liver disease and is helpful in the term of follow-up examinations. Computed tomography is mainly performed to clarify the presence of liver disease detected by ultrasound. In this context, accurate examination of the vascular structures of the liver as well as extrahepatic situation, is of the essence. Diagnosis of diffuse liver disease and characterization of morphologic changes is improved using contrast-enhanced MR imaging with liver specific contrast media. Combined magnetic resonance imaging can provide comprehensive evaluation of cirrhosis. An improved detection rate and characterization of regenerating nodules can be achieved compared to imaging modalities such as ultrasound and computed tomography. MR imaging can be performed in a one-stop-technique using unenhanced and liver-specific-contrast-enhanced sequence protocols to evaluate the liver parenchyma itself, MR cholangiography to verify the bile duct system, and MR angiography to specify the vascular situation. This technique is the optimal protocol for diagnostic imaging in patients suffering from liver cirrhosis and the method of choice to reach the final diagnosis.

Diagnostic Imaging↗

PubMed2001

Interleukin-12 in the treatment of chronic hepatitis B and C.

Interleukin-12 plays a central role in mounting an effective cellular immune response directed towards elimination of intracellular pathogens. In two open label, multicenter, dose-escalation phase I/II studies tolerability, pharmacokinetics, pharmacodynamics, and efficacy of subcutaneously administered recombinant human interleukin-12 (rHuIL-12) was assessed in the treatment of chronic hepatitis B and C. Forty-six patients with chronic hepatitis B and 60 patients with chronic hepatitis C were treated for 12 and 10 consecutive weeks, respectively. rHuIL-12 was generally well tolerated, but was associated with temporary decreases in neutrophils and lymphocyte counts, and with elevations in serum transaminases and bilirubin. Serum IL-12 levels observed were higher at 0.5 microg/kg compared with 0.25 microg/kg doses, suggesting a dose-related increase in systemic exposure of IL-12. Measurable levels of interferon-gamma were also observed at the highest dose of 0.5 microg/kg. At the end of treatment HBV DNA clearance was greater in patients treated with 0.50 microg/kg (25%) or with 0.25 microg/kg (13%) compared with those given 0.03 microg/kg. In patients with chronic hepatitis C, HCV RNA remained detectable in all patients. A more than 50% decrease in pretreatment HCV RNA levels was observed in 3/16 patients (0.03 microg/kg), in 3/14 (0.10 microg/kg), in 6/15 (0.25 microg/kg), and in 8/15 patients of the 0.5 microg/kg dose group. In conclusion, antiviral activity of rHuIL-12 in patients with chronic hepatitis B or C does not appear to be advantageous in comparison to other currently available treatments.

Adolescent↗

PubMed2001

The kinetics of hepatitis C virus infection.

Mathematical modeling of viral dynamics reveals high turnover rates of pretreatment viral production and clearance (10(11)-10(13) virions/day) and permits the estimation of in-vivo half-lives of a few hours for HCV free virions. The balance between virus production and clearance in untreated patients with chronic hepatitis C virus results in a decline of viremia when active antiviral treatment is initiated. During the first phase of IFN-alpha therapy, the kinetics of the viral load is characterized by a rapid, dose-dependent decline. After about 24 to 48 hours, the viral decline enters a second phase of a relatively slow exponential decay during the following weeks of therapy which may reflect the death rate of infected hepatocytes. The second-phase decay is predictive for the virologic end-of-treatment status and, even more so, for the likelihood of sustained response. Nonresponding patients typically show constant viremia or even a rebound during this second phase.

Antiviral Agents↗

PubMed2001

Activation of a cryptic splice site of PTEN and loss of heterozygosity in benign skin lesions in Cowden disease.

Cowden disease is an autosomal dominant syndrome characterized by facial trichilemmomas, acral keratoses, papillomatous papules, mucosal lesions, and an increased risk for breast and nonmedullary thyroid cancer. Here, we describe a novel PTEN splicing site mutation in a family with classical Cowden disease and we studied benign skin lesions typical for Cowden disease for loss of heterozygosity. We found a PTEN IVS2 + 1G > Alpha 5'-splicing acceptor mutation resulting in activation of a cryptic splice site. Activation of this cryptic splice site is predicted to result in a frameshift with a premature stop codon, thus disrupting the phosphatase core motif of PTEN. Loss of heterozygosity analysis of two trichilemmomas, one fibroma, and three acanthomas of the index patient demonstrated loss of heterozygosity at the PTEN locus in four of these lesions. In conclusion, our data demonstrate that a PTEN splicing site mutation causes activation of a cryptic splice site, which results in aberrant transcripts.

Aged↗

PubMed2001

Randomized, placebo-controlled, double-blind trial with interferon-alpha with and without amantadine sulphate in primary interferon-alpha nonresponders with chronic hepatitis C.

In primary interferon-alpha (IFN-alpha) nonresponders with chronic hepatitis C, retreatment with IFN-alpha has only limited efficacy with sustained response rates below 10%. Therefore, the aims of the present study were to compare the efficacy and safety of IFN-alpha alone or in combination with amantadine sulphate in nonresponders to previous IFN-alpha monotherapy. Fifty-five IFN-alpha nonresponders with chronic hepatitis C (mean age: 46.6 years) received IFN-alpha 6 MIU thrice weekly for 24 weeks followed by 3 MIU thrice weekly for additional 24 weeks. Amantadine sulphate (n=26) or a matched placebo (n=29) was given orally twice daily for 48 weeks. Because of a low initial response rate at week 12 (13/55 patients) and a high breakthrough rate (8/13 patients) after IFN-alpha dose reduction in week 24, a virological end-of-treatment response with undetectable serum HCV-RNA (< 1000 copies/mL) was achieved in only five patients (IFN-alpha/amantadine sulphate, one patient; IFN-alpha/placebo, four patients). After 24 weeks follow-up a sustained virological response was observed in only two patients receiving IFN-alpha and placebo. Health-related quality-of-life analysis showed a substantial improvement of the Profile of Mood States (POMS) scale concerning the subscales fatigue (P < 0.05) and vigor (P < 0.05) in patients receiving combined IFN-alpha/amantadine sulphate treatment compared with those treated with IFN-alpha alone. IFN-alpha/amantadine sulphate combination therapy was well tolerated without any serious adverse events. In conclusion, retreatment with IFN-alpha and amantadine sulphate does not increase the low sustained virological response rates of IFN-alpha therapy in primary IFN-alpha nonresponders with chronic hepatitis C, but may lead to a sustained improvement of health-related quality-of-life.

Adolescent↗

PubMed2001

Viral kinetics in patients with chronic hepatitis C treated with standard or peginterferon alpha2a.

BACKGROUND & AIMS: Covalent attachment of a 40-kilodalton polyethylene glycol moiety to interferon alpha2a (peginterferon alpha2a) results in sustained delivery and reduced clearance compared with standard interferon alpha2a. The aim of the study was to compare viral kinetics in patients treated with standard or peginterferon alpha2a. METHODS: Patients with chronic hepatitis C were randomly assigned to receive either standard interferon alpha2a thrice weekly (n = 16) or 180 microg peginterferon alpha2a once weekly (n = 17) for 48 weeks. HCV RNA was quantitated before and frequently during treatment. RESULTS: The extent of the second-phase decline of HCV RNA, representing the degradation rate of infected cells during therapy for responding patients, was 0.02 +/- 0.03 day(-1) (HCV-1), 0.88 +/- 0.64 day(-1) (HCV non-1), 0.06 +/- 0.08 day(-1) (HCV-1), and 0.44 +/- 0.33 day(-1) (HCV non-1) in patients treated with standard or peginterferon alpha2a, respectively. The second-phase decline was low (<0.05 day(-1)) in most patients without a virological end-of-treatment response, and the second-phase decline was high (>0.25 day(-1)) in all patients with sustained virological response. CONCLUSIONS: The degradation rate of infected cells is HCV genotype dependent. Treatment with peginterferon alpha2a may reinforce the death rate of infected cells (particularly in HCV-1-infected patients) or stabilize the therapeutic effect on viral production. The second-phase decline of HCV RNA is predictive of virological sustained response.

Adult↗

PubMed2001

Interferon alfa down-regulates CD81 in patients with chronic hepatitis C.

CD81 protein has been shown to bind hepatitis C virus (HCV) envelope 2 (E2) glycoprotein in vitro and may act as a (co)receptor for HCV. Regulation of CD81 expression by interferon alfa (IFN-alpha) and ribavirin could thereby affect the response to antiviral therapy. In the present study, the effects of IFN-alpha and ribavirin on CD81 protein and CD81 mRNA were assessed in peripheral blood lymphocytes (PBL) and isolated human hepatocytes by fluorescence-activated cell sorter (FACS) analysis and real-time polymerase chain reaction (PCR), respectively. In addition, regulation of CD81 in PBL was investigated in 10 patients treated with combination therapy. Incubation with IFN-alpha (50 U/mL) down-regulated total CD81 in PBL (81.7 +/- 11.6% of control; P =.003) and in isolated human hepatocytes (91.6 +/- 8.1% of control; P =.034). Incubation with IFN-alpha with and without ribavirin (2.2 microg/mL) significantly reduced cell surface-associated CD81 protein (83.9 +/- 10.3% of control; P =.003). PBL of untreated patients chronically infected with HCV had significantly higher levels of total CD81 protein compared with PBL obtained from healthy donors (631.1 +/- 93.3 vs. 538.9 +/- 95.2 relative fluorescence units [RFU]; P =.030). Pretreatment cell surface-associated CD81 protein was lower in patients infected with genotype HCV-3 than those infected with HCV-1 (111.8 +/- 15.0 vs. 162.0 +/- 41.3 RFU; P =.019). Furthermore, cell surface-associated CD81 protein was lower 4 weeks after initiation of therapy in patients with an initial virologic response compared with initial virologic nonresponders (110.5 +/- 8.5 vs. 139.8 +/- 27.5 RFU; P =.057). In conclusion, IFN-alpha and ribavirin regulate CD81 expression in vitro and in vivo. CD81 expression correlates with HCV genotype and initial virologic response in patients with chronic hepatitis C.

Antigens, CD↗

PubMed2001

[Hypertransaminasaemia and impaired liver function in a patient with oligosymptomatic celiac disease].

Hypertransaminasaemia and impaired liver function in a patient with oligosymptomatic celiac disease. We describe the case of a 45-year-old man who was referred for evaluation of elevated aminotransferases. One year before referral the patient developed an ischemic stroke followed by a subdural hematoma three months later. In our outpatient clinic the patient presented with a malabsorption syndrome including diminished vitamin-K-dependent clotting factors. Serologic testing was positive for IgA antigliadin antibodies and IgA antiendomysial antibodies. Celiac disease was confirmed by an upper endoscopy examination and biopsies obtained from the distal duodenum. Histological examination showed villous atrophy, crypt hyperplasia and an increase in intraepithelial lymphocyte count consistent with celiac disease. After initiation of a gluten-free diet the malabsorption syndrome as well as liver dysfunction improved. Serum aminotransferase levels normalized within 6 months. The clinical course demonstrates involvement of the liver in patients with celiac disease.

Alanine Transaminase↗

PubMed2001

What is (cost) effective in patients with chronic hepatitis C virus infection?

Hepatitis C virus (HCV) infection often progresses to chronic hepatitis, cirrhosis, and possibly hepatocellular carcinoma. Chronic hepatitis C infection is a leading cause of chronic liver disease and the most common indication for liver transplantation. Combination therapy of interferon alpha and ribavirin is currently the standard regimen for chronic hepatitis C. This combination can achieve viral clearance in approximately 40% of patients, and improve histology and prognosis. The most cost-effective approach to guide duration of combination therapy is HCV genotyping. Cost effectiveness cannot be improved further by taking other well-defined predictive factors for sustained virological response into account. Recent insights into HCV kinetics and the correlation between initial viral decline and sustained virological response will allow us to optimize and individually tailor antiviral treatment Individualized treatment according to the initial viral decline, together with further improvements in drugs (e.g. by long-acting pegylated interferons), will have new impact on antiviral efficacy and cost effectiveness.

Antiviral Agents↗

PubMed2001

A de novo deletion of chromosome 5q causing familial adenomatous polyposis, dysmorphic features, and mild mental retardation.

Familial adenomatous polyposis (FAP) is an autosomal dominant disorder that typically presents with colorectal cancer secondary to extensive adenomatous polyps of the colon. The molecular basis and clinical phenotype of FAP are well known. Recurrent episodes of severe abdominal pain and a positive fecal occult blood test in an 18-yr-old boy with mild mental retardation and slight dysmorphic features of the face, head, and skeletal system led to the diagnosis of FAP. The clinical workup revealed the presence of over 100 sessile colonic polyps but no polyp formation in the upper GI tract, no cancer development, nor other FAP-associated lesions. To find out whether there is an association between mental retardation and FAP we performed a chromosome analysis including comparative genomic hybridization and an indirect genotype analysis with polymorphic markers from the APC gene region. Cytogenetic analysis showed an interstitial deletion of chromosomal region 5q that was confined to the region 5q21-q22 by comparative genomic hybridization. The deletion, spanning about 10 centimorgans, encompassed the complete APC gene and can be considered as causative for FAP. Moreover, molecular genetic analysis with polymorphic markers flanking the APC gene demonstrated a de novo deletion on the paternal chromosome. Cytogenetically detectable deletions on chromosome 5 including the APC gene generally lead to an associated gene deletion syndrome. Individuals who present with mild mental retardation and dysmorphic features should therefore be investigated for chromosomal deletions. If the deletion encompasses the APC gene, these patients are at high risk of developing FAP and associated complications.

Abnormalities, Multiple↗

PubMed2001

Assessment, by transcription-mediated amplification, of virologic response in patients with chronic hepatitis C virus treated with peginterferon alpha-2a.

Transcription-mediated amplification (TMA) is an isothermal, autocatalytic target amplification method which has the potential to detect less than 50 hepatitis C virus (HCV) RNA copies/ml (10 IU/ml). The TMA assay was used to assess the presence of residual HCV RNA in plasma from patients treated with polyethylene glycol-modified interferon alpha-2a (peginterferon alpha-2a) who showed a virologic relapse after the end of therapy. Stored end-of-treatment and end-of-follow-up plasma samples from 177 of 267 patients treated with peginterferon alpha-2a (S. Zeuzem et al., N. Engl. J. Med. 343:1666--1672, 2000) were available for retesting by TMA. Plasma samples from patients in the same study who exhibited virologic relapse after treatment with standard interferon alpha-2a served as controls. Virologic response during the trial was defined as HCV RNA that was undetectable using a PCR-based test system with a sensitivity of 50 IU/mL (Cobas Amplicor HCV version 2.0) and was compared with TMA-based retesting results (VERSANT HCV RNA Qualitative Assay). Residual HCV RNA was detected in 4 of 60 cases (7%) by the TMA technology in end-of-treatment plasma samples from patients who relapsed after receiving peginterferon alpha-2a and in 6 of 18 patients (33%) following therapy with standard interferon alpha-2a. For peginterferon alpha-2a-treated patients with sustained virologic response, HCV RNA was detectable by TMA in end-of-treatment samples in 3 of 78 cases but in none of the end-of-follow-up samples. For all end-of-treatment and end-of-follow-up plasma samples of virologic nonresponders, a complete concordance between the PCR-based assay and TMA was observed. In conclusion, in patients with virologic relapse after the end of therapy, according to PCR, who were treated with peginterferon alpha-2a or standard interferon alpha-2a, residual HCV RNA was detectable in end-of-treatment samples by the TMA-based assay in 7 or 33% of cases, respectively. The lower rate of residual HCV RNA detection by TMA for patients treated with peginterferon alpha-2a than that for patients treated with standard interferon alpha-2a may be due to the maintained antiviral pressure of the long-acting peginterferon alpha-2a at the end-of-treatment visit.

Antiviral Agents↗

PubMed2001

Peginterferon alfa-2a (40 kDa) monotherapy: a novel agent for chronic hepatitis C therapy.

Current therapy for hepatitis C remains far from optimal. The modification of IFN by the attachment of a polyethylene glycol (PEG) moiety has produced long-lasting IFNs. A 40 kDa branched peginterferon alfa-2a (40 kDa) (PEG-IFN alfa-2a) has unique pharmacokinetic and pharmacodynamic properties. PEG-IFN alfa-2a is absorbed in a sustained manner and its clearance is reduced substantially compared with IFN alfa-2a, resulting in sustained serum drug concentrations. These constant serum drug levels stay above the EC(50) values (effective concentration 50%) needed for antiviral, antiproliferative and immunomodulatory actions. Sustained virological responses were significantly greater in patients who received PEG-IFN alfa-2a versus IFN alfa-2a, with a similar side effect profile. Histological improvements were seen in patients who achieved sustained virological responses and were frequently observed among patients who did not achieve a virological response. The advantages of PEG-IFN alfa-2a were also seen in patients with cirrhosis or hepatitis C virus (HCV) genotype 1.

Animals↗

PubMed2001

Comparative sequence analysis of the core- and NS5-region of hepatitis C virus from tumor and adjacent non-tumor tissue.

The sequence variability within the core- and non-structural 5 (NS5)-region of the hepatitis C virus (HCV) was investigated in tumor and non-tumor tissue of 8 patients with HCV-associated hepatocellular carcinoma (HCC). Analyses of multiple clones containing polymerase chain reaction-amplified HCV sequences revealed a significantly higher variability within the core-region of tumor tissue isolates than of isolates from non-tumor tissue. Mutant sequence diversity ranged from silent mutations, as well as amino acid substitutions, appearance of in frame stop codons and deletions leading to frame-shifts. In contrast, the variability of the NS5-region sequences between isolates from tumor and non-tumor tissue was not significantly different. These observations might have important implications on the pathology of HCV, especially its potential tumorigenicity.

Aged↗

PubMed2000

Peginterferon alfa-2a in patients with chronic hepatitis C.

BACKGROUND: Covalent attachment of a 40-kd branched-chain polyethylene glycol moiety to interferon alfa-2a results in a compound (peginterferon alfa-2a) that has sustained absorption, a slower rate of clearance, and a longer half-life than unmodified interferon alfa-2a. We compared the clinical effects of a regimen of peginterferon alfa-2a with those of a regimen of interferon alfa-2a in the initial treatment of patients with chronic hepatitis C. METHODS: We randomly assigned 531 patients with chronic hepatitis C to receive either 180 microg of peginterferon alfa-2a subcutaneously once per week for 48 weeks (267 patients) or 6 million units of interferon alfa-2a subcutaneously three times per week for 12 weeks, followed by 3 million units three times per week for 36 weeks (264 patients). All the patients were assessed at week 72 for a sustained virologic response, defined as an undetectable level of hepatitis C virus RNA (<100 copies per milliliter). RESULTS: In the peginterferon group, 223 of the 267 patients completed treatment and 206 completed follow-up. In the interferon group, 161 of the 264 patients completed treatment and 154 completed follow-up. In an intention-to-treat analysis in which patients who missed the examination at the end of treatment or follow-up were considered not to have had a response at that point, peginterferon alfa-2a was associated with a higher rate of virologic response than was interferon alfa-2a at week 48 (69 percent vs. 28 percent, P=0.001) and at week 72 (39 percent vs. 19 percent, P=0.001). Sustained normalization of serum alanine aminotransferase concentrations at week 72 was also more common in the peginterferon group than in the interferon group (45 percent vs. 25 percent, P=0.001). The two groups were similar with respect to the frequency and severity of adverse events, which were typical of those associated with interferon alfa. CONCLUSIONS: In patients with chronic hepatitis C, a regimen of peginterferon alfa-2a given once weekly is more effective than a regimen of interferon alfa-2a given three times weekly.

Adult↗

PubMed2000

Retroperitoneal endoscopic debridement for infected peripancreatic necrosis.

Standard management of infected peripancreatic necrosis consists of open surgical debridement and lavage--a traumatic intervention with substantial morbidity and mortality. As an alternative and novel approach with minimum invasiveness, we present fenestration of the gastric wall and debridement of infected necrosis by direct retroperitoneal endoscopy. In three patients, this strategy led to rapid clinical improvement and no serious complications. Transgastric endoscopic therapy may be a less traumatic alternative to surgery and should be further assessed in prospective studies.

Acute Disease↗

PubMed2000

Involvement of the platelet-derived growth factor receptor in angiotensin II-induced activation of extracellular regulated kinases 1 and 2 in human mesangial cells.

In mesangial cells angiotensin II (Ang II) has been shown to activate extracellular regulated kinases 1 and 2 (ERK1/2). Here, we studied the role of the epidermal growth factor receptor (EGFR) and platelet-derived growth factor receptor (PDGFR) in Ang II-induced ERK1/2 activation in human mesangial cells. Ang II induced activation of ERK1/2 via the AT(1) receptor, and this response was blocked by the PDGFR-selective tyrosine kinase inhibitor AG1295, but not by AG1478, an EGFR-selective tyrosine kinase inhibitor, indicating participation of the PDGFR, but not of the EGFR in Ang II-induced ERK1/2 activation. In agreement with this assumption, Ang II caused tyrosine phosphorylation of the PDGFR and the adapter protein Shc in an AG1295-sensitive fashion. In conclusion, our data show that Ang II-induced activation of mitogenic signalling cascade in human mesangial cells involves ligand-independent activation of the PDGFR, but not of the coexpressed EGFR.

Angiotensin II↗