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Biomedical subjects

A R Müller

Publications and source records attributed to A R Müller.

At least 37 records · Page 2Linked to original sources
PubMed2001

Prospective randomized trial to assess the value of preemptive oral therapy for CMV infection following liver transplantation.

BACKGROUND: With the development of sensitive tests to detect cytomegalovirus (CMV) viremia, preemptive approaches become a reasonable alternative to general CMV prophylaxis. We performed a randomized trial comparing pp65-antigenemia guided preemptive therapy using oral ganciclovir with symptom-triggered intravenous ganciclovir treatment. METHODS: Eighty-eight of 372 liver transplant recipients developed antigenemia early after orthotopic liver transplantation. Twenty-eight symptomatic patients with antigenemia were excluded from randomization and treated with intravenous ganciclovir. Sixty pp65-antigen-positive asymptomatic patients were randomized to receive either oral ganciclovir 3x1 g/day for 14 days (group 1) or no preemptive treatment (group 2). Patients that developed CMV disease were treated with intravenous ganciclovir 2x5 mg/kg body weight for 14 days. The high-risk (Donor+/Recipient-) patients were equally distributed in the two study groups. RESULTS: Three of 30 (10%) patients on oral ganciclovir developed mild to moderate CMV disease compared with 6/30 (20%) patients in the control group. In the Donor+/Recipient- patients, the incidence of CMV disease was 1/6 and 3/7. All disease episodes resolved after intravenous treatment. The 1- and 3-year patient and organ survival was the same in the study groups and in the patients with or without CMV infection. No deaths related to CMV occurred. CONCLUSIONS: The positive predictive value of pp65-antigenemia for the development of CMV disease was very low, and, in 28/88 patients (32%), antigenemia did not precede symptoms. Therefore, pp65-antigenemia is of limited value in deciding on the timing and need for ganciclovir therapy after liver transplantation.

Administration, Oral↗
PubMed2001

Incidence and indications for reintubation during postoperative care following orthotopic liver transplantation.

STUDY OBJECTIVE: To analyze the incidence and indications for reintubation during postoperative care following orthotopic liver transplantation (OLT). DESIGN: Retrospective chart review. SETTING: Large metropolitan teaching hospital. PATIENTS: 546 adult liver transplant recipients. MEASUREMENTS AND MAIN RESULTS: The medical charts of 546 patients who underwent OLT at our institution between January 1992 and September 1996 were reviewed for the incidence and indications of reintubation throughout primary hospitalization. Eighty-one of 546 patients (14.8%) required one or more episodes of reintubation after OLT. In the majority of cases, reintubation was performed for pulmonary complications (44.6%), followed by cerebral (19.1%) and surgical (14.5%) complications. Cardiac (9.1%) and peripheral neurologic (2.7%) complications were less frequent reasons for reintubation. Overall patient survival, according to the Kaplan-Meier estimates, was 89.9%, 87.5%, 86.5%, and 82.2% after 1, 2, 3, and 5 years, respectively. In patients with one or more episodes of reintubation, overall survival decreased to 62.5% after 1, 2, and 3 years, and to 56.4% after 5 years (p < 0.001). CONCLUSIONS: The main indications for reintubation after OLT were pulmonary, cerebral, and surgical complications. These reintubation events had a considerable influence on the patient's postoperative recovery, and were associated with a significantly higher rate of mortality, than for OLT patients who did not undo reintubation.

Anti-Infective Agents↗
PubMed2001

Occurrence and clinical outcome of lamivudine-resistant hepatitis B infection after liver transplantation.

Lamivudine treatment of hepatitis B after orthotopic liver transplantation (OLT) is often accompanied by fast viral-resistance formation. Although no clinical data are available, in vitro data indicate that lamivudine-resistant reinfection has a mild course because of defective viral replication. Between 1996 and 1999, a total of 34 patients were treated with lamivudine because of hepatitis B recurrence after OLT. All patients developed reinfection despite long-term passive immunoprophylaxis with hepatitis B immunoglobulin, diagnosed by positive hepatitis B surface antigen and positive hepatitis B virus (HBV) DNA. Before treatment with lamivudine, 21 of these patients underwent a course of famciclovir and developed resistance. Monthly laboratory tests and sequential liver biopsies were performed during the follow-up period. Nineteen of 34 patients (56%) developed lamivudine resistance during the follow-up period of 12 to 49 months. One- and 3-year graft survival rates after the diagnosis of lamivudine resistance were 89% and 66%, respectively. In most cases, lamivudine resistance was associated with high viral replication (3,012 +/- 574 pg/mL 1 month after the diagnosis of lamivudine resistance); however, liver enzyme levels were only moderately elevated (alanine aminotransferase [ALT], 45 +/- 16 U/L). Only 3 patients (15%) showed a rapid increase in ALT level to more than 500 U/L within 3 months after resistance developed. All other patients had mildly elevated liver enzyme levels during the first 6 to 8 months after lamivudine resistance. In the later course, liver enzyme levels increased in most patients. Fourteen patients with elevated transaminase levels were switched to lamivudine plus interferon alfa (n = 8) or lamivudine plus famciclovir therapy (n = 6). This combination was successful in most cases, decreasing HBV DNA and liver enzyme levels. Four patients with lamivudine resistance died during follow-up, only 1 patient because of HBV reinfection. In addition, 2 patients underwent retransplantation because of hepatitis B cirrhosis of the first graft. Compared with historic courses of wild-type recurrence, lamivudine-resistant reinfection is characterized by a milder clinical course. Fulminant cases were not observed; however, in three cases, chronic liver failure developed. The combination of different antivirals diminished viral replication after lamivudine resistance. In the future, new antiviral agents, such as adefovir, might further expand therapeutic options.

Drug Resistance, Microbial↗
PubMed2000

Additional interferon alpha for lamivudine resistant hepatitis B infection after liver transplantation: a preliminary report.

Resistance formation is a major problem in antiviral treatment of hepatitis B recurrence after liver transplantation. One possible therapeutic approach is an antiviral combination therapy with synergistic drugs. Four patients who were transplanted for chronic hepatitis B were analyzed retrospectively. All patients had reinfection of the graft and breakthrough of hepatitis B virus (HBV) during consecutive famciclovir and lamivudine monotherapy. Subsequently a combination therapy of lamivudine and interferon alpha 2a (3 times 3 million units weekly) was initiated. Addition of interferon markedly reduced viral replication rate in all patients. Three patients became HBV-DNA negative despite lamivudine resistance, but only two had a sustained response. No patient seroconverted to anti-HBe or lost HBsAg, but all patients showed a normalization of alanine aminotransferase and aspartate aminotransferase levels. No severe complications, and especially no rejection episodes occurred. Therefore lamivudine combined with interferon might be used for the therapy of hepatitis B reinfection after liver transplantation.

Adult↗
PubMed2000

Antiviral combination therapy for lamivudine-resistant hepatitis B reinfection after liver transplantation.

Development of resistance is a major issue in antiviral treatment of hepatitis B reinfection after liver transplantation. Antiviral combination therapy is discussed for therapy or prevention of this breakthrough of viral replication. Eight patients were enrolled into this retrospective analysis after liver transplantation for chronic hepatitis B infection. All had reinfection of the graft and breakthrough of HBV during consecutive famciclovir and lamivudine monotherapy. Subsequently a combination therapy with lamivudine and interferon-alpha 2a (group I, n = 4) or lamivudine and famciclovir (group II, n = 4) was initiated. Combination therapy was started 61 months (group I) and 25 months (group II) after liver transplantation. It markedly reduced the viral replication rate in all patients despite lamivudine resistance. In group I three of four patients and in group II two of four patients became HBV-DNA negative. Two long-term responders were observed in group I, and none in group II. No patient became HBsAg negative or lost HbeAg. Pretreatment elevated ALT and AST levels were significantly reduced. No severe complications, and especially no rejection episodes, occurred. Lamivudine in combination with other antiviral agents, especially interferon-alpha, might be a therapeutic option for hepatitis B reinfection after liver transplantation. Suppression of virus replication to the point of undetectable values is possible even in patients with lamivudine-resistant virus mutations.

2-Aminopurine↗
PubMed2000

Lamivudine as first- and second-line treatment of hepatitis B infection after liver transplantation.

Lamivudine and famciclovir have expanded therapeutical options for HBV infection after liver transplantation. First studies confirm good antiviral effects of both, but at present the major problem seems to be a rapid resistance formation in immunosuppressed patients. Thirty-four adult patients with HBV recurrence despite passive immunoprophylaxis and seven with de novo infection after orthotopic liver transplantation (OLT) were treated with 100-150 mg lamivudine daily. Patients were either treated directly after infection (n = 14) or after breakthrough of viral replication during an initial famciclovir therapy (n = 27). All patients except two responded to treatment with a reduction of serum HBV-DNA of over 50%. Thirty-one patients (76%) turned HBV-DNA-negative during lamivudine therapy. Viral breakthrough was observed in 14 of these patients after 4-13 months of treatment. A total of 17 patients (40%) remained HBV-DNA-negative for more than 12 months. Only nine patients eliminated HBsAg, of which four had and an HDV coinfection. None of the HBeAg-positive patients converted to anti-HBe. Most patients showed a prompt and significant reduction of aspartate aminotransferase (ALAT) levels. No severe complications occurred. Therefore, a safe and effective therapy of HBV infection after transplantation is possible with lamivudine. Viral replication is suppressed even in patients who revealed breakthrough during famciclovir therapy. Resistance formation as a major drawback occurred in one third of the patients within the first year of treatment.

2-Aminopurine↗
PubMed2000

Astrocytes in sensory circumventricular organs of the rat brain express functional binding sites for endothelin.

Sensory circumventricular organs bordering the anterior third cerebral ventricle, the subfornical organ and the organum vasculosum laminae terminalis, lack blood-brain barrier characteristics and are therefore accessible to circulating peptides like endothelins. Astrocytes of the rat subfornical organ and organum vasculosum laminae terminalis additionally showed immunocytochemical localization of endothelin-1/endothelin-3-like peptides, possibly acting as circumventricular organ-intrinsic modulators. Employing [125I]endothelin-1 as radioligand, quantitative autoradiography demonstrated specific binding sites throughout the rat organum vasculosum laminae terminalis and subfornical organ, and competitive displacement studies revealed expression of both ET(A) and ET(B) receptor subtypes for either circumventricular organ. ET(B) receptor binding prevailed for the whole brain and ET(A) receptors could be labelled in the peripheral vascular system. To characterize endothelin-specific receptors in astrocytes of both circumventricular organs, alterations in the intracellular calcium concentration due to endothelin-1/endothelin-3 stimulation were studied in primary culture of subfornical organ and organum vasculosum laminae terminalis cells obtained from early postnatal rat pups. Endothelin-1 and endothelin-3 induced Ca(2+) transients in 9-13% of either subfornical organ or organum vasculosum laminae terminalis astrocytes, respectively, and some glial cells (subfornical organ: 2%, organum vasculosum laminae terminalis: 5%) responded to both endothelin analogues. The antagonistic action of BQ123 specific for ET(A) receptors (74% of all astrocytes tested), and the pronounced responsiveness to the ET(B) receptor agonist [4Ala]ET-1 (subfornical organ: 27%, organum vasculosum laminae terminalis: 35%) demonstrated glial expression of both endothelin receptor subtypes. Agonist-induced elevations in the intracellular calcium concentration proved to be independent of extracellular Ca(2+). In summary, the results indicate that endothelin(s) interact(s) with circumventricular organ astrocytes. Competitive receptor binding techniques using brain tissue sections as well as a fura-2 loaded primary cell culture system of the subfornical organ and organum vasculosum laminae terminalis demonstrate glial expression of functional ET(A) and ET(B) receptors, with calcium as intracellular messenger emerging primarily from intracellular stores. Endothelin(s) of both circulating and circumventricular organ-intrinsic origin may afferently transfer information important for cardiovascular homeostasis to circumventricular organs serving as "windows to the brain".

Animals↗
PubMed2000

Administration of prostacyclin after liver transplantation: a placebo controlled randomized trial.

The shortage of suitable organs for liver grafts is responsible for the use of marginal donors for liver transplantation (OLT). If these liver grafts function poorly initially after OLT, a supportive therapy is necessary. The purpose of this study was to evaluate the effects of prostacyclin (PGI2) on postoperative liver graft function after OLT. A total of 30 adult recipients of primary OLT were randomized to either receive PGI2 (4 ng/kg per min body weight, n = 15) or a placebo for 6 d. To evaluate regional splanchnic oxygenation a fiberoptic pulmonary-artery catheter was inserted into a hepatic vein and the difference between mixed venous oxygen content and hepatic venous oxygen content was determined (deltaO2). Measurements were performed directly after transplantation and at 6, 12, 24 and 48 h postoperatively. A significant correlation between deltaO2 and the level of transaminases (ALT/AST) was observed 24 and 48 h after transplantation (p < 0.05). PGI2 treatment induced a significant decrease in deltaO2 after 24 and 48 h after reperfusion (p < 0.05). Peak AST levels tended to be lower in the PGI2 treatment group (418 +/- 99 vs. 638 +/- 156 U/L, p < 0.1). These results suggest that administration of PGI2 after OLT improves hepatic-splanchnic oxygenation and may thereby reduce reperfusion injury after OLT.

Adult↗
PubMed2000

[Therapy of recurrent hepatitis B infection after liver transplantation. A retrospective analysis of 200 liver transplantations based on hepatitis B associated liver diseases].

BACKGROUND: Before introduction of passive immunoprophylaxis and new antiviral nucleoside analogues the course of hepatitis B recurrence after liver transplantation could hardly be influenced. The result was a inferior graft survival. In the present retrospective analysis of the efficacy of hepatitis B therapy after liver transplantation was analysed retrospectively. PATIENTS AND METHODS: Between 1988 and 1998 in total 179 patients were transplanted due to hepatitis B related liver failure at our centre. All patients received passive immunoprophylaxis with hepatitis B immunoglobulin. In case of reinfection after 1993 an antiviral therapy with famciclovir 1500 mg daily was initiated (n = 26), since 1996 lamivudine (100-150 mg daily) was used (n = 12). In case of viral breakthrough under famciclovir treatment or prophylaxis therapy was switched to lamivudine (n = 22). In case of ineffectiveness of lamivudine an antiviral combination therapy with lamivudine and interferon (n = 4) or lamivudine and famciclovir (n = 4) was initiated. Before availability of antiviral agents or in case of viral breakthrough in total 12 patients were retransplanted due to acute or chronic reinfection. RESULTS: With passive immunoprophylaxis reinfection rate was 33%, 43% and 44% after 1, 3 and 5 years respectively. Without antiviral treatment 52% of patients died within the first year after reinfection. Antiviral therapy with lamivudine or famciclovir improved the one year survival after reinfection to 79%. Suppression of viral replication was more effective with lamivudine. Under lamivudine 26 patients (76%) became HBV-DNA negative, 9 patients HBsAg negative (26%). In contrast no patient became HBsAg negative during famciclovir therapy. Lamivudine was effective also after famciclovir breakthrough in 94% of patients. In case of lamivudine resistant reinfection viral replication could be suppressed with an antiviral combination therapy up to negative HBV-DNA in the hybridization assay. Severe side effects were not observed during any of the antiviral therapies. The graft survival after retransplantation for hepatitis B reinfection was 42% and 25% after one and 3 years. CONCLUSION: Whereas it is generally accepted, that passive immunoprophylaxis lowers the reinfection rate it could be shown in the present study, that antiviral treatment lowers mortality of hepatitis B reinfection. The major problem of lamivudine and famciclovir is viral resistance formation. In this case an antiviral combination therapy might be useful, whereas retransplantation for hepatitis B reinfection should be considered carefully due to inferior graft survival rates.

2-Aminopurine↗
PubMed1999

Dynamics of GB virus C viremia early after orthotopic liver transplantation indicates extrahepatic tissues as the predominant site of GB virus C replication.

The principal site of GB virus C (GBV-C) replication is unknown. To determine whether hepatic GBV-C replication is important for the maintenance of a measurable viremia level in GBV-C infection, the influence of hepatectomy followed by liver transplantation on GBV-C viremia was investigated. GBV-C RNA levels were determined by a quantitative TaqMan polymerase chain reaction (PCR) in 12 patients with pretransplantation GBV-C infection before and daily after orthotopic liver transplantation (OLT) for 25 to 28 days. Compared with the pretransplantation values (mean, 12.4 +/- 3.9 x 10(7) copies/mL), mean GBV-C RNA levels declined significantly by 1 log by day 1 after OLT (mean, 3.5 +/- 1.6 x 10(7) copies/mL), but subsequently remained relatively stable on this high level for the entire observation period, indicating ongoing high-level virus replication (mean GBV-C RNA levels on days 7 and 28 were: 1.7 +/- 0. 5 x 10(7) and 2.8 +/- 0.7 x 10(7) copies/mL; P = ns). Thus, at the end of the follow-up, mean GBV-C RNA levels were not significantly different from that of the 1st and 7th postoperative day and remained significantly lower compared with the pretransplantation values. However, in 2 of the 12 patients, different kinetics were observed. Both already had low-level viremia pre-OLT (0.02 and 0.002 x 10(7) copies/mL) and became persistently GBV-C RNA-negative 2 days after OLT. In 5 patients, liver tissues were collected 6 to 9 days after OLT and investigated for GBV-C RNA. All but 1 were GBV-C RNA-negative in the liver, although 2 of them had rather high serum GBV-C RNA levels at this time. The kinetics of GBV-C viremia observed in our study were neither influenced by the immunosuppressive therapy nor by the number of blood and blood product transfusions given after OLT. In addition, they were quite different from those observed in patients with chronic hepatitis C in whom early reinfection of the graft could be demonstrated by a steady increase in HCV RNA levels starting 3 days after OLT and exceeding preoperative levels by day 8. From our data, one can conclude that the liver is certainly not the major site of GBV-C replication in most patients. However, one cannot exclude that host or viral factors exist that predispose GBV-C replication predominantly in the liver.

Adult↗
PubMed1999

Long-term results of famciclovir for recurrent or de novo hepatitis B virus infection after liver transplantation.

Since the introduction of famciclovir in the treatment of hepatitis B virus (HBV) infection after liver transplantation, promising results have been published. In this study, the long-term efficacy and safety of famciclovir were assessed. Twenty-four patients with recurrent hepatitis B and 6 patients with de novo infection after liver transplantation were enrolled in an open prospective trial. Patients received oral famciclovir, 500 mg three times daily. Serum HBV-DNA, viral serology, and liver enzymes were measured sequentially; liver histology was taken before and during treatment in 12 patients. In the reinfected patients, 17 patients initially responded well to treatment, with a mean decrease of HBV-DNA of 82%, 5 patients became HBV-DNA negative. The drug was effective for 1-51 months (mean 16 months), then viral replication increased again in 13 out of 17 patients. One patient did not respond to treatment. Six out of 24 patients already had severe cirrhosis at the time of enrollment and died shortly afterwards, due to the HBV infection. The 6 patients with de novo infection all had a decline of HBV-DNA for 2-42 months (mean 14 months); 1 patient converted to HBV-DNA negative. Five out of 6 patients experienced a viral breakthrough later on. No severe side-effects were observed. Therefore, famciclovir is effective in certain HBV-infected patients after orthotopic liver transplantation (OLT), but in the long term, most of the patients relapse.

2-Aminopurine↗
PubMed1999

[Complications of percutaneous liver biopsy in patients after liver transplantation].

Percutaneous liver biopsy is an important diagnostic tool for the management of patients following liver transplantation. However, it may be associated with severe complications. To evaluate the incidence and type of complications after liver biopsy, we retrospectively analyzed 919 patients who underwent orthotopic liver transplantation (OLT) from September 1988 to May 1998. A total 3,670 biopsies were performed with ultrasound guidance and use of the Menghini needle (1.6 mm diameter). The biopsies were performed according to the protocol on the 7th postoperative day and one, three, five years after OLT, or when clinically indicated. Patients with severe coagulopathy (thrombocytes < 30,000/nl and Quick < 40%) were excluded from this protocol. Biopsy was complicated by bleeding in 13 of 919 patients (1.41%). The incidence of procedure related complications was 13 of 3,670 (0.35%). Five patients showed intrahepatic hematoma, four patients developed a hematothorax, three patients had intraabdominal bleeding and one patient suffered from hemobilia. Seven of 13 patients (53%) required surgical intervention (laparotomy four, thoracotomy two, retransplantation one). Graft dysfunction after liver transplantation requires rapid assessment and specific treatment to achieve good results. Percutaneous liver biopsy is an important procedure in the evaluation and identification of graft dysfunction such as acute rejection, hepatitis reinfection or toxic alterations. From our data we conclude that percutaneous liver biopsy is a safe procedure and advocate is liberal use.

Biopsy, Needle↗
PubMed1999

An unusual case of early pancreas graft loss.

Vascular thrombosis is the leading cause of nonimmunologic, technical graft loss following pancreas transplantation. An unusual case of early pancreas graft loss due to dissection of an atherosclerotic plaque -- presumably caused by clamping during implantation -- is described.

Adult↗
PubMed1998

Pretransplant virological markers hepatitis C virus genotype and viremia level are not helpful in predicting individual outcome after orthotopic liver transplantation.

BACKGROUND: Recurrence of hepatitis C viremia after orthotopic liver transplantation (OLT) is nearly universal, leading to variable outcome from no to severe recurrent disease. In the present study, the prognostic relevance of hepatitis C virus (HCV) genotypes and viremia for the development and severity of graft hepatitis was investigated. METHODS: A total of 79 patients with chronic hepatitis C who could be followed for 1 to 78 months (mean: 30 months) after OLT were included in this study. HCV RNA concentrations were measured before OLT, 1 month after OLT, as well as in the long-term follow-up after OLT in 54 of the 79 patients. RESULTS: Graft hepatitis could be documented in 40 of the 79 patients (51%), and 7 of them (9%) progressed to liver cirrhosis. More severe forms of graft hepatitis predominated in patients with subtype 1b infection, and all seven patients with progression to liver cirrhosis had subtype 1b (P=NS). Neither the pretransplant nor the posttransplant HCV RNA levels were significantly associated with the occurrence of graft hepatitis. However, there was a trend of more severe recurrent disease in subtype 1b-infected patients with high level viremia in the early course after OLT. CONCLUSIONS: Pretransplant HCV virological markers are not helpful to predict the outcome after OLT. However, it should be further investigated whether estimation of HCV genotype and viremia levels very early after OLT, i.e., within the first weeks, may be a better approach to recognize high-risk patients.

Adult↗