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Biomedical subjects

J Gerlach

Publications and source records attributed to J Gerlach.

At least 37 records · Page 2Linked to original sources
PubMed1999

Local liberation of cytokines during liver preservation.

In order to investigate locally produced mediators during the process of organ storage in liver transplantation, we collected the liver preservation solution effluent of 15 transplanted livers and compared it with serum samples taken preoperatively from donor and recipient, as well as 60 min after reperfusion. The mean ischemia time +/- SEM was 10 h 10 min +/- 53 min. Mean concentrations in University of Wisconsin preservation solution effluent were: interleukin-(IL-)1beta 154 +/- 77 pg/ml; IL-1 receptor antagonist (IL-1 ra) 1281 +/- 309 pg/ml; IL-6 412 +/- 90 pg/ml; and for tumor necrosis factor-(TNF-)alpha 74 +/- 21 pg/ml. Cytokine levels in the donors were lower than those detected in the effluent. All measured cytokines showed higher concentrations in the effluent compared to those of the recipient prior to the operation. With respect to a comparison of donor and recipient values, no correlation is evident. Likewise, the ischemic time does not correlate with effluent values. Further development of liver preservation concepts requires information about the state of the graft before reperfusion. Data on cytokine liberation may serve as a helpful tool for the further development of preservation concepts because they enable an estimation of cell activation during preservation.

Adenosine↗
PubMed1999

New and old antipsychotics versus clozapine in a monkey model: adverse effects and antiamphetamine effects.

RATIONALE: Neuroleptic primed Cebus apella monkeys have proven reliable in screening antipsychotics for extrapyramidal side effect (EPS) potential in humans, and the ratio EPS liability/antiamphetamine efficacy ["therapeutic index" (TI)] has fit well with clinical results. OBJECTIVES: 1) To find the TIs of one new (quetiapine), three potential [NNC 756 (dopamine (DA) D1 antagonist), NNC 22-0031 (alpha-1 adrenergic/5-HT2 serotonergic/DA D1 and D2 antagonist) and DOD 647 (DA D1 and D2 antagonist)] and three old antipsychotics (haloperidol, melperone and clozapine), 2) to test the model further and 3) to gain more insight as to clozapine's neuropharmacology. METHODS: Seven monkeys received haloperidol daily for 2 years; all were sensitized to dystonia. All drugs were given SC, in increasing doses until two animals had dystonia/other adverse effects (AE), and in decreasing doses with a fixed dose of dextroamphetamine producing motor unrest and stereotypies, to find the minimum significant antiamphetamine dose (AA). The ratio AE/AA = TI. RESULTS: Excepting clozapine and DOD 647, all drugs induced dystonia. At 2-4 mg/kg, clozapine caused uncoordinated movements, myoclonic jerks and rough tremor; unlike dystonia, the syndrome was not alleviated but worsened by the anticholinergic, biperiden. DOD 647 up to 2 mg/kg had no adverse effects. The TIs of the new and potential antipsychotics were 3-5 versus 4 for clozapine and 1 for haloperidol and melperone, suggesting that like clozapine, these new drugs will not produce EPS at antipsychotic doses.

Amphetamine↗
PubMed1999

Extrapyramidal side effects during chronic combined dopamine D1 and D2 antagonist treatment in Cebus apella monkeys.

Previous studies in non-human primates have shown that tolerance to dystonia occurs during chronic dopamine D1 (D1) but not D2 antagonism and induction/aggravation of oral dyskinesia (TD) during D2 but not D1 antagonism. We were therefore interested in determining the effects of combined chronic D1 + D2 antagonism on dystonia and dyskinesia. To this intent, 8 male Cebus apella monkeys were treated 10 weeks with gradually increasing doses of D1 antagonist (NNC 112) + a D2 antagonist (raclopride), followed by 2 weeks of treatment with the D2 antagonist alone. Due to previous neuroleptic exposure, 5 monkeys had TD and all were sensitized to dystonia. During the combined antagonist treatment, tolerance to dystonia occurred; the tolerance disappearing upon discontinuation of the D1 antagonist and continuation of the D2 antagonist alone. Parallel to these results, improvement of TD was seen during the combined antagonist treatment with worsening during the D2 antagonist alone. Both the combined antagonists and the D2 antagonist alone resulted in moderate/severe bradykinesia, with no tolerance. These findings indicate that supplementation of traditional D2 antagonism with a D1 antagonist would lessen the risk of dystonia and allow alleviation of preexisting TD, though parkinsonian side effects might still occur. The findings further indicate that separate dopaminergic mechanisms control dystonia/dyskinesia and parkinsonism.

Animals↗
PubMed1999

Chronic dopamine D1, dopamine D2 and combined dopamine D1 and D2 antagonist treatment in Cebus apella monkeys: antiamphetamine effects and extrapyramidal side effects.

To determine: (1) whether the apparent lack of efficacy of dopamine D1 (D1) antagonists in the clinic might be attributable to development of tolerance to antipsychotic effects; and (2) whether combined D1 and D2 antagonism might contribute to clozapine's clinical profile, eight Cebus apella monkeys were chronically treated with a D1 antagonist (NNC 756) ((+)-8-chloro-7-hydroxy-3-methyl-5-(7-(2,3- dihydrobenzofuranyl)-2,3,4,5-tetrahydro-1H-3-benzazepine), a D2 antagonist (raclopride) or a combination of the two antagonists. Prior neuroleptic exposure had resulted in oral dyskinesia in seven monkeys and sensitization to dystonia in all, yielding a model for acute and chronic extrapyramidal side effects (EPS). Dextroamphetamine-induced motoric unrest and stereotypies were used as a psychosis model. We found tolerance toward dystonic symptoms during D1 and D1 + D2 treatments but not during D2 treatment. D2 but not D1 or D1 + D2 antagonism caused exacerbation of dyskinesia. Both D1 and D1 + D2 antagonism were superior to D2 antagonism alone in counteracting the amphetamine-induced behaviors, with no tolerance to antiamphetamine effects. These findings suggest: (1) reasons other than tolerance (e.g., differences among antagonists) may explain the lack of efficacy in clinical trials with D1 antagonists; and (2) that D1 antagonism alone or combined and modest D1 and D2 antagonism offers the potential of antipsychotic efficacy with a lower risk of EPS than traditional D2 antagonism. Further clinical trials with D1 or combined D1 and D2 antagonists are, therefore, recommended.

Amphetamine↗
PubMed1999

Subjective experience and mental side-effects of antipsychotic treatment.

Many schizophrenic patients have a negative attitude towards antipsychotic drugs. This attitude is not only due to lack of insight into the disease, lack of recognition of the beneficial effects of the drugs, and to objective side-effects. The negative attitude is to a high degree due to mental side-effects and a sceptical opinion about antipsychotic medication in general. In a study of 53 chronic schizophrenic out-patients receiving maintenance depot antipsychotic treatment, we found that 60% were positive about the treatment, 32% were ambivalent and 8% had a negative attitude. Only 60% complained of side-effects, even though 94% had objective side-effects. Mental side-effects such as subjective akathisia, dysphoria and emotional indifference were most often observed by the patients, while hypokinesia and hyperkinesia were least noticed by them, but most often observed by the physician. No correlation was found between the patients' subjective assessment of their quality of life and the degree of psychosis and side-effects. With the new atypical antipsychotics this situation seems to be changing. These new drugs are primarily characterized by a lower level of motor extrapyramidal side-effects (EPS), and with fewer motor EPS, fewer mental EPS can be expected. In recent studies comparing the new antipsychotics with haloperidol, better effects have been observed with regard to negative symptoms and depression, and this may at least in part be a reflection of a lower level of mental side-effects of the atypical antipsychotics. This improved clinical profile of new antipsychotics is extremely valuable in the context of an integrated treatment in schizophrenia, consisting of early intervention, psychosocial rehabilitation and family/patient psycho-education.

Akathisia, Drug-Induced↗
PubMed1999

Replication-competent rhabdoviruses with human immunodeficiency virus type 1 coats and green fluorescent protein: entry by a pH-independent pathway.

We describe a replication-competent, recombinant vesicular stomatitis virus (VSV) in which the gene encoding the single transmembrane glycoprotein (G) was deleted and replaced by an env-G hybrid gene encoding the extracellular and transmembrane domains of a human immunodeficiency virus type 1 (HIV-1) envelope protein fused to the cytoplasmic domain of VSV G. An additional gene encoding a green fluorescent protein was added to permit rapid detection of infection. This novel surrogate virus infected and propagated on cells expressing the HIV receptor CD4 and coreceptor CXCR4. Infection was blocked by SDF-1, the ligand for CXCR4, by antibody to CD4 and by HIV-neutralizing antibody. This virus, unlike VSV, entered cells by a pH-independent pathway and thus supports a pH-independent pathway of HIV entry. Additional recombinants carrying hybrid env-G genes derived from R5 or X4R5 HIV strains also showed the coreceptor specificities of the HIV strains from which they were derived. These surrogate viruses provide a simple and rapid assay for HIV-neutralizing antibodies as well as a rapid screen for molecules that would interfere with any stage of HIV binding or entry. The viruses might also be useful as HIV vaccines. Our results suggest wide applications of other surrogate viruses based on VSV.

Animals↗
PubMed1999

The continuing problem of extrapyramidal symptoms: strategies for avoidance and effective treatment.

Antipsychotic agents remain the most effective treatment for both acute and chronic schizophrenia. However, conventional antipsychotic agents are frequently associated with significant side effects including, perhaps most notably, extrapyramidal symptoms (EPS). The emergence of EPS can significantly compromise patient compliance with treatment and can have profound effects on long-term treatment outcomes. Providing effective symptom relief with minimal side effects and without inducing EPS is, therefore, a primary goal in the treatment of schizophrenia. Atypical antipsychotic agents are now regarded as first-line therapies for the treatment of schizophrenia because of their lower propensity to induce EPS compared with conventional antipsychotics, and evidence exists that these agents are associated with a lower relapse rate, which perhaps reflects an improvement in patient compliance.

Adult↗
PubMed1998

Maintained function of primary human hepatocytes by cellular interactions in coculture: implications for liver support systems.

The application of primary hepatocytes in hybrid artificial liver systems has been hampered by the gradual loss of differentiated morphology and function in vitro. Therefore, we have established a coculture model of autologous human hepatocytes and biliary epithelial cells (BEC) in collagen gel in the presence of hepatotrophic growth factors. Furthermore, we examined the effect of hepatocyte cell perfusion in a women multicompartment capillary membrane system. Normal hepatocytes isolated from human liver produced albumin for more than 2 weeks in serum-free media, and were further stimulated by conditioned medium. When cocultured with BEC, albumin secretion was greatly enhanced, suggesting that cellular interactions promote tissue-specific differentiation. When perfused in bioreactors, albumin levels were maintained at steady state for longer than 2 weeks. These data indicate that differentiation of primary hum hepatocytes can be maintained by coculture interactions and three-dimensional hybrid organ devices, providing appropriate growth factors and matrix for tissue regeneration.

Cell Communication↗
PubMed1998

Guidelines for depot antipsychotic treatment in schizophrenia. European Neuropsychopharmacology Consensus Conference in Siena, Italy.

These guidelines for depot antipsychotic treatment in schizophrenia were developed during a two-day consensus conference held on July 29 and 30, 1995 in Siena, Italy. Depot antipsychotic medications were developed in the 1960s as an attempt to improve the long-term treatment of schizophrenia (and potentially other disorders benefiting from long-term antipsychotic medication). Depot drugs as distinguishable from shorter acting intramuscularly administered agents can provide a therapeutic concentration of at least a seven day duration in one parenteral dose. The prevention of relapse in schizophrenia remains an enormous public health challenge worldwide and improvements in this area can have tremendous impact on morbidity, mortality and quality of life, as well as direct and indirect health care costs. Though there has been debate as to what extent depot (long-acting injectable) antipsychotics are associated with significantly fewer relapses and rehospitalizations, in our view when all of the data from individual trials and metaanalyses are taken together, the findings are extremely compelling in favor of depot drugs. However in many countries throughout the world fewer than 20% of individuals with schizophrenia receive these medications. The major advantage of depot antipsychotics over oral medication is facilitation of compliance in medication taking. Non-compliance is very common among patients with schizophrenia and is a frequent cause of relapse. In terms of adverse effects, there are not convincing data that depot drugs are associated with a significantly higher incidence of adverse effects than oral drugs. Therefore in our opinion any patient for whom long-term antipsychotic treatment is indicated should be considered for depot drugs. In choosing which drug the clinician should consider previous experience, personal patient preference, patients history of response (both therapeutic and adverse effects) and pharmacokinetic properties. In conclusion the use of depot antipsychotics has important advantages in facilitating relapse prevention. Certainly pharmacotherapy must be combined with other treatment modalities as needed, but the consistent administration of the former is often what enables the latter.

Antipsychotic Agents↗
PubMed1998

[Use of normal human hepatocytes in a hybrid organ system].

Using the bioreactor model developed by J. Gerlach, we examined the potential of normal human hepatocytes for application in bioartificial liver devices. From normal human donor livers 1.5 x 10(8) hepatocytes were isolated. Hepatocytes were perfused in a woven multi-compartment capillary system in serum-free culture medium containing ammoniachloride over a period of 2 weeks. These cells demonstrated a well differentiated ultrastructure with formation of junctional complexes and bile canaliculi between adjacent cells. During reactor run, a constant albumin synthesis with levels above 11 mg/ml and maintenance of urea production and lignocaine metabolism (MEGX-test) were detected. These initial results indicate that normal human hepatocytes express typical morphology and ultrastructure and are able to keep differentiated functions in suitable perfusion models. Combination of the distinct human liver cell populations might enable promotion of further specific functions (clotting factors) and induction of liver cell proliferation.

Cell Survival↗
PubMed1997

Systemic liberation of interleukin-8 in the perioperative phase of liver transplantation.

Serum levels of interleukin-8 (IL-8) were investigated in the perioperative phase of liver transplantation (LTx) in order to help determine whether this cytokine might serve as a parameter for preservation injury. In a study of 45 patients undergoing LTx, systemic IL-8 was estimated at the end of the anhepatic phase, at 30, 60, and 120 min after reperfusion of the graft, and 24 h and 7 days after LTx. A maximum mean concentration of 665 +/- 135 pg/ml was seen 60 min after LTx. The minimum was found on the 1st postoperative day (POD 1): 328 +/- 33 pg/ml. Significant changes were found between 60 min and PODs 1 and 7, as well as between 120 min and POD 1. Differences in cold ischemia time were not found to be significant. We conclude that monitoring of systemic IL-8 levels is not useful in the development of new liver preservation concepts.

Adult↗
PubMed1997

Hepatitis B virus sequence changes evolving in liver transplant recipients with fulminant hepatitis.

BACKGROUND/AIMS: Patients undergoing liver transplantation for hepatitis B virus (HBV) related liver cirrhosis are at major risk of developing HBV recurrence, and occasionally fulminant hepatitis. Here we tested in a longitudinal study whether specific viral variants are associated with fulminant HBV infection in the graft. METHODS: The complete HBV genomes isolated from the sera of three patients with HBV and HBV and hepatitis delta virus (HDV) coinfection during chronic infection before and during fulminant reinfection after transplantation were amplified and directly sequenced. RESULTS: Twenty, 25 and 19 mutations, distributed over the entire genome, were identified which differed between the HBV genomes isolated from each patient during chronic and fulminant infection, respectively. This reflects a much higher rate of nucleotide sequence changes than expected from the natural variation of HBV. No common HBV mutation emerged in any of the three cases during fulminant infection. However, precore defective viruses were found to be present in all three patients at the time of fulminant infection and in two of the patients before fulminant infection. Two of the patients had preS2-defective HBVs both before and after transplantation. A point mutation in the 'a'-determinant of the surface protein emerged in one case after transplantation under treatment with polyclonal HBV specific immunoglobulins. CONCLUSIONS: Many new, but no specific common mutations emerged during fulminant HBV reinfection. Although HBeAg defective variants were found in all cases studied, the presence of these variants also during chronic infection in two cases demonstrates that they are not sufficient to cause fulminant hepatitis. Thus, other factors than the emergence of a specific viral strain seem to contribute to the development of fulminant reinfection in a liver graft.

Adult↗
PubMed1997

Effect of a hybrid liver support system on cardiopulmonary function in healthy pigs.

The aim of this study was to evaluate the effects of a hybrid liver support system (LSS) on cardiopulmonary function in nine healthy pigs. A hybrid LSS containing primary pig hepatocytes was connected to fully alert animals. The extracorporeal blood flow was maintained between 200-240 ml/min using a roller pump. Continuous plasma flow through the hybrid LSS was 50-60 ml/min. Hemodynamic and pulmonary gas exchange parameters were compared 1 hour before and 1 hour after connection to as well as 1 hour before and 1 hour after disconnection from the hybrid LSS. The hybrid LSS did not influence significantly hemodynamics and pulmonary gas exchange in this group of healthy and awake pigs. It can be concluded that the used LSS did not cause a cardiopulmonary effect per se and should be evaluated further concerning its function as a liver support system in an animal model of acute hepatic failure.

Animals↗
PubMed1996

High yield hepatocyte isolation from pig livers for investigation of hybrid liver support systems: influence of collagenase concentration and body weight.

Cultured hepatocytes would be required in large quantities if a hybrid liver support system became available. We have therefore performed a study of larger scale enzymatic hepatocyte isolation on whole pig livers. A new method of open-loop and recirculating perfusion in five steps using both the portal venous and the hepatic arterial vascular systems has been developed. In a study of the yield and cell viability of hepatocytes afer isolation, the collagenase concentration of the perfusate was investigated over a range of 0.02 to 0.15%. The effect of animal weight on yield and cell viability was determined within the body weight range of 6 to 40 kg. At collagenase concentrations of less than 0.08%, yield and viability declined. As collagenase concentration increased, the yield continuously increased while the viability peaked at 0.1%. There was a decline of viability and yield with rising body weight. Optimal results were obtained with the lowest body weight (6 kg) which gave a yield of 95% (g wet weight) and a viability of 98% (trypan blue). This novel five-step collagenase perfusion technique with arterial perfusion appears to be reproducible and safe. Application of this method enables the large scale investigations to be undertaken towards the development of hybrid liver support.

Animals↗
PubMed1996

Systemic liberation of interleukin-1 beta and interleukin-1 receptor antagonist in the perioperative phase of liver transplantation.

We measured systemic serum levels of interleukin-1 receptor antagonist (IL-1ra), interleukin-1 beta (IL-1 beta), tumor necrosis factor alpha (TNF-alpha), and interleukin-6 (IL-6) during the preoperative, anhepatic, and postreperfusional phases up to the 7th postoperative day in 60 patients undergoing orthotopic liver transplantation (LTx). In contrast to IL-1 beta, IL-1ra, TNF-alpha, and IL-6 showed a significant elevation in relation to the early phase after reperfusion, while TNF-alpha displayed a high grade of scatter. In addition, IL-1ra levels were significantly elevated during the anhepatic phase. Maximum serum levels were found at 15 min after reperfusion, 120 min after reperfusion, and on the 1st postoperative day, respectively. Serum levels decreased considerably at 24 h and 7 days after reperfusion. The comparative monitoring of systemic cytokine and cytokine antagonist levels, in particular the liberation of IL-1ra and IL-6 may provide useful parameters for the development of new liver preservation theories for LTx.

Adult↗