Biomedical subjects
Publications and source records attributed to J Wiesner.
We have described compound 1 as a lead structure for a novel class of anti-malarial agents. Replacement of the 3-phenylpropionyl moiety of the lead structure 1 by a 4-propoxycinnamic acid residue resulted in a significant improvement in antimalarial activity. Compound 3q represents an important step in the development of lead structure 1 into an anti-malarial drug candidate.
From a library of 61 compounds available from former studies 2,5-bis-acylaminobenzophenone 7p was identified as a lead structure for a novel class of anti-malaria agents active against multi-resistant Plasmodium falciparum strain Dd2. Some structural modifications of this initial lead demonstrated the potential for further improvement of the anti-plasmodial activity of this novel class of anti-malarials.
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In a variety of organisms, including plants and several eubacteria, isoprenoids are synthesized by the mevalonate-independent 2-C-methyl-D-erythritol 4-phosphate (MEP) pathway. Although different enzymes of this pathway have been described, the terminal biosynthetic steps of the MEP pathway have not been fully elucidated. In this work, we demonstrate that the gcpE gene of Escherichia coli is involved in this pathway. E. coli cells were genetically engineered to utilize exogenously provided mevalonate for isoprenoid biosynthesis by the mevalonate pathway. These cells were then deleted for the essential gcpE gene and were viable only if the medium was supplemented with mevalonate or the cells were complemented with an episomal copy of gcpE.
We have identified compound 1 as a lead structure of a novel class of anti-malarial agents. Here, we report on our continuing studies towards the establishment of structure-activity relationships by varying the terminal phenyl moiety and the alkyl linker of the acyl substituent at the 5-amino function of the benzophenone core structure. Most of the derivatives of our lead structure 1 essentially display the same anti-plasmodial activity as the lead.
Two Pseudomonas aeruginosa genes encoding the enzymes 1-deoxy-D-xylulose 5-phosphate (DXP) synthase and DXP reductoisomerase, both involved in the mevalonate-independent biosynthesis of isoprenoids, have been expressed as recombinant enzymes in Escherichia coli. The purified P. aeruginosa DXP reductoisomerase was inhibited by submicromolar concentrations of the antibiotics fosmidomycin and FR-900098 in a well established method. A novel and convenient spectrophotometric assay was developed to determine activity and inhibition of P. aeruginosa DXP synthase. Fluoropyruvate is described as a first inhibitor of DXP synthase.
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A mevalonate-independent pathway of isoprenoid biosynthesis present in Plasmodium falciparum was shown to represent an effective target for chemotherapy of malaria. This pathway includes 1-deoxy-D-xylulose 5-phosphate (DOXP) as a key metabolite. The presence of two genes encoding the enzymes DOXP synthase and DOXP reductoisomerase suggests that isoprenoid biosynthesis in P. falciparum depends on the DOXP pathway. This pathway is probably located in the apicoplast. The recombinant P. falciparum DOXP reductoisomerase was inhibited by fosmidomycin and its derivative, FR-900098. Both drugs suppressed the in vitro growth of multidrug-resistant P. falciparum strains. After therapy with these drugs, mice infected with the rodent malaria parasite P. vinckei were cured.
Combining fluvoxamine and clozapine may be a strategy to improve therapeutic effects on negative symptoms in schizophrenic patients. Fluvoxamine, however, markedly inhibits the metabolism of clozapine, and hazardous side effects may result. This study prospectively investigated the safety and tolerability of an add-on therapy with fluvoxamine to a clozapine monotherapy in schizophrenic patients. Sixteen schizophrenic patients received 50 mg fluvoxamine as a comedication after having reached steady-state conditions under clozapine monotherapy. Patients were monitored for subjective adverse events, laboratory parameters, EEG and ECG recordings, orthostatic hypotension and their psychopathology. Concomitantly, serum concentrations of clozapine and metabolites were measured during monotherapy and after addition of fluvoxamine. In all patients, the serum concentrations of clozapine and metabolites were markedly increased (average: 2-3 fold, up to 5 fold for clozapine) after addition of fluvoxamine. Side effects remained almost unchanged in frequency and severity in spite of the pharmacokinetic interactions. ECG or laboratory parameters and orthostatic tests were similar under monotherapy and comedication. Minimal increases of EEG abnormalities were observed, but they were not associated with clinical impairment. Epileptic activities were always absent. The psychopathology improved which continued after start of the comedication. Though the addition of fluvoxamine to clozapine medication was well tolerated and critical side effects were absent, the combined treatment should be controlled by drug monitoring, as serum concentrations of clozapine increased to unpredictably high levels. Further studies have to find out if the combined treatment could be advantageous to clozapine monotherapy.
Here we describe the identification and characterization of a physiological marker that is associated with the chloroquine-resistant (CQR) phenotype in the human malarial parasite Plasmodium falciparum. Single cell in vivo pH measurements revealed that CQR parasites consistently have an elevated cytoplasmic pH compared to that of chloroquine-sensitive (CQS) parasites because of a constitutively activated Na+/H+ exchanger (NHE). Together, biochemical and physiological data suggest that chloroquine activates the plasmodial NHE of CQS parasites, resulting in a transitory phase of rapid sodium/hydrogen ion exchange during which chloroquine is taken up by this protein. The constitutively stimulated NHE of CQR parasites are capable of little or no further activation by chloroquine. We propose that the inability of chloroquine to stimulate its own uptake through the constitutively activated NHE of resistant parasites constitutes a minimal and necessary event in the generation of the chloroquine-resistant phenotype.
The malaria parasite Plasmodium falciparum that infects humans encodes several extremely large proteins with molecular masses in the hundreds of thousands to megadalton range. Studies on the structure, function and antigenicity of these ;giant proteins' are hindered by the inability to resolve them effectively in conventional polyacrylamide gels. In this report, Jochen Wiesner, Denise Mattei, Artur Scherf and Michael Lanzer describe a convenient gel system, based on a composite polyacrylamide-agarose matrix, which facilitates analysis of giant proteins.
Pharmacokinetic interactions of clozapine and its metabolites N-desmethylclozapine and clozapine N-oxide with the selective serotonin reuptake inhibitors (SSRIs) fluvoxamine and paroxetine were investigated in a prospective study in schizophrenic patients under steady-state conditions. Thirty patients were treated with clozapine at a target dose of 2.5 to 3.0 mg/kg of body weight. After gradual dose escalation, serum concentrations of clozapine and two metabolites were determined twice at 7-day intervals after steady-state conditions had been reached. Then, fluvoxamine (50 mg/day) or paroxetine (20 mg/day) was added in 16 and 14 patients, respectively. Serum concentrations of clozapine and its metabolites were measured after 1, 7, and 14 days of coadministration with the SSRI. Mean trough concentrations of steady-state serum concentrations of clozapine, N-desmethylclozapine, and clozapine N-oxide were markedly elevated under fluvoxamine by about threefold of baseline concentrations whereas paroxetine induced only minor, nonsignificant changes. Estimation of the mean elimination half-life of clozapine 2 weeks after start of fluvoxamine comedication revealed an increase from 17 hours to about 50 hours whereas there was no change under paroxetine coadministration. The N-desmethylclozapine/clozapine ratio did not change significantly with either SSRI. Under monotherapy, clozapine mean serum concentrations in smokers were significantly lower by 32% compared with nonsmokers. Similarly, N-demethylation ratios were about 20 to 50% higher in smokers. Thus, in all patients, fluvoxamine induced relevant increases in serum concentrations of clozapine and its metabolites, probably by the inhibition of enzymes catalyzing the degradation of clozapine and N-desmethylclozapine, whereas paroxetine, at a usual clinically effective dosage of 20 mg/day, did not cause significant pharmacokinetic interactions.
Here we demonstrate that components of the entire complement cascade are fixed on the surface of erythrocytes infected with the human malarial parasite Plasmodium falciparum. Despite the activation of lytic complement factors, no complement-mediated lysis of P. falciparum-infected erythrocytes occurred only in the absence of functional intrinsic CD59. These data suggest that the restriction of the complement attack of P. falciparum-infected erythrocytes is principally mediated by intrinsic host cell factors, in particular CD59.
Plasmodium falciparum var genes encode a diverse family of proteins, located on the surfaces of infected erythrocytes, which are implicated in the pathology of human malaria through antigenic variation and adhesion of infected erythrocytes to the microvasculature. We have constructed a complete representative telomere-to-telomere yeast artificial chromosome (YAC) contig map of the P. falciparum chromosome 8 for studies on the chromosomal organization, distribution, and expression of var genes. Three var gene loci were identified on chromosome 8, two of which map close to the telomeres at either end of the chromosome. Analysis of the previously described chromosome 2 contig map and random P. falciparum telomeric YAC clones revealed that most, if not all, 14 P. falciparum chromosomes contain var genes in a subtelomeric location. Mapping the chromosomal location of var genes expressed in a long-term culture of the P. falciparum isolate Dd2 revealed that four of the five different expressed var genes identified map within subtelomeric locations. Expression of var genes from a chromosomal domain known for frequent rearrangements has important implications for the mechanism of var gene switching and the generation of novel antigenic and adhesive phenotypes.
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Preclinical data indicated that seroquel (ICI 204 636), a dibenzothiazepine with 5-HT2 and D2-like receptor antagonistic properties, might be an effective antipsychotic agent, causing fewer extrapyramidal side effects than typical neuroleptics. In the present study, 12 patients suffering from schizophrenia or schizophreniform disorder with predominantly positive symptomatology were treated in an open clinical trial for 4 weeks with seroquel at a maximum dosage of 750 mg/day. The drug was generally well tolerated, and virtually no adverse extrapyramidal side effects such as acute dystonia, parkinsonism or akathisia were observed. Total scores for BPRS (item score 0-6; baseline: 42.0 +/- 2.3; mean +/- SEM), SAPS (64.5 +/- 4.8) and SANS (55.0 +/- 4.3) showed a moderate decrease at the end of treatment (BPRS: 30.0 +/- 3.5; SAPS: 36.1 +/- 6.7; SANS: 42.5 +/- 5.9), when intention-to-treat analysis was applied. There were considerable interindividual differences in treatment response, with some subjects showing almost full remission of positive symptoms, in contrast to about half of the patients who showed no satisfactory clinical improvement. Interestingly, patients showing good antipsychotic response reported slight initial side effects like mild sedation. Prolactin and TSH levels were not altered during seroquel administration. As to pharmaco-EEG investigations, seroquel caused a moderate increase of the absolute power in the alpha, theta, and beta frequency bands, paralleled by a decrease of delta activity. There were no signs of paroxysmal EEG activity under seroquel.(ABSTRACT TRUNCATED AT 250 WORDS)