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J K Seydel

Publications and source records attributed to J K Seydel.

At least 19 recordsLinked to original sources
PubMed1996

Syntheses and biological activities of new N1-aryl substituted quinolone antibacterials.

A series of quinolones with a systematically varied substitution at the phenyl ring at N1 has been synthesized. Three lipophilicity descriptors (log K, log P, Rm) and the pKa values have been determined as well as the microbiological activity: The MIC values for eight different strains of three Gram-positive and three Gram-negative species and the inhibitory concentrations of DNA supercoiling (IC90 and IC100) were determined. From a principal component and a QSAR analysis relationships between antibacterial activity concerning the whole-cell system and electronic properties as well as the length of the substituents at the phenyl rings could be derived. The activity in a cell-free system was governed by the lipophilicity and the width of the substituents. It is speculated that the quinolones take a defined place in the DNA gyrase-DNA complex which is characterized by polar amino acids. This is in agreement with findings from studies of mutant gyrases.

4-Quinolones↗
PubMed1996

Membrane interactions of some catamphiphilic drugs and relation to their multidrug-resistance-reversing ability.

The multidrug-resistance (MDR)-reversing ability of the catamphiphilic drugs could be mediated through their interaction with the membrane phospholipids. This could lead directly (through changes in membrane permeability and fluidity) and/or indirectly (through inhibition of P-glycoprotein phosphorylation via inhibition of the phosphatidylserine-dependent protein kinase C or changes in the conformation and functioning of the membrane-integrated proteins via changes in the structure organization of the surrounding membrane bilayer) to the reversal of MDR. Using differential scanning calorimetry and NMR techniques and artificial membranes composed of phosphatidylcholine or phosphatidylserines we found a significant correlation between the MDR-reversing activity of the drugs in doxorubicin-resistant human breast carcinoma MCF-7/DOX and murine leukaemia P388/DOX tumour cells (data taken from the literature) and their ability to interact with phosphatidylserines. Trans- and cis-flupentixol were found to interact most strongly with both the phospholipids, followed by trifluoperazine, chlorpromazine, triflupromazine, flunarizine, imipramine, quinacrine and lidocaine. Differences in the interaction of trans- and cis-flupentixol with the phospholipids studied are suggested to be responsible for their different MDR-reversing ability. Verapamil showed moderate membrane activity, assuming that the membrane interactions are not the only reason for its high MDR-reversing ability. Amiodarone showed very strong interactions with phosphatidylserines and is recommended for further MDR-reversal studies.

Amiodarone↗
PubMed1996

Studies on the toxicity of analogues of dapsone in-vitro using rat, human and heterologously expressed metabolizing systems.

Three metabolizing systems (rat, heterologously expressed CYP3A4 and human liver) were used to evaluate 12 analogues of dapsone (4,4'diaminodiphenylsulphone) in-vitro. Methaemoglobin formation in a two-compartment and cytotoxicity in a single-compartment model were studied using human erythrocytes and neutrophils, respectively, as target cells. In the two-compartment system using rat microsomes as a generating system and methaemoglobin as an endpoint, the least potent methaemoglobin formers tested were the 2-methyl-4-propylamino (AXDD14), 2-hydroxy-4-4'amino (ABDD5) derivatives and a sulphone/trimethoprim derivative (K-130). Dapsone itself, a 2-methoxy-4-ethylamino (W10) and a 2-hydroxyl-4-ethylamino compound (ABDD39) were the most toxic. In the single-compartment cytotoxicity test using rat microsomes, AXDD14 was again among the least toxic, as was a 2-methyl 4-cyclopentyl derivative (AXDD17) and surprisingly ABDD39. The most cytotoxic compounds again included dapsone itself as well as two 2-trifluoromethyl derivatives. The only significant methaemoglobin formation and cytotoxicity shown with the heterologously expressed human CYP 3A4 was with AXDD14, which was extensively activated. Interestingly, metabolism of dapsone was low using the expressed CYP 3A4. In the two-compartment system using human liver microsomes, AXDD14, K-130 and ABDD5 were oxidized to a significantly lesser extent compared with dapsone and these preliminary findings indicate that future development of these compounds may be worthwhile.

Animals↗
PubMed1994

Synthesis and quantitative structure-activity relationships of anticonvulsant 2,3,6-triaminopyridines.

The synthesis of 2,3,6-triaminopyridine derivatives, representing a unique chemical structure for anticonvulsants, is described. The synthetic program was performed (a) to identify more potent analogs, (b) to determine structural properties controlling potency as well as neurotoxicity, and (c) to reduce the requirements for animal testing. As a result, besides other structural properties, the overall molecular lipophilicity (log k', octanol-coated column) explained changes in anticonvulsant potency and neurotoxicity. Mimicking the interaction of the amphiphilic triaminopyridines with biological membranes, NMR experiments in the presence of lecithin vesicles were conducted in order to measure the phospholipid-binding parameter log delta (1/T2). Replacement of log k' with log delta (1/T2) in the correlation analysis afforded a more significant equation describing the anticonvulsant activity of 21 derivatives.

Aminopyridines↗
PubMed1994

Drug membrane interaction and the importance for drug transport, distribution, accumulation, efficacy and resistance.

Some aspects of drug membrane interaction and its influence on drug transport, accumulation, efficacy and resistance have been discussed. The interactions manifest themselves macroscopically in changes in the physical and thermodynamic properties of "pure membranes" or bilayers. As various amounts of foreign molecules enter the membrane, in particular the main gel to liquid crystalline phase transition can be dramatically changed. This may change permeability, cell-fusion, cell resistance and may also lead to changes in conformation of the embedded receptor proteins. Furthermore, specific interactions with lipids may lead to drug accumulation in membranes and thus to much larger concentrations at the active site than present in the surrounding water phase. The lipid environment may also lead to changes in the preferred conformation of drug molecules. These events are directly related to drug efficacy. The determination of essential molecular criteria for the interaction could be used to design new and more selective therapeutics. This excursion in some aspects of drug membrane interaction underlines the importance of lipids and their interaction with drug molecules for our understanding of drug action, but this is not really a new thought but has been formulated in 1884 by THUDICUM: "Phospholipids are the centre, life and chemical soul of all bioplasm whatsoever, that of plants as well as of animals".

Animals↗
PubMed1994

Experimental drugs and combination therapy.

The worldwide increase in tuberculosis, the additional problem of increasing multiple drug resistance (MDR) and the primary resistance of Mycobacterium avium requires new strategies in drug development and in therapy. The reason for development of MDR is manifold. One important factor is the change in cell wall construction which limits the penetration of the drug to the target receptor. This is supported by the observation that within a class of tuberculostatic drugs (identical mode of action) the more lipophilic derivative is more effective. In addition, it has been shown that mycobacteria within macrophages are able to synthesize additional multilamellar cell wall components. Several possibilities exist to overcome MDR. Besides improving the permeation properties of drugs, the development of synergistic drug combinations based on their special mode of action is a promising approach. This is illustrated with the highly synergistic combination of newly developed hydrazones and thiacetazone respectively with rifampicin. Chance combinations which may even lead to antagonism have to be avoided. Examples of antagonistic behavior of the combinations clofazimine-dapsone and ofloxacin-rifampicin are discussed. An optimization procedure has been developed based on the determination of the specific resistance of patient-derived mycobacteria against single drugs and their combinations. With its use, an individual optimal treatment becomes feasible. Preliminary clinical experience is encouraging.

Anti-Bacterial Agents↗
PubMed1994

Effect of hydroxypropyl-beta-cyclodextrin on the antimicrobial action of preservatives.

The interaction between hydroxypropyl-beta-cyclodextrin (HP-beta-CyD) and several preservatives with different chemical structures was investigated in aqueous solution. Complex stability constants of the 1:1 complexes were calculated from differential spectra. Using the serial dilution test the antimicrobial activities of the preservatives and their complexes against Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli and Candida albicans were tested and MIC values determined. For highly water-soluble substances like thimerosal and bronopol, low or no inactivation was found; the more lipophilic substances, such as the phenolic compounds, showed strong inactivation when used in combination with HP-beta-CyD. The loss in activity by complex formation correlated with the bound fraction, thus suggesting that the appropriate antimicrobial substance for the preservation of cyclodextrin solutions can be selected according to the results of this study.

2-Hydroxypropyl-beta-cyclodextrin↗
PubMed1993

In vitro and in vivo results of brodimoprim and analogues alone and in combination against E. coli and mycobacteria.

New diaminodiphenylsulfone inhibitors of dihydropteroate synthase are described with increased inhibitory activity against mycobacteria and plasmodia, whereas their side effect of methemoglobin formation could be suppressed. The optimization of diaminobenzylpyrimidines, inhibitors of dihydrofolate reductase, led to derivatives with increased inhibitory effect against mycobacteria, especially M. leprae and plasmodia. Some of these derivatives show autosynergism. Finally the combination of brodimoprim (BDP) and dapsone (DDS) was developed for the treatment of leprosy. First clinical trials in Paraguay and Ethiopia show that combinations of BDP/DDS and BDP/DDS plus rifampicin were highly effective and may become an alternative multi-drug therapy for the treatment of leprosy. The tolerance of the regimens used was generally good.

Dapsone↗
PubMed1992

A time hierarchy-based model for kinetics of drug disposition and its use in quantitative structure-activity relationships.

By using the time hierarchy of the processes determining the fate of drugs in biosystems (absorption, transport, distribution, protein binding, and elimination), a one-compartment open model is formulated at a subcellular level for the disposition phase of pharmacokinetics. The resulting disposition function describes the kinetics of the intracellular disposition of drugs as determined by their hydrophobicity, acidity or basicity, affinity to proteins, and rate parameters of elimination. Structure-activity relationships, based on the function with incorporated extrathermodynamic relations, fit the literature data well (fixed-time bioactivity-hydrophobicity profiles, kinetics of microbial degradation of organic compounds, and kinetics of analgesic effects of fentanyl derivatives in rats). Application of the approach, creating a basis for the construction of model-based quantitative structure-time-activity relationship, to biosystems of varying complexity is discussed.

Animals↗
PubMed1992

Penetration of rifampicin into the cerebrospinal fluid of adults with uninflamed meninges.

The penetration of rifampicin into CSF was studied in seven patients who had undergone external ventriculostomy for occlusive hydrocephalus without major disturbance of the blood-CSF barrier. After the first dose of rifampicin 600 mg i.v. over 3 h, blood and CSF concentrations were determined serially by HPLC. Peak CSF concentrations obtained 0-8 h (median = 1 h) after the end of the infusion ranged from 0.57 to 1.24 mg/L (median = 0.73 mg/L). Elimination from CSF was slower than from serum (T1/2 beta CSF: 9.1-21.0 h (median = 14.5 h, n = 5); T1/2 beta serum: 2.2-5.8 h (median = 3.6 h, n = 7)). Based on the ratios of the areas under the concentration-time curves in CSF and serum, the overall penetration of rifampicin into CSF was 0.13-0.42 (median = 0.22). These results demonstrate effective CSF penetration and favourable pharmacokinetics of rifampicin in the absence of meningeal inflammation. They support the use of rifampicin as part of a combination therapy not only for tuberculosis of the central nervous system (CNS), but also for staphylococcal and listerial infections of the CNS in which there may be little meningeal inflammation.

Aged↗
PubMed1992

Development of effective drug combinations for the inhibition of multiply resistant mycobacteria, especially of the Mycobacterium avium complex.

Rationally designed combinations of rifampicin (RAMP) and thiacetazone plus isonicotinic acid hydrazide and/or ethambutol are highly effective in the treatment of patients (including HIV-positive) infected with multiply resistant mycobacteria of the Mycobacterium avium complex (MAC). Clinical results are very promising. The high efficacy of these combinations is due to the synergistic potentiation of single-drug activities. As soon as rifabutin is marketed, it should replace RAMP in the combination treatment of patients with highly RAMP-resistant MAC bacteria.

Chromatography, High Pressure Liquid↗
PubMed1992

[A new, highly synergistic drug combination for the treatment of infections with multiresistant mycobacteria, especially the mycobacterium avium complex].

Rationally designed combinations of rifampicin/thiacetazone plus isoniazid and/or ethambutol are highly effective in the treatment of patients (including HIV-pos.) infected with multiply resistant mycobacteria of the M. avium complex (MAC). Clinical results are very promising. The high efficacy of these combinations is due to the synergistic potentiation of single drug activities. As soon as rifabutin is marketed it should replace rifampicin in the combination treatment of patients with highly rifampicin-resistant MAC bacteria.

Acquired Immunodeficiency Syndrome↗
PubMed1992

Critical comments on the treatment of leprosy and other mycobacterial infections with clofazimine.

The usefulness of clofazimine (CLO, CAS 2030-63-9) in the treatment of mycobacterial infections with special emphasis on treatment of leprosy is critically discussed. Skin discolouration which decreases compliance, placenta passage, excretion in mother's milk which endanger the embryo or baby respectively, saturation kinetics in absorption and difficulties to determine free drug concentration are severe problems. The observed antagonism in the combination of CLO with other drugs, especially with dapsone, is another argument against its application in the therapy of mycobacterial infections. In Germany CLO has not been approved by the Bundesgesundheitsamt.

Clofazimine↗
PubMed1991

Interaction of prostaglandin E1 with alpha-cyclodextrin in aqueous systems: stability of the inclusion complex.

Prostavasin, an inclusion complex of prostaglandin E1 (PGE1) with alpha-cyclodextrin (alpha-CD), is used in the therapy of thrombosis. Nuclear magnetic resonance measurements have been made to study the interaction of PGE1 with alpha-CD. The observed interaction (chemical shift) and the derived dissociation constant prove that only weak interaction forces are operative and that complete dissociation occurs upon dilution.

Alprostadil↗
PubMed1991

Pyrimethamin-resistant Plasmodium falciparum lack cross-resistance to methotrexate and 2,4-diamino-5-(substituted benzyl) pyrimidines.

Methotrexate resistance induced in cultured Plasmodium falciparum depends on an altered dihydrofolate reductase with decreased affinity for methotrexate as well as for pyrimethamine. In contrast, pyrimethamine-resistant field isolates of P. falciparum lack cross-resistance to methotrexate and 2,4-diamino-5-(substituted benzyl) pyrimidines. The structure of the latter class was optimized by the use of trimethoprim as a lead and the substitution of methoxy groups at the benzyl ring by 3-(4'-aminophenyl-4-sulfonylphenylamino)propoxy or by (4'-aminophenyl-4-sulfonylphenyl)methoxy, which resulted in antimalarials of high potency. The efficiency of these newly designed 2,4-diamino-5-(substituted benzyl) pyrimidines was confirmed by their strong inhibitory effect on plasmodial dihydrofolate reductase as well as by in vitro screening against drug-sensitive and -resistant strains of P. falciparum.

Animals↗
PubMed1991

A kinetic description of the fate of chemicals in biosystems.

A simple kinetic description of the fate of low-molecular-weight compounds in biosystems was derived using the mass action law. Michaelis-Menten kinetics of enzymatic reactions was considered with respect to its two boundary cases, namely first- and zero-order kinetics. Absorption, membrane accumulation, non-covalent protein binding, biotransformation, and excretion have been included in the model, with only the last two steps being considered as time-dependent on the pertinent time scale of hours and days. This time hierarchy allowed for simplification of the resulting expression. In accordance with the results of uptake experiments and contrary to previous approaches, transport of organic molecules into the cell was not considered as the rate-limiting step. The decisive compound properties were found to be hydrophobicity and the intrinsic rate parameters of biotransformation and excretion. The model was applied to the elucidation of the dependence of the observed biotransformation rate parameters on hydrophobicity. The resulting equations are consistent with literature data.

Biotransformation↗