Effect of centrally active drugs on dopamine oxidation by rat brain catecholamine oxidase.

Centrally active drugs of the phenothiazine-, butyrophenone- and iminodibenzyl class markedly decreased the rate of dopamine oxidation in the presence of rat brain catecholamine oxidase.     

Effect of centrally active drugs on dopamine oxidation by rat brain catecholamine oxidase

Summary Centrally active drugs of the phenothiazine-, butyrophenone- and iminodibenzyl class markedly decreased the rate of dopamine oxidation in the presence of rat brain catecholamine oxidase.The financial support from Gotfred Lie and Marie Lie's Fond is gratefully acknowledged.     

Antibacterial properties of several drug categories

Summary Several drugs of various pharmacological classes were tested for antimicrobial activity by the agar diffusion technique and minimal inhibitory concentration (MIC) estimation. Among them diclofenac sodium, haloperidol, meclastine fumarate, chlorpromazine, chlorimipramine and promethazine were the more active.     

Sleeping sickness and the brain

Recent progress in understanding the neuro-pathological mechanisms of sleeping sickness reveals a complex relationship between the trypanosome parasite that causes this disease and the host nervous system. The pathology of late-stage sleeping sickness, in which the central nervous system is involved, is complicated and is associated with disturbances in the circadian rhythm of sleep. The blood-brain barrier, which separates circulating blood from the central nervous system, regulates the flow of materials to and from the brain. During the course of disease, the integrity of the blood-brain barrier is compromised. Dysfunction of the nervous system may be exacerbated by factors of trypanosomal origin or by host responses to parasites. Microscopic examination of cerebrospinal fluid remains the best way to confirm late-stage sleeping sickness, but this necessitates a risky lumbar puncture. Most drugs, including many trypanocides, do not cross the blood-brain barrier efficiently. Improved diagnostic and therapeutic approaches are thus urgently required. The latter might benefit from approaches which manipulate the blood-brain barrier to enhance permeability or to limit drug efflux. This review summarizes our current understanding of the neurological aspects of sleeping sickness, and envisages new research into blood-brain barrier models that are necessary to understand the interactions between trypanosomes and drugs active against them within the host nervous system. Received 10 October 2001; received after revision 29 November 2001; accepted 5 December 2001     

Conserved amino acids participate in the structure networks deputed to intramolecular communication in the lutropin receptor

The luteinizing hormone receptor (LHR) is a G protein-coupled receptor (GPCR) particularly susceptible to spontaneous pathogenic gain-of-function mutations. Protein structure network (PSN) analysis on wild-type LHR and two constitutively active mutants, combined with in vitro mutational analysis, served to identify key amino acids that are part of the regulatory network responsible for propagating communication between the extracellular and intracellular poles of the receptor. Highly conserved amino acids in the rhodopsin family GPCRs participate in the protein structural stability as network hubs in both the inactive and active states. Moreover, they behave as the most recurrent nodes in the communication paths between the extracellular and intracellular sides in both functional states with emphasis on the active one. In this respect, non-conservative loss-of-function mutations of these amino acids is expected to impair the most relevant way of communication between activating mutation sites or hormone-binding domain and G protein recognition regions.     

Die Wirkung von Herzglykosiden und Kalzium auf den Kaliumtransport im Herzmuskel

Summary In isolated perfused guinea pig hearts, both strophanthin and calcium produced positive inotropic effects and contracture increasing with the concentration of the drugs. Strophanthin caused a net loss of potassium from the heart to the perfusing fluid whereas calcium did not interfer in the same way with potassium exchange. The data are consistent with the view that the positive inotropic effect of cardiac glycosides depends mainly on the increased intracellular calcium concentration, perhaps due to inhibition of the active potassium and sodium transport.     

Colloidal drug carriers: achievements and perspectives

Colloidal drug carriers such as liposomes and nanoparticles are able to modify the distribution of an associated substance. They can therefore be used to improve the therapeutic index of drugs by increasing their efficacy and/or reducing their toxicity. If these delivery systems are carefully designed with respect to the target and route of administration, they may provide one solution to some of the delivery problems posed by new classes of active molecules such as peptides, proteins, genes, and oligonucleotides. They may also extend the therapeutic potential of established drugs such as doxorubicin and amphotericin B. This article discusses the use of colloidal, particulate carrier systems (25 nm to 1 μm in diameter) in such applications. In particular, systems which show diminished uptake by mononuclear phagocytes are described. Specific targeting of carriers to particular tissues or cells is also considered. Received 8 April 2002; received after revision 25 June 2002; accepted 26 June 2002     

Plasmids controlling the resistance to several antibiotics in C. perfringens type A, strain 659]

A strain of C. perfringens type A, isolated from a patient, was found to be resistant to four antibiotics: tetracycline (Tet), chloramphénicol (Chl), erythromycin (Ero) and clindamycin (Cli). Clones resistant to only two drugs (Tet-Chl or Ero-Cli), or sensitive to all drugs were found in cultures of the wild-type strain treated by acridine dyes or ethidium bromide. DNA analysis by equilibrium centrifugation confirmed that the original strain contains two resistance plasmids, one called Rip 401 (Tet-Chl) and the other Rip 402 (Ero-Cli), which represent respectively 1.8 +/- 0.2% and 2.3 +/- 0.2% of the total amount of DNA in this strain of Cl. perfrigens.     

Cytochromes P450 and metabolism of xenobiotics

Cytochromes P450 (henceforth P450s) are involved in a variety of metabolic and biosynthetic processes. The number of known P450 enzymes exceeds 1000, while the endogenous substrates of most of them remain unknown. All P450 enzymes exhibit similarity in their structure and general mechanism of action; however, there are significant differences in the detailed function of individual enzymes as well as in the structures and properties of their active sites. This review discusses the properties of the most important P450 enzymes taking part in drug metabolism in humans. P450 3A4 is of paramount importance, because it is the most abundant P450 in the human liver and is known to metabolize the majority of drugs whose biotransformation is known. Genetically dependent variabilities of individual P450 activities and levels are described, documenting the importance of pharmacogenetics aimed at explaining differences in the response of the organism to various drugs. Received 7 November 2000; received after revision 9 January 2001; accepted 10 January 2001     

Age-related changes of the pattern of non-histone proteins in active and condensed fractions of mouse liver chromatin and hepatocarcinoma

Electrophoretic analysis of histones and non-histone acid-soluble proteins in active (nuclease sensitive) and inactive chromatin from liver of young and old CBA mice and in age-related hepatocarcinomas showed a higher ratio of NHP:histones in active chromatin in old cells. Some liver- and hepatoma-specific fractions of non-histone proteins have been identified as chromatin matrix proteins.     

Age-related changes of the pattern of non-histone proteins in active and condensed fractions of mouse liver chromatin and hepatocarcinoma

Summary Electrophoretic analysis of histones and non-histone acid-soluble proteins in active (nuclease sensitive) and inactive chromatin from liver of young and old CBA mice and in age-related hepatocarcinomas showed a higher ratio of NHP: histones in active chromatin in old cells. Some liver- and hepatoma-specific fractions of non-histone proteins have been identified as chromatin matrix proteins.     

The fungal glutathione S-transferase system. Evidence of new classes in the wood-degrading basidiomycete Phanerochaete chrysosporium

The recent release of several basidiomycete genome sequences allows an improvement of the classification of fungal glutathione S-transferases (GSTs). GSTs are well-known detoxification enzymes which can catalyze the conjugation of glutathione to non-polar compounds that contain an electrophilic carbon, nitrogen, or sulfur atom. Following this mechanism, they are able to metabolize drugs, pesticides, and many other xenobiotics and peroxides. A genomic and phylogenetic analysis of GST classes in various sequenced fungi—zygomycetes, ascomycetes, and basidiomycetes—revealed some particularities in GST distribution, in comparison with previous analyses with ascomycetes only. By focusing essentially on the wood-degrading basidiomycete Phanerochaete chrysosporium, this analysis highlighted a new fungal GST class named GTE, which is related to bacterial etherases, and two new subclasses of the omega class GSTs. Moreover, our phylogenetic analysis suggests a relationship between the saprophytic behavior of some fungi and the number and distribution of some GST isoforms within specific classes.     

Annonacin, a novel, biologically active polyketide from Annona densicoma

A new linear polyketide, Annonacin (I), has been isolated from active extracts of the stembark of Annona densicoma Mart. Annonacin (I) is highly cytotoxic and is active in an assay designed to detect antimitotic agents. The structure of (I) was determined by analysis of spectroscopic data.     

Know your enemy: understanding the role of PfCRT in drug resistance could lead to new antimalarial tactics

The prevention and treatment of malaria is heavily dependent on antimalarial drugs. However, beginning with the emergence of chloroquine (CQ)-resistant Plasmodium falciparum parasites 50 years ago, efforts to control the disease have been thwarted by failed or failing drugs. Mutations in the parasite's 'chloroquine resistance transporter' (PfCRT) are the primary cause of CQ resistance. Furthermore, changes in PfCRT (and in several other transport proteins) are associated with decreases or increases in the parasite's susceptibility to a number of other antimalarial drugs. Here, we review recent advances in our understanding of CQ resistance and discuss these in the broader context of the parasite's susceptibilities to other quinolines and related drugs. We suggest that PfCRT can be viewed both as a 'multidrug-resistance carrier' and as a drug target, and that the quinoline-resistance mechanism is a potential 'Achilles' heel' of the parasite. We examine a number of the antimalarial strategies currently undergoing development that are designed to exploit the resistance mechanism, including relatively simple measures, such as alternative CQ dosages, as well as new drugs that either circumvent the resistance mechanism or target it directly.     

Hydrogen peroxide and hydroxyl radical involvement in the activation of caspase-3 in chemically induced apoptosis of HL-60 cells

Apoptosis of HL-60 cells induced by actinomycin D, H7, or daunorubicin was shown to involve the activation of caspase-3-like protease, 2 h after the addition of these drugs, based on microassay of enzyme activity by high-performance liquid chromatography. Catalase and a spin trap, N-t-butyl--phenylnitrone, which effectively inhibited the apoptosis induced by these drugs, also inhibited the activation of caspase-3-like protease. These results suggest that hydrogen peroxide and the hydroxyl radical are common mediators of caspase-3 activation caused by these chemicals, with apparently different functional mechanisms. Based on mitochondrial activity determined by oxygen consumption, complexes I, II, and IV were inhibited by actinomycin D. H7 inhibited complexes I and IV, 1 and 1.5 h respectively, after the addition of the drug to HL-60 cells. Daunorubicin inhibited complex IV, 1.5 h after the addition of the drug to HL-60 cells. Inhibition of complex IV by actinomycin D, H7, and daunorubicin were almost fully restored by the addition of cytochrome c. The release to the cytosol of cytochrome c by these drugs was also demonstrated by Western blot analysis. Addition of catalase inhibited the depression of complex IV activity induced by actinomycin D and H7. These observations indicate a direct relationship between hydrogen peroxide and the release of cytochrome c during apoptosis caused by actinomycin D, H7, and daunorubicin. Received 24 November 2000; received after revision 2 January 2001; accepted 30 January 2001     

区域经济一体化:中国参与世界经济活动的主要方式

经济全球化是我们在世纪之交面临的一个重大发展趋势。受这一趋势的影响，我国理论界也开始了对经济全球化的研究，并主张中国应积极参与经济全球化。笔者在分析经济全球化的特点和我国经济发展状况的基础上认为，我国当前应侧重于对区域经济一体化的研究与利用。     

An improved flow-through chamber for time-lapse film analysis of oogenesis and embryogenesis

Summary A simple flow-through chamber for time-lapse film analysis of developing organisms has been constructed. The medium is replaced efficiently and uniformly in the chamber which is, therefore, ideally suited for studying the effect of various drugs on development.Acknowledgment. This work was supported by the Deutsche Forschungsgemeinschaft (grant to H.G.).