Su un criterio di valutazione dell'attività di un farmaco antitubercolare nella cavia infettata con carica massiva

Summary It is reported that the data of index of tuberculous process obtained after 70 days of massive infection (with 1 mg bacilli) and immediately treated with antitubercular drug, are similar to the data observed in the guinea pig infected with a low dosage of bacilli and not treated with any antitubercular drug. The authors therefore suggest the use of this comparision for a test of the antitubercular activity of a drug.     

Intensification of amphetamine-induced excitation by methysergide,a serotonergic receptor blocker

Summary Methysergide, a serotonergic receptor blocker, was studied to determine its effects against d-amphetamine-induced excitation as measured by convulsions elicited by handling in mice. Significant intensification (p<0.01) of the action of d-amphetamine was observed in mice. These results indicate that reduction in serotonergic activity in the central nervous system enhances excitation induced by d-amphetamine.This work was supported by the Pharmaceutical Manufacturer Association Starter Grant, No. 5 S01 RR 05654-06 and the Air Force Office of Scientific Research Grant. The authors are grateful to Ben Wiggins, Michael Wallace, Maria Salazar, and Sanford Futterman for their technical assistance. The authors are also grateful to Dr Boris Tabakoff for supplying the formula of the CSF used in this experiment and we are indebted to San Antonio College for the use of their computer facilities. Dr Blum is a Career Teacher in drug addiction sponsored by NIDA, grant No. 1-T01-DA00290-01.     

Autophagy in mouse hepatocytes induced by lysine acetylsalicylate

Summary I.v. administration of lysine acetylsalicylate inces autophagy in mouse liver cells. Single and multiple membrane-bounded vacuoles were found. The latter seems to be an unusual morphological form of the sequestration process. These findings could express a transitory sublethal liver cell injury induced by the drug.Acknowledgments. The authors are indebted to Mrs M. T. Correia and to Mrs M. E. Pereira for technical assistance.     

Effects of ethidium bromide in diploid and duplication strains of Aspergillus nidulans

Summary Unstable duplication and diploid strains of Aspergillus nidulans were treated with ethidium bromide, and it was shown that this drug reduces the number of sectors produced by such strains. The mechanisms which could be responsible for the partial stabilization of the strains are discussed and it is suggested that a similar mechanism is responsible for the production of sectors in both strains. It is also suggested that ethidium bromide could be useful for the reduction of instability of industrial strains.Acknowledgment. The authors are thankful to the National Council for the Development of Science and Technology (CNPq) for financial assistance.     

Effects of tranylcypromine on the concentrations of some trace amines in the diencephalon and hippocampus of the rat

Summary Concentrations of 4 trace amines in diencephalon and hippocampus of the rat were measured by integrated-ioncurrent mass spectrometry after administration of the antidepressant drug, tranylcypromine. Much larger increases were observed for 2-phenylethylamine and tryptamine than for m- and p-tyramine.Financial support has been provided by the Medical Research Council of Canada, the Psychiatric Services Branch, Province of Saskatchewan, the Alberta Mental health Research Fund, and the Special Services and Research Committee, University of Alberta Hospital.Acknowledgments. The authors wish to thank Dr B.A. Davis for synthesizing the deuterated internal standards and Dr D.A. Durden for supervising the mass spectral analyses. Expert technical assistance was provided by Mr R.C. Mag-Atas and Ms D.G. Calverley. The advice and encouragement of Professors W. G. Dewhurst and A. A. Boulton are gratefully acknowledged.     

The role of hyperoxygenation in facilitating the induction of pulmonary histiocytosis by low doses of chlorphentermine

Summary Hyperoxygenation modified the susceptibility of neonatal rat lung to respond to chlorphentermine with an accumulation of hypertrophic macrophages, a morphologic change undetected when an anorectic drug was given alone. Implications of this observation for pediatrics are discussed.This work was supported by grants from the Medical Research Council of Canada.Acknowledgments. Skilled technical assistance was provided by Mr V. Kapal and Miss G.A. Calderwood, Jr. The authors wish to thank Dr I.M. Nielsen, H. Lundbeck and Company. Copenhagen, Denmark, for the generous supply of chlorphentermine.     

Diphasic action of the aliphatic amide,HOE 17879, on hepatic microsomal drug metabolizing enzymes in the mouse

Summary -Hydroxy--ethylbutyryl-diethylamide (HOE 17879) influences the hepatic microsomal drug hydroxylating enzyme system of mice in a two-phasic way: First it reduces the overall reaction of drug hydroxylation but not the single enzymes whilst in the second period it increases enzyme activities.Acknowledgments. The authors are indebted to their colleague, Dr.K. Schmitt, for making the substance HOE 17879 available. They wish to thank to Mr.Mayer, Mr.Paulusch Mrs.Fey, Mrs.Stein, and MissFehlings for their skilful assistance in the project.     

Liver enzyme induction by the anion exchanger resin,Dowex 1×2, in the rat

Summary Peroral treatment of rats with the anion exchanger resin, Dowex 1×2, for 8 days leads to liver enlargement and increase of alkaline and acid phosphatases, glucose-6-phosphate dehydrogenase, malic enzyme, catalase, and the enzymes of microsomal drug metabolism in the liver. The sequestration of bile acids by this treatment mimics the biochemical effects of clofibrate- and phenobarbital-like drugs in the liver.Acknowledgment. The authors want to thank Mrs Fey, Mrs Kremer and Mr Weinrauch for their skilful technical assistance.     

Protein NMR in biomedical research

Nuclear magnetic resonance (NMR) spectroscopy is a versatile biophysical technique with wide applicability in drug discovery research, particularly for the detection and characterization of molecular interactions. This review highlights in a comprehensive manner the aspects of biomolecular NMR which are most beneficial for pharmaceutical research and presents them as contributions to the different stages of a drug discovery program: target selection, assay development, lead generation and lead optimization. Emphasis is put on the concept of the particular NMR application, rather than on technical details, and on recent examples. Finally, an appendix of frequently asked questions is given.Received 7 October 2003; received after revision 11 November 2003; accepted 27 November 2003This revised version was published online in September 2004. In the previous version, the authors were listet in reverse order.     

Modulation of chemokine receptor activity through dimerization and crosstalk

Chemokines are small, secreted proteins that bind to the chemokine receptor subfamily of class A G protein-coupled receptors. Collectively, these receptor-ligand pairs are responsible for diverse physiological responses including immune cell trafficking, development and mitogenic signaling, both in the context of homeostasis and disease. However, chemokines and their receptors are not isolated entities, but instead function in complex networks involving homo- and heterodimer formation as well as crosstalk with other signaling complexes. Here the functional consequences of chemokine receptor activity, from the perspective of both direct physical associations with other receptors and indirect crosstalk with orthogonal signaling pathways, are reviewed. Modulation of chemokine receptor activity through these mechanisms has significant implications in physiological and pathological processes, as well as drug discovery and drug efficacy. The integration of signals downstream of chemokine and other receptors will be key to understanding how cells fine-tune their response to a variety of stimuli, including therapeutics. Received 19 October 2008; received after revision 7 November 2008; accepted 11 November 2008 C. L. Salanga, M. O’Hayre: These authors contributed equally.     

The effect of bisamidines of 2,6-diaminoanthraquinone onEntamoeba histolytica infections in rats and hamsters

Summary Bisamidines of 2,6-diaminoanthraquinone have demonstrated potent activity against cecal and hepaticEntamoeba histolytica infections in rats and hamsters, respectively. A number of these compounds compared favorably, in overall drug efficacy, with metronidazole and other standard agents.Acknowledgements. The authors wish to thank Dr B. Jackson and co-workers for the results in the Dominant-Lethal test and N.A. Kuck for the results in the Ames test.     

Resistance to ethidium bromide inAspergillus nidulans

Summary A mutant ofAspergillus nidulans resistant to ethidium bromide was isolated and the semi-dominant gene responsible for this resistance was allocated on linkage group II at 17.42±3.05 units of recombination from thewA₃ gene. The gene also confers cross-resistance to acriflavin, malachite green and crystal violet. It was also shown that riboflavin is antagonistic to the toxic effect of ethidium bromide, at certain concentrations. The mechanisms which could be responsible for the toxic effect of this drug are discussed and compared with those of acriflavin. The use of theEtb ₁ gene in genetical analysis through the parasexual cycle is suggested.Acknowledgements. The authors are thankful to the National Council for the Development of Science and Technology (CNPq) for financial support through PIG-SIP 04/053 FAPESP.     

Are some interactions between NADH oxidase and succinate oxidase in beef heart non-phosphorylating submitochondrial particles artifacts?

Summary Critical review of literature and experiments by the authors are suggestive that some interactions between mitochondrial respiratory complexes could be due to a minimal matrix enzymes contamination.Acknowledgments. The authors are grateful to Dr Wanda De Luca for technical assistance.     

Computational inhibitor design against malaria plasmepsins

Plasmepsins are aspartic proteases involved in the degradation of the host cell hemoglobin that is used as a food source by the malaria parasite. Plasmepsins are highly promising as drug targets, especially when combined with the inhibition of falcipains that are also involved in hemoglobin catabolism. In this review, we discuss the mechanism of plasmepsins I–IV in view of the interest in transition state mimetics as potential compounds for lead development. Inhibitor development against plasmepsin II as well as relevant crystal structures are summarized in order to give an overview of the field. Application of computational techniques, especially binding affinity prediction by the linear interaction energy method, in the development of malarial plasmepsin inhibitors has been highly successful and is discussed in detail. Homology modeling and molecular docking have been useful in the current inhibitor design project, and the combination of such methods with binding free energy calculations is analyzed. S. Bjelic, M. Nervall: These authors contributed equally to this work. Received 27 February 2007; received after revision 17 April 2007; accepted 26 April 2007     

In vitro studies on lysosomes radiosensitivity in different gaseous atmospheres

Summary Radiosensitivity of lysosomes was investigated in vitro in different gaseous atmospheres. Results show a higher sensitivity when X-irradiation was performed in nitrous oxide. Possible reasons for this observation are considered.Acknowledgments. The authors wish to acknowledge with much appreciation the many excellent suggestions and very helpful discussion offered by Dr Giorgio Cittadini.     

Receptors for thymosin fraction V on rat thymic lymphocytes

Summary Binding by rat thymus lymphocytes of thymosin V, labeled with colloidal gold, was studied. Under the experimental conditions employed at least 2.8% cells exhibited thymosin binding sites. Supported by Polish Academy of Sciences. Fellows of Humboldt's Fellowship. The authors thank Dr A.L. Goldstein for the gift of thymosin. Also are grateful to Dr J. Jaroszewski for helpful discussion.     

Effect of muscimol on dopamine metabolism of the rat hypothalamus

Summary Muscimol, a potent GABA receptor agonist, produced increases in DOPAC and dopamine concentrations in the rat hypothalamus. GABAergic receptors, therefore, modulate hypothalamic dopaminergic neurones.This work was supported by the National health and Medical Research Council of Australia. The authors are grateful to Dr P. Krogsgaard-Larsen, Copenhagen, for providing muscimol.     

Influence of metiamide and atropine on pepsinogen secretion in the conscious rat

Summary Activity of peptic cells is influenced directly by cholinolytic or cholinergic agents. Histamine H₂-antagonists influence the activity of the chief cells through changes of acidity of gastric juice.Acknowledgment. The authors are indebted to J. Angus for valuable advice.     

The influence of aromatic amines and folate on acid production byEscherichia coli

Summary Folinic acid, adrenaline and noradrenaline, substances known to stimulate oxygen consumption byE. coli, are shown in this experiment to do so by different mechanisms. This work demonstrates stimulation of acid production by folinic acid and inhibition by adrenaline and noradrenaline.Acknowledgment. The authors thank Mr C.A. James for his technical assistance with this work.     

Effect of vincristine on glucose-induced insulin secretion in man

Summary 60 min after the injection of therapeutic doses of vincristine for cancer chemotherapy, there is a reduction of the total (40%) and of the acute phase (43%) areas of insulin secretion induced by a 5-g i.v. glucose load, and the constant of glucose utilization is reduced by 25%. No differences are observed after 3 5-g i.v. glucose loads given at hourly intervals in control subjects.Acknowledgment. The authors are grateful to Mr S. Castiglioni and to Miss Maria Luisa Fuser for their skillful technical assistance.