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At least 199 records · Page 11Linked to original sources
PubMed1988

Cationic antitrypanosomal and other antimicrobial agents in the therapy of experimental Pneumocystis carinii pneumonia.

Cationic compounds used in the treatment of veterinary African trypanosomiasis have structural properties similar to those of pentamidine, which has been used in the therapy of human trypanosomiasis and infection with Pneumocystis carinii. We have compared the activities of these drugs and other antimicrobial agents in an immunosuppressed rat model of P. carinii pneumonia. Diminazene, imidocarb, amicarbalide, quinapyramine, and isometamidium showed efficacy greater than or equal to that of pentamidine in the therapy of P. carinii infection, whereas ethidium and methylglyoxal bis(guanylhydrazone) were only slightly active against the organism. Diminazene and pentamidine also exhibited comparable efficacy in P. carinii prophylaxis, alpha-Difluoromethylornithine (DFMO), a polyamine inhibitor, was ineffective therapy when used alone and did not improve the effectiveness of pentamidine or diminazene. Quinine, quinidine, quinacrine, chlorpromazine, spiramycin, Pentostam, Astiban, dehydroemetine, ampicillin, gentamicin, chloramphenicol, and spectinomycin also showed little or no activity against the organism. Thus, in this model anti-P. carinii activity appears to be a common property of veterinary cationic trypanocidal compounds. This should be important in studying structure-activity relationships and in developing new drugs for the treatment of P. carinii infection in humans.

Amidines↗
PubMed1979

Transient growth inhibition of Escherichia coli K-12 by ion chelators: "in vivo" inhibition of ribonucleic acid synthesis.

The ion chelators picolinic acid, quinaldic acid, 1,10-phenanthroline, and 8-hydroxyquinoline, but not ethylenediaminetetraacetate, ethyleneglycol-bis-(beta-aminoethyl ether)-N,N-tetraacetate, or dipicolinic acid, rapidly but transiently arrest growth of Escherichia coli K-12. Cells adapt and become resistant to growth inhibition by these agents, a process which requires protein synthesis. Mn2+, at low concentrations, decreases the time required for resumption of growth. Proteins synthesized during the lag are quantitatively and qualitatively different from those synthesized during normal growth. Inhibition of growth can explained by an effect on RNA polymerase, a known metalloenzyme.

Adaptation, Physiological↗
PubMed1983

Effect of sidestream tobacco smoke components on alpha/beta interferon production.

Mouse embryo fibroblast cell cultures were treated with chemicals that are major components of sidestream (passive) cigarette smoke. These components were 4-aminobiphenyl and aniline-HCl. The cultures produced severely reduced levels of alpha/beta interferon after challenge with polyriboinosinic-polyribocytidylic acid when compared to control cultures. Treatment of additional cell cultures with 2-methylquinoline, and intermediate-level component of sidestream tobacco smoke, or hydrazine-sulfate, a minor component of sidestream tobacco smoke but a major component of mainstream (active) tobacco smoke, also resulted in inhibition of interferon induction with polyriboinosinic acid-polyribocytidylic acid. Therefore, treatment of the cell cultures with chemicals that are carcinogenic was equally effective in inhibiting alpha/beta interferon induction without regard to the sidestream or mainstream smoke origin of the chemical.

Aminobiphenyl Compounds↗
PubMed1986

A study on the neurotoxicity of broxyquinoline and brobenzoxaldine combination in therapeutic doses.

The neurotoxicity of a combination of broxyquinoline and brobenzoxaldine (Intestopan Forte, containing 500 mg and 100 mg of the drugs respectively per capsule) was investigated by prospective clinical and electrophysiological studies in patients and volunteer subjects given the drugs in therapeutic doses (two capsules three times a day for 5 days). Of 16 patients with intestinal amoebiasis given the drugs (study A), 13 (81.25%) were cured. Adverse effects were mild and did not affect treatment. No neurological adverse effect was reported. Neurological examinations revealed no abnormality in any patient after treatment. Seven volunteer subjects underwent medical, neurological and ophthalmological examinations, and electrophysiological studies of ulnar and peroneal nerve conduction before and after treatment with the drugs in therapeutic doses (study B). Transient paresthesias were reported by one subject on the fourth day of treatment. No medical, neurological or ophthalmological abnormality was detected in any subject after treatment. There was no significant change in motor nerve conduction velocities. There was a significant (P less than 0.001) increase in the stimulus strength for distal ulnar stimulation and a significant (P less than 0.01) decrease in stimulus duration for proximal and distal ulnar stimulation. No significant changes were seen in the peroneal nerves in these parameters. No qualitative abnormality was seen in the oscilloscopic patterns of nerve conduction after treatment. Literature on the neurotoxicity of the halogenated hydroxyquinolines is reviewed. It is concluded that broxyquinoline and brobenzoxaldine (and probably other halogenated hydroxyquinolines as well) are safe and effective in therapeutic doses; neurotoxicity is unlikely to occur when these drugs are used according to therapeutic recommendations.

Adult↗
PubMed1986

Impairment of exercise tolerance due to broxyquinoline-brobenzoxaldine combination.

A case report of impaired exercise tolerance during administration of broxyquinoline-brobenzoxaldine combination in therapeutic doses is presented. The first author of this paper, a 28-year-old healthy male, volunteered as a subject for a prospective study on the neurotoxicity of halogenated hydroxyquinolines and took a course of broxyquinoline-brobenzoxaldine combination. The author, who is a karate enthusiast, observed impairment of exercise tolerance during the course of treatment with the drugs. A challenge course of treatment with the same drugs in the same doses produced similar effects. Since halogenated hydroxyquinolines are still used widely in many countries, such an adverse effect would be of practical relevance, particularly in asymptomatic cyst-passers of Entamoeba histolytica whose occupations involve physical labour.

Adult↗
PubMed1992

Angiotensin II stimulation of plasminogen activator inhibitor-1 gene expression in astroglial cells from the brain.

In this study, we investigated the mechanism of angiotensin II (Ang II) induced secretion of plasminogen activator inhibitor-1 (PAI-1) from astroglial cells prepared from 21-day-old rat brain. Competition-inhibition experiments with the use of selective antagonists for Ang II receptor subtypes indicated that astroglial cells contain chiefly Ang II type 1 (AT1) receptors. The interaction of Ang II with AT1 receptors resulted in a time- and concentration-dependent stimulation of PAI-1 gene expression. A maximal, 20-fold induction of PAI-1 messenger RNA (mRNA) steady-state levels was observed with 10 nM Ang II. This effect of Ang II was blocked by DuP753, an AT1 receptor antagonist, but not by PD123177, an AT2 receptor antagonist. Raise in PAI-1 mRNA levels was followed by an elevation in PAI-1 concentration in culture media reaching its maximum after 24 h. Interaction of Ang II with AT1 receptors also resulted in a time- and concentration-dependent stimulation of inositol phospholipid (IP) hydrolysis. A maximal, 3- to 5-fold stimulation of IP hydrolysis was observed with 10 nM Ang II. The time course experiments indicated that Ang II-induced stimulation of IP hydrolysis precedes the stimulation of PAI-1 mRNA. This suggested that activation of phospholipase C, IP hydrolysis system and possibly protein kinase C (PKC) may mediate Ang II's effect on PAI-1 mRNA. Direct stimulation of PKC by phorbol ester, phorbol 12,13-dibutyrate (PDB), resulted in a time- and concentration-dependent elevation of PAI-1 mRNA levels, similar to that caused by Ang II (maximal stimulation of 20-fold with 100 nM PDB for 4 h). This effect was totally blocked by the protein kinase C inhibitor, H7. In addition, Ang II stimulation of PAI-1 mRNA was also blocked by H7. In contrast, Ang II did not elevate PAI-1 mRNA levels in astroglial cultures from neonatal rat brains. However, treatment of neonatal cultures with PDB increased levels of this mRNA species. These observations indicate that the coupling of AT1 receptors with IP hydrolysis and PKC activation may be important for Ang II stimulation of PAI-1 gene expression. The lack of Ang II's effect on PAI-1 mRNA in neonatal astroglia may be explained either by a low coupling efficiency between AT1 receptors and the second messenger system, or by a low AT1 to AT2 receptor level ratio.

Angiotensin II↗
PubMed2006

Glomerulus-specific, long-latency activity in the olfactory bulb granule cell network.

Reliable, stimulus-specific temporal patterns of action potentials have been proposed to encode information in many brain areas, perhaps most notably in the olfactory system. Analysis of such temporal coding has focused almost exclusively on excitatory neurons. Thus, the role of networks of inhibitory interneurons in establishing and maintaining this reliability is unclear. Here we use imaging of population activity in vitro to investigate the mechanisms of temporal pattern generation in mouse olfactory bulb inhibitory interneurons. We show that activity of these interneurons evolves slowly in time but that individual neurons fire at reliable times, with a timescale similar to the slow changes in the patterns of odor-evoked activity and to odor discrimination. Most strikingly, the latency of a single granule cell is highly reliable from trial to trial during repeated stimulation of the same glomerulus, whereas this same cell will have a markedly different latency when a different glomerulus is activated. These data suggest that the timing of granule cell-mediated inhibition in the olfactory bulb is tightly regulated by the source of input and that inhibition may contribute to the generation of reliable temporal patterns of mitral cell activity.

Action Potentials↗
PubMed1996

The impact of crystallinity on Brequinar sodium hygroscopicity.

The hygroscopicity of Brequinar sodium, an organ transplant immunosuppressant, at 75% relative humidity highly depends on the crystal form or crystallinity of the drug substance. Hygroscopicity and ease of water uptake of three lots of Brequinar sodium were investigated. Those lots contained different impurities at levels ranging from 0.26% to 0.5%. DSC thermograms of the hydrated samples suggest that unbound/loosely bound water was released around 90 degrees C and water of hydration was released at 175 degrees C. At equilibrium, 2% of the water was tightly bound. Stoichiometry suggests that this is a hemihydrate. Unbound/loosely bound water has no impact on the hemihydrate crystal structure as indicated by x-ray powder diffraction patterns. The results suggest that the less perfect crystals exhibited a faster water uptake and converted to a stable hemihydrate when stored at 75% relative humidity. Both the anhydrous and the hemihydrate forms of Brequinar sodium exhibited rapid dissolution rate and comparable water solubility.

Biphenyl Compounds↗
PubMed1989

Cellular pharmacology of DUP-785, a new anticancer agent.

DUP-785, a new inhibitor of dihydroorotate dehydrogenase, is currently undergoing clinical evaluation for anticancer activity. We developed a GC/MS method to quantitate dihydroorotate that accumulates in cultures of L1210 cells exposed to growth inhibitory concentrations of DUP-785. This method was used to follow the onset, extent, and duration of inhibition of de novo pyrimidine synthesis in intact L1210 cells and to compare this inhibition with cell proliferation and cellular concentrations of pyrimidine nucleotides. There were direct relations between inhibition of de novo pyrimidine synthesis, changes in pyrimidine nucleotide concentrations, and cell proliferation following short (less than 24 hr) drug exposures; with prolonged exposures (greater than 24 hr), however, there was a departure from these relationships in that restoration of pyrimidine nucleotide pools and de novo pyrimidine pathway activity did not restore cell proliferation. Exposure of L1210 cells to 15 microM DUP-785 produced a maximum cell kill (99.9% as determined by cloning efficiency) at 24 hr, and no increase in cell kill was observed with drug exposure up to 96 hr.

Animals↗
PubMed1975

Babesiosis in the newborn foal.

A short account is given of babesiosis (equine biliary fever) caused by the tick-borne protozoan Babesia equi and B. caballi, endemic in the Cape Province of South Africa. The clinical picture, diagnosis and treatment are described. In the absence of any prophylactic measures, prognosis is poor; control of the parasites in the tick-infested areas is essential.

Animals↗
PubMed1975

Inhibition by quinaldate of dehydrogenases.

Quinaldate (quinoline-2-carboxylate) inhibits pyridine-, and flavin nucleotide-dependent dehydrogenases, both inside the mitochondria and in isolated form. Other mitochondrial functions and some other isolated enzymes (with one exception) are not influenced by quinaldate at all. Thus, quinaldate can be regarded as a specific "dehydrogenase inhibitor". The inhibition of alcohol dehydrogenase (EC 1.1.1.1) and lactate dehydrogenase (EC 1.1.1.27) by quinaldate is of mixed type, both with respect to NAD+ and ethanol or lactate, respectively. The Ki for alcohol dehydrogenase is 4.5 mM, that of lactate dehydrogenase 7.5 mM. It can be assumed that the inhibition by quinaldate of dehydrogenases is a consequence of its binding to that part of the active centre which takes part in the dehydrogenation itself and might possess very similar structure in all dehydrogenases.

Alcohol Oxidoreductases↗