Common structural features determine the effectiveness of carvedilol, daunomycin and rolitetracycline as inhibitors of Alzheimer beta-amyloid fibril formation.
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One of the major pathological features of Alzheimer's disease is the deposition of beta-amyloid peptide (Abeta). Cellular toxicity has been shown to be associated with fibrillar forms of Abeta; preventing this fibril formation is therefore viewed as a possible method of slowing disease progression in Alzheimer's disease. With the use of a series of tetracyclic and carbazole-type compounds as inhibitors of Abeta fibril formation, we here describe a number of common structural features that seem to be associated with the inhibitory properties of these agents. Compounds such as carvedilol, rolitetracycline and daunomycin, which are shown to inhibit Abeta fibril formation, also prevent the formation of species of peptide that demonstrate biological activity in a human neuroblastoma cell line. Molecular modelling data suggest that these compounds have in common the ability to adopt a specific three-dimensional pharmacophore conformation that might be essential for binding to Abeta and preventing it from forming fibrils. Understanding such drug-peptide interactions might aid the development of disease-modifying agents. (+info)
4'-iodo-4'-deoxydoxorubicin and tetracyclines disrupt transthyretin amyloid fibrils in vitro producing noncytotoxic species: screening for TTR fibril disrupters.
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Transthyretin Leu55Pro is one of the most aggressive mutations in familial amyloidotic polyneuropathy, an autosomal dominant disorder characterized by extracellular deposition of fibrillar amyloid protein. This variant has the ability to form fibrils in vitro under physiological conditions (PBS, pH 7.4). We studied by transmission electron microscopy the effect of the drug 4'-iodo-4'-deoxydoxorubicin (I-DOX) on the in vitro assembly of TTR Leu55Pro fibrils by following fibril growth over a 15 day period. Our results showed that I-DOX at a concentration of 10-5 M/100 microg fibrils does not inhibit fibril formation in up to 10 days since fibrils identical to the ones present in the untreated sample were observed. However, after 15 days of treatment, only round particles, resembling soluble native TTR, were observed. We also tested the ability of tetracyclines and nitrophenols to interfere with amyloid fibril formation for 17 days; the group of compounds tested showed fibril disruption activity to different extents: doxycycline and 2,4-dinitrophenol resulted in complete disaggregation of fibrils. The species generated upon I-DOX and tetracyclines treatments were nontoxic, as revealed by the lack of significant caspase-3 activation on a Schwannoma cell line, making them potential therapeutic drugs in TTR-related and other amyloidosis. (+info)
The international standard for rolitetracycline.
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An International Standard for Rolitetracycline has been established and the international unit of this antibiotic defined as the activity contained in 0.001004 mg of the international standard. The definition of the international unit was based on the results of a collaborative assay in which 8 laboratories in 6 different countries participated; a total of 133 assays were performed. The assay was in terms of the Working Standard of the USA Food and Drug Administration; mean potencies for individual laboratories varied within a range of only 2% of the mean for all assays although 7 different test organisms were used in both diffusion and turbidimetric assays. Individual assays, however, provided potencies that varied within a range of 40%. (+info)
Effect of tetracyclines and 4-epiderivatives on the ureter.
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1. The effect of tetracyclines on the isolated dog ureter is dependent on: (a) the tetracyclines used-mepicycline and doxycycline antagonizing, and tetracycline and rolitetracycline increasing the contractor action of barium chloride; (b) the percentage of 4-epiderivatives in the tetracyclines used-the higher the epiderivative concentration, the smaller the effect of mepicycline or doxycycline, and the greater the action of tetracycline or rolitetracycline.2. In vivo the addition of the antibiotics into the renal pelvis shows no significant differences between the various tetracyclines or different 4-epiderivative concentrations on the intra-ureteral flow of the dog or guinea-pig.3. Intravenous injection of mepicycline or doxycycline does not induce a significant change in the intra-ureteral flow, while intravenous administration of tetracycline or rolitetracycline produces a triphasic response: (a) a marked decrease of the intra-ureteral flow for a few minutes; (b) a return to the control condition for 30-60 min; and (c) a lesser but persistent decrease in flow for 60-120 minutes. In the first phase the ureteral smooth muscle is directly affected by the antibiotics circulating in the blood, while in the third phase the tetracyclines act via the intra-ureteral mucosa.4. Neurogenic effects on the ureter-bladder junction in vivo are not affected by the tetracyclines tested. (+info)
Recent developments in the treatment of gonorrhoea.(5/8)
A high performance liquid chromatographic system for the analysis of tetracycline drug standards, analogs, degradation products and other impurities.
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This paper describes the high performance liquid chromatographic (HPLC) analysis of eight parent tetracycline standards: tetracycline, chlortetracycline, rolitetracycline, oxitetracycline, minocycline, doxycycline, democlocycline, methacycline; and three tetracycline epimers: epitetracycline, epianhydrotetracycline, and anhydrotetracycline. The HPLC system employs an octadecylsilane reverse phase column and an isopropanol-diethanolamine-phosphate-ammonium EDTA-water mobile phase. This system produced at least partial resolution of all eight parent compounds and many of their degradation products. (+info)
Accidental intra-arterial injection.
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Accidental intra-arterial injection of intramuscular antibiotic preparations is described in 3 cases in infants. In 2 benzathine penicillin was injected, and in 1 rolitetracycline. The clinical features are dominated by arteriolar obstruction which produces gangrene of the most severely affected limb. In addition, neuroloigcal involvement occurs when vessels to nerves or spinal cord are involved. The arteriolateral aspect of the thigh is preferable to the buttock as a site for intramuscular injection, and a short (2.5 cm) needle should be used to minimise the risk of intra-arterial injection. (+info)
[Combination of bacteriostatic and bactericidal drugs: lack of significant in vitro antagonism between penicillin, cephalothin, and rolitetracycline].
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Although it is generally believed that bactericidal and bacteriostatic drugs should not be combined in vivo, in vitro experiments using the checkerboard dilution technique revealed no antagonism between penicillin/cephalothin and rolitetracycline but rather additive or synergistic activity of either drug combination in 40 to 50% of 20 Escherichia coli, and 14 Staphylococcus aureus strains. Slight antagonism occurred only between 3 and 8 h after combining penicillin/cephalothin and rolitetracycline in either bacteriostatic or bactericidal concentrations, but not after 24 h of incubation, nor was antagonism found with combinations of these drugs in bacteriostatic concentrations. Neither bacteriostatic nor bactericidal activity of penicillin/cephalothin and rolitetracycline was inhibited by pretreatment of one E. coli strain with bacteriostatic rolitetracycline or bacteriostatic penicillin/cephalothin concentrations. Penicillin and cephalothin could exert a bactericidal effect after 2-h exposure of the E. coli strain to bacteriostatic rolitetracycline concentrations. Combined action of subinhibitory penicillin and rolitetracycline concentrations resulted in more pronounced inhibition of growth than either drug alone. The higher activity of penicillin/cephalothin in combination with rolitetracycline on some E. coli and S. aureus strains might be due to a better access of rolitetracycline into bacterial cells whose cell walls have been weakened by cell wall-active, bactericidal drugs. Thus, growth of penicillin-induced spheroplasts of E. coli and stable staphylococcal L-forms was inhibited by much lower concentrations of rolitetracycline than were the corresponding parent cells with intact cell walls. (+info)