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At least 919 records · Page 51Linked to original sources
PubMed1999

Disposition of antimony and aminosidine combination after multiple subcutaneous injections in dogs.

The disposition of a combination of antimony (Sbv) (12.8 mg/kg) and aminosidine (AM) (10 mg/kg) in 10 healthy Beagle dogs after multiple subcutaneous injections is described. Sbvplasma concentrations were determined by atomic absorption spectrometry, and AM by ion-pair liquid chromatography, using a fluorimetric detector. Sbvreached Cmaxat 60 min, and for about 1 h plasma levels were homogeneously stabilized between 10.78 and 11.76 microgram/mL; by 12 h, Sbvplasma concentrations were close to the detection limit (0.3 microgram/mL). AM Cmaxvalues were recorded after 1 h (30.6+/-3.11 microgram/mL, mean +/- SD), and plasma levels reached values close to the detection limit (0.15 microgram/mL) between 7 and 8 h after injection. Sbvkinetic parameters did not appear modified by the presence of AM. Moreover, repeated injections of the combination did not modify the kinetic behaviour of the two drugs and did not alter the renal function of the animals. The superimposition analysis of the Sbvdata suggests that a twice daily injection of the metal at a dose of 12.8 mg/kg would be sufficient to maintain inhibitory Sbvconcentrations similar to those recorded in humans.

Amebicides↗
PubMed2004

Correction of ATM gene function by aminoglycoside-induced read-through of premature termination codons.

Approximately 14% of genetic mutations in patients with ataxia-telangiectsia (A-T) are single-nucleotide changes that result in primary premature termination codons (PTCs), either UAA, UAG, or UGA. The purpose of this study was to explore a potential therapeutic approach for this subset of patients by using aminoglycosides to induce PTC read-through, thereby restoring levels of full-length ATM (A-T mutated) protein. In experiments using a modified in vitro cDNA coupled transcription/translation protein truncation test, 13 A-T cell lines carrying PTC mutations in different contexts exhibited read-through expression of ATM fragments, with three of four aminoglycosides tested. In ex vivo experiments with lymphoblastoid cell lines, we used radiosensitivity, radioresistant DNA synthesis, and irradiation-induced autophosphorylation of ATM Ser-1981 to show that the aminoglycoside-induced full-length ATM protein was functional and corrected, to various extents, the phenotype of A-T cells. These results encourage further testing of other compounds in this class, as well as follow up animal studies. Because some A-T patients with 5-20% of normal levels of ATM protein show slower neurological progression, A-T may prove to be a good model for aminoglycoside-induced read-through therapy.

Aminoglycosides↗
PubMed2006

Mutant LYS2 mRNAs retained and degraded in the nucleus of Saccharomyces cerevisiae.

We previously demonstrated that mRNAs retained in the nucleus of Saccharomyces cerevisiae are subjected to a degradation system-designated DRN (degradation of mRNA in the nucleus), that is diminished in cbc1-Delta or cbc2-Delta mutants lacking components of the cap-binding complex and in rrp6-Delta mutants lacking Rrp6p, a 3' to 5' nuclear exonuclease. Two mutants, lys2-187 and lys2-121, were uncovered by screening numerous lys2 mutants for suppression by cbc1-Delta and rrp6-Delta. Both mutants were identical and contained the two base changes, one of which formed a TGA nonsense codon. LYS2 mRNAs from the lys2-187 and related mutants were rapidly degraded, and the degradation was suppressed by cbc1-Delta and rrp6-Delta. The U1A-GFP imaging procedure was used to show that the lys2-187 mRNA was partially retained in the nucleus, explaining the susceptibility to DRN. The creation of several derivatives of lys2-187 by site-directed mutagenesis revealed that the in-frame TGA by itself was not responsible for the increased susceptibility to DRN. Thus, mRNAs susceptible to DRN can be formed by a 2-bp change. Furthermore, this "retention signal" causing susceptibility to DRN is lost by altering one of the base pairs, establishing that mRNAs susceptible and unsusceptible to DRN can be attributed to a single nucleotide in the proper context.

Base Sequence↗
PubMed1972

The attachment site of streptomycin to the 30S ribosomal subunit.

The 16S RNA dissociated from 30S ribosomal subunits of Escherichia coli strains either sensitive or resistant to streptomycin contains the attachment sites for two streptomycin molecules, as does the undissociated particle from a streptomycin-sensitive strain. Since no streptomycin binds to undissociated 30S subunits from a streptomycin-resistant strain, it is suggested that protein P10, specified by the strA locus-known to be responsible for drug sensitivity-controls the availability to streptomycin of the attachment sites. These sites remain exposed in the strA(+) wild-type, and become masked in strA streptomycin-resistant mutants. The 16S RNA molecule binds streptomycin specifically; it binds two drug molecules in its native state, binds many more after its secondary structure is unfolded by melting out, and again binds two molecules after reannealing. The binding is stable to exhaustive dialysis, but it is reversed by exposure of the streptomycin-RNA complex to high-salt concentration. The complex can not be used to reconstitute functional ribosomes, but the 16S RNA reacquires this property after streptomycin elimination. The biological significance of this stable streptomycin binding is questioned, since in strA mutants exhibiting phenotypic masking, exposure to streptomycin induces a modified 30S behavior that persists even after streptomycin has been dialyzed away, and is reversed only by exposure of the modified RNA to high-salt concentration.

Binding Sites↗
PubMed1988

Molecular evidence for somatic recombination in the ribosomal DNA of Tetrahymena thermophila.

The ribosomal DNA (rDNA) in Tetrahymena thermophila is a 21-kilobase-pair palindromic DNA molecule that replicates autonomously in the macronucleus and is maintained at the level of about 10,000 copies per macronucleus. The rDNA of inbred strain C3 outreplicates the rDNA of inbred strain B in most B/C3 heterozygous macronuclei, generating macronuclei containing exclusively C3 rDNA sequences. In 1% or less of the B/C3 heterozygous macronuclei, however, rDNA sequences derived from both B and C3 strains persist in the macronucleus (co-maintainers). We report here that long-term culture of co-maintainers has yielded recombinant rDNA molecules combining sequences from both parental inbred strains. The genetic structure of such molecules also gives us virtual certainty that the differential replication of C3 rDNA with respect to B rDNA is due to the DNA sequence difference previously reported in domain 2 of the rDNA replication regions of the two strains.

Animals↗
PubMed1993

An accuracy center in the ribosome conserved over 2 billion years.

The accuracy of translation in Escherichia coli is profoundly influenced by three interacting ribosomal proteins, S12, S4, and S5. Mutations at lysine-42 of S12, originally isolated as causing resistance to streptomycin, increase accuracy. Countervailing "ribosomal ambiguity mutations" (ram) in S4 or S5 decrease accuracy. In the eukaryotic ribosome of Saccharomyces cerevisiae, mutations in SUP46 and SUP44, encoding the proteins equivalent to S4 and S5, lead to omnipotent suppression--i.e., to less accurate translation. The evolution of ribosomal protein S12 can be traced, by comparison with archaebacteria and Tetrahymena, to S28 of S. cerevisiae, even though the two proteins share only very limited regions of homology. However, one region that has been conserved contains a lysine residue whose mutation leads to increased accuracy in E. coli. We have introduced into S28 of yeast the same amino acid substitutions that led to the original streptomycin-resistant mutations in E. coli. We find that they have a profound effect on the accuracy of translation and interact with SUP44 and SUP46, just as predicted from the E. coli model. Thus, the interplay of these three proteins to provide the optimal level of accuracy of translation has been conserved during the 2 billion years of evolution that separate E. coli from S. cerevisiae.

DNA↗
PubMed1999

Inhibition of RNase P RNA cleavage by aminoglycosides.

A number of aminoglycosides have been reported to interact and interfere with the function of various RNA molecules. Among these are 16S rRNA, the group I intron, and the hammerhead ribozymes. In this report we show that cleavage by RNase P RNA in the absence as well as in the presence of the RNase P protein is inhibited by several aminoglycosides. Among the ones we tested, neomycin B was found to be the strongest inhibitor with a Ki value in the micromolar range (35 microM). Studies of lead(II)-induced cleavage of RNase P RNA suggested that binding of neomycin B interfered with the binding of divalent metal ions to the RNA. Taken together, our findings suggest that aminoglycosides compete with Mg2+ ions for functionally important divalent metal ion binding sites. Thus, RNase P, which is an essential enzyme, is indeed a potential drug target that can be used to develop new drugs by using various aminoglycosides as lead compounds.

Anti-Bacterial Agents↗
PubMed1996

Therapeutic effect of reference antileishmanial agents in murine visceral leishmaniasis due to Leishmania infantum.

A sensitive, culture-based, microtitration technique has recently been developed for determining parasite burdens in organs recovered from Balb/c mice infected with Leishmania infantum. In the present study, this technique was used to examine the efficacy of three, first-line, antileishmanial agents in reducing parasite burdens and eradicating parasites from target organs in mice. Treatment with meglumine antimoniate (50 mg SbV/kg.day) significantly reduced the parasite burdens in the livers and lungs (by about 10-fold and > 100-fold, respectively) but not those in the spleens. Although use of a higher dose of meglumine antimoniate (200 mg SbV/kg.day) resulted in an even more dramatic reduction in the parasite burdens in the livers, it had no significant effect on the burdens in the spleens. Treatment with amphotericin B (0.8 mg/kg every other day) resulted in significant reductions in the parasite burdens in the livers, spleens and lungs of infected mice. Although low doses of aminosidine (20 mg/kg.day) had no effect, high doses (200 mg/kg.day) resulted in undetectable parasite burdens in the livers, for at least 100 days post-treatment, and marked reductions in burdens in the spleens. These results are consistent with previous data from studies using animal models of visceral leishmaniasis. Thanks to the sensitivity of the technique, culture microtitration revealed that none of the drug schedules achieved the elimination of all parasites in all target organs. The murine model used mimics some important features of HIV/Leishmania infantum co-infections in humans.

Amphotericin B↗
PubMed1998

Comparative efficacy of meglumine antimoniate and aminosidine sulphate, alone or in combination, in canine leishmaniasis.

Thirty-two domestic dogs naturally infected with Leishmania infantum and showing viscero-cutaneous signs of canine leishmaniasis were treated with aminosidine sulphate (11 dogs) meglumine antimoniate (10 dogs) or with a combination of the two drugs (11 dogs) for 21 consecutive days. Clinical and laboratory assessments, made on day 21 and at 2, 4 and 6 months after initiation of treatment, showed that the drug combination gave the best score in terms of clinical efficacy, incidences of early clinical relapse, any clinical relapse or apparent parasitological cure, and reduction in parasite densities in bone-marrow and lymphnode aspirates (even though a lower dose of antimonial was used in the combination than for antimonial monotherapy). For each of the above parameters, however, the higher efficacy of the drug combination was not statistically significant, probably because of the large variations caused by using naturally infected animals of various ages and breeds.

Animals↗