RIT 2214, a new biosynthetic penicillin produced by a mutant of Cephalosporium acremonium.
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A number of lysine-requiring auxotrophs of Cephalosporium acremonium were investigated for incorporation of side-chain precursors and for accumulation of beta-lactam compounds. One of the auxotrophs, Acremonium chrysogenum ATCC 20389, producing cephalosporin C and penicillin N only if grown in media supplemented with DL-alpha-amino-adipic acid (DL-alpha-AAA), was found to use L-S-carboxymethylcysteine (L-CMC) as a side-chain precursor for the synthesis of a new penicillin (RIT 2214). No corresponding cephalosporin was detected. The penicillin present in the culture filtrate, was concentrated by adsorption on activated carbon and successive column chromatography on Amberlite IRA-68 and Amberlite XAD-4. Final purification was achieved by cellulose column chromatography. RIT 2214 was identified as 6-(D)-[(2-amino-2-carboxy)-ethylthio]-acetamido]-penicillanic acid by spectral analysis, bioactivity spectrum, elucidation of side-chain structure and finally by semisynthesis. Its biological properties were also evaluated. (+info)
Stimulation of central cholinergic neurons by (-)clausenamide in vitro.
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AIM: To study the neurotrophic effects of (-) and (+)clausenamide on frontal cortex neurons in culture. METHODS: The activity of the choline acetyltransferase (ChAT) was determined by spectrophotometric method; protein content was assayed by Folin phenol method. RESULTS: (-)Clausenamide increased the activity of ChAT and protein content in cultured neurons, as well as stimulated proliferation of neuronal cells, support survival and neurite outgrowth of neurons. The neurotrophic action of (-)clausenamide (0.001-10 mumol.L-1) was similar to that of nerve growth factor. The (+)clausenamide had no neurotrophic action, even at high concentrations (0.1-10 mumol.L-1), but neurons were damaged. CONCLUSION: (-)Clausenamide stimulated central cholinergic neuron development. (+info)
Protein adducts of iso[4]levuglandin E2, a product of the isoprostane pathway, in oxidized low density lipoprotein.
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Levuglandin (LG) E2, a cytotoxic seco prostanoic acid co-generated with prostaglandins by nonenzymatic rearrangements of the cyclooxygenase-derived endoperoxide, prostaglandin H2, avidly binds to proteins. That LGE2-protein adducts can also be generated nonenzymatically is demonstrated by their production during free radical-induced oxidation of low density lipoprotein (LDL). Like oxidized LDL, LGE2-LDL, but not native LDL, undergoes receptor-mediated uptake and impaired processing by macrophage cells. Since radical-induced lipid oxidation produces isomers of prostaglandins, isoprostanes (isoPs), via endoperoxide intermediates, we postulated previously that a similar family of LG isomers, isoLGs, is cogenerated with isoPs. Now iso[4]LGE2-protein epitopes produced by radical-induced oxidation of arachidonic acid in the presence of protein were detected with an enzyme-linked immunosorbent assay. Iso[4]LGE2-protein epitopes are also generated during free radical-induced oxidation of LDL. All of the LGE2 isomers generated upon oxidation of LDL are efficiently sequestered by covalent adduction with LDL-based amino groups. The potent electrophilic reactivity of iso-LGs can be anticipated to have biological consequences beyond their obvious potential as markers for specific arachidonate-derived protein modifications that may be of value for the quantitative assessment of oxidative injury. (+info)
In-vitro activity of levofloxacin against Streptococcus pneumoniae with various levels of penicillin resistance.
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This in-vitro study was designed to compare the activity of levofloxacin with that of ciprofloxacin, ofloxacin, erythromycin, penicillin, amoxycillin, loracarbef, cefaclor, cefpodoxime, ceftriaxone, trimethoprim-sulphamethoxazole, clindamycin and vancomycin against a collection of 202 Streptococcus pneumoniae isolates (56% susceptible to penicillin, 34% intermediate, 10% resistant). The isolates (60% nasopharyngeal, 40% middle ear) were obtained from otherwise healthy children at child care centres in urban and rural Nebraska, and at a paediatric clinic in rural Kentucky. MICs were determined by NCCLS agar dilution methodology using an inoculum of 10(4) cfu/spot. Using NCCLS breakpoints, the percentage of penicillin-intermediate and -resistant strains susceptible to the evaluable agents were, respectively, as follows: levofloxacin (99%, 100%), ofloxacin (87%, 100%), erythromycin (52%, 65%), ceftriaxone (93%, 25%), trimethoprim-sulphamethoxazole (7%, 0%), clindamycin (93%, 100%) and vancomycin (100%, 100%). Without NCCLS interpretive criteria, no conclusions could be made concerning the susceptibility of penicillin-intermediate and -resistant strains to the other study drugs. All beta-lactam antibiotics, erythromycin and trimethoprim-sulphamethoxazole were less active against penicillin-resistant strains, indicating that these may be suboptimal agents for empirical therapy for suspected S. pneumoniae infections in these patient populations. However, levofloxacin, ofloxacin, clindamycin and vancomycin were equally active against penicillin-susceptible and -resistant strains. These data suggest that the efficacy of levofloxacin should be examined in both adult and paediatric S. pneumoniae infections involving body sites where levofloxacin concentrations > 2 mg/L can be achieved safely. (+info)
Susceptibilities of Streptococcus pneumoniae and Haemophilus influenzae to 10 oral antimicrobial agents based on pharmacodynamic parameters: 1997 U.S. Surveillance study.
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The susceptibilities of Streptococcus pneumoniae (1,476 strains) and untypeable Haemophilus influenzae (1,676 strains) to various oral beta-lactam, macrolide-azalide, and fluoroquinolone antimicrobial agents were determined by broth microdilution. Organisms were isolated from specimens obtained from outpatients in six geographic regions of the United States. MIC data were interpreted according to pharmacodynamically derived breakpoints applicable to the oral agents tested. Among H. influenzae strains, 41.6% were beta-lactamase positive. Virtually all H. influenzae strains were susceptible to amoxicillin-clavulanate (98%), cefixime (100%), and ciprofloxacin (100%), while 78% were susceptible to cefuroxime, 57% were susceptible to amoxicillin, 14% were susceptible to cefprozil, 9% were susceptible to loracarbef, 2% were susceptible to cefaclor, and 0% were susceptible to azithromycin and clarithromycin. Among S. pneumoniae isolates, 49.6% were penicillin susceptible, 17.9% were intermediate, and 32.5% were penicillin resistant, with penicillin MICs for 50 and 90% of the isolates tested of 0.12 and 4 microg/ml, respectively. Overall, 94% of S. pneumoniae isolates were susceptible to amoxicillin and amoxicillin-clavulanate, 69% were susceptible to azithromycin and clarithromycin, 63% were susceptible to cefprozil and cefuroxime, 52% were susceptible to cefixime, 22% were susceptible to cefaclor, and 11% were susceptible to loracarbef. Although ciprofloxacin has marginal activity against S. pneumoniae, no high-level fluoroquinolone-resistant strains were found. Significant cross-resistance was found between penicillin and macrolides-azalides among S. pneumoniae isolates, with 5% of the penicillin-susceptible strains being macrolide-azalide resistant, compared with 37% of the intermediate isolates and 66% of the resistant isolates. Resistance was highest in S. pneumoniae isolates from patients younger than 10 years of age, middle ear and paranasal sinus specimens, and the southern half of the United States. With the continuing rise in resistance, judicious use of oral antimicrobial agents is necessary in all age groups. (+info)
In vitro antibacterial activity of LJC 11,036, an active metabolite of L-084, a new oral carbapenem antibiotic with potent antipneumococcal activity.
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LJC 11,036 is the active metabolite of L-084, a novel oral carbapenem that exhibits potent broad-spectrum activity. Antibacterial activities of LJC 11,036 against clinical isolates from respiratory infections, such as Streptococcus pneumoniae (n = 52), Streptococcus pyogenes (n = 19), Haemophilus influenzae (n = 50), Klebsiella pneumoniae (n = 53), and Moraxella catarrhalis (n = 53), and from urinary-tract infections, such as Escherichia coli (n = 53) (MICs at which 90% of the isolates were inhibited [MIC(90)s], 0.1, +info)
Effects of naloxone on l-clausenamide-induced long-term potentiation in dentate gyrus of anesthetized rats.
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AIM: To investigate the mechanisms of l-clausenamide-induced long-term potentiation (LTP) in the dentate gyrus of anesthetized rats. METHODS: Extracellular recording technique was used to record the population spike (PS) in the dentate gyrus of anesthetized rats. RESULTS: I.c.v. injection of naloxone 1 nmol, affecting neither the basal PS amplitude nor the LTP induced by tetanus, reduced the l-clausenamide-potentiated LTP only when it was administrated prior to clausenamide. Naloxone 1 nmol (i.c.v.), administrated 10 min before l-clausenamide, reduced the PS amplitude at 20 min, 55 min, and 90 min after i.c.v. injection of l-clausenamide 4 nmol from 138% +/- 10%, 170% +/- 10%, and 169% +/- 12% to 111% +/- 7%, 124% +/- 14%, and 123% +/- 11%, respectively. All P < 0.01 (n = 8). The same dose of naloxone (i.c.v.), delivered 10 min after l-clausenamide, did not affect the l-clausenamide-induced potentiation. CONCLUSION: The activation of opioid receptors contributes to the induction of l-clausenamide-induced LTP of synaptic transmission in dentate gyrus of anesthetized rats. (+info)
Effects of 7-nitroindazole on long-term potentiation induced by l-clausenamide and high-frequency stimulation in rat hippocampus in vivo.
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AIM: To study the antagonistic effect of selective neuronal nitric-oxide synthase (nNOS) inhibitor 7-nitroindazole on the long-term potentiation (LTP) induced by l-clausenamide (Cla) in rat hippocampus in vivo. METHODS: Population spike (PS) of evoked potentials was determined by extracellular recording technique in the hippocampal dentate gyrus (DG) of anesthetized rats. RESULTS: 7-Nitroindazole 2 nmol icv blocked the induction of LTP elicited by high-frequency (100 Hz) stimulation or Cla 5 nmol icv (P < 0.01), and L-arginine 225 mg.kg-1 i.p. prevented the action of 7-nitroindazole (P < 0.01). CONCLUSION: Nitric oxide produced by nNOS plays a role in the induction of Cla-induced LTP in hippocampus. (+info)