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Biomedical subjects

A Novelli

Publications and source records attributed to A Novelli.

At least 19 recordsLinked to original sources
PubMed1992

Domoic acid-containing toxic mussels produce neurotoxicity in neuronal cultures through a synergism between excitatory amino acids.

In 1987, an intoxication by cultured mussels produced neurological problems, such as headache, confusion, and loss of memory, particularly severe at times. Neuronal damage was found in the hippocampus and amygdala of four patients. The intoxication was attributed to the presence in mussels of domoic acid, a rare excitatory amino acid acting at the non-NMDA receptor. We now report that a domoic acid-containing mussel extract is more neurotoxic for cultured neurons than purified domoic acid. Moreover, we show that this increase in neurotoxicity is selectively due to domoic acid potentiation of the excitotoxic effect of glutamic acid and aspartic acid present in high concentrations in mussel tissue. We also show that subtoxic concentrations of domoic acid are sufficient to potentiate glutamic acid and aspartic acid neurotoxicity, and we present evidence suggesting that the neurotoxic synergism may occur through a reduction of the voltage-dependent Mg2+ block at the NMDA receptor-associated channel, following activation of non-NMDA receptors by domoic acid. Thus, based on our results, we suggest that the contemporary presence in the brain of concentrations of domoic acid insufficient alone to be toxic, together with excitatory amino acids, of endogenous and eventually of diet-related origin, may have been relevant in the occurrence of the neurological problems reported.

Amino Acids↗
PubMed1992

Pharmacokinetic drug interactions of macrolides.

The macrolide antibiotics include natural members, prodrugs and semisynthetic derivatives. These drugs are indicated in a variety of infections and are often combined with other drug therapies, thus creating the potential for pharmacokinetic interactions. Macrolides can both inhibit drug metabolism in the liver by complex formation and inactivation of microsomal drug oxidising enzymes and also interfere with microorganisms of the enteric flora through their antibiotic effects. Over the past 20 years, a number of reports have incriminated macrolides as a potential source of clinically severe drug interactions. However, differences have been found between the various macrolides in this regard and not all macrolides are responsible for drug interactions. With the recent advent of many semisynthetic macrolide antibiotics it is now evident that they may be classified into 3 different groups in causing drug interactions. The first group (e.g. troleandomycin, erythromycins) are those prone to forming nitrosoalkanes and the consequent formation of inactive cytochrome P450-metabolite complexes. The second group (e.g. josamycin, flurithromycin, roxithromycin, clarithromycin, miocamycin and midecamycin) form complexes to a lesser extent and rarely produce drug interactions. The last group (e.g. spiramycin, rokitamycin, dirithromycin and azithromycin) do not inactivate cytochrome P450 and are unable to modify the pharmacokinetics of other compounds. It appears that 2 structural factors are important for a macrolide antibiotic to lead to the induction of cytochrome P450 and the formation in vivo or in vitro of an inhibitory cytochrome P450-iron-nitrosoalkane metabolite complex: the presence in the macrolide molecules of a non-hindered readily accessible N-dimethylamino group and the hydrophobic character of the drug. Troleandomycin ranks first as a potent inhibitor of microsomal liver enzymes, causing a significant decrease of the metabolism of methylprednisolone, theophylline, carbamazepine, phenazone (antipyrine) and triazolam. Troleandomycin can cause ergotism in patients receiving ergot alkaloids and cholestatic jaundice in those taking oral contraceptives. Erythromycin and its different prodrugs appear to be less potent inhibitors of drug metabolism. Case reports and controlled studies have, however, shown that erythromycins may interact with theophylline, carbamazepine, methylprednisolone, warfarin, cyclosporin, triazolam, midazolam, alfentanil, disopyramide and bromocriptine, decreasing drug clearance. The bioavailability of digoxin appears also to be increased by erythromycin in patients excreting high amounts of reduced digoxin metabolites, probably due to destruction of enteric flora responsible for the formation of these compounds. These incriminated macrolide antibiotics should not be administered concomitantly with other drugs known to be affected metabolically by them, or at the very least, combined administration should be carried out only with careful patient monitoring.(ABSTRACT TRUNCATED AT 400 WORDS)

Anti-Bacterial Agents↗
PubMed1992

Teicoplanin--its role as systemic therapy of burn infections and as prophylaxis for orthopaedic surgery. Italian Study Groups for Antimicrobial Prophylaxis in Orthopaedic Surgery and Burns.

Two randomized studies have been initiated to establish the role of teicoplanin as systemic therapy for infections in burns patients and as short-term prophylaxis for orthopaedic implant surgery. Opportunistic micro-organisms causing infections in burn patients are often acquired in hospital. These infections commonly involve Gram-positive organisms which may be resistant to several antibiotics. Teicoplanin, alone and in combination with additional antibacterial drugs, is effective in the treatment of Gram-positive infections of various types. In addition, teicoplanin has proved useful as prophylaxis against infection in orthopaedic surgery. Deep prosthetic infections are very difficult to cure without removing the infected device; the outcome can be devastating, such as total loss of joint function, amputation, and, occasionally, death. Preliminary results from the two studies are encouraging and show that teicoplanin has a role to play both in treatment of infection and as prophylaxis against hospital-acquired infection.

Adult↗
PubMed1991

Assembly of adenovirus type 2 fiber synthesized in cell-free translation system.

Physicochemical and functional analyses of the translation products of fiber mRNA in rabbit reticulocyte lysate suggested that fiber polypeptide chains (monomers) were capable of self-assembling in vitro, forming trimeric fibers (trimers) without direct intervention of any other adenovirus-coded protein or cell nuclear matrix component. Kinetic studies showed that trimer formation occurred at a rate six times lower than that of fiber polypeptide synthesis. Fiber assembly was found to be relatively inefficient in vitro, with only 25-30% fiber polypeptides trimerized after 4-h translation reaction. The rate constant for fiber subunit assembly, extrapolated from the kinetic curves of trimer formation, was found to be in the order of magnitude of 10(5) M-1 s-1, with a t 1/2 of 1.3 h at 30 degrees C. A latence phase of approximately 40 min in the appearance of the first detectable trimers indicated that fiber assembly did not occur co-translationally, suggesting the existence of rate-limiting intermediate step(s) during assembly.

Adenoviruses, Human↗
PubMed1991

The marine toxin okadaic acid is a potent neurotoxin for cultured cerebellar neurons.

The tumor promoter okadaic acid (OKA), is a marine toxin of algal origin, identified as a potent inhibitor of protein phosphatases 1 and 2A, and possibly enhancing calcium influx through voltage dependent calcium channels (VSSC). We now report that OKA at concentrations as low as 0.5 nM produced neurotoxicity, characterized first by the desintegration of the neurites and swelling of cell bodies, and later by cellular death. Non-neuronal cells viability and morphology were unaffected up to at least 5 nM OKA. Neurons sensitivity to the toxin changed with age in culture. Maximum neurotoxicity was observed in neurons at 9 DIC, when the OKA concentration producing half of the maximum reduction in neuronal survival (EC50) was approximately 0.65 nM. At 5 DIC or 19 DIC (EC50 approximately 2.5 nM and approximately 4.5 nM respectively), neurons appeared to be less sensitive to OKA. Neurotoxicity by OKA was not reduced by VSCC antagonists such as nifedipine and verapamil, nor by antagonists of excitatory aminoacid (EAA) receptors including APV, MK801 or CNQX. VSCC antagonists and EAA receptors antagonists fully protected from neurotoxicity induced by depolarization with KCl. These results suggest that OKA mechanism of neurotoxicity may not directly involve VSCC, endogenous EAA release and EAA receptors, but may depend upon other neurochemical events.

Animals↗
PubMed1991

Deletion analysis of functional domains in baculovirus-expressed adenovirus type 2 fiber.

Various forms of Ad2 fiber were expressed in insect cells using recombinant baculoviruses and phenotypically characterized with respect to the following properties: trimerization, binding to penton base, nuclear targeting, and glycosylation. The morphology and dimensions of full-length fiber produced by invertebrate cells were indistinguishable from those observed in extracts from lytically infected mammalian cells. The domain required for trimer formation was mapped to the C-terminus, between amino acids 541 and 582. The N-terminal domain, between amino acids 1 and 16, negatively influenced the trimerization efficiency. Fiber gene products reduced to the shaft portion of the fiber capsomer formed significant amounts of stable dimers. Recognition with penton base only occurred with trimeric forms of fiber and was apparently not affected by deletion of the first 60 amino acids from the N-terminus. Fiber deleted of the Met1-Gly60 sequence was found to localize within the nucleus at levels similar to those of full-length fiber. All recombinant fibers, including tail-and-know-deleted forms, were found to be glycosylated using three separate assays, (i) in vivo labeling with [3H]glucosamine, (ii) binding to WGA, and (iii) reaction with monoclonal antibody RL2 directed against O-GlcNAc-containing glycopeptide. This implied that Ad2 fiber is a substrate for GlcNAc O-seryl transferase in insect cell cytoplasm and that at least one major glycosylation site is located in the shaft domain, between Met61 and Asn410.

Adenoviruses, Human↗
PubMed1991

Systemic absorption of 3H-fenticonazole after vaginal administration of 1 gram in patients.

Fourteen women, five with normal cervicovaginal mucosa (Group 1), five with cervical carcinoma (Group 2) and four with relapsing vulvovaginal candidiasis (Group 3) were enrolled and completed this open clinical trial. Each subject received a single dose of 1.82 +/- 0.3 g on average of vaginal paste (for ovules) containing about 1000 mg of 3H-fenticonazole nitrate (266 microCi). Twelve hours after vaginal administration, the paste was removed by vaginal washing. Blood, urine and stool samples were collected at specified time intervals for five days. Plasma, urine, stools and all used material in contact with the paste were assayed for radioactivity. No measurable levels of radioactivity were detected in plasma of subjects of Groups 1 and 3 while in 4 of the 5 subjects with cervical carcinoma (Group 2) fenticonazole was detected during the 24 h after administration with a peak level at about 8 hours. For a period of 5 days, 0.4-1.5% of the dose on average was recovered from urine, and 0.18-0.32% from feces. Based on the excretion data, the extent of vaginal absorption of fenticonazole nitrate in women with vulvovaginal candidiasis was 1.81 +/- 0.57% of the dose, while in women with normal cervicovaginal mucosa it accounted for 0.58 +/- 0.28% of the administered dose. In patients with cervical carcinoma, absorption was 1.12 +/- 0.53%. The maximum amount absorbed corresponds to an exposure of about 0.4 mg/kg of fenticonazole nitrate (for a subject weighing 50 kg). Consequently, the vaginal administration of one ovule containing 1000 mg of fenticonazole nitrate seems to be devoid of risk for patients.

Absorption↗
PubMed1991

Tissue distribution of cefotetan in patients with Crohn's disease.

Concentrations of cefotetan in the intestinal wall of patients with Crohn's disease were investigated with the method of tissue homogenates with the aim to evaluate the effects of inflammation on tissue distribution. Twenty-four patients who underwent surgery were treated with a 2-gram single dose of cefotetan intravenously before the operation. The mean tissue levels in inflamed intestinal wall were constantly higher than in normal wall, but the difference was statistically significant only in samples taken more than 2 h after cefotetan administration (31.0 +/- 17.8 vs 14.7 +/- 11.4 mg/kg; p less than 0.05). The mean residence time was 284.3 min for inflamed tissue and 123.9 min for normal. The areas under the curve were significantly higher in inflamed wall than in normal, with mean values of 4,789 and 3,020.2 mg/l.h, respectively (p less than 0.05). Inflammation seems to facilitate the penetration of cefotetan into the intestinal wall of patients with Crohn's disease but above all, it increases the mean residence time in inflamed tissue.

Adult↗
PubMed1990

Efficacy and tolerance of cefpodoxime proxetil compared with co-amoxiclav in the treatment of exacerbations of chronic bronchitis.

This European, multicentre trial evaluated the efficacy and tolerance of cefpodoxime proxetil in comparison with co-amoxiclav (amoxycillin plus clavulanic acid) in the treatment of acute exacerbations of chronic bronchitis. The study design was double-blind and double-placebo controlled. Doses of either 200 mg bd of cefpodoxime proxetil or 500 mg/125 mg tds amoxycillin plus clavulanic acid were given orally for 9.6 +/- 1.8 days. Two hundred and fifty-one patients were enrolled in 27 centres in West Germany, France, and Italy. The overall clinical efficacy was 97.2% in the cefpodoxime proxetil group compared with 94.7% in the co-amoxiclav group. Fifty-eight adverse events, mainly gastrointestinal, occurred in 42 patients with no significant difference between the groups. A significant difference in the number of resistant pathogens on pre-treatment culture to the advantage of cefpodoxime was noted. In our experience, both drugs were of similar value in the treatment of respiratory tract infections. Thus, cefpodoxime proxetil should be an effective antibiotic for the treatment of acute exacerbations of chronic bronchitis.

Adult↗
PubMed1990

Excitatory amino acids toxicity in cerebellar granule cells in primary culture.

Primary cultures of cerebellar granule cells represent a valuable neuronal system for the study of the physiology, biochemistry and toxicology of excitatory amino acids. Using this system, we now report the characterization of the biochemical and toxicological action of a toxic mussels extract, containing the excitatory amino acid domoic acid. The results obtained using toxic mussels extract, non-toxic mussels extract and purified domoic acid, provide evidence for a synergistic action of domoic acid with other potentially neurotoxic excitatory amino acids, normally present in mussels.

Amino Acids↗
PubMed1989

Comparative in vitro activity of the new oxazolidinones DuP 721 and DuP 105 against staphylococci and streptococci.

The in vitro activity of DuP 721 and DuP 105, two orally active members of the oxazolidinones, was compared with that of glycopeptides and ciprofloxacin against 185 gram-positive isolates. Ninety percent of Staphylococcus aureus isolates, including penicillin- and methicillin-resistant strains, were inhibited by DuP 721 at 1 micrograms/ml and by DuP 105 at 16 micrograms/ml; DuP 721 inhibited 90% of coagulase-negative staphylococci tested at 1 micrograms/ml. The MIC90 for Streptococcus faecalis was 4 micrograms/ml with DuP 721 and 16 micrograms/ml with DuP 105; DuP 721 inhibited 90% of beta-hemolytic streptococci of group A at 0.5 micrograms/ml. Similar results on selected strains were obtained by continuously recording the optical density of cultures.

Anti-Bacterial Agents↗
PubMed1989

Developmental induction of glutaminase in primary cultures of cerebellar granule cells.

Glutaminase mRNA levels increased over 3-fold relative to total RNA, poly(A)+ RNA, and beta-actin mRNA in neonatal rat cerebellar granule cells as the cells differentiated between days 3 and 8 in culture. In contrast, mRNA levels of another glutamate cycle enzyme, glutamine synthetase, remained constant. Glutaminase protein levels increased per cell more than 2-fold between days 3 and 8, and at least 3-fold by day 10 in these cells. The total amount of glutamate per cell increased about 40% during this period. Glutaminase induction paralleled the development of Ca2+-dependent glutamate release, and the formation of neurites, synaptic vesicles, and synapses. The induction of glutaminase in developing granule cells is consistent with a special role for glutaminase in the synthesis of neurotransmitter glutamate.

Animals↗
PubMed1989

Neurotoxicity at the N-methyl-D-aspartate receptor in energy-compromised neurons. An hypothesis for cell death in aging and disease.

Our results demonstrated that the neurotoxicity of glutamate and closely related agonists was mediated by the NMDA receptor in rat cerebellar granule cells. Evidence was presented to support our hypothesis that the pivotal event in the transition of these EAAs from neurotransmitters to neurotoxins is relief of the voltage-dependent Mg++ block of the NMDA channel due to changes in membrane potential which can be caused by depletion of highly phosphorylated nucleotides or by other depolarizing stimuli. Persistent stimulation of NMDA receptors whose channels are unblocked by Mg++ can permit excessive influx of Na+ and Ca++ and neuronal death can follow by a mechanism not yet understood. Glutamate is not toxic at kainate receptors although they are present on these cells. These findings underline the potential importance of perturbations in energy metabolism in a variety of neurodegenerative disorders and in the normal process of aging which share the common feature of the loss of neurons.

Aging↗
PubMed1989

In vitro activity and beta-lactamase stability of a new carbapenem, SM-7338.

SM-7338, a new carbapenem, inhibited most members of the family Enterobacteriaceae at MICs of 0.015 to 0.25 microgram/ml, including Klebsiella oxytoca, Citrobacter freundii, Enterobacter cloacae, and Proteus vulgaris isolates resistant to cefotaxime, ceftazidime, piperacillin, and gentamicin. It was two- to eightfold more active than imipenem, but it inhibited Pseudomonas aeruginosa at 1 to 8 micrograms/ml, which was comparable to the activity of imipenem. Haemophilus, Neisseria, and Branhamella species were inhibited by less than or equal to 0.25 microgram/ml, which was superior to the activity of imipenem. SM-7338 inhibited Staphylococcus aureus and coagulase-negative staphylococci at 0.25 microgram/ml, but for methicillin-resistant isolates MICs were 4 to 16 micrograms/ml. Group A, B, and C streptococci and Streptococcus pneumoniae were inhibited by less than or equal to 0.03 microgram/ml. Bacteroides species, including clindamycin-resistant isolates, were inhibited by 0.25 microgram/ml. There was no major inoculum size effect, and the MBCs were within a dilution of the MICs. SM-7338 was more active than imipenem at an acid pH under anaerobic conditions. Plasmid beta-lactamases of TEM-1, TEM-2, TEM-3, TEM-5, SHV-1, SHV-2, PSE-1, PSE-2, PSE-3, OXA-2, OXA-3, OXA-4, OXA-5, and OXA-7; Staphylococcus aureus enzymes; and the chromosomal beta-lactamases P-99 and K-1; Morganella species; and Proteus vulgaris did not hydrolyze SM-7338. The repeated transfer of organisms increased the MICs of SM-7338, as it did the MICs of imipenem.

Anti-Bacterial Agents↗
PubMed1989

Comparative in vitro activity of a new quinolone, AM-1091.

The in vitro activity of a new quinolone, AM-1091 [7-(3-amino-1-pyrrolidinyl)-8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro- 4-oxo- 3-quinoline carboxylic acid hydrochloride], was compared with those of ciprofloxacin, ofloxacin, beta-lactams, and gentamicin. AM-1091 inhibited 90% of the isolates of the family Enterobacteriaceae at less than or equal to 0.12 micrograms/ml. For many species AM-1091 was 2-fold more active than ciprofloxacin and 2- to 32-fold more active than ofloxacin. It inhibited Enterobacter, Citrobacter, and Klebsiella species resistant to ceftazidime and gentamicin. Ninety percent of Pseudomonas aeruginosa isolates were inhibited by 0.5 micrograms/ml, so for this species AM-1091 was twofold less active than ciprofloxacin. AM-1091 was more active against Pseudomonas cepacia and Xanthomonas maltophilia, inhibiting isolates resistant to imipenem and gentamicin. Most Haemophilus influenzae, Neisseria gonorrhoeae, Neisseria meningitidis, and Branhamella catarrhalis isolates were inhibited by less than or equal to 0.06 micrograms/ml. The MICs for 90% of Staphylococcus aureus, Staphylococcus epidermidis, and Enterococcus faecalis isolates were 0.06, 0.06, and 2 micrograms/ml, respectively. AM-1091 inhibited hemolytic streptococci and Streptococcus pneumoniae at 0.25 micrograms/ml and was more active than ciprofloxacin or ofloxacin against gram-positive species. AM-1091 inhibited 90% of the Bacteroides species at 0.5 micrograms/ml. The frequency of spontaneous resistance was less than 10(-10) for most organisms, but resistant strains could be selected by repeated subculturing. Although AM-1091 had lower in vitro activity at pH 5.5 and in the presence of high concentrations of Mg2+, it still inhibited most organisms at </= 0.5 micrograms/ml under these conditions. AM-1091 rapidly killed Escherichia coli and P. aeruginosa and had a prolonged postantibiotic suppressive effect on these bacteria.

4-Quinolones↗
PubMed1989

Clinical pharmacokinetic properties of the macrolide antibiotics. Effects of age and various pathophysiological states (Part I).

The pharmacokinetic aspects in humans of macrolide antibiotics that are currently or soon to be on the market (i.e. erythromycin, oleandomycin, spiramycin, josamycin, midecamycin, miocamycin, rosaramycin, roxithromycin and azithromycin) are reviewed. Macrolide antibiotics are basic compounds, poorly soluble in water, which are mostly absorbed in the alkaline intestinal environment. They are acid unstable, but the newer semisynthetic derivatives (i.e. roxithromycin and azithromycin) are characterised by increased stability under acidic conditions. Macrolides are highly liposoluble and consequently penetrate well into tissue, especially bronchial secretions, prostatic tissue, middle ear exudates and bone tissues, as evidenced by tissue/serum concentration ratios greater than 1. They do not penetrate well into the CSF. Macrolides undergo extensive biotransformation in the liver. With a few exceptions (e.g. miocamycin), the metabolites of these drugs are characterised by little or no antimicrobial activity. Plasma protein binding is variable from one compound to another. At therapeutic concentrations, protein-bound erythromycin accounts for 80 to 90% of the total drug present in the blood, and the fraction is 95% for roxithromycin. The lowest values of protein-bound fraction are observed for midecamycin and josamycin (about 15%), and intermediate values are reported for spiramycin and miocamycin. However, the clinical relevance of this parameter is not clearly established. Plasma half-life (t1/2) values vary for the macrolides described: erythromycin, oleandomycin, josamycin and miocamycin have a t1/2 ranging from 1 to 2 hours; spiramycin, erythromycin stearate, the mercaptosuccinate salt of propionyl erythromycin and rosaramicin have an intermediate t1/2 (about 7, 6.5, 5 and 4.5 hours, respectively); the newer semisynthetic compounds roxithromycin and azithromycin are characterised by high t1/2 values (i.e. 11 and 41 hours, respectively). Under normal conditions, the major route of elimination is the liver. Renal elimination also takes place but it contributes to total clearance only to a small degree, as evidenced by low renal clearance values. The degree of modification of macrolide pharmacokinetics by renal insufficiency or hepatic disease is usually not considered clinically relevant, and no recommendation for dose modification is necessary in these patients. The pharmacokinetics of macrolides are modified in elderly patients. Accordingly, their use must be accompanied by a closer than usual clinical monitoring of the older patient.(ABSTRACT TRUNCATED AT 400 WORDS)

Aging↗