Biomedical subjects

C Carbon

Publications and source records attributed to C Carbon.

At least 55 records · Page 3Linked to original sources

PubMed2000

Chronic nifedipine dosing enhances cephalexin bioavailability and intestinal absorption in conscious rats.

Cephalexin, a beta-lactam antibiotic, is rapidly absorbed via the di-and tripeptide intestinal transporters, as for many peptidomimetic drugs. Acute nifedipine has been shown to increase intestinal absorption of several beta-lactams: amoxicillin and cefixime in humans, and cephalexin in the rat. We showed previously that the nervous system was involved in the increasing effect of nifedipine on cephalexin intestinal absorption in anesthetized rats. The aim of the present study was 2-fold: 1) to investigate whether the effect of nifedipine is maintained in conscious rats, and 2) to determine whether the nifedipine effect will persist during chronic nifedipine administration. Acute and chronic oral administration of nifedipine significantly increased oral cephalexin area under the plasma concentration-time curve (34 and 25%, respectively) and maximum concentration in plasma (57 and 51%, respectively), while the distribution and elimination parameters of intra-arterial cephalexin were not affected by acute or chronic nifedipine administration. In conclusion, acute nifedipine effect on intestinal absorption of cephalexin is independent of anesthesia in rats. Since nifedipine could still enhance cephalexin intestinal absorption after a 7-day b.i.d. treatment, it can be envisaged to apply this effect to increase bioavailability of poorly absorbed peptidomimetic drugs in man.

Animals↗

PubMed1999

Nebulized cyclosporine in the rat: assessment of regional lung and extrapulmonary deposition.

BACKGROUND: Nebulized cyclosporine (CsA) has been shown to limit lung allograft rejection as well as intramuscular (IM) CsA, with limited blood diffusion. The present study determined the pharmacokinetic parameters of nebulized CsA, by the assessment of regional lung deposition and extrapulmonary diffusion of CsA. METHODS: CsA was given either by IM injection (10 mg/kg) or by aerosol (at 10 and 25 mg/kg doses); 70 rats were killed at 25 and 50 min, and at 2, 4, 6, 8, 12, 24, or 48 hr after CsA administration. CsA levels were measured in the whole lung, in central and peripheral parts of the lung, in whole blood, kidney, and heart. The areas under the concentration time curves (AUCs) were determined. RESULTS: In blood, kidney, and heart, CsA levels were significantly higher for IM than for aerosol administrations at 10 and 25 mg/kg doses. In the whole lung, the AUC was greater for the aerosol route at 25 mg/kg doses (588 ng x hr/mg) than for the low-dose (200 ng x hr/mg) or IM administration (200 ng x hr/mg). The central to peripheral index of CsA (ratio of AUC central/peripheral part of the lung) was not significantly different for both aerosol administrations (0.63 and 0.69, respectively) and for the IM route (0.81). CONCLUSIONS: Nebulized CsA allows better pulmonary concentration than IM administration, with equivalent central and peripheral deposition whatever the mode of administration, and results in lower levels in blood, kidney, and heart.

Administration, Intranasal↗

PubMed1999

[Development of pharmaco-epidemiology in France].

A new scientific discipline: Progress in scientific knowledge, advances in therapeutic innovation, the development of new drugs and the continuing need for optimal drug use impose a new approach to the rational assessment of public health needs and the risks and benefits of therapeutic intervention. In the near future, a new scientific discipline, pharmaceutical epidemiology, will play a leading role. France seems to be a bit behind other western countries in this area. Goal setting: The objectives of industrial firms do not necessarily cover all aspects of the overall goals of society. If the scientific community leaves the development and implementation of pharmaceutical epidemiology in the hands of industrial firms alone, they risk seeing its field of action limited to industrial objectives. The goals of this new discipline must be defined within an unbiased framework aimed at meeting the needs of society in general. Organization: The development of pharmaceutical epidemiology as an integral part of medical research requires a clear definition of its objectives, methods, working hypotheses and time and human allocations. In this context, pharmaceutical epidemiology should be organized within the University and scientific settings currently contributing to scientific research in France (INSERM, CNRS, ORSTOM, etc.). Creating favorable conditions: A pharmaceutical epidemiology network with adequate human and material resources is needed. The wide range of needs expressed by existing institutions (Drug Agency, Prescription and Drug Use Observatory, industrial firms, the national health insurance system, physician and pharmacist associations) pleads for a nationally organized project working in the public domain.

Drug Prescriptions↗

PubMed1999

Influence of socioeconomic status on features and outcome of community-acquired pneumonia.

The influence of socioeconomic status on the features and evolution of community-acquired pneumonia in 107 consecutive hospitalized patients was investigated. Thirty-four (31.8%) patients were considered to have a low socioeconomic status. These patients were more likely immigrants, middle-aged, with fewer comorbid illnesses, and were more often tobacco, alcohol, or drug consumers (P<0.01). The distribution of etiologies was significantly different according to socioeconomic status, with tuberculosis occurring more frequently in the low socioeconomic group (P < 0.05). Low socioeconomic status was not associated with a more severe presentation or outcome of pneumonia but was an independent factor that predicted a significantly longer length of hospitalization (5.9 days longer; 95% confidence interval, 2.2-9.5 days; P<0.003), entailing a substantial excess cost per hospital stay.

Adult↗

PubMed1999

Active intestinal elimination of ciprofloxacin in rats: modulation by different substrates.

1. Two in vivo models, in the rat, were used to investigate, in the presence of different substrates, the overall and net intestinal elimination of ciprofloxacin: an open-intestinal perfusion model and an intestinal loop model respectively. 2. In the presence of quinidine, verapamil and cyclosporin (substrates of the P-glycoprotein (P-gp)), plasma AUCs of ciprofloxacin were 1.5 - 2 fold increased, while biliary clearance (1.5 - 2 fold), intestinal overall and net clearances (2 - 4 fold and 1.5 - 8 fold respectively) decreased. The weak effect obtained with cyclosporin as compared to verapamil and especially quinidine, suggests, for ciprofloxacin, the existence of transport systems distinct from the P-gp, as the OCT1 transporter which could be inhibited by quinidine. 3. With cephalexin and azlocillin, two beta-lactam antibiotics, plasma AUCs of ciprofloxacin increased and biliary and intestinal overall clearances decreased in a similar fashion (1.3 - 2 fold), suggesting the involvement of organic anion and/or cation transporters. 4. In the presence of structural analogues, the effect was dependent on the compound administered: Sparfloxacin had no effect on intestinal clearance of ciprofloxacin. In contrast, with pefloxacin, overall intestinal clearance of ciprofloxacin was decreased and net intestinal clearance increased. 5. The specificity of ciprofloxacin intestinal transport appears to be different from P-gp as outlined by the lack of competition with sparfloxacin, a P-gp substrate. Ciprofloxacin intestinal elimination seems to be mediated by organic anion and/or cation transporters and a mechanism sensitive to quinidine and verapamil.

Animals↗

PubMed1999

Prosthetic joint infection: when can prosthesis salvage be considered?

Management of prosthetic joint infection (PJI) remains a therapeutic challenge. We retrospectively studied 69 infected total hip or knee arthroplasties managed between 1980 and 1996 in our institution. Treatment failure, defined as relapse of PJI in the first year following the last antimicrobial treatment, occurred for 14 patients (20.3%). None of the potentially contributive parameters analyzed was significantly predictive of treatment failure. Of the subgroup of 34 patients with PJI who initially underwent debridement with retention of the prosthesis, the 13 (38.2%) who did not require further surgical treatment had symptoms for a significantly shorter duration before debridement (4.85 vs. 54.24 days; P < .0001). Because debridement with retention of the prosthesis rarely enables control of PJI, this therapeutic approach should be considered only when the duration of symptoms is very short.

Adult↗

PubMed1999

Levofloxacin: serum bactericidal activity against methicillin-resistant Staphylococcus aureus isolates.

The aim of this study was to assess the serum bactericidal activity (SBA) of levofloxacin compared with that of ofloxacin against methicillin-resistant Staphylococcus aureus (MRSA) isolates. Serum from 10 healthy volunteers (seven females, three males) was collected after a single oral dose of either levofloxacin (500 mg) or ofloxacin (400 mg). Subjects were allocated randomly to treatment after at least a 1 week interval between antibiotic regimens. Three well-defined MRSA strains were tested, each susceptible to levofloxacin and ofloxacin, with different levels of resistance to methicillin (HBD 456, HBD 3 and HBD 2; class 1, 2 and 3 Tomasz heterogeneous resistance, respectively) together with a methicillin-susceptible (MSSA) reference strain (S. aureus ATCC 25,923). SBA was tested in vitro by a microtitration method 15 min before dosing and at 1, 4, 8 and 12 h after drug absorption. Levofloxacin was significantly more bactericidal than ofloxacin against all strains of S. aureus tested (SBA > or = 1:2). An SBA was recorded for only a short period with ofloxacin, and thereafter only bacteriostatic activity remained. This study, therefore, confirms the superior activity of levofloxacin over that of ofloxacin against MSSA and MRSA.

Anti-Infective Agents↗

PubMed1999

Costs of treating infections caused by methicillin-resistant staphylococci and vancomycin-resistant enterococci.

Infection with methicillin-resistant Staphylococcus aureus (MRSA) or vancomycin-resistant Enterococcus faecium (VREF) increases the risk of mortality and results in prolonged hospitalization and high utilization of costly treatment modalities. Measures to prevent the spread of MRSA (and possibly VREF) include patient isolation and decontamination, hygiene measures, ward closure, and screening of patients and staff for carriage. In seriously ill patients, the increased use of vancomycin for the treatment of MRSA can lead to the emergence of VREF colonization/infection. Quinupristin/dalfopristin is effective in the treatment of MRSA infections, including nosocomial pneumonia, skin and soft tissue infection, and septicaemia. In the treatment of nosocomial pneumonia, clinical success rates were equivalent between quinupristin/dalfopristin and vancomycin. In the context of a hospital policy which emphasizes effective hygiene measures and the prudent use of antibacterials, quinupristin/dalfopristin is an effective antimicrobial that can help to control the high costs associated with multiresistant MRSA and VREF infections.

Enterococcus faecium↗

PubMed1999

Activity and diffusion of LY333328 in experimental endocarditis due to vancomycin-resistant Enterococcus faecalis.

The activity of LY333328 against Enterococcus faecalis JH2-2, which is susceptible to glycopeptides, and against its transconjugants E. faecalis BM4281 and BM4316, with VanB and VanA phenotypes, respectively, was investigated. LY333328 was active in vitro against the three strains, for which MICs were 2 microg/ml on agar and 0.25 microg/ml in broth. LY333328 was bactericidal in broth against E. faecalis JH2-2 and BM4281 at a concentration of 8 microg/ml and against BM4316 at a concentration of 30 microg/ml. The protein binding of LY333328 to rabbit serum was >99%, and the bactericidal activity of LY333328 in broth was reduced when it was tested in the presence of 90% rabbit serum. Autoradiographic studies performed in rabbits with enterococcal endocarditis showed that 14[C]LY333328 was distributed heterogeneously throughout cardiac vegetations. In rabbits with aortic endocarditis, a regimen of 20 mg of LY333328 per kg of body weight administered intramuscularly twice a day for 5 days after a loading dose of 40 mg/kg was active against the three strains in vivo (P < 0.01), whereas vancomycin was not active against the VanB-type strain and teicoplanin was not active against the VanA-type strain. We conclude that the activity of LY333328 is not significantly modified by acquired resistance to glycopeptides in E. faecalis either in vitro or in experimental endocarditis.

Animals↗

PubMed1999

Two-step acquisition of resistance to the teicoplanin-gentamicin combination by VanB-type Enterococcus faecalis in vitro and in experimental endocarditis.

The activity of vancomycin and teicoplanin combined with gentamicin was investigated in vitro against strains of Enterococcus faecalis resistant to vancomycin and susceptible to teicoplanin (VanB type) and against mutants that had acquired resistance to teicoplanin by three different mechanisms. In vitro, gentamicin selected mutants with two- to sixfold increases in the level of resistance to this antibiotic at frequencies of 10(-6) to 10(-7). Teicoplanin selected teicoplanin-resistant mutants at similar frequencies. Both mutations were required to abolish the activity of the gentamicin-teicoplanin combination. As expected, simultaneous acquisition of the two types of mutations was not observed. In therapy with gentamicin or teicoplanin alone, each selected mutants in three of seven rabbits with aortic endocarditis due to VanB-type E. faecalis BM4275. The vancomycin-gentamicin combination selected mutants that were resistant to gentamicin and to the combination. In contrast, the teicoplanin-gentamicin regimen prevented the emergence of mutants resistant to one or both components of the combination. These results suggest that two mutations are also required to suppress the in vivo activity of the teicoplanin-gentamicin combination.

Animals↗

PubMed1999

Influence of renal failure on intestinal clearance of ciprofloxacin in rats.

Following intravenous doses, ciprofloxacin pharmacokinetics in control and nephrectomized rats were studied. There were no differences between control and nephrectomized rats for area under the concentration-time curve in plasma or biliary clearance. The intestinal clearance of ciprofloxacin was increased in nephrectomized rats. Intestinal elimination seems to compensate partially for the decrease in urinary excretion of ciprofloxacin in nephrectomized rats.

Animals↗

PubMed1999

In vivo efficacies of combinations of beta-lactams, beta-lactamase inhibitors, and rifampin against Acinetobacter baumannii in a mouse pneumonia model.

The effects of various regimens containing combinations of beta-lactams, beta-lactam inhibitor(s), and rifampin were assessed in a recently described mouse model of Acinetobacter baumannii pneumonia (M. L. Joly-Guillou, M. Wolff, J. J. Pocidalo, F. Walker, and C. Carbon, Antimicrob. Agents Chemother. 41:345-351, 1997). Two aspects of the therapeutic response were studied: the kinetics of the bactericidal effect (treatment was initiated 3 h after intratracheal inoculation, and bacterial counts were determined over a 24-h period) and survival (treatment was initiated 8 h after inoculation, and the cumulative mortality rate was assessed on day 5). Two clinical strains were used: a cephalosporinase-producing strain (SAN-94040) and a multiresistant strain (RCH-69). For SAN-94040 and RCH-69, MICs and MBCs (milligrams per liter) were as follows: ticarcillin, 32, 64, 256, and >256, respectively; ticarcillin-clavulanate, 32, 64, and 512, and >512, respectively; imipenem, 0.5, 0.5, 8, and 32, respectively; sulbactam, 0.5, 0.5, 8, and 8, respectively; and rifampin, 8, 8, 4, and 4, respectively. Against SAN-94040, four regimens, i.e., imipenem, sulbactam, imipenem-rifampin, and ticarcillin-clavulanate (at a 25/1 ratio)-sulbactam produced a true bactericidal effect (>/=3-log10 reduction of CFU/g of lung). The best survival rate (i.e., 93%) was obtained with the combination of ticarcillin-clavulanate-sulbactam, and regimens containing rifampin provided a survival rate of >/=65%. Against RCH-69, only regimens containing rifampin and the combination of imipenem-sulbactam had a true bactericidal effect. The best survival rates (>/=80%) were obtained with regimens containing rifampin and sulbactam. These results suggest that nonclassical combinations of beta-lactams, beta-lactamase inhibitors, and rifampin should be considered for the treatment of nosocomial pneumonia due to A. baumannii.

Acinetobacter↗

PubMed1999

Microbiological and inflammatory effects of murine recombinant interleukin-10 in two models of polymicrobial peritonitis in rats.

A protective effect of interleukin-10 (IL-10) against the development of lethal shock has been demonstrated in various animal models. In contrast, the immunosuppressant properties of this mediator have been minimally evaluated in low-mortality models of infections. The clinical, microbiological, and inflammatory effects of murine recombinant IL-10 (mrIL-10) therapy were evaluated in two models of peritonitis in rats, which differed in the degree of severity of peritoneal inflammation 3 days after inoculation of Escherichia coli and Bacteroides fragilis with or without Enterococcus faecalis. The severity of the disease remained unchanged compared to that in control animals. A dose-related decrease in the peritoneal phagocyte count was observed in the treated groups compared to the counts in control animals. The subsequent experiments were performed exclusively in the mixed gram-positive-gram negative model, which exhibits an intense and prolonged inflammatory response with similar criteria. The early effects of mrIL-10 (evaluated 6 h after inoculation), repeated injections of mrIL-10 (four doses injected from 0 to 9 h after bacterial challenge), and pretreatment (two doses injected 6 and 3 h before inoculation) were evaluated. The clinical and microbiological parameters remained unchanged in the treated animals. Decreases in the peritoneal phagocyte count and the peritoneal concentration of tumor necrosis factor were observed following repeated injections of mrIL-10. In summary, our data suggest that mrIL-10 does not worsen the manifestations of sepsis. However, these results need to be confirmed in clinical practice.

Animals↗

PubMed1999

The role of newer macrolides in the treatment of community-acquired respiratory tract infection. A review of experimental and clinical data.

The macrolide class of antibiotics is well established and often recommended for use in the treatment of community-acquired respiratory tract infection (RTI). The newer agents clarithromycin and azithromycin are frequently prescribed as first- or second-line therapy, and have been considered as superior to erythromycin in microbiological activity and clinical efficacy. In-vitro data show that clarithromycin and azithromycin have good activity (MIC < or = 0.5 microg/ml) against certain RTI pathogens. However the activity of both compounds is intrinsically low against Haemophilus influenzae whilst several other important RTI pathogens - notably Streptococcus pneumoniae and Streptococcus pyogenes - exhibit a high prevalence of resistance to them. In many countries, the prevalence of resistance to clarithromycin and azithromycin is still rising with cross resistance with erythromycin. Maximum serum concentrations of clarithromycin and azithromycin are lower than the MIC90s for these agents against H. influenzae and S. pneumoniae. Concentrations in tissues have been reported to be much higher than those in serum. However, the high concentrations observed in tissues are largely a reflection of high concentrations inside cells. Concentrations of clarithromycin and azithromycin in extracellular tissue fluids, where Haemophilus and streptococci are located, are in equilibrium with concentrations in the serum, and remain low. It has been suggested that phagocytes deliver azithromycin to infection sites in a targeted fashion, but the evidence in support of this hypothesis is weak. Recent clinical experience with clarithromycin and azithromycin is consistent with preclinical results, and suggests that these agents have limited efficacy against certain respiratory infections. Clarithromycin and azithromycin are the first choice treatment of atypical infections caused by intracellular pathogens. For community-acquired RTIs, where H. influenzae and S. pneumoniae are present, they may no longer be an appropriate choice for first-line therapy. Indeed, in areas where levels of drug resistant S. pneumoniae are high, their use may be questionable as second-line therapy.

Anti-Bacterial Agents↗

PubMed1999

What is the place of fluoroquinolones in the treatment of community-acquired respiratory tract infections?

The newest (third generation) fluoroquinolones are potentially useful agents in the management of community-acquired respiratory tract infections. This is mainly due to their increased activity against Streptococcuspneumoniae, a pathogen poorly susceptible to the second-generation compounds, and playing a major role in upper and lower respiratory tract infections. Also, their spectrum includes the other main pathogens involved in those infections, comprising Haemophilus influenzae and intracellular agents, against which the newest fluoroquinolones exhibit a similar activity to that of the previous compounds. The pharmacokinetic and pharmacodynamic properties of the newest quinolones make them suitable for effective therapy of lower respiratory tract infections. However, careful attention should be paid to the dose and dosing regimen of each compound in clinical usage in order to select the most adapted drug. In clinical trials, the fluoroquinolones have been shown to be at least as effective as the comparators in the treatment of community-acquired pneumonia, acute exacerbations of chronic bronchitis (AECB) or sinusitis, including documented pneumococcal infections. Their tolerance is generally considered to be good. The main question regarding the fluoroquinolones in the treatment of community-acquired respiratory tract infections is their role as first-line agents used in single drug therapy. Cost-effectiveness studies are needed to define this role further. Identification of subpopulations of patients at risk of being infected by penicillin-resistant pneumococci or Gram-negative bacilli who could benefit from a fluoroquinolone could be useful. Also, it must be considered that a large use of fluoroquinolones as first-line agents in very common infections such as AECB or sinusitis could contribute to the selection of bacteria, including S. pneumoniae, resistant to this class of antibiotics. Careful control of fluoroquinolone usage and development of bacterial resistance is of great importance.

Anti-Infective Agents↗

PubMed1999

Nodular lesions of the liver revealing multiple myeloma.

Liver involvement in multiple myeloma (MM) has been reported very rarely in living patients. Here we describe a rare case in whom investigation of liver nodules by biopsy, revealed MM. The Role of cytadhesin molecules in the spread of plasma cell neoplasia is discussed and a review of the Literature is given.

Aged↗

PubMed1999

Neural modulation of cephalexin intestinal absorption through the di- and tripeptide brush border transporter of rat jejunum in vivo.

Intestinal absorption of beta-lactamine antibiotics (e.g., cefixime and cephalexin) has been shown to proceed through the dipeptide carrier system. In a previous study, nifedipine (NFP), an L-type calcium channel blocker, enhanced the absorption of cefixime in vivo but not in vitro, and it was suggested that neural mechanisms might be involved in the effect of NFP. The aim of the present study was to assess the involvement of the nervous system on the intestinal absorption of cephalexin (CFX). To investigate this, we used a single-pass jejunal perfusion technique in rats. NFP and diltiazem enhanced approximately 2-fold the plasma levels of CFX in treated rats versus untreated controls. NFP also increased approximately 2-fold the CFX level in portal plasma and increased urinary excretion of CFX, thus indicating that CFX did effectively increase CFX intestinal absorption. Perfusing high concentrations of dipeptides in the jejunal lumen competitively reduced CFX absorption and inhibited the enhancement of CFX absorption produced by NFP. Hexamethonium and lidocaine inhibited the effect of NFP, whereas atropine, capsaicin, clonidine, and isoproterenol enhanced CFX absorption by the same order of magnitude as NFP. Thus, complex neural networks can modulate the function of the intestinal di- and tripeptide transporter. Sympathetic noradrenergic fibers, intestinal sensory neurons, and nicotinic synapses are involved in the increase of CFX absorption produced by NFP.

ATP-Binding Cassette Transporters↗

PubMed1999

[Selection of virulent mutants of Streptococcus pneumoniae. Utilization of a murine model of septicemia].

Genetic construction of virulence deficient mutant is a strategy to analyse virulence genes of Streptococcus pneumoniae and was used to virulence factors as capsule, pneumolysin, autolysin and PspA. We perform a model allowing the in vivo positive selection of virulent S. pneumoniae mutants. Mice which are the most susceptible animals to pneumococcal infection, offer the best model for screening virulent S. pneumoniae. Indeed, after intraperitoneal injection of bacterial mix which was composed to a lot of avirulent bacteria (6 log10 CFU per mouse) (V1015 strain, DL50 = 7.05) and few virulent pneumococci (1 to 2 log10 CFU per mouse) (P4241 strain, DL50 < 1), mice cleared all avirulent bacteria but not virulent pneumococci. Thus, mice dead in 3 to 4 days with septicaemia and positive hemoculture contained only virulent strain. This model was validated by in vivo selection of a virulent mutant (V1042, DL50 = 4.1) which was obtained after transformation of avirulent strain V1015 with the genomic fragment of virulent strain P4241. Our model of screening was the only one allowing detection of virulent S. pneumoniae mutants. This new genetic strategy which consisted in gene addition and used mouse as selection agent, could be used to discover new virulence genes required to in vivo bacterial development.

Animals↗