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El Moukhtar Aliouat - One of the best experts on this subject based on the ideXlab platform.

  • RESEARCH ARTICLE SYTO-13, a Viability Marker as a New Tool to Monitor In Vitro Pharmacodynamic Parameters of Anti-Pneumocystis Drugs
    2016
    Co-Authors: Cécile-marie Aliouat-denis, Anna Martinez, Sara Khalife, Muriel Pottier, Nausicaa Gantois, Eduardo Dei-cas, El Moukhtar Aliouat
    Abstract:

    While Pneumocystis pneumonia (PcP) still impacts the AIDS patients, it has a growing importance in immunosuppressed HIV-negative patients. To determine the anti-Pneumo-cystis therapeutic efficacy of new compounds, animal and in vitromodels have been devel-oped. Indeed, well-designed mouse or rat experimental models of pneumocystosis can be used to describe the in vivo anti-Pneumocystis activity of new drugs. In vitromodels, which enable the screening of a large panel of new molecules, have been developed using axenic cultures or co-culture with feeder cells; but no universally accepted standard method is cur-rently available to evaluate anti-Pneumocystismolecules in vitro. Thus, we chose to explore the use of the SYTO-13 dye, as a new indicator of Pneumocystis viability. In the present work, we established the experimental conditions to define the in vitro Pharmacodynamic Parameters (EC50, Emax) of marketed compounds (trimethoprim/sulfamethoxazole, pent-amidine, atovaquone) in order to specifically measure the intrinsic activity of these anti-P. cariniimolecules using the SYTO-13 dye for the first time. Co-labelling the fungal organisms with anti-P. carinii specific antibodies enabled the measurement of viability of Pneumocysti

  • SYTO-13, a Viability Marker as a New Tool to Monitor In Vitro Pharmacodynamic Parameters of Anti-Pneumocystis Drugs.
    PLOS ONE, 2015
    Co-Authors: Annie Standaert-vitse, Cécile-marie Aliouat-denis, Anna Martinez, Sara Khalife, Muriel Pottier, Nausicaa Gantois, El Moukhtar Aliouat
    Abstract:

    While Pneumocystis pneumonia (PcP) still impacts the AIDS patients, it has a growing importance in immunosuppressed HIV-negative patients. To determine the anti-Pneumocystis therapeutic efficacy of new compounds, animal and in vitro models have been developed. Indeed, well-designed mouse or rat experimental models of pneumocystosis can be used to describe the in vivo anti-Pneumocystis activity of new drugs. In vitro models, which enable the screening of a large panel of new molecules, have been developed using axenic cultures or co-culture with feeder cells; but no universally accepted standard method is currently available to evaluate anti-Pneumocystis molecules in vitro. Thus, we chose to explore the use of the SYTO-13 dye, as a new indicator of Pneumocystis viability. In the present work, we established the experimental conditions to define the in vitro Pharmacodynamic Parameters (EC50, Emax) of marketed compounds (trimethoprim/sulfamethoxazole, pentamidine, atovaquone) in order to specifically measure the intrinsic activity of these anti-P. carinii molecules using the SYTO-13 dye for the first time. Co-labelling the fungal organisms with anti-P. carinii specific antibodies enabled the measurement of viability of Pneumocystis organisms while excluding host debris from the analysis. Moreover, contrary to microscopic observation, large numbers of fungal cells can be analyzed by flow cytometry, thus increasing statistical significance and avoiding misreading during fastidious quantitation of stained organisms. In conclusion, the SYTO-13 dye allowed us to show a reproducible dose/effect relationship for the tested anti-Pneumocystis drugs.

  • In Vitro Pharmacodynamic Parameters of Sordarin Derivatives in Comparison with Those of Marketed Compounds against Pneumocystis carinii Isolated from Rats
    Antimicrobial Agents and Chemotherapy, 2000
    Co-Authors: Pablo Aviles, El Moukhtar Aliouat, Antonio Martinez, Esperanza Herreros, Lucien Dujardin, Domingo Gargallo-viola
    Abstract:

    Pneumocystis carinii is an important opportunistic pathogen that remains a significant cause of lethal pneumonia in immunocompromised individuals such as patients with AIDS and patients receiving chemotherapy or immunosuppressive drugs for organ transplantation or other pathological conditions. Patients suffering from P. carinii pneumonia (PCP) are usually treated with trimethoprim-sulfamethoxazole (TMP-SMX) or pentamidine (24). However, the relatively high frequency of adverse reactions to these drugs reflects the need for new therapeutic approaches. For this reason, the pharmaceutical industry is investigating more effective and less toxic agents. Sordarin derivatives are a new class of antifungal agents that target protein synthesis (11), with marked in vitro activity against P. carinii (13) and excellent in vivo activity in experimental PCP (E. Dei-Cas, E. M. Aliouat, C. Mullet, E. Mazars, and D. Gargallo, Abstr. 37th Intersci. Conf. Antimicrob. Agents Chemother., abstr. F-65, 1997). Well-defined mouse, rat, or rabbit experimental models (2, 4, 22) can be used to describe the in vivo anti-PCP activity of new compounds. Several in vitro tests for evaluating compound activity against P. carinii have been described using axenic cultures or coculture with feeder cells (8, 10, 14). However, no universally accepted standard method is presently available for the in vitro evaluation of anti-P. carinii molecules (10). The anti-Pneumocystis activity of any given antimicrobial could be evaluated in terms of its intrinsic activity (in vitro) and serum time profile (in vivo) (12). However, the results obtained with different in vitro assays (8, 10) yield limited information on the intrinsic activity of anti-Pneumocystis compounds. Furthermore, comparisons between product activities and extrapolation to in vivo activity remain unreliable. The Hill equation, which describes sigmoid concentration-effect relationships, has proven its utility by revealing in vitro Pharmacodynamic properties of several antibiotics (17, 30). This approach offers at least three Parameters which can be used to describe the in vitro activity of antimicrobial compounds (17): the maximum effect (Emax) as a measure of efficacy, the 50% effective concentration (EC50) as a parameter of intrinsic activity, and the slope (γ) of the concentration-effect relationship. The aim of the present work was to establish the experimental conditions allowing definition of the in vitro Pharmacodynamic Parameters of tested drugs for defining the intrinsic activity of anti-Pneumocystis molecules, as well as the relationships between their in vitro activities and in vivo effects on microorganisms. (This work was presented in part at the 38th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Diego, Calif., 24 to 27 September, 1998 [E. M. Aliouat, P. Aviles, E. Dei-Cas, E. Herreros, L. Dujardin, and D. Gargallo-Viola, abstr. J-15].)

Asunción Fenoll - One of the best experts on this subject based on the ideXlab platform.

  • lactams in a mouse sepsis model β Pharmacodynamic Parameters of on streptococcus pneumoniae effects of specific antibodies against
    2014
    Co-Authors: Asunción Fenoll, I. Jado, L Aguilar, Jesus Casal, Jose Yuste, M J Gimenez
    Abstract:

    -lactam-susceptible serotype 6B iso-late) was performed with a BALB/c mouse model. Hyperimmune serum was obtained from mice immunizedwith the heat-inactivated strain. The rate of mortality was 100% in nontreated animals in the absence ofspecific antibodies. A single injection of a one-half or one-quarter dilution of hyperimmune serum produced 60to 40% survival rates. In the absence of specific antibodies, the minimal effective doses of amoxicillin andcefotaxime that produced survival rates of 100 and 80% were 25 and 50 mg/kg of body weight (three times a dayfor up to six doses), respectively. These doses produced times that the levels in serum remained above the MIC(T

  • Effects of specific antibodies against Streptococcus pneumoniae on Pharmacodynamic Parameters of β-lactams in a mouse sepsis model
    Antimicrobial Agents and Chemotherapy, 2002
    Co-Authors: Jesus Casal, I. Jado, M J Gimenez, L Aguilar, J Prieto, Jose Yuste, Asunción Fenoll
    Abstract:

    A dose-ranging study to investigate the in vivo effects of the presence of specific antibodies on the efficacy of beta-lactam treatment of sepsis caused by Streptococcus pneumoniae (non-beta-lactam-susceptible serotype 6B isolate) was performed with a BALB/c mouse model. Hyperimmune serum was obtained from mice immunized with the heat-inactivated strain. The rate of mortality was 100% in nontreated animals in the absence of specific antibodies. A single injection of a one-half or one-quarter dilution of hyperimmune serum produced 60 to 40% survival rates. In the absence of specific antibodies, the minimal effective doses of amoxicillin and cefotaxime that produced survival rates of 100 and 80% were 25 and 50 mg/kg of body weight (three times a day for up to six doses), respectively. These doses produced times that the levels in serum remained above the MIC (deltaT > MICs) approximately 30% of the dosing interval. When specific antibodies were present (by administration of a one-half or one-quarter dilution of hyperimmune serum), the minimal effective doses of the antibiotics were 3.12 and 6.25 mg/kg ( approximately 8 times lower), with the deltaT > MICs being approximately 3 and 5% of the dosing interval for amoxicillin and cefotaxime, respectively. This in vivo combined Pharmacodynamic effect offers possibilities that can be used to address penicillin resistance.

M J Gimenez - One of the best experts on this subject based on the ideXlab platform.

  • lactams in a mouse sepsis model β Pharmacodynamic Parameters of on streptococcus pneumoniae effects of specific antibodies against
    2014
    Co-Authors: Asunción Fenoll, I. Jado, L Aguilar, Jesus Casal, Jose Yuste, M J Gimenez
    Abstract:

    -lactam-susceptible serotype 6B iso-late) was performed with a BALB/c mouse model. Hyperimmune serum was obtained from mice immunizedwith the heat-inactivated strain. The rate of mortality was 100% in nontreated animals in the absence ofspecific antibodies. A single injection of a one-half or one-quarter dilution of hyperimmune serum produced 60to 40% survival rates. In the absence of specific antibodies, the minimal effective doses of amoxicillin andcefotaxime that produced survival rates of 100 and 80% were 25 and 50 mg/kg of body weight (three times a dayfor up to six doses), respectively. These doses produced times that the levels in serum remained above the MIC(T

  • azithromycin iv Pharmacodynamic Parameters predicting streptococcus pneumoniae killing in epithelial lining fluid versus serum an in vitro Pharmacodynamic simulation
    Journal of Antimicrobial Chemotherapy, 2006
    Co-Authors: David Sevillano, M J Gimenez, Luis Alou, L Aguilar, Olatz Echevarria, Jose Prieto
    Abstract:

    Results: Significant (P < 0.05) azithromycin antibacterial activity versus antibiotic-free controls was found in serum and ELF against the susceptible and mef(A) positive strains, but not against the erm(B) positive strain. AUC0–24/MIC values around or higher than 25 were needed to achieve (time to 99.9% reduction of initial inocula of around 6 h) and maintain (24 h inocula reduction ‡3 log10cfu/mL) bactericidal activity without regrowth. This was achieved only with the susceptible strain in serum, but also with the mef(A) positive strain exhibiting an MIC of 2 mg/L in ELF. Conclusions: The results of this study support that the suggested breakpoint for susceptibility (£2 mg/L) may be adequate to predict S. pneumoniae eradication with ELF but not with serum concentrations obtained after a 500 mg iv once a day regimen.

  • Effects of specific antibodies against Streptococcus pneumoniae on Pharmacodynamic Parameters of β-lactams in a mouse sepsis model
    Antimicrobial Agents and Chemotherapy, 2002
    Co-Authors: Jesus Casal, I. Jado, M J Gimenez, L Aguilar, J Prieto, Jose Yuste, Asunción Fenoll
    Abstract:

    A dose-ranging study to investigate the in vivo effects of the presence of specific antibodies on the efficacy of beta-lactam treatment of sepsis caused by Streptococcus pneumoniae (non-beta-lactam-susceptible serotype 6B isolate) was performed with a BALB/c mouse model. Hyperimmune serum was obtained from mice immunized with the heat-inactivated strain. The rate of mortality was 100% in nontreated animals in the absence of specific antibodies. A single injection of a one-half or one-quarter dilution of hyperimmune serum produced 60 to 40% survival rates. In the absence of specific antibodies, the minimal effective doses of amoxicillin and cefotaxime that produced survival rates of 100 and 80% were 25 and 50 mg/kg of body weight (three times a day for up to six doses), respectively. These doses produced times that the levels in serum remained above the MIC (deltaT > MICs) approximately 30% of the dosing interval. When specific antibodies were present (by administration of a one-half or one-quarter dilution of hyperimmune serum), the minimal effective doses of the antibiotics were 3.12 and 6.25 mg/kg ( approximately 8 times lower), with the deltaT > MICs being approximately 3 and 5% of the dosing interval for amoxicillin and cefotaxime, respectively. This in vivo combined Pharmacodynamic effect offers possibilities that can be used to address penicillin resistance.

Liu Minqian - One of the best experts on this subject based on the ideXlab platform.

  • the gender influence on the Pharmacodynamic Parameters of cis atracurium in tuberculosis patients
    Guangdong Medical Journal, 2015
    Co-Authors: Liu Minqian
    Abstract:

    Objective To investigate the Pharmacodynamic Parameters of cis-atracurium in tuberculosis patients with different gender. Methods Eighty patients( ASA Ⅰ or Ⅱ) received selective general anesthesia were enrolled in this study. They were divided into tuberculosis group( Group T,n = 40) andnon-tuberculosis group( Group N,n =40),whom were subsequently subdivided into male( TM and NM) and female( TF and NF) subgroups. All patients received an intravenous injection of midazolam( 0. 1 mg / kg),fentanyl( 4 μg / kg) and propofol( with target plasma concentration of 1-4 μg / m L). The neuromuscular block level was measured by neuromuscular transmission monitor after patients' consciousness disappeared. With an intravenous 0. 15 mg / kg of cis-atracurium,the responses were defined in terms of the percentages of maximum suppression at the first contraction( T1) of the train-of-four of the adductor pollicis muscle. Endotracheal intubation was conducted when T1 fell to its lowest and repeated no less than 3 times. The onset time,the maximum inhibition of T1,the clinical effect time,the recovery index,the pharmacological effect time and the endotracheal intubation conditions were recorded. MAP and HR were measured before anesthesia induction( t0),and 5min( t1),15 min( t2),30 min( t3),45 min( t4),and 1 h( t5) after general anesthesia. Results The onset time of cis-atracurium in Group TF was significant shorter than that in Group TM,with significantly longer clinical effect time( P 0. 01). However,there was no significant difference between Group NM and NF( P 0. 05). Compared with Group N,the clinical effect time and pharmacological effect time in Group T were significantly shorter( P 0. 05),while there was no significant difference in the onset time,the maximum inhibition of T1,the clinical effect time,the recovery index,or the pharmacological effect time between the two groups( P 0. 05). No significant difference was found in the endotracheal intubation conditions or hemodynamics before or after induction among the four subgroups( P 0. 05). Conclusion Female tuberculosis patients are more sensitive to a single intravenous injection of cis-atracurium,presenting with shortened onset time,and lengthened clinical effect time and pharmacological effect time.

  • determining the Pharmacodynamic Parameters of vecuronium in tuberculosis patients with different genders
    Guangdong Medical Journal, 2014
    Co-Authors: Liu Minqian
    Abstract:

    Objective To determine the Pharmacodynamic Parameters of vecuronium in tuberculosis patients with different genders. Methods Eighty patients(ASA grade Ⅰ or Ⅱ) received selective general anesthesia were enrolled in this study,and divided into tuberculosis group(Group T) and non- tuberculosis group(Group N). They were further divided into male groups(Group TM and NM) and female groups(Group TF and NF). Each patient received intravenous injection of midazolam by 0. 1 mg /kg,fentanyl by 4 μg /kg,and propofol with target plasma concentration of 1 ~ 3 μg /mL. The neuromuscular block efficacy was measured by neuromuscular transmission monitor after patients' consciousness disappeared. With an intravenous vecuronium by 0. 1 mg /kg,the responses were defined in terms of the percentages of maximum suppression at the first(T1) of the train-of-four(TOF) of the adductor pollicis muscle. Endotracheal intubation was conducted when T1 fell to its lowest and repeated no less than 3 times. The onset time,the maximum inhibition of T1,the clinical effect time,the recovery index,the pharmacological effect time and the endotracheal intubation conditions were recorded. MAP and HR were measured before anesthesia induction( t0),and 5 min(t1),15 min(t2),30min(t3),45 min(t4),and 1 h(t5) after general anesthesia. Results Compared with Group N,the clinical effect time of vecuronium in Group T was significantly shorter( P 0. 05),but there was no significant difference between genders(P 0.05). However,the clinical effect time of vecuronium in Group NF was longer than Group NM(P 0.05). No statistical difference was found in the maximum inhibition of T1,the onset time,the recovery index,the pharmacological effect time,the endotracheal intubation conditions or,hemodynamics before or after anesthesia induction among the four groups. Conclusion Anesthesiologists could neglect the consequence of blocking aging of vecuronium in tuberculosis patients with different gender.

William A Craig - One of the best experts on this subject based on the ideXlab platform.

  • evidence to support the rationale that bacterial eradication in respiratory tract infection is an important aim of antimicrobial therapy
    Journal of Antimicrobial Chemotherapy, 2001
    Co-Authors: Ron Dagan, William A Craig, Keith P Klugman, Fernando Baquero
    Abstract:

    Clinical outcome is dependent upon antibiotic-mediated bacterial eradication in a number of infections. However, in respiratory tract infections, the need for bacterial eradication has been controversial. Clinical data are now available that support the need for active bacterial eradication in otitis media. This may also be the case for other respiratory tract infections. An increase in antimicrobial resistance reduces the probability of achieving eradication. Conversely, failure to eradicate bacteria may promote the emergence and dissemination of antimicrobial-resistant clones. Pharmacokinetic/Pharmacodynamic Parameters can be used to predict the bacteriological efficacy of antimicrobial therapy. In conclusion, the aim of antimicrobial therapy in respiratory tract infections should be the eradication of the infecting organism.

  • Pharmacodynamics of fluoroquinolones in experimental models of endocarditis
    Clinical Infectious Diseases, 1998
    Co-Authors: David R Andes, William A Craig
    Abstract:

    We calculated the magnitude of various serum Pharmacodynamic Parameters for fluoroquinolones in models of experimental endocarditis (EE) described in the literature. Nineteen publications contained data that allowed calculation of these Parameters. Data were available for eight fluoroquinolones against methicillin-susceptible Staphylococcus aureus, methicillin-resistant S. aureus, methicillin-resistant Staphylococcus epidermidis, viridans streptococci, Enterobacter aerogenes, and Pseudomonas aeruginosa in rabbit or rat models. Enterococci were excluded because of poor bactericidal activity. A 24-hour area under the concentration curve (AUC)/minimal inhibitory concentration (MIC) ratio > or = 100, a peak level/MIC ratio > 8, and continuous levels above the time were associated with a significantly lower number of cfu per vegetation after 3-6 days of therapy. The 24-hour AUC/MIC exhibited the best linear correlation with cfu per vegetation after 3-6 days of therapy (r2 = 45%). The Pharmacodynamic Parameters predictive of efficacy for fluoroquinolones in the treatment of experimental endocarditis are similar to those for other infectious models.

  • pharmacokinetic Pharmacodynamic Parameters rationale for antibacterial dosing of mice and men
    Clinical Infectious Diseases, 1998
    Co-Authors: William A Craig
    Abstract:

    Investigations over the past 20 years have demonstrated that antibacterials can vary markedly in the time course of antimicrobial activity. These differences in Pharmacodynamic activity have implications for optimal dosage regimens. The results of more recent studies suggest that the magnitude of the pharmacokinetic/Pharmacodynamic Parameters required for efficacy are relatively similar in animal infection models and in human infections. However, there is still much to learn. Additional studies are needed to further correlate pharmacokinetic/Pharmacodynamic Parameters for many antibacterials with therapeutic efficacy in a variety of animal infection models and in human infections. The potential value of using pharmacokinetic/Pharmacodynamic Parameters as guides for establishing optimal dosing regimens for new and old drugs and for new emerging pathogens and resistant organisms, for setting susceptibility breakpoints, and for reducing the cost of drug development should make the continuing search for the therapeutic rationale of antibacterial dosing of mice and men worthwhile.