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Article ; Online: Targeted dosing for susceptible heteroresistant subpopulations may improve rational dosage regimen prediction for colistin in broiler chickens.

Mead, Andrew / Toutain, Pierre-Louis / Richez, Pascal / Pelligand, Ludovic

2023 Volume 13, Issue 1, Page(s) 12822

Abstract: The dosage of colistin for the treatment of enteric E. coli in animals necessitates considering the heteroresistant (HR) nature of the targeted inoculum, described by the presence of a major susceptible population (S1, representing 99.95% of total ... ...

Abstract	The dosage of colistin for the treatment of enteric E. coli in animals necessitates considering the heteroresistant (HR) nature of the targeted inoculum, described by the presence of a major susceptible population (S1, representing 99.95% of total population) mixed with an initial minor subpopulation of less susceptible bacteria (S2). Herein, we report the 1-compartment population pharmacokinetics (PK) of colistin in chicken intestine (jejunum and ileum) and combined it with a previously established pharmacodynamic (PD) model of HR in E. coli. We then computed probabilities of target attainment (PTA) with a pharmacodynamic target (AUC
MeSH term(s)	Animals ; Colistin/therapeutic use ; Anti-Bacterial Agents/therapeutic use ; Chickens ; Escherichia coli ; Microbial Sensitivity Tests
Chemical Substances	Colistin (Z67X93HJG1) ; Anti-Bacterial Agents
Language	English
Publishing date	2023-08-07
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-023-39727-w
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Article: The Decline and Fall of Materia Medica and the Rise of Pharmacology and Therapeutics in Veterinary Medicine.

Lees, Peter / Bäumer, Wolfgang / Toutain, Pierre-Louis

Frontiers in veterinary science

2022 Volume 8, Page(s) 777809

Abstract: Materia Medica is a Latin term, relating to the history of pharmacy. It describes the sources (vegetable, animal and mineral), nature, preparation, and properties of substances or mixtures of substances, which were used as remedies for the treatment of ... ...

Abstract	Materia Medica is a Latin term, relating to the history of pharmacy. It describes the sources (vegetable, animal and mineral), nature, preparation, and properties of substances or mixtures of substances, which were used as remedies for the treatment of diseases. Bourgelat authored the first veterinary Materia Medica book. This review describes the evolution and ultimate downfall of Materia Medica concepts and practices. Its survival for more than two millennia reflected the impact of religion and dogmas on therapy. The consignment of Materia Medica to history was signified by publication of the first modern book of veterinary pharmacology and therapeutics by Meyer Jones in 1953. Previously, the dominance of Materia Medica was linked to an hippiatry culture, which was shared with farriers and quacks. The Pasteurian and pharmacological revolutions of the second half of the nineteenth century led to its gradual abandonment. This review explains why the existence of authentically active substances, such as opioid analgesics, cardiotonics and general anesthetics either were not used for those actions or were badly prescribed, in part because of historical precedence and in part from lack of pathophysiological knowledge to justify rational use. The modern concept of dosage, in particular inter-species differences, was not understood. There were also major dogmas, supporting false indications, such as failure to recognize pain as a symptom to be treated, whereas inflammation was only a disease symptom involving excess of activity of the blood system, which had to be vigorously addressed by bleeding and purging. This review covers a well-defined period, ranging from Bourgelat, who wrote the first book of Materia Medica for veterinary studies to the first edition of Meyer Jones textbook in 1953, which marked the end of Materia Medica and the beginning of pharmacology in veterinary medicine.
Language	English
Publishing date	2022-01-20
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2834243-4
ISSN	2297-1769
ISSN	2297-1769
DOI	10.3389/fvets.2021.777809
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Article ; Online: A New Drug-Drug Interaction Between Hydroxychloroquine and Metformin? A Signal Detection Study.

Montastruc, Jean-Louis / Toutain, Pierre-Louis

Drug safety

2020 Volume 43, Issue 7, Page(s) 657–660

Abstract: Introduction: Hydroxychloroquine was recently promoted in patients infected with COVID-19 infection. A recent experimental study has suggested an increased toxicity of hydroxychloroquine in association with metformin in mice.: Objective: The present ... ...

Abstract	Introduction: Hydroxychloroquine was recently promoted in patients infected with COVID-19 infection. A recent experimental study has suggested an increased toxicity of hydroxychloroquine in association with metformin in mice. Objective: The present study was undertaken to investigate the reality of this putative drug-drug interaction between hydroxychloroquine and metformin using pharmacovigilance data. Methods: Using VigiBase Results: Of the 10,771 Individual Case Safety Reports (ICSR) involving hydroxychloroquine, 52 were recorded as 'fatal outcomes'. In comparison with hydroxychloroquine alone, hydroxychloroquine + metformin was associated with an ROR value of 57.7 (23.9-139.3). In comparison with metformin alone, hydroxychloroquine + metformin was associated with an ROR value of 6.0 (2.6-13.8). Conclusion: Our study identified a signal for the association hydroxychloroquine + metformin that appears to be more at risk of fatal outcomes (particularly by completed suicides) than one of the two drugs when given alone.
MeSH term(s)	Adult ; Adverse Drug Reaction Reporting Systems/statistics & numerical data ; Betacoronavirus/isolation & purification ; COVID-19 ; Coronavirus Infections/diagnosis ; Coronavirus Infections/drug therapy ; Coronavirus Infections/epidemiology ; Drug Interactions ; Drug Therapy, Combination/adverse effects ; Drug Therapy, Combination/mortality ; Female ; Humans ; Hydroxychloroquine/pharmacokinetics ; Hydroxychloroquine/therapeutic use ; Hypoglycemic Agents/pharmacokinetics ; Hypoglycemic Agents/therapeutic use ; Male ; Metformin/pharmacokinetics ; Metformin/therapeutic use ; Middle Aged ; Pandemics ; Pharmacovigilance ; Pneumonia, Viral/diagnosis ; Pneumonia, Viral/drug therapy ; Pneumonia, Viral/epidemiology ; SARS-CoV-2
Chemical Substances	Hypoglycemic Agents ; Hydroxychloroquine (4QWG6N8QKH) ; Metformin (9100L32L2N)
Keywords	covid19
Language	English
Publishing date	2020-06-02
Publishing country	New Zealand
Document type	Journal Article
ZDB-ID	1018059-x
ISSN	1179-1942 ; 0114-5916
ISSN (online)	1179-1942
ISSN	0114-5916
DOI	10.1007/s40264-020-00955-y
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Article: Time-Kill Analysis of Canine Skin Pathogens: A Comparison of Pradofloxacin and Marbofloxacin.

Azzariti, Stefano / Mead, Andrew / Toutain, Pierre-Louis / Bond, Ross / Pelligand, Ludovic

Antibiotics (Basel, Switzerland)

2023 Volume 12, Issue 10

Abstract: Time-kill curves (TKCs) are more informative compared with the use of minimum inhibitory concentration (MIC) as they allow the capture of bacterial growth and the development of drug killing rates over time, which allows to compute key pharmacodynamic ( ... ...

Abstract	Time-kill curves (TKCs) are more informative compared with the use of minimum inhibitory concentration (MIC) as they allow the capture of bacterial growth and the development of drug killing rates over time, which allows to compute key pharmacodynamic (PD) parameters. Our study aimed, using a semi-mechanistic mathematical model, to estimate the best pharmacokinetic/pharmacodynamic (PK/PD) indices (ƒAUC/MIC or %ƒT > MIC) for the prediction of clinical efficacy of veterinary FQs in
Language	English
Publishing date	2023-10-17
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2681345-2
ISSN	2079-6382
ISSN	2079-6382
DOI	10.3390/antibiotics12101548
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Article ; Online: Quantitative Pharmacodynamic Characterization of Resistance versus Heteroresistance of Colistin in E. coli Using a Semimechanistic Modeling of Killing Curves.

Mead, Andrew / Toutain, Pierre-Louis / Richez, Pascal / Pelligand, Ludovic

Antimicrobial agents and chemotherapy

2022 Volume 66, Issue 9, Page(s) e0079322

Abstract: Heteroresistance corresponds to the presence, in a bacterial isolate, of an initial small subpopulation of bacteria characterized by a significant reduction in their sensitivity to a given antibiotic. Mechanisms of heteroresistance versus resistance are ... ...

Abstract	Heteroresistance corresponds to the presence, in a bacterial isolate, of an initial small subpopulation of bacteria characterized by a significant reduction in their sensitivity to a given antibiotic. Mechanisms of heteroresistance versus resistance are poorly understood. The aim of this study was to explore heteroresistance in
MeSH term(s)	Anti-Bacterial Agents/pharmacology ; Colistin/pharmacology ; Drug Resistance, Bacterial/genetics ; Escherichia coli ; Escherichia coli Proteins/genetics ; Microbial Sensitivity Tests ; Plasmids
Chemical Substances	Anti-Bacterial Agents ; Escherichia coli Proteins ; MCR-1 protein, E coli ; Colistin (Z67X93HJG1)
Language	English
Publishing date	2022-08-30
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	217602-6
ISSN	1098-6596 ; 0066-4804
ISSN (online)	1098-6596
ISSN	0066-4804
DOI	10.1128/aac.00793-22
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Zs.A 809: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Pharmacokinetics/pharmacodynamics cut-off determination for fosfomycin using Monte Carlo simulation in healthy horses.

Kuroda, Taisuke / Minamijima, Yohei / Niwa, Hidekazu / Mita, Hiroshi / Tamura, Norihisa / Fukuda, Kentaro / Toutain, Pierre-Louis / Ohta, Minoru

The Journal of veterinary medical science

2024 Volume 86, Issue 4, Page(s) 413–420

Abstract: Fosfomycin (FOM) is an approved veterinary medicinal product for large animals in Japan, but Clinical breakpoint (CBP) for antimicrobial susceptibility test (AST) is not defined for animals. This study aimed at conducting a pharmacokinetics/ ... ...

Abstract	Fosfomycin (FOM) is an approved veterinary medicinal product for large animals in Japan, but Clinical breakpoint (CBP) for antimicrobial susceptibility test (AST) is not defined for animals. This study aimed at conducting a pharmacokinetics/pharmacodynamics (PK/PD) analysis to determine the PK/PD cutoff for the CBP in horses. Drug concentrations following single intravenous administration (IV) of 20 mg/kg body weight (BW) FOM in nine horses were measured using liquid chromatography/mass spectrometry. The data were modelled using a nonlinear mixed-effects model, followed by Monte Carlo simulations. A 90% probability of target attainment for a PK/PD target of the ratio of Area Under the free plasma concentration-time curve divided by the minimal inhibitory concentration (MIC) >24 hr was set as PK/PD cut-off. The PK/PD cutoff for FOM 20 mg/kg BW q12 hr IV was estimated with the MIC value of ≤16.0 mg/L, and this regimen was considered effective against E. coli (MIC
MeSH term(s)	Humans ; Animals ; Horses ; Fosfomycin/pharmacology ; Fosfomycin/therapeutic use ; Anti-Bacterial Agents/therapeutic use ; Escherichia coli ; Monte Carlo Method ; Escherichia coli Infections/veterinary ; Microbial Sensitivity Tests/veterinary ; Horse Diseases/drug therapy
Chemical Substances	Fosfomycin (2N81MY12TE) ; Anti-Bacterial Agents
Language	English
Publishing date	2024-02-12
Publishing country	Japan
Document type	Journal Article
ZDB-ID	1071753-5
ISSN	1347-7439 ; 0916-7250
ISSN (online)	1347-7439
ISSN	0916-7250
DOI	10.1292/jvms.23-0476
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Article ; Online: Comparison of toxicokinetic properties of eleven analogues of Bisphenol A in pig after intravenous and oral administrations

Gély, Clémence A. / Lacroix, Marlène Z. / Roques, Béatrice B. / Toutain, Pierre-Louis / Gayrard, Véronique / Picard-Hagen, Nicole

Environment International. 2023 Jan., v. 171 p.107722-

2023

Abstract: Due to the restrictions of its use, Bisphenol A (BPA) has been replaced by many structurally related bisphenols (BPs) in consumer products. The endocrine disrupting potential similar to that of BPA has been described for several bisphenols, there is ... ...

Abstract	Due to the restrictions of its use, Bisphenol A (BPA) has been replaced by many structurally related bisphenols (BPs) in consumer products. The endocrine disrupting potential similar to that of BPA has been described for several bisphenols, there is therefore an urgent need of toxicokinetic (TK) data for these emerging BPs in order to evaluate if their internal exposure could increase the risk of endocrine disruption. We investigated TK behaviors of eleven BPA substitutes (BPS, BPAF, BPB, BPF, BPM, BPZ, 3-3BPA, BP4-4, BPAP, BPP, and BPFL) by intravenous and oral administrations of mixtures of them to piglets and serial collection of blood over 72 h and urine over 24 h, to evaluate their disposition. Data were analyzed using nonlinear mixed-effects modeling and a comparison was made with TK predicted by the generic model HTTK package. The low urinary excretion of some BPs, in particular BPM, BPP and BPFL, is an important aspect to consider in predicting human exposure based on urine biomonitoring. Despite their structural similarities, for the same oral dose, all BPA analogues investigated showed a higher systemic exposure (area under the plasma concentration-time curve (AUC) of the unconjugated Bisphenol) than BPA (2 to 4 fold for 3-3BPA, BPAF, BPB and BPZ, 7–20 fold for BP4-4, BPAP, BPP, BPFL, BPF and BPM and 150 fold for BPS) due mainly to a considerable variation of oral bioavailability (proportion of BP administered by oral route that attains the systemic circulation unchanged). Given similarities in the digestive tract between pigs and humans, our TK data suggest that replacing BPA with some of its alternatives, particularly BPS, will likely lead to higher internal exposure to potential endocrine disruptive compounds. These findings are crucial for evaluating the risk of human exposure to these emerging BPs.
Keywords	bioavailability ; bisphenol A ; blood ; digestive tract ; environment ; environmental monitoring ; excretion ; humans ; intravenous injection ; nonlinear mixed effects models ; oral administration ; risk ; swine ; urine ; Bisphenols ; Toxicokinetics ; Oral exposure ; Mixture ; Pig model ; TK ; BPs ; BPF ; BPA ; BPB ; BPAF ; 3-3BPA ; BPZ ; BPM ; BPS ; BP4-4 ; BPAP ; BPFL ; BPP ; DHDPE ; QC ; UHPLC ; NCA ; NLME ; HTTK ; AUC ; MRT ; Cl ; F ; Cl_F ; HL
Language	English
Dates of publication	2023-01
Publishing place	Elsevier Ltd
Document type	Article ; Online
ZDB-ID	554791-x
ISSN	1873-6750 ; 0160-4120
ISSN (online)	1873-6750
ISSN	0160-4120
DOI	10.1016/j.envint.2022.107722
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Rational determination of cefazolin dosage regimen in horses based on pharmacokinetics/pharmacodynamics principles and Monte Carlo simulations

Kuroda, Taisuke / Minamijima, Yohei / Mita, Hiroshi / Tamura, Norihisa / Fukuda, Kentaro / Kuwano, Atsutoshi / Toutain, Pierre‐Louis / Sato, Fumio

Journal of Veterinary Pharmacology and Therapeutics. 2023 Jan., v. 46, no. 1 p.62-67

2023

Abstract: A pharmacokinetics/pharmacodynamics (PK/PD) approach was used to determine the best empirical dosage regimen of cefazolin (CEZ) after intramuscular (IM) administration of CEZ in horses. Seven horses received a single IM or intravenous (IV) administration ...

Abstract	A pharmacokinetics/pharmacodynamics (PK/PD) approach was used to determine the best empirical dosage regimen of cefazolin (CEZ) after intramuscular (IM) administration of CEZ in horses. Seven horses received a single IM or intravenous (IV) administration of CEZ of 5 mg/kg bodyweight (BW) according to a crossover design. CEZ plasma concentrations were measured using LC–MS/MS. The plasma concentrations in these seven horses and those of six other horses obtained in a previous study with an IV CEZ dose of 10 mg/kg were modelled simultaneously using NonLinear Mixed‐Effect modelling followed by Monte Carlo simulations to establish a rational dosage regimen. A 90% Probability of Target Attainment (PTA) for a PK/PD target of a free plasma concentration exceeding MIC₉₀ (fT > MIC) for 40% of the dosing interval was set for selecting an effective dosing regimen. The typical half‐life of absorption and bioavailability after IM administration were 1.25 h and 96.8%, respectively. A CEZ dosage regimen of 5 mg/kg BW q12h IM administration achieved therapeutic concentrations to control both Streptococcus zooepidemicus and Staphylococcus aureus. For the same dose, the fT > MIC after IM administration was significantly longer than after IV administration, and the IM route should be favoured by clinicians for its efficiency and convenience.
Keywords	Staphylococcus aureus ; Streptococcus equi subsp. zooepidemicus ; absorption ; bioavailability ; body weight ; cefazolin ; cross-over studies ; half life ; intravenous injection ; pharmacodynamics ; pharmacokinetics ; probability
Language	English
Dates of publication	2023-01
Size	p. 62-67.
Publishing place	John Wiley & Sons, Ltd
Document type	Article ; Online
Note	JOURNAL ARTICLE
ZDB-ID	435216-6
ISSN	1365-2885 ; 0140-7783
ISSN (online)	1365-2885
ISSN	0140-7783
DOI	10.1111/jvp.13099
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Doxycycline serum protein binding in pigs reveals a relatively high free fraction

Portugal, Felipe Ramon / Lacroix, Marlène Z. / Roques, Béatrice B. / Gayrard, Véronique / Toutain, Pierre‐Louis / Bousquet‐Mélou, Alain

Journal of Veterinary Pharmacology and Therapeutics. 2023 Mar., v. 46, no. 2 p.112-118

2023

Abstract: Doxycycline is an antibiotic widely used in pig farming. As with all antibiotics, only the free concentrations are considered to be bacteriologically active. Historically, the free fraction (fu) in pig plasma has been estimated at 7%, which, given the ... ...

Abstract	Doxycycline is an antibiotic widely used in pig farming. As with all antibiotics, only the free concentrations are considered to be bacteriologically active. Historically, the free fraction (fu) in pig plasma has been estimated at 7%, which, given the effective dosage regime used in pigs, leads to free plasma concentrations of doxycycline largely lower than the minimum inhibitory concentrations of the target pathogens. This apparent inconsistency led us to reassess plasma protein binding of doxycycline in pigs. Using an equilibrium dialysis method, the extent of doxycycline binding was measured individually in 26 pigs for total doxycycline concentration ranging from 10 to 1000 μmol/L. Analysis of the data using a non‐linear mixed‐effects model demonstrated linearity of plasma protein binding with a mean fu value of 31% and a relatively low inter‐subject variability of approximately 10%. This new data showing that the free fraction is four times greater than what could have been anticipated from historical data is discussed in particular for the calculation of the PK/PD cut‐offs, which are used to establish the clinical breakpoints for antimicrobial susceptibility testing.
Keywords	antibiotic resistance ; blood proteins ; dialysis ; doxycycline ; models ; pharmacology ; swine ; therapeutics
Language	English
Dates of publication	2023-03
Size	p. 112-118.
Publishing place	John Wiley & Sons, Ltd
Document type	Article ; Online
Note	JOURNAL ARTICLE
ZDB-ID	435216-6
ISSN	1365-2885 ; 0140-7783
ISSN (online)	1365-2885
ISSN	0140-7783
DOI	10.1111/jvp.13111
Database	NAL-Catalogue (AGRICOLA)

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Article: A New Drug-Drug Interaction Between Hydroxychloroquine and Metformin? A Signal Detection Study

Montastruc, Jean-Louis / Toutain, Pierre-Louis

Drug Saf

Abstract: INTRODUCTION: Hydroxychloroquine was recently promoted in patients infected with COVID-19 infection. A recent experimental study has suggested an increased toxicity of hydroxychloroquine in association with metformin in mice. OBJECTIVE: The present study ...

Abstract	INTRODUCTION: Hydroxychloroquine was recently promoted in patients infected with COVID-19 infection. A recent experimental study has suggested an increased toxicity of hydroxychloroquine in association with metformin in mice. OBJECTIVE: The present study was undertaken to investigate the reality of this putative drug-drug interaction between hydroxychloroquine and metformin using pharmacovigilance data. METHODS: Using VigiBase®, the WHO pharmacovigilance database, we performed a disproportionality analysis (case/non-case study). Cases were reports of fatal outcomes with the drugs of interest and non-cases were all other reports for these drugs registered between 1 January 2000 and 31 December 2019. Data with hydroxychloroquine (or metformin) alone were compared with the association hydroxychloroquine + metformin. Results are reported as ROR (reporting odds ratio) with their 95% confidence interval. RESULTS: Of the 10,771 Individual Case Safety Reports (ICSR) involving hydroxychloroquine, 52 were recorded as 'fatal outcomes'. In comparison with hydroxychloroquine alone, hydroxychloroquine + metformin was associated with an ROR value of 57.7 (23.9-139.3). In comparison with metformin alone, hydroxychloroquine + metformin was associated with an ROR value of 6.0 (2.6-13.8). CONCLUSION: Our study identified a signal for the association hydroxychloroquine + metformin that appears to be more at risk of fatal outcomes (particularly by completed suicides) than one of the two drugs when given alone.
Keywords	covid19
Publisher	WHO
Document type	Article
Note	WHO #Covidence: #505983
Database	COVID19

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