The Canadian Veterinary Journal La Revue Veterinaire Canadienne, Sep 1, 2006
The susceptibility to antimicrobials of bacterial species most frequently isolated from companion... more The susceptibility to antimicrobials of bacterial species most frequently isolated from companion animals in a veterinary teaching diagnostic laboratory was evaluated retrospectively. A significant decrease between 1990-1992 and 2002-2003 was noted in the susceptibility of dog isolates to the following antimicrobials: Escherichia coli to cephalothin (86% to 61%, P < 0.001); E. coli to ampicillin (85% to 67%, P < 0.001); Proteus spp. to ampicillin (92% to 71%, P < 0.01); coagulase-positive staphylococci (Staphylococcus aureus and Staphylococcus intermedius) to enrofloxacin (99% to 95%, P < 0.01). Significantly increased susceptibilities were also noted as follows: coagulase-positive staphylococci to erythromycin (78% to 90%, P < 0.001) and tetracycline (61% to 77%, P < 0.001). Despite a limited number of results available for cats, a significant increase in susceptibility was noted for Pseudomonas spp. to gentamicin (40% to 100%, P < 0.05) and for E. coli to tetracycline (59% to 80%, P < 0.05). Regular updates on the resistance to antimicrobials used in veterinary medicine are required.
Cationic compounds are diverse and atypical therapeutic substances. In the present study we exami... more Cationic compounds are diverse and atypical therapeutic substances. In the present study we examined whether a prototypical class effect of cationic drugs in the cardiovascular system exists and whether this might be predictable on the basis of chemistry. The dose-dependent effects of cationic compounds of varying molecular weights and charge were examined on the blood pressure (BP), heart rate (HR) and the ECG in anesthetized rats. The compounds examined were protamine, hexadimethrine, tetraethylammonium (TEA), low molecular weight poly-L-lysine (LMW-PLL) and high molecular weight PLL (HMW-PLL). All of the compounds examined except TEA produced a dose-dependent reduction in BP. No changes occurred in HR even when high doses were administered. The ECG effects of these cationic compounds included a dose-dependent prolongation of the QT interval, especially at higher doses. All compounds transiently decreased the size of the P-wave after i.v. bolus administration whereas only protamine and hexadimethrine prolonged the PR and QRS intervals and only at the highest dose (32mg/kg) administered. All cationic compounds, except TEA and saline, evoked ventricular premature beats (VPB), and protamine and HMW-PLL also evoked brief episodes of ventricular tachycardia (VT). The incidence and frequency of arrhythmias was not dose-dependent and no animals experienced protracted episodes of arrhythmia incidence. These dose dependent effects of the polycationic compounds tested suggest a collective mechanism of action that relates the effect of charge of the compound to the onset and persistence of observed cardiovascular toxicity, and adverse cardiovascular effect risk appears to be predictable on this basis.
Journal of pharmacological and toxicological methods, Jan 6, 2015
The relative importance of the discipline of safety pharmacology (which integrates physiology, ph... more The relative importance of the discipline of safety pharmacology (which integrates physiology, pharmacologyand toxicology) has evolved since the incorporation of the Safety Pharmacology Society (SPS) as an entity on August 10, 2000. Safety pharmacology (SP), as a synthesis of these other fields of knowledge, is concerned with characterizing the safety profile (or potential undesirable pharmacodynamic effects) of new chemical entities (NCEs) and biologicals. Initially focused on the issue of drug-induced QT prolongation it has developed into an important discipline over the past 15years with expertise beyond its initial focus on torsades de pointes (TdP). It has become a repository for interrogation of models for drug safety studies and innovative non-clinical model development, validation and implementation. Thus, while safety pharmacology consists of the triumvirate obligatory cardiovascular, central nervous system (CNS) and respiratory system core battery studies it also involves ...
Journal of Pharmacological and Toxicological Methods, 2015
As with other professional disciplines there is a growing need from within industry as well as gl... more As with other professional disciplines there is a growing need from within industry as well as global regulatory authorities for implementation of a certification process in order to assure that appropriate expertise is developed and quality standards are identified for professionals involved in the practice of Safety Pharmacology (SP). In order to meet this need, the Safety Pharmacology Society (SPS) has developed the Diplomate in Safety Pharmacology (DSP) certification process. There are many benefits to certification including authentication of the discipline within the overall pharmaceutical community and with regulatory authorities. It also encourages participation in SPS activities by other professionals (toxicologists, clinicians, academics) who wish to broaden their professional expertise. It provides an opportunity for candidates to strengthen their fundamental scientific knowledge, and stimulates the sharing of data, methods and model development in the form of publications and presentations on relevant topics in SP. Accreditation in SP occurs after candidates successfully complete a written certification examination conducted at the annual SPS meeting. The DSP exam consists primarily of material pertinent to the conduct of SP vital function core battery studies (i.e., cardiovascular, respiratory and central nervous systems), supplemental SP studies (i.e., renal/urinary, gastrointestinal, immunology, and hematology), Regulatory Guidelines (ICH Guidelines) as well as relevant cross-functional knowledge (e.g., physiology, pharmacology, toxicology, biochemistry, pathology, pharmacokinetics, dosing formulation, analytical methods, and statistics). Maintenance of the DSP certification results from the accrual of credits which are gained from a range of educational and scientific contributions. Eligibility requirements include a combination of at least a bachelor degree in science and two years of relevant professional SP experience and one poster presentation on a SP topic as first author at a recognized major scientific meeting.
The Role of the Study Director in Nonclinical Studies, 2014
ABSTRACT This chapter presents common aspects of studies that should be considered and utilized t... more ABSTRACT This chapter presents common aspects of studies that should be considered and utilized to foster quality for the conduct of most safety pharmacology study evaluations. Following these study points to consider, a discussion specific and pertinent to the various physiological systems involved will be conducted. Validation studies represent an opportunity to evaluate and refine standard operating procedures (SOPs). The statistical analysis for repeated measures offers the advantage of an increased sensitivity to detect low-magnitude changes that occur over a long period of time. The safety pharmacology studies include cardiovascular safety pharmacology studies, central nervous system (CNS) safety pharmacology studies, respiratory safety pharmacology studies, and supplemental safety pharmacology model. The Study Director has a central role during interpretation of safety data and benefits from proactive communications with multidisciplinary team members.
Journal of pharmacological and toxicological methods
A number of drugs in clinical trials are discontinued due to potentially life-threatening airway ... more A number of drugs in clinical trials are discontinued due to potentially life-threatening airway obstruction. As some drugs may not cause changes in core battery parameters such as tidal volume (Vt), respiratory rate (RR) or minute ventilation (MV), including measurements of respiratory mechanics in safety pharmacology studies represents an opportunity for design refinement. The present study aimed to test a novel non-invasive methodology to concomitantly measure respiratory system resistance (Rrs) and conventional respiratory parameters (Vt, RR, MV) in conscious Beagle dogs and cynomolgus monkeys. An Airwave Oscillometry system (tremoFlo; THORASYS Inc., Montreal, Canada) was used to concomitantly assess Rrs and conventional respiratory parameters before and after intravenous treatment with a bronchoactive agent. Respiratory mechanics measurements were performed by applying a short (i.e. 16s) single high frequency (19Hz) waveform at the subject's airway opening via a face mask. ...
Journal of pharmacological and toxicological methods
Non-clinical seizure liability studies typically aim to: 1) confirm the nature of EEG activity du... more Non-clinical seizure liability studies typically aim to: 1) confirm the nature of EEG activity during abnormal clinical signs, 2) identify premonitory clinical signs, 3) measure plasma levels at seizure onset, 4) demonstrate that drug-induced seizures are self-limiting, 5) confirm that conventional drugs (e.g. diazepam) can treat drug-induced seizures and 6) confirm the no observed adverse effect level (NOAEL) at EEG. Our aim was to originally characterize several of these items in a three species comparative study. Cynomolgus monkey, Beagle dog and Sprague-Dawley rat with EEG telemetry transmitters were used to obtain EEG using the 10-20 system. Pentylenetetrazol (PTZ) was used to determine seizure threshold or as a positive seizurogenic agent. Clinical signs were recorded and premonitory signs were evaluated. In complement, other pharmacological agents were used to illustrate various safety testing strategies. Intravenous PTZ doses required to induce clonic convulsions were 36.1 (...
Journal of pharmacological and toxicological methods
A number of drugs in clinical trials are discontinued due to potentially life-threatening airway ... more A number of drugs in clinical trials are discontinued due to potentially life-threatening airway obstruction. As some drugs may not cause changes in core battery parameters such as tidal volume (Vt), respiratory rate (RR) or minute ventilation (MV), including measurements of respiratory mechanics in safety pharmacology studies represents an opportunity for design refinement. The present study aimed to test a novel non-invasive methodology to concomitantly measure respiratory system resistance (Rrs) and conventional respiratory parameters (Vt, RR, MV) in conscious Beagle dogs and cynomolgus monkeys. An Airwave Oscillometry system (tremoFlo; THORASYS Inc., Montreal, Canada) was used to concomitantly assess Rrs and conventional respiratory parameters before and after intravenous treatment with a bronchoactive agent. Respiratory mechanics measurements were performed by applying a short (i.e. 16s) single high frequency (19Hz) waveform at the subject's airway opening via a face mask. ...
Journal of pharmacy & pharmaceutical sciences : a publication of the Canadian Society for Pharmaceutical Sciences, Société canadienne des sciences pharmaceutiques, 2008
Because oxytocin (OT) is potentially useful in cardiovascular therapy but has hormonal roles on t... more Because oxytocin (OT) is potentially useful in cardiovascular therapy but has hormonal roles on the cardiovascular and renal systems, we characterized its pharmacokinetic (PK) properties as a function of dose. A single intravenous bolus of OT was given at doses of 200, 300, 500, 1000, 3000, 5000 and 10000 ng/kg to anesthetized male rats (n >= 4 per dose). Blood samples (6) were taken over 72 min to 150 min, depending on dose. The individual time-courses of plasma OT concentrations were analyzed with a one- or an open two-compartment PK model. Kruskal-Wallis tests (alpha=0.05) were used to compare the PK parameters among groups. At doses up to 500 ng/kg, OT showed a higher median systemic clearance (CLT = 0.0624 L/(min*kg); 0.0622 +/- 0.0228 as mean +/- SD value), a higher median central compartment volume of distribution (VC = 0.7906 L/kg; 0.6961 +/- 0.1754), and a lower median elimination half life (t(1/2)(lambdaz) 7.94 min; 9.08 +/- 4.3) with respect to the higher doses (CLT = ...
The Canadian Veterinary Journal La Revue Veterinaire Canadienne, Sep 1, 2006
The susceptibility to antimicrobials of bacterial species most frequently isolated from companion... more The susceptibility to antimicrobials of bacterial species most frequently isolated from companion animals in a veterinary teaching diagnostic laboratory was evaluated retrospectively. A significant decrease between 1990-1992 and 2002-2003 was noted in the susceptibility of dog isolates to the following antimicrobials: Escherichia coli to cephalothin (86% to 61%, P < 0.001); E. coli to ampicillin (85% to 67%, P < 0.001); Proteus spp. to ampicillin (92% to 71%, P < 0.01); coagulase-positive staphylococci (Staphylococcus aureus and Staphylococcus intermedius) to enrofloxacin (99% to 95%, P < 0.01). Significantly increased susceptibilities were also noted as follows: coagulase-positive staphylococci to erythromycin (78% to 90%, P < 0.001) and tetracycline (61% to 77%, P < 0.001). Despite a limited number of results available for cats, a significant increase in susceptibility was noted for Pseudomonas spp. to gentamicin (40% to 100%, P < 0.05) and for E. coli to tetracycline (59% to 80%, P < 0.05). Regular updates on the resistance to antimicrobials used in veterinary medicine are required.
Cationic compounds are diverse and atypical therapeutic substances. In the present study we exami... more Cationic compounds are diverse and atypical therapeutic substances. In the present study we examined whether a prototypical class effect of cationic drugs in the cardiovascular system exists and whether this might be predictable on the basis of chemistry. The dose-dependent effects of cationic compounds of varying molecular weights and charge were examined on the blood pressure (BP), heart rate (HR) and the ECG in anesthetized rats. The compounds examined were protamine, hexadimethrine, tetraethylammonium (TEA), low molecular weight poly-L-lysine (LMW-PLL) and high molecular weight PLL (HMW-PLL). All of the compounds examined except TEA produced a dose-dependent reduction in BP. No changes occurred in HR even when high doses were administered. The ECG effects of these cationic compounds included a dose-dependent prolongation of the QT interval, especially at higher doses. All compounds transiently decreased the size of the P-wave after i.v. bolus administration whereas only protamine and hexadimethrine prolonged the PR and QRS intervals and only at the highest dose (32mg/kg) administered. All cationic compounds, except TEA and saline, evoked ventricular premature beats (VPB), and protamine and HMW-PLL also evoked brief episodes of ventricular tachycardia (VT). The incidence and frequency of arrhythmias was not dose-dependent and no animals experienced protracted episodes of arrhythmia incidence. These dose dependent effects of the polycationic compounds tested suggest a collective mechanism of action that relates the effect of charge of the compound to the onset and persistence of observed cardiovascular toxicity, and adverse cardiovascular effect risk appears to be predictable on this basis.
Journal of pharmacological and toxicological methods, Jan 6, 2015
The relative importance of the discipline of safety pharmacology (which integrates physiology, ph... more The relative importance of the discipline of safety pharmacology (which integrates physiology, pharmacologyand toxicology) has evolved since the incorporation of the Safety Pharmacology Society (SPS) as an entity on August 10, 2000. Safety pharmacology (SP), as a synthesis of these other fields of knowledge, is concerned with characterizing the safety profile (or potential undesirable pharmacodynamic effects) of new chemical entities (NCEs) and biologicals. Initially focused on the issue of drug-induced QT prolongation it has developed into an important discipline over the past 15years with expertise beyond its initial focus on torsades de pointes (TdP). It has become a repository for interrogation of models for drug safety studies and innovative non-clinical model development, validation and implementation. Thus, while safety pharmacology consists of the triumvirate obligatory cardiovascular, central nervous system (CNS) and respiratory system core battery studies it also involves ...
Journal of Pharmacological and Toxicological Methods, 2015
As with other professional disciplines there is a growing need from within industry as well as gl... more As with other professional disciplines there is a growing need from within industry as well as global regulatory authorities for implementation of a certification process in order to assure that appropriate expertise is developed and quality standards are identified for professionals involved in the practice of Safety Pharmacology (SP). In order to meet this need, the Safety Pharmacology Society (SPS) has developed the Diplomate in Safety Pharmacology (DSP) certification process. There are many benefits to certification including authentication of the discipline within the overall pharmaceutical community and with regulatory authorities. It also encourages participation in SPS activities by other professionals (toxicologists, clinicians, academics) who wish to broaden their professional expertise. It provides an opportunity for candidates to strengthen their fundamental scientific knowledge, and stimulates the sharing of data, methods and model development in the form of publications and presentations on relevant topics in SP. Accreditation in SP occurs after candidates successfully complete a written certification examination conducted at the annual SPS meeting. The DSP exam consists primarily of material pertinent to the conduct of SP vital function core battery studies (i.e., cardiovascular, respiratory and central nervous systems), supplemental SP studies (i.e., renal/urinary, gastrointestinal, immunology, and hematology), Regulatory Guidelines (ICH Guidelines) as well as relevant cross-functional knowledge (e.g., physiology, pharmacology, toxicology, biochemistry, pathology, pharmacokinetics, dosing formulation, analytical methods, and statistics). Maintenance of the DSP certification results from the accrual of credits which are gained from a range of educational and scientific contributions. Eligibility requirements include a combination of at least a bachelor degree in science and two years of relevant professional SP experience and one poster presentation on a SP topic as first author at a recognized major scientific meeting.
The Role of the Study Director in Nonclinical Studies, 2014
ABSTRACT This chapter presents common aspects of studies that should be considered and utilized t... more ABSTRACT This chapter presents common aspects of studies that should be considered and utilized to foster quality for the conduct of most safety pharmacology study evaluations. Following these study points to consider, a discussion specific and pertinent to the various physiological systems involved will be conducted. Validation studies represent an opportunity to evaluate and refine standard operating procedures (SOPs). The statistical analysis for repeated measures offers the advantage of an increased sensitivity to detect low-magnitude changes that occur over a long period of time. The safety pharmacology studies include cardiovascular safety pharmacology studies, central nervous system (CNS) safety pharmacology studies, respiratory safety pharmacology studies, and supplemental safety pharmacology model. The Study Director has a central role during interpretation of safety data and benefits from proactive communications with multidisciplinary team members.
Journal of pharmacological and toxicological methods
A number of drugs in clinical trials are discontinued due to potentially life-threatening airway ... more A number of drugs in clinical trials are discontinued due to potentially life-threatening airway obstruction. As some drugs may not cause changes in core battery parameters such as tidal volume (Vt), respiratory rate (RR) or minute ventilation (MV), including measurements of respiratory mechanics in safety pharmacology studies represents an opportunity for design refinement. The present study aimed to test a novel non-invasive methodology to concomitantly measure respiratory system resistance (Rrs) and conventional respiratory parameters (Vt, RR, MV) in conscious Beagle dogs and cynomolgus monkeys. An Airwave Oscillometry system (tremoFlo; THORASYS Inc., Montreal, Canada) was used to concomitantly assess Rrs and conventional respiratory parameters before and after intravenous treatment with a bronchoactive agent. Respiratory mechanics measurements were performed by applying a short (i.e. 16s) single high frequency (19Hz) waveform at the subject's airway opening via a face mask. ...
Journal of pharmacological and toxicological methods
Non-clinical seizure liability studies typically aim to: 1) confirm the nature of EEG activity du... more Non-clinical seizure liability studies typically aim to: 1) confirm the nature of EEG activity during abnormal clinical signs, 2) identify premonitory clinical signs, 3) measure plasma levels at seizure onset, 4) demonstrate that drug-induced seizures are self-limiting, 5) confirm that conventional drugs (e.g. diazepam) can treat drug-induced seizures and 6) confirm the no observed adverse effect level (NOAEL) at EEG. Our aim was to originally characterize several of these items in a three species comparative study. Cynomolgus monkey, Beagle dog and Sprague-Dawley rat with EEG telemetry transmitters were used to obtain EEG using the 10-20 system. Pentylenetetrazol (PTZ) was used to determine seizure threshold or as a positive seizurogenic agent. Clinical signs were recorded and premonitory signs were evaluated. In complement, other pharmacological agents were used to illustrate various safety testing strategies. Intravenous PTZ doses required to induce clonic convulsions were 36.1 (...
Journal of pharmacological and toxicological methods
A number of drugs in clinical trials are discontinued due to potentially life-threatening airway ... more A number of drugs in clinical trials are discontinued due to potentially life-threatening airway obstruction. As some drugs may not cause changes in core battery parameters such as tidal volume (Vt), respiratory rate (RR) or minute ventilation (MV), including measurements of respiratory mechanics in safety pharmacology studies represents an opportunity for design refinement. The present study aimed to test a novel non-invasive methodology to concomitantly measure respiratory system resistance (Rrs) and conventional respiratory parameters (Vt, RR, MV) in conscious Beagle dogs and cynomolgus monkeys. An Airwave Oscillometry system (tremoFlo; THORASYS Inc., Montreal, Canada) was used to concomitantly assess Rrs and conventional respiratory parameters before and after intravenous treatment with a bronchoactive agent. Respiratory mechanics measurements were performed by applying a short (i.e. 16s) single high frequency (19Hz) waveform at the subject's airway opening via a face mask. ...
Journal of pharmacy & pharmaceutical sciences : a publication of the Canadian Society for Pharmaceutical Sciences, Société canadienne des sciences pharmaceutiques, 2008
Because oxytocin (OT) is potentially useful in cardiovascular therapy but has hormonal roles on t... more Because oxytocin (OT) is potentially useful in cardiovascular therapy but has hormonal roles on the cardiovascular and renal systems, we characterized its pharmacokinetic (PK) properties as a function of dose. A single intravenous bolus of OT was given at doses of 200, 300, 500, 1000, 3000, 5000 and 10000 ng/kg to anesthetized male rats (n >= 4 per dose). Blood samples (6) were taken over 72 min to 150 min, depending on dose. The individual time-courses of plasma OT concentrations were analyzed with a one- or an open two-compartment PK model. Kruskal-Wallis tests (alpha=0.05) were used to compare the PK parameters among groups. At doses up to 500 ng/kg, OT showed a higher median systemic clearance (CLT = 0.0624 L/(min*kg); 0.0622 +/- 0.0228 as mean +/- SD value), a higher median central compartment volume of distribution (VC = 0.7906 L/kg; 0.6961 +/- 0.1754), and a lower median elimination half life (t(1/2)(lambdaz) 7.94 min; 9.08 +/- 4.3) with respect to the higher doses (CLT = ...
Uploads
Papers by Simon Authier