Brian Guth's research while affiliated with North-West University and other places

Publications (72)

Article
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Defining an appropriate and efficient assessment of drug‐induced clinical QTc prolongation (a surrogate marker of Torsades de Pointes arrhythmia) remains a concern of drug developers and regulators worldwide. In use for over 15+ years, the nonclinical ICH S7B and clinical ICH E14 guidances describe three core assays (S7B: in vitro hERG/IKr current...
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Introduction Alterations in cardiac contractility can have significant clinical implications, highlighting the need for early detection of potential liabilities. Pre-clinical methods to assess contractility are typically invasive and their translation to human measures of cardiac function are not well defined. Clinically, cardiac function is most o...
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Safety pharmacology is an essential part of drug development aiming to identify, evaluate and investigate undesirable pharmacodynamic properties of a drug primarily prior to clinical trials. In particular, cardiovascular adverse drug reactions (ADR) have halted many drug development programs. Safety pharmacology has successfully implemented a scree...
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We compared a published computational model of the action potential of a specific type of human induced pluripotent stem cell -derived cardiomyocytes (hiPSC-CM) with experimental field potential data with regard to their inter-beat interval and the duration of repolarization. In particular, concomitant changes in inter-beat interval and duration of...
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Contractility of the myocardium engines the pumping function of the heart and is enabled by the collective contractile activity of its muscle cells: cardiomyocytes. The effects of drugs on the contractility of human cardiomyocytes in vitro can provide mechanistic insight that can support the prediction of clinical cardiac drug effects early in drug...
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Drug-induced effects on cardiac contractility can be assessed through the measurement of the maximal rate of pressure increase in the left ventricle (LVdP/dtmax) in conscious animals, and such studies are often conducted at the late stage of preclinical drug development. Detection of such effects earlier in drug research using simpler, in vitro tes...
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This meeting report is based on presentations given at the first Drug Safety Africa Meeting in Potchefstroom, South Africa from November 20–22, 2018 at the North-West University campus. There were 134 attendees (including 26 speakers and 34 students) from the pharmaceutical industry, academia, regulatory agencies as well as 6 exhibitors. These meet...
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Introduction: The sensitivity of a given test to detect a treatment-induced effect in a variable of interest is intrinsically related to the variability of that variable observed without treatment and the number of observations made in the study (i.e. number of animals). To evaluate test sensitivity to detect drug-induced changes in myocardial con...
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Southern Africa (South Africa as well as neighboring countries) has not had an infrastructure for testing the safety of new drugs or other therapeutic entities, including plant-based or herbal treatments coming from the indigenous cultures, according to the current practice and regulatory requirements. Simultaneously, Southern Africa is challenged...
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Introduction: A newly developed total implant telemetry system for cardiovascular (CV), electrophysiological and body temperature measurement was evaluated. A cloud-based transmission of the physiological signals allowed an assessment of the quality of the physiological signals despite the physical separation between the instrumented animals and t...
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Repeated anaesthesia may be required in experimental protocols and in daily veterinary practice, but anaesthesia is known to alter physiological parameters in GPs (Cavia porcellus, GPs). This study investigated the effects of repeated anaesthesia with either medetomidine-midazolam-fentanyl (MMF) or isoflurane (Iso) on physiological parameters in th...
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Introduction: The importance of drug-induced effects on the inotropic state of the heart is well known. Unlike he-modynamic and cardiac electrophysiological methods, which have been routinely used in drug safety testing for years, the non-clinical assessment of drug effects on myocardial contractility is used less frequently with no established tra...
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Introduction: The importance of drug-induced effects on the inotropic state of the heart is well known. Unlike hemodynamic and cardiac electrophysiological methods, which have been routinely used in drug safety testing for years, the non-clinical assessment of drug effects on myocardial contractility is used less frequently with no established tra...
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Guinea pigs (GPs) are difficult to anaesthetize successfully, the choices for anaesthesia are limited and physiological parameters are likely to be influenced substantially under anaesthesia. We implanted blood pressure radio-telemetry devices into 16 male GPs and subjected them to anaesthesia with ketamine-xylazine (KX), medetomidine-midazolam-fen...
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Introduction: Field potential duration in human pluripotent stem cell (hiPSC)-derived cardiomyocytes is discussed as parameter for the assessment of drug-induced delayed repolarization. In spontaneously beating hiPSC-derived cardiomyocytes field potential duration varies depending on beating rate but beating rate can also be influenced by field po...
Article
The aim of this study was to identify an adequate formulation for a poorly soluble lead molecule (BI-A) that would achieve sufficiently high plasma concentrations after oral administration in dogs to enable a robust cardiovascular safety pharmacology assessment in telemetry-instrumented conscious dogs during lead optimization in drug discovery. A s...
Chapter
This chapter highlights various non-automated classical in vitro techniques used today to evaluate drug effects on cardiac electrophysiology. It then outlines a three-pronged preclinical initiative called the Comprehensive In Vitro Proarrhythmia Assay (CiPA), which consists of understanding the effects of new molecular entities on multiple ion chan...
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Introduction: Guinea pigs (GPs) are a valuable cardiovascular pharmacology model. Implantation of a radio-telemetry system into GPs is, however, challenging and has been associated with a high failure rate in the past. We provide information on a novel procedure for implanting telemetry devices into GPs and we have measured the hemodynamics (arter...
Chapter
In pharmaceutical drug development, cardiovascular side effects are the main safety reason for drug attrition, serious adverse drug reactions, and withdrawal from the market. Drug-induced functional cardiovascular changes (i.e., chronotropy, inotropy, lusitropy, and blood pressure) and associated sequelae account for a significant proportion of tho...
Article
Human induced pluripotent stem cell-derived cardiomyocytes are available from various sources and they are being evaluated for safety testing. Several platforms are available offering different assay principles and read-out parameters: patch-clamp and field potential recording, imaging or photometry, impedance measurement, recording of contractile...
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Introduction: Drug-induced effects on the cardiovascular system remain a major cause of drug attrition. While hemodynamic (blood pressure (BP) and heart rate (HR)) and electrophysiological methods have been used in testing drug safety for years, animal models for assessing myocardial contractility are used less frequently and their translation to...
Article
Thorough QT studies conducted according to the International Council on Harmonisation E14 guideline are required for new nonantiarrhythmic drugs to assess the potential to prolong ventricular repolarization. Special considerations may be needed for conducting such studies with antidiabetes drugs as changes in blood glucose and other physiologic par...
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Background: This study evaluated the influence of repeated anaesthesia using isoflurane (ISO, 2-3 Vol%), ketamine-xylazine (KX, 100 mg·kg(-1) + 5 mg·kg(-1), i.m.) or a combination of medetomidine-midazolam-fentanyl (MMF, 0.15 mg·kg(-1) + 2.0 mg·kg(-1) + 0.005 mg·kg(-1), i.m.) on heart rate (HR), arterial blood pressure (BP), body temperature (BT),...
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Introduction The hERG (human ether-a-go-go-related gene) potassium channel (KV11.1) is an important anti-target in drug discovery as its inhibition by small molecules has considerable promiscuity and is linked to an increased risk of the potentially fatal ventricular arrhythmia torsade de pointes. Therefore, great efforts are taken in the pharmaceu...
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Background This study investigated effects on cardiovascular parameters during anaesthesia with isoflurane (ISO, 2¿3 Vol%), ketamine-xylazine (KX, 100 mg¿kg¿1¿+¿5 mg¿kg¿1) or a combination of medetomidine-midazolam-fentanyl (MMF, 0.15 mg¿kg¿1¿+¿2.0 mg¿kg¿1¿+¿0.005 mg¿kg¿1) in rats throughout induction, maintenance and recovery from anaesthesia. Rat...
Chapter
The inclusion of pharmacological studies (also known as general, secondary, or ancillary pharmacology) in the safety evaluation of new drugs is a well-established practice (Zbinden 1966; Alder and Zbinden 1973). These studies contribute to the safety profile of potential new drugs and provide pharmacological data that can be used for optimization o...
Article
Introduction: In order to differentiate heart rate (HR)-induced changes from drug-induced positive or negative inotropic effects, HR-dependent effects need to be taken into account. Left ventricular (LV)dP/dt(max), the maximal value of the first derivative of a left ventricular pressure signal, is a convenient index for LV contractile state. The o...
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A cardiovascular safety pharmacology assessment is routinely conducted prior to first administration of a new chemical entity or biopharmaceutical to man. These assessments are used to inform clinicians of potential effects in those initial clinical studies. They may also indicate more subtle effects having more relevance for longer term patient tr...
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Introduction: The QT interval of the electrocardiogram (ECG) reflects the duration of ventricular depolarization and repolarization. A drug-induced prolongation of ventricular repolarization, and thereby QT prolongation, is recognized to be a marker for an enhanced risk for ventricular arrhythmia. The assessment of a drug's effect on the QT interv...
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There are several recent examples where clinically significant, safety-related, drug effects on hemodynamics or cardiac function were not apparent until large clinical trials were completed or the drugs entered the consumer market. Such late-stage safety issues can have significant impact on patient health and consumer confidence, as well as ramifi...
Article
In drug development, early recognition of a potential for blocking the human ether-a-go-go related gene (hERG) channels is perhaps the best way to avoid later disappointment when QT interval prolongation shows up in clinical trials. Knowledge of the hERG blocking liability offers the chance to modify the molecule to reduce, or even eliminate, this...
Article
Testing for possible cardiovascular side effects of new drugs has been an essential part of drug development for years. A more detailed analysis of the electrocardiogram (ECG) to detect effects on ventricular repolarization (effects on the QT interval), as a marker for possible proarrhythmic potential has been added to that evaluation in recent yea...
Article
The objective of this study was to use a newly established cardiovascular model using freely moving minipigs to document the hemodynamic and electrocardiographic effects of known pharmacological agents. The data generated are to serve as the basis of pharmacological drug safety evaluations using this new model. 6 Göttingen minipigs were equipped wi...
Article
The objective of this study was to evaluate the normal cardiovascular and ECG parameters in freely moving minipigs and to use these data as the basis of pharmacological drug safety evaluation. 7 Göttingen Minipigs were equipped with radiotelemetry transmitters (ITS). Aortic pressure (AP), left ventricular pressure (LVP), lead II of the ECG and body...
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Safety pharmacology assessments of new drug candidates have recently been described in regulatory guidances (International Conference on Harmonisation [ICH] S7A and ICH S7B) in which the objectives of such studies have been laid out and experimental approaches recommended. It is also clearly stated that when these studies support clinical developme...
Article
The objective of this study was to define the normal LVdP/dt (an index of myocardial contractility)-heart rate relationship in telemetered conscious dogs, primates and mini-pigs in our laboratory and to use these data as the basis for an additional parameter useful in drug safety evaluation. Trained dogs, Rhesus monkeys, Cynomolgus monkeys and mini...
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Monocyte chemoattractant protein-1 (MCP-1) is a stimulator of collateral artery growth and has been shown to increase collateral artery conductance in rabbits and pigs. The minimal infusion duration and the minimally effective dose of MCP-1 are currently unknown, as is the sustainability of the therapeutic effect over a longer observation period th...
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The objective of this study was to test the influence of housing conditions on hemodynamics during cardiovascular general pharmacological studies. Our goal was to optimize both the quality of the data through an optimization of the physiological conditions, as well as to ensure the dog's well-being in general pharmacological studies. Two groups of...
Article
Solubility is often a limiting factor when testing new compounds in animal experiments. Various solubilizing agents may be used, but each have their own pharmacological effects. We investigated the effects of selected vehicles having different chemical characteristics on gastrointestinal, renal, and liver function. Rats were treated orally, intrave...
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Local infusion of recombinant monocyte chemoattractant protein-1 (MCP-1) has been shown to enhance collateral artery formation in rabbit and pig hindlimb models. Owing to clinical disadvantages of protein infusion, a nonviral, liposome-based MCP-1 gene transfer was developed. Collateralization in a porcine hindlimb model served to provide a proof-o...
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Estimation of possible cardiovascular side effects belongs to the safety assessment of every drug candidate. This paper describes a new strategy for treating conscious labrador dogs with drugs by inhalation using a specially designed mask and a novel inhaler device. Labrador dogs (male or female) were used that had transducers implanted for the mea...
Article
To characterize the pharmacokinetics of terbogrel, a new combined thromboxane A2 (TxA2) receptor and synthase inhibitor, in healthy human subjects after single or multiple oral administration. Forty-eight healthy male subjects received a single oral dose (10, 25, 50, 100, 150 or 200 mg) of terbogrel or placebo and 32 different subjects received one...
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The aspects for developing a strategy for the preclinical testing of drug candidates for proarrhythmic potential are presented. The rationale for such a strategy reflects primarily the needs for efficient and scientifically based drug development and also attempts to anticipate the possible outcomes of the currently ongoing regulatory activity (ICH...
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For an appropriate extrapolation to patients with peripheral arterial obstructive disease, we tested the efficacy of monocyte chemoattractant protein 1 (MCP-1) treatment in a porcine hindlimb ligation model. In 40 minipigs, a femoral artery ligation was performed. Control animals were examined immediately after ligation (n = 4) or after 2 wk of int...
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The general pharmacologist in the pharmaceutical industry is challenged to generate physiologically relevant data on possible safety liabilities or on secondary therapeutic uses as early as possible in drug development. This implies the need for efficient use of usually only small supplies of test article. For this reason, we have developed a new a...
Article
A new series of omega-disubstituted alkenoic acid derivatives derived from samixogrel 5 were designed and synthesized as combined thromboxane A2 receptor antagonists/thromboxane A2 synthase inhibitors with improved solubility and reduced protein binding compared to 5. Hexenoic acid derivatives with a 3-pyridyl group and 3-(2-cyano-3-alkyl-guanidino...
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The objectives of general pharmacology (GP) studies from the point of view of pharmacologists working in the pharmaceutical industry are presented and compared with the requirements of regulatory authorities, using the Japanese Guidelines as an example. Based on these requirements, as well as the internal requirements of other departments involved...
Article
The glycoprotein (GP) IIb/IIIa (the alphallb beta3 integrin) found on platelets binds fibrinogen or von Willebrand factor when the platelet is activated, thereby mediating the aggregation of platelets. Blockade of the GPIIb/IIIa should prevent platelet aggregation independent of the substance or substances responsible for activating the platelets....
Article
Combined thromboxane A2 receptor blockade and thromboxane synthetase inhibition facilitates local prostacyclin production at the site of platelet activation thereby providing a potent antithrombotic effect. The efficacy of DTTX30, a combined thromboxane A2 receptor blocker-thromboxane synthetase inhibitor, in inhibiting recurrent coronary thrombosi...
Article
Using acetylsalicylic acid-dipyridamole, a combined thromboxane receptor antagonist-thromboxane synthase inhibitor, and a fibrinogen receptor antagonist as examples, this article discusses the predictive value of several methods that may be employed in the evaluation of antiaggregatory effects and their suitability as surrogate markers for the plan...
Article
This study determined the antithrombotic efficacy of BIBV308SE, a combined thromboxane A2 receptor antagonist and thromboxane synthetase inhibitor, in a model of an injured human blood vessel in vitro. The role of vascular cells in modifying the antithrombotic effect of this agent was also addressed. Human whole blood was allowed to flow over throm...
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This article reviews the mode of action of pharmacologic agents for anti-thrombotic therapy. It refers to both clinically established drugs and new approaches currently under preclinical or clinical development. Advantages and limitations of the different pharmacologic strategies are discussed with special attention to their effects on local intera...

Citations

... In 2018, a working group was assembled to develop International Council for Harmonisation (ICH) E14/S7B Questions and Answers (Q&As) for clarification of the proarrhythmia guidelines (ICH, 2020). The hiPSC-CMs model is discussed in this guidance, and it is expected that using both nonclinical and clinical data will enable a more comprehensive, but flexible, clinical risk assessment strategy for QTc monitoring (Strauss et al., 2021;Vargas et al., 2021). In general, hiPSC-CMsbased assays have not been fully accepted as validated methods to make a significant impact on the safety assessment of drug candidates. ...
... On the other hand, regulatory agencies seem to struggle to interpret some of the data generated with NAMs for risk assessment purposes. As described in Section 2, the guidance documents are unclear in regards to NAMs that are currently readily used and accepted (as in example 3.2) and which NAMs may require (Guns et al., 2020) Overview of cardiovascular toxicity testing (not specifically NAMs) ...
... Koivumäki et al. developed an improved hiPSC-CM ventricular model by using the membrane ion current equations of the Paci 2013 ventricular model combined with the cell geometry and Ca 2+ dynamics equations of a mouse embryonic ventricular cardiomyocyte model [178]; the enhanced model was used to simulate changes associated with Brugada syndrome, LQT syndrome and catecholaminergic polymorphic ventricular tachycardia (CPVT), concluding that immature Ca 2+ handling in hiPSC-CM prevents accurate in silico modeling of the arrhythmogenic consequences of these diseases [179]. Another recent study comparing simulation results using the Paci 2018 ventricular hiPSC-CM model with experimental extracellular field potential recordings showed that the model failed to accurately reproduce interbeat intervals and durations of repolarization, presumably due to the approximate equations for the ''funny'' hyperpolarization-activated current [180]. ...