DSP Flashcards
According to ICH S7B, what concentration of a positive control substance is sufficient to demonstrate the responsiveness of ion channel assays and should be included in every study? (ED = effective dose)
EDsub-maximally effective
Which subunits of Troponin is/are good biomarkers of acute cardiac tissue damage?
Troponin I and T
The ICH S7A guideline provides a definition, general principles, and recommendations for safety pharmacology studies. Which of the following is a correct statement?
Supplemental studies are meant to evaluate potential adverse pharmacodynamic effects on organ system functions not addressed by the core battery or repeated dose toxicity studies when there is a cause for concern
Which of the following would be expected to decrease gastrointestinal motility?
Fentanyl, Morphine, Loperamide
The correct configuration of ECG limb leads can be summarized as:*-
I = LA-RA, II = LL-RA, III = LL-LA
What is the circle of Willis?
The arterial structure providing blood supply to the brain
Which parameter should be referred to as “proportion of variance which can be explained by the model” when you fit a linear regression?
R2 (coefficient of determination)
Which of the following statements is correct in relation to respiratory safety pharmacology evaluations?
Respiratory changes after drug administration observed in safety pharmacology studies are commonly secondary effect from general toxicity (i.e., not direct effects on the pulmonary system)
Lesions in what system are the most common reason for increase in serum alanine aminotransferase?
Hepatic
In toxicology, which of these are critical factors to consider when selecting a 2nd species?
Metabolite profile is similar to man
Expression of target
Non-rodent (if 1st species is a rodent)
Pharmacokinetic profile of active compound
Cardiac contractility is an important measure of cardiac function. Which of the following would not be considered a measure of cardiac contractile function?
JT interval
The Comprehensive In vitro Proarrhythmia Assay (CiPA) is a new paradigm proposal that is currently being developed for the evaluation of cardiac safety of new drugs. Which of the following statements is incorrect about CiPA?
CiPA would replace ECG Evaluation on clinical studies
Which of the following is a biomarker of renal toxicity?
Neutrophil gelatinase-associated lipocalin
A compound with a total plasma exposure of 900 ng/mL, Fu of 0.01 and a molecular weight of 450 would have a free exposure of?
20nM
Adverse Drug Reactions in human fall into 5 types (A to E). Which one is primarily predicted by safety pharmacology studies?
A
What is the fixative used at necropsy for the eyes?
Modified Davidson’s Solution
What is the primary difference between a Single Compartment and a Multiple Compartment in PK modeling?
A Single Compartment model produces a linear line, as it assumes all tissues are located in a single compartment, and is the simplest model; A Multiple Compartment model does not produce a linear line (non-linear) as it assumes there are multiple factors and compartments that influence drug kinetics and disposition.
What is the most sensitive indicator for skeletal or cardiac muscle injury?
Creatinine Kinase (CK)
Among the cytochrome P450 (CYP) isoforms, which is the most abundantly expressed and involved in the metabolism of approximately 50% of all clinically administered drugs?
3A4
Which of the following statements regarding Standard Operating Procedures (SOPs) is correct with respect to Good Laboratory Practices (GLPs
Outdated SOPs must be retained in the archives
Which one of the following assays would not be performed to evaluate the potential pharmacological effects of a non-biological test article on the heart? (
In vitro Ames assay
According to ICH S7A, a screening battery to further evaluate neurobehavioral safety of a test article should include? (CNS; source ICH S7A)
functional observational battery, an evaluation of motor activity and body temperature
In-vivo, over production of the cytokine tumor necrosis factor alpha (TNFα) can produce? (Cardiovascular; source Veterinary Internal Medicine, Vol 2, page 1156)
Inflammation
Which of the following is utilized as a serum biomarker to assess drug-induced cardiac injury?
Troponins
Which one of the following statements is not true regarding Material Safety Data Sheets (MSDSs)? (Regulatory; General Knowledge of MSDSs and OSHA requirements)
MSDSs are required for all food or cosmetics
GLP regulations require all of the following except?
The study director must have a masters or doctoral degree
Which of the following dose schedules within an experimental design would most likely give the maximal information of a test article? (
One no effect, one no adverse effect and one adverse effect dose
For a cardiovascular safety pharmacology study in dogs, the animals administered test article were housed in laboratory dose room A while the controls for the study were housed in laboratory dose room B at the other end of the hall next a noisy cage wash facility. This may hinder interpretation due to?
Confounding of effects
According to the FDA GLP’s the final report of a preclinical study must contain all of the following except?
Age and weight of each investigator involved in the study
Resistance to the pharmacologic effects of some drugs can be rapidly determined following only a few doses of the test article over a period of hours. Therefore, subsequent doses of the test article fail to elicit the response regardless of the size of the dose. This is an example of? (General Toxicology/General Safety Pharmacology)
Tachyphylaxis
A monkey has a respiratory rate of 30 breaths/min and a tidal volume of 100 mL/breath. This monkey has a minute volume equal to which of the following?
3.0 liters/min
When compared across species, the dose of a drug is generally most closely proportional to?
BSA
Which of the following represent the most efficient and also the most scientific approach to a study in which 12 rats are used (4 rats/3 doses groups) and 2 laboratory technicians making the same observations?
Randomize assignment of doses to animals and have the laboratory technicians blinded to the doses of the study
Phase 0 of the ventricular action potential best represents which of the following?
Sodium ions entering the cell through the Nav1.5 channel
Rapid upstroke phase representing cellular depolarization
All of the following are members of the potassium (K+) ion channel group except?
KP11.1
Which of the following cardiac potassium ion currents does not play a role in Phase 3 of the action potential duration?
IKto
Calcium ions responsible for Phase 1 of the ventricular action potential flow through which subunit of the L-Type calcium protein channel?
CaV1.2
Na+ channel blockade of fast Na+ channels (Class Ia antiarrhythmics) would result in the following change(s) to the electrocardiogram?
QRS prolongation
The rat is not an acceptable test system to assess ventricular repolarization due to the lack of which of the following?
IKr channels
The guinea pig has all the cardiac ion channels similar to man, except?
IKto
Blocking the IKf or “funny channel” with a drug like zatebradine or ivabradine will result in which of the following?
Reduction in heart rate
The ratio of true positive findings to the total number of positive findings or total actives is the definition of:
Sensitivity
According to ICH S7A, the definition of Safety Pharmacology includes all of the following, except
Investigate the potential undesirable pharmacokinetic effects
How is the pressure rate product derived?
Heart rate x systolic blood pressure
Which one of the following refers to the period right before the onset of seizure activity?
Pre ictal
Which one of the following compounds may be used as a marker for the rate of gastric emptying?
Paracetamol
What pharmacokinetic effect of an IV administered drug would be expected if the drug decreases blood flow:
An increase in half life
Sharp waves, as measured by an EEG, are most accurately defined as:
Concomitant depolarization of adjacent neurons
The following factors are important in considering seizurogenic potential of a test compound, except:
Body weight
In the first derivative of a pressure wave form known as dP/dtmax, the “t” refers to:
Time
The time from the initial rapid deflection of the atrial wave to the initial rapid deflection of the His bundle (H) potential is known as what interval?
AH
A commonly used positive control drug used to induce seizurogenic activity is?
Ptz
Which one of the following is not one of the three regulatory proteins involved in contraction of skeletal and cardiac muscle?
J
A phenomenon of increased sensitivity of the heart to epinephrine caused by exposure to hydrocarbons is known as?
Cardiac sensitization
The dyssynchrony between the thoracic and abdominal regions during the respiration cycle is known as?
Paradoxical respiration
What ECG interval is typically the shortest in duration in the dog?
QRS
The cardiac myocyte sodium ion channel is known as
Nav 1.5
Which one of the following parameters are considered a functional endpoint of respiratory measurements?
Tidal Volume
Minute Volume
Fractional Inspiratory Time
Breathing (respiratory) rate
Which of the following are commonly used enzyme to assess liver function?
ALT (alanine aminotransferase)
AST (aspartate aminotransferase)
ALP (alkaline phosphatase)
GGT (gamma-glutamyltransferase
Which of the following is not a commonly used enzyme to assess liver function?
IL6 (interleukin-6)
Tryptophan is converted to ____________ and then to serotonin?
5-HTP
Prothrombin time (PT) and Activated Partial Thromboplastin Time (APTT) are common indicators of what?
Blood coagulation properties
When measuring left ventricular contractility using the Cyon-Frank-Starling curves, what physiological parameters must be held constant?
Heart rate
Aortic stiffness
Left ventricular compliance
Although used frequently, dP/dtmax, in fact, may or may not be an index of cardiac contractility since it is influenced by which of the following:
Afterload
Preload
Heart rate
Left ventricular radius
According to this phenomenon, dP/dtmax and all other indices of contractility are influenced by heart rate.
Bowditch effect
Which of the following intervals is typically the shortest in duration regarding a normal mammalian electrocardiogram?
QRS
The QA interval is defined as the duration from the onset of the Q wave (on an ECG) to the:
Initial upstroke on the aortic pressure wave
Which of the following is a potential end point of the Langendorff isolated heart model assay?
Heart Rate
Left ventricular pressure
Protein biomarkers
Electrocardiogram
What is the period of reduced amplitude of the EEG signal following a seizure?
Postictal
Which of the following compounds are considered positive inotropic agents?
Pimobendan
A study requires the collection of blood pressure and ECG as well as a toxicological assessment of hematological parameters in the same animal model. The FDA would recommend the following:
Conduct a standalone safety pharmacology study using implanted telemetry that is separate from the toxicology study
According to ICH S7A, safety pharmacology studies are defined as those studies that investigate the potential pharmacodynamic effects of a substance on physiological functions in relation to exposure in the .
therapeutic range and above
According the ICH S7A, safety pharmacology studies are defined as those studies that investigate the potential effects of a substance on physiological functions in relation to exposure in the therapeutic range and above
pharmacodynamic
Studies on the mode of action and/or effects of a substance in relation to its desired therapeutic target are pharmacodynamic studies. Studies on the mode of action and/or effects of a substance not related to its desired therapeutic target are pharmacodynamic studies.
primary/secondary
Which of the following respiratory system parameters are not mentioned in the ICH S7A guidelines section 2.7.3?
compliance
Which of the following is considered to be a supplemental safety pharmacology study and not considered part of the core battery
Renal/Urinary System
Autonomic Nervous System
Gastrointestinal System
Other Organ Systems
What is the common substance administered as an oral suspension and measured in travel distance in assays performed to measure gastrointestinal tract transit time?
charcoal
What is the common substance administered orally and the absorbance measured in assays performed to measure gastric emptying?
Phenol red
Which of the following research models should have the highest basal respiratory rate?
Sprague-Dawley rat
Which of the following compounds is often used as a positive control to induce bronchoconstriction?
methacholine
Which of the following are CNS targets associated with the rewarding effects of drugs of abuse?
dopaminergic receptors
cannabinoid receptors
nicotinic receptors
GABAergic receptors
You are investigating a pharmaceutical compound that is found to significantly prolong the QT corrected interval in both dog and guinea pig animal models in a dose proportional manner. What should your suggestion be for moving forward with the compound assessment?
suggest to further assess the data with QT cloud analysis, QT restitution analysis, and QT variability analysis to determine the torsadogenic risk of the prolongation.
You are investigating a pharmaceutical compound that has a significant effect on pulse pressure but no significant change in systolic or diastolic pressure. What are possible causes of this scenario?
though not significant individually, the systolic and diastolic pressures are diverging and creating a synergistic and significant impact on the pulse pressure.
though not significant individually, the systolic and diastolic pressures are converging and creating a synergistic and significant impact on the pulse pressure.
While monitoring heart rate (HR) and cardiac output (CO) in an anesthetized pig, HR increased and CO decreased compared to baseline levels. This is a direct result of which of the following?
A decrease in stroke volume
An upper respiratory irritant would be expected to cause which of the following respiratory wave forms.
End inspiratory pauses
Saxitoxin is a product of which of the following organisms.
Dinoflagellates
Amiodarone is used to treat which of the following cardiovascular irregularities.
Ventricular Fibrillation
IV. Ventricular Tachycardia
Bleomycin is commonly used in-vivo to induce which of the following respiratory models.
Fibrosis
According to ICH S7A when selecting and designing Safety Pharmacology studies all of the following should be considered except.
Action potential parameters in isolated cardiac preparations or specific electrophysiology parameters indicative of action potential duration in anesthetized animals.
Benzodiazepines are commonly used as a positive control for which of the following CNS test.
Elevated Plus Maze
Which of the following physiologic factors potentially alter sensory evoked potentials (SEP’s
Temperature
II. Hypotension
III. Hypoxia
IV. Hypocarbia
V. Isovolemic hemodilution
The global regulatory submission requirement developed by the Clinical Data Interchange Standards Consortium referred to as “SEND” is an acronym for the following:
Standard for Exchange of Nonclinical Data
An example of an immune mediated hypersensitivity response to administration of liposomal based therapy referred to as “CARPA” is an acronym for the following:
C activation-related pseudoallergy
The assessment of beat-to-beat variation in either heart rate or duration of the R-R interval using time and frequency domain analysis is referred to as:
HRV
This digestive organ is comprised of the ascending, transverse, descending, sigmoid and rectal regions
Large intestine
Descriptions for animal models in Cardiovascular Safety Pharmacology studies should be conducted in the following, except:
anesthetized
True or False. According to Laverty et al (2011), over the past 15 years, adverse drug reactions (ADRs) and drug withdrawal from the market place revealed that hepatotoxicity occurred more frequently than cardiovascular toxicity?
False; cardiovascular toxicity occurs more frequently and hepatotoxicity
According to ICH S7A, of the following endpoints, which should be evaluated in a respiratory safety pharmacology study:
Respiratory rate
Clinical observations
According to ICH S7A, all of the following should be evaluated in a CNS safety pharmacology study, except:
electrocardiogram
According to ICH S7A, follow-up (Supplemental) studies are recommended, of the following endpoints, which would be recommended for a respiratory safety pharmacology follow-up study?
Lung compliance
Blood gases
Blood pH
Pulmonary arterial pressure
Bioavailability of a drug is defined by the fraction of the drug in the blood or plasma (administered dose), which route of administration would result in 100% bioavailability?
IV
Drugs can be reduced or eliminated via multiple routes from the body, which of the following are examples of how drugs are reduced or removed from the body?
Exhalation via the lungs
Urine via the kidney
Biotransformation in the liver
Which of the following study designs provides the most statistical power using the fewest animals?
Latin-square cross-over design
Oral dosing is the most common route of delivery as it is convenient, relatively safe and economical. However, what is a disadvantage?
It cannot be used for drugs that can irritate the gut
The Tetrad test is a series of behavioral paradigms in which rodents treated with cannabinoids such as THC show effects. It is widely used for screening drugs that induce cannabinoid receptor-mediated effects in rodents. The four behavioral components of the tetrad are:
spontaneous activity, catalepsy, hypothermia, and analgesia.
Spontaneous activity as part of the Tetrad test is determined by:
An open field test, in which a rodent is placed in an arena with perpendicular grid lines, usually spaced by approx. 1 inch. An experimenter counts the number of line crossings by the rodent in a given amount of time.
Which of the following is a vasoactive compound which may cause dilatation of the blood vessels, rash, increased mucus production, and bronchoconstriction.
Histamine
Drug abuse-related studies in animals would consist of which of the following:
General behavioral observations from safety pharmacology studies, drug discrimination study, self-administration study, and physical (drug) dependence study
Repeated dosing for 2-4 weeks and evaluate signs of withdrawal from drug – including clinical signs, body weights, food intake, and other relevant assessments would best describe:
Physical (drug) dependence study
Absolute bioavailability is defined best
The amount of drug from a formulation that reaches the systemic circulation relative to an intravenous (IV) dose.
Which one of the following factors does influence bioavailability?
Absorption
Drug Metabolism/biotransformation
CYP450 isozymes
Which of the following statistical analysis techniques are considered to improve the sensitivity of the analysis?
Include a baseline covariate
Parametric analysis instead of nonparametric analysis
Use a quantitative response instead of a qualitative response
In 1972, Ronald J. Racine developed a method to split the severity of seizures into 5 stages. Which are some of the 5 classical stages?
Mouth and facial movement
Head nodding
Forelimb clonus
Rearing with forelimb clonus
Safety Pharmacology assessments are required to be conducted for all new chemical entities (NCE) with the exception of which of the following:
NCEs of oncology indication
Which of the following is an ICHS7A accepted measure of respiratory function:
Arterial blood gas analysis
Which of the following is considered to be a known biomarker for lowered seizure threshold:
Organized sharp waves
Which of the following are considered to be an acceptable measure for assessing proarrhythmic risk:
TQ/QT ratio
QT Instability
TRIaD
This is a known biomarker for kidney function
Glomerular Filtration Rate
Which of the following drugs is known to cause lowered seizure threshold:
Pentylenetetrazol
Which of the following endpoints would provide the most accurate assessment for dosimetry calculation:
Minute Volume
A seizure which propagates from one hemisphere of the brain across the midline is known as:
Generalized Seizure
Electrographic seizures are observed in 6/6 monkeys following an intravenous bolus dose of compound X at 15 mg/kg. No seizures are observed following an infusion (10 minutes) of compound X at 30 mg/kg despite 2X increase in AUC following infusion of 30 mg/kg.
Which of the following statements is true:
The liability is rate dependent
This receptor is commonly involved with the treatment of seizure disorders:
GABA
What is the definition of catalepsy?
A nervous condition characterized by muscular rigidity and fixity of posture regardless of external stimuli, as well as decreased sensitivity to pain
What term encompasses a decrease in body weight, anorexia, fatigue and muscle loss?
Cachexia
What is one function of the Rotarod test?
Evaluating balance and coordination of the subjects
What are the effects of CB1 receptor agonism?
Analgesia
Hypothermia
Catalepsy
Hypolocomotion
Decrease in operant response
What are the effects of CB1 receptor agonism?
Analgesia
Hypothermia
Catalepsy
Hypolocomotion
Decrease in operant response
There are 5 main types of muscarinic receptors. Which receptor is located in many places throughout the body including the detrusor muscle and urothelium of the bladder, causing contraction, and also increased ciliary function?
M3
What is the name of the electrophysiological test that assess the visual cortices?
Visual Evoked Potential (VEP)
What is the name of the electrophysiological test that assess the visual cortices?
Visual Evoked Potential (VEP)
Cardiac valvopathy is driven by which serotonin receptor?
5HT2B
What is the term meaning a “reduced bile flow from the liver?”
Cholestasis
What is the term meaning a “reduced bile flow from the liver?”
Cholestasis
Concomitant consumption of verapamil with grapefruit juice can cause what potential effects?
Amplification of blood pressure/dromotropy/chronotropy (i.e., increase bioavailability)
Concomitant consumption of verapamil with grapefruit juice can cause what potential effects?
Amplification of blood pressure/dromotropy/chronotropy (i.e., increase bioavailability)
Grapefruit juice is known to alter the PK of oral medications by different mechanisms. What enzyme, found in the intestinal apical enterocytes and hepatocytes, whose normal function is to oxidize drugs before they enter the systemic circulation, is grapefruit juice known to inhibit?
CYP3A4
