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K.SHIRISHA
170117887005
G. Pulla Reddy College of Pharmacy
13/7/2018

I Safety Pharmacology Core Battery
? Safety pharmacology core battery is to investigate the effects of the test
substance on vital functions.
? Central Nervous System
? Cardiovascular System tier 1
? Respiratory System
Follow-up Studies For Safety Pharmacology Core Battery
? These are meant to provide a greater depth of understanding than, or
additional knowledge to, that provided by the core battery on vital
functions for potential adverse pharmacodynamic effects

II Supplemental Safety Pharmacology Studies
? To evaluate potential adverse pharmacodynamic effects on organ
system functions not addressed by the core battery or repeated dose
toxicity studies
? Renal/Urinary System tier 2
? Gastrointestinal System
? Other Organ Systems Skeletal system
Immune & endocrine functions

I Safety Pharmacology Core Battery
1. Central Nervous System
In core battery In follow up studies
? Motor activity learning and memory
? Behavioral changes ligand-specific binding
? Coordination Neurochemistry
? Sensory/motor reflex response Visual & auditory examination
? Body temperature

Evaluation methods
? Functional observation Battery (FOB)
? Modified Irwin's test
FOB
neurotoxicological and
neuropathological investigations

Other established techniques
? Rotarod
? Hot plate test, Tail flick, paw pressure
? photoelectric beam interruption techniques
? passive avoidance tests
? Pentylenetetrazol (PTZ) seizure tests
? Electroencephalography (EEG)
Emerging techniques
? Automated video systems
? Integrated video and EEG systems

2. Cardiovascular system (CVS)
? Core battery Follow up studies
? Blood pressure Cardiac output
? Heart rate Ventricular contractility
? Vascular resistance
? endogenous & exogenous substances
on the cardiovascular responses

Evaluation methods
? Electrocardiogram (ECG)
Established techniques
In vitro
hERG assay
The effects of an NCE on the hERG channel can be detected using
screening methodologies such as
? Manual patch clamp
? Automated high-throughput patch clamp
? Isolated organ preparation
? Whole heart preparation
? Isolated purkinje fibres

hERG assay (human Ether-a-go-go Related Gene)
? The alpha subunit of a potassium ion channels in the heart that codes for a
protein known as Kv11.1
? ion channel proteins (the 'rapid' delayed rectifier current (IKr)) that conducts
potassium (K+) ions out of the muscle cells of the heart
? Inhibition of the hERG current causes QT interval prolongation resulting in
potentially fatal ventricular tachyarrhythmia called Torsade de Pointes.

3.Respiratory system
? Core battery Follow up studies
? Respiratory rate Airway resistance
? Tidal volume compliance
? Haemoglobin oxygen saturation pulmonary arterial pressure
? blood gases
? blood pH.

Evaluation methods
? Plethysmography
? Head out Plethysmography
? whole body plethysmography
? Respiratory parameters:
? Inspiratory Time (Ti, ms)
? Expiratory Time (Te, ms)
? Peak Inspiratory Flow (PIF, ml/s)
? Peak Expiratory Flow (PEF, ml/s)
? Tidal Volume (TV, ml)
? Respiratory Rate (ResR, breaths/min)
? Relaxation Time (Tr, ms)

II Supplemental Safety Pharmacology Studies
1.Renal/Urinary System
Renal parameters should be assessed are
? Urinary volume,
? specific gravity,
? osmolality,
? pH, fluid/electrolyte balance,
? proteins, cytology, and
? blood chemistry determinations such as blood urea nitrogen, Na+,
Cl-, K+, creatinine and plasma proteins

Kidney injury markers
Functional markers leakage markers
? urinary glucose aspartate aminotransferase (AST),
? Protein alanine aminotransferase (ALT),
? Albumin lactate dehydrogenase (LDH),
? Calcium ��-glutamyl transferase (GGT),
? alkaline phosphatase (ALP)
? N-acetyl-��-D-glucosaminidase (��-NAG)
? new kidney injury molecule-1 (KIM-1) and
? markers Clusterin (CLU)
? These kidney injuries are assessed primarily using histology

2. Gastrointestinal System
? Gastric secretion
? Gastrointestinal injury potential
? Bile secretion
? Transit time in vivo
? Ileal contraction in vitro
? Gastric pH measurement
? Gastric emptying
? Intestinal motility
? Emesis induction

Evaluation methods
? Barium sulphate (BaSO4) or a charcoal test meal
? pylorus ligation test
Emerging techniques
? Endoscopy
? Biomarkers
? EMG Citrulline
? miR-194
? Calprotectin

Alternate models
? Zebrafish model: anticonvulsant activity, locomotor activity, behavioural
paradigms such as addiction, memory and anxiety.
? human embryonic stem cell derived cardiomyocytes (hESC-CM) and
human inducible pluripotent stemcell derived cardiomyocytes (hiPS-CM) as
models of in vitro high throughput drug screening and CVS safety assessment.

Conditions under which Studies are not Necessary
? Safety pharmacology studies may not be needed for locally applied agents.
e.g., dermal or ocular
? cytotoxic agents with novel mechanisms of action, there may be value in
conducting safety pharmacology studies.
? For biotechnology-derived products that achieve highly specific receptor targeting,
it is often sufficient to evaluate safety pharmacology endpoints as a part of
toxicology and/or pharmacodynamic studies, and therefore safety pharmacology
studies can be reduced or eliminated for these products.
? For biotechnology-derived products that represent a novel therapeutic class and/or
those products that do not achieve highly specific receptor targeting, a more
extensive evaluation by safety pharmacology studies should be considered.
? A new salt having similar pharmacokinetics and pharmacodynamics properties-
safety pharmacology studies are not necessary.

REFERENCES
? Safety Pharmacology Studies for Human Pharmaceuticals S7A, Current Step
4 version , dated 8 November 2000.
? Toxicology and Applied Pharmacology, Safety pharmacology �� Current
and emerging concepts, YTAAP-12785; No. of pages: 10; 4C: 3
? https://www.cyprotex.com/toxicology/cardiotoxicity/hergsafety

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