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Pharmacodynamics

Verifying the efficacy of your lead molecules is of crucial importance prior to investing further on lead optimization. A number of in vitro and in vivo models to study the effect of the drug in different therapeutic applications are available. In vitro systems are often proposed in the early phases of drug discovery, while the in vivo models are used to support the regulatory strategy.
In particular, bone/cartilage, CNS and tumor models have been developed.

Bone and cartilage
In vitro test: Cultures of osteoblasts, osteoclasts, synoviocytes and chondrocytes can be used for mimiking the disease and assess drug functionality by measuring:

  • cytokine release
  • collagen synthesis
  • hyaluronic acid synthesis
  • GAG synthesis
  • Enzyme activities
  • Bone mineralization
  • Bone resorption/formation
  • Phenotype
  • Gene expression (PCR, qPCR, microarrays)
  • Proteome analysis


In vivo models:

  • osteoporosis (by ovariectomy, immobilization, GC-induced).
  • osteoarthritis (by ACL resection).
  • rheumatoid arthritis (induced by collagen injection).
  • osteointegration of titanium implants.
  • fracture healing.


Observation: histology, histomorphometry and immunohistochemistry
Blood and urine analyses for the detection of specific markers.
Gene expression and proteomic analysis on biological samples.

CNS
In vitro test: Neurons can be cultured and submitted to different stress conditions: cumene hydroperoxyde-induced oxydative stress, oxygen/glucose deprivation.
The efficacy of the drug can be evaluated by cell viability, LDH assay, ROS inhibition, enzymatic activities.

In vivo models:
Cerebral ischemia (MCAO): we have settled a model of focal cerebral ischemia induced by transient middle cerebral artery occlusion in obese, diabetic and hypertensive rats. This model is much more robust and valid, in comparison with other methods, and is a good predictor of therapeutic efficacy since it has more similarity to the human conditions. A number of analysis can be performed on this model to monitor the evolution of the disease and to evaluate the impact of drug treatment:

  • blood pressure
  • brain circulation
  • animal behaviour
  • brain histology
  • enzyme activity
  • proteomic analysis
  • miRNA
  • gene expression.


Mood disorders:

  • Elevated plus-maze
  • Black/white box
  • Chronic mild stress
  • Forced swim
  • Open field
  • Appetite behaviour


Seizures: Induced convulsions in mice (electroshock, chemicals)

Oncology
In vitro test: In vitro cell growth/viability

In vivo models: Human tumor xenografts in SCID and athymic nude mice (subcutaneous or orthotopic).

Haematology

  • Iron deficiency anemia in rats
  • Bone marrow ablation in rats


Dermatology

  • Psoriasis (mouse tail para/orthokeratosis)


All our studies are tailored on the customer’s request. We also offer development a novel disease models, including the analytics capabilities in Galileo Research, including genomics, proteomics, gross and histopathology, biochemical, clinical chemistry, hematology etc.