Professional Documents
Culture Documents
FA-5111 (3 sks)
Aspek Umum & Regulasi
Dosen: Tutus Gusdinar Kartawinata
Laboratorium Biokimia Medik & Kimia Klinik
Kelompok Keilmuan Farmakokimia
Sekolah Farmasi Institut Teknologi Bandung
gusdinar@fa.itb.ac.id
Drugdiscoveryandpreclinicaltrials
Thedevelopmentofnewdrugsoverthepast
30yearshasrevolutionalizedthepracticeof
medicineandhasforinstanceseenthe
increaseduseofnewantihypertensives and
drugsthatreducecholesterolsynthesisor
dissolvebloodclotswhichledtoa50%
reductioninthenumberofdeathsfrom
cardiovasculardiseasesandstrokeamong
otherdiseases.
ConventionalapproachestoDrugdiscovery
Traditionalknowledgeapproach
Thisisthediscoveryofdrugsbasedontraditionalmedicalknowledge.
Thebestexampleisthedocumentedanalgesiceffectsofextractsfrom
opiumpoppythatledtotheisolationofmorphinefromtheplantand
thesubsequentsynthesisofrelatedanalgesics.
Discoverythroughserendipity
Thisistheaccidentaldiscoveryofnoveldrugsbasedontheingenuityof
ascientistinvestigatingaprobleminitiallyunrelatedtotheobserved
phenomenon;examplesofsuchdiscoveriesincludetheobservationby
AlexanderFlemmingsthatpenicilliummouldcouldinhibitthegrowthof
bacteria.Thisfindingledtothediscoveryofantibiotics.Discoveryof
therapeuticusefulnessofasideeffecte.g.clonidineoriginallyusedasa
nasaldecongestantwasfoundtohaveantihypertensive properties
while,thehypoglycemiceffectsofsulphonamidesusedinthetreatment
oftyphoidfeverledtothedevelopmentofstructurallyrelated
sulphonylureasasoralhypoglycemicdrugs.
Discoveryfromeffectsofendogenousagentsintestanimals
Anexampleofdiscoveryarisingfromstudiesofendogenous
agentsintestanimalsistheanticoagulantactionofthe
venomfromtheMalayanviperthatledtotheidentification
oftheanticoagulantancrod.
Modernapproachestodrugdiscovery
Thesearethoseapproachesthatformabasisfortherational
designofdrugs.
Bioprospecting
Thisisthescreeningofalargenumberofnaturalproducts,
chemicalentities,largelibrariesofpeptides,nucleicacids
andotherorganicmoleculesforbiologicalactivity.This
approachmayleadtoidentificationanddevelopmentof
newdrugmolecules.
Metabolomics
Thisistheprofilingofnaturalproductsofrelatedplant
speciesscreeningusingeitherliquidorgaschromatography
massspectrometrytodetermineactivemetabolitesthat
maybepresentinnovelcrudeherbalmedicalpreparations.
Insilicoscreening
Thisisthemostadvancedtechniquefordrugdiscovery.It
entailsvirtualscreeningordockingofcompoundsonthe3
D structureofaknownreceptorbasedonhomologiesof
thetestdrugmoleculeswithaknowntestparentdrug.In
silicoscreeningcanformabasisforthemodificationofa
knowndrugmoleculetodeterminepossibletherapeutic
applicationsandmayleadtothedevelopmentofputative
drugs againstnewtargets.
Screeningofputativedrugmolecules
Selectionofmoleculesforfurtherstudyisusuallyconductedinanimalmodels
ofhumandiseaseandthepharmacologicaltestsincludeboththeinvitro
andinvivostudiesaftertheinitialscreeningforbiologicalactivity.For
instance,antibacterialactivityofdrugsisassessedbytheirabilitytoinhibit
growthofavarietyofmicroorganisms,whilehypoglycemicdrugsaretested
fortheirabilitytolowerbloodpressure.
Theinvitromethodsincludeincubationofaparentcompoundwithvarious
subcellularfractionssuchasmicrosomes,individualrecombinantdrug
metabolizingenzymesfromcellsortissueslices.Theinvivostudiesinvolve
workingontypicalanimalmodelssuchasdogsorrats.Someoftheinvitro
andinvivostudiesthatmaybeperformed
If an agent possesses useful activity it would be further studied for
possible adverse effects on other major organs. These studies might
suggest the need for further chemical modification to achieve desirable
pharmacokinetic/ pharmacodynamic properties (pharmacomodulation).
Development
Clinical studies
Early Clinical
Development
CHEMISTRY/
PHARMACOLOGY
IND*
PHASE I
PHASE II
PHASE III
Search for
active
substances
Regulatory
review
Efficacy
studies on
healthy
volunteers
Clinical
studies on a
limited scale
50150
persons
100200
patients
Comparative
Regulatory
Continued
studies on a
review
comparative
large
studies
number of
KNOWLEDGE
patients
LEVEL
Registration,
market
5005,000
introduction
patients
*Investigational
New Drug
Toxicology,
Application for
efficacy
permission to
administer
a new
studies on
drug
to
humans
various types
of animals
KNOWLEDGE
NDA**
**New Drug
Application
Application for
permission to market
a new drug
LEVEL
TIME SPAN
24 yrs.
26 months
36 yrs.
13 yrs.
10/09/2013
13
PHASE IV
Preformulation
Salt screening
Polymorph screening
Solubility
API excipient interaction
Novel technologies for highly insoluble APIs (nano technology)
Formulation development
IV and oral preclinical formulations
Clinical formulations
Solid
Semi-solid
Oral Liquids
Sterile (aseptically prepared) liquids
DRUG DEVELOPMENT
Drug development is a blanket term used to
define the entire process of bringing a new drug
or device to the Market. It includes drug
discovery/product development, pre-clinical
research(microorganisms/animals) and clinical
trials (on humans).
Few people still refer to the drug development as
mere preclinical development.
NCE DEVELOPMENT
New chemical entities (NCEs) are compounds which
emerge from the process of drug discovery. These will
have promising activity against a particular biological target
thought to be important in disease; however, little will be
known about the safety, toxicity, pharmacokinetics and
metabolism of this NCE in humans.
It is the function of drug development to assess all of
these parameters prior to human clinical trials. A further
major objective of drug development is to make a
recommendation of the dose and schedule to be used the
first time an NCE is used in a human clinical trial "first-inman" (FIM) or First Human Dose (FHD).
NCE DEVELOPMENT
NCE DEVELOPMENT
NCE DEVELOPMENT
NCE DEVELOPMENT
NCE DEVELOPMENT
NCE DEVELOPMENT
COST ?
Studies published in 2003 report an average pre-tax cost of
approximately $800 million to bring a new drug (i.e. a drug with
a New Chemical Entity) to market.
A study published in 2006 estimates that costs vary from around
500 million to 2,000 million dollars depending on the therapy
or the developing firm.
These figures relate only to new, innovative drugs (drugs with a
New Chemical Entity NCE, also called New Active Substance
NAS). Each year, worldwide, only about 26 such drugs enter the
market (2005: 26, 2004: 24, 2003: 26, 2002: 28). The
development cost of the thousands of other drugs are much
smaller. The $800 million quoted include the cost of all drug
development which did not result in a new drug. It also includes
some $400 million of opportunity costs.
CLINICAL TRIAL
Clinical trials are conducted to allow safety and
efficacy data to be collected for new drugs or
devices. These trials can only take place once
satisfactory information has been gathered on the
quality of the product and its non-clinical safety,
and Health Authority/Ethics Committee approval
is granted in the country where the trial is taking
place.
CLINICAL TRIAL
CLINICAL TRIAL
Gene therapy
In the 1980s, there were high hopes that gene therapy would
open up a wealth of new treatments, particularly for inherited
conditions. The idea is that a gene is delivered into cells and
begins to make a therapeutic protein. So people with cystic
fibrosis, who lack a working version of a protein known as
CFTR, would receive a copy of the CFTR gene.
Unfortunately, the promise has yet to be realised. It has proved
difficult to get active DNA into the nucleus and stably active.
Progress has been slower than expected, and also suffered after
the death of a patient, Jesse Gelsinger, in a clinical trial in 1999.
A further setback came in 2003, when French patients developed
cancer linked to the integration of a viral vector into their DNA.
Nevertheless, clinical trials are underway in a number of
conditions, including muscular dystrophy and Parkinson's
disease. Gene therapy is also being tested in some cancers,
though the aim is to kill cells rather than repair them. Routine
use, however, remains a long way off.
RNAi
RNA interference (RNAi), which gained a Nobel Prize for its
discoverers in 2006, is a new and highly promising strategy.
RNAi is used to eliminate (or 'knock down') specific proteins
from a cell, such as those causing a disease. It is based on an
unusual phenomenon: short RNA molecules triggering highly
specific destruction of messenger RNA molecules containing the
same RNA sequence. Its normal role is probably to protect
against viruses invading the cell.
The medical possibilities are very broad. Examples include
knocking down the receptor for a virus, or an overactive protein
causing cancer or messenger molecules promoting inflammation.
A small number of clinical trials have begun, for example for
macular degeneration (a form of blindness). But it is early days.
As in gene therapy, it is difficult to deliver the RNA and there are
worries that other, useful proteins might be eliminated. One
study in mice led to severe liver damage in animals, possibly
because large doses of RNA were used.
Nanotechnology
Nanotechnology-based solutions are being tested in a variety
of conditions.
Some applications depend on the unusual properties of
materials at the nanoscale. Nanoscale silver is toxic to bacteria
and is being used in wound dressings (silver-impregnated
pyjamas have been suggested for hospitals). Gold
nanoparticles can convert some wavelengths of light into
intense heat, and are being tested as a possible cancer
treatment (a 'thermal scalpel').
Critical to many applications will be targeting. Antibodies
could target a toxin-linked nanoparticle to a cancer cell.
More generally, because they are so small, weight-for-weight
nanoparticles have a very high surface area. There is interest
in using this property for controlled release of drugs.
A living thing
As well as chemically produced agents, researchers are also looking at living organisms.
In doing so, they are reviving a long and colourful medical history.
Leeches may not be everyone's cup of tea, but they produce a very useful anti-bloodclotting agent (hirudin) and are very effective at draining blood. They are used clinically in
microsurgery, helping to improve blood flow when digits are reattached.
Maggots may be similarly repellent to most, but they have long been medicinally useful. In
World War I, infections with maggots kept bacterial infections in check. Experiments have
been carried out with maggots to clean wounds; they also seem to secrete compounds that
promote wound healing. They have been shown to be just as good (and cost-effective) as
conventional medications for chronic wounds, and greenbottle larvae are commercially
available for use in medicine. The main obstacle to their wider use is patient
squeamishness
An area of growing interest is the use of parasites or their secretions or eggs to manipulate
the immune response. There is a school of thought that the current high incidence of
asthma, inflammation and allergy in the West is due to a lower parasite burden. In parts of
the world where parasites are common, asthma is rare. Various trials have been carried out
of parasitic worm eggs for inflammatory bowel disease, with some success. In the UK,
hookworms are being tested as a treatment for asthma.
Much effort is being put into identifying the active substances produced by parasites, so
that they can be given medicinally without a patient having to be infected with the real thing
CELL COMMUNICATION
&
CELL SIGNALING
CELL SIGNALING
Cell signaling is part of a complex system of
communication that governs basic cellular activities
and coordinates cell actions. The ability of cells to
perceive and correctly respond to their microenvironment is the basis of development, tissue repair,
and immunity as well as normal tissue homeostasis.
Errors in cellular information processing are
responsible for diseases such as cancer, autoimmunity,
and diabetes.
By understanding cell signaling, diseases may be
treated effectively and, theoretically, artificial tissues
may be yielded.
RECEPTORSFORCELLSIGNAL
CELLS COMMUNICATION
Within endocrinology (the study of intercellular signalling in animals) and the
endocrine system, intercellular signalling is subdivided into the following
classifications:
Autocrine signals affect only cells that are of the same cell type
as the emitting cell. An example for autocrine signals is found in
immune cells.
Many cell signals are carried by molecules that are released by one
cell and move to make contact with another cell.
Paracrine signals target only cells in the vicinity of the emitting cell.
Neurotransmitters represent an example. Some signaling
molecules can function as both a hormone and a neurotransmitter.
For example, epinephrine and norepinephrine can function as
hormones when released from the adrenal gland and are
transported to the heart by way of the blood stream.
Norepinephrine can also be produced by neurons to function as a
neurotransmitter within the brain. Estrogen can be released by the
ovary and function as a hormone or act locally via paracrine or
autocrine signaling.
OVERVIEW OF SIGNAL
TRANSDUCTION PATHWAYS
Signal Transduction
In biology, signal transduction refers to any
process by which a cell converts one kind of
signal or stimulus into another. Most processes
of signal transduction involve ordered
sequences of biochemical reactions inside the
cell, which are carried out by enzymes and
activated by second messengers, resulting in a
signal transduction pathway.
Signaling molecules
Most signal transduction involves the binding of extracellular signaling
molecules (or ligands) to cell-surface receptors that face outward
from the plasma membrane and trigger events inside the cell. Also,
intracellular signaling cascades can be triggered through cellsubstratum interactions, as in the case of integrins, which bind
ligands found within the extracellular matrix. Steroids represent
another example of extracellular signaling molecules that may cross
the plasma membrane due to their lipophilic or hydrophobic
nature.
Many, but not all, steroids have receptors within the cytoplasm, and
usually act by stimulating the binding of their receptors to the
promoter region of steroid-responsive genes.
Within multicellular organisms, there is a diverse number of small
molecules and polypeptides that serve to coordinate a cell's
individual biological activity within the context of the organism as a
whole.
1PMIhumanrantes
sekian
Lihat: Medicinal Chemistry and Drug Discovery