The document summarizes the key events in the discovery and development of penicillin. Alexander Fleming first discovered penicillin in 1928 after noticing bacteria-killing properties of the Penicillium mold in one of his petri dishes. However, he was not able to purify or characterize penicillin at the time. In the 1940s, a team at Oxford led by Howard Florey and Ernst Chain managed to purify and mass produce penicillin, paving the way for clinical trials. The first successful human trials demonstrated penicillin's ability to cure bacterial infections. By the mid-1940s, large-scale production was established. Fleming, Florey and Chain received the 1945 Nobel Prize for their discoveries. Over time, resistance
3. INTRODUCTION
• A drug may be broadly defined as any chemical
agent that affects living protoplasm
• Drug invention - process by which drugs are
sculpted and brought into being based on
experimentation and optimization of many
independent properties;.
• There is little serendipity!!!!!
7. SOURCE OF DRUGS
1. Serendipity
2. Screen a collection of chemicals –Library-HIGH
THROUGHPUT SCREENING
3. Synthesis from congeners of a specific enzyme
substrate
SMALL MOLECULES
8. 1. Recombinant DNA technology-gene cloning
2. Protein therapeuticsproduction of proteins from
expression of cloned gene in bacteria/eukaryotic cells
3. Engineering of mouse-Replacement of critical mouse
genes with human equivalents
LEAD OPTIMIZATION- HITS (identified via
screening) LEADS
LARGE MOLECULES-Insulin,GH
,Growth
factors,cytokines,monoclonal Ab
• Affinity
• Agonist/ant
agonist
• Permiability
• ADME
9. • X ray crystallography
• Molecular modelling
• Computational chemistry
• Nuclear Magnetic resonance
• Assay development – activity of drug- substrate –
enzyme interactions
Drug-target
structure
10. • SAR studies-identifying Pharmacophore- more
specific
• In silico screening-Computer simulated screening of
chemicals • Helps in finding structures that are
most likely to bind to drug target.
• Filter enormous Chemical space
• Economic than HTS
11.
12. TARGET SELECTION
• Drugability refers to the ease with which the
function of a target can be altered in the desired
fashion by a small organic molecule. If the protein
target has a well-defined binding site for a small
molecule (e.g., a catalytic or allosteric site), chances
are excellent that hits will be obtained. If the goal is
to employ a small molecule to mimic or disrupt the
interaction between two proteins, the challenge is
much greater
13. • Finding an agent with a particular biological action
that is anticipated to have therapeutic utility
• influenced by a complex balance of scientific,
medical and strategic considerations.
• Target identification: to identify molecular targets
that are involved in disease progression. •
• Target validation: to prove that manipulating the
molecular target can provide therapeutic benefit for
patients.
14. CLASSES OF DRUG TARGETS
• G-protein coupled receptors - 45%
• Enzymes - 28%
• Hormones and factors - 11%
• Ion channels - 5%
• Nuclear receptors - 2%
15. TECHNIQUES
• CELLULAR AND GENETIC TARGETS-
identification of the function of a potential
therapeutic drug target and its role in the disease
process.
• Drugs usually act on either cellular or genetic
chemicals in the body, known as targets, which are
believed to be associated with disease.
• GENOMICS- understand the structure of the
genome, mapping genes and sequencing the
DNA to find new drug targets
16. • PROTEOMICS - study of the proteome, the complete set
of proteins produced by a species, using the technologies
of large – scale protein separation and identification.
• Complexity of biological system- the analysis of proteins
(including protein-protein, protein- nucleic acid, and
protein ligand interactions)
1. Systematic high-throughput separation
2. Characterization of proteins within biological systems
3. Comparison between healthy and diseased tissues
2D PAGE
17. • BIOINFORMATICS- branch of molecular biology
• extensive analysis of biological data using computers,
• target identification computer screening of
chemical compounds and pharmacogenomics
• Transform the raw sequence into meaningful
information (eg. genes and their encoded proteins) and
to compare whole genomes (disease vs. not). Can
compare the entire genome of pathogenic and non-
pathogenic strains of a microbe
• Identify genes/proteins associated with pathogenism
• Micro arrays and gene chip technologies
19. • Affinity and selectivity for interaction with the target
• Pharmacokinetic properties (ADME)
• Issues of its large-scale synthesis or purification
• Pharmaceutical properties (stability, solubility, questions of
formulation)
• Safety. One hopes to correct, to the extent possible, any
obvious deficiencies by modification of the molecule itself or by
changes in the way the molecule is presented for use.
GOOD LABORATORY
PRACTICE
20. •Subcellular components (Ribosomes,
mitochondria) • Cellular/ subcellular
extracts (wheat germ, reticulocyte
extract) • Purified molecules
(DNA,RNA)
IN
VITRO
• Rodent/non rodent
• • Metabolic profile • Toxicology • Drug
interaction
• Animal models of disease states • Test
conditions involving induced disease or
injury similar to human conditions. •
• Behavioural Studies Functional Imaging
IN
VIVO
• tissue in an artificial environment
outside the organism with the
minimum alteration of natural
condition
•tissue properties • Realistic models for
surgery
EX
VIVO
21. 1. Carcinogenicity
2. Genotoxicity
3. Reproductive toxicity
• Reason for toxicity 1) whether it is mechanism
based (i.e., caused by interaction of the drug with
its intended target)
2) caused by an off-target
effect of the drug,
22. IND APPLICATION
• Before the drug candidate can be administered to humsponsor
must file an IND application, a request to the U.S. FDA (see
“Clinical Trials”) for permission to use the drug for human
research. The IND describes the rationale and preliminary
evidence for efficacy in experimental systems, as well as
pharmacology, toxicology, chemistry, manufacturing, and so
forth. It also describes the plan (protocol) for investigating the
drug in human subjects. The FDA has 30 days to review the
IND application, by which time the agency may disapprove it,
ask for more data, or allow initial clinical testing to proceed.
25. • Ethically designed investigation
• Human subjects
• Objectively discover/verify/ compare the results of two or
more therapeutic measures DRUGS
• FDA requires the trials to be atleast two replicate types
1. Adequate and well-controlled
2. randomized,
3. double blind,
4. placebo (or otherwise) controlled
1. PRIMARY END
POINT
2. SURROGATE/SE
CONDARY
ENDPOINT
26. • Each country has a drug regulatory body which
governs the approval process
• India- CDSCO (central drugs standards and control
organization)
• US- FDA (food and drug administration)
• UK- MHRA (medical and healthcare products
regulatory agency)
• European Union- EMEA (european medicines
agency)
27. • FDA's Center for Drug Evaluation and Research
(CDER) - responsible
• Prescription and non prescription or over-the-
counter (OTC) drug
• Performance of drug reviews,
• post-marketing risk assessment,
28.
29.
30.
31.
32. • The U.S. NIH identifies seven ethical principles
that must be satisfied before a clinical trial can
begin:
• 1. Social and clinical value
• 2. Scientific validity
• 3. Fair selection of subjects
• 4. Informed consent
• 5. Favorable risk-benefit ratio
• 6. Independent review
• 7. Respect for potential and enrolled subjects (NIH,
2011
33. • After scrutiny and approval by an independent
ethics committee as per the ‘Good Clinical Practice’
(GCP) guidelines. I
• In India, the ICMR (2006) ‘Ethical guidelines, for
biomedical research on human participants:
• A written Informed consent of the patient/trial
subject
• .
34. • Autonomy: Freedom, dignity and confidentiality of
the subject; right to choose whether or not to
participate in the trial or to continue with it.
• Beneficence: Motive to do good to the subject and/or
the society at large.
• Non-maleficence: Not to do harm or put the
participant at undue risk/disadvantage.
• Justice: Observence of fairness, honesty and
impartiality in obtaining, analysing and
communicating the data
35. 1. PHASE 1
2. PHASE 2
3. PHASE 3
Sponsor (usually a pharmaceutical company) applies
to the FDA for approval to market the drugNDA or
a BLA.
4. PHASE 4 –Post marketing surveilance
SAFETY AND
EFFICACY
• INDIVIDUAL
CASE
REPORT
FORMS
• REVIEWED
BY
SPECIALISTS
• DECIDE ON
LABEL
36. PHASE 0/ HUMAN MICRO-
DOSING STUDIES
• • First in human trials
• to study exploratory investigational new drug.
• Preliminary data on the drug’s pharmacodynamics
and pharmacokinetics
• Efficacy of pre-clinical studies.
37. PHASE 1-FIRST IN HUMANS
• 10–100 participants
• Usually healthy volunteers; occasionally patients
with advanced or rare disease
• Open label
• Safety and tolerability
• 1–2 years
• U.S. $10 million
• Success rate: 50%
Pharmacologists
Clinical
investigators
• 2 types
1. SAD
2. MAD
38. PHASE 2-FIRST IN
PATIENTS/THERAPEUTIC
EXPLORATORY
• 50–500 participants
• Patient-subjects receiving experimental drug
• Randomized and controlled (can be placebo
controlled); may be blinded
• Safety – Efficacy – Drug Toxicity – Drug Interaction
• 2–3 years
• U.S. $20 million
• Success rate: 30%
clinical
investigator
39. PHASE 3-MULTISITE TRIAL
• A few hundred to a few thousand participants
• Patient-subjects receiving experimental drug
• Randomized and controlled (can be placebo controlled) or
uncontrolled; may be blinded
• Confirm efficacy in larger population
• 3–5 years
• U.S. $50–100 million
• Success rate: 25%–50%
40. PHASE 4-POST MARKETING
SURVEILLANCE
• Many thousands of participants
• Patients in treatment with approved drug
• Open label
• Adverse events, compliance, drug-drug interactions
• Pharmacovigilance.
• No fixed duration
41.
42. PHARMACOVIGILANCE
WHO- Science and activities related to
1. Detection
2. Assessment
3. Understanding
4. prevention
Adverse effects
Drug related
problems
43. • Post marketing period 4 YEARS
• Periodic Safety Update Report (PSUR)
• Every 6 months for 1st 2 years
• Once annually for next 2 years
• Integrated data transmitted through VIGIFLOW
interface to WHO –Uppsala Monitoring centre ADR
database- VIGIBASE 1. Practising
doctors
2. Nurse
3. Hospital
pharmacists
4. CRO
44.
45.
46. ORPHAN DRUGS
• Pharmaceutical agent that has been developed
specifically to treat a rare medical condition, the
condition itself being referred to as an orphan disease.
• National Organization for Rare Disorders • European
Organization for Rare Diseases
• Advantages: • Tax incentives. • Enhanced patent
protection and marketing rights. • Clinical research
financial subsidization. • Rise in research and
development
47. • Orphan Drugs Act:
• • 4th January 1983
• • 6000 Orphan Diseases
• • Unprofitable Drug Development
• • Affecting < 2,00,000 Persons
• • Orphan Drug Status to 1,090 Drugs
• • 1985 Amendment- Marketing Exclusivity
48. DISEASE CAUSE ORPHAN DRUG
Gaucher’s
Disease
Glucocerebrosid
ase
Miglustat
Fabry’s Disease Galactosidase Galsidase
Mucopolysaccha
ridosis
Lysosomal
Enzyme
Laronidase
Tourette’s
Syndrome
Lamotrizine
Wilson disease Copper
deposition
Trientine
SCID Adenosine
Deaminase
Pegadimase
G
F
G
L
T
L
U
C
A
P
51. TIMELINE OF EVENTS
• 1940s and 1960s - Golden era of antibiotic research
• 1928- Alexander Fleming, a bacteriologist working at
St. Mary’s hospital in London, noticed that one of his
petri dishes containing staphylococci that he left on a
bench was contaminated
• Penicillium notatum, Penicillin Fleming thought
that penicillin could be useful as a local antiseptic, but
did not manage to purify penicillin or characterize its
activity
52. • 1929- Recorded his observations in the article in
The British Journal of Experimental Pathology,
where he showed that penicillin is able to inhibit
bacterial growth in vitro
• Antiseptic
• Couldn’t manage to purify penicillin or characterize
its activity
53. OXFORD’S BREAKTHROUGH 1939 TO
1941
• Ernst Chain
• Howard Florey
• Norman Heatly
• By the mid-1940s, enough penicillin was available at the Sir
William Dunn School of Pathology in Oxford to set up trials of
its efficacy in mice
• Culture
fungus
• Penicilli
n
purificat
ion
IN VIVO
54.
55.
56. PENICILLIN PRODUCTION 1941 TO
1943
• Heatley and Florey then arranged the vessel to be
mass produced by a pottery firm about 100 meters
away from Oxford, which was suggested to him by
his acquaintance in potteries
• In the end of 1940, Florey and colleagues received
the vessels, and Heatley inoculated them with the
fungus on December 25th. By the start of February
1941, the Oxford team had purified sufficient
material for clinical trials in humans.
57. THE FIRST TRIALS IN HUMANS
• 1st patient – Cancer patient Fever and rigor d/t
impurities
• Edward Abraham – pyrogens purified
• 2nd patient - policeman at the Radcliffe Infirmary
who had severe staphylococcal and streptococcal
infection [5].
• Repeated intravenous injections of penicillin over 5
days had a profound effect on his recovery
Re extraction
from patients
urine
D/T short
supplyrelapse
and death
58. AFTER 1941……
• Clinical trial with 170 patients
• THE PENICILLIN PROJECT with American
colleagues
1. Purification
2. Find more strains
3. Tie up with Pharmaceutical
companies
59. • 1944- Manufactured on D Day
• 1945 - Fleming, Florey and Chain were awarded the
Nobel Prize for “the discovery of penicillin and its
curative effect in various infectious diseases
60. MECHANISMS OF PENICILLIN, A
REVOLUTIONARY AND
INSPIRATIONAL THERAPEUTIC OF
MODERN MEDICINE
X-ray
Abraham first proposed the beta-
lactam structure. This was confirmed
by Dorothy Hodgkin and Barbara
Low using X-ray crystallography
62. RESISTANCE TO NATURAL
PENICILLINS…
• BENZYLPENICILLIN- Gram-positive bacteria in
particular cocci, such as staphylococci, pneumococci,
and other streptococci, and bacilli,
including Bacillus anthracis, Clostridium
perfringens, and Corynebacterium diphtheriae
beta-lactamase-resistant penicillins
(i.e. second generation penicillins):
oxacillin, methicillin, and
dicloxacillin, also defined as anti-
staphylococcal penicillins,
63. • 1960sthe third generation and broad-spectrum
penicillins also known as aminopenicillins
• Amoxicillin and Ampicillin, third generation
penicillins more effective against a wider group of
Gram-negative bacteria (including Haemophilus
influenzae, Escherichia coli, Salmonella spp.,
and Shigella spp.
• Fourth Generation- carboxypenicillins and
ureidopenicillins further broadened the spectrum
and displayed potent activity against Pseudomonas
aeruginosa
• Since the late 1970s, penems, carbapenems, and
monobactams