SALVARSON TO STEM CELL THERAPY

by
PAHUP SINGH
Emeritus Scientist, CSIR
Department of Chemistry
University of Rajasthan, Jaipur-302004
Mercury (Hg) Syphilis

Bark of Cinchona tree Malaria

Roots of Ipecacaunha tree Dysentry

 Alternative Systems of Treatment of
Diseases in Various Countries
India Ayurvedic,Siddha and Unani System

China Traditional Chinese medicines and

acupressure technique

Japan Kampoh, Hydropathy System

Europe Naturopathic System and Homeopathic

medicines

America Osteopathic and Chiropractice

medicines, Massage therapy
 Now in the world more than 70,000
medicines or their formulations are
available
Discovery ratio

70,000 / 100 = 700 drugs/year

= 2 drugs/day

Time taken by a drug to come in market

According to Pharmaceutical Research and
Manufacturer of America the average time is 14.2
years ( in completion of phase I,II & III testings).
 H2N NH2

HO As As OH

Salvarsan or Arsphenamine
(First Drug)

Discovered by Paul Ehrlich in 1907

Nobel Prize-1908
Syphilis, a contagious venereal disease caused by
Treponema pallidium
 Diseases
Diseases are of two types :

1.Genetic diseases

2.Infectious diseases microbes

Protozoa
Bacteria
Virus
Fungus
 Genetic Diseases
1.Sickle cell anaemia 9. Diabetes 17. Duchenne Muscular
dystrophy
2.Hemophilia 10. Hypertension 18. Huntington’s
Chorea
3.Thalassemia 11. Asthma 19. Mycocardial
infarction
4.Leukemia 12. Mongolism 20. Lesch-Nyhan
Syndrome
5.Migrain 13. Albinism 21. Parkinson disease
6.Gout 14. Alzheimer 22. Phenyl ketonuria
(PKU)
7.Arthritis 15. Cystic fibrosis 23. Myopia
8.Squint 16. Retinoblastoma
 H2N
O
H2N N N S NH2
O
Prontosil

Discovered by Gerhard Domgak in 1935

Nobel Prize-1939
 Mechanism of Action of Sulpha Drugs in
Body

H2N H2N
O O
H2O
H2N N N S NH2 H2N N O + H2N S NH2
O O

Prontosil Sulphanilamide
Active agent against
Streptococcus

(Ernest Fourneau)
Pasteur Institute,Paris
Lock & Key Theory
D.D.Woods (1940)
H H H H
N N

6.7Ao 6.9Ao

C S
HO O O O
NH2
Bacteria .
2 3 Ao
.
2 4 Ao

p-Amino benzoic acid Sulphanilamide

 Sulpha-drugs
Sulphapyridine, Sulphaguanidine, Sulphadiazine,

Sulphadimetine, Sulphadimidine, Sulphadimethoxine,

Sulphaethidole, Sulphaurazole, Sulphamerazine,

Sulphamethazene, Sulphamethizole, Sulphamethoxazole,

Sulphamezathine, Sulphamylon, Sulphanilamide,

Sulphamethoxypyridazine, Sulphanemia Sulphamethyldiazine,

Sulpharsphenamine, Sulphatase, Sulphasuxidine,

Sulphathalidine, Sulphathiazole, *Succinoyl sulphathiazole,

*Phthaloyl sulphathiazole, etc.

*Life of thousands of wounded soldiers could be saved during world war II
 1928
Alexander Fleming (British Bacteriologist)

Culture of Staphylococcus Bacteria

Blue-green mold in petri-dish

(Penicillium notatum)

Penicillin
 Later on Howard Walter Florey - British
Scientist
&
Ernest Boris Chain - German Scientist
USA+UK+Canada

Production of Penicillin on Industrial Scale

First experiment on human was conducted on
British Policeman on 12 Feb. 1941
( Fleming, Florey & Chain Nobel Prize-1945)
 TUBERCULOSIS

There was no treatment for Tuberculosis till

1944

Koch’s Chest – Robert Koch

Identified the bacteria to cause this disease

as Microbacterium tuberculosis
 In 1944 An American Bacteriologist –
Selmen Waksman
was working on
“Theory of Bacterial Warfare in Soil”
 He had examined 10,000 different soil
samples for the presence of microbes.
 All samples contained microbes except one
sample that showed the presence of
Streptomyces griseus fungus.
 Streptomycin - tuberculosis

(Selmen Waksman)
Nobel Prize 1952
 Antibiotics
 Penicillium notatum Penicillin Broad Spectrum Antibiotic.

 Streptomyces griseus Streptomycin Tuberculosis.

 Streptomyces aureofaciens Aureomycin Typhoid.

(Chlor-tetracycline)
 Streptomyces rimosus Terramycin Trachoma
(Oxy-tetracycline)

 Streptomyces venezuelae Chloromycetin Typhoid.

(Chloramphenicol)
 Anti Tuberculor Drugs

 (i) First Line Drugs

Streptomycin, Isoniazid, Pyrazinamide, Rifampicin and
Ethambutol

 (ii) Second Line Drugs

Thiacetazone, p-Amino salicylic acid, Cycloserine
Kanamycin, Capreomycin, Ethionamide
 DOTS Programme
(Directly Observed Treatment Short Course)

1. Intensive phase – 2-3 months

2. Continuation phase – 4-6 month

(Multiblister Combipack)
 Discovery of Vaccine
Edwards Jenner Small Pox

Max Theiler, USA Yellow Fever

Jonas Salk, USA Poliomyelitis

Max Theiler
Nobel Prize 1951
 Vaccination of Viral Diseases

1. Small pox 8. Poliomyelitis

2. Measles 9. Rubella
3. Mumps 10. Congenital
Rubella Syndrome
4. Diphtheria 11. Hepatitis -A
5. Pertussis 12. Hepatitis –B
6. Tetanus 13. Influenza &
pneumococcal vaccine
7. Neonatal tetanus 14. Tuberculosis
 Diabetes
 Banting & Macleod deficiency of Insulin
leads to diabetes
Nobel prize of Medicine -1923

 Federick Sanger –for giving the structure of

Insulin.
Nobel prize in Chemistry -1958

 Rosalyn Yalow – to measure Insulin by

radioimmunoassay method.
Nobel prize in Medicine -1977
 There was no treatment of diabetes till 1953
because it was metabolic disease.

It is of two types :-

(i) Diabetes type – I is an autoimmune disease that

results in the permanent destruction of insulin-
producing beta cells of the pancreas.

(ii) Diabetes type – II malfunctioning of insulin

Pancreas – 1-2 % part called Islets of Langerhans

-cells -cells
Glucagon Insulin

Metabolise
glucose
 Human Insulin

Chain A,21 amino acids

Chain B,30 amino acids

Federick Sanger
Nobel prize in Chemistry-1958
 1953
Psychochemicals (Mentally sick patients)

Tranquillizers Chloropromazine
Promazine
(Phenothiazine derivatives)

Antianxiety drugs Nitrazepam

Diazepam
Lorazepam
Medazepam
Oxazepam
Flurozepam
(Benzodiazepine derivatives)
 1960
Drugs for Leprosy
(Mycobacterium leprae)
Multiple Drug Therapy (MDT)
Dapsone
+
Rifampicin
+
Clofazamine

(Mixture of above Drugs for 6 months to 3 years)

 Heart Transplant

First Human heart transplant was done in 1967

By

Dr. Christian Barnard at Captown, South Africa

No. of hearts transplanted in 1990 – 4400

No. of hearts transplanted in 2002 – 3000

(due to less heart donors)
 In vitro fertilization technique
was developed in 1978 by

Dr. Patrick Steptoe –a famous gynaecologist, UK

&
Dr. Robert Edwards – Physiologist, UK

First test tube baby (Louise Brown) was

born on 25th July,1978 at Oldham Royal
hospital, England
 Anti-Cancer Drugs (1980-1992)
 Alkylating Agents: Nitrogen Mustard, Chlorambucil,
Cyclophosphamide, Melfalan, Busulfan, Nitrosoureas,
Triazine

 Anti-metabolites: (1)5-Flurouracil (2) Methotrexate

(3) 6-Mercaptopurine (4) 6-Thioguanine

 DNA Binding Agents:(1) Actinomycin-D (2) Donomycin

(Donorubicin) (3) Adreamycin (Doxorubicin)

 Radioactive Isotopes & Other Agents : Radio-iodine,

Radio-gold, Cis-platin, Hydroxyurea
Naturally Occurring Anti Cancer Drugs
Plant Drugs Disease
1.Vinca rosea Vinblastine (Velfan) Hodgkin’s disease
Vincristine (Oncovin) Acute leukemia

2.Camptotheca Camptothecin (Topotecan)

acuminata

3.Podophyllum Podophyllotoxin (Etoposide)

peltatum

4.Taxus Taxol (Paclitaxel) Advanced Uterus Cancer

brevifolia Taxotere (Docetexel) Breast cancer
 AIDS (1990)
(Acquired Immunodeficiency Syndrome)
Virus – Human Immunodeficiency Virus (HIV)

Immune or defence system and Central Nervous

System become weak

Anti- Aids drugs are anti-retroviral drugs

Only 19 drugs are approved for clinical use by USA.

 Anti-AIDS drugs
1.Nucleoside Reverse transcriptase Inhibitors (NRTI)
(i) AZT or Zidovudine (ii) Stavudine (iii) Didanosine
(iv) Zalcitabine (v) Lamivudine (vi) Abacavir (vii) Tenofovir

2.Non Nucleoside Reverse transcriptase Inhibitors (NNRTI)

(i) Nevirapine (ii) Delavirdine (iii) Efavirenz

3.Protease Inhibitor (PI)

(i) Squinavir (ii) Retoxavir (iii) Indinavir
(iv) Nelfinavir (v) Amprenavir (vi) Atazanavir

4.Fusion (or Entry) Inhibitors : Enfuvirtide

 HUMAN GENOME MAP AND GENE THERAPY
(1990-2000)

Gene therapy is used for the treatment of disease caused

by gene defect or gene disorder.
For example Hemophilia,Sickle cell Anaemia,Thalassemia.

Human Genome Map : Determination of sequence of bases

in DNA molecule is called human genome map. It is also
called a book of life. This test can be done by one drop of
blood.
There is a two metre long DNA molecule remains folded
in a cell.
The sequence of bases in a DNA molecule is always
fixed. Number of bases are more than 300 crores in a
DNA molecule. If we determine the sequence of bases
from one end to another at the rate of one base/second
for 24 hrs/day take 100 years. So it is very tedious job.

In this programme six countries participated including

USA, UK, Germany, France, Japan and China and
worked at 16 different research centres involving 1100
Biologists, Chemists, Computer Scientists and
Technicians. This project was financed by Medical
Charity Wellcome trust and completed in 13 years
.

On 26th June,2000. 97% of base sequence of human

DNA molecule was determined. One third of this project
was completed by Sanger Research
Centre,Cambridge,U.K.

Every human being has half a dozen defective genes

and out of ten one human being develops genetic disease
later stage of life. It depends entirely on nature of
defective gene whether it is recessive or dominant gene.

In gene therapy a defective gene is replaced by a

normal or working gene through genetic engineering.
 Single Gene defects-current targets for
gene therapy (examples)
Disease Defective Gene
 Cystic Fibrosis CFTR
 Pituitary Dwarfism hGH
 Emphysema Familian -1 antitrypsin
 Hypercholesterolaemia LDL Receptor
 -Thalassemia -Globin
 Sickle cell anaemia -Globin
 Haemophilia A Factor VIII
 Haemophilia B Factor IX
 Gaucher’s Disease Glucocerebrosidase
 Phenylketonuria Phenylalanine hydroxylase
 SCID ADA, Purine nucleotide-
Phosphorylase
 DMD Dystrophin
The Structure of DNA
DNA Structure
 Stem Cell Therapy (2000 onwards) or
Embryonic Stem Cell Transplantation

(1) Totipotent Stem Cells (2) Pluripotent Stem Cells

(3) Multipotent Stem Cells

Leukemias Hodgkin’s lymphoma

1. Malignant Lympho proliferative disorders Non Hodgkin’s ,,
Solid tumors-Wilson’s tumour Multiple Mycloma

Bone marrow failure Syndrome (Aplastic order)

2. Non Malignant Immunodeficiency states
Hematological disorders-Thalassemia
 2007
Nobel Prize in Medicine

Mario R. Kepachi,USA
Oliver Smithis,USA
Martin J. Evans,UK

Researches on Embryonic Stem Cells

 2012
Nobel Prize in Medicine
John Gurdon, UK
Shinya Yamanaka, Japan

For the discovery that the adult mature cells can

be reprogrammed into stem cells (Pluripotent
cells).These stem cells can be used for
finding cures of genetic diseases such as
cancer , diabetes, etc.