Pharma Unit 1

8/3/2019 Pharma Unit 1

http://slidepdf.com/reader/full/pharma-unit-1 1/24

Dr. N.Sangeetha M.sc., M.Phil., Ph.D

Achariya Arts and Science College

Puducherry

Pharmaceutical Biotechnology Unit 1

1

Pharmaceutical BiotechnologyUnit 1

Pharmaceutical substances form the backbone of modern medicinal therapy. Most traditional

pharmaceuticals are low molecular mass organic chemicals. Although some (e.g. aspirin) were

originally isolated from biological sources, most are now manufactured by direct chemical

synthesis. Two types of manufacturing companies thus comprise the ‘traditional’ pharmaceutical

sector; the chemical synthesis plants, which manufacture the raw chemical ingredients in bulk

quantities, and the finished product pharmaceutical facilities, which purchase these raw bulk

ingredients, formulate them into final pharmaceutical products, and supply these products to the

end-user.

In addition to chemical-based drugs, a range of pharmaceutical substances (e.g. hormones and

blood products) are produced by or extracted from biological sources. Such products may thus be

described as products of biotechnology. In some instances, categorizing pharmaceuticals as

products of biotechnology or chemical synthesis becomes somewhat artificial, e.g. certain semi-

synthetic antibiotics are produced by chemical modification of natural antibiotics produced by

fermentation technology.

Terminologies

Pharmacology: It is the science that deals with drugs.

Pharmcognosy: It is the science of identification of drugs.

Pharmacy: it is the science of identification, selection, preservation, standardization

compounding and dispensing of medicinal substances.

Pharmacodynamics: it is the quantitative study of the biological and therapeutic effects of drugs.

This deals with the mechanism of action of a drug and correlation of drug action with their

chemical structure.





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Pharmacokinetics: It is the study of absorption, distribution, metabolism and excretion of drugs

and their relationship to pharmacological response of the body.

Toxicology: It is the science of poison and includes measurement, detection and treatment of

poisons.

Pharmacopoea: It is an official code containing a selected list of the established drugs and

medicinal preparations with descriptions of their physical properties, tests for their identity,

purity and potency. It defines the standards for these preparations and their average doses for an

adult.

Pharmacophore: The physiological acitivity of drugs has been found to depend upon the

presence of particular functional group or structural unit. Such a part of the drug which causes

actual physiological effect is known as pharmacophore.

Drug:

A drug is defined as any substance used for diagnosis, prevention, relief or cure of a disease in

man or animals.

Sources of drugs:

The various sources of drugs are

Plants:

Various medicinal compounds have been extracted from plant sources. Pharmacologically active

principles in plants are

Alkaloids – These are basic substances containing cyclic nitrogen and form water soluble

salts with acids. Eg. Morphine, Atropine etc.,

Glycosides – An organic substances linked with sugar on acid hydrolysis it yields a sugar

component and a non-sugar component (aglycone). Eg. Digoxigenin.





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Oils

Fixed oils- fixed oils are glycerides of oleic, palmitic and stearic acids. They are

fats and many have food values and used for cooking and as solvents. Eg.

Coconut oil, Olive oil, Castor oil

Volatile oils – These oils are volatalised by heat. These oils are known as

essential oil and they have immense importance as

Carminitives eg. Oil of eucalyptus Antiseptics eg. Mouthwash

Analgesics eg. Oil of clove

Mineral Oils – this derived from hydrocarbons obtained from petroleum and is

used as lubricant purgative. Eg. Liquid paraffin.

Gums – These are secretory products of plants and are used as emulsifying agents. Eg.

Agar

Resins – These are foundin plants and are formed by oxidation and polymerization of

volatile oils and are insoluble in water. Jalab used as purgative.

Tannins – These are non- nitrogenous plant constituents. They have astringent action

upon mucous membrane. Eg. Tincture of catechu used in the treatment of diarhhoea.

Animals:

Drugs manufactured from animal sources are insulin, thyroxine, heparin etc.,

Genetic Engineering: By using DNA recombinant technology several drugs are being produced.

Pharmaceutical Biotechnology- overview of products

Pharmaceutical biotechnology refers to the use of biological systems (eg. Cells or tissues)

or biological molecules (eg. enzymes or antibodies) for the manufacturing of commercial





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products. The common pharmaceutical biotechnology products that are made by the biotech

pharmaceutical companies include Antibodies, Proteins, and Recombinant DNA Products.

Antibodies

Antibodies are proteins that are produced by white blood cells and are used by the

immune system to identify bacteria, viruses, and other foreign substances and to fight them off.

In the recent years, monoclonal antibodies are one of the most exciting developments in

biotechnology pharmaceuticals.

Proteins

Proteins made of amino acids are large, complex molecules that do most of the work in

cells and are required for the structure, function, and regulation of the body’s tissues and organs.

Protein biotechnology is emerging as one of the key technologies of the future for understanding

the development of many diseases like cancer or amyloid formation for better therapeutic

intervention.

Recombinant DNA Products

Recombinant Deoxyribonucleic Acid is the genetically engineered DNA created by

recombining fragments of DNA from different organisms. Some of the Recombinant DNA

Products include

• Recombinant Vaccines

• Recombinant Enzymes

• Recombinant Growth Hormone• Recombinant Insulin

Recombinant DNA technology has had a four-fold positive impact upon the production of

pharmaceutically important proteins:





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It overcomes the problem of source availability. Many proteins of therapeutic potential

are produced naturally in the body in minute quantities. Examples include interferons,

interleukins and colony stimulating factors. This rendered impractical their direct

extraction from native source material in quantities sufficient to meet likely clinical

demand. Recombinant production allows the manufacture of any protein in whatever

quantity it is required.

It overcomes problems of product safety. Direct extraction of product from some native biological sources has, in the past, led to the unwitting transmission of disease. Examples

include the transmission of blood-borne pathogens such as hepatitis B, C and HIV via

infected blood products and the transmission of Creutzfeldt–Jakob disease to persons

receiving human growth hormone preparations derived from human pituitaries.

It provides an alternative to direct extraction from inappropriate/dangerous source

material. A number of therapeutic proteins have traditionally been extracted from human

urine. The fertility hormone FSH, for example, is obtained from the urine of post-

menopausal women; while a related hormone, hCG, is extracted from the urine of

pregnant women Urine is not considered a particularly desirable source of pharmaceutical

products. While several products obtained from this source remain on the market,

recombinant forms have now also been approved.

Other potential biopharmaceuticals are produced naturally in downright dangerous

sources. Ancrod, for example, is a protein displaying anti-coagulant activity and, hence,

is of potential clinical use; however, it is produced naturally by the Malaysian pit viper.

While retrieval by milking snake venom is possible, and indeed may be quite an exciting

procedure, recombinant production in less dangerous organisms, such as Escherichia coli

or Saccharomyces cerevisiae, would be considered preferable by most.





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It facilitates the generation of engineered therapeutic proteins displaying some clinical

advantage over the native protein product. Techniques such as site-directed mutagenesis

facilitate the logical introduction of pre-defined changes in a protein’s amino acid

sequence. Such changes can be minimal, such as the insertion, deletion or alteration of a

single amino acid residue, or can be more substantial, e.g. the alteration or deletion of an

entire domain, or the generation of a novel hybrid protein. Such changes can be made for

a number of reasons and several engineered products have now gained marketing

approval.

Classification of drugs

Classification based on source:

Drugs can be classified on the basis of their origin into four broad categories

Natural preparations or Galenicals





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These are relatively crude preparations obtained by drying or extracting plant or animal

materials (eg. Digitalis leaf, tincture of bella donna)

Medicines prepared according to the formulae of Galen. It is prepared by extraction of

crude vegetable drugs (active principles) with suitable solvent(s).

Galenicals are pharmaceutical preparations obtained by macerating or percolating drugs

with alcohol of appropriate strength or some menstrum carefully selected to remove as

thoroughy the desired principle and to leave the inert and other undesirable constituents

of the plant undissolved.

Pure compounds

These are isolated by physical or chemical extraction and purification procedures from

natural sources. Eg. Morphine from opium.

Plant Pure compound Action

Coco leaves Cocaine Local anaesthetic

Digitalis leaf Digoxin Treat heart failure

Opium Morphine Analgesic

Tobacco Nicotine Increase heart beat

Cincona bark Quinine antimalarial

Semi synthetic substances

These are obtained by the chemical modification of the pure compounds from natural

sources.

Eg. Acetylation of 2-OH group in morphine yields diacetyl morphine (Heroin).

Pure synthetic compounds





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This is the most recent class. Most drugs are synthetic now

Classification based on chemistry

The crude drugs are divided into different groups according to the chemical nature of

their most important constituent. Since the pharmacological activity and therapeutic significance

of crude drugs are based on the nature of their chemical constituents. According to this

classification drugs may come under one or more of these categories such as Quinones, Azo

compounds, Amides, Alcohols, Ketones, Hydrocarbons, Halogenated compounds Guanides,

Esters etc.,

The importance of this classification is that similar chemical structure should yield

similar biological activities.

An out of this classification is as follows:

1. Carbohydrates – Carbohydrates are polyhydroxy aldehydes or ketones containing an

unbroken chain of carbon atoms.





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Gums Acacia, Guargum

Mucilages Plantago seed

Others Starch, Honey, Agar, Pectin, Cotton

2. Glycosides – Glycosides are compounds which upon hydrolysis give rise to one or more

sugars (glycone) and non-sugar (aglycone).

Anthraquinone Glycosides Aloe, Cascara, Rhubarb, Senna

Saponins Glycosides Quillaia, Arjuna, Glycyrrhiza

Cyanophore Glycosides Wild cherry bark

Isothiocyanate Glycosides Mustard

Cardiac Glycosides Digitalis, Strophantus

Bitter Glycosides Gentian, Calumba, Quassia, Chirata, Kalmegh

3. Tannins – Tannins are complex organic, non-nitrogenous derivatives of polyhydroxy benzoic

acids.

Examples- Pale catechu, Black catechu, Ashoka bark, Galls, Myrobalan, Bahera, Amla

4. Volatile oils – Monoterpenes and sesquiterpenes obtained from plants

Examples- Cinnamon, Fennel, Dill, Caraway, Coriander, Cardamom, Orange peel, Mint,

Clove, valerian

5. Lipids

Fixed oils – Castor, Olive, Almond, Shark liver oil

Fats – Theobroma, Lanolin

Waxes – Beeswax, Spermaceti

6. Resins – Complex mixture of compounds like resinols, resin acids, resinotannols, resenes.





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Examples Colophony, Podophyllum, Cannabis, Jalap, Capsicum, Turmeric, Balsam of

Tolu and Peru, Asafoetida, Myrrh, Ginger

7. Alkaloids – Nitrogenous substance of plant origin

Pyridine and Piperidine – Lobelia, Nicotiana

Tropane - Coca, Belladonna, Datura, Stramonium, Hyoscyamus, Henbane

Quinoline – Cinchona

Isoquinoline – Opium, Ipecac, Calumba

Indole – Ergot, Rauwolfia

Amines – Ephedra

Purina – Tea, coffee

8. Protein – Gelatin, Ficin, Papain

9. Vitamins - Yeast

10. Triterpenes – Rasna, Colocynth

Phytopharmaceuticals

A phytochemical is a natural bioactive compound found in plant foods that works with nutrients

and dietary fiber to protect against disease. There are more than thousand known

phytochemicals. Some of the well-known phytochemicals are lycopene in tomatoes, Isoflavones

in soy and Flavonoids in fruits.

There are many phytochemicals and each works differently. These are some possible actions:

· Antioxidant - Most phytochemicals have antioxidant activity and protect our cells against

oxidative damage and reduce the risk of developing certain types of cancer. Phytochemicals with





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antioxidant activity: allyl sulfides (onions, garlic), carotenoids (fruits, carrots), flavonoids

(fruits, vegetables), polyphenols (tea, grapes).

· Hormonal action – Isoflavones, found in soy, imitate human estrogens and help to reduce

menopausal symptoms and osteoporosis.

· Interference with DNA replication - Saponins found in beans interfere with the replication of

cell DNA, thereby preventing the multiplication of cancer cells. Capsaicin, found in hot peppers,

protects DNA from carcinogens.

· Anti-bacterial effect - The phytochemical allicin from garlic has anti-bacterial properties.





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Screening

Definition

Screening is the process of separation and isolation of active principle from plant sources.

Screening are helpful-

- To get lead for “Discovery of new therapeutic agents”.

- To find “New sources” for economic material.

- To help expand “CHEMOTAXONOMY”.

- To produce “Semisynthetic” derivatives.

For this purpose, following 3 essential steps are prescribed-

* Selection of plant.

* Phytochemicals screening.

* Phytopharmacological evaluation.

Phytochemical Screening Approaches

The goal in surveying plants for biologically active or rnedicinally useful compounds should be

to isolate the one or more constituents responsible for a particular activity. alkaloid-containing

plants for study on the premises that (a) normally exert some type of pharmacologic activity

usually on the center nerves system but not always so; m(b) the greatest majority of natural products used in medicine today are alkaloidal in nature;(c) tests for the presence of these

compounds in plants are simple, can be conducted rapidly, and are reasoanably reliable,

and(d)because of their chemical nature, alkaloids are more easily manipulated making extraction

and isolation less of a problem





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General considerations

A method for use in phytochemical screening should be

(a) Simple,

(b) Rapid,

(c) Designed for a minimum of equipment

(d) Reasonably selective for the class of compounds under study

Alkaloid screening

Alkaloids are more or less toxic substances which act primarily on the central nervous system

have a basic character contain heterocyclic nitrogen and are synthesized in plants from amino

acids or their immediate derivatives.

Test for alkaloids

A quantity (0.2 g) of the dry extracts was boiled with 5 ml of 2% HCl on a steam bath for 10

min. The mixture was filtered and 1ml portion of the filtrate was measured into four test tubes.

Each of the 1 ml filtrate was treated with 2 drops of the following reagents:

Dragendorff’s test: Dragendorff’s reagent was added in 2ml of filtrate. Formation of orange-

brown precipitate indicated the presence of alkaloids.

Mayer’s reagent: To a 1ml of test filtrate in a watch glass, a few drops of mayers reagent were

added. If the formation of cream colored precipitate it shows the presence of alkaloids.

Wagner’s reagent: A reddish-brown precipitate indicates the presence of alkaloids.

Picric acid (1%): A yellow precipitate indicates the presence of alkaloids.

The terpenoids, sometimes called isoprenoids, are a large and diverse class of naturally-

occurring organic chemicals similar to terpenes, derived from five-carbon isoprene units

assembled and modified in thousands of ways. Plant terpenoids are used extensively for their





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aromatic qualities. They play a role in traditional herbal remedies and are under investigation for

antibacterial, antineoplastic, and other pharmaceutical functions. Terpenoids contribute to the

scent of eucalyptus, the flavors of cinnamon, cloves, and ginger, and the color of yellow flowers.

Well-known terpenoids include citral, menthol, camphor, Salvinorin A in the plant Salvia

divinorum, and the cannabinoids found in Cannabis

Test for steroids and terpenoids

A quantity (9 ml) of ethanol was added to 1 g each of the extracts and refluxed for a few

minutes and filtered. Each of the filtrates was concentrated to 2.5 ml in a boiling water bath.

Distilled water, 5 ml was added to each of the concentrated solution, each of the mixtures was

allowed to stand for 1 h and the waxy matter was filtered off.

Each of the filtrates was extracted with 2.5 ml of chloroform using a separating funnel.

To 0.5 ml each of the chloroform extracts in a test tube was carefully added 1 ml of concentrated

sulphuric acid to form a lower layer. A reddish-brown interface shows the presence of steroids.

Another 0.5 ml each of the chloroform extract was evaporated to dryness on a water bath and

heated with 3 ml of concentrated sulphuric acid for 10 min. on a water bath. A grey colour

indicates the presence of terpenoids.

Knollar’s test

5 mg of extract is treated with 2ml of 0.1% anhydrous stannic chloride in pure thionyl chloride.

A deep purple color that changes to red indicates the presence of terpenoids.

Test for terpenoids (Salkowski test)

To 0.5 g each of the extract was added 2 ml of chloroform. Concentrated H2S04 (3 ml) was

carefully added to form a layer. A reddish brown colouration of the interface indicates the

presence of terpenoids.





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Drugs derived from Marine organisms

ω-Conotoxin MVIIA

After more than two decades of research and development, ziconotide, a synthetic form

of ω-conotoxin MVIIA, became the first marine-derived drug approved by the US Food and

Drug Administration (FDA). Now known under the trade name Prialt, it is approved for the

specificindication of chronic pain.

Ziconotide (SNX-111; Prialt) is a non-opioid and non-NSAID analgesic agent used for

the amelioration of severe and chronic pain. Derived from Conus magus ("Cone Snail"), it is the

synthetic form of an ω-conotoxin peptide. Ziconotide is derived from the toxin of the cone snail

species Conus magus.

Ziconotide, a synthetic form of ω-conotoxin MVIIA, became the first marine-derived

drug approved by the US Food and Drug Administration (FDA). Now known under the trade

name Prialt, it is approved for the specific indication of chronic pain. The venom of fish-hunting

cone snails (genus Conus) contains a myriad of toxic peptides (conotoxins) that act

synergistically to immobilize prey by targeting the neuromuscular system.

ω-Conotoxin MVIIA from the Pacific piscivorous marine snail Conus magus has been

an exceptional lead for drug development in the management of severe and chronic pain. It was

originally discovered by the group of olivera at the University of Utah, USA, in 1979 via a

bioassay that elicited a characteristic shaking behaviour in mice after the peptide was

administered by intracerebral injection.

ω-Conotoxin MVIIA is a linear 25 amino acid, polycationic peptide containing six

cysteine residues linked by three disulphide bridges that stabilize its well-defined

threedimensional structure. Its complete chemical synthesis was achieved in 1987, and N-type

voltage-sensitive calcium channels (NVSCCs) were subsequently identified as its target site16. It

potently inhibits the conduction of nerve signals by specifically blocking the NVSCC. In the





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complex with NVSCC, it forms a compact folded structure with a binding loop between Cys8

and Cys15 that also contains Tyr13, an important amino-acid residue located at the binding site

NVSCCs are found exclusively in presynaptic neurons where they regulate depolarization-

induced calcium influx, which subsequently control a variety of calcium-dependent processes.

NVSCCs are abundantly present in the superficial lamina of the spinal-cord dorsal horn, where

they have an important role in the spinal processing of nociceptive afferent (pain signalling)

activity. The potent inhibition and highly selective affinity of ω-conotoxin MVIIA to NVSCCattracted interest to develop this peptide into an antinociceptive agent.

Ecteinascidin-743

Ecteinascidin-743 (ET-743/trabectedin) illustrates a significant milestone in the

development of marine derived drugs. Almost 40 years after its discovery and 17 years after the

publication of its structure, it became the first marine-derived anticancer drug to reach the

market.

Extracts of the Caribbean tunicate Ecteinascidia turbinata have been reported to possess

antitumour activity as early as 1969; however the minute amounts of active component obtained

from laborious isolation work precluded their identification for almost two decades. Finally, in

1990, Rinehart and Wright published the structure of the alkaloids named ecteinascidins. The

structure of the most abundant active component, ET-743, and its N-demethyl analogue ET-729,

is comprised of three fused tetrahydroisoquinoline rings and is related to the simpler isoquinoline

alkaloid saframycin A from various Streptomyces spp.

The connection of the third tetrahydroisoquinoline ring to the base structure by a

thioether bridge completes a 10-membered lactone — a distinctive structural feature of

ecteinascidins. Initially, ecteinascidins were found to be cytotoxic against leukaemia cells and

were later shown to possess strong in vivo antitumour effects in various mice models bearing





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lymphoma, melanoma, ovarian sarcoma, human lung carcinoma, and human mammary

carcinoma xenografts.

ET-743 was licensed by PharmaMar to johnson & jonhson/orthoBiotech for drug

development in the United States.

The mechanism of action of ET-743 is ascribed to covalent modification of DNA by

guanine-specific alkylation at the N2 position, a property similar to another minor-groove

alkylating agent, anthramycin. In contrast to anthramycin, ET-743 is selective for GC-rich

sequences and forms an adduct with duplex DNA, which is reversible upon denaturation, and

induces a bend in the DNA helix directed towards the major groove.

Molecular dynamics calculations show protrusion of ring C of ET-743 into the minor

groove and interference with DNA-binding factors. This partly accounts for the potency of ET-

compared with other N2 alkylating agents such as saframycin A and anthramycin that have

smaller groups corresponding to ring C. ET-743 also affects transition-coupled nucleotide

excision repair and triggers cell death.

ET-743, under the trade name yondelis, was approved for the treatment of refractory soft-

tissue sarcomas by the European Commission in july 2007. Results of Phase II trials of ET-743

for Ewing’s sarcoma and soft-tissue sarcomas, colorectal cancer, pretreated advanced breast

cancer, ovarian cancer, and other sarcomas have been disclosed.

Dolastatin 10.

Collaborative endeavours of Pettit’s group at the Arizona State University, USA, and the

US National Cancer Institute resulted in a highly interesting compound: dolastatin 10. The

discovery of the dolastatins had its beginnings in 1972 during an explorative expedition to the

island state of Mauritius in the Western Indian ocean.

A series of cytotoxic peptides were isolated from the sea hare Dolabella auricularia found

in the Indian ocean. Among these was dolastatin 10, which exhibited outstanding in vitro





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cytotoxic activity against cancer cells. Alcohol extracts of D. auricularia showed exceptionally

potent activity against murine NCI P388 lymphocytic leukaemia cells at subnanomolar

concentrations (ED50 value of 4.6 × 10–5 μg per ml)179. A laborious bioassay-guided isolation

of dolastatin 10 — made highly challenging because of extremely low yields — required a large-

scale collection (~2 tonnes) of D. auricularia to produce the first milligram180.

Dolastatin 10 is a novel linear depsipeptide containing four unprecedented amino acids:

N,N-dimethylvaline, dolaisoleucine, dolaproine and dolaphenine (possibly biosynthesized from phenylalanine). Dolastatin 10 is a potent antimitotic agent that inhibits microtubule assembly and

tubulin polymerization. It binds to tubulin at a distinct site for peptide antimitotic agents close to

the vinca peptide binding site182,183, where HTI-286 and Crp-1 bind, and consequently causes

the accumulation of cells that are arrested at the mitosis stage and depleted of cellular

microtubules.

Dolastatin 10 demonstrated in vitro inhibitory activity against various human cancer cell

lines, including melanoma, sarcoma and ovarian cancer cells, and entered several Phase I and II

clinical trials as a single agent. Phase I clinical trials on dolastatin 10 identified a maximum

tolerated dose of 300–400 μg per m2 for patients with advanced solid tumours, and documented

granulocytopaenia as its major dose-limiting toxicity.

Drugs derived from Terrestrial organisms

Morphine

Morphine is a potent opiate analgesic medication and is considered to be the prototypical

opioid. It took its name from the Greek God of dreams Morpheus. Morphine was discovered as

the first active alkaloid extracted from the opium poppy plant in December 1804 in Paderborn,

Germany, by Friedrich Sertürner. The drug was first marketed to the general public by Sertürner

and Company in 1817 as an analgesic, and also as a treatment for opium and alcohol addiction.





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Commercial production began in Darmstadt, Germany in 1827 by the pharmacy that became the

pharmaceutical compary Merck, with morphine sales being a large part of their early growth.

Morphine is the most abundant alkaloid found in opium, the dried sap (latex) derived

from shallowly slicing the unripe seedpods of the opium, or common or edible, poppy, Papaver

somniferum. Morphine was the first active principle purified from a plant source and is one of at

least 50 alkaloids of several different types present in opium.

In clinical medicine, morphine is regarded as the gold standard, or benchmark, of

analgesics used to relieve severe or agonizing pain and suffering. Morphine acts directly on the

central nervous system (CNS) to relieve pain.

Morphine can be used as an analgesic to relieve:

* pain in myocardial infarction

* pain in sickle cell crisis

* pain associated with surgical conditions, pre- and postoperatively

* pain associated with trauma

* severe chronic pain, e.g., cancer.

* pain from kidney stones (renal colic, ureterolithiasis)

* severe back pain.

Apomorphine hydrochloride, a short-acting dopamine D1 and D2 receptor agonist, is a

potent dopamine receptor agonist used to treat Parkinson’s disease, a chronic neurodegenerative

disease caused by the loss of pigmented mesostriatal dopaminergic neurons linking the substantia

nigra (pars compacta) to the neostriatum (caudate nucleus and putamen). Apomorphine is a

derivative of morphine isolated from poppy (Papaver somniferum). Subcutaneous apomorphine

is currently used for the management of sudden, unexpected and refractory levodopa-induced off

states in fluctuating Parkinson’s disease.





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Penicillin

The penicillins were the first antibiotics discovered as natural products from the mold

Penicillium. In 1928, Sir Alexander Fleming, professor of bacteriology at St. Mary's Hospital in

London, was culturing Staphylococcus aureus. He noticed zones of inhibition where mold spores

were growing. He named the mold Penicillium rubrum. It was determined that a secretion of the

mold was effective against Gram-positive bacteria.

Penicillins as well as cephalosporins are called beta-lactam antibiotics and are

characterized by three fundamental structural requirements: the fused beta-lactam structure

(shown in the blue and red rings, a free carboxyl acid group (shown in red bottom right), and one

or more substituted amino acid side chains (shown in black). The lactam structure can also be

viewed as the covalent bonding of pieces of two amino acids - cysteine (blue) and valine (red).

Penicillin-G where R = an ethyl pheny group, is the most potent of all penicillin

derivatives. It has several shortcomings and is effective only against gram-positive bacteria. It

may be broken down in the stomach by gastric acids and is poorly and irregularly absorbed into

the blood stream. In addition many disease producing staphylococci are able to produce an

enzyme capable of inactivating penicillin-G. Various semisynthetic derivatives have been

produced which overcome these shortcomings.

Powerful electron-attracting groups attached to the amino acid side chain such as in

phenethicillin prevent acid attack. A bulky group attached to the amino acid side chain provides

steric hindrance which interfers with the enzyme attachment which would deactivate the

pencillins i.e. methicillin.

Finally if the polar character is increased as in ampicillin or carbenicillin, there is agreater activiity against Gram-negative bacteria.





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Combretastatin

Combretastatin is a small organic molecule found in the bark of the African bush willow

tree Combretum caffrum (photo, right), identified 21 years ago by Professor George R. Pettit, the

Director of the Cancer Research Institute based at Arizona State University in the USA.

Members of the combretastatin family possess varying ability to cause vascular

disruption in tumors. Combretastatin binds to the β-subunit of tubulin at what is called the

colchicine site, referring to the previously discovered vascular disrupting agent colchicine.

Inhibition of tubulin polymerization prevents cancer cells from producing microtubules.

Microtubules are essential to cytoskeleton production, intercellular movement, cell movement,

and formation of the mitotic spindle used in chromosome segregation and cellular division. The

anti-cancer activity from this action results from a change in shape in vasculature endothelial

cells. Endothelial cells treated with combretastatin rapidly balloon in shape causing a variety of

effects which result in necrosis of the tumor core. The tumor edge is supported by normal

vasculature and remains, for the most part, unaffected. As a result it is likely that any therapeutic

use will involve a combination of drugs or treatment options.





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Alkaloids

1. Contains nitrogen - usually derived from an amino acid.2. Bitter tasting, generally white solids (exception - nicotine is a brown liquid).

3. They give a precipitate with heavy metal iodides.

o Most alkaloids are precipitated from neutral or slightly acidic solution by Mayer's

reagent (potassiomercuric iodide solution). Cream coloured precipitate.

o Dragendorff's reagent (solution of potassium bismuth iodide) gives orange

coloured precipitate with alkaloids.

o Caffeine, a purine derivative, does not precipitate like most alkaloids.

4. Alkaloids are basic - they form water soluble salts. Most alkaloids are well-defined

crystalline substances which unite with acids to form salts. In plants, they may exist

o in the free state,

o as salts or

o as N-oxides.5. Occur in a limited number of plants. Nucleic acid exists in all plants, whereas, morphine

exists in only one plant species.

Alkaloids can be classified;

• in terms of their BIOLOGICAL activity,

• CHEMICAL structure (nucleus containing nitrogen),

• BIOSYNTHETIC pathway (the way they are produced in the plant).





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Terpenoids

Terpenoids may be defined as a group of molecules whose structure is based on a various but

definite number of isoprene units (methylbuta-1,3-diene, named hemiterpene, with 5 carbon

atoms).

A rational classification of the terpenes has been established based upon the number of isoprene

(or isopentane) units incorporated in the basic molecular skeleton:

Terpenes Isopreneunits

Carbonatoms

1 Monoterpenes 2 10

2 Sesquiterpenes 3 15

3 Diterpenes 4 20

4 Sesterpenes 5 25

5 Triterpenes 6 30

6 Carotenoids 8 40

7 Rubber > 100 > 500

Mono-, sesqui-, di-, and sesterpenes contain the isoprene units linked in a head to tail fashion.

The triterpenes and carotenoids (tetraterpenes) contain two C15 and C20 units respectively

linked head to head.

Date post:	06-Apr-2018
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Pharma Unit 1

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