DDD (REPORTS)

ASPIRIN
INTRODUCTION

 Aspirin is currently the most widely used drug worldwide and has been clearly one of the most important
pharmacological achievements of the twentieth century. Historians of medicine have traced its birth in 1897,
but the fascinating history of aspirin actually dates back 3500 years, when willow bark was used as a
painkiller and antipyretic by Sumerians and Egyptians, and then by great physicians from ancient Greece
and Rome. The aspirin story continues today with the growing evidence of its chemo preventive effect
against colorectal and other types of cancer, now awaiting the results of ongoing primary prevention trials in
this setting.
HISTORY OF ASPIRIN
c3000 – 1500 BC: Willow is used as a medicine by ancient civilizations like the Sumerians and Egyptians. The Ebers
papyrus, an ancient Egyptian medical text, refers to willow as an anti-inflammatory or pain reliever for non-specific
aches and pains.
c400 BC: In Greece, Hippocrates administers willow leaf tea, which contains the natural compound from which
aspirin is derived, to women to ease the pain of childbirth.
1763: Edward Stone left the willow bark to dry on the outside of a baker's oven for 3 months then pounded and sifted
it into a powder. He reported: ‘It has been given in fifty persons, and never failed in the cure, except in a few
autumnal and quartan agues, with which the patients have been long and severely afflicted’. This letter is likely to be
the driving force behind the use of willow bark to treat fevers by many physicians of the time.
1828: Johann Buchner, professor of pharmacy at Munich University, Germany, succeeds in extracting the active
ingredient from willow, producing bitter tasting yellow crystals that he names salicin.
1830: Salicin is also found in the meadowsweet flower by Swiss pharmacist Johann Pagenstecher and later by
German researcher Karl Jacob Latwig.
1853: Structure of Asprin

 The French chemist, Charles Gerhardt, was the first to modify salicylic acid with the introduction of an acetyl
group in place of a hydroxyl group, but the compound was not stable. Gerhardt has one of the first true
claims to be the person to discover aspirin but the lack of stability of his newly derived compound stopped
him from developing it further. Acetylation of salicylic acid later proved to be the key step in reducing its
irritant properties.
1876: Early evidence for salicin

 In 1876, the first clinical trial of salicin was published by Thomas Maclagan a Scottish physician at the
Dundee Royal Infirmary. He investigated the effects of salicylate in relieving the symptoms of rheumatic
fever. His first step was to take salicin himself.
 He proceeded to treat eight patients with rheumatic fever with 12 grains of salicin every 3 hrs.,
demonstrating its antipyretic and anti-inflammatory effects Despite the clear antipyretic benefits of salicin, it
was not taken up more widely due to complications with gastritis.
1890-1897: A Breakthrough produces aspirin

 German chemist Felix Hoffmann, possibly under the direction of colleague Arthur Eichengrün, finds that
adding an acetyl group to salicylic acid reduces its irritant properties and Bayer patents the process.
 Eichengrün decided to develop a form of salicylate that did not cause gastric irritation. He allocated this task
to Hoffmann.
 Upon being allocated this task by Eichengrün, Hoffmann set to work trying to manipulate the salicylic acid
that he extracted from dry meadowsweet leaves. He was able to acetylate a phenol group of salicylic acid,
producing acetylsalicylic acid.
 The acetylsalicylic acid (soon to be known as aspirin) was put through clinical trials by Dreser's
pharmacology division. Initial reports were that it was a successful antipyretic, but Dreser rejected it on the
grounds that it may cause tachycardia and palpations. Ten days after his discovery of acetylsalicylic acid,
Hoffmann produced a second famous drug: diacetylmorphine, also known as heroin. This drug was
extraordinarily effective for pain relief and there was great hope that it would prove to be a non-addictive
form of morphine
1899: Acetylsalicylic acid is named Aspirin by Bayer. The letter ‘A’ stands for acetyl, “spir” is derived from the plant
known as Spiraea ulmaria (meadowsweet), which yields salicin, and “in” was a common suffix used for drugs at the
time of the first stable synthesis of acetylsalicylic acid.
1918: The Rise of Aspirin

 In 1918 following World War I, the world was hit by another tragic event, a worldwide outbreak of influenza.
Approximately 50 million people died from the outbreak: more than died from fighting in the whole of World
War I. No cure could be found and vaccination was unsuccessful. Aspirin became widely used and was
efficacious in relieving the symptoms of influenza, although it was not effective in reducing mortality. Its
popularity was maintained thereafter and aspirin went on to be considered by the public and the medical
profession as an effective antipyretic and analgesic, with few side effects when taken at standard doses
1949: 15 years after the publication of the report attributing the discovery to Hoffmann, Arthur Eichengrün, published
a manuscript emphasizing that the work was performed under his direction. He went on to point out that he identified
acetylsalicylic acid as the best compound they had isolated and was the first to call for clinical trials. He reported he
had tested it on himself and had initiated the first trials. These trials demonstrated the antipyretic and analgesic
effects of acetylsalicylic acid as well as its favorable side effect profile.
1950: Aspirin enters the Guinness World Records for being the most frequently sold painkiller.
1971: Mechanism of action

 John Vane, professor of pharmacology at the University of London, publishes research describing aspirin’s
mechanism of action (dose-dependent inhibition of prostaglandin synthesis) He later won a Nobel prize
(1982) for this work, along with Bengt Samuelsson and Sune Bergström
1974: Through the 1970s there was an increased interest in the use of aspirin as an antiplatelet agent. The first
randomized controlled trial using aspirin was published by Elwood et al (1974). A total of 1239 men discharged from
hospitals in the UK with a myocardial infarction were identified. Participants were visited at home by the trial team
and provided with either aspirin 300 mg daily or a matching gelatine capsule. While fewer participants treated with
aspirin died in the following 6 months, the difference was not statistically significant and the trial was considered
inconclusive. However, as further randomized controlled trial evidence accumulated, the overall benefit from the
introduction of aspirin in this setting was a 25% reduction in recurrent myocardial infarction.
1997: Results from the CAST (Chinese acute stroke trial) study of early aspirin use in 20,000 patients with acute
ischemic stroke show that aspirin started early in hospital produces a small but definite net benefit
1998: Results from the HOT (hypertension optimal treatment) trial show that aspirin significantly reduces major
cardiovascular events in hypertensive patients, with the greatest benefit seen in preventing heart attacks
2004: Famously, the drug rofecoxib (Vioxx) was withdrawn from the market in 2004 because of heart concerns. A
recent study found that painkillers called opioids heightened heart attack risk in addition to bone fracture when
compared with patients taking NSAIDs such as aspirin and ibuprofen. And research published in June found that
some NSAIDs may increase risk of cardiovascular death.
2011:

 A meta-analysis of eight clinical trials finds that, after five years of follow-up, trial participants who took
aspirin daily for a mean of four years have a 44% reduced risk of dying from cancer compared with
participants who took a placebo
 Approximately one quarter of patients with acute upper gastrointestinal bleeds or hemorrhagic strokes are
taking an antiplatelet agent and the management is unclear.
 Aspirin has come a long way since the use of willow bark by the ancient Sumerians and Egyptians. It is now
the most commonly used drug in the world and has proved life saving in the prevention of cardiovascular
disease. It is unclear what the future will bring for aspirin with the development of new antiplatelet
medications. However, we owe an enormous debt to all those who discovered aspirin, identified its
mechanism, and demonstrated how it reduces the risk of cardiovascular death.
 Overall, despite aspirin being more than 100 years old, it continues to occupy a prominent place in the
treatment of cardiovascular disease and there are no clear signs at present of it being displaced in the near
future.
PENICILLIN
We have all, at one point or the other, heard about penicillin. From its accidental discovery and massive use in World
War II to the Nobel Prize for Medicine in 1945 by its rightful owners, penicillin has made its proof as the “Miracle
Drug” that revolutionized the course of the medical industry.
Without further ado, let us take a look at an important aspect that made penicillin accessible to the market

WHAT IS PENICILLIN?

 First true naturally-occurring antibiotic ever discovered: a great medical breakthrough.

 Penicillin is a group of antibiotics that are commonly used to treat different types of gram positive and gram
negative bacterial infections.
 Penicillin is derived from the Penicillium mould “Penicillium notatum” having bactericidal action on
Staphylococci in 1928.
 It destroys bacteria by inhibiting the enzymes responsible for the formation of the cell wall in the bacterial
cells.
History: Discovery of Penicillin

 1928: Scottish biologist, Alexander Fleming discovered that the Staphylococcus culture he had mistakenly
left growing in open was contaminated with a mould which had destroyed the bacteria.
 After isolating a sample and testing it, he found that it belonged to the Penicillium family. Later the mould
was classified as Penicillium notanum.
 But later (1939), using Fleming’s work, two medical researchers, Howard Florey and Ernst Chain managed
to purify penicillin in a powdered form.
 1941: They successfully treated a human.
 1943: They produced penicillin on a large scale. This helped immensely to treat casualties during the WWII
that had bacterial infections due to their wounds.

Uses of Penicillins

 Streptococcal infections: Pharyngitis (Streptococcus pyogens always sensitive), pneumonia, otitis media,
meningitis
 Meningococcal meningitis
 Diphtheria
 Tetanus/gas gangrene
 Syphilis
 Rare infections : Anthrax / Actinomycosis
  Prophylaxis
 Rheumatic fever, gonorrhea, endocarditis

MORPHINE
Did you know?
Sigmund Freud, an Austrian neurologist known as the founding father of psychoanalysis, died from taking a large
dose of Morphine.

 In September 1939, Freud who was suffering from cancer and in severe pain, persuaded his doctor and his
friend, Max Schur to help him commit suicide.
 On 21st and 22nd of September, he administered a large dose of Morphine that resulted in Freud's death on
September 23, 1939.
What is morphine?

 Morphine is a highly potent opiate (narcotic) analgesic that is used to treat moderate to moderately severe
chronic pain. Morphine is said to be the most powerful pain reliever medicine has to offer and sets the
standard by which all other opiate potency is tested. 
 The potential for morphine addiction is very high, both physically and psychologically.
 Morphine, the main alkaloid of opium, was first obtained from poppy seeds in 1805. It is a potent analgesic,
though its use is limited due to tolerance, withdrawal, and the risk of abuse.
 Morphine is still routinely used today, though there are several semi-synthetic opioids of varying strength
such as codeine, fentanyl, methadone, hydrocodone, hydromorphone, meperidine, and oxycodone.
 Morphine was granted FDA approval in 1941.
Discovery of Morphine
(Opium Poppy)

 Morphine was discovered by Friedrich Wilhelm Adam Serturner (1783-1841), a 21-year-old pharmacist’s
assistant.
 He wondered about the medicinal properties of opium, which was widely used by 18th-century physicians.
 In a series of experiments, performed in his spare time and published in 1806, Serturner managed to isolate
an organic alkaloid compound from the resinous gum secreted by the opium poppy.
 He found that opium with the alkaloid removed had no effect on animals, but the alkaloid itself had 10 times
the power of processed opium. Sertuner named that substance morphine, after Morpheus, the Greek god of
dreams, for its tendency to cause sleep.
Rise of the opium addiction

 In the 18th century, Europe had a high demand for Chinese goods such as tea and silk but the Chinese did
not have a high demand for European goods, creating a trade deficit. In order to pay China back for their
goods, Britain gave China the only commodity they would accept which was silver. However, to obtain
enough silver, the British had to buy it from other European countries, creating further debt.
 In 1773 ,the British conquered the Bengal Province in India which the World's largest producer of opium at
the time. With the Indian poppy fields now under British control, Britain decided to start trading opium as a
way of addressing the trade imbalance between China and Britain. Soon, opium addiction had spread
across China and in 1839 the emperor seized and burned all opium brought in by British ships. This marked
the beginning of the opium wars, during which the British defeated the Chinese and resumed the opium
trade.
Morphine as Pain Reliever

 In 1818, French physician Francois Magendie published a paper that described how morphine brought pain
relief and much-needed sleep to an ailing young girl. This stimulated widespread medical interest. By the
mid-1820s morphine was widely available in Western Europe in standardized doses from several sources,
including the Darmstadt chemical company started by Heinrich Emanuel Merck.
 In 1853, the hypodermic needle was developed, and the use of morphine became more widespread. From
its earliest application, it was used as a form of pain relief and that is still how it is meant to be used today.
Since then, various delivery systems for morphine have been developed, including epidural injection and
pumps that allow patient-controlled analgesia.
 Although morphine was originally touted as a cure for many maladies, even for alcohol and opium addiction,
by the 1870s physicians had become increasingly aware of its own addictive properties. Many new pain
relievers have been synthesized since the crystallization of morphine from opium almost 200 years ago
TAXOL
TAXOL: INTRODUCTION
Generic Name: Paclitaxel
Drug Type: anti-cancer ("antineoplastic" or "cytotoxic") chemotherapy drug.
Taxol is classified as a "plant alkaloid," a "taxane" and an "antimicrotubule agent.“
Uses:
treatment of breast, ovarian, lung, bladder, prostate, melanoma, esophageal, as well as other types of solid tumor
cancers.
It has also been used in Kaposi's sarcoma.
HISTORY

 The discovery of paclitaxel began in 1962 as a result of a NCI-funded screening program. A number of
years later it was isolated from the bark of the Pacific yew, Taxus brevifolia, hence its name "taxol".
 The discovery was made by Monroe E. Wall and Mansukh C. Wani at the Research Triangle Institute,
Research Triangle Park, North Carolina, in 1971. These scientists isolated the natural product from the bark
of the Pacific yew tree, determined its structure and named it "taxol", and arranged for its first biological
testing. The compound was then developed commercially by BMS, who had the generic name assigned as
"paclitaxel"
Plant screening program

 In 1955, the NCI in the United States set up the Cancer Chemotherapy National Service Center (CCNSC) to
act as a public screening center for anticancer activity in compounds submitted by external institutions and
companies.
 Although the majority of compounds screened were of synthetic origin, one chemist, Jonathan Hartwell, who
was employed there from 1958 onwards, had experience with natural product derived compounds, and
began a plant screening operation.
 After some years of informal arrangements, in July 1960, the NCI commissioned the United States
Department of Agriculture (USDA) botanists to collect samples from about 1,000 plant species per year.
 On 21 August 1962, one of those botanists, Arthur S. Barclay, collected bark from a single Pacific yew tree
in a forest north of the town of Packwood, Washington, as part of a four-month trip to collect material from
over 200 different species.
 The material was then processed by a number of specialist CCNSC subcontractors, and one of the tree's
samples was found to be cytotoxic in a cellular assay on 22 May 1964.
 Accordingly, in late 1964 or early 1965, the fractionation and isolation laboratory run by Monroe E. Wall in
Research Triangle Park, North Carolina, began work on fresh Taxus samples, isolating the active ingredient
in September 1966 and announcing their findings at an April 1967 American Chemical Society meeting in
Miami Beach. They named the pure compound taxol in June 1967. Wall and his colleague Wani published
their results, including the chemical structure, in 1971.
 The NCI continued to commission work to collect more Taxus bark and to isolate increasing quantities of
taxol.
 By 1969, 28 kg (62 lb) of crude extract had been isolated from almost 1,200 kg (2,600 lb) of bark, although
this ultimately yielded only 10 g (0.35 oz) of pure material, but for several years, no use was made of the
compound by the NCI.
 In 1975, it was shown to be active in another in vitro system; two years later, a new department head
reviewed the data and finally recommended taxol be moved on to the next stage in the discovery process.
This required increasing quantities of purified taxol, up to 600 g (21 oz), and in 1977 a further request for
7,000 lb (3,200 kg) of bark was made.
 In 1978, two NCI researchers published a report showing taxol was mildly effective in leukaemic mice. In
November 1978, taxol was shown to be effective in xenograft studies. Meanwhile, taxol began to be well
known in the cell biology, as well as the cancer community, with a publication in early 1979 by Susan B.
Horwitz, a molecular pharmacologist at Albert Einstein College of Medicine, showing taxol had a previously
unknown mechanism of action involving the stabilization of microtubules. Together with formulation
problems, this increased interest from researchers meant that, by 1980, the NCI envisaged needing to
collect 20,000 lb (9,100 kg) of bark. Animal toxicology studies were complete by June 1982, and in
November NCI applied for the IND necessary to begin clinical trials in humans.