|HISTORY OF MEDICINE
|Year : 2018 | Volume
| Issue : 3 | Page : 110-111
Paracetamol, digoxin, cisplatin
|Date of Web Publication||9-Nov-2018|
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
. Paracetamol, digoxin, cisplatin. Curr Med Issues 2018;16:110-1
Source: CMC Pharmacy Bulletin, a publication of the Pharmacy Service (DISH), CMC, Vellore.
A brief history of some medications used in modern medicine
PARACETAMOL – History of origin and synthesis
Probably all of us must have self-administered paracetamol tablets at least a couple of times in our recent past. It would be the first choice for most of us when it comes to mild pain, sprain, toothache or fever. Though it is omnipresent today, it had a humble beginning two centuries ago. The history of paracetamol dates back to the latter part of 19th century. In 1886, Drs. Arnold Cahn and Paul Hepp of France were treating a patient suffering from intestinal parasites. They had been investigating naphthalene for its beneficial effect in the treatment of this condition. However, an inexperienced pharmacist mistakenly filled the prescription with acetanilide. Acetanilide was discovered in 1852 by the French chemist Charles Gerhardt and was still an obscure drug at this time. Providentially, the physicians observed significant fever reduction in one of their patients who, along with intestinal parasites, had fever. As Drs. Cahn and Hepp continued to prescribe acetanilide, they also noticed its analgesic properties. But its unacceptable side effects, methemoglobinemia in particular limited its wide clinical use.
On the other hand, paracetamol was first synthesized in 1877 by Harmon Northrop Morse, but it was not until 1887 that clinical pharmacologist Joseph Von Mering tried paracetamol in humans. In 1893, Von Mering published a paper which favoured phenacetin compared to paracetamol. Paracetamol was then quickly discarded in favour of phenacetin. Aspirin was also introduced for clinical use during that time which added to the disregard of paracetamol. The situation continued for half a century and later in 1947, David Lester and Leon Greenberg found strong evidence that paracetamol was a major metabolite of acetanilide in the blood and in a subsequent study they reported that large doses of paracetamol in rats did not cause methemoglobinemia. In three papers published in 1948, Bernard Brodie, Julius Axelrod and Frederick Flinn confirmed using specific methods that paracetamol is the major metabolite of acetanilide, and established that it was as effective as its precursor. They also established that methemoglobinemia is induced by another metabolite, phenyl-hydroxylamine. A follow-up paper by Brodie and Axelrod in 1949 established that phenacetin was also metabolized to paracetamol. These series of discoveries led to the resurgence of paracetamol in the clinical arena. Paracetamol was commercially made available in the early 1950s. Though increased concern was raised about the toxicity of analgesics during 1960s and 1970s, paracetamol exhibited a consistent safety profile and still hold its reputation.
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DIGOXIN – From Botany to Cardiology
The physicians in Royal College of Physicians in Edinburgh wouldn't have expected digitalis to save millions of people with ailing hearts when they decided to get rid of digitalis from the Edinburgh Pharmacopoeia judging digitalis as useless. Nevertheless, they had to regret their decision soon after in 1785 when Dr. Erasmus Darwin (grandfather of Charles Darwin the naturalist) published a paper. Actually, the man credited with the introduction of digitalis into clinical practice was Dr. William Withering who was an English physician born to a surgeon, who later got attracted to plants and botany. As a result of his love towards botany, in 1776, Withering published “The botanical arrangement of all the vegetables naturally growing in Great Britain” a comprehensive British flora.
Once, Withering happened to meet an old woman in Shropshire who had sometimes cured patients with severe oedema whom physicians washed their hands of, with her secret polyherbal formulation. After constant pestering, the old woman disclosed all the 20 different ingredients of her formulation. For the next nine years, he experimented different plant parts of all the 20 different ingredients and noticed only one that he considered potentially active—‘foxglove’ (Digitalis purpurea).
While he was working with Dr. Erasmus Darwin as a consulting physician, he was asked for a second opinion on a female patient with severe oedema. By this time the patient was very sick, anuric, hypoxic, arrhythmic and she started showing symptoms of cyanosis. Though he realized its potential, Withering was reluctant to prescribe digitalis fearing that an unfavourable outcome in this patient would discredit digitalis which otherwise holds a promise for mankind. However, his compassionate heart yielded him to prescribe digitalis but only to result in a marvelous resuscitation of the patient. Withering had reported that the patient continued to live for more than nine years after this treatment encounter. Darwin was very much impressed by this and he went on to praise the healing effects of floxglove in his popular poem “The Loves of the Plants”. In 1785 Darwin submitted a paper entitled “An account of the successful use of foxglove in some dropsies and in pulmonary consumption” to the College of Physicians in London. While the paper was still in the press, Withering published many successful cases with digitalis treatment which created estrangement between them.
In the following years, research works of pharmacists and pharmacologists in particular Claude Adolphe Nativelle (France) and Oswald Schmiedeberg (Germany) resulted in the discovery of digoxin from digitalis and was first marketed in 1957 which still continues to be invincible. Digoxin discovery is truly a breakthrough in medicine.
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Cisplatin is known to be the “penicillin of cancer drugs,” because it has been one of the first, most widely prescribed, and most effective treatment for many cancer diagnoses. Cisplatin was first described by Michele Peyrone in 1845, and was known as Peyrone's salt or Peyrone's chloride. But the really important event was its fortuitous discovery as a cancer treatment by Barnett Rosenberg, a biophysical chemist at Michigan State University. At the time, Rosenberg was trying to study the effect of electric fields on bacterial growth. During his experiments, he found bacteria grew 300 times their normal size but never divided, a very unusual result, when he used platinum electrodes to generate the electric fields. It took a while to figure out what was going on, but in the end he discovered the platinum electrodes were corroding in the test solution, producing cisplatin. He published his remarkable findings in the journal Nature in 1965, and three years later, published another paper showing cisplatin could cure tumours in mice. Rosenberg had discovered a number of platinum-containing chemicals that could kill bacteria and cancer cells, but it wasn't clear which of these if any, would be suitable for human use. Con-temporarily, Sir Alexander Haddow, then Director of London's Chester Beatty Research Institute was hunting for novel anticancer drugs. He heard about Rosenberg's findings and put a pharmacologist Dr. Tom Connors in-charge of sifting through all the platinum derivatives to find out the suitable candidate for human use. Eventually, they were convinced with a compound known as cis-[PtCl2(NH3)2] or cisplatin as it is called now and by 1971 it was ready to go into clinical trials. At the Royal Marsden Hospital, a team led by Dr. Eve Wiltshaw gave cisplatin to patients for the first time. Despite challenging side-effects, the drug showed promising results in women with ovarian cancer. During the same time, cisplatin showed astounding activity against many types of cancer. The drug was finally approved by the US FDA in the year 1978 for use in cancer patients. The drug is on its 40th year now and still looks young and potent.
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