A boon or a curse- the story of a miracle drug

For all the happiness mankind can gain Is not in pleasure, but in rest from pain.

DRYDEN

Often in the history of science the news of some important breakthrough or discovery made by a rival group or an enemy power had provided either the intellectual motivation or the military necessity for the scientific establishment of some other region of the globe to reach a similar goal by making accelerated efforts.

A case in point is the race for space research. The news that the Russians had sent a rocket successfully into space had shaken the Americans out of a sense of complacency and had made them step up their research work with increased vigour and enthusiasm to achieve spectacular results within a short time.

Another similar development, which had occurred much earlier in medical history is the discovery of the wonder drug, cortisone.

During World War II, it had been rumoured that the German Air Force had discovered a remarkable substance which when injected into pilots had developed in them among other things the ability to fly and fight at very high attitudes without experiencing stress.

Many laboratories in the United States which had already been studying the adrenal cortex, began to feverishly look for this magic elixir, and their search resulted in the discovery of the miracle drug cortisone with amazing properties—similar to those of the substance the Germans were thought to have developed.

Following five years of intense research Dr Edward Kendall of the Mayo Clinic in the United States isolated five compounds from the adrenal cortex. (There are two adrenals, yellow, and brown, triangular glands located just above the kidneys and each weighing about quarter ounce. Each gland has an inner part called the medulla and an outer covering called the cortex.)

A number of hormones are produced by the adrenal cortex out of which only a few are particularly relevant for maintaining the body’s equilibrium and hence essential to life. Three of these are cortisol or hydrocortisone from which cortisone can be made, aldosterone and cortisone. Scientists had noticed that they could obtain similar results by giving people either cortisone (17-hydroxy- 11-dehydrocorticosterone) or the adrenal cortex stimulating hormone (ACTH) a substance secreted by the pituitary gland which stimulates the adrenals to produce hydrocortisone.

While ACTH has to be injected, cortisone can be injected, swallowed, inhaled or rubbed onto the human body. It can influence vital processes such as fluid distribution, blood-cell production and the human body’s response to stress. The most promising of the five adernal compounds isolated by Kendall was a substance known as compound E which can increase the physiological resistance of animals, such as rats.

The race to overtake the German Air Force in research centred on finding a more efficient manner of developing this compound E, though by 1944 the information that the Germans had actually succeeded in producing a miracle drug had been discounted. In that year working in a pharmaceutical company a chemist succeeded in synthesizing compound E, and the small amounts produced were used to treat Addison’s disease caused due to adrenal hormone insufficiency.

A doctor who had been working at the Mayo Clinic had long been intrigued by the fact that in pregnant women, in whom the adrenal gland output gets speeded up, there was a tendency for arthritis to disappear. After the pregnancy ended, resulting in stoppage of the extra adrenal hormone supply, the arthritis mysteriously returned!

The doctor, therefore, concluded that Kendall’s compound E could perhaps be useful in treating rheumatoid arthritis; in 1978, a dose of compound E did in fact bring quick relief from pain to a patient.

The following year he revealed these remarkable findings to other doctors and the discovery of compound E, which later came to be known as cortisone was hailed as one of the most important medical triumphs of the twentieth century Hence, Kendall and another researcher Tadeus Reichstein were jointly awarded the Nobel Prize in 1950 for their epoch-making work.

The production of cortisone and its close relatives the corti­costeroids is now a million dollar business. Many synthetic corticosteroid preparations are now available in the market and millions of prescriptions are being written out for them all over the world. The corticosteroids are being used to treat a variety of ailments, including burns, kidney disease, myasthenia gravis, temporal arthritis (inflammation of the blood vessels that can cause blindness), arthritis and breast cancer.

Women who are unable to conceive because of an allergy to sperm have borne normal babies after being given corticosteroids. When premature delivery is anticipated, administering cortisone to the mother can hasten the development of the lungs of the unborn baby—a measure that can prevent hyaline membrane disease (a fatal birth disorder in premature babies).

In some cases it is able to bring at least temporary relief if not total cure; following cortisone therapy a person in coma due to a malignant brain tumour and another patient paralysed below the waist due to spinal cord pressure could function normally for a while; similarly persons suffering from anorexia nervosa developed appetite.

Cortisone seems to act in two ways. It reduces inflammation by inhibiting the production of irritating histamines. It suppresses the immune response desirable when the body is reacting against its own tissue.

In some cases cortisone can save life. Pemphigus, an ulceratic skin condition that used to cause deaths in more than 90 per cent of the cases, as well as lupus, a fatal disease resembling arthritis, both respond to cortisone. Similarly, drugs used for leukemia in children seem to act more effectively when given along with cortisone.

However, cortisone, for all its miraculous medicinal properties, also produces undesirable side-effects. Thus, while it can make allergic rashes on the skin disappear, it can also cause acne. While it makes organ transplant possible by suppressing the body’s rejection of foreign tissue, it can also increase the risk of infection because of the very same reason.

In small doses there is positive response in minor skin problems, but excessive use can thin the skin rather than heal it. In children if cortisone is used for nappy rash, it could result in serious ulceration. There are also indications that at times cortisone can awaken a dormant disease. A ten year old girl with severe arthritis who had been on the way to speedy recovery following cortisone therapy suddenly developed diabetes. Stoppage of treatment brought back the arthritis with renewed vigour. In small doses the drug is manageable, but in larger doses over a long period of time, the side- effects seem to lead to very serious complications. Hence, caution is warranted while using cortisone for treating chronic conditions.

Initial optimism that it is the drug of choice in arthritis has been replaced by a feeling that the drug can only bring symptomatic relief as aspirin does for a headache. But corisone is still considered effective as ‘replacement therapy’ in Addison’s disease.

It has also been noticed that after cortisone therapy involving large doses the intake would have to be the reduced gradually, for abrupt or rapid withdrawal can lead to adrenal insuffiency. When the body is used to massive doses of cortisone the adrenal glands themselves appear to go to sleep. Under such circumstances if cortisone therapy is stopped, the patient may experience a steep drop in blood pressure leading to death.

Even though the adrenal glands do start making cortisone, after very gradual withdrawal they do not become alert enough for a long time (six months to two years) to be able to release sufficient quantities of the hormone to handle situations involving extra stress such as high fever, a fracture or surgery.

This tendency can be dangerous if there is an imminent prospect of a major operation. A new round of cortisone would have to be started to enable the patient cope with the crisis, even if this means going through the process of weaning all over again.

Cortisone can also cause other undesirable side-effects such as a round moon face, deposits of unwelcome fat on the body, greater susceptibility to infection, slower tendency for wounds to heal, wasting of muscles and congestive heart failure. In high doses it can interfere particularly in women with the body’s ability to use calcium and consequently lead to a thinning of the bones and possibility of fractures.

One other serious side-effect of cortisone seems to be its tendency to make a person feel euphoric.There could also be alternate feelings of joy or depression. The person may claim to hear certain kinds of noises repeatedly. These effects may be temporary or permanent. Some doctors are of the view that in the latter category, cortisone merely precipitates some dormant psychosis already present in the patient.

Scientists are now concerned with the problem of how to make cortisone drug therapy useful. Their ultimate aim is to rearrange the chemistry of the corticosteroid molecule itself to make it specific for a certain tissue, thus, eliminating unwanted side-effects on other tissues. Since corticosteroids are expected to play a prominent role in treatment of diseases for a long time to come, all research is concentrated designing these drugs in such a way as to reduce or eliminate their harmful side-effects..

Doctors feel that the control of asthma can be achieved by treatment with inhaled corticosteroids (ICS), theophylline, long acting beta2-agonists and antileukotrienes. No wonder that Beta2-agonists and corticosteroids dominate asthma therapy. Corticosteroids are the most effective drugs available to clinicians for the control of inflammation in patients with asthma. ICS have revolutionized the treatment of asthma and are now the first-line treatment for chronic asthma in all ages.

There was initial optimism that Glucocorticoids would be useful in the treatment of Duchenne muscular dystrophy (DMD), the most common degenerative neuromuscular disease, which is caused by the deficiency of dystrophin, an anti-dystrophy protein. DMD usually occurs in childhood and has no effective cure. Patients with DMD generally lose their ability to walk when ~12 years old, and often require the use of a wheelchair. Numerous studies have shown that it was thought that Glucocorticoids prolong autonomous walking, reduce scoliosis, and improve cardiopulmonary function, quality of life and the survival rate of patients

However despite their efficacy, the clinical use of glucocorticoids for DMD is known to be associated with adverse reactions, including osteoporosis, obesity, short stature, delayed puberty and adrenal insufficiency. Therefore some more detailed research is being conducted by scientists who advise doctors not to delay the use of Glucocorticoids in treatment of DMD.