Friday, December 18, 2009

Welcome back to the NH Pediatric Cardiology blog. We are in the process of exploring the developmental history of drugs used in the Pediatric Cardiology.

Birth of a child and the process of labour had always been a matter of philosophical and scientific interest for human race from time immemorial. However, the chemical interest in the process of childbirth began around 1930. The men who thought of this novelty were Dr Raphael Kurzrok and Dr Charles Lieb working in the Department of Obstetrics and Gynecology at Columbia University in New York. It was the time when artificial insemination in humans was thought of. In this process, the animal experiments were going in full swing. In one of the earliest human trails, they had an interesting observation. The uteri of women undergoing artificial insemination sometimes contracted violently and on other occasions relaxed! They failed to determine the cause of the phenomenon but documented that such behaviour was common and unpredictable in their series.

Before their report was forgotten, about 5 years later, Ulf von Euler was working with the chemical nature of seminal fluids of animals at the Karolinska Institute in Stockholm, Sweden. In the seminal contents of monkey, sheep and goat, he detected an acid that lowered blood pressure and caused smooth muscle contraction. His initial presumption for the acidic nature of this substance was the contribution from Prostate. Unable to think of any other name, He named it ‘prostaglandin’ and conveniently forgot!

Sune Bergstrom was a student of von Euler. Bergstrom’s area of interest was the utility of Craig countercurrent extraction apparatus purifying the extracts. For his work, he was able to obtain a $100 000 grant from the Upjohn Company in the mid-1950s. Recalling the work of von Euler, he decided to go with the analysis of Prostaglandins and was successful in isolating small amounts of several different highly potent prostaglandins. He also elucidated their structures. They were subsequently classified as types A to F. Each type was being given a subscript indicating the number of unsaturated centres in the side chains.

Bergstrom’s work paid off well. In 1957, he isolated crystals of alprostadil (the original prostaglandin E1) from sheep prostate glands. In next five years, the structures of alprostadil, dinoprost (the prostaglandin F2a) and dinoprostone (prostaglandin E2) were determined.

Although Dinoprostone is one of the most commonly occurring and most potent of the mammalian prostaglandins, it proved to be unstable due to its chemical structure. The same effect was found in all prostaglandins of E series. The stability factor became a major issue for Upjohn and the bosses decided to recruit more scientists on this job. In this process, Phillip Beal and his colleagues could achieve laboratory synthesis of a naturally occurring prostaglandin in 1965. Inspired by their success, they also synthesised alprostadil in 1969.

At the same time, some of the Harvard scientists took interest in this problem and started working on it. Elias Corey not only synthesised dinoprostone in 1970, he also succeeded in modifying the structure to obtain dinoprost.

The availability of synthetic prostaglandins opened a new door of opportunity. The volumes could allow a decent clinical trial. Upjohn decided to supply prostaglandins free of cost to any research team for understanding the therapeutic advances. But, out of the sixteen naturally occurring prostaglandins only three were proved to be of any clinical value.

In 1967, a research team discovered the link between the prostaglandin inhibition and Peptic Ulcer. Some of the Prostaglandins of E series inhibited gastric acid secretion. This led to the hope that prostaglandins could be used in the treatment of peptic ulcer. However the therapeutic effects could not be evaluated because none of them were active by mouth. Although an injectable formulation was prepared, it had a very brief duration of action. Also, the prostaglandins of the E series lacked any site specificity of action and ended up producing more unwanted effects than therapeutic ones. Adverse effects were mainly due to vasodilation, which caused facial flushing, headache and hypotension.

The vasodilating properties of alprostadil led to a new avenue of therapeutic use that has saved thousands of newborns. The use of prostaglandins to dilate the ductus arteriosus in neonates with duct dependent congenital heart diseases gave a new lease of life to such newborns. It also added a new drug to the limited list of drugs used in Pediatric Cardiology.

Slowly, but steadily, Prostaglandins found a formidable place in the Pharmacopeia. Due to its proven ability to induce contraction of the uterus, intravenous infusion of dinoprostone found its place in inducing labour. It is now given by the vaginal route, either as pessaries, tablets or gels. In 1972, it was also being used for the induction of abortion after the first trimester of pregnancy.

Chemical modification of prostaglandin was the new objective for research scientists. In this way, John Vane of Burroughs Wellcome could isolate a prostaglandin-like substance (prostanoid ) called Epoprostenol which was found to be a prostacyclin. These naturally occur in the walls of blood vessels, and are responsible for producing vasodilation. It also prevents clotting. As for any prostaglandins, it is rapidly metabolised. The half life is being three minutes when given by injection.
Later generation of prostacyclins are being developed now and is one of the most promising therapeutic options for the treatment of PPHN.

In the next post, we shall see the development of one more class of cardiac drugs.

On a personal note, the delay in the present post was largely due to the sudden CMEs I had to attend for a couple of guest lectures. The one on previous Sunday was in the heritage city of Mysore, a beautiful place located 3 hours from Bangalore. The JSS medical college in Mysore is presently celebrating its Silver Jubilee. To commemorate the event, the dynamic team of JSS Pediatricians have arranged a monthly CME of all pediatric sub-specialties. This time, it was the turn of Cardiology and Endocrinology.

I am feeling a bit philosophical off late. Life poses multiple problems and one among them is to stand up against your own people. We often find ourselves in such a situation and wonder what the right course of action is. I must have read the holy “Bhagavad Gita” good number of times. This is exactly what the mighty Arjuna had faced in the epic Mahabharata. What lord Krishna preached him might be for the entire universe, wherein every human being is confronted with a similar situation at least once in a life-time. Tackling a stranger doing wrong things might be easier. But, tacking the people whom you respect when they are deliberately erring is one of the toughest jobs. And, when that error affects you directly, then the tackling becomes inevitable. Is the matter you are fighting for is more important than the relationship? If the other party had respected the relationship, then they would not have committed the deliberate error. The expression of error from their side shows how meagre a respect they have for your regard, respect and relationship. In this scenario, is it better to express your discomfort with the situation and accept the ensuing wrath or continue respecting the relationship and accept the changes with a perpetual grinding of teeth? Is there a via-media solution? I felt it might be better to voluntarily give up your right and make them feel guilty of their motives and actions. But one should be ready for the losses if the other party does not feel guilty at all!!

Also, it may be OK if it is an individual decision. But, if a number of people are involved in the sufferers group, this individual decision would find no place. “Fight for the Right” would be the only solution left. The ancient wisdom seldom changes and is aptly called the “roots” of culture!

What is the best indicator of the Pre-op assessment of PA anatomy in TOF? We use the McGoon ratio. Nakata index is an equally popular modality. However, we often see the surgeon disagreeing on the data provided by cath and echo on PA sizes. They quote the “underfilling” concept and accept low McGoons for total correction. Is there any way of “fool-proofing” the measurements? They whole idea of subjecting a patient to a semi-invasive procedure becomes redundant if the data obtained is uncertain. What is the current trend? Even the CT scan cannot escape this “underfilled” hypothesis. If anyone is using a better modality, please let me know.

We often see adult population with TOF physiology. We had a man in his 30s, presenting with cyanosis and hemoptysis. Echo revealed TOF physiology and the cath showed fairly large collaterals. However, his chest radiograph also had a lesion which looked cavitatory. Pulmonary Kochs is a common problem in the developing world and commoner in TOF. Eventually, we relearned an important lesson: Not all patients with hemoptysis in TOF are due to collaterals!
We saw an 11-year-old boy with single ventricle physiology, saturating 73% in room air. His mean PA pressures were 15mmHg and ventricular EDP was 14mmHg. Although the McGoon’s was 2.3, the same underfilled hypothesis came up. This time, it was in the opposite direction! When this boy has PA pressure of 15mmHg on controlled conditions of anesthesia, how much would the PA pressures be on regular wakeful state? Should we consider a simultaneous PA tightening? Would ACEI help? If BD Glenn is not feasible, can we simply add a BTT shunt and call it a final palliation? With complete Fontan repair not an option due to criteria, should we address the cyanosis with only BD Glenn in an 11-year-old or leave him for his natural history? Some problems of third-world do not even find a place in the regular text books!!

We see some of the older children, who at the current era look OK for 2-pump repair. However, few years back, they have undergone a Glenn repair, putting them on single pump pathway. It is likely that the expertise available at that time might have led to the plan. With the learning curves for this young field getting better, those kids (who are adolescents now) look good for 2-pump. But, how practical is it? Is taking down a Glenn which is almost a decade old is easy? When their SVC looks quite dilated, re-attaching it to RA would be a real task in the process. How difficult is the task? What is the surgical experience in this regard? It is worth discussing. Any inputs from the surgical fraternity?

What should be the ideal management for an obstructed homograft conduit with ventricular dysfunction? We had a26-year-old man who has undergone a classical repair for cTGA VSD PS (VSD closure with LV to PA homograft) at UK about 10 years back. At present, his homograft conduit is heavily calcified leading to LV dysfunction. RV has started to fail as a part of natural history. His PA pressure was a mean of 45mmHg. Is there a role of re-doing the conduit repair? One suggestion was to undo the original repair and redo a Senning with Rastelli (definitive repair). How practical is it with a biventricular dysfunction? Is there a role of heart transplantation with a PA mean of 45mmHg? Is heart-lung transplantation an option? If anyone had an experience in this regard, please let me know.

We had an ethical issue to address. This 17-year-old girl with TOF physiology had severe cyanosis and small branch PAs. McGoon was <1. Our obvious thinking was a BTT shunt as the final palliation. But our surgical team came up with a practical issue. They argued that the addition of BTT shunt may not contribute to major relief in quality of life. It may add on to the existing load on the ventricle. More so, the family can never understand the palliative nature of the procedure, despite best of your efforts to make them understand. They seek a certain degree of respite from the surgery, which they will never get from the addition of BTT shunt in this age. This actually increases their burden. So, the argument was to accept the natural history than making the social scenario worse for a small improvement in cyanosis. The eventual cost-benefit may not be worth it. However, some of us refused to accept this hypothesis. Since all the people who disagreed with the principle were young, the balance favoured the experience. “You are yet to burn your fingers on it” was the comment! The people who were neutral and did not raise their hand for either of the opinion bothered. What is your take on it? Please let me know.

Come up with your opinions in the comments. You can also send in your opinions and your experiences to my email: I shall post them on your behalf with full credits to the contributor!




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