Friday, December 25, 2009

Hearty welcome to the NH blog again! We are witnessing the historical development of some of the drugs used in contemporary pediatric cardiology. Hitherto, we have seen histories of Digoxin, Diuretics, Beta-blockers, ACE inhibitors and Prostaglandins. It is time to raise to the history of something exciting; the story of Viagra AKA Sildenafil!

In the year 1985, the research team of Pfizer in UK took a step that literally changed its fortune. It was serendipity at its best. The research team headed by Simon Campbell and David Roberts decided to target Atrial Natriuretic Peptide (ANP). Their intention was to develop a compound that could lower blood pressure by enhancing the activity of ANP.

ANP had found its place in the human physiology by that time. It was a vasodilator which increased the excretion of sodium and water by kidneys. It was logical to conclude that elevating its level would reduce blood pressure. The biochemistry of ANP had revealed that the peptide worked by stimulating guanylate cyclase to increase the synthesis of cGMP.

The Pfizer research team decided to formulate a phosphodiesterase inhibitor which would destroy the cGMP in the renal tissue. Their superior technology allowed them to isolate known isoenzymes totally uncontaminated. Yet, these isoenzymes failed to show any desired response.

In the pharmacopeia, there were no known potent selective inhibitors of the Phosphodiesterases till then. This prompted the team of Nicholas Terrett to seek the help of contemporary research. They sought out the data from any other research team working on the same issue and compounds, irrespective of the success they have produced for their respective teams.

In their hot pursuit, they tripped on the research team of Rhone-Poulenc. The mighty organization had its UK division named May and Baker. Their team had come up with a compound called zaprinast, which was yet to be marketed. Surprisingly, it was meant to be an anti-allergy drug. Being a xanthine analogue, Zaprinast was designed to deliver an anti-anaphylactic and anti-inflammatory effect. In the trails, it not only turned out to be a weak inhibitor of the Phosphodiesterase, it also lowered blood pressure in vitro. This had put in the molecule in the back seat.

The Pfizer team took it from there. They did a detailed comparison between zaprinast and cGMP. An elaborate computer graphic application was made to compare the finer aspects of the stereochemistry and the quarternary structures.

With Zaprinast as the base molecule, various variations in the heterocyclic ring system of it were prepared. Out of hundreds of variations, a pyrazolopyrimidinone was found to be most promising. Its potency was about ten times that of zaprinast.

The development of this intermediate molecule encouraged the team. The stereochemistry of the new molecule gave them the idea on the direction to proceed and enhance its potential further. The phosphodiesterase against which it was potential was found to be a subset called PDE5.

With the new molecular structure in their kitty and the detailed structure of cGMP, the next generation of molecular development was clearly on its way. Finally, two further modifications in the intermediate molecule led to the development of sildenafil as a specific PDE5 inhibitor in the year 1989. Not only the molecule of sildenafil was about 100 times more potent than zaprinast, it was also very highly specific in its site of action.

The initial objective of Pfizer to produce an effective anti-hypertensive was met with a disappointment when the phase III trials of Sildenafil did not meet the target levels of end points. Never before in its history, had Pfizer chased about 1600 compounds to come to a compound of this target value. The drug neither proved to be a good antihypertensive, nor a good coronary vasodilator for angina as a secondary effect. The initial lab reports were no way matchable to the outcome of phase III human trials. Pfizer research team had a lost product after such gruelling effort. The trial had lost its battle and the Pfizer team decided to call it a day. They recalled all the remaining drugs from the human volunteers in 1992. To their surprise, none of the 30 men who participated in the sildenafil trial returned unused tablets even on repeated requests from the research team.

The progress in this effect enraged the physician in charge. He decided to have a personal talk to all these participants. On repeated questioning and assurance to continue the supply of the said tablets for some more time, the male volunteers revealed that the tablets were increasing their erectile function.

The research team did not initially realise the mountain of gold they were sitting on. After the initial reluctance of the team to continue the trial, they decided to investigate the drug for the confirmation of side effects. The continuation of the trial not only confirmed the same effect in healthy volunteers, it also showed the benefit in patients of erectile dysfunction.

The research team was perplexed by these serendipitous effects. At the same time, there were advances in understanding the role of nitric oxide as a signalling molecule. The bottom-line was simple; it stimulated guanylate cyclase and formed cGMP. The same mechanism occurred during sexual stimulation, in which Nitric Oxide was released, raising the cGMP levels in the corpus cavernosum in the penile apparatus, letting the blood to fill the area and cause a sustained erection.

Although the Pfizer research team did not realise, the marketing team immediately knew where to strike! Pfizer marketing team used their influence in the media to raise an awareness campaign about the erectile dysfunction. Series of articles were written in the major newspapers and journals. Once the awareness about this sensitive issue was created in the general public and the inhibition about talking on the issue thinned out, Pfizer decided to launch Sildenafil under the name Viagra in 1998. It did not speak of hypertension or angina, but only as a treatment for erectile dysfunction! The molecule changed the financial graph of Pfizer and changed its fortunes forever. So much for the serendipity and patience for investigating any issue without any bias! Further research is in progress for improving the molecule further so as to take away the possible adverse effects and improve the area of its present action!!

On a personal note, it was time for new faces and new blood. We had selections for the RGUHS fellowship in Pediatric cardiology for the session 2010-11 recently. There were 5 aspirants for 2 seats. Finally, after a theory and Viva test, Dr Prashanth Patil and Dr Hemanth were selected. We extend our happiness in welcoming the new members to the team. I sincerely hope at least they would contribute something to this blog!

I had been to the fort city of Karnataka – Chitradurga. There was a conference on Critical care in Pediatrics. I had to do an arrhythmia quiz there. Due to some constraints from other speakers, I ended up consuming the stage for about 90 minutes and covered the topics on ICU management of Blue neonate and management of CHF also. The response from the post-graduate students was good, but the attendance of the practicing Pediatric community was disappointing. Anyway, the experience was worth the effort.

High PVRI can be caused by increased Qp or due to long standing high pulmonary venous pressure. In the latter, how would one evaluate the reversibility of high PVRI if the cause is treated? Our data on the high PVRI and the decision making on reversibility are based on high antegrade flow. Is there any data on reversibility in the setting on high pulmonary venous pressure? If there is a case of cor-triatriatum or supramitral membrane with high PVRI, how operable are these lesions? If we operate, can the PVRI fall? Can the Heath-Edward classification of histological changes applicable to such situations too? If there is a combined lesion involving high Qp and pulmonary venous hypertension, is there any way of calculating the PVRI contributed by either of them separately? How to estimate the reversibility in such cases? If not, is there any use of doing a diagnostic cath study in such situations? If you have any reference or personal experience in handling these scenarios, please let me know.

In cases of pulmonary bleeding in a Post-BD Glenn physiology, should we do a diagnostic bronchoscopy to find out the source of bleed? We had an unfortunate incident in which a 7-year-old who had undergone a single lung BD Glenn few years back (due to single branch PA anatomy) came back with severe hemoptysis. We could initially control his hemoptysis, transfused and as the first part of diagnostic modality, did a cath study with the idea of blocking the bleeding vessel if found. We could not find any such vessel on cath and patient was shifted to ICU. Late night, the patient had a massive bout of hemoptysis and passed away. One “ever-alert” member of our surgical team pointed towards the possibility of using bronchoscopy to find out the source of bleeding. On the side of utility of bronchoscopy, he suggested the idea of blocking the bronchus of the bleeding lung to limit the bleeding to the same side, thereby avoiding the flooding of the other lung with the bleed. This would buy us some time for therapeutic intervention and prevent the sudden death of the patient. The idea is innovative and looks life-saving. I remembered the suggestion of one of the Pediatric Surgeons who taught us to push the tracheal foreign body to one bronchus if it cannot be removed in a choking patient, which is really life saving. Are there any caveats to this? Please let me know your views.

We often come across “Canal Tets” – The complete AV canal defects with subaortic extension of VSD and severe PS. Do such cases always require transannular patch correction? We have seen that in such cases even if the size of pulmonary valve annulus is in an acceptable Z score range, surgeons still prefer to do transannular patching. The argument is that the VSD patch involving inlet and subaortic regions would inevitably narrow the RVOT. Any experience in this regard? Please send it to me or post it in comments.

We came across a 3-month-old with huge RA. It was so big that it had compressed all the other chambers to a negligee! The AV valves were at normal levels, ruling out an Ebstein anomaly. There was a functional TR due to non-coaptation, which could not have been a primary lesion. What is this condition called? Does the term Idiopathic Dilatation of RA exist? What may be the etiology of such a lesion? How to manage these? Is there an option of surgical reduction? If you have come across any such lesion, please tell me.

I came across a 10-year-old boy with a perimembranous VSD which was restricted by prolapsing RCC. The effective VSD was small and the AR was trivial. Technically, neither of the lesions by themselves would warrant any surgical intervention. How should we go about this combination in that age? Should we wait for the AR to progress? I don’t see any reason why the VSD would enlarge in size from here on. A previous echo report showed the VSD to be a moderate one earlier and there on, the boy was lost for follow-up as the family thought that nothing was much wrong with him. Should we just go about operating such a scenario or wait for the progress of AR? Can we trust the family to be alert to bring him for timely follow-ups? Should we make any decisions that may sound unscientific, as the patient’s family cannot be trusted on follow ups? This is another of “third-world” problems! Any inputs?

Pen in your inputs. Use my email for sending your questions or comments. It will be of great use to our readership.



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