Thanks for returning 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, Prostaglandins and Sildenafil. Let us witness some history of drugs that set our rhythm right: The Antiarrhythmics!
The first victory on the war against malaria came from natives of Peru. The Cinchona bark, also known as Peruvian bark, Jesuits’ powder, or Devil’s bark was probably the first ever medication to be effective against malaria. This medical remedy from the New World (the American continent) caught the attention of Europe around AD 1650s and very soon ended up being the fancy of medical world. This also started an indiscriminate use there on. It did not take much time for the unscrupulous to realise the potential profit making in the Peruvian bark. To beat the competition, many used fake bitter tasting preparations to mimic the Cinchona bark. Worse were the people who used larger doses imagining faster and more effective recovery. This started the downfall of cinchona bark when cases of dangerous relapses (due to fake medicines) and sudden deaths (due to overdose) appeared.
Soon after the introduction of cinchona bark, the German physician Georg Stahl had recognised its action on the heart and subsequently sporadic attempts were made to exploit this. When the side effects of cinchona bark continued to dominate, further attempts to delineate its effect on heart stopped. Celebrity physician of the time, Thomas Sydenham did an extremely careful study on the Cinchona bark. The prevalent belief of the time was a “Peruvian curse” on the cinchona bark. Sydenham argued vehemently against the “curse hypothesis” and proved that the drug was a safe one, provided the discipline of dosage, timing, and duration of treatment were properly taken care of. Despite the best efforts by Sydenham, the scepticism on Cinchona bark continued.
Around 1820, the purified form of quinine was extracted from Cinchona bark and within the next decade, quinine in its purified form was used all over. This gave the opportunity to few physicians around 1850s to prescribe quinine in supranormal doses for management of heart problems, albeit without any scientific evidence. This practice went on for a few years in a selected group of physicians.
As the Dutch had dominated the Cinchona plantations worldwide, availability of Quinine was the best in Netherlands. Not surprisingly, a patient of atrial fibrillations, who visited the famous Dutch cardiologist Karl Wenckebach in 1912, boasted that he himself can control the fibrillations. The surprised cardiologist asked the patient to prove himself. When the patient returned the next day, to the surprise of Wenckebach, his heart rate was well in control.
On enquiry, the patient revealed the secret. He had simply taken quinine to bring his atrial fibrillation under control! What’s missed was the dose the patient had taken which Wenckebach had forgotten to ask. He presumed the regular dose and tried quinine on about a dozen patients. To his annoyance, only one responded favourably. In 1914, Wenckebach brought out his book on cardiac arrhythmias (please note the year: ECG was yet to be used in clinical practice!!)in which he referred to the matter of Quinine’s anti-arrhythmic action just in passing.
Walter Frey was a busy practicing physician in Berlin, Germany. In 1918, he reported about the use of Quinidine in controlling atrial arrhythmias in a prominent Viennese medical journal. He claimed that quinidine was the most effective of the four principal cinchona alkaloids when it came to anti-arrhythmic action. Although Quinidine was supposed to be the least toxic of all the four components it was still a pretty hazardous drug. That made the medical supervision mandatory.
Quinidine was not a new drug. When the cinchona bark was getting purified, many isomers were isolated. Quinidine was one of these isomers that was isolated in 1833 by Henry and Delondre. When tested as antimalarial, it nowhere matched the effect of quinine. The anit-arrhythmic action gave a new lease of life for the once discarded quinidine. From then on, it has never looked back. It can still be used for treatment of supraventricular and ventricular arrhythmias in many occasions.
Procainamide and Its Analogues
A renowned cardiac surgeon of Cleveland, Ohio, Frederick Mautz was a worried man due to the recurrent per and post operative arrhythmias. He had set out to investigate drugs that could be applied directly to the heart surface prevent these arrhythmias. He was logical in assuming that application of local anaesthetics, like procaine, could act as prophylactic medication against these arrhythmias. Added to this, Procaine had already shown to have similar effect on heart.
With this, the animal experiments started. To the excitement of Mautz, procaine indeed showed highly effective action.
With the success of animal experiments, Mautz proposed the use of intrapericardial instillation of procaine for irregular beats of the heart during surgery. Till then, the only option was the use of quinidine which itself had a temperamental action. Procaine was found to be superior to the effects of quinidine.
The problem with procaine was its short duration of action. Added to this, if used repeatedly, the cumulative effect was dangerous to central nervous system. To overcome this, procaine was researched extensively to improve the duration of action, reduce CNS side effects and to improve the cardio-specificity. The result was Procainamide, which is useful till today to treat ventricular arrhythmias on acute basis. When efforts were made to use the drug for long-term, the risk of inducing systemic lupuserythematosus appeared. Hence, it is not for long term therapy.
Efforts were made to improvise the molecule for long term use. In this bargain, the team of French scientists headed by Laville and Justin-Besanc of Laboratoires Delagrange tested 2-chloroprocainamide. Although it had negligible anti-arrhythmic action, it was found to be a very effective antiemetic on oral administration. This was further improved to create metoclopramide.
In the next post, we shall see the development of another group of drugs. Just before that, let me tell you that I am about to finish this series on the “developmental history” of drugs used in Pediatric Cardiology. I need some ideas for the new series. If anyone can give me some ideas for the new series, it would be very helpful. Please note that the responsibility of the research on your ideas would be entirely mine! I would not disturb you for any further help, unless you wish to provide me some. However, the credit for the idea will be fully acknowledged in the blog with the full name of the contributor!!
On a personal note, the New Year is fast approaching. Our team is depleted as of now! Consumption of remaining leaves or the wretched climate of Bangalore causing respiratory problems has taken the toll on the rest!! With half the team doing more than full work, the time available for decent academics and discussions get progressively shorter. Hope, we shall get back to full strength soon.
VENTRICULIZATION OF PAs
What if the cath tracing of PA mimic that of RV? We had a 4-year-old who had undergone ICR for TOF with transannular patching a couple of years back. He came back with an aneurysmally dilated RVOT. On cath, PA tracing was as described above. Unless we see the location of catheter on screen, we cannot make out the PA entry on tracing. Traditionally, homograft repair is considered as the surgical option. However, our surgical team felt that a reduction plasty of RVOT can be done. Is the impingement of this dilated RVOT on LPA very common? If any data with anyone, please let me know.
AMPULLA Vs DUCTAL CONSTRICTION
What should be the ideal device for a bizarre PDA? We used a regular PDA device in a bizarre PDA in a 34-year-old. The larger side of device sat nicely in the ampulla and before the release, it slipped into the duct and found its home at one of the constrictions of the duct. Before we could make any other change, the device seemed to settle well there. We decided to leave the device as it is. What might be the possible complications? Is the muscular duct as good as the ampulla for accommodating the device? Any experiences in this regard? Please comment your ideas on it.
NOT HOLMES’, NOT JOUBERT’S
The DILV with NRGA would be a Holmes’ heart; the same with malposed GA would be a Joubert’s heart. How about a DILV with side-by-side great arteries? We happened to see one like this. This baby had a classical DILV, but with PA from LV and Aorta from OC. On short axis, they had a side-by- side relationship. Is there a name for such a combo? How common are these entities? If you have seen one, please tell me.
EBSTEINS IN CTGA
Is the TV anatomy in Ebsteins with AV concordance any different from Ebsteins with AV-VA discordance? We know that physiologically, they connect to different great arteries and different pressures. But, anatomically, is the displacement or histology any different? Does it translate to any difference in surgical approach and outcome? What does the surgical team opine about this? We had one of our senior surgeons mentioning the practical difficulties of treating a CTGA with Ebsteins. If there are issues, can we take any measures to ensure better outcome in the post-surgical period? If any research has been made on this which you have come across, please send it to us.
SINGLE DILEMMA
We often come across infants with Single Ventricle physiology with a moderate PS. Many times these babies saturate around 75-80% on baseline. What can be done for them? The PS would not be sufficient to enable BD Glenn. The saturations do not allow PA tightening. BT shunt would be negative for future Glenn. How should we be going about? Please drop in your suggestions.
TRANSITIONAL CYANOSIS
We saw a 2-year-old with Transitional AVCD with common atrium and uncertain pulmonary venous drainage. The pulmonary veins were draining into the roof of common atrium all around. The IVC was interrupted and there was bilateral SVC. There was an inevitable mixing at the atrial level, as for any other common atrium. However, this baby had mild cyanosis and clubbing with the saturation of 80%. Such picture does not occur in regular cases of common atria. How does the streaming affect the situation? We are planning to establish the correct anatomy of pulmonary veins in this baby with a cardiac CT. Can the interrupted IVC explain this picture? If you have come across such a picture, please tell me about your observations.
Pen in your comments. Use my email drkiranvs@gmail.com if you find any problem posting your comments.
Happy, prosperous and eventful 2010 to all of you
Regards
Kiran
ಬುಧವಾರ, ಡಿಸೆಂಬರ್ 30, 2009
ಶುಕ್ರವಾರ, ಡಿಸೆಂಬರ್ 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.
“REVERESE” PVRI
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.
BLOCKING BRONCHUS AS TREATMENT
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.
PATCHY COMPROMISE
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.
CONGENITAL NON-EBSTEIN HUGE RIGHT ATRIUM
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.
TO CLOSE OR NOT TO?
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 drkiranvs@gmail.com for sending your questions or comments. It will be of great use to our readership.
Regards
KIran
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.
“REVERESE” PVRI
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.
BLOCKING BRONCHUS AS TREATMENT
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.
PATCHY COMPROMISE
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.
CONGENITAL NON-EBSTEIN HUGE RIGHT ATRIUM
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.
TO CLOSE OR NOT TO?
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 drkiranvs@gmail.com for sending your questions or comments. It will be of great use to our readership.
Regards
KIran
ಶುಕ್ರವಾರ, ಡಿಸೆಂಬರ್ 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: drkiranvs@gmail.com I shall post them on your behalf with full credits to the contributor!
Regards
Kiran
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: drkiranvs@gmail.com I shall post them on your behalf with full credits to the contributor!
Regards
Kiran
ಗುರುವಾರ, ಡಿಸೆಂಬರ್ 3, 2009
Welcome back to NH blog. We are in witness of “developmental history” of Cardiac medications pertinent to Pediatric Cardiology.
In the last 3 posts, we have seen the historical aspects in the development of Digoxin, Diuretics and Beta-blockers. This post will see another class of drugs, termed as “the most useful class of cardiac drugs” by contemporary Cardiologists: the ACE inhibitors.
The advent of beta-blockers was an epoch making event in the field of cardiology. It inspired a generation of scientists to undertake research in the crucial field of drug development. When the beta-blockers were found to be successful as anyi-hypertensives also, many a minds drifted their attention towards achieving the anti-hypertensive effect with other compounds.
John Vane was one of the researchers working on this issue. In 1960, after witnessing the beta-blocker saga, he shifted his attention towards anti-hypertensives. He was a man of extremely sound fundamentals and true to his nature, he started his research investigating the causes of hypertension. At that period, he was working in the Institute of Basic Medical Sciences at the Royal College of Surgeons of England.
One of his Brazilian post-doctoral students, Sergio Ferreira, brought an extract of the venom of Brazilian arrowhead viper, (Bothrops jararaca), to London. As a matter of interest, they evaluated it. To his surprise, he discovered its capability in blocking the formation of angiotensin II from angiotensin I. This conversion reaction was mediated through an enzyme called Angiotensin Converting Enzyme.
Vane could immediately sense the possible effects of this in the human body. He expressed the findings of his research with some of the leading clinicians. He was disappointed to see the reaction of them. The clinicians were not trained in understanding the developmental research of drugs. They would start with a possible clinical trial, but nothing less than that.
Vane’s initial disappointment could not stop him. His ability to trace something new was impeccable. He had solid belief in his findings and its possible impact on the future of medicine. He decided to approach scientists instead of physicians this time. He made a trip to the famous Squibb Institute for Medical Research in New Jersey and was able to convince the researcher team on the novel concept called “The use of ACE inhibitor in controlling high blood pressure”.
Vane’s honesty, belief and commitment impressed the chief scientist of Squibb, Miguel Ondetti. Ondetti gave the responsibility of fractionating the viper venom to his colleagues. His team did a wonderful job and could elucidate the structure of several peptides from the venom. This confirmed the existence of a very active peptide inhibiting ACE. Vane had already reached this point and had called this compound teprotide. After coinciding with Vane’s observation, Squibb scientists went a step ahead. They could now synthesise the compound and start an animal trial.
Teprotide was administered intravenously in patients with elevated plasma renin levels as a part of first clinical trial. It sure proved to be an effective hypotensive agent. However in the control group with hypertension but normal rennin levels also showed a similar and comparable hypotensive effect. Since it was a peptide, teprotide was obviously inactive orally. So, the next step was an attempt to synthesise an orally active analogue of teprotide.
The Squibb research team started a massive mission for this. They ended up screening about 2000 non-peptides, but all these were in a vain. The team head thought that a new approach would be more worthwhile. At the same time, publication of a scientific paper caught their attention. This paper by Byers and Wolfenden dealt with inhibition of digestive enzyme carboxypeptidase A by benzylsuccinic acid. The authors had found the site called C-terminal phenylalanine residue of of carboxypeptidase A to which substrates were bound. As benzylsuccinic acid had a similar enough structure it could competitively inhibit it.
The Squibb researchers made use of this fact and used numerous techniques for quite some time to finally create a compound which was one-thousand-fold strong in inhibitory activity. This was called captopril which was the first non-peptide ACE inhibitor suitable for oral use and thereby introduction into the clinical use. The scepticism prevailed. To add on to this chaos, an early clinical trial showed captopril with renal damage or granulocytopenia. The Committee on Safety of Medicines of United Kingdom put up the clause of “to be limited for the use only in patients with severe hypertension who had not responded to standard therapy” for captopril when it was marketed.
The scepticism was short lived. An intensive postmarketing surveillance was enough to prove the minor nature of side effects with low incidence for captopril. This led to the extension of licence in 1985 for use in mild to moderate hypertension. Newer modifications of Captopril led to the development of other ACE inhibitors. All these are now firmly established in the treatment of heart failure and in hypertension and are considered as the treatment of choice.
In the next post, we shall see the development of one more class of drugs.
On a personal note, with the advent of December, the numbers of people taking leaves are increasing! The foolish rules of “You cannot carry over your leaves to next session” would leave every unfortunate soul who is “not on leave” strangled! Anyway, life goes on and it is time to realise that pain is an integral part of human suffering!
Many centres wake up in December and start conducting their mandatory quota of CMEs. Hence, we people are in demand. This adds on to the woes of consulatants who are at the hospital working. On the other hand, most of the CMEs happen on a Sunday and pain of losing a precious Sunday increases with this. We can neither refuse nor whole heartedly accept these invitations. Overall, December ends up being “pain, pain”!
Last year, we reported a case of Truncus with Tricuspid Atresia in the Indian Heart Journal. It is a rare combination indeed. We had another boy aged 14 years with this combination. He had a Tricuspid atresia with the common arterial trunk committed more to RV. The age precluded us from defining his PA anatomy on Echo. On cath, we found a Type 2 Truncus with the origin of LPA stenosed. RPA pressures were systemic. No further management options exist in him. How frequent are such combinations? What is the embryological basis of such lesions? Is a single lung with more than normal pressure tide over such a lesion for such a long time? Are there any other protective issues that we are missing? If so, how to detect them with the available technology? Some questions lead to more questions and minimal answers. Any data, please transfer!
We saw a 6-year-old boy with history of Kawasaki disease. He was treated with Immunoglobulins on day 14 of illness in the past. He is otherwise asymptomatic. On follow up echo, we found an echogenic mass in the dilated LAD along with some aneurysms. His effort tolerance on a treadmill was normal. On the cath study, we found a near complete occlusion of LAD. Some collaterals and retrograde filling of RCA was seen. Since the child was asymptomatic, it was decided to have a close follow up. Is the treadmill a good idea? Can we do it with less invasive methods like Stress thalium instead of TMT? Are there any guidelines for the timing of cath? What are the guidelines for the surgical intervention in such scenarios? AHA has come out with guidelines for Kawasaki disease. Are they pertinent for Developing countries also? Any data with anyone?
What determines the shunt in ASD? Looks like an exam question! It is the RV EDP obviously. We had a 4-year-old girl with ASD R to L, Smallish muscle bound RV, with SO2 of 85%. The desaturation led to cath study. The RV EDP was 12mmHg, which was lesser than LV EDP. Are the EDPs dynamic? Can the RV EDP keep fluctuating? Can it be severe enough to cause cyanosis? Can repairing the ASD a good option? It was decided to go for a BDG with fenestrated ASD closure? Can we follow the same strategy for other instances with high RV EDPs also? Let me know your take on this.
Is there a linear relationship between the AV valve Z score and 2-pump repair? Till what Z scores do we accept the 2-pump repair? We had a 5-year-old with intact IAS, moderate VSD, moderate PS and TV Z score of minus 3. The RV was reasonably sized and reached apex. The RA was not dilated much. It was decided to go for VSD closure, pulmonary valvotomy and PFO open. How would such lesions behave post surgery? The surgical team felt that since the RA was not dilated, the impact of TV narrowing was not much and hence the surgical repair was acceptable. Are there any criteria for 2-pump repair in such instances? Pen your opinions.
We had an interesting coincidence during our cath study. Although it was a shock for the surgeons on the table, their efficiency could tackle the situation. This 4-year-old was operated outside with a right sided BTT shunt 2 years for pulmonary atresia. On echo, the windows were very compromised and we could not see the PA confluence. In the cath study, the arch injection filled both LPA and RPA. We presumed confluence and went ahead. On the table, we found that the PAs were non-confluent. The LPA originated from ascending aorta posteriorly and the RPA filled though the PDA. No doubt that both the PAs filled on the aortic injection simultaneously! We relearned a precious lesson of not presuming without considering the alternatives!! What could have been a surgical disaster was managed by superior surgical skills of our experienced surgical team.
What is the impact of a severe Shone physiology on PDA? We had a 6-year-old girl with severe subvalvar MS, bicuspid aortic valve with severe AS and a large PDA shunting bidirectional. With the aortic pressures being low due to severe MS and AS, and PA pressures being high due to MS, can we decide operability of PDA by the direction of shunt? The child saturated 94% on upper limb and 86% on lower limbs, would it suggest Eisenmengarization? Should we cath the child? The surgical team opined that the child should be cathed for operability. It is again the question of sequential lesions that we had discussed few posts back. We had some surgical success in such lesions in the past, but the patient then was a toddler. The age is against us this time. Is there any way of clinical decision making? Please let me know if you have any experience in this regard.
Pen in your opinions in the comments. You can also send in your opinions and your experiences to my email: drkiranvs@gmail.com I shall post them on your behalf with full credits to the contributor!
Regards
Kiran
In the last 3 posts, we have seen the historical aspects in the development of Digoxin, Diuretics and Beta-blockers. This post will see another class of drugs, termed as “the most useful class of cardiac drugs” by contemporary Cardiologists: the ACE inhibitors.
The advent of beta-blockers was an epoch making event in the field of cardiology. It inspired a generation of scientists to undertake research in the crucial field of drug development. When the beta-blockers were found to be successful as anyi-hypertensives also, many a minds drifted their attention towards achieving the anti-hypertensive effect with other compounds.
John Vane was one of the researchers working on this issue. In 1960, after witnessing the beta-blocker saga, he shifted his attention towards anti-hypertensives. He was a man of extremely sound fundamentals and true to his nature, he started his research investigating the causes of hypertension. At that period, he was working in the Institute of Basic Medical Sciences at the Royal College of Surgeons of England.
One of his Brazilian post-doctoral students, Sergio Ferreira, brought an extract of the venom of Brazilian arrowhead viper, (Bothrops jararaca), to London. As a matter of interest, they evaluated it. To his surprise, he discovered its capability in blocking the formation of angiotensin II from angiotensin I. This conversion reaction was mediated through an enzyme called Angiotensin Converting Enzyme.
Vane could immediately sense the possible effects of this in the human body. He expressed the findings of his research with some of the leading clinicians. He was disappointed to see the reaction of them. The clinicians were not trained in understanding the developmental research of drugs. They would start with a possible clinical trial, but nothing less than that.
Vane’s initial disappointment could not stop him. His ability to trace something new was impeccable. He had solid belief in his findings and its possible impact on the future of medicine. He decided to approach scientists instead of physicians this time. He made a trip to the famous Squibb Institute for Medical Research in New Jersey and was able to convince the researcher team on the novel concept called “The use of ACE inhibitor in controlling high blood pressure”.
Vane’s honesty, belief and commitment impressed the chief scientist of Squibb, Miguel Ondetti. Ondetti gave the responsibility of fractionating the viper venom to his colleagues. His team did a wonderful job and could elucidate the structure of several peptides from the venom. This confirmed the existence of a very active peptide inhibiting ACE. Vane had already reached this point and had called this compound teprotide. After coinciding with Vane’s observation, Squibb scientists went a step ahead. They could now synthesise the compound and start an animal trial.
Teprotide was administered intravenously in patients with elevated plasma renin levels as a part of first clinical trial. It sure proved to be an effective hypotensive agent. However in the control group with hypertension but normal rennin levels also showed a similar and comparable hypotensive effect. Since it was a peptide, teprotide was obviously inactive orally. So, the next step was an attempt to synthesise an orally active analogue of teprotide.
The Squibb research team started a massive mission for this. They ended up screening about 2000 non-peptides, but all these were in a vain. The team head thought that a new approach would be more worthwhile. At the same time, publication of a scientific paper caught their attention. This paper by Byers and Wolfenden dealt with inhibition of digestive enzyme carboxypeptidase A by benzylsuccinic acid. The authors had found the site called C-terminal phenylalanine residue of of carboxypeptidase A to which substrates were bound. As benzylsuccinic acid had a similar enough structure it could competitively inhibit it.
The Squibb researchers made use of this fact and used numerous techniques for quite some time to finally create a compound which was one-thousand-fold strong in inhibitory activity. This was called captopril which was the first non-peptide ACE inhibitor suitable for oral use and thereby introduction into the clinical use. The scepticism prevailed. To add on to this chaos, an early clinical trial showed captopril with renal damage or granulocytopenia. The Committee on Safety of Medicines of United Kingdom put up the clause of “to be limited for the use only in patients with severe hypertension who had not responded to standard therapy” for captopril when it was marketed.
The scepticism was short lived. An intensive postmarketing surveillance was enough to prove the minor nature of side effects with low incidence for captopril. This led to the extension of licence in 1985 for use in mild to moderate hypertension. Newer modifications of Captopril led to the development of other ACE inhibitors. All these are now firmly established in the treatment of heart failure and in hypertension and are considered as the treatment of choice.
In the next post, we shall see the development of one more class of drugs.
On a personal note, with the advent of December, the numbers of people taking leaves are increasing! The foolish rules of “You cannot carry over your leaves to next session” would leave every unfortunate soul who is “not on leave” strangled! Anyway, life goes on and it is time to realise that pain is an integral part of human suffering!
Many centres wake up in December and start conducting their mandatory quota of CMEs. Hence, we people are in demand. This adds on to the woes of consulatants who are at the hospital working. On the other hand, most of the CMEs happen on a Sunday and pain of losing a precious Sunday increases with this. We can neither refuse nor whole heartedly accept these invitations. Overall, December ends up being “pain, pain”!
Last year, we reported a case of Truncus with Tricuspid Atresia in the Indian Heart Journal. It is a rare combination indeed. We had another boy aged 14 years with this combination. He had a Tricuspid atresia with the common arterial trunk committed more to RV. The age precluded us from defining his PA anatomy on Echo. On cath, we found a Type 2 Truncus with the origin of LPA stenosed. RPA pressures were systemic. No further management options exist in him. How frequent are such combinations? What is the embryological basis of such lesions? Is a single lung with more than normal pressure tide over such a lesion for such a long time? Are there any other protective issues that we are missing? If so, how to detect them with the available technology? Some questions lead to more questions and minimal answers. Any data, please transfer!
We saw a 6-year-old boy with history of Kawasaki disease. He was treated with Immunoglobulins on day 14 of illness in the past. He is otherwise asymptomatic. On follow up echo, we found an echogenic mass in the dilated LAD along with some aneurysms. His effort tolerance on a treadmill was normal. On the cath study, we found a near complete occlusion of LAD. Some collaterals and retrograde filling of RCA was seen. Since the child was asymptomatic, it was decided to have a close follow up. Is the treadmill a good idea? Can we do it with less invasive methods like Stress thalium instead of TMT? Are there any guidelines for the timing of cath? What are the guidelines for the surgical intervention in such scenarios? AHA has come out with guidelines for Kawasaki disease. Are they pertinent for Developing countries also? Any data with anyone?
What determines the shunt in ASD? Looks like an exam question! It is the RV EDP obviously. We had a 4-year-old girl with ASD R to L, Smallish muscle bound RV, with SO2 of 85%. The desaturation led to cath study. The RV EDP was 12mmHg, which was lesser than LV EDP. Are the EDPs dynamic? Can the RV EDP keep fluctuating? Can it be severe enough to cause cyanosis? Can repairing the ASD a good option? It was decided to go for a BDG with fenestrated ASD closure? Can we follow the same strategy for other instances with high RV EDPs also? Let me know your take on this.
Is there a linear relationship between the AV valve Z score and 2-pump repair? Till what Z scores do we accept the 2-pump repair? We had a 5-year-old with intact IAS, moderate VSD, moderate PS and TV Z score of minus 3. The RV was reasonably sized and reached apex. The RA was not dilated much. It was decided to go for VSD closure, pulmonary valvotomy and PFO open. How would such lesions behave post surgery? The surgical team felt that since the RA was not dilated, the impact of TV narrowing was not much and hence the surgical repair was acceptable. Are there any criteria for 2-pump repair in such instances? Pen your opinions.
We had an interesting coincidence during our cath study. Although it was a shock for the surgeons on the table, their efficiency could tackle the situation. This 4-year-old was operated outside with a right sided BTT shunt 2 years for pulmonary atresia. On echo, the windows were very compromised and we could not see the PA confluence. In the cath study, the arch injection filled both LPA and RPA. We presumed confluence and went ahead. On the table, we found that the PAs were non-confluent. The LPA originated from ascending aorta posteriorly and the RPA filled though the PDA. No doubt that both the PAs filled on the aortic injection simultaneously! We relearned a precious lesson of not presuming without considering the alternatives!! What could have been a surgical disaster was managed by superior surgical skills of our experienced surgical team.
What is the impact of a severe Shone physiology on PDA? We had a 6-year-old girl with severe subvalvar MS, bicuspid aortic valve with severe AS and a large PDA shunting bidirectional. With the aortic pressures being low due to severe MS and AS, and PA pressures being high due to MS, can we decide operability of PDA by the direction of shunt? The child saturated 94% on upper limb and 86% on lower limbs, would it suggest Eisenmengarization? Should we cath the child? The surgical team opined that the child should be cathed for operability. It is again the question of sequential lesions that we had discussed few posts back. We had some surgical success in such lesions in the past, but the patient then was a toddler. The age is against us this time. Is there any way of clinical decision making? Please let me know if you have any experience in this regard.
Pen in your opinions in the comments. You can also send in your opinions and your experiences to my email: drkiranvs@gmail.com I shall post them on your behalf with full credits to the contributor!
Regards
Kiran
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