Thank you very much Dr. Siegel, it's a pleasure to be here. As was indicated John was unfortunately unable to join us today because of a problem he's had with chronic sinusitis. We all wish John well in his speedy recovery. I'm going to be discussing a group of antihistamines and then eventually we'll talk about the next generation antihistamines drugs as compared to the older generation drugs and what we know about them. Wherein we can see that advances have been made. We've made advances in safety, perhaps some advances in efficacy, but clearly some advances in safety in comparing some of the next generation with some of the older generation agents. Taking a look at antihistamines and allergic rhinits, everyone understands the fact that one of the goals of treatment of allergic rhinitis is to control symptoms while not having adverse affects on the functioning of patients. The last thing we want to do is try and help someone in terms of symptom control but in the same time hurt them, in terms of activities of daily living, in terms of ability to drive, ability to learn. All of which can be aversely affected by first generation of antihistamines. We now have enormous amounts of data showing for instance that drugs like Diphenhydramine have effects on driving equivalent to the effects of legally intoxicating level of alcohol. That diphenhydramine can adversely affect learning in children. And drugs like Chlorpheniramine can have a significant hang over effect, even when administered in the evening. So we know that the older drugs clearly can cause impairment, can affect cognition, can induce sedation, and can even affect mood. And these are thing that clearly are undesirable. So therefore, the development of newer generation agents to try to prevent these adverse consequences of antihistamine therapy. Now the first generation drugs aren't very detailed are drugs that by in large were very effective in symptom relief. When we look at the newer generation drugs, we're not really looking at improving symptom relief as much as we're looking at limiting or eliminating completely many of the adverse effects. The adverse effects of some of these older drugs by an large is related to the fact that they rapidly penetrate the blood brain barrier, they literally saturate the receptors in the brain, if you take a look at some recent studies that have been done, looking at receptor saturation by chlorpheniramine, hydroxyzine, diphenhydramine, all of which are capable of saturating 70, 80, or even 90 percent of histamine receptors in the central nervous system. Beyond that they are a very non-selective agents. You look at hydroxyzine for instance, not only is it an antihistamine but it's anticholinergic, antiseratonergic, antidopaminergic, anti-alpha andrenergic, sort of the profile that may be appropriate for tricyclic anti-depressant or a drug you are going to use to treat psychiatric illness, but certainly not the sort of profile you'd want a drug to have to treat allergic rhinits. Therefore some of the advances have been moving away from non-selective to highly selective H1 receptor antagonists in that regards to its design or drug concept. They can now tailor drugs that have very limited penitrance of the blood brain barrier and are highly selective in terms of what they are antagonizing. Another big problem with the older drugs is you can see problems with gastrointestinal side effects especially in the elderly. You have problems with constipation for instance, you get problems also with urinary retention from the older drugs related to the anticholinergic effects. And so take a look at an elderly population; where prostatism is a problem, or constipation may be inherently a problem, these older antihistamines clearly lead to undesirable side effects. Now the newer generation drugs by and large are highly receptor selective, by in large give you much less penintrance of the blood-brain barrier. Now they do penetrate somewhat and some studies that have been done recently have shown that anywhere between 5 to 15-16 percent penetrates in terms of blocking H1 receptors in the brain. Yet, they remain highly selective. A great example of that is cetirizine versus hydroxyzine where cetirizine is devoid of non H1 receptor a blockade at least in animal models, wherein receptor selectivity were studied. The newer drugs seem to be lower in terms of side effects, of course there are some differences we have already eluded to and there are some problems with the fact that cetirizine and acrovastine and astemizole also can give sedation approximately twice that of placebo and they do have labeling In their product inserts relating to avoiding activities such as driving, or combining them with alcohol or doing things that require significant ability to function with eye hand coordination such as operating machinery all of which should really be avoided or done with great caution. And if your using cetirizine, azelastine or acrovastine as opposed to the situation with fexofenadine and loratadine where that's not an issue. Terfenadine and astemizole were great drugs in terms of response to receptor selectivity and in terms of freedom from adverse central nervous system side effects. Of course the only problem there was the occasional in whom cardiac toxicity was noted. And there was already noted that very few people overall considering the exposure to these drugs succumb but still there is really no excuse of death in an illness where there is no intrinsic mortality and this is essential to the FDA's approach to cardiac toxicity that potentially could be induced by drugs like, astemizole and like terfenadine. This issue has been raised again a bit with the drug not available in the United States like ebastine which was put before the FDA for consideration about a year ago and major questions arose in regards to its' potential to affect potassium polarization channels, even though some studies in humans had suggested that even with dose ranging you didn't seem to see this in effect.

Let's take a look at the oral antihistamine decongestant combinations and what the advantage is there. Well the reason for using these sort of combination drugs is that oral antihistamines as a class don't do all that much for the symptom of nasal congestion. If you read the studies carefully and some people have been talking about how they have been carefully perusing the literature, often the symptom of nasal congestion is deleted from the final analysis where you will get the total symptom reduction minus congestion, if you read the fine print. The reason for this is we don't have much evidence that loratadine, fexofenadine, and cetirizine did all that much for nasal congestion. And yes sometimes you can see some modest benefit, maybe 5% reduction in symptoms, but not nearly the level of benefit you would see for the other symptoms you would see for other than congestion. Therefore, we add in pseudoephedrine to essentially mechanically relieve congestion, by decreasing blood flow that would normally occur into the venous sinuses, the mucosa of the nose, which essentially causes obstruction and congestion. If you take a look at one of the failings of the oral antihistamines it has been this failure to get sufficient relief from congestion. There are some exceptions when you go into topical agents, for instance there is data suggesting that topical azelastine will relive nasal congestion and I think does leave some hope for an improved agent. Agents perhaps with improved potency, greater anti-inflammatory capability. Perhaps, some of these newer agents orally will be able to effect nasal congestion, without adding pseudoephedrine. Now one issue of pseudoephedrine, I think clinicians don't understand is that Pseudoephedrine does not eliminate impairment. And there have been studies that have been done with acrovastine showing that while there is some reduction in the amount of lane weaving which occurs with 8mg of acrovastine versus 8mg of acrovastine with 60 of pseudoephedrine, you don't eliminate the impairment. So just adding on a drug which is a stimulant does not in fact eliminate the impairment that these older antihistamines induce. Nevertheless if you take a look at the combination therapy, antihistamine-decongestant, clearly there are more effective antihistamines alone and there are more effective decongestants. Not just individually but specifically with the reduction of symptoms with congestion.

Universally, there is a problem with insomnia, which can be induced by these agents. So take a look at the pseudoephedrine literature typically using a dose of 240mg yields an incidence of anywhere between 9-15 percent of insomnia. This is not a minor issue clinically, because if you look at what your patients' are doing, many of them will be taking these bid products only in the morning and deleting the evening dose. And in doing so, they compromise the efficacy of the antihistamine. You could take a look at the literature for instance with loratadine, literature of fexofenadine, 5mg loratadine and 60mg of fexofenadine, clearly are not effective doses if given on just a once daily basis to adults. And this is in essence is somebody only takes one Allegra a day or only one Claritin-D12 a day to avoid the evening dose because of insomnia. Now there are certain ways around this, you can devise new formulations as was done with loratadine plus pseudoephedrine D-24 formulation where insomnia can be reduced down to about 5%, simply because most of the pseudoephedrine is released during the day time and less is released over night. Now another approach has been to combine antihistamines with anti-leukotriene agents, there have been a number of recent articles by and large studies were conducted by Merck which have looked at montelukast alone dose ranging combined loratadine and as shown here there is evidence of synergism more in the montelukast plus the loratadine taken together do better than either entity alone as shown here in terms of day time nasal symptom reduction, ocular symptom reduction, significant evidence that together you are getting a greater benefit than you are with either entity alone and this has spurred a new initiative wherein we are now trying to develop new therapies which will combine H1 antagonists plus leukotriene antagonists into one tablet that can be used to antagonize both the effects of histamines and leukotrine both simultaneously in order to get relief of symptoms of allergic disease.

Now the next generation antihistamines really should be familiar to you simply because you've already had available Fexofenadine which of course affects the metabolite of terfenadine. Desloratadine, Levocetirizine, Tecastemizole all are under development. Levocetirizine and desloratadine both are available internationally, they are available in Europe and they are available in some cases in South America. As you have already heard we are talking about either metabolites or isomers of the currently available second-generation antihistamines. So what's interesting in that approach is that in essence our patients have already been exposed to these agents. Because when you're taking loratadine, when you're currently taking the cetirizine you are in fact getting some desloratadine or some levocetirizine. And so there already is some safety data so to speak of real life use of the currently available second-generation antihistamines. Of course, we cannot say the same for Tecastemizole which is novel agent being developed as one of the major metabolite's of astemizole. What we're talking about in terms of the next generation drugs, perhaps there is some gain in efficacy and some of this remains to be established. If you take a look at fexofenadine versus terfenadine for instance, there really isn't any published literature showing that fexofenadine is more efficacious than terfenadine. There is really a birth and then an absence of head on trials of fexofenadine and terfenadine in the literature. If you take a look at levocetirizine versus cetirizine, essentially the same situation currently exists where head on clinical trials have yet to be reported. There are studies comparing they're abilities to block histamine responses but not head on clinical trial in allergic rhinitis. And so far the same holds true for desloratadine where we've had studies of it as an entity alone, but not compared to the parent drug, loratadine. With respect to safety, clearly fexofenadine is superior to terfenadine, there is no doubt about the fact what we have achieved, there is a freedom of cardiac toxicity, there is a freedom from risk with the respect to potentially blocking potassium polarization channels. There are some compromises however, if you take a look at for instance if you take a look at the bio-availability of terfenadine, there is fairly good bio-availability reported previously approximately 70%, initial bio-availability report of fexofenadine illustrated about a 33% report of bio-availability, and there have been some unique interactions reported recently with fexofenadine based upon it's reliance on intestinal transporters including organic anion transporting polypeptide which allows you to absorb it and pediaglyca protein which allows you to excrete it. These transport proteins in the gut can be effected by high salt load, or by administration of fruit juice, in essence reducing the bio-availability absorption effects of fexofenadine and the outward absorption of proteoglycan protein can be induced for instance by revamping, by St. John's Wort, potentially causing some dumping of drugs. So there can be some issues there and in addition to the fact that Fexofenadine is as was previously named, a carbocsilic acid derivative of terfenadine or terfenadine carboxylate and has the ability to bind with poorly absorbed antacids such as Maalox and Mylanta in essence reducing it's bio-availability about 40%, potentially impacting it's efficacy. So in that regard there are some changes that sometimes occur when you go to a new generation drug, which may not be adventitious, but you have to do an analysis. You may happen to gain safety and sometimes you may lose a bit in terms of bioavailability issues.
Let's look first at terfenadine versus fexofenadine, when you are taking terfenadine and about 2/3 of it was metabolized to terfenadine carboxylate which has been re named fexofenadine. In terms of blockade of wheal and flare response, these drugs are fairly comparable, in terms of bioavailability, there was a bit of a difference to studies that were presented to the FDA. Consistently 60mg of terfenadine yielded us a bit more bio-availability of drug than 60mg of fexofenadine, yet the FDA didn't feel that this was significant enough to warrant any dosage change with respect to the number of milligrams of fexofenadine ultimately approved. One very interesting point is about many of these drugs is that they have a very flat dose response curve and that's clearly shown here. This is a dose ranging study that was done with fexofenadine going from 60 to 120 to 240 milligrams twice daily. And if you take a look at the relief of sneezing, rhinorrhea, itchy nose, itchy watery red eyes, there is no evidence that as you push the dose beyond 60mg, you gain additional efficacy. Where there is evidence of a problem is right here with respect to nasal congestion. Where yes there is some improvement in nasal congestion, but if you take a look at the magnitude of the benefit for congestion, the magnitude for the benefit of the other symptoms, clearly it's not of the same order of magnitude. So, in this regard 2 points are illustrated, lack of dose ranging and for many of these agents we have a flat dose response curve and failure to get much relief of nasal congestion. As you back down on the dose, below 60mg, there is a point where efficacy may begin to be compromised and that is illustrated in the product insert of fexofenadine and situations such as combining it with these magnesium containing antacids, to a 40% less drug or for the Allegra-D product combining it with a high fat diet will make it 40% less drug. In essence our situation is usually devoid as 40% less drug potentially could drop you below the therapeutic range. There was a study done by Ed Bronsky done some years ago for an event and it showed 40mg showed some benefits to allergic rhinitis, it was inconsistent when compared to 60 and 120 milligrams in that study. In terms of over all symptom relief, especially for ocular symptoms associated with allergic rhinitis. Here is loratadine and here is desloratadine now unlike the situation with fexofenadine versus terfenadine, the metabolite of loratadine, desloratadine, was not developed to enhance safety. Safety was not an issue with regards to loratadine, whether there is a difference between desloratadine and loratadine, is potency in terms of blocking the H1 receptor. Here it depends on what model system you want to look at, if you look at conventional, inhibition of receptor binding using radioisotope studies, there is about a 15 fold difference, whereas desloratadine is more potent that loratadine. If you look at some of the newer models, you look at calcium flux into cells, which is induced by histamine interacting with the H1 receptor, and then desloratadine becomes 50-100 fold more potent than loratadine. If you look at in vivo models, where the animals eat either drug than you have a 2-4-fold difference in favor of desloratadine blocking histamine responses to a greater extent than what you see with loratadine. There is some other interesting aspects to desloratadine its more water-soluble than loratadine, it has more predictable pharmacology than loratadine, and it's more linear, minimal drug interactions have been reported and essentially no interactions with food. So in that regard it may be a little bit easier to use in terms of less over all considerations with regards to dosing. There was a very interesting study that was recently done looking at total symptom reduction and reduction in nasal congestion in subjects with a 5mg of desloratadine and what it illustrates is that in fact there is relief of nasal congestion that has been noted in the desloratadine literature. There are actually now 9 studies that have been reported showing a benefit for the symptom of nasal congestion even though this is an oral antihistamine. Perhaps this benefit is because of the greater potency of the agent compared to some of the earlier agents we have used previously or perhaps it has something to do with anti allergic effects, it has been noticed at concentrations as low as 10 to minus 9th molar, that it may inhibit side econolaboration from mast cells it may inhibit a number of adhesion molecules in addition to it inhibiting a cytokine elaboration and perhaps also cellular trafficking. Now these are things which are in common with those other antihistamines where desloratadine may have an edge is that the dosage required or the concentration required tends to be lower than that reported for some of the other antihistamines. For instance, it's about 6 logs more potent that loratadine in inhibiting some selected generation of cytokines and endothelial cells which are stimulated by histamines. Several recent studies however done with desloratadine has shown its ability to relieve congestion and it may in fact be comparable to a 120 milligrams of pseudoephedrine given twice daily or even 240 milligrams given once daily. And one recent and very intriguing study of asthma has suggested that the seasonal asthma related to allergic rhinitis may be comparable to achieve with montelukast. Now here we have cetirizine versus levocetirizine and with cetirizine as Estelle Simons has already mentioned. Half of the mixture is active and half of the mixture is in essence inactive. What has been done is to take this mix and isolate the active entity, which is the levocetirizine and then put it out as a preparation. Now, we do have this available in Europe, in Europe it's at a 5mg dose. This of course raises the question, if in fact you are taking cetirizine, you are getting you are getting 5mg of levocetirizine and if you eliminate the dextrose, and only give 5mg of levo, where is the edge? Well the question really remains to be answered and as we do not have data showing that levocetirizine is safer than cetirizine. We don't have data showing that it's more efficacious than cetirizine, but we do have data showing it at least seems to be comparable. When you take a look at histamine induced sneezing, and some experiments that were done with levocetirizine, what you see is that levocetirizine consistently gives you relief that is essentially comparable to cetirizine as a whole, whereas the dextrose does not and you have more total sneezing. Again, just illustrating the point that Levocetirizine is the active entity. But, keep in mind that the currently available product essentially is giving you the same amount of Levocetirizine as you get when taking it as the resemic mixture of Ceratek. Now here we have the situation of astemizole and tecastemizole formally known as norastemizole, tecastemizole is one of the metabolites of astemizole. Astemizole has a rather complex metabolism. Techastemizole has the major advantage of freedom from cardiac toxicity. Some animal studies have shown that it does not appear to have the same problem as inducing weight gain as it was a problem with Astemizole and it also seems to work much more quickly than Astemizole in terms of onset of actions. If you take a look at it's ability to inhibit histamine induced wheal and flare response as in the skin, this is something you see with tecastemizole, this is what you see with astemizole and clearly if you take a look at a similar amount of histamine applied to the skin, techastemizole is consistently giving greater inhibition of the wheal and flare response than you are seeing here with astemizole. So at least it's comparable if not more potent than astemizole in terms of this animal model of wheal and flare response. If you take a look at cardiac issues and this study takes a look at heart rate and QTC interval and this was done again in an animal model of dogs. What you see here is that tecastemizole causes considerably less problems with increase in heart rate than you see with astemizole and even in very large amounts given IV, essentially gives no problem in respect with QTC prolongation only when you get into well above the physiologic amounts that ever would be achieved is there any evidence that you do begin to see effects on the QT interval. This would not be a realistic amount that should ever be achieved either through drug overdose or interactions, which are minimal with this agent.

So in summary, if you take look at the pre-clinical pharmacology, tecastemizole is higher H1 receptor affinity, we didn't show you that data, we did show you the wheal and flare response in terms of it's comparison with the parent drug astemizole. tecastemizole has greater potency in vivo models, again we didn't show you that data, but there is 10 to 20 fold greater potency over astemizole in terms of histamine mediated in vivo models. And when you take a look at cardiac issues and it is clearly the major issue here as tecastemizole is being developed for the exact same reason fexofenadine was developed which is to get around the cardiac toxicity of the parent molecule. This really is the ultimate reason that this drug will come into being and that it does not alter QTC intervals in vitro and in vivo animal models so now we have achieved the sort of safety that we already have with cetirizine and loratadine in terms of cardiac toxicity. So looking at a comparison of these agents, fexofenadine why was it developed? It has freedom of cardiac toxicity, it has little or no hepatic metabolism under 4% liver metabolism, but the body has t handle it someway and the way it handles it is via intestinal transport proteins and so the perturbations that come with fexofenadine as far as bio-available drug all occur with these interactions to these transport proteins, for instance the recent paper on pediaglycoprotein saying that there may be some genetic variance that can lead up to 40% differentials in overall bio-availability of fexofenadine in selected individuals. desloratadine is being developed because of potency; it also has a long duration of acting. It has about a 27 and ½ hour half life and there is some intriguing data with nasal congestion and 24 hour symptoms relief, I'm suggesting that this may have added efficacy when it comes to the parent drug.

Levocetirizine improved potency I think has not yet been demonstrated when compared to cetirizine, again you get 5mg of Levo when taking 10mg of recemic cetirizine. Lower instances of sedation again, I think we have to see more data to see if in fact there is any difference in the over all sedation compared to what we see with cetirizine. The tecastemizole pre clinical data clearly is very promising and freedom from cardiac toxicity, hepatic metabolism, their potency and more rapid onset of action, all that have very favorable attributes when compared to astemizole.

Thank you