Thank you very much for the opportunity of participating in this session today. As a very Americanized-Canadian, hopefully I have quite an international view and I'm looking forward to sharing the rational for Next Generation Antihistamines. We'll have some discussion at the end I hope as to why we should choose this road. Our objectives are, that at the end of our discussion, we'll be able to describe characteristics of next generation antihistamines with regard to their clinical pharmacology, their efficacy and their safety. This is an important subject; the U.S. antihistamine market H1 antihistamine market is enormous and is growing at about 20% per year. H1 antihistamines are one of the largest classes of drugs in use not only in allergy, but in the world it is also a very well studied class of drugs. There are at least 400-500 papers coming out on histamines and H1 antihistamines every single year, a huge literature.

What is called first generation, second generation and next generation in terms of antihistamines is a rather arbitrary thing. First generation, we generally confine this term to the old sedating antihistamines, nearly all that were introduced before the mid to late 1980's. Second generation, well that was a revelation, a revolution, a brand new thing in the mid to late 80's when Terfenadine and Astemizole where introduced. First truly non-sedating antihistamines that were available. These medications are still with us out there in some countries. Fortunately in most countries where there is strong regulation in regard with pharmaceuticals, they are no longer in common use. Although, other second generation H1's which don't have any adverse cardiac affects, I'm thinking now of med's such as, loratadine and cetirizine, are very much with us and an important part of our allergy practice.

What then is the next generation of antihistamines, well I've listed for the purpose of this discussion this afternoon, 4 antihistamines as next generation. Fexofenadine or Allegra which is a metabolite of Seldane, desloratadine or Clarinex which is a metabolite of Claritin, Alevitzoterazine or Xyzal which is an antimerism or not a metabolite of cetirizine, and tecastemizole which was formerly known as norastemazole which is of course a metabolite of astemizole, which also goes by the name Soltara. The order of the drugs on this slide is directly proportional to the amount of the published literature on the drugs. In case you were wondering, if you are wondering why they weren't alphabetical. With quite a lot out there about Fexofenadine, some started to come out on desloratadine and even less on levocetirizine and tecastemizole. And we'll look at some of this data this afternoon. I just want to before leaving the ideal of a metabolite or an enantiomer, I just wanted to clarify what I mean by an enantiomer, I'm not actually going to be talking any more this afternoon about levocetirizine. But, the fact is that if patients take cetirizine, in the body what is active, the active principal of cetirizine is in fact the levocetirizine. This dextro isomer is completely and totally inactive in the body. This is a one-way street by the way; we're talking about roads and highways. If you take the enantiomer, it's not converted or obviously back to the parent compound in the body. An enantiomer just means these compounds are mirror images of each other. They can't be super imposed and it relates to the asymmetric carbon atom and around there. And that's it for levocetirizine; it's actually been launched in Germany, the United States, and the United Kingdom, throughout the European union and is in use for allergic rhinitis and urticaria overseas.

Histamine has been as the quintessential mediator of information and everybody is completely familiar with the affects of histamines and the acute allergic response. How it acts at H1 receptors to produce vasodilatation, vascular, to increase vascular permeability, extravasations, to produce edema. It produces gland secretions, it increases sneezing and itching. But, there is a world beyond this in terms of histamines; it also unfortunately up regulates cells and mediators that are delayed in the hypersensitivity response. In other words, in the chronicity of allergic disorders, these cells might be T-cells, or eosinophils or macrophages or mast cells, a variety of cells. But, it does have a rule; the mediator of regulation does play a role in the acute response. It follows therefore, H1 antihistamines are found to have anti-allergic and anti-inflammatory affects. These involve decrease in release chemical mediators of inflammation, definitely not related to their H1 antagonistic affect. But, other affects as well decreased migration and activation of inflammatory cells; I will talk a little bit more about this. Decreased adhesion protein expression, ICAM-1, VCAM-1. These last two affects shown on the slide may in fact be class affects. Mediated through transcription factor, nuclear factor kappa-beta. Here is a macrophage, a cell that is in fact involved in the inflammatory response and I want to show just one illustration of hundreds and hundreds of papers now, in vitro studies are showing how H1 antihistamines down regulate the immune response in terms of areas of that response that may be involved in delayed type reactions. This one which comes from Marrone's group in Italy involves IL- 6 release from human macrophage. You can see that in the control bar there is certain amount of IL-6 production of macrophages removed from human lung bits and incubated at human body temperature. If you put histamine into the system, you may get a doubling in the output of cytokines. And if you put an antihistamine into the system, in the case of fexofenadine's the case that was studied, you get down regulation. In other words, you get an effect that might be quite effective in down regulating the response. The really important thing to notice about this slide is that in years past, we have been very critical of some of the anti-allergic, anti-inflammatory affects of antihistamines by saying, well that's fine they are there in the test tube, but only possible to take enough of that antihistamine to get affect in the body. Not so with regard to this particular down regulating effect, these concentrations are achievable, even at low doses. A 60mg dose of Fexofenadine taken by mouth would give you such concentrations in vitro. So it's a clinically relevant effect as far as I am concerned. It's still not what's actually happening in the body, and I want to speak just a minute about how H1 antihistamines decrease symptoms, mediator release and chemotaxis after allergen challenged in vivo. I'll show one study in this regard, and I also want to talk about real life effects in allergic rhinitis and asthma. Atopic dermatitis again, I'll use one study in which allergic rhinitis was the disorder that was under investigation. This slide comes from a paper we published in the Annals earlier this year, and this was a study in which patients who were moderately allergic took a lot of intradermal tests with small amounts of allergen on their forearms. Two antigen units of the allergen were used and what we're looking at here is indurations in this allergen. We're looking at the late phase response the indurations that are after injection. And what you can see is the baseline on any drug that had been given to any of the patients had been on any day, there is obviously a late phase response. Itchy, soft red swelling that lasted was actually quite profound because they were quite allergic. Into this system at steady state we studied an antihistamine, leukotriene modifier, and the combination. And we found excellent down regulation of the late phase response. Something that hasn't been shown with some antihistamines in previous studies in previous years, and I think maybe this might be clinically relevant. Now, Eli mentioned a little bit ago about Phase 1 and Phase 2 studies with new drugs. The kinetic and the dynamic studies. We're on a highway this afternoon and I can tell you that on this highway, the rules of the road are getting stricter and stricter and stricter. Every new antihistamine that comes along, it's getting a little harder to actually do all the required studies mandated by the regulatory agencies. A drug at this stage being introduced for allergic rhinitis an H1 antihistamine has to have rapid absorption, it has to not accumulate as it is given day after day, week after week, month after month because that's how some patients' take these drugs. It has to be totally free from drug interactions. Somebody has to investigate herbals in the question period. Patient's take a lot of things we don't know about and some non medicinal, some foods. St. John's Wort, for instance would be an example, grapefruit juice would be an example, some of them interfere with the metabolism of some of the old antihistamines, even some of the second generation ones. And so a drug has to be clean in this regard, and some do fail in this regard. There are no special dosing regimens in the population. Dynamically it has to have a rapid onset of actions, patients don't want to have to wait forever to get relief. 24 hour duration that gives them convenience, the rapid offset of action I probably more important to the allergist than to the patient although, it might be important to the patient to if he has to drive back a 100 miles from his home just to see you because you couldn't skin test him the first day he was there he had an antihistamine onboard and of course no response to the antihistamine as time goes by, that has to be a given.

Now, I mentioned there's not that much out there about tecastemizole as mentioned in the published literature. At this meeting however, if you check the poster session, the poster's that are going up tomorrow will be up Saturday and Sunday. There are five abstracts, five posters on tecastemizole and I think that they show quite convincingly the kinetics of this new antihistamine aren't affected by age, or dosing regimens, renal or hepatic impairment or by co-administration of erythromycin. And this is the sort of study that has to been done at the very beginning of development of the drug. Many antihistamines along the way have failed just with these studies. Tecastemizole has not and it's on its way in terms of phase two and phase three studies as well.

I'll show just a couple of examples of kinetic dynamic studies; we can get objective measurements in these studies. We can look at H1 activity and observe how it persists even after the plasma level of the drugs decrease. We can even look at concentrations in tissue, the tolerance issue no evidence of loss in tolerance has been studied for months and months with antihistamines. No tachyphylaxis, I'm not going to show any of that data this afternoon in the interest of time and of course this type of study is very nice for comparative work. These are totally objective tests in these studies and the number of patients are much smaller than the required large clinical trials. So these are great cost effective studies. I'll show just one of our recent studies was published in JCI (Journal of Clinical Investigation) just a couple of months ago, in addition to doing skin tests in these studies, we did skin biopsies and by the way with regard to the skin test, we all do them on a daily basis either in the clinic or in the office, I must remind you that for the purposes of research, the test sizes can be digitized or scanned and actually you can get a very accurate output and a very accurate means of following the onset of action potency of action and offset of action of an antihistamine in humans. This is how we took the biopsies, a 3mm accu-punch, a local anesthetic was used. This is what the tissue looked like; it's blotted totally free from blood so we are totally certain that what we see we are dealing with is tissue concentrations and not blood concentrations. And I will show how one of newer antihistamines, one of the next generations actually performed quite well in this kind of study. In this study, patients were tested with pre dosed of course there was nothing in either the plasma which are the blue lines or in the skin which is the yellow triangles before the dosing. You can see how the yellow triangles go right across the top of the slide. I other words, the antihistamine stayed in the skin, it had an excellent ratio of skin to plasma. Where do we want it? We want it in the tissue, not in the blood. So, this in fact I think is a good marker in the history of antihistamine. The 168 hours refers to the study state, biopsy and plasma sample. After the first hour there was excellent suppression of the wheal and flare and that persisted right out in the steady state and this correlated in fact with the skin levels, wheal and flare suppression, particularly wheal correlating with skin levels. Now we had a comparator in this study, that was the still much beloved in some quarters I'm not quite sure why, that was the diphenhydramine 50mg dose and we found that this old antihistamine neither penetrated the skin nor produced very good H1 blockade. And you can see here the triangles; the skin concentrations are very close to the blue circles, the plasma concentrations. At best there was a 8-fold ratio of skin to plasma and not very good suppression of the wheal and flare and it was significant only at 3 hours maybe 6 hours. So we have useful and very objective way of comparing drugs when we do these pharmacokinetic dynamic studies. But, we are focusing on rhinitis this afternoon and t o get back to that I want to show a clinical pharmacology study that was done by Jim Day in Kingston, Ontario, Queens University in which out of season he got some patients with ragweed hay fever and got them into a classroom, a sealed classroom and piped in ragweed and monitored using the little counters which monitored the concentrations of ragweed pollen concentrations in the air. They were extremely high 4 to 5 thousand grains per cubic millimeters. The patients are primed, they come in and get a dose of antihistamine and then over the next 6 hours their symptom relief is monitored. You can see they look thrilled to be there. In this type of model tecastemizole was studied and was compared with loratadine again easier to do the comparisons perhaps in the clinical pharmacology studies early on in the development of the drug. This is percent change in total symptom score 6 hours after taking the drug, I should mention though, it's the obvious you are a sophisticated audience so I didn't actually go into this, but all these clinical studies are randomized, double blind, placebo controlled, so they are rigorously designed. And basically what he found here was basically the placebo did relieve the symptoms, there is a terrific placebo effect in all these studies. The tecastemizole, the usual dose or what will be the usual dose of 30 milligrams did very well as did the higher dose as did loratadine. But, what this slide didn't show is that he also got as good onset of action data with this study and in fact in 20 minutes the tecastemizole was working where the loratadine was not working until about two hours after ingestion. So that's it for the clinical pharmacology studies, the kinetic dynamic studies, I'll move on and talk just a little bit about clinical trials done in real patients with real symptoms. I think that as allergists we uniquely appreciate the serious morbidity of allergic rhinitis and I think that it has been a privilege for many of us to participate in the these types of studies eventually leading to better drugs for control of this disease. This is the usual diary card study not a lot of objective information here, mostly subjective information and here again the rules of the road are getting stricter and stricter. It used to be you could do this kind of a study in a hundred patients, now more likely it's a thousand. Several hundred patients in each of the treatment groups as you know a few who have participated in these projects.

This is one of the next generation antihistamines that has been studied using this format. Here we have total symptom score, reduction from baseline, in this particular study the patients were moderately symptomatic at time of entry with symptom scores of 14 out of 20 and you will see here that there is about a 30% reduction in symptoms. The desloratadine is shown in the yellow lower line, low in the slide is good. And you will also note that this occurred very promptly within a day of the initial dose. So you can see here that the studies meet all our expectations, the drugs, the new drugs meet all our expectations and I really think that there was no evidence of tachyphylaxis, no evidence of resistance to the antihistamine as time goes by is quite clearly showed studies such s one and it an important aspect. Patients will come and tell us this antihistamine or that antihistamine doesn't work. It's not the drug, it's not the H1 receptors, and we should be exploring other reasons as to why the H1 isn't working. Now, on this road to the next generation antihistamines, I know a lot of us would like to think that somewhere there is going to be an new H1 that someone is going to tell them that they are if no vastly more effect at least considerably more effective than the H1's that we currently have. Well, the purpose of showing this next study is to suggest to you in terms of efficacy, and effectiveness that if that happens it would be very nice, it would almost be a miracle, but data so far suggests that we are not going to be that fortune. The drugs in other words are going to be very similar in terms of efficacy and effectiveness.

Here again, we have a clinical trial, 722 patients completed this study and the primary outcome was mean change in 24-hour reflective total symptom score. In this study, placebo didn't have a significant effect in ameliorating symptoms but, fexofenadine in 2 different doses 120 once daily and 180 once daily, that's the dark yellow bar and the comparator which was cetirizine 10mg, all significantly relieved symptoms, compared to placebo. But, the story doesn't stop there and there is a very important learning point for all of us in this juncture. In this study there was a significant difference in terms of side effects, and I'm sure you're not surprised to see that. If we looked at sedation and fatigue combined, the cetirizine had an incidence of 9%, whereas the 2 doses of fexofenadine and placebo had an incidence of 4%. The fexofenadine had a placebo like profile in terms of prospects. And I think that that is a pattern we've seen repeated again and again and again. This is a study that came out a couple of years ago, but we've seen it in early studies and we continue to see it today in more recently reported studies. And you're thinking probably, well I know that I have seen some studies with differences in efficacy especially in regards to congestion and that is true and we can maybe in get into some discussion on this at the end of the talk. For every study we use, to find a difference a significant difference, we ask is clinically relevant, and we also have to ask where is the counter balancing issue, usually there is another study done by another company or another group of investigators that shows exactly the opposite. So in other words, the differences in efficacy and effectiveness are very small and they may show up more in one study than in another, but they are probably not very clinically relevant, the differences that mean an important thing for our patients or the differences in the side effects. And speaking of side effects we are going to have to go back here a bit, we've skipped ahead. We usually think of them in 2-3 groupings, the minor annoying ones, not so minor if it is you that is thirsty all day long, or having problems with urination all day long or all night long, still they are called minor. The main issues of course are the central nervous system adverse effects and the cardiovascular adverse effects. Even the general public is quite aware of the adverse CNS effects of antihistamines. Unfortunately these old antihistamines still are being used on a wide basis and again in the discussion, we may get into some of the pros and cons, mostly cons in regards to their use in out patients. The real problem is this, out there in the real world a lot of people are at increased risk for adverse central nervous system side effects from antihistamines because of intrinsic things that they can't change. There are either small women or young teens who often have small body mass and a very large milligram to kilogram dose as a result when they take an ordinary adult dose of an antihistamine. Old folks or those with preexisting CNS disorders, other conditions and patients who have allergic disorders, if you have rhinitis or you have urticaria, you are at high risk for CNS dysfunction from an H1 antihistamine because you may not be sleeping well that night before or you may be sleeping regardless of what medication you take or don't take the next day. And the real thing is these effects are often sub-clinical.

In the questions following Eli Meltzer's talk, there was some interest in pharmaco vigilance studies. And I'm actually going to show one of those studies right now. This is a study that came out in the British Medical Journal a year ago and it is based on the British system of pharmaco vigilance. It involves a large computerized database and every prescription that is filled is entered into this database. The pharmaco vigilance system kicks in with new drugs and not just with antihistamines but with all new drugs and it depends on family doctors' who get a card every couple of months on which they report events with the particular drug named on the card.

So this study is huge, it involves over 43,000 patients, it's important to note, that the drugs in this study were studied within different times. The fexofenadine was studied most recently, 1997; the other 3 were studied in the early 90's, shortly after the time when they were launched. They were new and physicians were interested in them and they were looking at them pretty closely and when they happened to give them to patients. And this study, even though it is not around in my double blind, placebo controlled trial, is a real life trial so these folks that took these antihistamines were probably on other drugs or they may have been old or may have had other allergies and for that reason, I think the information is very useful. What happened in this study is that overall the incidence of CNS effects or adverse effects from the enunciated antihistamines was low, and that is a really important point. The incidence was about 1 in 140, so very few patients who took these drugs complained to their family doctor of a problem. Incidence density by the way means number of events per 1,000 patient months, so that will help us understand we are seeing very few numbers of events here overall. Look at the drowsiness panel, it is the second panel in, the cetirizine in that panel is in orange, the acrovastine is in pinky-red and you will see that they really seem to stand out a bit and in fact, that panel itself is the only thing, the only outcome where there was a significant difference in the antihistamines. And both acrovastine and cetirizine were significantly "more drowsy", if you will than the comparators loratadine and fexofenadine. The interesting thing was that this did not seem to have much of an effect in terms of real world events, such as accidents or fracture injuries or road traffic incidents. And that I think reflects on all of these medications, the 3 that we have designated as second generation and also the next generation. All of them are extremely non-sedating in comparison to the old sedating first generation drugs although there are differences among these new ones. And the fexofenadine of course has gone on to have a very good track record in this regard, in terms of patients being able to take extra large doses, even doses up to 360mg without getting adverse CNS effects, study impress. I mentioned earlier that there were hundreds maybe thousands of patients in the clinical trials for efficacy and for safety, where subjective assessments have been going on. If you have good objective tests, objective tests where you get a number, when you do the measurements and where feelings are not so important as actual outcomes, productive outcomes. You only need 6 patients in a study to be able to demonstrate the differences between the old sedating and in this case Phenergan, promethazine and the new non-sedating, in this case we've taken the next generation fexofenadine again because it had the most data published about it, 6 patients in a rigorous crossover design. Here we have sleep latency, the ability to fall asleep, that means achieve stage 1 EEG sleep, when you are in a darkened or semi-darkened room. It happened at all time points after ingestion with the old sedating, with the next generation it didn't happen in a significant way at any time. Similar results were found with all the performance tests, with all the cycle performance tests and there was quite a number of them. I show just show just video vigilance here, this is one of the most boring tests you'll ever hope to take in your life, or not hope to take. We're looking at percent incorrect responses, how this test is done, you are staring at a computer monitor and numbers are coming across, one per second and you're looking for a little sequence of three consecutive odd numbers and you do this for 5, 10, 15 minutes and a lot of people actually fall asleep during this test. Well Phenergan, the results were bad, the results were bad with reaction time, they were bad with everything on the Phenergan. But, with the next generation a placebo like outcome in terms of the objective tests. This is not subtle this difference between the old first generation and the newer drugs.

I'll finish by talking a little about cardiac toxicity, again I must emphasize this is not a class effect. The mechanism is a blockade of the IKR current in the ventricular myocardium. This effect actually is quite rare it took years and years of astemizole and terfenadine use for this to show up, in fact the total number of fatalities world wide was not many more than 200. However, the regulatory agencies take a very, very serious view of this because the diseases for which we use antihistamines, rhinitis, and urticaria are the symptoms themselves never fatal. I had also mentioned and we'll get into this in just little bit, again some patients will without a doubt have increased susceptibility to these cardiac toxicities effects from antihistamines and so, some of those factors increasing the susceptibility are beyond the control of any physician. This is of course what we hope will never happen again with H1 antihistamines, the ventricular atopic beat leading to the post atopic pause, the abnormal Q-wave and terse at the point. It's just as well the keep this picture in mind again with overdose situations, we really don't expect any problem with the next generation antihistamine, but it's good to know what we're looking for. Here's those risk factors for cardiac toxicity, female gender again pre-existing or cardiac ECG abnormalities, hepatic or renal disease and the big unknown, the impossible to control concurrent use of medications that increase the QT interval which may not be prescription medications as I mentioned earlier, the grapefruit juice, the St. John's Wort and other herbs do come to mind. All the next generation antihistamines, I showed tecastemizole in terms of some early work that was actually published back in 94', by Chanin Woosley, all of these next generation antihistamines have been so thoroughly screened and vented I think the likelihood of cardiac to abnormalities or any of them even in overdose, even in patients at increased risk is probably very, very low, if not negligible, but in medicine we always have to keep those possibilities in mind. The screening process again is getting tougher and tougher, these rules of the road for companies wishing to introduce the new antihistamine are tighter than they have ever been and volunteers take doses not just in 2 or 3 fold in excess, maybe 9 to 10 fold excess. And they take them in overdose; small overdose amounts not just for a day or a week but also, for periods of time up to a year with intense ECG monitoring, so hopefully we're pretty safe with these next generation ones.

In the future, we need to look for more active metabolites, we mentioned 4 next generation drugs here this afternoon but there are more out there, there are other enanteriums out there for the levocetirizine that I had mentioned, we may be looking for combined antagonists. Drugs which intrinsically have not just an H1 antihistamine effect but an H1 plus an H2 antihistamine effect or an H1 plus a leukotriene modifier effect, those drugs do exist and they have been studied in vitro and in vivo in animal models and of course with the cloning of the H1 antagonist receptors some years ago and with increased understanding of receptor polymorphisms and how histamine and H1 antihistamines actually bind to this receptor, I think it really isn't outside the realm of the possibility that we will sometime in this century have designer antihistamines, designer H1 antihistamines, we will be able to tailor the H1 antihistamine to the patient who needs that drug, that's a little bit on the way out there. We've looked at next generation antihistamines with regard to their clinical pharmacology, their efficacy and safety, I hope I have conveyed to you that the rules of the road have been getting tougher and tougher and tougher and that these new drugs, these next generation drugs, at least the 4 that I talked about this afternoon, have really been very stringently investigated, imbedded and they are good medications and I think that the whole world of less toxicity, fewer CNS side effects is just there waiting to be tapped by ourselves and by our patients.

Thank you very much indeed.

Dr. Charles Siegel: Again we'll keep with the program by entertaining a few questions and answers. You may write them down on the cards and submit them to the isles for collection or please come to the microphone stands stationed in the isles.

Questions & Answers

Q: Hi, yes I would like to just comment on the Howard study was cited by, that you mentioned, was cited by the Medical Letter as an indication of equivalency among antihistamines, but in studying that paper carefully, unless I over read it, I noticed that a couple of things, one there was a multi centered trial that sounds good, but it was in three continents, South Africa, France, three countries not continents I'm sorry, South Africa, France and England a seasonal allergy study-of what pollen? How did they luck out and how was it different and how was their exposure's different and from what I understand multi centered studies tend to and I don't do the research, I just try to read it, I know you guys do, does that tend to decrease differences and why drug A, B or C. And the second point that I wanted to point out they threw out severe patients and I don't think I've ever seen that done before, I don't think that Jim Day has ever shown that much concern and the ideal was severe patients couldn't tolerate the placebo, that is done regularly than I'd like to know because I haven't seen it done. And then there was a statistical manipulation on the side effect profile, the value that you gave for the combined instances, the incidence of fatigue and insomniance was .07 P value and I wasn't aware that that was relevant?

A: Well let's take all these questions in order, first of all the issue of multi centered trials, when you get into the large numbers that are required for these clinical efficacy, subjective safety studies, it's impossible for most investigators to find that number of patients quickly, in seasonal allergic rhinitis ideally the study would be done in the same season and as you know that season can be longer or shorter, quite variable depending on the year. So we have to go to multi-centered trials for this type of study. The pollen in the study that you mentioned was grass pollen and the grasses I believe are the same around the world, South Africa has very good reputation in terms of studies of all sorts, not just with antihistamines but with, well they have a very good medical tradition there, a very strong medical tradition and they have some incredibly well trained allergists named on that paper. I don't have much of a problem with South African grass pollen, grass pollen in Europe as opposed to grass pollen in South Africa. Some of the other things you mentioned, the issue of not having patients in the study that had really severe rhinits, that is absolutely true, patients in that study had scores at entry of about 7, with a rigorous entry period of 3 to 5 days than the study was conducted over a period of 2 weeks. In this particular study the investigators devised in advance that the score that was going to get patients in was a certain score and they did throw out the severe patients and that does happen in a number of these trials. That particular study did not involve patients with severe congestion, that was something that they were not looking at in that study, it is just a decision that they made and it is quite valid to do that as long as the parameters are laid down in advance of the study and certainly well in advance of the data log of the study. This is not something after the fact, after you've seen the data, so the study met regulatory requirements not only for the European union but also for any other regulatory agency, there was not a problem in the way it was conducted. The adverse effects, it is true and I did say when I presented it that the sedation and fatigue were combined in this study and that was where the 9% came from. I would be pleased to debate this study further at length later, the study does meet current standards it wouldn't have been published in the Journal of Allergy and Clinical Immunology in the knowledge if it had not. You could look at all the studies, and for example I alluded to the fact that for every study showing efficacy, superior in 1 or 2 parameters, you can find a counter veiling study showing exactly the opposite. Actually I was going to show, but in the amount of time I could only show 2 recent studies with this in mind where loratadine was compared to fexofenadine. There was a European study that showed that in fact that loratadine was superior, not overall but in terms of congestion, that was a study that involved congestion and in terms of quality of life, a very nice study and the problem is that it doesn't stop there, because Hal Kaiser has just published in his clinical drug investigation, a study which was a study of loratadine versus fexofenadine, it showed just the opposite, it showed that loratadine is superior. So my point I think is valid if you go through all the studies, you will find that for efficacy and they're effectiveness overall there is not a whole lot of difference that we could depend on, look our patients in the eye and say, H1 antihistamine A is superior to H1 antihistamine B in terms of efficacy or effectiveness. We can however say that in safety parameters if we take the literature as a whole and I just gave one study as an example. That's a very long answer, but it was a very long question, please forgive me.

Q: Is there any difference between the normal norastemizole and tecastemizole?

A: Thank you for allowing me to clarify this, they are the same thing and in fact when I started planning for this talk this afternoon, we were all talking about norastemizole and the name has changed along the way and now it's called tecastemizole. So I really appreciate that Sam, thanks.

Q: I really only have one question here that I found was rather intriguing, does current antihistamines have any effect on H2 or H3 receptors and what do receptor H3 antagonists, or receptors and their antagonists do?

A: Thank you for this question. First of all, one of the things that has been really, really helpful to us is our understanding of histamine receptors is in fact the cloning of these receptors and the ability to study them and to see how much overlap there is amongst them. I can tell you for sure categorically that the H1 and H2 receptors, there is very little homology, less than 40% of any of the studies in any of the species. That's in contrast to homology between H1 receptors and muscarnic receptors, where there is a lot more overlap in terms of a lot more inter related homology, maybe 70%, maybe even 72-73%. This makes sense cause cholinergic side effects are problem with some of the H1, some of the old H1 antihistamines, that's where the dry mouth and the thirst and everything comes from. The last part of the question was in regards to H3 receptors, well we don't have clinically tested H3 antagonist or antagonists at this time, but when we do get them it will actually be quite interesting to study them. It seems that so far one of the important roles of the H3 receptor is that it is a pre-synaptic receptor in the central nervous system. We know that histamine is a really important neuro-transmitter, there are thousands as a matter of fact 64,000 histamine receptors in the posterior hypothalamus in all mammalian species in that constant number in a very constant location, and it's a very restricted location. Histamine is a neuro-transmitter and it's responsible for vigilance in the waking state. We know that H1 antihistamines of the old sort, the first generation sort really interferes with that. Whether H3 agonists or antagonists will have any effect remains to be seen. So far all the work is in animals but I think it might be interesting. Those of you with good memories will remember a few years ago, Peter Barnes looked at H3's in terms of the airways the lower airways and that work I think has kind of plateau, I don't know that there is any interesting therapeutic possibilities that are going to come out of it. The central nervous system aspects of H3 are absolutely real and there is an H4 receptor, that one is on white blood cells and is present in every organ in the body in which you have blood flowing and that one was just discovered, actually by a Californian several years ago and again you have agonists and antagonists being studied in animals and whether there is any therapeutic possibilities for humans with allergic disease, early days yet to tell.