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Discussion Starter · #1 ·
I have noted the following:1)Lotronex results show no statisical benefit for males. Statistical apparently doesn't mean that some males were not helped-- it only means the number was no greater than placebo. 2)Zelnorm studies in Mexico recruited 1500 female and no males.What's going on? Has any chemical/physical explanation been given for the no statistical benefit in males statement for Lotronex? Should Lotronex make it back to the market, will males be excluded from use?Why are males being left out the important Zelnorm studies?What's a male to do?
 

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Men and woman process drugs differntly. We have different levels of enzymes in part from the fact that ya'll process lots of testosteron and woman process lots of estrogen and that seems to take different enzymes in the liver.Drugs are metabolized by enzymes in the liver. So some possible explainations (none that I think they have worked out in toto for IBS drugs but are known to effect other xenobiotics--things your body don't make but get into it one way or another). Many drugs are in an inactive form and the liver enzymes activate them. Men and woman may have differnt levels of these enzymes and in men not enough/no drug gets activated. The drug may be deactived by the liver enzymes. Men may deactivate the drug much faster than woman and cannot maintain enough of it to be active. Men and woman also have differnt levels of certain enzymes in the GI tract. Men get less drunk that woman on alcohol because they have enzymes in the GI tract that deactivate it before it can get in the blood stream. Woman don't. So even at the same body fat and weight we get more alcohol in the blood than men do.This is fall out from the problems realized in the late 1980's early 1990's from the days when drugs were ONLY tested on men. See most drugs on the market probably should be approved only for men as they haven't been shown to be safe and effective in woman and at that time they looked at a few drugs and found that woman weren't being hysterical uncompliant patients and there were some drugs that just didn't work for us the way they worked for men or caused us side effects not seen in the male population studied. AND they did something with some medications that were being developed but were shelved because it didn't do squat in men, but they tried it on a woman and it worked well.So now they HAVE TO do all initial testing on both men and woman in the US. FDA can't force other countries to do the same thing. After the phase II testing (which is done on a few hundred people) they do a gender analysis to see if this drug is one of the ones that happens to be gender specific or not. If it is gender specific then they typically only spend the money to approve it for that gender because, for the most part, until the drug is approved spending a few million dollars to in all likelyhood confirm it doesn't do squat doesn't really appeal to the bottom line. After approval when there is some cash coming in from the drug there seems to be some willingness on the part of the drug companies to look more closely at the gender that didn't respond well in the intial studies.Placebo cure rates are fairly high for most everything (as alot of disorders wax and wane an some people will just get better for awhile for no particular reason, and the psychosocial needs of the patients are more likely to be met in a clinical trial where they will listen and be nice to you as the HMO isn't breathing down the doctors neck to treat more patients per hour than is good for anybody. After all they want to KEEP you in the trial so they are NICE to you and take you seriously most of the time....it keeps people from dropping out of the trial).I expect over the next couple of decades we will see any number of drugs be approved for a single gender. It just so happens that IBS drugs got started just after the new rules requiring woman to be studied came out and they are the ones most of us follow.K.AuthorsBeierle I. Meibohm B. Derendorf H.InstitutionDepartment of Clinical Pharmacy, College of Pharmacy, University of Tennessee, Memphis, USA.TitleGender differences in pharmacokinetics and pharmacodynamics. [Review] [114 refs]SourceInternational Journal of Clinical Pharmacology & Therapeutics. 37(11):529-47, 1999 Nov.Local MessagesHSL has complete holdings.AbstractSeveral years ago regulatory authorities requested to include women in all phases of clinical drug development in order to thoroughly investigate potential gender differences in the pharmacokinetics and pharmacodynamics of newly developed therapeutic agents. Since then, numerous reports have been published that evaluate the potential existence and impact of gender differences on all aspects of clinical pharmacology. With regard to pharmacokinetics, differences in absorption rate and duration have been reported for several drugs, but generally lack to have major clinical relevance. Differences in oral bioavailability, however, seem to be more important and are usually caused by sex differences in the activity of major intestinal and hepatic metabolic enzymes. Distributional differences have also been identified for numerous compounds. Although the majority of these findings were merely weight effects as women generally have a lower body weight, some of the gender-specific distribution differences persisted after normalization for weight. Possible explanations are differences in body composition between men and women and/or physiological changes during the menstrual cycle as well as differences in plasma protein binding secondary to hormonal characteristics. Frequent and sometimes clinically relevant gender differences could be identified for drug elimination processes and were predominantly linked to the sex-specific expression of metabolic enzyme systems, e.g. CYP3A4 and CYP1A2. In contrast, gender-related differences in renal elimination are generally only of minor importance. With regard to pharmacodynamics, gender differences have been observed in baseline characteristics as well as in drug response, which might both, at least in part, be the consequence of modulation by sex hormones. Some of the most striking examples identified were in pain therapy and perception, glucose management and arrhythmia susceptibility. Since clinical endpoints of efficacy and toxicity are often difficult to monitor and are frequently substituted by surrogate markers that might increase variability and thus mask gender effects, sex-specific differences in pharmacodynamic characteristics can often remain uncovered and further intensive research in this area seems imperative. For the majority of investigated drugs in the past few years, however, no or only very minor gender differences could be detected in pharmacokinetics and/or pharmacodynamics. In addition, the clinical significance of those gender differences identified seem very limited and was only very rarely linked to treatment success or failure. Hence, it is undoubtedly necessary to include women in the clinical drug development process, but it seems questionable whether women of child-bearing capability should be exposed to potential risks in early phase I clinical trials. [References: 114]------------------I have worked for the government and at universities doing scientific research primarily in the area of the environment and the impact of environmental factors on human health, I have never done any independant clinical testing for the pharmaceutical industry, nor have I ever worked for a drug company. I have no financial, academic, or any other stake in any commercial, natural, or any other product mentioned by me.My story and what worked for me in greatly easing my IBS: http://www.ibsgroup.org/ubb/Forum17/HTML/000015.html
 

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Men and woman process drugs differntly. We have different levels of enzymes in part from the fact that ya'll process lots of testosteron and woman process lots of estrogen and that seems to take different enzymes in the liver.Drugs are metabolized by enzymes in the liver. So some possible explainations (none that I think they have worked out in toto for IBS drugs but are known to effect other xenobiotics--things your body don't make but get into it one way or another). Many drugs are in an inactive form and the liver enzymes activate them. Men and woman may have differnt levels of these enzymes and in men not enough/no drug gets activated. The drug may be deactived by the liver enzymes. Men may deactivate the drug much faster than woman and cannot maintain enough of it to be active. Men and woman also have differnt levels of certain enzymes in the GI tract. Men get less drunk that woman on alcohol because they have enzymes in the GI tract that deactivate it before it can get in the blood stream. Woman don't. So even at the same body fat and weight we get more alcohol in the blood than men do.This is fall out from the problems realized in the late 1980's early 1990's from the days when drugs were ONLY tested on men. See most drugs on the market probably should be approved only for men as they haven't been shown to be safe and effective in woman and at that time they looked at a few drugs and found that woman weren't being hysterical uncompliant patients and there were some drugs that just didn't work for us the way they worked for men or caused us side effects not seen in the male population studied. AND they did something with some medications that were being developed but were shelved because it didn't do squat in men, but they tried it on a woman and it worked well.So now they HAVE TO do all initial testing on both men and woman in the US. FDA can't force other countries to do the same thing. After the phase II testing (which is done on a few hundred people) they do a gender analysis to see if this drug is one of the ones that happens to be gender specific or not. If it is gender specific then they typically only spend the money to approve it for that gender because, for the most part, until the drug is approved spending a few million dollars to in all likelyhood confirm it doesn't do squat doesn't really appeal to the bottom line. After approval when there is some cash coming in from the drug there seems to be some willingness on the part of the drug companies to look more closely at the gender that didn't respond well in the intial studies.Placebo cure rates are fairly high for most everything (as alot of disorders wax and wane an some people will just get better for awhile for no particular reason, and the psychosocial needs of the patients are more likely to be met in a clinical trial where they will listen and be nice to you as the HMO isn't breathing down the doctors neck to treat more patients per hour than is good for anybody. After all they want to KEEP you in the trial so they are NICE to you and take you seriously most of the time....it keeps people from dropping out of the trial).I expect over the next couple of decades we will see any number of drugs be approved for a single gender. It just so happens that IBS drugs got started just after the new rules requiring woman to be studied came out and they are the ones most of us follow.K.AuthorsBeierle I. Meibohm B. Derendorf H.InstitutionDepartment of Clinical Pharmacy, College of Pharmacy, University of Tennessee, Memphis, USA.TitleGender differences in pharmacokinetics and pharmacodynamics. [Review] [114 refs]SourceInternational Journal of Clinical Pharmacology & Therapeutics. 37(11):529-47, 1999 Nov.Local MessagesHSL has complete holdings.AbstractSeveral years ago regulatory authorities requested to include women in all phases of clinical drug development in order to thoroughly investigate potential gender differences in the pharmacokinetics and pharmacodynamics of newly developed therapeutic agents. Since then, numerous reports have been published that evaluate the potential existence and impact of gender differences on all aspects of clinical pharmacology. With regard to pharmacokinetics, differences in absorption rate and duration have been reported for several drugs, but generally lack to have major clinical relevance. Differences in oral bioavailability, however, seem to be more important and are usually caused by sex differences in the activity of major intestinal and hepatic metabolic enzymes. Distributional differences have also been identified for numerous compounds. Although the majority of these findings were merely weight effects as women generally have a lower body weight, some of the gender-specific distribution differences persisted after normalization for weight. Possible explanations are differences in body composition between men and women and/or physiological changes during the menstrual cycle as well as differences in plasma protein binding secondary to hormonal characteristics. Frequent and sometimes clinically relevant gender differences could be identified for drug elimination processes and were predominantly linked to the sex-specific expression of metabolic enzyme systems, e.g. CYP3A4 and CYP1A2. In contrast, gender-related differences in renal elimination are generally only of minor importance. With regard to pharmacodynamics, gender differences have been observed in baseline characteristics as well as in drug response, which might both, at least in part, be the consequence of modulation by sex hormones. Some of the most striking examples identified were in pain therapy and perception, glucose management and arrhythmia susceptibility. Since clinical endpoints of efficacy and toxicity are often difficult to monitor and are frequently substituted by surrogate markers that might increase variability and thus mask gender effects, sex-specific differences in pharmacodynamic characteristics can often remain uncovered and further intensive research in this area seems imperative. For the majority of investigated drugs in the past few years, however, no or only very minor gender differences could be detected in pharmacokinetics and/or pharmacodynamics. In addition, the clinical significance of those gender differences identified seem very limited and was only very rarely linked to treatment success or failure. Hence, it is undoubtedly necessary to include women in the clinical drug development process, but it seems questionable whether women of child-bearing capability should be exposed to potential risks in early phase I clinical trials. [References: 114]------------------I have worked for the government and at universities doing scientific research primarily in the area of the environment and the impact of environmental factors on human health, I have never done any independant clinical testing for the pharmaceutical industry, nor have I ever worked for a drug company. I have no financial, academic, or any other stake in any commercial, natural, or any other product mentioned by me.My story and what worked for me in greatly easing my IBS: http://www.ibsgroup.org/ubb/Forum17/HTML/000015.html
 

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In the clinical drug trials of Zelnorm in the U.S. there were zero to negative results for the effectiveness of the drug (in other words the treatment group was either no different from the placebo group or worse than the treatment group) in males. Only females appeared to respond to the drug. Check out the Zelnorm discussion forum, I provided links to the clinical drug trial documents on the FDA site for Zelnorm if you want to get into the details.
 

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In the clinical drug trials of Zelnorm in the U.S. there were zero to negative results for the effectiveness of the drug (in other words the treatment group was either no different from the placebo group or worse than the treatment group) in males. Only females appeared to respond to the drug. Check out the Zelnorm discussion forum, I provided links to the clinical drug trial documents on the FDA site for Zelnorm if you want to get into the details.
 

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Discussion Starter · #12 ·
The differences between male and female response to IBS drugs is astounding!There has to be a message there. Either the mechanism of IBS is different or there is a complete lack of understanding how drugs are absorbed in males and females, or both.I have long suspected that females responded quite differently (more positively) to antidepressants used for depression relative to males. This perceived difference was "explained" by men not following through or men quitting before the effects took effect. Perhaps not! Perhaps they just don't work as well (or at all). It would be interesting to see the statistics for antidepressant failure rate broken down into gender. (Right now about 30% don't respond to regemes of antidepressants for depression -- you won't get your treating Dr or Ann Landers to admit this.) It may be more much lower for females than males. Given a 5:1 ratio of females/males being treated for depression the failure rate could be 20% for females and 90% for males. This would be more consistent with how IBS drugs seem to work.
 

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Discussion Starter · #13 ·
The differences between male and female response to IBS drugs is astounding!There has to be a message there. Either the mechanism of IBS is different or there is a complete lack of understanding how drugs are absorbed in males and females, or both.I have long suspected that females responded quite differently (more positively) to antidepressants used for depression relative to males. This perceived difference was "explained" by men not following through or men quitting before the effects took effect. Perhaps not! Perhaps they just don't work as well (or at all). It would be interesting to see the statistics for antidepressant failure rate broken down into gender. (Right now about 30% don't respond to regemes of antidepressants for depression -- you won't get your treating Dr or Ann Landers to admit this.) It may be more much lower for females than males. Given a 5:1 ratio of females/males being treated for depression the failure rate could be 20% for females and 90% for males. This would be more consistent with how IBS drugs seem to work.
 

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quote:Been waiting like a sucker for this drug, all the RANT about how good it is, then you hear the rumors its doesnt work on MEN.
What you are hearing is just that, RUMORS. They are not an accurate reflection of reality.The clinical studies did not include a lot of men because they could not get men to participate in them. Perhaps it's too macho for some men to admit that they have a bowel disorder.I understand that studies will continue with men so that they can get some meaningful data which will indicate efficacy in men.I can assure you that there is no conspiracy against men and IBS medicines or studies.Jeff
 

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quote:Been waiting like a sucker for this drug, all the RANT about how good it is, then you hear the rumors its doesnt work on MEN.
What you are hearing is just that, RUMORS. They are not an accurate reflection of reality.The clinical studies did not include a lot of men because they could not get men to participate in them. Perhaps it's too macho for some men to admit that they have a bowel disorder.I understand that studies will continue with men so that they can get some meaningful data which will indicate efficacy in men.I can assure you that there is no conspiracy against men and IBS medicines or studies.Jeff
 

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Discussion Starter · #18 ·
Jeffrey,I don't believe what you say about men volunteers is true.It is a fact that 4-5 years ago the manufacturer of Lotronex was recruiting only women for their studies! You could look up clinical studies on the internet and see that not one would accept men.It is a true statement that you can't prove a product works in men if you don't include them in studies.I agree about there being no conspiracy. The more likely explanation is that it was determined early that men didn't respond as desired. Also most of the market is women with about a 7:1 ratio of suffers. Thus the bottom line could be more effectively served by dropping men early.
 

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Discussion Starter · #19 ·
Jeffrey,I don't believe what you say about men volunteers is true.It is a fact that 4-5 years ago the manufacturer of Lotronex was recruiting only women for their studies! You could look up clinical studies on the internet and see that not one would accept men.It is a true statement that you can't prove a product works in men if you don't include them in studies.I agree about there being no conspiracy. The more likely explanation is that it was determined early that men didn't respond as desired. Also most of the market is women with about a 7:1 ratio of suffers. Thus the bottom line could be more effectively served by dropping men early.
 

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Some of the "rumors" are from the medical literature and the raw data found in the reports filed with the FDA.They did have to test some men in the Phase II trials (can't exclude a gender in the US in Phase II no matter how reluctant they are) and maybe only men who don't respond to the drugs enrolled and only woman who do respond did, but in some of the published data it is quite clear that the men's response AS A GROUP was not statistically significant (In papers filed with the FDA with zelnorm the men did better on the placebo than they did on the zelnorm at all dose levels and there was no trend indicating higher doses worked less badly than lower doses). Now INDIVIDUALLY some men may have responded very well but unless people, men, woman AS A GROUP respond in a statistically significant way there usually isn't any reason to test that subset further as for regulatory purposes it is how the GROUP responds not how well any particular individual in the group responded.K.------------------I have worked for the government and at universities doing scientific research primarily in the area of the environment and the impact of environmental factors on human health, I have never done any independant clinical testing for the pharmaceutical industry, nor have I ever worked for a drug company. I have no financial, academic, or any other stake in any commercial, natural, or any other product mentioned by me.My story and what worked for me in greatly easing my IBS: http://www.ibsgroup.org/ubb/Forum17/HTML/000015.html
 
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