Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Drug interaction wikipedia , lookup
Environmental impact of pharmaceuticals and personal care products wikipedia , lookup
Neuropharmacology wikipedia , lookup
Drug discovery wikipedia , lookup
Pharmaceutical industry wikipedia , lookup
Pharmacogenomics wikipedia , lookup
Psychopharmacology wikipedia , lookup
PUBLIC MEETING ON THE SAFETY OF DIETARY SUPPLEMENTS CONTAININGEPHERDINE ALKALOIDS VOLUME I of II Date: August 8, 2000 Pages: 1 through 298 DHHS OFFICd ON WOiXN’S HEAi,TH DOES NOT GUARANTEETHE ACc'~RM!Y 3 THE TRANSCRIPT. 1 PUBLIC MEETING ON THE SAFETY OF DIETARY CONTAINING SUPPLEMENTS EPHEDRINE ALKALOIDS VOLUME I of Tuesday, August II 8, 2000 U.S. Public Health Service Cohen Building Auditorium Washington, D.C. The meeting qas convened, pursuant MOFFITT in to the above-entitled notice, at 9:00 matter a.m. REPORTING ASSOCIATES (301) 390-5150 2 Public Meeting: Safety Ephedrine Alkaloids Tuesday, 8:00 August am 8, AGENDA of Dietary Supplements Containing 2000 Registration 9:00 am OPENING Wanda K. Jones, DrPH, Director Office of Women's Health 9:lO am Ephedra-containing Compounds: Historical Pharmacologic Context Harry H.S. Fong, Phased, University of Illinois, Chicago 9:50 am BREAK LO:05 am -1:50 am Adverse Event Reports : Database and Clinical Studies Lori A. Love, MD, PhD, FDA Julie G. Bietz, MD, FDA George Ricaurte, MD, PhD, Johns Hopkins University School of Medicine Raymond L. Woosley, MD, PhD, Georgetown University School of Medicine Cynthia Culmo, Texas Department of Health Q&A .2:10 pm LUNCH 1:lO pm 2:55 pm Adverse Event Reports: Ephedra Education Panel of Experts Review Steven E. Kimmell, MD, MSCE, University of Pennsylvania Theodore M. Farber, PhD, DABT, Toxichemica International Norbert P. Page, DVM, MS, Toxichemica International Grover M. Huchins, MD, Johns Hopkins University School of Medicine Steven B. Karch, MD, City of San Francisco John W. Olney, MD, Washington University Medical School Edgar H. Adams, MS, SCD, Harris Interactive Q&A 3:15 pm BREAK (on your MOFFITT own) REPORTING ASSOCIATES (301) 390-5150 and 3 Public Meeting: Safety Ephedrine Alkaloids 3:30 3:30 3:45 Abstract Barbara Q&A 3:50 4:05 James Q&A 4:lO Linda Golodner League Q&A 4:25 Col. U.S. Q&A 4:30 4:45 of Dietary Session I J. Michael, S. Turner, Esther F. Air Force Kay], Myers, PhD. McGuffin, Association 5:25 Michael Products Q&A 5:30 5:45 Robert Q&A M. Stark, >:50 Public Comment 5:50 5:53 5:56 1. 2. 3. 5:59 4. 5:05 5:lO 6:02 p.m. & Turner [Brett Fugh-Berman, Containing HEAT Swankin Adraine Network Q&A 4:50 Supplements National RD, FADA MD National President, MD, FACP, Session Women's American Yale Consumers Health Herbal University A Samieh Wood, Private Citizen Hanna K. Zewchzer, Private Citizen David Molony, American Association of Oriental Medicine Pablo Francisco Semiao, Private Citizen Adjourn MOFFITT REPORTING ASSOCIATES 390-5150 (301) ct 4 LISTENING Deputy Aaron H. Clinical Clinical Building Bethesda, PANEL Chair: Wanda Jones, Dr. P. H. Assistant Secretary for Health (Women's Health) Director of the Office of Women's Health U.S. Department of Health and Human Services Burnstein, PharmD Pharmacokinetics Research Center Pharmacy Department 10, Room IN-257 MD Paul Coates, PhD Director 3ffice of Dietary NIH Supplements Harris Lieberrnan, PhD Supervisor Research Psychologist US Army Research Institute of 42 Kansas Street Natik, MA 01760-5007 Environment Rossanne M. Philen, M.D., MS Xealth Studies Branch Yational Center for Environmental Centers for Disease Control and 1600 Clifton Road, NE vIailstop E-23 Atlanta, GA 30333 !4ary Ann Richardson, Program Officer Yational Center for \Jational Institutes Laboratory Medicine Health Prevention Dr.P.H. Complementary of Health and Alternative !Iarcel Salive, MD, MPH ?revention Scientific Research Group 1ivision of Epidemiology and Clinical \Jational Heart, Lung and Blood Institute dational Institutes of Health 3erne Schwetz, DVM, PhD lcting Deputy Commission ?ood and Drug Administration 5600 Fishers Lane iockville, MD 20857 MOFFITT for Food and Applications Drugs REPORTING ASSOCIATES (301) 390-5150 Medicine ct 5 1 PBQcEBQLEGs 2 [Time 3 DR. 4 is 5 Women's 6 scientific 7 supplements Wanda JONES: Jones. Good morning, I am the Health. We are information During scientific meeting, 10 questions addressed 11 organizations 12 These 13 physiologic 14 on its 15 information 16 dietary supplements 17 adverse events, 18 system, psychotropic, 19 directed. 20 21 there are 22 dietary 23 What 24 indications 25 support four many come to what Does are such containing of is the ephedra the ephedrine when quality as the which use alkaloids? needed for any use? MOFFITT used for for of and nervous circumstances are of alkaloids ephedrine use based use center events any adverse available indications duration and what the and of between other there and positive cardiovascular, or specific information. be expected well-established and provide containing public individuals an association supplements does have is available alkaloids. to would on dietary we hope First, that of two-day constituents? Second, safety My name the this by the actions show address a.m.1 Office of are: known to the course who have questions of ephedrine the 9 here 9:00 everyone. Director on the containing 8 noted: REPORTING ASSOCIATES (301) 390-5150 those data to of ct 6 1 Third, how would 2 seriousness and/or 3 alkaloids 4 enhancement 5 demographics, 6 consumed severity 7 or 8 yohimbine, or 9 individual sensitivity labeled for taking age, across synthetic 11 these 12 characteristics 13 conditions, 14 other 15 the duration Well, Office of Women's 18 Office of Public 19 forum. 20 supplements 21 immediate 22 Office Well, 25 appropriate types are the outcomes on Women's and this public synephrine, and associated predisposing the these it with affected by means? why Public Science use Is by others health with health as combining issue natural we in the Health is Service, convening products central this as dietary to concerns the of the Health. and for take other by user compounds? at amount products? may be wondering addition, informational or such or the with these other as user exercise by dosage, makes such to Health, broader of as age ephedrine as caffeine, stress many women and use such Health which In is population, exposure you 17 24 ethnicity, race of exercise or behaviors of and sex, added or loss the risks issues such or the account affected stimulants 23 weight fourth, products 16 of stimulants, the characterize into the And, 10 one this MOFFITT since not the regulatory, meeting to purpose it be held of is the more outside REPORTING ASSOCIATES (301) 390-5150 meeting of a ct 7 1 regulatory context. 2 Of course 3 discussions 4 and 5 ephedra. 6 in over Drug 8 helpful 9 key to so we'll provide events 10 published 11 dietary 12 This 13 use. 14 provided 15 area. two in during days it's will our help ongoing deposit As we begin that a record our discussion a brief historical have brought a proposed rule supplements proposal the Food assessment of of this meeting today, it may be of this on the In 17 announcement, 18 public. 19 audited 20 proposed 21 issues 22 dose the about procedures 25 consumers, and addition by FDA, General FDA had the to and manufacturers, MOFFITT the interest and registration comments health from its a number at of its the new the Office developing arrived audit, is Reqister raised openness the the of and proposal Accounting in safety on dosage Federal The audit about In alkaloids. in the FDA ephedrine numerous agency's 1997, the table the of addressed Register the how the limits collected to In limits Federal addition rulemaking. 24 suggested FDA received In 23 that information response overview us here. containing mainly A copy 16 , next obtained FDA docket. 7 1 the data Administration And the any of proposed process. information expressed care REPORTING ASSOCIATES (301) 390-5150 by providers led ct 8 1 FDA to 2 past withdraw part of the 1997 proposal this spring. 3 The 4 provide 5 the 6 products. agency reopened an opportunity information for related And 7 that has The purpose 8 management, 9 all but available 10 these 11 that 12 together 13 epidemiology, 14 preventive 15 assist end, the the of let to our a panel safety this forum to weight federal medicine, and of energy. Health has in And to brought pharmacokinetic, and clinical assess safety and nutrition, and regulatory the experts toxicology, forum. obtain loss of these not to on Women's of is to assessment public related for period to an effort Office comment and information used the discussion of rather products behavior, pharmacology to us. 16 The 17 the 18 questions 19 needed. role discussion within Let format of we have 20 21 a large and 22 23 presentation logistics 24 assessment 25 alkaloids. of context and for focus is to of seek to listen, the to four clarity guide specific where briefly describe the meeting. right after on issues supplements we will MOFFITT to the and dietary Then the a moment morning will panel asked me take This this have our lunch concerning the containing ephedrine first abstract REPORTING ASSOCIATES (301) 390-5150 safety ct 9 1 session followed 2 Tomorrow 3 are 4 by more by a few morning abstract public 7 there 8 the 9 things in are your of with the 11 agenda 12 help 13 proceeds. 16 scheduled. 17 lights 18 and is have 19 time. forward is speakers sign when 22 and give you 23 on time. 24 to 25 speak be sure has to to will followed to are a warning that everyone seats in so that and the public the the meeting comment will who has to and as we have to the their green approximately can the period presentations, about move we can comment start toward help name chair flash red where corresponds your them some available MOFFITT that public so you a flashing are will be visible queue try it number that as the that there And that there lunch, numbered and be timing We will the in including signs 21 then particularly, preceding my goal We will 20 comment. comment are the a seat presentations the after Tomorrow section that and public middle number It all during there find 14 public comment and you, you move you 15 of if and public before agenda. the along 10 speakers a lot front of comment. The numbered with sessions, 5 6 opens minutes audience remaining light two minutes wrap up, mean stop. and registered present REPORTING ASSOCIATES (301) 390-5150 or left the end We want for his show or time her to ct 10 1 views. All 2 3 for the 4 from 5 source of 6 source of 7 ready record -- to the record funding for their activities, funding for their travel 10 welcomes 11 public docket 12 30th. This 13 that 14 presented the I would your written comments as of August docket Agency at will has this also to as quickly 18 15 working 19 public 20 reg ,istration 21 ins days. and very special 24 come to share 25 many of you thank you that FDA reopened the has 2000 all through of September the information the information meeting be including this will as possible. submit comments your and be available We expect about how to certainly is is within access the included on the with table area. we begin, you their here remind transcripts registration 23 approaches. additional Information materials Before 22 be for requested 17 the Please meeting. The meeting at as time lOth, received transcribed. docket as well time and display 16 docket to you're affiliation here. limited state where name, as your like should no matter their podium we had We have the agenda for comments, 15 the speakers, come to the in all Because open shown -- state 8 9 speaker in views this MOFFITT I would advance with morning. like to us. to extend everyone I am glad I think I've REPORTING ASSOCIATES (301) 390-5150 a who has to talked see so to 11 virtually every really 3 in been recent one of spectrum of doubt, has strongly very for all organizations professional 11 their us 12 speakers for 13 for cooperation. your 14 this 15 of 16 Human 17 the 18 Administration, 19 Prevention, and 20 contributed a great 21 and Services restrooms has I've done this consumer organizations, trade groups for us, like within Public staff deal Health, for of of very and grateful of the Food and to all Health Services Disease time represent my thanks and agencies, and Drug Control my office and who have energy to planning possible. a little are allowed that's the bad MOFFITT to Department Health of the the extend the Centers no useful panelists to now, in on umbrella the with everyone, very part also beverages are and And we are forum an agenda and meeting. an the And, 25 in Institutes making assemble views identify people National sorry, things parties, and to I would 24 It consider. relied and other to to societies, members and telephone. exciting held including 10 23 most interested We have 22 on the attempted a full the you the We have information 9 of years. 4 5 one news long housekeeping. in of this No food auditorium, the meeting. corridors. If REPORTING ASSOCIATES (301) 390-5150 and I'm The you exit the 12 auditorium, turn 3 to turn right right, or left, And then and and go to you'll that see main signs cross area, directing you restrooms. 4 5 of places 6 are very 7 at 8 auditorium. where you close all in For 10 interpreters 11 front 12 providing 13 need 14 you 15 always of the the see deaf Lisa Beth 17 staff 18 attendance. 19 can that And 21 cell phones 22 alert for to guide 25 questions the we have Robison, here interpretation. So, free to the in be if move you do forward lighting will emergency around and we can is a very close your needs so not are taken ask or least of the at described MOFFITT within earlier, get care that you that we are context turn them and to here of clarify. REPORTING ASSOCIATES (301) 390-5150 we of. you set let off on silent meeting. me underscore, discussion please by a clinic I would beepers, duration So let 24 hearing who will a medical finally, and the the Schaefer, feel the name badge enter are There 20 of because have They be sure to you lunch strong. you know. 23 better for wear Yvonne please them If hard a map available bite to and and language be this 16 need building, interpretation can a quick us today, and sign we have grab You'll with me, lunch, can by. times 9 for to the listen, four ct 13 1 So, 2 expert panel 3 at far 4 Dietary Supplements 5 Health; Dr. 6 Institute 7 Massachusetts. 8 the 9 Health; 10 Center 11 the 12 from 13 Science 14 Administration. 15 Salive 16 Institute the 18 of the to Mary at Ann the of at the Now, us but Without 20 waiting for 21 microphone Good. 23 It's open first work 22 proceed further our Food Lung one speaker and and Office of Blood Health. member to arrives. I know this Schwetz Marcel Panel she at Drug Dr. other until National the of adieu, from of Berne and Institutes we do expect Army Medicines here, Heart, National we will the Dr. I am hiding of Burstein from the of Institutes Health; from Office Natik, Aaron Commissioner National the Dr. National of And the him, at the Starting U.S. and Alternative Administration from the Medicine Richardson Institutes Office the of Institutes from the on Complementary National from National Environmental members on stage. Coates Lieberman Center 19 r at the me here Paul Next Dr. me introduce with Dr. Harris Clinical join let who are end, 17 s now, that morning. you're Is that now? my pleasure 24 now to the 25 on Ephedra-Containing meeting MOFFITT to with Invite Dr. a background Compounds or their REPORTING ASSOCIATES (301) 390-5150 Harry S. presentation Historical Fong ct 14 1 and Pharmacological 2 all of 3 questions 4 is this in if about need a Herculean Jones. 8 going to 9 Elizabeth 30 minutes Fang , welcome DR. FONG: say not be politically 11 try to stand 14 historical 15 to this is the 16 University 17 Botanical 18 one 19 with 20 thanks of way that of under 23 I will 24 expert, 25 Jones not but what do him So it you. much public walks Secretary I was speaking around. and is But I guess and being Jones Illinois us getting the she said in -- this well, from Coates some we look may I'll at and NIH funds. I would like place, the Center I think has So let come and the unique Research. up there to and a very Chicago Supplement Dr. asked pharmacology in for we are something me make to do my public advertisement. When Dr. 22 ask incorrect, for I come Dietary 21 very politically appreciate As Dr. out and we can to up. perspective two him presentation. thank you correct you. point and Thank I really to his my inspiration 10 talk asked so that be following Dr. Dole 13 And we've task. I know 12 ? Context. impression disagree at this kind of MOFFITT Jones asked that with me to speak, I am some kind her point an expert that I think that she of was an expert. I am some kind I should I am. REPORTING ASSOCIATES (301) 390-5150 tell And of Dr. expert by 15 definition 2 and is able to a person say, "Have 3 [Laughter.] 4 DR. 5 get down 6 Good. to 7 FONG: dry area 9 ephedra of 10 names, the 11 name. As you 12 the 13 yellow 14 ephedra 15 what it 16 the plant most of for looks In world 20 Central 21 Americas. we all than of 24 years 25 the in treatment a Chinese the a stem here rlmaIr means is of the the not know knows to Asia there are give and you what has asthma, MOFFITT about been some in 10 species brief used for the North in and the history. more China's congestion, there throughout even a slight as traditionally of distribution distributed in ma huang China -- everyone the vernacular who might geographical 30 species America; know you is related "huang" is me working? ma huang, tongue; let Ephedra means sure willing like. particularly 23 mike other is of is way, many names, Here I'm terms Try or which drug. like. looks has few the ephedra. literally the of this Seneca on the the Seneca 19 it action color more out is who Travel." Is of town Will what famous know of that Ephedra astringent were With ephedra species. 18 Slides define part 17 out my presentation. Let's 8 from than medicine colds, REPORTING ASSOCIATES (301) 390-5150 and As 5000 for so on 16 ct 1 and so forth. And 2 ephedrine 3 guide in Japan 4 years later Merck 5 same species in 6 with the alkaloids 7 isolated two from work which 10 by Dr. 11 the drug into 16 ephedrine 17 to the 18 of ephedra 19 dietary to and the at the 1924 as the Kay K. Dr. 22 detailed 23 thought 24 speaking 25 than 2 percent or six from a world the apart alkaloids Union being of look Chen for 1927. use his a pitcher contains alkaloids more and conducted and back work Schmidt. active synthesized the as a weight street using reduction drugs. the giving us a very, with -the this you. could major REPORTING ASSOCIATES (301) 390-5150 ahead promotion we had in or we jumped me is work in particular the Then to us and of MOFFITT this a more was ago was followed by pioneering College as alternative visiting of was years share and ephedrine Peking for or ephedra of in recapitulation I would use 1930 ephedrine Chin classical significant Twenty-five 21 the to model supplements 20 major amphetamine 199Os, and later got introduction an effort compound early two the and toxic years binding same plant. in In less the medicine 14 five isolated So you've Western publication 15 Europe. Chen 20s was pseudoephedrine my opinion K. early and isolated leads Kay 1887 the In 8 9 in itself pleasure area of very so I Chemically be up to alkaloids more are 17 ct 1 three stereoisomeric 2 Norephedrine, 3 with 4 alkaloid. being Let's 5 all in 7 differs 8 configuration 9 sci sync what and the at group in methyl group so one is the all 18 So one or specific norephedrine look would example. way back 24 ephedra 25 of the note that is the expect the the basic that effect may be differences species to I don't expect in the Seneca, total of difference lack of has skeleton the a two there the biological are basically in the degree And you I just ephedrine MOFFITT different species. room. alkaloids the to and and alkaloids this read want account a and methylephedrine at 3 and effects. from 23 a carbon no pseudoephedrine norephedrine The occurrence vary one pharmacological There similar. the chemical same. 16 activity at we are as methylephedrine and methyl total Ephedrine stereo group and the about. by the same difference and of so that talking no ephedrine ephedrine Methylpseudoephedrine structure hydroxy methylpseudoephedrine between the we are the pseudoephedrine, 90 percent pseudoephedrine of chain, and 40 to look of from again Ephedrine, Methylephedrine ephedrine 6 pairs, this to for 65 percent is just slide emphasize about of REPORTING ASSOCIATES (301) 390-5150 some from in 60 percent it 18 ct 1 pseudoephedrine 2 particular 3 pseudoephedrine the second largest. the only species that slide than Now, 4 5 and it 6 treatment of 7 is is good 8 asthma. 9 of ephedrine what proven a very -- being are types of 10 primary 11 decongestion and 13 this type of 14 are major 15 along 16 sympathomimetic 17 Alpha 18 receptors 19 release 20 it 21 then to at an overview related 1 and and of act Beta more one of for treatment But the the pharmacology before, of and 2 receptors of athonergic indirect from neuron release of they potent stimulating by of pseudoephedrine by the stimulating the And stores. norepinephrine so and effect. looks at 23 and norepinephrine 24 and pseudoephedrine one 25 and the being amino it directly like some direct If I said commonly acts treatment and compounds norepinephrine primarily have as that Beta and as a nasal of ephedrine compound, the ailments use stress and dilation. constituents, with decongestant the can ephedra, hypertension. like bronchial Looking 22 partial I would use, in one more for associated dilator this intermedia. uses as a nasal broncho narcolepsy has ephedra primary And a secondarily 12 the compared group MOFFITT / the effective various is In structure structures its sees the of the basic same. epinephrine to carbon The REPORTING ASSOCIATES (301) 390-5150 ephedrine skeleton difference 19 ct 1 being the 2 methyl 3 directly 4 ephedrine 5 the hydroxy group So it's group. on the and release I would pseudoephedrine and 8 activity except that 9 compound when it the 13 norepinephrine 14 not necessarily think I was 17 effect the 18 used 19 professor 20 Dysmenorrhea 21 condition, 22 sorry to the terms of do act primarily to emphasize induce its that the same spectrum is a weaker hypertensive effect uterine relieve on repeated allowed of and by you the can't and of can depletion the the health, reason ephedrine where color really does being Every people to I does is dysmenorrhea. red of use consequently slide lessen same effect. health, women's one unlike the have women's pain dosing So continuing will muscle the of stores. to can read. emphasize the the red. So I'm the alpha adrenergic muscles, and see that. Ephedrine 23 they we said, have because invited about to to mean you is extra a like pseudoephedrine from 16 and ephedrine effect In that act compound biological 15 the effect. Either 12 and surprising like comes CNS stimulant 11 chain norepinephrine. Now, the not pseudoephedrine 7 10 a side same receptors of 6 in 24 receptor in 25 increase the the also bladder, resistance MOFFITT stimulate small to the outflow of REPORTING ASSOCIATES (301) 390-5150 one urine does so this 20 ct 1 would 2 aneurin. the be good one category action the 9 epinephrine 10 mediated 11 activation by of norephedrine 14 and 15 this 16 pressure as well. 17 systemic razor 18 from will produce systolic peripheral a blood pressure and overdose diastolic Most 20 ephedrine 21 because 22 receptor 23 than epinephrine 24 both ephedrine 25 decongestants, its as a very of The lungs. but it's and is one rate resistance Elevate the both pulse stimulates the gets hypertens The compounds potent the so much pseudoephedrine and due to the branchial Beta effect and MOFFITT cardiac rise. effect. activation the the ion use. dilation especially activities vascular and the receptors. the importantly excessive Broncho beta they of and pressures restrictions or that stimulate the type ephedrine The release and this in us is. than the alpha of using but effective. in us male effects orally the of cardiovascular longer or those it is increase in as it output of from enough times both few for and 13 19 refrain of The alkaloid that the as epinephrine ten of and incontinence BPH and tough terms persists 12 I is same action 8 of for should it In the management experience one compounds; have the unfortunately, But, audience that of in adrenergic is to less pronounced sustain longer are alpha dilator useful as nasal adrenergic receptor REPORTING ASSOCIATES (301) 390-5150 21 ct 1 mediated razor constriction 3 material, let's 4 continued use 5 one 6 don't know 7 call rebound relies one of ephedrine is already important thing stimulate the eccubens area released it then us the the must binds us the And effect. use I said dopamine from As the the feeling I do not judiciously. system effect The earlier. related if aid, that it and with days nervous as brain. of as a medical central of three decongestants ephedrine release The adrenergic ephedrine compounds the nucleus dopamine Dl and of a well compound receptors contributes to and located our feeling another Now, product nasal active of gives than type is D2 receptors being and a high. 16 weight of this a rebound So one effect. terms give have many then more of decongestants too of use after can In which 18 say on nasal 8 9 continued However, 2 effect. appetite like in of also the also being. is with Hence suppression. the CNS which well CNS effect activates anuretic one has or also a that. as I said Now, 23 ephedrine and 24 1990s. In 25 because I haven't for ephedra terms of efficacy read MOFFITT earlier, too weight the loss I have many promotion was in of the a question clinical REPORTING ASSOCIATES (301) 390-5150 reports. early mark Of 22 1 the ones I could 2 is somewhere 3 to six 4 include 5 it 6 definitely 7 know. between months and the or effective four to ten pounds effective in the is it that effects suppressed the side effects of has the peripheral the more reason digress of said like they are bit for 23 of the 24 compounds 25 formulas make and effect a better MOFFITT to burn that perhaps the of one up the is a the like to strength As we amines. dextroamphetamine of also that's relative various will drug. and or it I would at pseudoephedrine way is caffeine and one which note is been central so forth. And methamphetamine have has is so on and and look it I don't medication, together. and CNS effect. It effect is alkaloids appetite agent put last actions. of wonder, But type two also one it ephedra kind to methamphetamine ephedrine diet. and DCNS stimulant synthesize the thermogenic a little the this thermogenic why from to triglycerides potent make two enuretic -- so, loss over studies how long has used clinical the it weight and some effect; I would 18 the Theoretically fats, 16 of diet, ephedrine had hold some of a restricted 8 9 get greater And, coincidentally, used as in then norephedrine weight all reduction another. REPORTING (301) ASSOCIATES 390-5150 the in of terms these 23 ct I would 1 2 methamphetamine 3 in 4 primarily 5 to 6 '50s 7 was overweight, 8 but a lot 9 ate just 10 the like and 1950s appetite point out that amphetamine was really '60s and as to to as an anoretic appetite '60s and I was of us like develop but very a student at that us did take also not lose weight, Not as before. 12 obtained 13 1980s 14 Again, 15 opinion, 16 work act In the a lot of us amphetamine a lot names of us or that. from ephedra as weight the they tolerance the naming And phenylpropanolamine 11 the time, of did and quickly. so a lot as well anything agent suppression suppression prescribed and reduction effectiveness because is it's been with or come after three in another used compound since without caffeine. a question, months of the in use my they may not anymore. In 17 18 formulation 19 scientific 20 anoretic 21 peripheral 22 work. 23 of 24 adverse 25 system terms the base of theoretical because effect, combination events events the and of ephedrine has effect has so the I would like to product also have of and CNS and it MOFFITT caffeine mechanism caffeine whereas, thermogenic However ephedrine other may have action the the central greater combination point out anemic should that potentially been have this a lot peripheral synergistic REPORTING ASSOCIATES (301) 390-5150 CNS type of 24 1 stimulation between the There's and various of within 7 product, 8 you 9 than herbal get two the 11 inclusion what and also is the 14 index 15 adverse 16 mild, 17 one 18 though 19 have 20 flushing, 21 on and 22 of 23 ephedrine, 24 So there is the this this I didn't take this or not, but profile ephedrine You draw principal times your like my heart will idiosyncratic own this and one and be pumping can reaction have are or whatnot now even morning; one can palpitation, urinary to therapeutic conditions skin retention, I can't I take event take pseudoephedrine a mile is a minute. hypertension. REPORTING ASSOCIATES (301) 390-5150 so decongestion reactions. severe MOFFITT does I am having Personally If the dizziness, tremors product. the 60 milligram ephedrine tingling, adverse adverse 30, insomnia, The most the the even whether different of the dosages nervousness are another available two of have of of still particularly Most so forth. variation know the At low. headaches, that means. particularly can alkaloids things to different. events events. product a total CNS stimulation very the a great contents quite of of 1 don't is One has Adverse 12 is -- content one one ecstasy, other are us there from lots. alkaloids 13 and same product 10 25 that alkaloids the on the products me was content 6 a study diet intrigued two. or 25 ct 1 That is 2 prolonged 3 and 4 these 5 the the most important Arrhythmia use. in the case events in concomitant caffeine dump on and and of tachycardia our opinion used the Now, 10 drug 11 stimulant. 12 cardiacthycal 13 be taking 14 agents 15 totally ephedrine ephedra, Of course like this or it kind among of amino in Now, 17 couple 18 are 19 sympathomimetic 20 as decongestants. 21 reduction 22 mark 23 convince 24 does work; people 25 loss worth it. for and can be very agents I keep agent, because I have me in to terms of have MOFFITT of the lost to others make ephedrine a alkaloids short-term in bronchial asthma as a weight that more not thing. like effectiveness see should among sort and saying this on sympathomimetic particularly The of a CNS patients useful so coadministered I would Ephedra or event. inhibitors conclusion, observations. useful be not that you ephedrine people oxidase like then It's heart stuff, contraindicated 16 should with interactions a drug. digitalis drugs an adverse drug is results be associated with or death particularly have potential also other along One can so forth. to and dose potentially of antihistamine, by high tachycardia and phenylpropanolamine 9 caused administration and in event it's clinical risk a few to a question papers benefit pounds, REPORTING AsSOCIATES (301) 390-5150 to ratio. but is It that 26 ct In 1 2 manifested or terms of as I said prolonged use from or the use 6 Thank or very both of much this for product your 8 DR. JONES: Thank you Dr. 9 Let me turn first to panel questions for Dr. 11 [No response.] 12 DR. 13 have 14 you 15 question, would if you Fong Dr. brevity is the should of Yes sir. proceed. please is as street drugs. Fong. members, the to there a microphone if you the If floor. are microphones. and ask wit you If your for all Identify of us. yourself record. Jeffrey MR. REINHART: Pure me turn to would 18 19 Let proceed Please 16 17 for recommend Fong. JONES: questions be attention. [Applause.] have can sensitivity do not 7 10 it individual I absolutely production you reactions overdose. One thing 4 5 mild/severe Reinhart, People for Foods. Dr. 20 21 stereo 22 phenylpropanolamine Fang , would specificity DR. 23 24 you know 25 doesn't comment difference and FONG: how to work you the way MOFFITT clarify on the between the This do these or plan of high-tech things. I want it to ephedrine? stuff is good Some of it just work. REPORTING A.SS~OCIATES (301) 390-5150 if 27 ct Phenylpropanolamine The is and phenylpropanolamine stereo Is chemistry. is with that what I was has you are asking the same asking? the racemic My understanding used mixture racemic okay. about phenylpropanolamine. phenylpropanolamine plus/minus ephedrine, ephedrine that MR. REINHART: situation low in commerce whereas in is the plant it is And you think that minus. DR. 10 a tremendous difference given elucidated, DR. 14 particular 15 able 16 norephenephrine 17 But, 18 activity 19 and 20 of to you the one know, in not 23 things cardiac look at over minus? the of the adverse I am not just I have can MOFFITT least to be minus that of CNS stimulation and great in terms whatnot. phenylpropanolamine not of difference that effect comment the the be not period a colleague this answer between that cautioning you the at phenylpropanolamine. saying a prolonged be can't have is will to I really difference at effect? needs I don't the is issue. racemic effect I'm safe. Jerry, 24 time my conviction terms it sorry, the or Now, is 25 I think I'm FONG: in pharmacological thalidomide differentiate 21 22 the moment okay. in MR. REINHART: 11 12 Yeah, FONG: to time on the who used to use or those overdose. racemic versus be a professor REPORTING ASSOCIATES (301) 390-5150 28 ct 1 then he decided to 3 from Nature 4 company. 5 So look 6 in 7 different 8 bonds 9 we call the are Sunshine See if at there structure of erythrol, going that off in if different we put pseudoephedrine have different at makes one 18 Nor the means up with about the the doesn't 24 guys; go one of methyl just make of in those are the out, one and way, of see T or they is the gone the over Harry puts here. compounds; It actually the also we end talked another methyl So we end up with and plant makes structure REPORTING ASSQCIATES 390-5150 (301) by here. So, the so look structure all these okay. MOFFITT go other if Okay? gone. compound. one ephedrine it's which these So I think what same a line. three make substitutions in Remember, ephedrine all these atoms we can series complicate methylephedrines mixture one isomers servers. of switch actually going you off, nor carbon Now, of we go. Okay. can the here Okay? carbons we further methyl structure 23 them possible that the huge 25 four Now, that. taking the directions. Now, that -- all here, ephedrine both is, an herb asymmetric we just So the Okay. around. two in McLaughl it's work ephedrine. if Jerry now will are structures direction in products, my pointer here, I'm Yes, DR. MCLAUGHLIN: 2 16 go make money. of on a 29 which phenylpropanolamine but structure, in here without giving carbon, you so you right; only at phenylpropanolamine 8 of 9 it's 10 the materials probably plant DR. floor or to the 14 DR. JONES: 15 DR. BRAY: Baton 17 of 18 studies 19 would 20 clinically 21 Rouge, that Yes, of -- plant because either from there the a statistically why you 23 I thought 24 executed FONG: MOFFITT of the trial. about as nicely Okay. in That problem Denmark combination question for Bray and so many ask the from you could in published 22 was George has double-blind trial I'm caffeine is put morning, ephedrine placebo, DR. does the randomized, as you a mixture probably interested effect 25 .:i good Astrup, that that what have the in none. significant comment all compounds does questions Louisiana, Arne suggest isomers sure mimic one materials. Seeing My reading weight. it it of of panel? [No response.] from mixture really if Other 13 16 not somewhat a mixture JONES: from but chemistries potential synthetic going makes 11 12 being -- stereo more four So I'm is; this a racemic least phenylpropanolamine. 7 the potentially know, have essentially defining us not but, is in his I wondered if marks because designed a clinical trial. study you're that and REPORTING ASSOCIATES (301) 390-5150 ,,. ,., 30 talking about, personal yes, a valid 4 be total 5 of 6 the 7 statistics 8 whether 9 long 10 and 11 events weight mark study that you're talking question was loss weight 33.5 question My only study. body the The thing. 3 I have was lost kilo as compared the is does five or six over prolonged 14 in 15 meeting 16 my position 17 medication 18 status. 19 professor in 20 an agent that 21 three, 22 index 23 the 25 the five and But at taken the on the of just a member ago ephedra not a low I like least statistical 10 to see 1, JONES: Further of adverse that for the those of are ephedrine from index of the with regulatory and that of questions? REPORTING ASSOCIATES (301) 390-5150 as a using two to therapeutic my question study. and good as a pharmacist is you FDA ad hoc and an agent in nest aspect this how Okay? [No response.] MOFFITT is maintained; I questioned significance DR. mark on regulatory hand is isn't a hornet's therapeutic to Now in there into of pharmacochemistry has risk be banned other and time. getting years kilogram group mark is that placebo. off worth it's should usually of I'm even was seven My question is I was about the about I think be placebo periods But audience, to weight. pounds So I know 24 to weight discussion. or My question reduce patients five as compared significance. it this about that as a mark not 31 ct DR. 1 2 concluded on time. 3 have the 4 for 5 scheduled 6 chance 7 to done us for to pick the note Fong Dr. impossible it and I would day. for a 15-minute get acquainted up the lunch hear from our 10 evening reports 11 as they appear 12 available. in Thank 13 14 will see 15 time at you panel the in lo:05 send this that you background now we're will lay give of you the a facility, everything. after the will and docket that much break look the at FDA has for we will adverse clinical your We will 15 minutes. Thank we are a nice It that very a.m. out the that appear laid database the you does with map and first then break. When we come back 8 9 I would JONES: studies made attention. We be starting on you. 16 17 [Brief 18 DR. JONES: Dr. Julie Bietz, Dr. Ray Woosley, and Cynthia 19 Ricaurte, 20 your 21 clinical agenda with studies DR. 22 recess this at discussion and LOVE: guests, 24 ephedrine alkaloid 25 including new of adverse Dr. morning 23 9:45 Jones, dietary in FDA's Dr. George Culmo, database shown in and Thank reports. panel present containing MOFFITT the event I will information a.m] members, an overview you. and on the supplements recent REPORTING ASSOCIATES (301) 390-5150 assessment of 32 ct 1 the public 2 ephedrine health The are associated alkaloid-containing 3 4 risk available 5 documents publicly in can safety of see from about the 7 long time. We first became a we received a report of 9 been 10 for purposes, 12 this report, 13 there were 14 with. 15 is 16 which 17 very potent 18 just explain of to Ingredients a Chinese were refer for to for all Besides 19 in were 21 literature 22 the 23 databases to 24 with same product 25 contained this thing this that see if MOFFITT among because man who had significance the of products we were for and unfamiliar which we now know contains alkaloids alkaloids means, he took, that Dr. as are Fong has us. aware raised we did there or ingredient a enhancement that we reviewed also issue a young the in products, which back purposes. as ephedrine of FDA concerns this for ephedra becoming 20 other these in ma huang, sympathomimetic 0091200. goes of ingredients like name of assessment slide, aware evaluate that whose this supplements products we noted use No. enhancement trying ones the a death athletic In 11 dietary a number from FDA docket 6 using the products. complete As you with our was these the level to scientific of look ingredients conce~rn; in and available were other adverse events with other products that and we found cases REPORTING ASSOCIATES (301) 390-5150 of these. ct 33 1 So in 1993, I'm 2 not 1993 concerns about 4 we held a formal 5 examined the 6 we had received 7 was the a which 9 hazard. of alkaloid to of a number 12 the data 13 public 14 working group of scientific 15 working group to our 16 the 17 in ia available 19 virtual 20 still today 21 types products. are meeting 22 public And at of that And it 23 working group that 24 dietary supplements 25 contain ephedrine containing where we have on these. the they known alkaloids that members' to the that was the we have almost safe contain may cause at of or and use feeling of a I think these this certain suspected consumers REPORTING ASSOCIATES (301) 390-5150 is all time use as a which evaluated that we had served Committee at agreed discussed ad hoc committee indicate we have 1995 a special really information MOFFITT In we really There was health meetings Advisory This combination morning, experts which events. this time would adverse 1994 that for mentioned information. absence of advisory this board a significant Food scientific In product we convened this. its evaluation number available where use products. a particular represent had that these caffeine Jones how to indicated hazard 11 FDA. of a large As Dr. general FDA first health felt I know safety safety ephedrine 10 if was when 3 was sure to to a 34 experience serious In 2 3 new 4 adverse 5 levels 6 milligram 7 members a Committee 9 but events and that the working opinion 11 could 12 with and on, attempt these Over 14 stated that, 15 levels of 16 use 17 recommended ia Other 19 that 20 reduce 21 establishing 22 use 23 as well based proposed 25 by certain Food the Advisory reviewed specific public Food on the all their ways health of of the that FDA concerns of for be identified products safes, ephedrine per for they from Committee conditions events members no safe consequently Advisory adverse both as other rule these Food reasonable Committee data, could and establish risk Advisory available alkaloid removal Out 24 for supplements agency levels the they of that and provided the the ephedrine members the full again, And, address below The group. number indicating suggested information half dietary the been of products. 13 in had because an increasing were a rationale to 1996, analyses convened. data in included alkaloids limits was year, product ephedrine of events. following which available 10 25 the information of adverse of use the market. suggested that including serving, alkaloids and and these public in 1997, June MOFFITT meetings 4th, 1997, came FDA's and REPORTING ASSOCIATES (301) 390-5150 daily ephedrine requirements. of would this 35 ct 1 proposed 2 limitation 3 of 4 certain rule had a number on the ephedrine does per warning 6 information were 7 were in a information 9 alkaloids, placed about the sources the morning, 11 pharmacological 12 finally the adverse 13 derived both from 14 adverse event about 17 alkaloid-containing ia Fang , there 19 they are 20 the direct 21 both 22 and 23 heard today? are 24 talking 25 are of This of use. other meetings and included ephedrine as you heard and alkaloids ephedrine scientific the and alkaloids literature products are a wide as as well primarily use for about talking any of about MOFFITT of as these that dietary for use and under are drugs but products supplements cough You have as asthma. of Dr. these, allergy, REPORTING ASSOCIATES 390-5150 (301) from there alternative, type ephedrine conditions OTCs mainly drug talking heard practitioner as well street variety respiratory and the we are medicines health-care preparations, that As you've traditional prescriptions only and alkaloids, products. are about required public ephedrine effects There 16 of a milligrams reporting. What 15 data these the a conditions physiological effects the of it containing of known this and docket. products 10 cold public than and amounts at including less serving presented our was statements Considerable 5 features which alkaloid label of we're today. that not We contain 36 ct n 1 ephedrine alkaloids. These 2 3 products Almost States. the They ingredients. stimulants well all and 9 10 for are include four lung This 11 12 variety of 13 somewhere 14 that 15 groups 16 bodybuilding products. for weight The 17 ia ephedra 19 botanical 20 seta cordifolia, 21 that extracts 22 of 23 synthetic 25 Dr. Fong We estimate that 400 and and which may cetera. are types again energy wider there different and of or Ma Huang are ephedrine also pinoyella; from they and of products fall into ergogenic botanicals and of a these ephedra, MOFFITT as Dr. alkaloid Fong alkaloids are can said, These possible. however, alkaloids, sources are fitness the market The major 24 are showing et as products. sources ephedrine energy, category sources species they a picture loss type yohimbine cetera. we see and United other other 3 and now on the with of just between are loss purposes is et the multiple Sometimes that a general in combined minerals, weight and bodybuilding, usually uses sold contain caffeine. The primary marketed widely products are including as vitamins are it is listed finally but other include most common as the there be can source be alkaloids. as you pseudoephedrine, have heard norephedrine, REPORTING ASSOCIATES (301) 390-5150 from 37 ct norpseudoephedrine 1 methylephedrine, 2 methylpseudoephedrine. 3 nature 4 nature. in you don't The sources 5 6 wide 7 practice. a medicine 9 In variety of been 11 ever-growing 12 research 13 surveillance. 14 containing 15 reporting. see Dr. been used at least in And area in ephedrine 16 Along with types of the different ia preclinical 19 give 20 observational, 21 And 22 standard. 23 the 24 usually has only 25 usually for a relatively are case of dietary of of trials But have these are is and several hundred short there in vitro and to clinical been are the information usually on voluntary animal the trials. gold probably A well-controlled infrequent. a supplements include of have evidence and kind use. postmarketing These epidemiological, MOFFITT .a type of based is sources a traditional is there usually a mechanistic clinical most There this in from alkaloids and evidence. which in literature alkaloids 17 us the salts centuries now. in medical that five scientific the or from state occurs come ephedrine 75 years medical done come Fong the what information a these medicine are mixtures our They areas. there's L forms racemic of You heard allopathic 10 The and are usually clinical patients duration. in trial it, and So the is most REPORTING ASS,OCgATES (301) 390-5150 ” _ . __,. 1. _. .. c. ,. ._ 38 ct information that occur in event monitoring case the we learned postmarketing period which would where adverse events we use adverse be considered a type of reports. And 6 detect 7 at a patients to 9 clinical trials just for a relatively 1 percent have subjects As Dr. of amphetamine-like and 16 cardiovascular 17 depend la the the any of mentioned the nervous alkaloid most part do not a lot about These amines, I've The them. The already the are they primarily system. and 500 literature we know they to that. alkaloids. effects, to occurring three published for trial one least detect sympathomimetic and event, at the ephedrine indirect upon in Fong characteristics direct in alkaloids many adverse reliably are a clinical e, require to that 11 this would be able now on ephedrine an examp common rate 10 14 on possible have affect exact the effects talked about L forms. The pharmacology 19 spoke about, mechanism 20 also 21 review. 22 basal 23 increased contractility, increased 24 increased stroke central 25 stimulation, In the but and I am just cardiovascular constriction and and volume, other MOFFITT cardiac effects of action going to quickly system it can stimulation, heart nervous including REPORTING ASSOCIATES (301) 390-5150 cause including rate, system and he ct 39 1 bronchodilation 2 muscle and and various From adverse these So the and in angina, and 10 we see cardiac cerebral associated and system and vascular of the affect nervous we have the ephedrine we see system hypertension, infarction events most with that cardiovascular ischemia smooth derived effects cardiovascular and glands. effects adverse the the and known that predominantly on skeletal organs effects alkaloids. effects cardiomyopathy including hemorrhage any infarction. 11 In 12 stimulant 13 seizures 14 be abuse, myopathies, 17 effects ia and nervous effects and 15 16 the system as well I have abuse dependence, and And there uropathies, on the GI dermatologic 19 20 do we evaluate 21 no different 22 considerations 23 pattern 24 ingredients. 25 supplements here psychosis but it should just addiction. have including system, and central been reports urinary including of retention, vascular effects reactions. This of as mania drug finally we have slide is dietary than use and products including the type The population includes MOFFITT just supplements? other for use, a reminder both the in And what it that we look the population, of products for these general is context really at. The the and dietary population REPORTING ASSOCIATES (301) 390-5150 but 40 special subpopulations. 2 amount, frequency, 3 conditions 4 hard, 5 cetera, 6 ingredients, 7 have of 10 and use physical in finally These known stimulants 11 it include as particular may be used, including restriction, the type of are sympathomimetic the et products and amines that they are often which combined can cause with other an interactive affect. This 12 what we know 13 know in 14 ephedra 15 health-care 16 for 17 with 18 defined 19 combinations 20 use 21 supplements 22 dietary 23 they 24 previously 25 bodybuilding; is just to again traditionally dietary was only practitioner short are term. products The supplements; the different used, the the they the current use of is weight were duration selects the had loss, of are products; been energy, the REFORTING ASSOCIATES (301) 390-5150 I the dietary these than very than that selects herbs different and purposes manufacturer predominantly of today, consumer including MOFFITT used are U.S. we with formulation that used in It selected combinations that for the what Historically prescribed, disorders; contrast to a medicine. practitioner herbal and ephedra today. considered health-care compare about supplements respiratory used use as well caloric ingredients synergistic very which of effects. Further or duration, exercise, and 8 9 The pattern ingredients 41 1 and the 2 different 3 finally 4 prolonged. combinations than the what to 6 little evolution 7 actually did 8 for proposed 9 have this heard 10 criticisms 11 heard data what that for its "FDA based and And proposed events 15 contain ephedrine 16 from 17 ephedra alkaloids 19 FDA's 20 However," and 21 about strength 22 to 23 level the support and aspects the duration not performed this, a causal MOFFITT of There were many data; but, what FDA's use want to products also impacts types steps their of to Besides 24 and there's all indicating and consideration that sure It adversely The number the the of to use they analysis you of to evidence that ingestion of individuals. warranted safety issue. "we have information proposed the for used address the you isn't thought errors 'however' some of of of data reports some GAO of quote on numerous alkaloids. rule, of I just literature use be on our proposed support with can we were our the rule associated scientific the I'm did but where from of again ; and, undefined said. use are previously to And been the which evaluated rule. reason. its is us back GAO really adverse 25 use used used safety, has 14 18 of a study about is been get of are had duration Just 5 that rule, concerns FDA used the dosing limits.1' also indicated of individual REPORTING ASSOCIATES (301) 390-5150 that we had adverse ct 42 1 events; 2 and 3 event that that many we did should 4 of not the have criticisms. 6 meeting 7 happened a number 9 taken and since of the want efforts use; Certain concerning 10 for 11 scientific literature 12 products; FDA has 13 expert 14 questions with 15 GAO; and, finally, 16 evaluation 17 adverse events. And 18 experts reviews besides there have In 19 20 are many more 21 effects of 22 frame. And 23 some 24 pseudoephedrine 25 patterns cases that been states and dosage the deficiencies a continuing by receipt and reported we have sought outside review. literature there monographs on the available information emerging these outside some of in-house alkaloids. MOFFITT of voluntarily of medical safety a number alkaloids effects the on the abstracts, have instructions in answer a industries and scientific the public have too the this There had these are of rule. or articles, injury point considered medical or these has to we have the which what impact were time heard new articles spontaneous this determine about commissioned ephedrine to of been reviews the talk the that scientific of the to proposed efforts. to we have now to we really documentation; serious. me, So we are lacked criteria be considered And believe 5 cases dietary We are besides in is this specific supplements seeing in or that cardiovascular REPORTING ASSOCIATES (301) 390-5150 time other ct 43 1 and nervous 2 there is 3 mechanisms. system information 4 these been of that 6 potential 7 may be direct a system have of 9 last two interest these as well use of There have 10 clinical 11 first 12 controlled 13 point of hemorrhagic 14 very large study 15 increased 16 weight 17 will ia issues these is study the stroke be the subject of In 20 area, 21 abstract 22 randomized, 23 a ma huang 24 Sixty-seven 25 In in from that been put to people trial of in MOFFITT which The was 49 looking And a case- at this was the was a for an FDA docket to end any used dietary and address the supplement was publication Luke's of an on a double-blind, 8-week containing-product indicated there alkaloids. there botanical St. were that published meeting placebo-controlled guarana abuse PPA. FASEB there Columbia things nervous products a public ephedra in of central PPA. in specific the 1999, in showed has 19 18 to particularly are the PPA study persons This the suggestion a number Yale that of products. been loss. that thought on ephedrine of risk, one the in investigations of bullets, as the these And pathogenic is neurotoxicity from effects. on potential For 5 this stimulant-related efficacy in only while appeared REPORTING ASSOCIATES (301) 390-5150 of obesity. randomized, there trial 48 completed. to be some ct 44 efficacy there also hypertension and 3 And, 4 2000 have 5 randomized, 6 effect 7 salicin 8 controls. palpitations finally, of 11 these published of outside with and of trial of synepherin 30 test we had caffeine subjects and commissioned clinical looked One of at the properties botanical ephedra 30 a number reviews. that in in versus alkaloids. The question sources has 16 botanical 17 problems that the 18 Enchiosa was able to 19 publications that have 20 pharmacokinetics 21 supplement 22 differences 23 botanical sources 24 synthetic products. 25 only al, double-blind, pharmacodynamics toxicities et. eight-week Enchiosa, pharmacokinetics, 15 another that scientific was by Dr. ephedrine Calman, an ephedrine, but including seen. a study obesity product, relative effects recently I mentioned 10 adverse placebo-controlled in 9 14 were are as potent synthetic sources product look, or was MOFFITT or because addressed that of the there properties dietary a study that somehow don't cause cause. number issue of really when are Quib of new of dietary no compare supplements by Dr. the directly the you the And Dr. the pharmacodynamics is these There been not and in always sources Ray, REPORTING ASSOCIATES (301) 390-5150 to looking at ct 45 1 the 2 and, 3 health-care 4 the use of ephedra again, it was purposes of assessment of 7 events dietary 8 alkaloids. 9 that and the reporting were rate 11 interim 14 the 15 alkaloids containing 16 a fairly cons istent 17 proportion 18 supplements 19 with events. events, his dietary have been 23 alkaloids 24 is 25 calculated just than 1 percent. look at day, this the all We have had a 40 percent events at are ephedrine supplements. those continued these are about is the FDA has these to was in that dietary are associated alkaloids. is from number you adverse and by report adverse due of ephedrine time proportion our This the this If dietary for an conclusion less supplements, all ephedrine the far is a used we had containing review of under not rates much underreported cumulative 20 reporting adverse of Walker very 13 term energy. this the medicine; but, from to other short and by Dr. likely 12 receive loss was probably In 22 used supplements And these Chinese practice, finally, 6 differently, commonly weight And, 21 traditional practitioner's 5 10 in of looking 1997 adverse containing to the events dietary data current reported bit time, you for supplement through the first part this out based on receipt MOFFITT little of can see ephedrine year August, today REPORTING ASSOCIATES (301) 390-5150 2000. but this if It you number ct 46 1 would be somewhere receive serious here. adverse What's Well, in what documentation, et 6 have concerted 7 documentation 8 investigations 9 the made very 10 labeling, 11 number used the Center for 14 our colleagues 15 Research, 16 include 17 Stolle. in and Dr. 19 What these cases 21 a time 22 typo 23 we published 24 a 22-month 25 actually the frame, there, the period look Dr. will at for of hear Which is proposed MOFFITT and very so the cut These to about So we picked the we took have Dr. morning. different 1997, off and this them. and we would and Ricaurte lst, in from Evaluation was close a staff Nutrition, this, we study June performed review Dr. what product experts. some of how including outside say FDA about we have Drug rule. so that better records, and Applied we picked these then the so we additional medical Benowitz, is get information research how should and 07. us Center we did and to about events, evaluations Safety Woosley, And you adverse And by a number 18 these product, clinical Food to events? said including clinical the have give labeling. adverse others cases the continuing these efforts can in-depth for 20 of on these and in-house cetera that of about GAO and 5 we are events. different we heard consumer So, time I have time that it through to was March REPORTING ASSOCIATES (301) 390-5150 a 31st, 47 1999, with 2 in-house 3 takes 4 be able 5 information any by follow-up the end us anywhere to investigate reported in 8 evaluated 9 clinical were this from 10 adverse 11 using three to six these adverse for least 140 on at amount months events 143 longer and to to get outcome, events consumers and product use, information, of it or adverse least diagnoses, events, Typically evaluation. demographic course, be received 1999. at time could December we need There 7 of from that 6 that classification documentation, and we of reason for Of the 140 product. 12 This is our 13 reports 14 These were cases of 15 cases where the event 16 an adverse 17 product 18 drug. 19 relationship 20 confounding cut we considered event, with In one that and by the 22 as I stated, 23 supporting 24 that had 25 They were and of was was then in one MOFFITT case product we did these information the signs if it and it was there was which was the a into make symptoms REPORTING ASSOCIATES (301) 390-5150 GBL. evaluation not including to was temporal an in-depth relationship insufficient 48 where or tell an incorrect screened a causal patients, we decided supplement cases unevaluable. we couldn't co-ingested The other 21 were reported where there there reports. unidentified being dietary case eight multiple cases the on these those assessments. were not not 48 consistent with ephedrine 2 cases 3 impossible to 4 alkaloids, there 5 were 6 or 7 two. where too cases 8 9 so many products ascribe many of were other 10 attribution 11 and 12 of 13 was we used scheme these we've difference between 15 causality? Well, 16 some link 17 from 1965, 18 association 19 automatically, 20 association, 21 specificity 22 biological 23 experiment, Cases or that attributable been asked was there there 11; were population. structured we could into it factors, our a formal that where abuse, of nine ephedrine complicating look and and I'm is nine which means at them supporting the the and and this that's It the quote association, is doesn't the is really from Dr. Hill whether mean causation of the association, the temporality, plausibility, the or as to strength of what there viewpoints consistency gradient, schemes using times attribution means causation. and of and association there many association the coherence, analogy. I should such used were relationship. 14 25 cases. 55 percent analysis Now, 24 effects misuse 45 percent a causal the two intentional we divided been of or there had any confounding So this The alkaloids; mention also there's MOFFITT really that there are no consensus or REPORTING ASSOCIATES 390-5150 (301) _, “,,., _. .^ / , i x _ many no gold ct 49 1 standards event on what monitoring voluntary This analysis, if event and 9 attribution temporal use the adverse had been care 10 evidence of 11 when product 12 -- 13 took there the the attribution event. the for the to adverse professional there consumer discontinued, and came back between We wanted whether i.e., ad symptoms clinical for sought adverse reports, relationship event, dechallenge, for with was health-care adverse was use spontaneous though, the of signs we did and to associated we checked whether the schema for that what medical 8 best its or is products know the whether reports, trials. the is when if the was got the better symptoms person again product. How the 14 or was product 15 direction 16 other 17 What 18 products; were 19 were they bodybuilding 20 Were the 21 likely 22 looking 23 finally, 24 of 25 known products was it used, used the at reason they ephedrine time they weight of the were loss, event physiological MOFFITT or or or likely event? these products, they or others? use event? This a more is explanations, the known extensions pharmacological Were product with per adverse were alternates consistent alkaloids the energy or used abused? using adverse or Was it or of products alternatives the the conditions explanation is misused that underlying at was used. effects REPORTING ASSOCIATES (301) 390-5150 of and affects the of cn 1 ephedrine alkaloids. 2 This 3 structured 4 as well 5 these 6 full 7 reported a of 9 energy product. 10 events being 11 in previous was data the our 12 13 64 percent 14 of age; 15 or younger. 16 that Although range of the injured all men; that most 19 according of and most 21 majority 22 temporally impacted consumers to the the reported directions looking of use first time MOFFITT i since the more loss and adverse than we saw that _,. ‘, at duration it ranged of use 39 years were event, they use label the and related of the of from 19 we noted product labeling practitioner temporally use adults; characteristics on the the young adverse to on the .-_,. on the related even are persons consumer were 25 events under injured them duration from percent were of wide is more persons saw a health-care 24 seen mostly them In And weight 39.8 of 23 case. this is When we evaluated ia the again 16 percent may have docket serious. age that the be expected we are for The 17 and adverse could a very in on each more we see with available we see Overall reported and is that women which products as I said, results results series. for which individual the case done, form as the are all and the closely product. use there under on up to was one very a day, or chronic REPORTING ASSOCIATES (301) 390-5150 . / ._ <_ / . . ), <. ., i v. I, ct 51 1 use, 2 associated 3 than 4 longer-term and you see with or the spread; short-term equal to one use week 30 percent which meaning we defined that are as 70 percent less were use. When we looked 5 6 documentation 7 reported by consumers. a the of 9 about flow that of them 11 predominantly health-care 12 a third 13 36 percent overall 14 In at 15 over 16 including 17 of label are of 18 as we've 20 serious 21 also class 22 that we couldn't 23 overwhelming 24 this 25 And adverse fact if the the you center, our records and you know, So, which are and approximately professionals. we have evaluated, additional many just reporting, that of at are field health-care some kind look Medwatch center. cases events of information them had copies labeling. done classified previously nervous into system, them new case the from We clinically 19 of professionals to has and in of come through come directly medical a lot come through a third all amounts come into investigators, 50 percent the And 10 looking at we have, how they a third this approximate and according tell serious other to not as being majority of adverse series were four probably reflects MOFFITT the adverse cardiovascular, adverse events. serious or unclear. a bias in in We cases The events serious events that adverse reporting REPORTING ASSOCIATES (301) 390-5150 we saw events. more in ct 1 serious adverse 2 events Cardiovascular 3 myocardial infarction, 4 and hypertension. 5 slide 6 the 7 events 8 supporting severe that total data And in showing the slide, what I'm calling the both groups would attribution; to The serious reported as an adverse that or had insufficient system effects included and addiction assess. nervous depression, adverse attributable group further first between be attributable the be able the differences cardiovascular included dysrhythmias this serious i events stroke, for psychoses, event and was seen was also across all of groups. Other serious cardiovascular or gastritis, 18 adverse ischemia, seizure, these serious. group and to less system I am just supporting 16 than nervous hepatitis, nephrogenic factors could things products for 23 could 24 for 25 bodybuilding evaluated impact on the we noticed is different loss system that included weren't neuropathies, and a case of insipidus. be expected, weight events rebnomyallises, diabetes We also first adverse whether certain product adverse event. One of that reported but and the men and women uses. many more men use of it And the for fitness REPORTING ASSOCIATES (301) 390-5150 the the I think women use purposes. MOFFITT use use this it ct 53 However, 1 2 of 3 a different 4 many 5 mean you adverse when events by gender pattern more you based 6 more And if you serious adverse a looking at the weight 9 similar to what you 10 cardiovascular 11 involved. 12 high proportion 13 It loss see in fitness possibly 15 on a cardiovascular adverse 16 least of 17 events reports that were In ia associated 19 information, 20 cases, looked 21 on the product 22 contained information 23 including the 24 of 25 Many them we in at stated the the but it's in have in of a very facts. exercise besides also impacted that we had at label and labeling, exercise. all of and supporting that and use the was all the of other available these product durations. precautionary consumers at adverse strenuous interminable or at very cardiovascular and in the you in frequency have by use, really that events looking that whereas looking group on how to you this, this information MOFFITT women type the actions In events. group with warnings there's predominantly all dose contained is serious to that men, women, with addition note adverse strenuous 14 seven the system that involved in what nervous appeared being in classification events, category is the the subset just system of also system further events But you adverse nervous 7 at on gender. cardiovascular have look Almost all statements. should REPORTING ASSOCIATES (301) 390-5150 take in ct 54 1 the event 2 ingredient 3 these 4 them. of an adverse products. had could of evaluate a related 9 a very and proportion of that 11 contributed to 12 containing the from 15 the 16 dechallenge. 17 was And product In of 19 the 20 these consumers 21 other medications 22 a dietary 23 alkaloids. of the in looked are at where we temporally a criteria, there is event of of stimulants subset them them was the adverse of and in health-care caused or ephedrine at alkaloid at supplement health MOFFITT for weight consumers indicating loss improve when positive proportion of them there rechallenge. other you used were the smaller positive event, underlying these all much Furthermore, of majority course, discontinued Looking 24 of of almost was evidence 18 of use The majority purposes. in adverse the multi- products. 13 14 were we specifically all was, attribution all sources association that 10 25 other that that; because high and I said likelihood and The overwhelming caffeine Again the event, alternative know, other the a very dietary same time product many explanations high containing of conditions. them proportion supplements that for of and they were using ephedrine had certain However, REPORTING ASSOCIATES (301) 390-5150 it types was the 55 1 opinion 2 factors, 3 medication use 4 not a more likely 5 And the 6 alkaloids 7 contributed of the 11 extension 12 we had the concerning the previous rate to of and alkaloids and, consumers are FDA believes and use 23 alkaloids 24 concern, 25 along of dietary continues in to in evaluations known of ephedrine public a listening and if products. containing be a serious FDA These be anticipated current of MOFFITT actions that all our the these here current and events. from again agreement. alkaloids, be using we are And literature the the likely scientific should but with the adverse supplements the were was or cases. activity. pharmacological to these summarize, be predicted going caused consistent ephedrine therefore, event. whether there the from can physiological where with effects events all and/or briefly information adverse have we evaluated were was ephedrine in pharmacological consistent adverse to alkaloids high condition the event other other containing symptoms their a very are of adverse ephedrine these health clinically finally, So just data underlying thought and of 13 the that supplements supplements signs of dietary explanation to observed reviewers of or And, effects 18 usr were 10 16 clinical dietary 8 9 the availability ephedrine health mode. presentations REPORTING ASSOCIATES (301) 390-5150 All at ct 56 1 public meetings 2 any information 3 our evaluation hoping we have that and we hear been could very open in be available assessment some today, of to safety. thank soliciting impact on And we're you. [Applause.] DR. 7 guests, this 8 adverse event 9 dietary supplements. 10 11 Jones, I will reports present for JONES: F the I'm sorry? 13 DR. JONES: Give your record, for Risk I'm and Julie, of containing please recorded BIETZ: with name -- just for the record. Oh, certainly. FDA CEDER, My name Office of is Julie Postmarketing Drug Assessment. 18 I will 19 events 20 postmarketing 21 and 22 available 23 1200. the 24 25 the DR. 17 alkaloid record, BIETZ: Bietz, members an analysis ephedrine DR. 16 panel yourself. 15 . morning DR. identify Dr. 12 14 " BIETZ: that present were conducted drug complete for risk review public for review; MOFFITT of by CEDER's assessments document inspection CFSAN provided materials an analysis our adverse office this that under office event the past adverse of February we prepared Docket with reports the No. is OON following that were REPORTING ASSOCIATES (301) 390-5150 k ct 57 received by CFSAN on 139 through March extensive information was made available tabulations 8 received 9 tabulations 10 only 11 139 from cases 18 use attributed to possible to There not several could event. In ascertain six were be identified. was 35 years with age a range for the by the may have cases it reports was of cases disease, named This MOFFITT that left of of and but these six had been that were in two reports consumer cases. 108 days not events no unique 108 focus Thirty-one confounded Three by an underlying individuals will review consumer but above-mentioned an EADS product evaluable. The median 24 information, cases. nine whether they These presentation were products that 1999. 139 other summary reports. further 11 cases the were the review. us with The the of from of readily confounded of our reports these additional this for November among review concurrent were 25 remainder reasons: used. 23 The excluded following us information. included were obtain some demographic are clinical to 1997 CFSAN conducted and event through clinical 12 cases, adverse included cases to these of heard CFSAN provided 1,176 1990 limited on the of addition, of June investigations on many In from As you've information 7 16 1999. follow-up 6 13 of cases remaining to cases 67 years. REPORTING ASSOCIATES (301) 390-5150 t 58 More cases involved involved the system. There room visits were 8 that sources. Most product 108 reports, EADS dose products the that events. 16 with a range women 18 than in occurred cases the range 23 two-thirds 24 reported 25 death, the report one In 30 cases or use of does reduction. from cases to the and cardiothoracic stroke. MOFFITT Both from a variety the were week over one either arrest, health-care a of reports. cardiovascular cases was 39 years More cases occurred reported to of product year of have use product was seven being in with use. used roughly deaths sudden cardiac providers and REPORTING ASSOCIATES (301) 390-5150 in Seventeen occurred were in content EADS product there overuse. contained an EADS product. one of EADS or estimate these Hospitalization cases combination alkaloid 64 years. were misuse to these All emergency were taking reported within of of in of nervous deaths. information ephedrine to 15 Most possible age men. during were weight of of cases The median nine apparent we found Forty-six or reported was not or central caffeine amount cases EADS products cases. without the it or were contained as directed daily the the individuals Given the there 45 different also Most system and least among products men. 49 hospitalizations reported identified than cardiovascular At 6 women 59 1 consumers reported these events in roughly events included equal numbers. 3 Cardiovascular 4 arrest, cerebral 5 cardiac ischemia, 6 rhythm disturbances. 7 cardiovascular 8 of 9 known risk factors. 10 known risk factors 11 concurrent use 12 contributed to cases system cases 15 system conditions 16 psychiatric 17 effects and 18 central nervous 19 number events were categorized each category that Overall one-half such of was 20 have range 15, 22 risk factors 23 use of 24 the event. The I'm sorry the 46 and the number to of have cases could no had illness no or have -- nervous central nervous stimulant or without central This table with each risk 41 central central within shows were events, stimulant how the categorized category that 41 and appear the to factors. overall one-half as underlying product age how appear that the events such another for system Again, 21 cardiac event. seizures. no known product included cases shows and as an underlying another the stroke, events, table events of including This The age 14 events hypertensive within 13 25 vascular cardiac that range MOFFITT for of cases illness could the have or had no known concurrent contributed 41 central REPORTING ASSOCIATES (301) 390-5150 nervous to ct 60 1 system 2 in 3 effects 4 reported 5 EADS products 6 or 7 cardiovascular 8 frequently 9 central 10 cases women was than in were 13 hematologic 14 were 15 category were and appear 17 known risk 18 concurrent use 19 contributed to of So in 21 depth rev .i ew of 22 CFSAN between 23 general, 24 particularly 25 weight these June cases women, loss. the number weight lost reported less More reported by have shows of and how these cases within no known risk of cases these product events each factors. had no illness that could or have event. then, cases of CEDER conducted that 1997 had and describe using and REPORTING (301) March young who were Cardiovascular MOFFITT The reported. as an underlying summary 139 for renal table another the seizures. included This such use providers. 40 percent factors of was were events to stimulant Unlike musculoskeletal, Roughly for used events remaining that 20 and no deaths health-care occurred central hospitalization system categorized cases durations bodybuilding. events. 16 longer predominantly there The of events events than More onset with for nervous gastrointestinal, The were and 12 men. psychiatric as enhancers 11 51 years. shortest for consumers 15 to been of reported 1999. to In adults, EADS product central ASSOCIATES 390-5150 an in- nervous for system ct 61 1 adverse events 2 available 3 risk 4 use were roughly factors of 6 adverse 7 presence 8 evaluated 9 events of this the EADS product 12 and 13 cases. known In have 16 prior 17 may have 18 events played 19 adverse 20 of 21 higher. concurrent known such of hypertension were in in JONES: 23 DR. RICAURTE: ladies 25 George Ricaurte. and the Is gentlemen, reported, ha If the general Ricaurte Dr. Jones, good as a arrhythmia more series nature the of actual population Dr. may such the of factors cardiac that of we 're a voluntary I am an associate MOFFITT in risk implies DR. panel, and reporting 22 24 factors or these proximity that some of reported; occurring between as hypertension, a role the events events these products similarity pre-existing a role played all temporal risk with given in close adverse addition event events no known EADS products The the of history the or pharmacological and absence 15 illness suggested, review. use 14 had alkaloids alkaloids, the cases the with ephedrine and 11 of as strongly in ephedrine on information products. events 10 Based as underlying An association 5 common. one-half such other most number would be here? members morning. professor REPORTING ASSOCIATES (301) 390-5150 of the My name of is ct 62 1 neurology at 2 Medicine where 3 the 4 laboratory the Bayview Johns Hopkins I direct campus movement and where I am a board 6 a Ph.D. 7 the neurotoxicity 8 for greater in of 12 Health of than the Public with 15 slide, 16 meant 17 ephedrine 18 ephedrine, 19 methylephedrine. to refer and terms. as I will to plant related Fang , ephedrine mentioned, 25 forms ingredient active in two related on substances in known derive the I would like term material racemic four begin first today is and previously regarded in of include discussed although Office containing These been to on the the and Department discussion. generally exist two, today's Ephedrine, to U.S. norephedrine ephedra, corresponding MOFFITT the be using has is one, by As shown substances. is I hold research points alkaloids. As I believe 24 for pseudoephedrine, 20 other of confusion, of ephedra and predefined Science Services a definition 23 on a research conducted be address and Human 14 active direct and questions To avoid 22 clinics neurologist amphetamine I will Health 13 Dr. of 15 years. ephedra and 21 I also I have of Today 11 disorders certified pharmacology. 9 four School on neurotoxicology. 5 10 University as the by main there are as has been stereo isomeric mixtures. REPORTING ASSOCIATES (301) 390-5150 also ct 63 1 Structurally is best Other and characterized sympathomimetic include dopamine, would 8 of the 9 directly mental increased 12 increased 13 vasoconstriction, 14 dilatation, rate 17 and 18 of 19 effects. of indeed years, these but been generally, 22 exaggeration 23 and 24 agitation, 25 hypertension, may include mania, either of increased well-being, bronchial with circumstances be considered medically due of regard always, disturbance psychoses, seizures, for a number adverse alkaloids represent sleep an pharmacological drug and effects anxiety, dependence cardiac I arrhythmia, REPORTING ASSOCIATES (301) 390-5150 a positive over ephedrine milder MOFFITT stimulation degrees particular their stroke, those appetite. exploited not are systems, stimulation, effects although of following other pressure, might usually of ephedra produce blood I those nervous on the Adverse 21 and effects have occur sense decreased Depending of typically cardiac and Like To varying 11 heart epinephrine sympathetic indirectly. arousal, on this effects to amines 20 _' and or shown ephedra. be predicted sympathomimetic number slide the 10 16 amines amines central 15 amine. and sympathomimetic ephedrine as a sympathomimetic norepinephrine, phenylpropanolamine, that pharmacologically ct 64 1 myocardial 2 anorexia. infarction, 3 These 4 individuals 5 can 6 containing and adverse who take also occur in some can 9 known and about 10 ethnicity, 11 complications 12 several 13 These 14 certain 15 significant 16 include 17 coronary 18 or 19 subjects 20 suffer the the of shown anxiety 23 developing 24 Finally, 25 of slide -- arteries While in but ephedra- to be at possible are MOFFITT more those with or and are with with would hypertension, aneurysms, possibly more obese likely to disease. or family be at history higher risk complications of individuals with likely are risk. latter known vascular that or there increased The occult neuropsychiatric race, populations and individuals may also gender, is serious include a family, mood disorder little compounds individuals with alkaloids very of malformations, these dependence ephedra, ephedra disease. atherosclerotic is fatal. and disease, venous it of disorders with Persons effects developing cardiovascular from of or seen who use appear neuropsychiatric 21 22 of that since doses ephedra-containing on this people loss typically influence risk population arterial drug indeed potential and are individuals adverse be serious weight as directed. Clearly 8 effects excessive products 7 excessive to abuse REPORTING ASSOCIATES (301) 390-5150 of for ephedra. a history ephedra- ct 65 1 containing products. Ironically, r L : individuals that 4 containing products c developing serious 6 deconditioned, 7 to 8 vascular 9 be true activity 11 tone. are most are 12 often research 14 with 15 individuals. 16 propensity 17 effects of 18 with the 19 the rule, 20 more been development and serious 21 high tolerance doses may also in are vigorous sympathetic risk associated groups known of about the tolerance to unfortunate likely the because escalating more may controlled develop is cerebral doses to are lead to complications. Thus far I and neuropsychiatric 22 cardiovascular 23 that 24 remainder of 25 insidious potential can is too of This by these to This and engaged little for be expected cardio little ephedra risk example, regarding individuals ephedra. highest increases very of ephedra- would the itself Similarly for at ephedra. conducted use of of For who are exercise long-term of those to individuals has use individuals Unfortunately, 13 for susceptible since same group complications. complications for very targeted overweight be more 10 the potentially my time MOFFITT have detailed occur. to effects I will a less adverse some of adverse of ephedra now devote well-known effect the of and ephedrine, REPORTING ASSOCIATES (301) 390-5150 the more CNS ct 66 1 neuro injury or 2 As indicated abundant shown and and the on the main next structured previously to 7 methamphetamine is 8 In to 11 attention. 12 initial 13 structure 14 a hydroxyl 15 but 16 carbon 17 anticipate would 18 ephedrine through the Based on that similarities First, and I must ephedrine group it's 19 the 20 my initial 21 largely devoid 22 earlier this 23 of proved 24 illustrated 25 where is molecule, they of blood expectation in incorrect. at MOFFITT the the to my has to see, on the beta might crossing of it would -- initial to expectation perhaps Martin was be As I alluded is physiologic your the one ephedrine of two barrier. mine study to difference, This an early looked that effects. of bring difficult brain in have methamphetamine structural central similarities located with that abuse. contrary unlike a moiety impression know, considered that's interfere of to somewhat group amine, confess, I first which which a hydroxyl of mine when As related As you like most ephedra. methamphetamine I would the closely remarkable and expectation is drug the and other in right. a well-known 10 is sympathomimetic ephedrine of ingredient on the addition structure ephedrine ephedrine another shown and active slide, methamphetamine 9 ir neurotoxicity. best and and REPORTING ASSOCIATES (301) 390-5150 colleagues subjective and ct 67 1 behavioral effects 2 derivatives 4 investigators 5 can 6 found 7 portion 8 in 9 And 10 just 11 intended 12 the 13 ephedrine 14 of 15 raising is that of the -- the open in having an I'm panel, to a tad to difference two 18 case 19 regard 20 for 21 dose 22 ephedrine 23 methamphetamine. second from with to is potency pressure The observation are if this that the psycho the and ephedra, was The the indeed other that MOFFITT nearly psycho in down this is account for the and efficacy this case in important was effect that of affect again by to similarities ephedrine you effect that to the with adjusted increasing the of of between like as was once stimulant comparable I would here equal. study potency, shown move what dose, and stimulant upper squares. could you the methamphetamine interesting sympathomimetic differences once amine's early open Because increasing is the you between the methamphetamine is sympathomimetic blood 17 you as you investigators methamphetamine it. in these see appreciate it which, don't slide you these study what 1971 afraid but by simply these early this show methamphetamine. what ephedrine find I'd and this in circles, amphetamines my surprise, was published 16 25 to showed see, of ephedrine Somewhat of a number including 3 24 of bring REPORTING ASSOCIATES (301) 390-5150 ephedrine to your and ct 68 1 attention today 2 compounds to 3 has produce 4 over 5 evidence 6 damage 7 may be aware 8 substantial 9 of the the out two that methamphetamine decades neurons nigra shows stem, send 11 region of 12 mobile function. brain These 14 Parkinson's disease 15 nerve in 16 the 17 disease cells movement has yielded the in these primarily the to with nerve indeed is Parkinson's that at the striatum, a paramedial degenerate that patients level cells degeneration disease disturbance as you the the that the to nerve estral cells strong neurons here there two very potential originate from these laboratories Dopamine involved are various so has that to of neurotoxicity. schematically and projections the or in neurons. are brain 13 carried dopamine potential dopaminergic last brain axon do with brain Research 10 in of accounts with these for Parkinson's experiences. 18 Before 19 that 20 ephedrine 21 what 22 methamphetamine. 23 ephedrine presenting to on the neurotoxic we collected I would we already 24 25 to like know neurotoxicity that about the on this in slide methamphetamine MOFFITT summarize neurotoxic this data some recent data potential briefly Hopefully As shown indicators to you will its has proper the for you potential help there of are place the context. a number potential REPORTING ASSOCIATES (301) 390-5150 of of to ct 69 1 damage brain dopamine 2 for 3 chemical and 4 indicate that a number 5 dopamine axon terminals 6 with methamphetamine anatomic 8 evidence 9 axonal markers, 10 axonal markers 11 and studies. the is unique of long-term due to the toxic or loss for brain in animals methamphetamine. structural of loss studies reduced doses evidence both chemical markedly the from markers evidence the these of dopamine these degeneration of dopamine dopamine axon terminals. 13 is highly selective 14 noradonergic, 15 or other neurons 16 exception certain 17 affected since thus far of effect of does not it cholinergic in methamphetamine involve neurons, gabaergic analyzed. With seratononic neurons neurons, the single which are some species. The next few 19 data 20 in 21 studies 22 methamphetamine 23 up to 2 milligrams per 24 given systemically at 25 doses were The slides on methamphetamine animals The are that Notably 18 of anatomical indicates 12 summary comes administered The axons In neurotoxicity previously 7 neurons. induced collected baboons in were MOFFITT representative dopamine my laboratory. given ranging given. depict various from animals In doses These these per doses intervals, were ity of . 5 milligrams kilogram. two-hour neurotoxic then REPORTING ASSOCIATES (301) 390-5150 kilogram were a total allowed four a two- ct 70 1 week drug-free 2 long-term 3 to period toxic acute so that effects of pharmacological 4 after number postmortem 6 specifically 7 dopa, a with 9 monoamine transporter 10 attriated dyhydrotetabenazine. 11 these 12 see 13 that 14 axonal 15 the 16 that dopamine in there axonal the is baboons before that's we tested 17 you in 19 laboratories 20 strongly 21 potential 22 shown 23 destruction 24 dopamine 25 markers. to that schematically in the even MOFFITT the can see each of are can is these axons And in lowest an as dose that I will we and collectively other which effects. data terminals -- as you you that methamphetamine here. various of in chemical, dopamine these a dihydro by methamphetamine anatomic damage of what labeled vesicular we measured, significant collected, indicates the with you, the the have and reduction produced a second, here Notably, Collectively 18 transporter produced striatum. a animals; Regardless a dose-related markers these labeled markers data we measured dopamine, Win35428 here drug. we measured dopamine called as opposed the from tissue, as the a compound here tissue striatae as well of treatment 5 measure methamphetamine effects Two weeks using we might it that has and is leads dopaminergic REPORTING ASSOCIATES (301) 390-5150 other data the axon that show terminal damage to loss axonal is or of 71 The detected 3 are 4 studies 5 showed the toxicity with imaging results of two carried out in you 6 the In 7 for a important 9 middle, because 11 quantitative 12 using 13 transporter 14 the 15 right, 16 the 17 profound 18 of the you can of carbon 23 emits 24 positron 25 elegant these please and I think are the 11 labeled positrons studies thus MOFFITT shown is top, the middle and we are that now dopamine on the shown what left, on the you there in on the of saw with is the a striatum top panel. about this panel is carried out with a study As you permits tomographic allow but animal. Win35428. that the transporters results me here a postmortem label is, interesting and emission that focus with just the where is treated Now, I complicated study animal dopamine that on the essentially And imaging panels, focus animal see bear three treated data. loss 19 22 -- to here from. represents when control of a somewhat are methamphetamine that is simply label chemical 21 after autoradiographic and important data Just The middle methamphetamine 20 types be Shown same baboons this bottom. tritiated the the can as well. different There an the top. techniques words, slide. the methamphetamine neurochemical other a minute 10 of for the What's may know carbon execution of studies. These direct visualization REPORTING ASSOCIATES (301) 390-5150 11 are of ct 72 1 dopamine terminals 2 DR. 3 seconds. 4 conclusion. JONES: So if 5 you the levels Dr. Ricaurte, would simply here 7 of 8 postmortem 9 PET imaging, is dopamine that during 10 human 11 and to 12 see that 13 methamphetamine 14 transporters. we've methamphetamine patients the 15 What directly 17 with that 18 some studies 19 given 20 for 21 simply 22 produces 23 and does compare of 24 you a loss to is of that them loss dopamine to of do with controls, you can to dopamine of done monkeys to To ephedrine recently And what like of ephedra? ephedrine ephedrine with and where potency. loss a study potential of shows exposed we have doses see are accommodate this slide methamphetamine transporters -- of dopamine transporters. In discussed have you in disease of 30 and information compared monkeys, and animal conducted neurotoxic higher a summary previously this squirrel difference dopamine is about And what that evidence the in shows done methamphetamine, fivefold the with subjects shows have confirmed Parkinson's human you this is users, with striatum. good. life Armed the towards that studies. 16 Very transporters what of move DR. RICAURTE: 6 25 at the summary, what cardiovascular MOFFITT I've and covered today neuropsychiatric REPORTING ASSOCIATES (301) 390-5150 are, I've ct 73 1 complications of 2 abuse 3 discussed 4 limitations of 5 limitations that 6 But 7 highlight for you the 8 ephedrine has for dopamine 9 you. DR. JONES: liability, the would 12 into I've the time, invite the 13 for neurotoxicity. are presenting to record. in our today neurons you, the full We would in Dr. is studies. to simply that the brain. R.icaurte. text welcome the animal potential Thank put also some of them neurotoxic I've Due to address I recognize you and their of full Thank We your remarks text. [Applause.] 14 DR. RICAURTE: record of 16 DR. JONES: 17 Dr. Woosley. 18 DR. WOOLSEY: 15 upon, I cannot for products, touched potential reason 10 11 ephedrine-containing complete 19 committee, 20 Woosley, 21 Georgetown 22 pharmacology 23 pharmacology. 24 board 25 president and I will. the written Very of University Pharmacology department. I am also certified of clinical the MOFFITT of a Ph.D. certified Society for at the in internist pharmacologist, American Raymond Medicine I am chair board you. the here, and I have a you. members as shown submit thank thank Jones, I am, where then remarks, good, Dr. guests, Professor I will and Clinical REPORTING ASSOCIATES (301) 390-5150 currently and ct 74 1 Pharmacology and 2 Therapeutics. I am a consultant for 3 government employee, working 4 few years, but I appear 5 for presenting 6 today to you I have this products i nvolved and 8 objective analysis of 9 to a year 10 12 also 13 came to the same results. 14 watched the other 15 is 16 it's 17 approaches 18 my approach based 19 however want Neil 20 pharmacologist 22 factors in 23 trying 24 variability. 25 studying, to any other I can give you that were are an presented take. on the look to those Often unfortunately, MOFFITT ago drug very the different today give background but studying or the response which drug variable of would action, toxicity. REPORTING ASSOCIATES (301) 390-5150 drugs explain many you biases my experiences. the it complex as a clinical factors studying were I will them; began contributed identify at I have same cases, between following and as those that And those analysis though, of cases of pharmacologist a similar differences people to my opinion a clinical 140 25 years that volunteer to I think My experience 21 you presentations there you last today. cases performed that that that 140 Benowitz, co llleague always the as an unpaid ties be giving cases. interesting hope a special CFSAN for information the 11 and FDA, so ago. I will Dr. with no financial 7 me about the times ct 75 1 2 suppression 3 1988. It lives, but the I was co-director trial. This was the the was study study of was antiarrhythmic taking of And cardiac a trial that drugs began ended to study ia in save prematurely under that arrhythm intended stopped drugs lives. the because actually were my interest in cardiac toxicity. It of was heightened seldane-induced 10 series studies 11 FDA to study rare in cardiac 1995, 14 products 15 cages 16 heavily 17 drugs 18 actions 19 drugs cardiac arrest with funding from factors responsible complication. So in had been reported to I have more recently reviewed, of over this period So I guess 21 the medwatch 22 we often 23 it. 24 looking 25 pharmacology reports knew And at in the the of in some of this the case, it been MOFFITT known fairly actually ephedrine FDA, and it the the 140 was the other cases cardiac cardiac classes of we were prescription pharmacology, pharmacology has many the of time. those often and a and -- with trials and NIH that of by my experiences antihistamines began reviewing reports antiarrhythmic and for that the medwatch I saw a case the of influenced 20 when 95 cases that in 1990 sudden often the in is or for very cases looking drugs but not different. where centuries. REPORTING ASSOCIATES (301) 390-5150 at where all of We are the And we are ct 76 1 looking 2 prescription 3 people 4 different at the come at said 7 of 8 reported 9 of is with use the I used I went one to five. is the through a different following scoring five cases sympathomimetic amines, resolution related the to report of the discontinuation information necessary, 15 contained the information necessary 16 evaluation of 17 So that would 18 similar to 19 temporally 20 dechallenge 21 reasonable the related, or some of So it included of or the the it the with five, the report a reasonable likely causes. would be very expected, report it may have information was lacked necessary for a amount of evaluation. 22 25 for generally but consequence product and other reactions reaction of the excluding a score a score with and the I as ephedrine, associated contained get the a dechallenge product, causation when them administration included the system. gave such 14 said and and as a medical the symptoms of and was used accepted or 24 usual situation backgrounds generally product evidence its different the And temporally 23 than approaches. -- was a different So it this But 6 in use. 5 10 drug that earlier, was was a slight available unlike intensive the in reports evaluation, MOFFITT reduction the in report. in 1995, affidavits REPORTING ASSOCIATES (301) 390-5150 the And these from as was ct 77 witnesses, family people injured members, in the A score accepted great evaluation 8 causes 9 one, 10 one to causation. 13 patients 14 reports 15 fluids 16 reports. there report and their which in 17 by many of 19 and 20 this already. 21 that in 22 take into 23 pharmacology 24 structural 25 amphetamine I will too the report. go quickly analyzing account of shown it MOFFITT of I was you is reports that cases to of by view the biological and postmortem heavily influenced already because have learned seen, you've to to -- And I had to the the and difference REPORTING ASSOCIATES (301) 390-5150 seen repeat about ephedrine simple other chemistry the have a allow of amines. the or a score important you I had between here; complete analytical these sympathomimetic similarities is that I think all for affidavits this, through these lacked assessed products structures there And was available doing But or generally incomplete my case ephedrine-containing the it. members, often was other records, family in been just in medical were Well, 18 was causation the it but explained assess of victims necessary may have have reasonably copies that information might And was consequence, of the 11 of three the that that 12 of of Two, sometimes report. as a medical deal and of a ct 78 1 methyl group 2 and group Methamphetamine ago. The very that was similar It's similar but isomer that is is 11 thing 12 sensitivities, 13 course they 14 because it 15 phenelylamine 16 alpha 17 nervous 18 like 19 vessels all at the were is backbone the 20 heart 22 increase 23 have 24 the 25 reports And there have which medical Well, these blood vessels, cardiac work and been looked centuries, those at and stimulant has it the to of same of does same interact the with sympathetic on the constrict amines increase and more sympathomimetic MOFFITT all market blood use. when will blood any including, in at And often products can an a different do the sorry. stimulate are pick different allows and phenylephrine and can which which receptors to looking as adrenaline a catecholamine beta from and very curve. potencies, acting of but compounds doses fact chemically response I got these different system. 21 that of the stereochemistry dose different and is same properties all a second a metabolite has that but also the The message this about structure, pseudoephedrine a different 10 talked by changing sensitivity, 9 here. chemical phenylpropanolamine ephedrine. 8 hydroxyl of pressure, these ephedrine recent years amines affect are REPORTING ASSOCIATES (301) 390-5150 and compounds carefully in the over clinical known to be ct 79 associated sudden with stroke, heart attack, arrhythmias I and death. 3 So this 4 analyzing the 5 104 cases of 6 find that the 7 here, 8 very 9 by or was under the there that fives associated shown that with the 11 Arrhythmia such 12 tachycardia, 13 awareness, syncope, dizziness, 14 myocardial infarction were 15 effects 16 amine Three that you given 17 to for would the this and 21 cases 22 to 23 personality change one 24 that I gave a score of 25 four was to cases of given four MOFFITT any of that the was caused and are would the cause I reviewed frequent cases here. and REPORTING ASSOCIATES (301) 390-5150 anxiety the a score occurred 24 cases, be lower and five, the people. to I gave most cardiac sympathomimetic affect tremors of and These psychoses -- seizures, to with And when five was pain, compounds cause there as a four. seen. expect CNS symptoms. that all of 20 threshold, chest class seizure death arrhythmias stimulate 19 ten that ventricular brain expected I found I felt rated population 18 other shown an ephedrine- were to a large And are as atrofibulation, palpitations the fours of product. at the use as look you sudden containing you in five the 10 fact four here, that that if scored cases evidence I used And I've are seven and cases. 140 140 were strong known, in 140 of five seven, reports a score of ct 80 1 Severely 2 given 3 felt 4 the a five, were use and of of 9 what to but that drugs are earlier almost 11 drug dosage 12 the labeling. 13 And I think 14 terfenadine 15 receptor diversity. 16 channels in 17 change 18 sensitivity 19 polymorphism 20 responsible 21 to -- over for and of one for kind so, receptor diversity 24 existed, beta 25 explain the heart, acid was the result I of that that in the And that or can fact all Fong and the as recommended all of there are that on this. learned there with is ion a simple protein can mutation response dosage a factor. drugs that an ion these in we've is caused as Harry explain example, a receptor that not are now, for alter or channel the that can be supersensitivity drug. I believe 23 was "drugs11 things an untoward of cases, the can't a drug. in all We know amino to clearly these drugs strokes which I think compounds and many the factors over, the were product. I said So dosage six probably dosage and these one 22 12 severe the occur? in were said this pressure, and I reviewed, 10 of were associated events cases These blood an ephedrine-containing be involved, the there clearly Well, kinds increased that and the receptors exaggerated MOFFITT and what we know receptor ion REPORTING (301) polymorphism channels cardiovascular are response ASSOCIATES 390-5150 about the that enough that to 81 are occurring in At these is 5 responsible 6 tolerate 7 occasional this and for this person Why is 10 that are 11 drug, 12 therapeutic 13 products 14 can 15 supersensitive never have ephedrine index with more said of only for 18 seizures, 19 effects 20 giving healthy some sudden in and 21 22 effective 23 because 24 she 25 until is in the people, use in and effective has moved and attack. medicine drugs past a two of cause is 20 which there heart less serious or the today. although individuals, other in stroke, other a many reactions out a -- 10 and ephedrine, causes death, the warning preventing the individuals susceptible they that heart an safe attack, adverse a normal people dosages. think I not can but We now have that susceptible excessive or tendencies clinically people problem, only two. therapeutic So I conclude 17 safe earlier, population 16 in And medicine Fong some a stroke It is where any take reaction. I believe not are available. be used that without will can a serious disconnect, there as Harry individuals have products Well, many diversity these today? individuals. same time receptor 8 9 the compounds 4 many take their MOPFITT the first will harmful often to labels effect do not adverse few not know effects doses. of ephedrine that he or of And REPORTING ASSOCIATES (301) 390-5150 be ephedrine for me ct 82 1 there 2 used 3 nutritional 4 standards 5 effects, adverse 6 people. So to 7 unacceptable. is no acceptably as a dietary even evidence to value offset effects, me the ephedrine using its expected risk it benefit has no proven current known to when harmful occur ratio in is some just you. [Applause.] 9 MS. 10 employed 11 here 12 Officials 13 meeting. by CULMO: the today Texas who has In to My name of paid light speak the for of the 1% impressive credentials, but 19 unsolicited long-term on-the-job 20 experience of Food 23 I am pleased 24 Drug issue. a state's I don't now category you offer AFDO is represents present Officials, to MOFFITT to comments state, and a lot I'm plenty of a the knowledge and products. a background herein in this regulatory have I have of a 104-year-old federal, expenses Drug through on this 22 Food get to give of I am so I should perspective I'll but my nervousness, 17 21 Health, I am and of this Culmo. time, 16 with of my travel going I am here Cynthia Association 15 time. fast is Department on behalf 14 25 of because, medical Thank 8 dosage supplement, or of safe on the referred on this to Association as AFDO, important organization local government, REPORTING ASSOCIATES (301) 390-5150 and issue. that ct 83 regulatory officials, 2 whom are 3 dietary 4 and Drug 5 for achieving 6 supplements. and involved in food supplements. more 9 consistently, specifically through placed 11 provision of 12 the 13 supplements. adequate consumers 14 15 often equated 16 concentrated 17 physiological 18 in 19 foods added extracts of and the 20 risk specific 22 those 23 related 24 and 25 dietary good dosage. to that This particularly is educate dietary is contained affects that profound result conventional fast purity tracking of particularly critical of safety the important supplements. MOFFITT and botanical. address and of have practices, consistency written help that to We had supplements many support manufacturing requirements to compared and safety to use botanicals unextracted AFDO continues numerous foods, when whole in dietary and pharmacological health these on product of conventional of docket. appropriate safety strategies this and Food dietary information and the to of priority label on safe Although issues of on the develop on a few testimony a high focusing of comment on the comments, to regulation to Many supports desire effective 10 efforts AFDO strongly AFDO wishes 8 associates. safety Administration's 7 21 industry REPORTING ASSOCIATES (301) 390-5150 areas ingredients for all ct 84 1 On several 2 concern regarding 3 information 4 regarding 5 product interactions, 6 has been 7 historical 8 people. deficiencies for safe 9 The 12 of 13 weight 14 physiologic 15 alkaloids, 16 other use; in traditional the information drug restrictions for by clinical addresses containing medical use products as dietary loss and exercise and pharmacological including safety ephedrine of these the labeled and actions in of products, enhancement, use as young alkaloids. supplements their safety or such the or which studies preparations docket its labeling problematic at-risk supplements expressed the including established Today's 11 and and uses dietary AFDO has contraindications, not 10 occasions the of use for known ephedrine combination with stimulants. 17 The 18 questions 19 additional 20 public 21 first 22 questions 23 actions 24 heard 25 actions following posed for this AERs and by the of the -the previous include and are speakers bronchial MOFiITT with that going expected dilation specific to was made In regards to read to the the physiological well-documented, allude the regard spring. I am not known ephedrine to information past and responses forum the FDA this question -- are as you to. and have The beneficia decongestant REPORTING ASSOCIATES (301) 390-5150 1 85 effects. Another 2 and 3 suppression overweight or and 4 also 6 including 7 serious 8 blood 9 seizures, expected action obese persons adverse and adverse known for pressure, events 12 and 13 reports 14 events 15 clearly 16 supplements 17 adverse is psychosis in states. Since are other included each of types attacks, these adverse AERs, reported to the all the products in the and since with all ephedrine association between containing ephedrine the use of alkaloids FDA adverse toxicity, the of elevated heart death. are stimulant and and the ephedrine consistent and potent have surprisingly, contain loss appetite actions arrhythmias, represented several this that cardiac stroke, 11 to neurologic events Not due be weight physiological cardiovascular 10 might thermogenesis. Serious 5 there is dietary and the events. And 18 19 reported 20 over 21 ephedrine-containing 22 recommended, 23 the just by FDA in 90 percent of or Not as well as in the 1997, this new series injured consumers the dietary manufacturer 24 25 positive to at lesser first supplement amounts, on the labeling. go over each as CFSAN and MOFFITT serious of CEDER there of AERs documents took the products than that as as directed the external was an evaluation REPORTING ASSOCIATES (301) 390-5150 reviewers by ct 86 performed by mention mispronounce 3 a PharmD 4 and 5 possibly 6 containing names within Center if the use Drug the of I Claudia for who describe division conservative Kowalski, Evaluation adverse ephedrine reactions 11 clinical 12 effectiveness, 13 adverse 14 that 15 history 16 events from of events as alkaloid- Drug reference have in drugs established It physicians familiar prescribed through Janet 18 as follows, and 19 most that 20 supplements, 21 The primary 22 one, 23 between the 24 dynamic properties likely reflects drugs reason two. I'll adverse Additionally MOFFITT for the most likely expectations patient's report medical the summarized adverse CEDER's these belief three: events and ephedrine although -- 'Ithe the it is dietary adverse is" report believe alkaloid-containing causing our tbe system. quote of safety "we nonetheless ephedrine EADSs are well-controlled their and Woodcock I quote: adverse drug and with the its evaluating the a well-established Dr. 17 also Evaluations' where contraindications, effects. Risk may reflect prescription trials and of evaluation frame 10 25 FDA's to CEDER's traditional I apologize products. 7 9 and an RPH and MS, CEDER, related more -- the Research, 8 -- effects. she lists, similarity known pharmaco alkaloids." many EADes REPORTING ASSOCIATES (301) 390-5150 may conta in ct 87 other ingredients these data the focuses of ephedrine 4 the adverse 5 alkaloids 6 taken 7 of 8 constituents on the 9 relationship between In are containing the adverse adverse fact that we are with EADes, it question Supplement Health supplements or 14 stricter 15 are 16 maintain normal 17 produced general and more to The two, the same level other the causal and the the diet and rather than drugs. to function And they affect or of body the the or well-being. central nervous alkaloids 20 appetite 21 increased 22 in combination with caffeine, 23 of weight for individuals and of Dietary dietary as foods supplement structure the Act, requirements ephedrine may play increasing loss risks produced effects are associated MOFFITT system a role perceived metabolism These significant the DSHEA, Education 19 25 at alkaloids regulated regulatory intended 24 that constituents, supports ephedrine fact ephedrine other not presence the with of associated the words, associated of events. Under 18 element, other a variety events 11 12 events interpretation common alkaloids. with cogent on the 3 10 most stimulation in suppressing energy levels. by ephedrine it on a low-calorie with effects, taking REPORTING ASSOCIATES (301) 390-5150 An particularly may increase drug of and the the rate diet. there products are ct 88 1 for 2 long 3 cardiovascular 4 alkaloids had 5 function, or energy or periods 6 weight of time. that 8 medicine, 9 conditions such 10 emphysema, and 11 diseases 12 supplements 13 cure, 14 TCM to ephedra is from for 17 taking 18 with 19 months 20 women are weight, of obese doses of 23 characterizing 24 use 25 bodybuilding. for women of expressed Chinese of medical congestion, asthma, conditions diseases to or and are in is treat, not fight duration used have on a low-calorie of diet times caffeine weight in fatigue. studies three either dietary diagnose, to ephedra, increased We are 22 iron, the structure, Medicine Ephedra 200 milligrams the of intended disease. for individuals. treatment dose experienced normal These pump and traditional nasal not any without 21 its characteristics that taking School short-term 20 milligrams or the in Considering demonstrated healthy bronchitis. prevent 16 in use by ephedrine maintaining as cough, and 15 in used TCM, or produced well-being Wei when The bronchodilation no role 7 lose particularly stimulation Dr. or loss, a day, for loss six compared with placebo. not ephedrine for the ephedrine aware of weight effective for The MOFFITT data evaluating loss or data and the dose increasing question addresses REPORTING (301) energy duration of or efficacy ASSOCIATES 390-5150 lower and not ct 89 1 safety. 2 The 3 agricultural 4 been 5 alkaloid-containing 6 programs 7 During 8 representatives 9 in health concerned with comment periods of review 11 ephedrine-containing 12 safe. eleventh 15 passage 16 regulatory of any Six still 19 The 20 to determine 21 manufacturers 22 ephedrine-containing 23 studies 24 the 25 subjects short in hearings, public the have of that will were sometimes been instrumental to on more have haven't financial claim suffered due duration of to of not in the the small the studies, out or at the delaying by touted the happened? a burden numbers the trial for in alone. or safety clinical dollars products were occasion. What pose that safety a large billion diet show delivered one and publish products produced. cost should that than to on going, improve passed been safety promised results state concern. supplement restrictions years this have long ephedrine Both to studies agencies 17 studies and of and have FDA, supplements. dietary hour as the testified journals The promises pharmacies aspect industries placebo 13 safety dietary AFDO have double-blind, as well the and peer 14 departments, departments, 10 18 states sales Have of for the subjects, number of L that dropped MOFFITT were eliminated REPORTING ASSOCIATES (301) 390-5150 due to ct 90 1 significant 2 were 3 individuals side subjects effects? that to were be part for 7 that 8 adverse 9 stimulant they clinical appears lasted, events 10 of of that even among the adverse events and 13 ephedrine 14 assumes that 15 ephedra as a dietary 16 medical benefit 17 ephedrine 18 supplements deliberation has in is safe The occurrence 21 supplement 22 pressure 23 unacceptable of and and heart -- persons. in his discussion a safe dose value a safe to lack of dose taking of proven containing benefit ratio serious in can in these events a previous effects series makes as a dietary increase the susceptible medical adverse side products they rates MOFFITT - of dosages without The series of of However, risk ephedrine-containing at 24 25 types unfavorable. 19 use deal The the the healthy supplements makes extent summarized medical dietary the sympathomimetic identify supplement. alkaloids the for supplements. there of to the and a great sought dietary to apparently so adequately were studies? known Woosley 12 what pattern Dr. review controlled studies, the and participants as healthy those the reported 11 20 in study, document agents studies a carefully noncompletion It the screened of physician-monitored, reasons If blood individuals supervision. reported to on dietary REPORTING ASSOCIATES (301) 390-5150 FDA in a supplements 91 containing 2 of the 3 occurring ephedrine iceberg 4 5 Harvard 6 one 7 dietary 8 proportion 9 or of alkaloids, the number from these The evaluation School percent of of only of adverse events by Dr. Walker, M.D. the tip products. Public the represent Health, serious supplements is may well concluded adverse reported events to be smaller the PhD of less than caused by FDA. The by an order of true magnitude more. 10 In 11 31, 12 60 of 13 containing 14 ephedrine 1999, the 20 months FDA received which could 15 producing 16 disabilities from 17 arrest, heart 18 Walkers estimates 19 to 20 serious, 21 events 22 alkaloids. 23 ephedrine 24 are 25 families. or and from attacks, of some cases, for MOFFITT to ephedrine- supported a role some affected of events. are permanent cardiac If correct, Dr. 300 may be suffering disabling serious, March events; disruption, a month dietary are to adverse deaths, rates supplements from 1997, and psychosis. reporting in alkaloids devastating adverse seizures individuals Risk or vascular more dietary of included cerebral 1, attributed these events June reports supplements, Adverse 3,000 140 be clearly dietary in from or containing fatal adverse ephedrine supplements containing and consequence the individuals REPORTING ASSOCIATES (301) 390-5150 and is their ct 92 1 Are 2 these 3 affected 4 the 5 loss 6 significant 7 But products outcomes affected dosage of of products data advisory Food Advisory 11 available 12 could indicate over be identified use The growing associated 15 ephedrine alkaloids 16 data lead must 17 Mario 18 stated 19 that 20 to 21 for in his these to the can are identify 1996, that based upon dietary an the the alkaloids supplements. the consistency of the safety today. Medical his review, of importance dose of containing lack Newark a safe of FDA in continued in dose. the ephedrine and from conclusions events. members same conclusion Enchioso, one the a safe supplements the relationships whether in dietary and one of number with AERS by level for 14 of weight propose an expected half of indicates for energy concluded no safe use may be adverse convened Committee data, 13 enhancing do not panel Outcomes marketed life-threatening addition, the available currently of expert with currently and risk In 10 Data bodybuilding these associated by dosage? by dosage. 8 9 the College "1 believe in of relation ephedrine supplements. In 22 23 would provide 24 consideration, 25 safe dose the absence some basis it of would ephedrine MOFFITT of clinical for risk not indication to benefit be possible considering that to user REPORTING ASSOCIATES (301) 390-5150 recommend a ct 93 1 characteristics. 2 appears 3 from 4 in Strenuous to increase dietary both men and f-) Dr. in our 7 Exercise 8 system 9 Ephedrine view 11 another 12 susceptibility." in adverse 15 consistent caffeine 16 ephedrine and 17 In 18 combination 19 increased addition, of it stimulants for 21 potentially 22 also account 23 with a combination in that and rate. the heart the could the stimulant be individual's three types a AERs he reviewed of the were properties for is well-established has a synergistic adverse Love positive Another taking nervous which difference in sympathic augment exercise known the exercise. of caffeine. As Dr. 24 alkaloids individuals during pressure concluded the risk 20 of for "several could reported with effects ephedr ,ine of blood stress events adverse events activation increases He also 14 25 adverse mechanism 13 serious of commented, suffered and/or cardiovascular exercise containing Benowitz which moderate women." results 10 risk supplements 5 6 the to of noted, it negative ephedrine-containing MOFFITT effect could have with a on thermogenesis increased these the events. impact the that adverse effects that may seen agents. result dietary documented supplement REPORTING ASSOCIATES (301) 390-5150 with products ct 94 1. is a positive urine 2 could 3 military 4 professional 5 ephedrine-containing screen be particularly Most adverse 7 supplements containing 8 last of 9 states occurred from months or of years 11 Safety 12 limiting use 13 adverse events 14 identified, 15 warnings 16 because of 17 protect these to why these 20 performance 21 easily 22 other 23 the these days or 24 these products 25 during Texas day these of products weeks. occurred in AERs, the to the use to after cannot young individuals with conditions. individuals or be assured by Life-threatening medical to at medical no Label increased risk conditions would not individuals. states products and are enhancers, demonstrated marketing states. dietary AERs reported first of medication 19 the of athletes. from and use use. directed The the being and advertising An example is ample consumed for of of the of the labeling consumers' in Health's evidence weight boosters. review and exemplified Department FDA have energy by FDA's MOFFITT - the preexisting 18 effects and the by their AERs and and collegiate, ephedrine the This athletes now prohibit products Serious for amateur organizations series amphetamines. problematic personnel. 6 10 for petitions This is products received perception received rule-making REPORTING ASSOCIATES (301) 390-5150 loss, and by of 95 1 procedures 2 speed, that and said please 3 It's 4 state 5 or 6 many 7 are expecting 8 and finally to sign states delayed and act for Could Chinese speed. an individual on sales products. action FDA to And because provide they leadership restrictions. you please wrap up or get wrap up here. a conclusion? In Okay. conclusion, I need being or regulatory oversight, address the regulation of encourages 16 committee ephedrine of the There have present It's aside 25 relied of AFDO advisory external have dietary illness to been utilized, supplements significant under reports, and containing or conditions unreasonable recommended manufacturers. 23 24 included specialties alkaloids or two series that injury products. many expeditiously. been concluded of I am compelled these act two medical have risk FDA to reports, scientific most the to a representative involved by for individual meaningful MS. CULMO: 18 Chinese distributed waiting with the restrictions nationally have the meaningful DR. JONES: to keep save impossible about these up today, to virtually bring labeling sign and upon time act to place responsibly by the general MOFFITT to politics and as the public health public to protect REPORTING ASSOCIATES (301) 390-5150 the money agency their 96 safety. 2 high 3 doing Recent regard polls by a good 4 the demonstrates general 5 needless injuries. 6 for opportunity 7 working 8 important with to all DR. that and trust We would held viewed as is FDA must like to comment, interested public 9 public FDA is in job. To continue this that and issue. JONES: thank Thank the to you. Ms. Culmo. these USPHS forward address Thank you, in we look parties health act to this [Applause.] DR. members for couple JONES: staying 18 first from since I have the panel, the role since of the of women 24 and 25 you even that to if all panel I needed the other might take of you have thyroid to the asking any some say midlife to condition effects. prod a first Any suggestions with compounds? these DR. WOOSLEY: I think on as 40 percent have obviously as the of condition might which just whatsoever as many later answers prerogative, the data contribute MOFFITT and as an underlying 20 -- about questions I will of thyroid interaction for a microphone, from and open panel. an estimated cardiac that on time to do any undiagnosed 23 thank times. We want 16 And clearly REPORTING ASSOCIATES (301) 390-5150 can of underlying the an the have role conditions hypothyroid ct 97 1 individuals 2 sympathomimetic 3 in 4 there 140 are cases if were, a potential increased to 10 based on the 11 that 12 unaware 13 risk. those of amine administration. there were in of I think But group disease be another their condition 15 these cases 16 that dosage 17 took the 18 risk factor. that wasn't DR. JONES: 20 DR. COATES: 21 DR. JONES: 22 state your 24 of 25 brief Dietary the are at hyperthyroid. data that I'm we have aware any pharmacology, illness, I would that often increased of there were is, thyroid Thank Thanks the at that you. some of supplements perfectly the could Dr. very and time if they be another Coates. much. record, say are be at it also I have Paul, -- would you the Office name? DR. 23 is on the the amine For that who might adjusted 19 call people than group taking sympathomimetic more or aspect were have based itself would these as are we would, recall hypothyroidism that any for I don't but we don't that risk I seem to arrhythmias The other 14 increased any. complication quantify group. be at knows, risk other 9 to made Lori so, of known COATES: I'm Supplements at Paul Coates, NIH. I have from two questions I questions for MOFFITT Dr. Love, REPORTING (301) and one brief ASSOCIATES 390-5150 question -- ct 98 for Dr. Ricaurte. Dr. 3 would 4 Luke's 5 you 6 Luke's 7 know you 10 you it's DR. published. was references for Calman study the in it abstract that but the which the form, St. St. do you since? I have not was published heard in that abstract it's form been in FASEB 1999. 11 DR. COATES: 12 DR. LOVE: The just recently 13 I missed You noted published LOVE: It for slide? study been maybe the and on your Roosevelt -- provide study referenced in to Roosevelt if would be able 8 9 Love journal it was 14 DR. were COATES: 15 number 16 to 17 reporting la between 19 those who were using 20 loss as opposed to 21 primarily be sure going 23 appeared 24 purposes. 25 classification by And fast system represented, bodybuilding DR. LOVE: to be using An in of that me. the that for our data the population events 2000. concerned adverse event occurred among for the more men, term? of bodybuilding looking at were REPORTING ASSOCIATES (301) 390-5150 weight products a better there the a difference of fitness -- I was primarily want the whether there who was using From it in I wonder that for adverse MOFFITT then products those I forget published reports the study? study, was event for Calman before I understood adverse the Calman that the 22 And the more course, ct 99 1 central 2 if you in some of nervous looked exercise that at did you could see COATES: of 10 you that 11 dopaminergic 12 in 13 the tantalizing brief 14 and monkeys. Can you 15 into 16 monkeys 17 had 18 human? about remarks 21 apologize. 22 potential in 23 methamphetamine 24 there you events what do not Dr. the remark about the ephedrine data MOFFITT be reflected ended ephedrine bit baboon it is to at with studies more that on the when on you as you compared of end were and know, insight done in that you in the be so tantalizing data although a paucity the Well, to you same conclusion in the then me a little to meant the could studies I will Ricaurte, studies baboon the mind towards and give you I think That seizures strenuous of humans RICAURTE: not if the that draw of of cardiovascular Ricaurte. in think were is And methamphetamine 20 also methamphetamine studies DR. the approach neurons could 19 25 the how you but cases irrespective Dr. a tantalizing similar more Particularly for. question said effects. were on just provided 9 of individuals, was used one type there impact DR. ask it these that product system brief the closing and neurotoxic that of a very the early stage; studies. clearly indicates to REPORTING ASSOCIATES (301) 390-5150 me that like I ct methamphetamine, 2 of 3 damage 4 system. ephedrine ephedrine, that dopamine studies. are lowest the 8 neurotoxicity neurons 9 whether 10 humans. or 11 12 that when 13 produce 14 orders of 15 that's also questions 18 Lieberman. 19 have 21 adjustment 22 tolerance 23 more 24 would 25 we don't of the ephedrine primate look at those the from is or the in we are of SCHWETZ: Dr. dosage, primates I can tell doses that are We don't two Dr. Schwetz and Berne Schwetz from Woosley. develops? MOFFITT the questions, made to And likely DR. WOOSLEY: the on the know if ephedrine. I have receptor what produce subjects nonhuman panel, less is, to for normally as yet the extrapolates case for with monkeys by some humans. the nervous know used JONES: to central that isomer We don't issues toxicity minus brain. methamphetamine you in the potential know the that have What the where With a question likely that's is primate data DR. 20 the the DR. 17 in not the 16 has that doses in this ephedrine I think current -- to How much account are for these more then the of polymorphism? It is an excellent REPORTING ASSOCIATES (301) 390-5150 FDA. I an the adjustments be made by people to Dr. who question and