Grant Application for Lipoprotein Methodology and Its Applications, Regents, Lawrence Berkeley Laboratory, University of California

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PUBLIC HEALTH SERVICE TYPE PROGRAM NUMBER Am NO 6.0 YES App rwd : 7. Ranarch Involving Human Subiscu [S8e ~mtNCti#S) Am NO B . 0 YES - Not prcvioudy reponed REGENTS, UNIVERSITY OF CALI FOR N lA LAW RE N CE E E RKE LEY LAB ORATORY BERKELEY, CALI FORI4 IA 94720 UNIVERSITY OF CALIFORNIA 10. NAME. TITLE, AN0 TELEPHONE NUMEER OF OFFICIALIS) SIGNING FOR APPLICANT ORGANIZATIONtS) ASSOCIATE DIRECTOR FOR ADMIN IS TR AT I ON LAW RE N CE BE RKELEY LAB ORATORY 11. TYPE OF ORGANIZATION (Check applrcable rrcml FEDERAL STATE LOCAL 0 OTHER (Specify) .12. NAME, TITLE, ADDRESS. A N 0 TELEPHONE NUMBER OF OFFICIAL I N BUSINESS OFFICE WHO SHOULD ALSO BE NOTIFIED IF AN AWARD IS MADE UNIVERSITY OF CALIF R NIA BERKELEY, CALI FORN 1 A 94720 8 h -2740x5, 3,Tslephonr Number a1C3 FOR ~NF~ITIJTIONAL GRANT PURPOSES ISW Innnrcrronrl REGENTS UNIVERSITY OF CALIFORNIA LAk'RE N CE BE RKE LEY LAB ORATORY

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isolate the lipid - containing particles or lipoprotein s. have been indicated as predisposing individuals to arteriosclerosis and coronary la tion,research on physical properties, chemical composition and metabolism of human plasma lipoprotein s. .is indicated in order to obtain insights on how to control such Benefits : Human blood plasma will be used in the present studies in order to Certain of the lipoprotein s Since coronary diseases cause more than 50% of the deaths in our popufrom donors by venipuncture by licensed clinical technologists under medical supervision of Donner Laboratory. determining frequency of donor use; thus, blood will be drawn at intervals of not less than 8 weeks and no more than 5times a year for any given donor.. blood, he mato cr its will be determined witha lower limit of 41for males and 39 for females. I f 25 m l or less blood is withdrawn, no hematocrit will be determined before blood withdrawal. A Consent Form will be executed for each withdrawal. Plasma will be isolated from the subject ' s to ultra cent ri fuga tion to isolate various lipoprotein components. Studies will be , carried out on the electro ph ore tic distribution, chemical composition, and electron microscopic structure of the isolated lipoprotein s, How subjects will be used: Not more than one unit of blood (500 cc) will be drawn Alameda County Blood Bank criteria will be used i n whole blood and the plasma fraction will be subjected 3. Desc rfp tion of subjects : Volunteer adults subjects,both male and female, will hyperlipemias, coronary disease,renal dysfunction o r thyroid disease. Some female - subjects on birth control pills will also be studied. 4.Risks and discomforts: There will be no deleterious effects to the subjects other than the minor discomfort of the venipuncture and the risk' encountered ina normal blood donation program. when donating blood, a few feel faint or weak during or following the blood donation. will be used solely for our research on lipoprotein,physical and chemical properties, Subjects will include normal individuals as well as patients with identified Although the majority of people experience no difficulty - ThPs research does not involve " violations of normal expectations" since all material 5. No deleterious effects or violations are anticipated. * 6.Written consent will be obtained. 7 . Should any lipoprotein abnormalities or low hematocrits be uncovered i n normal subjects during the course of our investigations,we would make such known to the subject ' s physician. A copy of Consent Form is attached.

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. CONSENT To ACT 26 SUBJECT FOR Name of person(s) idlo rsill pcrform procedure(s)or and/or such assistants as may be selected by h into per f om the follo;i.ing Withdrawal of not core than 500 c c of blood for sc run lipoprotein after a 500 cc donation before additional blood m y bc \cithdra\in, and thatI nay not have 500 cc with drain more frequently than five times per year. 1 understand that at lezist cight weeks x a st elapse been explained to EC by 3. I understand that - the pro ce ? urc(s) znd investigation (5) described in Paragraph 1 inv6lv.e the fo1'lo;iing possiblc risks and disc on forts : the minor disc on fort of venipuxcture; and the risk cncountercd ina r.ornal blood donation progran. (Although the x a j or it y of pcoplc e s ? cric ; ~ c e no difficulty tihen donating blood, a few feel faint or mak durra$ o r folloviing the blood donation.) g ation arc as follo \ i s : of pos sib lc lipoprotein abn omx ili ties. Advancement o f kno:iledge on the co c tro l of 4 . Should any lipoprotein ab norn ali ties or low hc mato cr its be uncovered during the course of this investigation,I agree t o having this i n -. .. . fon nation made knorin t o my physician... Name of physician I und cr stand that I may tern in atc my participation in the study at

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1 . The research wi 11benefit individual patients by providing thorough e val - u ation of hyper1i pide mic states,and careful monitoring of effects of lipid - lowering diets and drugs. better ' understanding of mechanisms control1 ing. concentrations of plasma lipids which are important in the development of atherosclerosis and its - . . The benefits to scientific knowledge include a 2.He par in will be ' administered intravenously after a 12-14 hour test ina after he par in administration for u p to 10 w;eks during evaluation and treat - ment of hyper lipid emi a. - Several of the subjects will also participate in the protocol for blood necessary ' consent form. These procedures will be performed at the Lipid Center at Merritt Hospital by Dr. Krauss'. The t r & at nen t procedure for each subject will be a modality generally considered to' be appropriate for the specific category of hyper lipid emi a found to be present : ' dose of IO units / kg. Blood samples will b e. .o bt a in ed before and 10 minutes. Total volume will be approximately 50 ml he ek.. - 1) Hyper beta lipoprotein emi a : * 2) Dys beta lipoprotein er nia .= specific diet ; if diet not effective, 3)hyper ch yl micron emi a,hyper pre beta lipoprotein eri a : Specific diet, 4) Combined hyper lipid emi a : Specific diet,if diet note ffcc ti vc, When more than one a ttern at iv c drug is involved,thein ; ti al drug wi1Ibe randomly selected with the patients consent.If initial treatment is not maximally effective, or if toxicity is demonstrated,one of the other drugs will be employed.

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1) Patients with chronic renal failure will be studied before and dur - . Ing therapeutic hypo dialysis (administered by the Dialysis Unit 2) Patients with hypo lipid er nia will be studied during replacement energy Patients on estrogen-containing steroid preparations will be studied both on and off(6 weeks) hormonal treatment, with assurance o f a1 ternate means of contraception where indicated. c) All protocols for evaluation and treatment will be selected and conducted with the express understanding and approval o f the patient ' s primary physician; *Results of all studies will be transmitted to the physician. 3. Subjects will consist of male and female patients with documented hyperlip: idemia, including minors aged 7 and up, and possibly including University ' of California students. Subjects will also include patients with primary d is e is es - associated with hyper l ipidernii:. Renal disease, hypothyroidism, Minin al risk of exacerbation ofa bl'eeding tendency after intravenous 'Remote risk of a1 ler gic reaction to heparin.for anticoagulant therapy). Discomfort of strict dietary and drug ?dherence.(3) -.,._.. (4) Risks o f cholestyramine treatment: a) Transient alterations of liver function tests b) Constipation, abdominal bloating, ' nausea, vomiting. (5) Risks of Cl of ib rate treatment: a) Transient elevations of liver function tests, CPK, aldolase; - (6) Disc on forts and risks of nicotinic acid tre a tmnt :

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7) Discomfort and risks o f hemodialysis. istered by accredited he m dialysis unit and only to patients with severe chronic renal faiiure' who are linked in the regular dialysis program &ing standard therapeutic indications and guidelines. treatment wi 1 1 be conducted outside the mechanism of the experimental protocol, the discomforts and risks wi 1 1 not be described in dctai 1 . It i s to be noted, h wever, that during dialysis, large doses of heparin (10,000 u) are administered, and thus,' administration o f - much smaller amounts of heparin between dialysis will not prevent an increDiscomfort and risks o f thyroid replacement:. . a) Nervousness, instability, a1 tered boijel and menstrual patterns. Discomfort and risk of discontinuing estrogen-containing medications (for n o more than 6 weeks). a) Appearance o f menopausal syrptonis. b) Wi thdradal uterine bleeding. This procedure will be adminPossible pregnancy while using alternate means o f contraception. Heans to minimize deleterious effects: history o f abnormal 'prothrombin time, or anticoagulant be avai lable to treat a1 lergic reactions to heparin. ne. Patients o n digital is o r thyroxine therapy wi 1 1 Patients will be questioned. as to degree o f abdominal discomfort and Constipation. inal discomfort or muscle pain o r tenderness. SGPT, alkaline phosphatase, and bilirubin, and once weekly for Blood will be sampled once every two b) Patients will be questioned as to symptoms of abdo;;- Blood wiII be sacpled plasma levels of the drug Clofibrate.

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c)Nicotinic acid. Patients with abnormal glucose tolerance o r hyperuric emi a will be excluded.. Patients on the drug will be questioned as t o degree of flushing, rash, visual problems, or abdominai dis - blood sugar, uric acid, SCOT; SGPT, a lk all ne phosphatase, and Blood will be-sarnpled once every two weeks for fasting bil i ruh in. 4) Precautions for other treatment. The physician staff of the Dia lys - i s Unit will use their standard criteria for selection and tre a tmnt of patients. * Treatment will not be prompted, delayed, or otherwise influenced bythe study protocol. b) Hypothyroidism: Patients with knm nor suspected heart disease will be excluded. Patients will be questioned as t o nervousness, t acha car dia,or chest pain. Cardiovascular physical examination (including blood pressure and EKG) wi11 be performed every two weeks, or wiI1 measurement o f serum thy rox in and T3-rzsin uptake, . Treatment will be administered with concurrence o f the patient ' s .j ects who do not desire or cannot obtain alternate means o f contrace pti on wi 11 be excluded. Assurance o f such alternate means will be ob.tained fron the primary physician. Subjects will be asked to report excess vaginal bleeding. - - Privacy of information will be ensured by assess,ment of patients on an individual basis in an off.ice setting by the physician and nutrition : . is t involved in the study. protected by maintenance of closed files of patient data and ident if i - cation other than by patient ' s name i n any publications of the research. Confidentiality of information will be - Principal In yest i gator

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CONSENT TO ACT AS A HUMAN SUBJECT I1 Subject ' s Name: Date: to perform on ,the following procedure (5) and / o r He par in will be administered intravenously after a 12 hour fast in a dose of 10 u/kg. This dose is less than one - fifth that ordinarily used to treat patients in whom it is necessary to prevent clotting of blood. Blood . samples wi 11 be obtained before and 10 minutes.after he par in twice per week (total volume approximately 50 ml per week) for up t o 10 weeks while on dict or other therapy drug. will take 30-45 minutes. These procedures gill be done in Merritt Hospital and The purpose of performing these procedures is to help 2. The procedures listed ' in paragraph I have been explained to ITE b y Dr. Krauss and / or.I understand that all mere procedures wi 1I be performed with the understanding and approval of my regular physician,and that all test results will be a vai ' lable to him(her), -. and that any abnormalities found. during testing of my blood will be reported. 3.I understand that the procedures described in paragraph1in vol v z the fol lo;ring possible risks and discomforts : clotting tine for 1-2 hours,and I agree to remain within Mcr rit t Hospital for 1) He par in may increase blood 2hours after he par in injection for ob serval. 2) I also understand that thc re isa remote possibility.that I may have,sn allergic reaction to the he par in and that my physician has ' imr ; cdi at ely available drugs vrhich .could be in j ec : e d to combat the reaction. used in man; hcaltCIy people without apparent harm. It has been explained to me that this drug has bc en I understand that the