Greater freedom for the

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2 Greater freedom for the

3 hemopliac & Ms fily. Now the hemophiliac can enjoy a more normal lifestyle with much greater freedom for himself his family. The key to this freedom is Kote#{174}concentrate. Whether at home or on the road, KoAte#{174}concentrate enables the hemophiliac to treat himself quickly, safely, conveniently. Ko#{227}te#{174} concentrate usually reconstitutes in less than five minutes. Provides approximately 250 AHF units per 10 ml of solution. Travels anywhere without refrigeration for up to six months. And comes with an easy-open, flip-top plastic cap. Just as importantly, Ko#{228}te#{174} concentrate has low fibrinogen and minimal non-ahf protein levels, pmviding the assurances you need to let him treat himself. Antihemophilic Factor self-reliance forthe hemophiliac. See following page for summary of prescribing informauon. (Human) cufter &oiogic Division of Cutter Laboratories. Inc. Berkeley CA Th16 OflO

4 Ko ate Factor (Human) SEE SE(TJONS ENTITLED INDI(ATIONS ANt) WARNINC FOR DES( RIPTION OF HEPATITIS RISK THIS PRODUCT IS PREPARED FROM HtMAN VENOUS PLASMA EA( H INDIVIDUAL UNIT OF PLASMA AND EACH WT OF FINAL PRODUCT HAS BEEN TESTED BY THE RADIOIMMtNOASSAY METHOD AND FOUND NONREACTIVE FOR HEPATITIS B SURFACE ANTIGEN UNFORTUNATELY. THIS TEST DOES NOT PRE( LUDE THE PRESEN( E OF HEPATITIS VIRUS SEE WARNING Indications: Antihemophilic Factor (Human) Ko#{224}te mdicated for the treatment ii) classical hemophilia (hemophilia A) in which hire is a demonstrated difictenis of actisits of he plasma clotting factor Factor VIII Kti#{227}tepros ides a means of temporarils replacing he missing clotting factor in order io correct present bleeding episodes or order perform or in iii emergent s and elector surgers on hemophiliacs Antihemophilic Factor (Human) is not effecimse in the treatment if ion Wfllebrand s disease Warning: Kim#{227}ie concenttate is a putmf med dtied fraction of pooled plasma obtained from mans paid donmmrs The presen..e of hepatitis cirus should he assummmed and the hazard of administering Ko3ie cmmncettiraie should be weighed against the medical consequemtcemm) ssmmhhiilding mm part mcularls in persons ssmth less precious transfusimmns ii) blmnmd and plasma products Kasper and Kipnms ha iccimtic (uded that host who had (mu1 esposure to blood products had a high misk mm)deselimping hepatitis after mntroduc mum ii) c limit mug fac tot cmmncentrates. such as thus product Emmu ihi.msc paimc rmts espec malls those with mild hemophilia thes rs c:mninsend single d:mn:mr prmmducms Howeser. for patmc mims cc mb mod-rate mir sc sc ic hcmtmophmlua scbim base recemse#{231}l numerumus unlustiuns bl:smd amid plasnia ii) products bk lee) that hi risk if hepatitis is small Thes beliese cloitumug lc muir concentrates hate great that the sii Is umprosed the management of seseme hemophilia that these products should mmiii be detited tim apprmmpruaic patients Precaulions: I. Antihemophilic Fat iii (Human) Ko#{228}ie.is intended treatment of dismirdirs arising from a for bleeding deliciencs in Factor VIII This di, licienm.s should he proven prior iii administering Ko#{227}te since nii benefit mac be espec ted from its use in treating other causes of hemorrhage 2. Alter reconstitutioti administer promptf (cc thin 3 h:murs Dim not refrigerate alter reconstitution NOTE The reciimmendatitmn mmadminister prompils alter reconsiiiuiiiin is intended mmaciiid the ill effect of ans possible bacterial c:int,iminat mmiii occurring during reconstitution Ko#{227}ie is lulls stable cc mthi,ut poteni.s loss for at least 24 hours at room temperature a)ts i reciinstiiution 3. Administer tin) hs the inteasenous toute 4. A lifter shtiuld ht used prior to administering the reconstituted Ko#{227}te#{176} solution mac be accomplished using the enclosed sterile filter needle See Reconstitution and Administration directions 5. Ko8te contains lesels of blood group isoagglutinins cchit,h are not clinically significant when controlling relattsels minor bleeding episodes When large or frequenihs repeated doses are required in patients blood groups A B or AB the ptissibilits of tniracascular hemimlssis should be considered 6. Administration equipment ans and ret.onstituted Ko3ie not used should be discarded Adverse Reactions: No severe adserse reactions were reported during the clinical trials of KoAte One patient enperienced transient chest discomfort and cough beginning 20 minutes after infusion and lasting for one hour During subsequent infusions this patient had no further reactions A second patient developed transient dizziness following each of eight infusions Mild allergic reactions mas result from the administration of AHF preparations When large or frequentl repeated doses are required in patients other than those of blood tpe 0. there is a possibilit of intravascular hemolssis Should this condition occur leading to pro ressoc anemia, administration of serologically compatible type packed red blood cells should be considered i Also the administration of t.pe specific crvoprectpitate has been recommended for maintaining adequate Factor VIII levels i Storage: Antihemophilic Factor (Human). Ko8te should be stored under refrigeration (2#{176} to 8#{176}C, 35#{176} to 46#{176}F)Stora4e of hophilized powder at room temperature (up to 25#{176}C or 77#{176}F) for six months. such as in home treatment situations may be done wilhoul loss of Factor VIII activity How Supplied: Antihemophilic Factor (Human). Kolte is supplied in single dose bottles with the total units of Factor VIII activity and total grams of protein stated on the label of each bottle A suitable volume of Sterile Water for Injection. US.P. and a sterile filter needle is provided. Limited Warranty: A number of factors beyond our control could reduce the efficacy of this product or even result in an ill effect following its use These include storage and handling of the product after it leaves our hands, diagnosis. dosage. method of administration, and biological differences in individual patients Because of these factors, it ts important that thts product be stored properls and thai the directtons be followed carefully during use. and that the risk of transmitting hepatttis be careful! weighed before the product is prescrtbed No warranty express or implied, including any warranty of merchantability or fitness is made Representatives of the Company are not authorized to vary the terms or the contents of the printed labeling including the package insert, for this product except by printed notice from the Company s Berkeley, California office Prescriber and user of this product must accept the terms hereof References: I. KasperCK, Kipnis SA: Hepatitis and clotting.factor concentrates JAMA 221: Rosati LA. Barnes B. Oberman HA. et al. Hemolytic anemia due to anti-a in concentrated antihemophilic factor preparations Transfusion Seeler RA Hemolysis due to anti-a and antib in factor VIII preparations Arch Intern Med This Fellowships at NIH Fellowship available July 1, 1979 for two years in clinical and laboratory research in blood coagulation, platelet physiology and biochemistry, and immunohematology. Candidates should have one or two years of residency in medicine. If qualified for appointment to the Public Health Service Commissioned Corps, salary starts at $20,500, part taxexempt with travel expenses and health care provided. Contact: Dr. N. Raphael Shulman, Clinical Hematology Branch, NIAMMD, National Institutes of Health, Public Health Service, Building 10, Room 9N250, Bethesda, MD 20014, (301) An Equal Opportunity Employer Cancer hasn t stopped 5OO,OOO people from living. They did it by not letting fear kill them. They did it by going to the doctor in time. They did it with the help of the effective methods of treatment today: surgery... radiation. - - chemotherapy. They did it because of the advances made through research. More than 1,500,000 Americans are living proof cancer can be cured. The American Cancer Society needs millions to save millions more. Please, give more today. We want to wipe out cancer in your lifetime. Amecan Cancer Society Th apacsconbsbuisdbv at. oiishse. iv BLOOD-THE JOURNAL OF THE ASH Qifter Bkog Division of Cutter Laboratories. Inc Berkele, California 94710

5 EEU2f= Hematology Analyzer with Platelets Now there is a single instrument that makes the complete blood count complete. By providing RBC, WBC, and platelet counts-plus the five other traditional parameters. In one run, in just one minute. From sample-in to hard copy output. On a single 90 ul whole blood sample. Before you make a move in hematology instrumentation, be sure to hear the complete ELT-8 story. Write for detailed information. The ELT-8. It changes the meaning of CBC. Ortho Instruments Clincal and Research Laboratory Instrument Systems 410 Unversty Avenue, Westwood, Mass Call toll-free 1 (800) , (617) ELT-8 is a trademark of Ortho Instruments

6 B OD The Journal of The American Society of Hematology Blood: The Journal of The A Fnerican Societr of Hematology is published monthly, in two volumes per year. Editorial correspondence should be addressed to: Dr. Paul A. Marks, Editor BLOOD Columbia University College of Physicians and Surgeons 701 W. 168 St. New York. N. Y Other correspondence (copyediti ng. production, subscriptions, changcs of address, etc.) should be add ressed to: Mr. Kenneth Brown. Managing Editor BLOOD Grune & Stratton. Inc. ill Fifth Aye, New York, N. Y Subscription rates: $58.00 per year within the United States: foreign, $62.00 per year. Students, Research Fellows. Interns, and Residents may receive a reduced subscription rate: S43.00 per year within the United States: foreign. S47.00 per year. A letter giving qualifying data must accompany such orders. Single copies: U.S.. $7.50: foreign, $8.00. Subscriptions are accepted on a calendar-year basis, Prices are subject to change. Back-issue and back-volume prices are those in current etlect - Change-of-address notices, including both the subscriber s old and new address, should be sent to the publisher at least one month in advance. Advertising Representative: Charles C. Cunningham, Inc., P.O. Box 308, Park Ridge, New Jersey 07656, telephone (201) Agents for Great Britain: Academic Press, Inc. (London) Limited, Oval Road. London NWI 7DX. England. Agents for Australia and New Zealand: Harcourt Brace Jovanovich Group (Australia) Ptv. Ltd.. P.O. Box 300. North Ryde. N.S.W Australia. The appearance of the code at the bottom of the first page of an article in this journal indicates the copyright owner s conselut that copies of the aricle may be made for personal or internal use, or for the personal or internal use of specific clients, This consent is given on the condition. hovever. that the copier pa the stated per-cops fee through the Copyright Clearance Center. Inc. for copying beyond that permitted by Sections 107 or 108 of the U.S. Cops right law. This consent does not extend to other kinds of copying. such as cops ing for general distribution, for advertising or promotional purposes. for creating ne collective works, or for resale. Absence of the code indicates that the material may not be processed through the Copyright Clearance Center. Inc. Postmaster: Send 3579 to 300 W cst Chestnut St., Ephrata, Pa Return postage guaranteed. Second-class postage paid at Ne York. N.Y.. and at additional mailing offices. The.1 nu rican Socic it- of IIematolot ceriifie.s i/la! the continuing i;iedit al education offering provith d hi- BLOOD, The Jouriial o/the -1 inerican Socieii of Hematology. meets the criteria for up to 22 hours of credit in (aiegorv 5a for the Phvsician.c Recognition -1 (lard of i/ic.-lmnerican,tledical Association , Grune & Stratton, Inc. 111 Fifth Avenue, New York A Subsidiary of Harcourt Brace Jovanovich, Publishers

7 BLOOD-THE JOURNAL OF THE ASH ix TO The The Doxoiubicin [129] Adriamycin)* dioimmunosay Kit For investigational Use Only. High circulating levels of Adriamycin may result in irreveisible myocardial damage, bone marrow depression, and gastrointestinal trauma. Knowledge of circulating Adriamycln concentrations therefore, is important. Our I Doxorubicin (Adriamycin) Radioimmunoassay Kit features a rapid, simple procedure with 100 picogram sensitivity in serum, plasma or urine. SIx precalibrated standards as well as a control serum are supplied. The stable I tracer and one hour incubation time makes this kit a unique tool in cancer management. 1. Bonadonna, G. et al: Phase I and preliminary Phase U evaluation of adilemysin (NSC ), Cancer Roe. 30, 2572, MIddleman, E. et 81: ClInical trials with adriamycln. Cancer, 28, 844, Wang, J. et al: Therapeutic effect and toxicity of adrlamycin in patients with neoplaati.c diseases. Cancer, 28, 837, 1971 Tradename Adria Labs. Cancer Diagnostic Biochemistry Inc Presents a Methotrexate (129] Radloimmunoassay Kit High dose Methotrexate therapy in combination with leuoorin rescue treatment creates a vital need for close monitoring of circulating Methotrexate plasma levels. Methotrexate overdose has been shown to bi easociated with severe myelosuppres$iofl, renal damage 2 and hepatotoxicity.5 Our 9 Methotrexs Radioimmunoassay Kit provides a simple method, with sensitivity of 10 ograms in serum, plasma, cerebrospinal fluid or urine. Results can be repovted in less than 1#{189} hours. Precalibr$ted human serum standards and control serum are provided as well as a stable 29 tracer and anti serum. 1. SW. Pitman et al: Clinical Trial of HighOoee Methotreiete (NSC-740). With Citrovorum Factor (NSC-3500)-Toxicologlc and Therapeutic Observations. Cancer Chemotherapy Reports Part 3 Vol. 6, No. 1, July Stoller, Ronald Cl. et al: Use of Plasma Pharmacokinetics to PredIct and Prevent Methotrexate ToxicIty. N.E. Jr. of Med. Vol. 297 No. 12: , Sept. 22, Jaffe N. and Traggls 0. Toxicity of hlgh.dose methotrexate (NSC- 740) and citrovorum factor (NSC-3590) rescue in osteogenic sarcoma. Cancer Chemother. Rep. Part 3, VoI.6(1)31 36, For further information call or writs: :nostic iochemistr y Inc. (714) O457H ROSELLE STREET #{149} SAN DIEGO, CA 92121

8 Abbott announces Abboki Urokinase Laboratories nase#{174} for Injection A unique thrombolytic agent for the management of acute massive pulmonary embolism Acute massive pulmonary embolism is a catastrophic phenomenon. It is estimated that between 140,000 and 200,000 persons die each year as a result of pulmonary embolism. Previously, anticoagulants or surgery have been the only measures available to the physician to combat this condition. The introduction of Abbokinase represents a significant addition to the limited therapeutic armamentarium available for the management of acute massive pulmonary embolism. While not without risks, thrombolytic therapy has proven capable of producing rapid dissolution of pulmonary emboli with prompt improvement of hemodynamic parameters. A new generation of thrombolytic agents Abbokinase acts on the endogenous fibrinolytic system by converting plasminogen to the proteolytic enzyme, plasmin. Plasmin, in turn, degrades fibrin clots as well as fibrinogen and other plasma proteins. The plasmin is rapidly inactivated by a variety of naturally occurring plasma inhibitors.2 Since plasminogen is present in the thrombus/embolus, activation by Abbokinase occurswithinthethrombus/ embolus as well as on its surface.3 Abbokinase Plasminogen..j Plasmin Fibrin (ogen) Soluble Degradation Products (FDP/fdp) Diagrammatic representation of the activation of plasminogen by Abbokinase, and the degradation of fibrin (ogen) by plasmin. Abbokinase is not a foreign protein. Originally derived from human urine, it is now obtainable from human kidney cells by tissue culture techniques developed by Abbott Laboratories. Unlike streptokinase, Abbokinase has been associated with few allergic responses. Induced antibody formation is not seen in intradermal tests. To make Abbokinase readily available throughout the U.S., it initially will be distributed from North Chicago, Illinois and 45 strategically located hospitals. For a copy of the ABBOKINASE REFERENCE MANUAL, please write Medical Services Depart- ri ment, Abbott Laboratories, -. Pharmaceutical Products Division, North Chicago, References 1. McNicol, G. P., The Fibrinolytic Enzyme System, Posfgraduate Medicine, August, 1973 (supplement). 2. Aoki, N., et al, The Behavior of a 2-Plasmin Inhibitor in Fibrinolytic States, Journal of Clinical Investigation, 60: , 1977.,,,o,, 3. Chesterman, C. N., et al, Relationship of Piasminogen Activator to Fibrin, Nature (New Biol.), 238:15-1 7, Please see following page for Brief Summary

9 XII Abbokinase#{174} Urokinase for Injection Brief Summary BLOOD-THE JOURNAL OF THE ASH ET R A010kleAsEierokiuuo or epecitoalshould ooly be used by physiciaos with wide espurleoce 0 the unoagoment of thrnmbotlc disease io hespilals where the recommended clinical and laboratory sweltering bee WARNINGS.PRECAUTIONS anddosageandadministrationi coobe performed. When considering treatment with urokinase. the physician should carefully osssssthe over oil clinical status and history of the patie,l. The hemostatic capability of the patient is mere profoundly altered and bleeding more trequent with urokinase therapy hoe with hepario or oral coumarin anticuagulaet therapy. When bleeding occurs Ills alsomoresevereandmore difficult to monoge. The peteellal risk of serious hemorrhagerelative to suchfactorsas age. physical cueditien. and nederlying bleeding tendency of the patieet las described under WARNINGS and PRECAUTIUNSIshouldhe weirbedarainstthe potentialbenefits of treatingthe patientwith urok louse. INDICATIONS Pulmonary Embolism A000KINASE urokinase br inlectionl 5 indicated n adutts for the lysis of acute massive pulmonary emboli defined as obstruction or significant filling defects involving two or more lobar pulmonary arteries or an equivalent amount of emboli in other vessels for ne Iysis ol pulmonary emboli accompanied by unstable nemodynamics e tailure to maintain blood pressure witnout supportive measures diagnosis snould be confirmed by obfectiue means Inc preferably pulmonary arteriograptty liroktnase treatment should be instituted as soon as possible alter onset of pulmonary em bolism and no later than live days alter onset Under tnese circumstances angiographic and ttemodynamic measurements demonstrate more rapid improvement Outing toe 24 a first tours of therapy than witit heparin therapy ITable II yowever t nas not been established that treatment with urokinase decreases morbidity mortality when compared to heparin or therapy Change alone in angiograpric Severity score based Dii 4-point system TABLE I ope I uspet Hour t2-ytur 2 24your Hepurn Lirokinase Ui,ia5e Urokirase tyy t7y Decrease in relative t 2: 29 2 percentage perfusion defect on lung scans Change in pulmonary - t I arlery 1mm Hgl pressure Change in cardiac - U 05 n 0 02 U 06 #{149} U 30 index 11mm m#{176}l dtokinase pulmonary embolism trial.. Urokinasestreptokinase pulmonary embolism trial Evaluations were obtained between 8 and 30 hours after ne start of nerap Utter several days there were no differences between the results the heparn treatec patients and those ih receiving urokiruase p Adapted from ill CONTRAINOICATIONS- Because trirombolytic therapy increases the risk if bleeding utokinase is contraindicated in the following situations I Surgery within ten days Liver or kidney biopsy lumbar puncture thoracentesis or paracentesis e tensiue or multiple cutdowns should be considerec surgical procedures Intraarterial diagnostic procedure within ten days 2 3 Ulcerative wound 4 Recent trauma with possibility of internal injuries 5 Visceral or intracranial malignancy 6 Pregnancy and the ten days first of the postpartum period 7 Ulcerative colitis, diverticulitis or an actively bleeding lesion or one with a significant potential for bleedingl of the gastrointestinal or gentourinary tract Severe hypertension 8 Acute or chronic hepatic or renal insufficiency Uncontrolled hypocoagulable state including 10 one that mar be caused toy a coagulation factor deficiency thrombocytopenia spontaneous fibrinolysis or an-other purpuric or hemorrhagic disorder 11 Chronic lung disease with cauitatioii e g tvbercuiosis t2 Subacure bacterial eriocarcitis ut rheumatic val.oldr OtseaSe 13 Recent cerebral embolism t7rombosis or hemorrhage Tteatme wtl it ease is contraindicated for at least two months after cerebral emboohsm trtro mbooss or hemiorrhage because patients with cerebral infarction remain at risk 1 bleeding ttti the ntarcted 14 Any oither conditoon inn whicr bleeding migho constitute a siqnilcant naoard it be particularly difficult to manage because of its location conditions listed above should not be regarded as the absolute co ntraiodicatioins Haiher he risk of hemorrhage must weighed carefully against the anticipated benefits urokinase be of therapy in an individual patient the benefits and ni5k5 associated With the use and of urokinase should be compared to the benefits and risks associated with other forms of therapy WARNINGS Bleeding Activation of the fibeinolytic system with uroirinase results in a more profound alteration of the hemostatic status of the patient than does anticoagulant therapy with heparin or coumarin agents The aim of urohinase therapy is the production of sufficient amounts of plasmin for the Ipso of intravascular deposits of fibrin, however. fibrin deposits which provide hemostasis. for example, at Sites of new dl e punctures, are also destined for fysis and bleeding from such sites may occur The possibility of bruising or hematoma formation, especially with intramuscular injections, is high during thrombofytic therapy Unnecessary handling of the patient should be avoided Strict attention should be given to this section and the contra/notca TI ONS section in order to minimize the risk of bleeding Because of the high risk hemaroma formation intramuscular inlections must be avoided of duting urokinase therapy as with heparin therapy Bleeding Sites of recent invasive procedures at may occur Hence arterial invasive procedures must also be avoided before and dur- ing treatment with urokinase Should an arterial puncture be absolutely necessary the femoral atleny must be avoided and the radial or brachial artery used It should be done catelully by a physiciar. e,pernenced in such a ptocedure Pressure should be applied for at least ts minutes, a pressute dressing applied, and the puncture site checked freguently for evidence of bleeding Also. uennpunctutes should be perfotmed as carefully and nnfteguently as possible If the bleeding from an invasive site 5 not serious trearment may be continued with appropriate clinical observation Local measures i e pressure should be initiated inmediately Spontaneous bleeding from internal sites lnot accessible for pressure applicatiohi may also occur the risk of spontaneous bleeding is greater in patients with preexisting hemostatic detects e patients with histories suggestive prior bleeding problems or without g of with demonstrable abnormalities in platelet count prothrombin time pattial thromboplastin time or bleeding time Such patients should be assessed catefully before initiating tteatment with ok nna se In addition to its fibrinolytic action plasmin also degrades fibrinogen Factot V Factor VIII and other proteins the products of plasmin degtadation of librinogen and fibtin lfdpofdpi possess anticoagulant effect Bleeding may be difficult to control because this anticoagulant an of effect Should serious spontaneous bleeding occur, infusion urokinase should be tetminated the of immediately and treatment instituted as described under ADVERSE REACTIONS Predisposition to Cerebral Embolism Treatment with urokinase of patients with atrial fibrillation or other conditions in which there is possible risk of cerebral embolism may be hazardous because he risk bleeding into of of the infatcted area Use of Ant icoagulants Concurrent use of annicoagulants with utokinase is not recommended and may be hazardous Before starting urokinase in patients being Ireated with heparin nrc effects of heparn should be allowed no diminish with time As a general rule a thrombin time of less than twice the normal control ualue 5 adequate tot starting urokinase infusions safely Similarly heparin Should not be started following utokinase therapy until the thrombin has returned time to less than twice the normal control value Rethrombosis has been observed after termination of urokinase treatment In order to minimize this risk the use of,00travenous heparin followed by oral anticoagulant therapy is considered a necessary adlunct toliowing urokinase therapy 15cc DOSAGE ANb ADMINIS TRAtlONi Use in Pregnancy See CONTRAINDICATIUNS Use no Children Safety and effectiveness of urokihase therapy in children have not been established rherefore treatment or such toatients is nit recommended PRECAUTIONS Drug Interactions Concurrent use it drugs that may alter platelet function e g aspirin ndomethacnn and phenyibutazone should be avoided The nn!eractnor. of ABBOKINOSE Iuroknnase for inlectioni With other drugs nas nor been studied Laboratory Monitoring In patients who have received heparin the thrombin time should be measured prior to starting urokinase See WARNINGS I Smilarlr the thrombin time Should be monitored following urokinase therapy prior to instituting heparin See DOSAGE AND ADMINISTRATION I Duting uroknase adminisnratnon the levels of fibrinogen plasminogen Factor V and Factor VIII are usually substantially diminished Concomitantly the level of fibrnlogenl degradation prod ucts IFDP-ldpi 5 increased The combination reduced Ibrinogen and increased FDPfdp of results in a prolongation of the thrombin time While changes in any of these parameters may serve as confirmation of the existence of a lytic state no adlustment of dosage should be made on the basis of these test results ADVERSE REACTIONS Incidence and Management Strict observance of tne contrandicannons wathihgs and precautions to the use of urokinase is essential to minimize the incidence and severity of adverse effects BLEEDING Incidence Where thromboiptic agents Istrepookinase and urokinasel were used in the same controlled clinical trial severe bleeding Ipatients receiving a transfusion of greater than two units of blonodl was seen in 4 and 6 respectively Several fatalities due to cerebral hemorrhage have occurred during utokinase thetapy Less severe spontaneous bleeding has been observed during urokinase treatment at approximately twice ne frequency as that occurring during heparn therapy Oozing blood of from sites percutaneous trauma is frequent hence all tnvasiue procedutes especially at- of teral punctures and intramuscular inlections must be avoided and intravenous punctures kept to a minimum before and treatment with urokinase during A moderate decrease in hematoctin not accompanied by clinically detectable bleeding occurred in approximately one out of five patients treated With urokinase Management of Severe Bleeding in case ot serious bleeding urokinase therapy muso be discontinued If blood loss nas been large packed red cells are indicated Plasma volume expanders lcther than Dexntanl are indicated to replace blood volume deficit If only whole blood is available it may also be used Althovgr the use of aminocaptnic acid IACA AMICAR I in humans as an antidote for - urokinase has not been documented it may be considered ifthe hemorrhage is unresponsive to, blood replacement See WARNINGS I ALLERGIC REACTIONS Although urokinase is a protein of human origin and in vitro tests With ne drug as well as inradermal test humans gave no evidence of induced antibody formation the possibility of in serious allergic reactions Including anaphylaxisl occurring with its use cannot be excluded Relatively mild allergic reacions e g bronchospasm and Skin rasn were reported rarely FEVER Febrile episodes occurred in approrimately two to three out of 100 patients A cause and effect relationship has not been established Symptomatic treatment is usually sufficient to alleviate discomfort The use of acetaminophen rathet than aspitin is recommended DOSAGE AND ADMINISTRATION Dosing ABBOKINASE is INTENDED FOR INTRAVENOUS INFUSION ONLY A priming dose of I U lb IU kgl of ABBOKINASE is given as the Abbokinase- Normal Saline admixture over a period of ten minutes This is followed by a continuous infusion of I U lb hr I U kg hri of ABBOKINASE given as the Abbokinase-Normal Saline admixturel for 12 hours The total volume of fluid administered Should not exceed 200 Administer ABBOKINASE lutokinase for inlecnionl by means of a constant infusion pump that is capable of delnueting a tonal volume p1 195 ml Anticoagulation After Terminating Urokinase Treatment Ar the end of urokinase therapy treatment with heparin by contihuous intravenous infusion is recommended Hepatmn treatment Should not begin until the thrombin time nas decreased to less than twice the normal control value See manufacturer s prescribing information for proper use of heparin

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11 In patients on renal dialysis ani re with -Du in nandrolone decanoate injection, NF Regular therapy with DecaDurabolinR may stimulate the production of red blood cells, and raise hemoglobin and hematocrit levels in patients on hemodialysis.14 BRIEF SUMMARY: Please consult full product information In the package Insert before prescribing. NAS/NRC review panels have classified Deca- Durabolin -- possibly effective adjuvant therapy in certain refractory anemias. CONTRAINDICATIONS: 1. Male patients with carcinoma of the prostate or breast 2. Carcinoma of the breast in some females. 3. Pregnancy. because of masculinizaf ion of the fetus. 4. Nephrosis or the nephrofic phase of nephrifis WARNING: Anabolic steroids do not enhance athletic ability PRECAUTIONS: 1. Hypercalcemia may develop both spontaneously and as a result of hormonal therapy in women with disseminated breast carcinoma If it develops while on this agent, the drug should be stopped. 2. Caution is required in administering these agents to patients with cardiac, renal or hepatic disease Edema may occur occasionally Concomitant administration with adrenal steroids or ACTH may add to the edema 3. If amenorrhea or menstrual irregularities develop the drug should be discontinued until the etiology is determined 4. Anabolic steroids may increase sensitivity to oral anticoagulants Dosage of the anticoagulant may have to be decreased in order to maintain the prothrombin time at the desired therapeutic level. 5. Anabolic steroids have been shown to alter glucose tolerance tests. Diabetics should be followed carefully and the insulin or oral hypoglycemic dosage adlusled accordingly 6. Anaboic steroids should be used with caution in patients with benign prostatic hyperfrophy 7. Serum cholesterol may increase during therapy. Therefore, caution is required in administering these agents to patients with a history of myocardial infarction or coronary artery disease Serial determinations of serum cholesterol should be made and therapy adjusted accordingly ADVERSE REACTIONS: 1. In Males: a. Prepuberfal: 1) Phallic enlargement, 2) Increased frequency of erections, b Post-pubertal 1) Inhibition of testicular function and oligospermia. 2) Gynecomastia. 2. In Females: a. Hirsutism, male pattern baldness, deepening of the voice and clitoral enlargement. These changes are usually irreversible even after prompt discontinuance of therapy and are not prevented by concomitant use of estrogens, b. Menstrual irregularities. c Masculinization of the fetus. 3. In Both Sexes a Nausea. b Increased or decreased libido, c Acne (especially in females and prepubertal males), d Inhibition of gonadotropin secretion, e. Bleeding in patients on concomitant anticoagulant therapy, f Premature closure of epiphyses in children 4. Alterations in these clinical laboratory Vests a. The melyrapone test, b. Glucose tolerance test, c The thyroid function tests a decrease in the PBI, in thyroxine-binding capacity and radioactive iodine uptake, d. The electrolytes: retention of sodium, chlorides, water, polassium, phosphates and calcium, e. Liver function Vests. 1) Increased serum cholesterol, 2) Suppression of clotting factors. II, V, VII, and X 5. There have been rare reports of hepatocellular neoplasms and peliosis hepatis in association with long-term androgenlc-anabolic steroid therapy SUPPLIED: Deca-Durabolin (in sterile sesame oil solution for intramuscular injection) is available n a potency of 50 mg ccc. with 10% benzyl alcohol (preservative) 1 cc ampuls, box of 4 NDC = cc multiple dose vial NDC = Also avatlable in a potency of 100 mg. cc -with 10% benzyl alcohol (preservative) 2 cc multiple dose vial NDC o REFERENCES: 1. Buchwald, D et al Nephron (1977) 2 Hendler, ED. et al. N EngI J Med (1974). 3 Williams. J S et al Arch Intern Med (1974) 4 Doane, B D et al. Arch Intern Med (1975) Organon Pharmaceuticals crancvn A DIVISIOn of Organon Inc. West Orange. N.J

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14 ICAR AMINOCAPROIC INTRAVENOUS TABLETS#{149} SYRUP ACID INDICATIONS: AMICAFIhas ptoved useful, in many instatces. in the teat sent of excessive bleeding which results torn systemic ltvperfibritto4osio and urinaryfibrinolysns In lifethreatening situations, ftesh whole blood ttanstuslons, libntnogen infusions, and other emergency measutes may be tequnred Systemichypedibtnolysis, a pathological condition, may ftequently beasso cnated with surgical complications following heart surgery (with ot wtthout catdiac bypass procedutes) and portacaval shunt. Itematological disorders such as aplastic anemia, abrupyo p/aentae, Itepatic cirrhosis, neoplastic disease such as catcinoma of theprostate, lung, stomach, and cervix Urinary fibninolysrs. usually a notmal physiological phenomenon. may frequently beassociatedwrth hfethreatening complicatlonsf ollowrng severe trauma, anoxia. and shock SymptomatIc of such complications is surgical ttematuria (following ptostatectomy and nephtectomyl ot nonsurgicalitematuria laccom panying polycystncor neoplastic diseases of the genitoorfnary system) CONTRAINDICATIONS: AMICARshouldnot beusedwhen there IS evidence of an active intravascular clotting process WARNINGS: Safe use of AMICAR has not been established with respect to adverse effects upon fetal development Therefore, it should not be used in women of childbearing potential and particularly during early pregnancy, unless in the ludgment of the physician the potential benefits outweigh the possible hazards PRECAUTIONS: AMICAR aminocaproic acid has a very specific action in that it inhibits both phasmlnogen activator substances and, to a lesser degree. plasmfn activity The drug should NOT be administered wtthout a definite diag nosis, and or laboratory findings indicative of hyperfibrinolysls (hyperphasmi nemlal Stefanini, M and Dameshek. W The Hemorrhagic DIsorders, Ed 2. New York, Grune and Stratton. pp , 1962 The use of AMICAR should be accompanied by tests designed to determine the amount of fibrinolysis present There are presently available (a) general tests, such as those for the determinatton of the lysis of a clot of blood or plasma and (b) mote specific tests for the study of various phases of librinolytic mechanisms These latter tests include both semiquantitatfve and quantitative fechnics for the determination of profibninolysin, fibrfnolystn. and antlfibninolysir AnImal experiments indicate particular caution should be taken in adminis feting AMICARto patients WIth cardiac, hepatic or renal diseases. Demonstrable animal pathology in some cases have shown endocardlal hemorrhages and myocardial fat degeneration The use of this drug should thus be restricted to patients in whom the benefit hoped for would outweigh the hazard Physicians Ore cautnoned in the use of this product because of animal data showing rat teratogenicfty and kidney concretlons Rapid intravenous administration of the drug should be avoided since this may itduce hypotension. bradycardia and. or arrhythmia One case of cardiac and hepayclesions observed in man has been reported The patient received 2 grams of aminocaproic acid every 6 heirs for a total dose of 26 grams Death was due to continued cerebral vascular hemorrhage Necrotic changesin the heart andliver were noted at autopsy If if is accepted that fibrinolysis is a normal process. potentially active at all times to ensure the fluidity of blood, then it must also be accepted that inhibition of fibninolysis by aminocaproic acid may result in clotting or thrombosis However, there is no definite evidence that administration ol aminocaproic acid has beenresponsible for the few reported cases of Intravascular clotting which followed this treatment Rather, it appears that such intravascular clotting was mostlikely aresult of the fibrinolytic disease being treated It has been postulated that extravascular clots formed In vivo with incorpo rated aminocaproic acid may not undergo spontaneous lysis as do normal clots Howevet, it is the consensus of experts that the few reported cases of extra vascular clotting could have occurred in the absence of aminocapnoic acid reatment ADVERSE REACTIONS: Occasionally nausea, cramps, diarrhea, dizziness. tinnitus. malaise, conlunctival suffusion, nasal stuffiness, headache, and skin rash have been reported as results of the administration of aminocaproic acid Onlyrarely has it been necessary to discontinue or reduce medication because of one or more of these effects Thrombophlebitis, a possibility with all intravenous therapy, should be guarded against bystrict attentton to the proper insertion of the needle and the fixing of Its position DOSAGE AND ADMINISTRATION: INITIAL THERAPY- An initial priming dose of 5 grams of AMICAR administered either orally or intravenously followed by 1 to t/ gram doses at hourly intervals thereafter should achieve and sustain plasma levels of 0130 mg ml of the drug This is the concentration apparently necessary for the inhibition of systemic hyperlibrinolysis Administration of mote than 3D grams in any 24-hour period is not recommended INTRAVENOUS: AMICAR aminocaproic acid Intravenous IS administered by infusion, utilizing the usual compatible Intravenous vehicles )e g Sterile Water for Inlection, physiologic saline. 5,1, dextrose or Ringer s Solution). RAPID INJECTION OF AMICAR INTRAVENOUSUNDILUTED INTO A VEIN IS NOT RECOMMENDED For the treatment of acute bleeding syndromes due to elevated fibninolytic activity, it is suggested that 16 to 2D cc 14to 5 grams) of AMICAR intravenous be administered by infusion during the first hour of treatment, followed by a cononuinginfusion at therate of 4cc It 0 gram) per hour This method of treatment would ordinarily be continued for about 8 hours or until the bleeding situation has beencontrolled ORAL THERAPY: If the patient is able to take medication by mouth, an denlical dosage regimen may be followed by administering AMICAR Tablets or 25% Syrup as follows For the treatment of acute bleeding syndromes due to elevated fibninolyticactivity, ills suggested that to tablets 15 gramsl or 4 teaspoonfuls of syrup IS gramsl of AMICAR be administered during the first hour of treatment, followed by a continuing rate of 2 tablets It graml or t teaspoonful of syrup Ii t/, grams) per hour This method of treatment would ordinarily be continued for about 8 hours or until the bleeding situation has been controlled REV 7,l72 PL1I LEDERLE LABORATORIES, A DivisIon of American Cyanamid Company. PeaFi RiVer, New York

15 NOW FROM PARKE-DAVIS RESEARCH A BREAKTHROUGH IN THE TREATMENT OF A MAJOR VIRAL DISEASE

16 Announcing New I arenteral (vidarabine for infusion) -.. -xr.

17 A significant contribution in reducins mortality of patients with Herpes simplex virus encephalitis Fig. I Morbidity and mortality in biopsy-proved Herpes simplex virus encephalitis. U) z w NIAIDSTUDY N18 N-TO LL 0 z 40- LU 0 cc LU #{176}20- VIRA-At PLACEBO THERAPY P = 0.03 AT DAY 30 Early diagnosis and treatment are essential Controlled studies indicate that VIRA-A (vidarabine for infusion) reduced the mortality caused by Herpes simplex virus encephalitis from 70- to 28% (Chi-square analyses, P = 0,03) (Fig.1).1 o ALIVE, NO OR MINOR SEQU ELAE IALIVE, MODERATE SEQUELAE #{149} ALIVE, SEVERE SEQU ELAE #{149}DEAD Nationat of Allergy Institute and Infectious Diseases -adapted from Whitley, et alt Of 28 patients who were brain-biopsy positive for Herpes simplex virus, 18 received VIRA-A and 10 received placebo. There is a direct relationship between the outcome of therapy and the state of consciousness at the time that VIRA-A therapy is initiated. Once the comatose state is reached in the patient with Herpes simplex virus encephalitis, therapy may be futile. In the same double-blind placebo-controlled study of VIRA-A, over half the comatose patients died in spite of active drug therapy, and all the survivors were severely neurologically debilitated. But no deaths occurred among lethargic patients treated with VIRA-A, and six of seven survivors had only minor or moderate neurologic complications. After localization of an intracerebral lesion by brain scan, electroencephalography, and/or computerized axial tomography, brain biopsy is required to confirm the etiologic diagnosis by means of viral isolation in cell cultures. Detection of Herpes simplex virus in the biopsied brain tissue can also be reliably done by specific fluorescent antibody techniques. Recommended Dosage: 15 mg/kg/day for 10 days Note: There are no clinical studies available to indicate that VIRA-A for infusion is effective in the management of encephalitis due to varicella-zoster or vaccinia viruses. VIRA-A is not effective against RNA viral or adenoviral infections. Itis also not effective against bacterial or fungal infections. There are no clinical data to indicate efficacy against cytomegalovirus, vaccinia virus, or smallpox virus. Some degree of immunocompetence must be present in order for VIRA-A to achieve clinical response. Please see following page for complete prescribing information, including contraindications, warnings, precautions, and adverse reactions.

18 New Pan1 VIRkA Mdarabine for infusion) A significant contribution to medicine FULL PRESCRIBING INFORMATION Description. Vira A for iniusion lana A. vidanabine, adenine arabinosidvl is a sterile antivinai drug or intravenous administration only. ViraA IVidaratvne for iniuston) a punine no is cieoside obtained fnom fermentation cultures ol Streptvmyces antibioticus. Each milliliten of suspension contains 200 milligrams ol vidarabine monohydnate equivalent to milligrams of vidanabine Each milliliter contains 0 r milligram Phemerol benzethonium chloride) as a pneservative. sodium phosphate dibasic milligrams. and sodium phosphaie mvnobasic. 4 t38 milligrams. as buttering agents Hydrochloric acid may have been added So adiusi ph Vira A is a white. crystalline solid with this empirical formula ch N,OH0 The molecular weight is 285.2: the solubility is 0 45 mg/mi at 25Cc. and the melting point ranges from to 270CC The chemical is 9ll D-arabinofunanosyi- 260 name adenine monohydraie. with the following structural formula Clinical Pharmacology. Following intravenous admin istnation, Vira-A is rapidly deaminated into arabinosylhypoxanihine IAna Hxl. the principal metabolite. which NH2 is promptly distributed into he tissues Peak AraHo I and AraA plasma levels ranging from 3 iv 6 pg/mi and N 0.2 to 04 pg/mi. nespectioeiy. are attained after slow in N iravenous infusion of Vira A doses of to mg/kg of body I I I weight. These levels reflect the nate of inlusion and tt:, N show no accumulation across time The mean haif-lile N of Ara-Ho is 3 3 hours Ana-Ho penetrates into the cenebrospinai fluid IcsFl to give a csf/piasma ratio 01 approximately t 3 HO-CH2.H2O Excretion of Vira-A Is principally via the kidneys Urinary excretion is constant oven 24 hours Forty-one to 53uu Of the daily dose is recovered in the urine as H OH Ara-Hx with t to 3uu appearing as the parent compound. There is no evidence vi Iecai encretion of drug H H or metabolites in patients with impaired renal function OH H AraHx may accumulaie in the plasma and reach levels severaitoid higher than those described above Microbiology. Vira A possessesin vitro and in vivo antvirai activity against Herpesvirvs simplex IHerpes simplex virus) types t and 2. The antiviral mechanism of action has not yet been established The drug is converted into nucleotides which appear iv be involved with the inhibition ot viral replication in KB cells infected with Herpes simplex virus type t. Vira-A inhibits viral DNA synthesis Vira-A is rapidly deaminated to Ara-Hx the principal metabolite. in cell cultures laboratory animals. and humans. Ara-He also possessesin vitro antivinal activity but this activity is signilicantly less than the activity of Wa-A Indications and Usage. Vira-A is indicated in the treatment of Herpes simplex virus en cephalitis controlled studies indicate that Vina A therapy will reduce the mortality caused by Herpes simplex virus encephalitis from 70 to 28u VinaA therapy does not appear to alter morbidity and resulting serious neurological sequeiae in the comatose patient Therefore, early diagnosis and treatment are essential Herpes simplex virus encephalitis should be suspecied in patients with a history of an acute febriie encephalopathy associated with disordered mentation altered level of con sciousness and focal cerebral signs Studies which may support the suspected diagnosis include examination of cerebrospinal and localization of an nina-cerebral by brain scan. electroencephalography fluid lesion or computerized axial tomography ICATI Brain biopsy is required in order to confirm the etiological diagnosis by means of viral isolation in cell cultures Detection of Herpes simplex virus in the biopsied brain tissue can also be reliably done by specific fluorescent antibody techniques Detection of Herpes virus-like particles electron by microscopy or detection of intranuclear inclusions by hisiopaihologic techniques only provides a presumptive diagnosis There are no available reports to indicate that Vita-A Ion intusion is effective in the manage ment of encephalitis due to vanicella-zoster or vaccinia viruses Vita-A is not effective against infections caused by adenovitus or RNA viruses ii is also not effective againsi bacterial or fungal infections There are no data to support efficacy of Vita-A against cytomegalovirus. vaccinia virus on smallpox virus Contraindications. Vita-A is contraindicated in patients who develop hypersensitivity reactions to it Warnings. Wa-A should nol be administered by the intramuscular or subcutaneous route because its low solubility and poor absorption of Precautions. Treatment should be discontinued in the patient with a brain biopsy negative for Herpes simplex virus in cell culture Special cane should be exercised when administering Vita-A to patients susceptible to fluid overloading or cerebral edema Examples are patienis with NS inlections and impaired renal function Patients with impaired renal function, such as posi-operalive renal transplant recipients. may have a slower rate renal excretion ol Ara-Ho Therelore. the dose vi may of Vita-A need lobe adiusted according to the severity ol impairment These patients should be carefully moniiored Patients with impaired liver Iunciioo should also be observed ton possible adverse effects Appropriate hemalologic iesis are recommended during Vita-A administralion he- since moglobin. hematocnit white blond cells and platelets may be depressed during therapy Some degree ot immunocompetence must be present in onder ion Vita-A to achieve clinical response Usage in Pregnancy: Vita-A given paronteraily is ienaioqenic in rats and rabbits Doses ot mg/kg on higher given intramuscularly to pregnant rabbits organogenesis induced 5 during feial abnormalities Doses of 3 mg/kg or less did not induce tenatogenic changes in pregnant rabbits Vita-A doses ranging from mg/kg were given intramuscularly to pregnant rats during organogenesis. signs maternal toxicity were induced at closes too mg/kg of ol or higher and frank fetal anomalies were tound at doses of t5vio 250 mg. kg A safe dose the human embryo or fetus has not been esiablished for Consequently, the use of Vira-A in pregnant patients should be limited to life.threatening illnesses where the possible benefits ouiweigh the potential risks involved it is not known whether Vira-A is excreted in human milk As a general rule, nursing should be undertaken while patient is under treatment since many drugs ate excreied hu- not a in man milk However. Vita-A is rapidly deaminated in the gastrointestinal tract Adverse Reactions. The principal adverse reactions involve the gastrointestinal tract and are anorexia, nausea. vomiting. diarrhea These reactions are mild to moderate. and and sddom require termination of Vita-A therapy. CNS disturbances been occasionally have reported at therapeutic doses These are iremor. dizziness. hallucinations. confusion. psychosis. and atavia Hematologic clinical laboratory changes noted in controlled and unconirolied studies were a decrease in hemoglobin or hematocnit. white blood cell count, and platelet count SGOT elevations were also observed Other changes occasionally observed were decreases in reticulocyte count and elevated total bilinubin Other symptoms which have been reported are weight loss. malaise, prunitus. rash. hematemests, and pain ihe iniection site. at Overdosage. Acute massive overdose ofthe intravenous lorm has been reported without any serious evidence of adverse effect Acute water overloading would pose a greater threat tothe patient than Vita-A. due to its low soiubiiity Doses of Vira-A over 20 mg/kg/day can produce bone marrow depression with concomitant thrombocytopenia and leukopenia if a massive overdose of the intravenous form occurs. hematologic. liver. and renal functions should be carefully moniiored. Acute massive oral ingestion is 001 expected 10 be toxic because drug absorption from the gasirointestinal tract is minimal. The oral LD,. Ion Vita-A is greater than mg/kg in mice and rats. Dosage and Administration. CAUTION- THE CONTENTS OF THE VIAL MUST BE DILUTED IN AN APPROPRIATE INTRAVENOUS SOLUTION PRIOR TO ADMINISTRAlION RAPID OR BOLUS INJECTION MUST AVOIDED BE Dosage. Herpes simplex virus encephaiitis-t5 mg/kg/day for to days. Method of Preparation. Each vial contains 200 mg of Vira-A per ml of suspension The solubility Nra-A in intravenous infusion fluids is limited Each one mg of Vita-A of requires 2 22 ml of intravenous infusion fluid for complete solubilization Therefore. each one liter of intravenous infusion fluid will scilubilize a maximum of45o ViraA mg of Any appropriate intravenous solution is suitable for use as a diluentexcept biologic or colloidal fluids leg.. blond products. protein solutions, etc.l. Shake the Vita-A vial well to obtain a homogeneous suspension before measuring and transferring Prepare the Vira-A solution for intravenous administration by aseptically transferring the proper dose of Vira-A into an appropriate intravenous infusion fluid. The intravenous infusion fluid used to preparethe Vira A solution may be prewarmed to 35 to 40#{176}C195#{176} to too#{176}fi iv facilitate solution ofthe drug following its transference Depending on the dose to be given, more than one of intravenous infusion fluid may required Thoroughly agitate the liter be prepared admixture until completely clear Complete soiubilizaiion ofthe drug. as indicated by a completely clear solution. is ascertained by careful visual inspection Final filtration with an inline membrane filter y pore size or smailerl is necessary. Once in solution, the drug has been found to be chemically stable at room temperature below 86uFI for at two weeks Dilution should be madelust prior to administration least and used at least within 48 hours Subsequent agitation. shaking. or inversion of the bottle is annecessary once the drug is completely solution. in Administration. Using aseptic technique. slowly infuse theiotal daily dose by intravenous infusion prepared as discussed abovel constant rate over 2- to 24-hour period at a a How Supplied. N OO7t 0-Vit 4t5Ol Nra-A IVidarabine for intusionl, a sterile suspension containing mg/mi, in 5-mi SteriVials. packages of 200 is supplied to Animal Pharmacology and Toxicity. Acute Toxicity: The intrapenitoneal LD0 for Vira A ranged from to mg/kg in mice. and from to 2.5t2 mg/kg in rats, suggesting a low order of toxicity to a single parenteral dose Hepatic megalocytosis was observed ix rats after single. intrapenitoneal inlections doses near and exceeding the LD50 value. The at hepatic megalocytosis appeared to regress compleiely over several months Acute intrave nous values could be obtained because ofthe limited solubility Vira A not of Subacute Toxicity. Rats. dogs. and monkeys have been given daily intramuscular iniecions of Vira A as a suspension for 28 days. These animal species showed related 20 dose decreases in hemoglobin. hematocrit. and lymphocytes Bone marrow depression was also observed monkeys. Except for localized. inlection-site inuny and weight gain inhibition or in loss, rats tolerated daily doses up to 50 mg/kg. and dogs tolerated daily doses up to 50 mg/ kg. Megalocytosis was not seen in the rats dosed by the intramuscular route for 28 days Rhesus monkeys were particularly sensitive to Vita-A. Daily iniramusculan doses vi t5 mg/kg were tolerable, doses of 25mg/kg on higher induced progressively severe clinical signs but of CNS toxicity. Three monkeys given slow intravenous infusions of ViraA in solulion at a dose of 5mg/kg daily for 28 days had no signilicani adverse reactions Tumorigenicity. Chronic parenteral I1M) studies ol vidarabine have been conducted in mice and nais. In the mouse study, there was a siatistically significant increase in liver tumor incidence among the vidarabine-ireated females in ihe same study, some vidarabine ireaied male mice developed kidney No renal tumors were found the vehicle.treaied control neopiasia in mice or the vidarabine-trealed lemale mice In the rat study. intestinal, testicular, and thyroid neoplasia occurred with greater frequency among the vidarabine-trealed animals ihan in the vehicie.treated controls The increases in thyroid adenoma incidence in he high-dose 150 mg/kgl males and the low-dose 130 mg/kgl lemales were statistically significani. Hepatic megalocytosis. associated with vidarabine treatment, has been found in sfiort- and long-ierm rodent (rat mousel sludies. his not whether on this represents a and clear not pneneoplasiic change. Mutagenicity. Results olin vitro experiments indicate that vidarabine can be incorporated into mammalian DNA and can induce mutation in mammalian cells L5t78Y cell Imouse linel Thus latin vivo studies have not been as conclusive, but is some evidence (dominant there leihal assay in mice) thai uidarabine may be capable vi producing mutagenic effects in male germ cells it has also been reported that vidarabine causes chromosome breaks and gaps when added inhuman leukocytesin vitro While ihe significance of these effects in terms of mutagenicity is not fully understood. thene isa well-known correlation between the ability of various agents to produce such effects and their ability produce heritable genetic damage to WK Reference: t Whitley RJ. Soong S-i. Dolin R. et al Adenine arabinoside therapy of biopsyproved herpes-simplex encephalitis National institute of Allergy and infectious Diseases Collaborative Antiviral Study N EngiJ Med August tt PD-JA-2559tP )t278) PARKE-DAVIS PARKE-DAVIS Division of Warner-Lambert Company Morris Plains, NJ 07950

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21 BLOOD-THE JOURNAL OF THE ASH xxv I ImmuneEffector Mechanisms in Disease Proceedings of the Fourth Irwin Strasburger Memorial Seminar on Immunology Edited by MARC E. WEKSLER. M.D.. ROBERT R. R1GGIO. M.D., STEPHEN D. LITWIN, M.D.. and GREGORY W. SISKIND, M.D. Sponsored by the Department of Medicine, Cornell University Medical College, The New York Hospital, New York, N.Y. CONTENTS: C. Bwnco and P. J. Edelson, Characterization of the Activated Macrophage. R. J. North, Macrophage Function in Antitumor and Antibacterial Resistance. T. C. Jones, Control of Intracellular Parasitism by Macrophages. R. II. Riggio et a!., Immunological Enhancement: Studies on Human Gamma Globulin of Retroplacental Origin. F. T. Rapaport, New Approaches to the Induction of Allogenic Unresponsiveness. J. Thomas et a!., A Search for Mechanisms Facilitating Human Non -Identical Allograft Survival: Some Pal ameters of Cell-Mediated Immunity in Long Term Human Renal Trans. Plant Recipients. C. B. Carpenter et a!., Specificity in Allograft Rejection. W. F. Paul, Immune Effector Mechanisms: Duality of Recognition Functions. I?. B. Ilerberntan, Natural Cell-Mediated Cytotoxicity Against Tumors. W. Strober, The Cellular Basis of Nonspecific Cytotoxicity Reactions. P. (. Doherty, Cell-Mediated Immune Response in Virus Infections. J. F. Woodru/7 et a!., Cytotoxic T Cells in Coxsackieviral Disease. 1977, 272 pp.. 14 i/las., $15.25 (8.50 ISBN: Clinicalilistocompatibility Testing, Volume2 Edited by CHARLES B. CARPENTER. M.D. A Transplantation Proceedings Reprint, December 1977 SECTION HEADINGS: Serologically Defined Antigens of the Major Histocompatibility Complex (10 papers). Mixed Lymphocyte Response: HLA-D and T-Cell Receptors (3 papers). Primed Lymphocyte and Cell-Mediated Lympholysis Testing (9 PaPers) - Clinical Transplantation and Transfusion (11 papers). The Major Histocompatibility Complex and Disease (11 papers). Granulocyte Symposium (5 papers). Report of the AACHT-NIH Standards Committee pp.- in preparation ISBN: Send payment with oi der and save postage plus 50e handling charge. Oi-dex-s under $15.00 must be accompanied by payment. Prices are subject to change without notice. U.S. customex s please note: On prepaid orders-payment will be refunded for titles on which shipment is not possible 1 within 120 days. GRUNE & STRATTON 5 A Subaidary of Harcourt Brace Jox anovich. Publishers 111 FIFTH AVENUE. NEW YORK, N.Y OVAL ROAD. LONDON NW1 7DX Please send me the following:...copies. Weksler et al.: Immune Eflector Mechanism in Disease _copies, Cax-penter: ( linical Histocompatibility Testing, Volume ii Check enclosed... Bill me_ NAM F CITY/STATE/ZI P New York residents please add sales tax. Direct all orders to Mr. Paul Negri, Media Dept. IF YOU ARE NOW USING CPK FOR EARLY MI. DETECTION, EXAMINE MYOGLOBIN (RIA) MYOGLOBIN IS TIlE EARLIEST DETECTABLE SERUM INDICATOR OF MYOCARDIAL INFARC- TION. MYOGLOBIN RIA OFFERS A SIGNIFICANT AID TO EARLY DIAGNOSIS. e STAT RESULTS 15 MIN. TOTAL INCUBATION. #{149}MORE SENSITIVE Faster post MI. rise than CPK. #{149}HIGHLY SIMPLIFIED RIA. 3 steps. #{149}HIGHCLINICALCORRELATIONWITHM.I. #{149}NO COLUMNS, NO ELUTIONS, NO DILUTIONS. #{149}NO TIME CONSUMING ELECTROPHORESIS. NMS PROVIDES AlA KITS & CONTROLS Neo T4, Neo TSH, E2, E3, HPL, Progesterone,Myoglobin, Gentamicin, Tobramycin, T3, T4, TBG & TSH. Hi & Lo levels AlA controls; each with 40 values. I

22 . are among the malignancies that have responded to Adriamycin Among the other disseminated neoplastic conditions that have responded to Adriamycin are Hodgkin s disease. breast carcinoma, acute lymphoblastic leukemia. acute myeloblastic leukemia. Wilms tumor. bone and soft tissue sarcomas. neuroblastoma. ovarian carcinoma, transitional cell bladder carcinoma, thyroid carcinoma, and bronchogenic lung carcinoma in which the small cell histologic type is the most responsive compared to other cell types. Adriamycin should be administered only under the direction of specialists qualified in the administration of such drugs. Severe local tissue necrosis will occur if there is extravasation during administration. Severe irreversible myocardial toxicity with delayed congestive failure often unresponsive to any cardiac supportive therapy may he encountered as total dosage approaches 550 mg/m2. This toxicity may occur at lower cumulative doses in patients with prior mediastinal irradiation or on concurrent cyclosphosphamide therapy. The incidence of bone marrow depression is high. Hematopoietic toxicity may limit dosage. In patients with impaired hepatic function. dosage should be reduced. For information on the use of Adriamycin. call collect: (614) (Photomicrographs courtesy of Dr J.E Ultmonn and Dr R.S.Stein).. Adnamvcin (doxorubicin hydrochloride) for Injection FOR INTRAVENOUS USE ONLY 10 mg and 50 mg vials Nodular lymphoma - poorly differentiated ls-mphocvtic. The cells are lymphocytes with marked nuclear variations. Nuclei are round to oval, and show indentation and angulation. Diffuse lymphoma - histiocyiic. Larger cells than in poorly differentiated type. Nuclei s-ar in size. Prominent, large nucleoli are present in sonic cells. Although the cells are probably transformed lymphocytes. histiocytic lymphoma remains the standard terminiilogv. For complete prescribing information, please see the following page. To receive a free copy of the review. Non-Hodgkin s Lymphomas: A Brief Introduction to Their Evaluation and Management, fill out and mail this coupon to: Adria Latxratories. Inc. P0. Box Columbus, Ohio Ati: P. McCarthy LABATES#sC Dr. Street Address City State Zip

23 AdrIa LaboratorIes kic. ADRIAMYCINThdoxorubicin hydrochloride) for Injection FOR INTRAVENOUS USE ONLY WARN Severe local tissue necrosis wrll occur it there is extravasation biting administration Adriamycin must not be given by the intramuscular or subcutaneous route 2. Serious irreversible myocardiul toxicity with delayed congestive failure often unresponsive to any cardiac supportive therapy may be encountered as total dosage approaches 550 mg/is This toxicity may occur at lower cumulative doses in patients with pninr mediastinal irradiation or on concurrent cyclopfrxsphamete therapy 3. Dosage should be reduced in patients with impaired hepatic function 4. Severe myelosuppressen may occur 5. Adriamycin should be administered only under the supervision of a physician who is experienced in the use of cancer clremotherapeutic agents DESCRIPTiON Doxorubicin is a cylotonic anthracycline antibiotic isolated from cuitures ot Sci piornyci s peucerius var #{163}s* sz.is It supplied a the hydrochloride form as a treeze.dried powder containing lactose CUNNAI. PHARMACOLOGY Though not comptetely ducetated. the mechanism of action of doxorubicin is reiated to its ability to bind to DNA and inhibit nucleic acid synthesis CeO cutture studies have demonstrateil rapid cell penetrabon and permucleolar ctwnmatin binding. rapid inhibition of mitotic activity and nucleic acid synthesis. mutagenesto and chromosomal ierrations Animal studies have shown activity in a spectrum of eopenimental tumors, immunosuppression. carcinogenic properties in rodents. induction of a variety of tooic effects. including delayed and progressive cardiac tooicity in rabbits. myelosup pression in all species and atrophy to testes in rats and dogs. Pftarmacokinetic studies show the mtravenous administratioe of normal or radiolabeled Adriamycin (donorubicin bydroctiloode) for Injectioe is followed by rapid plasma clearance and significant tissue binding. Urinary escretion, as determined by fluorimetric methods, accounts for appronimutely 4-5% of the administered dose a five days Biliary eocretien represents the major encretion route. 4O5Oo of the administered dose bong recovered in the hue or the feces in seven days tmpairment of liver functioe results a slower eocretion. and. consequently. increased retention and accumulation in plasma and tissues Adriamycin does not cross the blood brain barrier INDICATIONS Adriamycin has been used successfully to produce regression in disseminated neoplastic condi tions such as acute iymphoblastic leukemia. acute myeloblastic ieukemia. Wiims tumor. neurobiastoma. soft tissue and bone sarcomas. breast carcinoma. ovarian carcinoma, transitional cell bladder carcinoma. thyroid carcinoma. lymphomas of both Hodgkin and noekvdgkin types and bronchogenic carcinoma in whth tie small cell histologic type is the most respoesive compared to other cell types. A number of other solid tumors rave also shown some responsiveness but in numbers too limited to justify specific recommendation States to date have shown malignant melaooma. kidney carcinoma. large bowel carcinoma. brain tumors and metastases to the Central Nervous System not to be significantly responsive to Adriamycin therapy. CONTRAINOICATIONS Adriamycin therapy should not be started a patients who have marked myelosuppression induced by previous treatment with other untitumor agents or by radiotherapy Conclusive data are not available on xe-existing start disease as a cofactor of increased risk of Adriamycin induced cardiac tooicity Preliminary data suggest that in ouch cases cardiac toxicity may occur at doses lower than the recommended cumulative limit It is therefore not recommended to start Adriamycin C such cases Adriamycin treatment is contraindicated in patients who received previous treatment with complete cumulative doses of Adniamycin and daunorubcin. WARNINGS Special attention must be given to the cardiac fosicify eohibited by Adriamycin Although uncommon. acute left ventricular failure has occurred. particularly in patients who have received total dosage of the drug eoceedmg the currently recommended limit of 550 mg m This limit appears to be lower (400 mg/mrf in patients who received radiotherapy to the mediastinal area or concomitant therapy with other potentially cardiotoxic agents such as cyclophospetamide The total dose of Adriamycin administered to the u idividual patient should also lake into account a previous or concomitant therapy with related compounds such as daunorubicin Congestive heart failure and or cardiomyopathy may be encountered several weeks after discontinuation of Adriamycin therapy Cardiac failure is often not favorably affected by presently known medical or physical therapy tor cardiac support. Early clinical diagnosis of drug induced heart failure appears to be essential for successful treatment with digitalis, diuretics. low salt diet and bed rest. Seven cardiac toxicity may occur precipitously without antecedent EKG changes. Baseline EKG and periodic follow-up EKG during, and immediately after, active drug therapy is an advisable precaution Transient EKG changes. such as Twave ftattenmg. S-T depression, and arrhythmias are presently not conside,ed indications for suspension of Adriamycm therapy. A persistent reduction in the voltage of the ORS wave is presently considered more specifically predictive for cardiac toxicity If this occurs, the benefit of continued therapy must be carefully evaluated against the risk of producing irreversible cardiac damage. There is a high incidence of bone marrow depression, primarily of leukocytes. requiring careful hematologic monitoring. With the recommended dosage schedule. leukopenia is. usually transient. reaching its nadir at days after treatment with recovery usually occurring by the 21st day White blood cell counts as low as 1000/mm are to be expected daring treatment with appropriate doses of Adriamycitt. RedHood cell and platelet levels should also bemonitored since they may also be depressed. Hematofogic toxicity may regece dose reducten or suspension or delay of Adriamycin therapy. Persistent severe myetosuppressen may result a supermfecten or hemorrhage Adriamycin may potentate the toxicity of other anticancer therapies. Exacerbation ofcyclophosphamide induced hemorrhagic cystitis and enhancement of the hepatotosicity of 6mercaptopurine have been reported. Radiation induced toxicity In the myocardium, mucosae. skin and liver have been reported to be increased by the administration of Adriamycin Toxicity to recommended doses of Adriamycin is enhanced by hepatic impairment, therefore, prior to the individual dosing. evakiation of hepatic function is recommended using conventional clinical laboratory tests such as SGOT. SGPT, alkaline phosphatase. bilirubin. and BSP (See Dosage and Ackninistration.( On intravenous acbmnistration of Adrianycin. a stmging or burning sensation signifies a small degree of extravasatioe and even if blood return from aspiration of the nfssion needle is good. the injection or infusion shouldbe esmediately terminated and restarted in another vein Adriannycin and related compounds have also been shown to have mutagenic and carcinogenic properties when tested in experimental models. use of Adriamycin in pregnancy has not been established Adriamycin Is embryotoxic and teratogexic in rats and nmbryotooic and abortifacient in rabbits Therefore. the benefits to the pregnant patient should be carefully weighed against the potential toxicity to fetus and embryo The possible adverse effects on fertility in males and females in humans or enperimen. al animals have not been adequately evaluated PRECAUTIONS Initial treatment with Adriamycin requires close observation of the patieot and extensive labora tory monitoring It is recommended. therefore, that patients he hospitalized at least during the tirst phase of the treatment Like other cytotooic drugs. Adriamycin may induce hyperuricemia secondary lx rapid lysis of nevpiastic cells The clinician should monitor the patient s blood uric acid level and be prepared to use such sapportive and pharmacologic measures as might be necessary to controi this problem Adriamycin imparts a red coloration to the urine for t-2 days alter administration and patients should be advised to expect this during active therapy Adriamycin is not an antimicrobial agent ADVERSE REACTIONS Dose limiting tooicitres ot therapy ate myelosuppression and cardioroxicity see Waroirigsj Other reactions reported are Cutaneous-Reversible complete alopecia occurs in most cases Hyperpigmentariorr ol nailbeds arid derinal creases, primarily in children, have been reported in a few cases Recall of skin reaction due to prior radiotherapy has occurred with Adriamycin administration Gastrointestinal-Acute nausea and vomiting occurs trequeetty and may be severe This may be alleviated by antiemetic therapy Mucositis lstomatrtis anrlt esopfiagitisi may occur 5-tO days after adniioislration The effect may be severe leading to ulceration and represent a site of origin or severe infections The dose regimen consisting of administration of Adriamycin on three successive days results in the greater incidence and severity of mucositis Anvreo:a and diarrhea have been occasionally reported Vascular-Phlebosclerosis has been reported especially when sirrall veins are used or a single vein is used for repeated administration Facial flushing may occur it the inlectron is given too rapidly Local - Severe ceilulitis, vesicatiox arid tissue necrosis will occur if Adrianrycin is entraoasated during administration Erythematous streaking along tire veer proximal to the site of the inlection has been reported Hypersensitivity - Fever chills and urticaria have been reported occasionally Anaplrylanis nray occur A case of apparent cross sensitivity to lincurrrycin has been reported Other - Conjunctivitis and lacrimation occur rarely DOSAGE AND ADMINISTRATION Care in the administration of Adriamycin will reduce the chance of perivenous infiltration It may also decrease the chance of local reactions such as urtearia and erythematoxs streaking The recommended dosage schedule is mg m as a single intravenous injection adnrinislered at 2t-day intervals The lower dose should be given to patients with inan.sequatc marrow reserves due to old age. or prior therapy or nreoplastic marrow infiltration An alternative dose schedule is 30mg m ox each of three successive days repeated every 4 weeks Adriainycin dosage irrusl be reduced it hepalic unction is impaired according to he following table LAATrYeESI sc Serum Bilirubin Levels BSP Retention Recommended Dose 2-30 mg% 9T5% normal dose 3 mg% 15% normal dose Preparation of Solution Adniamycin to mg vials and 50 mg vials should he reconstituted with 5 ml and 25 nil, respectively. of Sodium Chloride Inlection U S P to give a final concentration of 2 nig ml ol dooorubicin hydrochloride. An appropriate volume of air should be withdrawn tronr the vial during reconslilution to avoid excessive pressure hoild-up Skin reactions associated with Adniamycin have been reported Caution in the handling and preparation ol the powder and solution must be exercised and the use of gloves is recommended If Adniamycin powder or solution contacts the skin or mocosae imnrediateiy wash thoroughly with soap and water After adding the diluent. the vial should be shaken and the isintents allowed to dissolve The reconstituted solution is stable for 24 hours at room temperature arid 48 hours under refrigeration Ci It should be protected from exposure to sunlight and any unused solution should be discarded II is recommended that Adriamycin be slowly administered into the rubing of a treeiy nunrnnng intravenous infusion of Sodium Chloride Injection U S P or Sun Dextrose Injection U S P The tubing shoxld be attached to a Butterfly needle riveted preferably into a large vein The rate of administration is dependent on the size of the vein arid the dvsaqe However, the dose should be adnninis tered n not less than 3 to 5 minutes Local erythematous streaking along the vein as well as facial flushing may be indicative of too rapid an administration A horning or stinging sensation may be indicative nf perivenoxs infiltration and the infusion should be immediately terminated and restarted in another vein Adriamycin should not be mixed with hepanix since it has been reported that these drugs are incompatible to the extent that a precipitate may form Until specific compatibility data air maniable. it is not recommended that Adriamycin be mixed with other drugs Adriamycin has been used in combination with other approved chemotherapeutic agents Though evidence is available that at least in some types of neoplastic disease conrbination chemotherapy is superior to single agents. the benefits and risks of such therapy have not yet been folly elucidated HOW SUPPUED ADRIAMYCIN dooorubicin hydrochloridel for Injection is available in two sizes to mg-each vial contains to mg ofdoxorubicin HCI and 50 mg of lactose U S P as a sterile red-orange lyophilized powder Packaged and supplied in tovial cartons SOC tO 50 mg-each vial contains 50 mg of doxorubicin HC1 and 250 mg of lactose U S P as a sterile red-orange Iyopkilized powder Packaged and supplied in a single vial carton SOC Rev August t97t TM Distributed by Adria Laboratories Inc T.?7 Manxfactured by Farmitalna S pa - Italy

24 Now, afasterwaytopredict methotrexatetoxicity Elevated 48-hour MIX plasma levels after highdose methotrexate therapy have been shown to correlate well with later toxic events. Stoller et al. found thatr Forty-eight hour levels of methotrexate greater than 9x10 M were associated with a high frequency of toxicity.. In contrast, no patient having less than 9x10 M at 48 hours experienced subsequent toxicity. In the graph at the right, each dot represents 48- hour MIX plasma levels from 395 individual MIX doses infused over 6-hour periods in 78 National Can- cer Institute patients. Ihe red dots represent 48-hour MIX levels in 6 of these pa- tients who later developed toxicities. All toxicities in this study were associated with MIX levels above 9x10TM. Other investigators found similar toxicity thresholds: Nirenberg and 10 co-workers2 observed that 25 of 68 patients with serum MIX concentrations 106 M at 48 hours developed clinical toxicity. 10 Wang, Lantin and Sutow conclude that..severe toxicity is unlikely if the methotrexate value at 48 hours Dose is below 4.5x10 mol/liter of plasma. Patients particularly at risk of developing toxicities are those on high-dose regimens; those with renal dysfunction, in whom serum creatinine studies are not considered as sensitive as MIX plasma levels2; and patients with third space reservoirs which can act as repositories of drug, releasing MIX slowly into the systemic circulation.4 Such MIX reservoirsm include pleural fluid, ascitic fluid, -edematous tissue and cerebrospinal fluid. To let you know the patients toxic potential quickly, the new EMIT#{174}Methotrexate Assay gives you the fastest possible results. As fast as within a few minutes from the time your laboratory receives the sample. And the EMIT#{174}method is the only commercially available MIX assay that can be done stat, when you need results immediately. Request the EMIT#{174} Methotrexate Assay. Because the sooner you can identify the potentially toxic patient, ii the sooner you can take preventive action. References: 1. Stoller RG, Hande R, Jacobs SA, Rosenberg SA, Chabner BA: N Engi J Med 297: , Nirenberg A, Mosende C, Mehta BM, Gisolfi AL, Rosen G: Cancer Treat Rep 61: , Wang YM, Lantin E, Sutow WW: ClinChem 22: , Friedman MA, Carter mg/kg SB: Seminars in Oncol- ogy 2: Syva Company, P0 Box 10058, 3181 Porter Drive, Palo Alto, CA In California: (415) Toll free (800) Telex USA: Syva PLA. #{149}Syva Diagnostics Ltd./Lt#{233}e Mountain Sights Ave. Montreal, Ouebec,H4P 2B5 Canada. usyva GmbH, Alsfelder Str. 6, 6100 Darmstadt, W Germany, Telex: (841) #{149}Syva UK, St. yes House, St. yes Ad, Maidenhead, Berkshire, YV SL6 1RD, England. Telex: (851) New EMIT#{174} Methotrexate Assay Quickly pinpoints patients at risk of toxicity 5yva Company, 1979

25 Adria Laboratories Inc. ADRIMYCINTM(dxoorutxicin hydrochloridel for Injection FOR INTRAVENOUS USE ONLY WARNINGS 1. Severe local tissue necrosis will occur if there is extravasatioe during administration Adrramycnnmust not be given by the intramuscular or subcutaneous route 2. Serious irreversible myocardial toxicity with delayed congestion failure often unrespon sine to any cardiac supportive therapy may be encountered as total dosage approaches 550 mg/is. This toxicity may occur at lower cumulative doses in patients with prior mediastinal irradiation or on concurrent cyclophosphamide therapy 3. Dosage should be reduced in patients with impaired hepatic function 4. Severe myelosuppression may occur 5. Adriamycin should be administered only under the supervision of a physician who is experienced in the use of cancer chemotherapeutic agents DESCRIPTION Dxxorubicrn is a cytotoxic anthracycline antibiotic isolated from cultures of Srreptocryces puceros var carsais It is supplied in the hydrochloride form as a freeze-dried powder containing lactose CUNICAL PHARMACOLOGY Though not completely elucidated. the mechanism of action of dooorubmcin is related to its ability to bind to DNA and mhibmfnucleic acid syxtheso Cell cufure stodies have demonstrated rapid cell penetration and perinucleolar chromatin binding, rapid inhibition of mitotrc activity and nucleic acid synthesis. mutagenesis and chromosomal ulterratroes. Animal studies have shown activity in a spectrum of experimental tumors. immunosuppression. carcinogenic properties in rodents. induction of a variety of toxic effects. including delayed and progressive cardiac toxicity in rabbits. myelosuppresuron in all species and atrophy to testes in rats and dogs. Pharmacskmetic studies show the intravenous administration of xormal or radiolabeled Adria. mycin Idoxorubicmx hydrochloridel for lnlectmon is followed by rapid plasma clearance and significant tissue binding Urinary excretion. as determined by fluonimetric methods. accoxots for approni. mately 45% of the administered dose in five days Bnlrary excretion represents the major excretion route, 40S0% of the administered dose being recovered in the bile or the feces in seven days Impairment of liver function results in slower excretion, and. consequently. increased retention and accumulation in plasma and tissues. Adriamycin does not cross the blood brain barrier INDICATIONS Adriamycin has been used successfully to produce regression in disseminated neoplastic condifixes such as acute lymphoblastic leukemia. acute myeloblastrc leukemia, Wnlms tumor, neuroblastoma, soft tissue and bone sarcomas, breast carcinoma. ovarian carcinoma. transitional cell bladder carcinoma. thyroid carcinoma. lymphomas xl both Hodgkin and sort-hodgkin types and brunchogenic carcinoma in which the small cell histologic type is the most responsive compared In other cell types A number of other solid tomors have also shown some responsiveness hot in numbers too limited to tustify specific recommendatiox. Studies to date have shown malignant melanoma kidney carcinoma. large bowel carcinoma. brain tumors and metastases to the Central Nervous System not to be significantly responsive to Adriamycmn therapy CONTRAINDICATIONS Adriamycin therapy should not be started in patients who have marked myelosuppression induced by previous treatment with other antitumor agents or by radiotherapy Conclusive data are nor available on preeonsting heart disease as a co-factor of increased risk of Adniamycin induced cardiac toxicity Preliminary data suggest that in such cases cardiac toxicity may occur at doses lower than the recommended cumulative limit It is therefore not recommended to start Adrnamycin in such cases. Adriamycin treatment is contraindicated in patients who received previous treatment with complete cumulative doses of Adriamycin and daunorubicin WARNINGS Special attention must be given to the cardiac toxicity exhibited by Adriamycin Although uncommon, acute left ventricular failure has occurred, particularly in patients who have received total dosage of the drug exceeding the cxrrently recommended limit of 550 mg.m This limit appears to be lower (400 mg/is ) in patients who received radiotherapy to the mediastinal area or concomitant therapy with other potentially cardiotoxic agents such as cyclophosphamide The total dose of Adriamycin administered to the individual patient should also take into account a previous or concomitant therapy with related compounds such as daunorubicin Congestive heart failure and or cardiomyopathy may be encountered several weeks after discxxtiouation of Adriamycix therapy Cardiac failure is often not favorably affected by presently known medical or physical therapy for cardiac support Early clinical diagnosis of drug induced heart failure appears to be essential for successful treatment with digitalis, diuretics. low salt diet and bed rest Severe cardiac toxicity may occur precipitously without antecedent EKG changes Baseline EKG and periodic follow-up EKG during, and immediately after, active drug therapy is ax advisable precaution Transient EKG changes, such as 1-wave flattening. ST depression, and arrhythmias are presently not considered indications for suspension xl Adriamycin therapy. A persistent reduction in the voltage of the ORS wave is presently considered more specifically predictive for cardiac toxicity If this occurs. the benefit of continued therapy must be carefully evaluated against the risk of producing irreversible cardiac damage There is a high incidence of bone marrow depression, primarily of leukocytes, requiring careful hematologic monitoring. With the recommended dosage schedule. Ieukopeeva is. usually transient, reaching its nadir at days after treatment with recovery usually occurring by the 2tst day White blood cell counts as low as 1000/mm are to be expected during treatment with appropriate doses xl Adriamycm. Red blood cell and platelet levels should also be monitored sixce they may also be depressed Hematologic toxicity may require dose reduction or susper-sion or delay of Adriamycin therapy Persistent severe myelosuppression may result in superinfectron or hemorrhage. Adriamycin may potentiate the toxicity of other anticancer therapies Exacerbation of cyclophos pfxamnie induced hemorrhagic cystitrs and enhancement of the hepatxtoxicrty xl 6-mercaptopurine have been reported. Radiation induced toxicity to the myocardixm. mxcosae. skin and liver have been reported to be increased by the administration of Adriamycin Toxicity to recommended doses xl Adrirenycin is entranced by frepatic impairment, therefore, prior to the individual dosing, evaluation of trepatic function is recommended using conventional clinical laboratory tests such as SGOT. SGPT. alkaline phospfratase. bilirubmn. and BSP (See Dosage and Administratron.l On intravenous administration of Adriamycm, a stinging or burning sensation signifies a small degree of extravasatron and even it blood return from aspiration of the rnfxsion needle is good. the injection or infusion should be immediately terminated and restarted in another vein Adriamycin and related compounds have also been shown to have mxtagenic and carcinogenic properties when tested in experimental models use of Adriamycin in pregnancy has not been established Adrnamycin is enrbryotooic and teratogenic in rats arid embryotoxic and ahortifacient in rabbits Therefore the benefits to the pregnant patient should be carefully weighed against the potential toxicity to fetus and embeyu The possible adverse effects ox fertility in males and females in humans or experinrenal animals have not been adequately evaluated PREcAUTIONS Initial treatment with Adriamycin requires close observation of the patient and extensive laboratory monitoring It is recommended, therefore, that patients be hospitalized at least during the first phase of the treatment Like other cytotoxic drugs. Adriamycin may induce hyperunicemia secondary to rapid lysis of neoplastic cells The clinician should monitnr the patient s blood uric acid level arid be prepared to use such supportive and pharmacologic measures as might be necessary to control Ihis problem Adriamycin imparts a red coloration tn the urine tot t.2 days after administration and patients should be advised to expect this during active therapy Adriamycin is not an antimicrobial agent ADVERSE REACTIONS Dose limiting toxicitnes of therapy are myelosuppression and cardiotoxicity isee Warningsi Other reactions reported are Cutaneous-Reversible complete alopecia occurs in most cases Hyperpignrenratioir of nailbeds and dermal creases. primarily in children have been reported in a few cases Recall ot skin reaction due to prior radiotherapy has occurred with Adriamycin administration Gastrointestinal-Acute nausea arid vomiting occurs frequently and may be severe This may be alleviated by antiemetic therapy Mucositis (stomatitis and esopfraqitns( may occur 5-tO days aher adnonistration The effect may be severe leading to ulceration and represent a site of origin for severe infections tire dose regimen consisting of administration of Adniamycin on three successive days results in the greater incidence and severity of mxcositis Anorex:a and diarrhea have been occasionally reported Vascular-Phlebosclerosis has been reported especially when small veins are used or a single vein is used for repeated administration Facial flushing may occur if the injection is given too rapidly Local - Severe cellulitis vesicatnon and tissue necrosis will occur if Adriamycin is extravasated during administration Erythematous streaking along the vein proximal to the site of the injection has been reported Hypersensitivity - Fever, chills and articania have been reported occasionally Anaphylaxis nay occur A case of apparent cross sensitivity to lincomycin has been reported Other - Conjunctivitis and lacrimation occur rarely DOSAGE AND ADMINISTRATION Care in the administration of Adriamycin will reduce the chance of perivenous infiltration It may also decrease the chance of local reactnoxs such as urticaria and erythematoxs streaking The recommended dosage schedule is mq is as a single ertiavenoxs irriection adnninisteed at 21-day intervals The lower dose should be given to patients with ivadeguatc marrow reserves due to old age. or prior therapy. or neoplastic marrow infiltration An alternative dose schedule is 30mg is on each of three successive days repeated every 4 weeks Adriainycin dosage must be reduced if hepatic function is impaired according to the following table Serum Bilirubin Levels ffsp Retention Recommended Dose 230 mg, 9.5% : normal dose 3 mg% S v normal dose Preparation ol Solution Adriamycin to mg vials and 50 mg vials should be reconstituted with 5 ml and 25 ml respectively of Sodium Chloride Iniection U S P to give a final concentration of 2 org ml oi doxorubicin hydrochloride An appropriate volume of air should be withdrawn troni the vial during reconstitution to avoid encessive pressure build-up Skin reactions associated with Adriamycin have been reported Caution in the handling and preparation of the powder and solution must be exercised and The use of gloves is ieconrnmended If Adriamycin powder or solution contacts the skin or mucosae immediately wash thoroughly with soap and water Aher adding the diluent. the vial should be shaken and the sontents allowed to dissolve The reconstituted solution is stable for 24 hours at room temperature and 48 hours under refrigeration dto C It should be protected from exposure to sunlight and any unused solution should be discarded It is reconrnnended that Adriamycin be slowly administered into the tubing of a freely running intravenous infusion of Sodium Chloride Injection U S P or 5% Dextrose Injection U S P The tubing should be attached to a Butterfly needle inserted preferably into a large vein The rate of administration is dependent on the size of the vein and the dosage However the dose should be adminnis. tered in not less than 3 to 5 minutes Local erythematous streaking along the vein as well as facial flushing may be indicative of ton rapid an administration A horning or stinging sensation may be indicative of perivenoxs infiltration and the infusion should be immediately terminated and restarted in another vein Adriamycin should not be mixed with heparin since it has been reported that these drugs are incompatible to the extent that a precipitate may form Until specific compatibility data are availa ble it is nut recommended that Adriamycin be mixed with other drugs Adriamycin has been used in combination with other approved chemotherapeutic agents Though evidence is available that at least ix some types of xeoplastic disease combination chemotherapy is superior to single agents. the benefits and risks of such therapy have not yet beer fully elucidated HOW SUPPLIED ADRIAMYCIN (doxorabxcin hydrochloride) for Injection is available in two sizes to mg-each vial contains to mg of doxorubicin HCI and 50 mg of lactose U S P as a sterile red-orange tyophilized powder Packaged and supplied in to-vial cartons SOC to 50 mg-each vial contains 50 mg of donorubicin HCI arid 250 mg of lactose U S P as a sterile red-orange lysphilrzed powder Packaged and supplied in a single vial carton SOC SO Rev August t978 TM Distributed by Adria Laboratories Inc Manufactured by Farmitalia S pa LA9.OSATOYCSAC Italy

26 BLOOD-THE JOURNAL OF THE ASH xxix INFORMATION FOR CONTRIBUTORS SUBMITTING THE MANUSCRIPT BLOOD, The Journal of the American Society of Hematology, provides an international forum for the publication of original articles, in English, describing basic laboratory and clinical investigations encompassed in the broad discipline of hematology. The scope of the ournal covers all aspects of hematology, including disorders of leukocytes, both benign and malignant, erythrocytes, platelets, hemostatic mechanisms, and immunology, as well as motor developments in clinical laboratory diagnosis and blood banking. Manuscripts are accepted for consideration on the condition that they are contributed solely to BLOOD. No substantial part of a paper may have been or may be published elsewhere, except for an abstract of 500 words or less. Manuscripts will be critically reviewed by the Editor or an Associate Editor with appropriate independent referees drawn from the Editorial Board and other experts. 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27 xxx BLOOD-THE JOURNAL OF THE ASH (Continued from preceding page) PREPARING THE MANUSCRIPT The original and two complete copies of the manuscript must be submitted. Manuscripts must be typewritten, double or triple spaced on good quality 8 i/by.11.inch white paper with margins of at least one inch. Please do not use erasable bond. The first page of the manuscript should contain the following information: (1) title of the paper; (2) authors names; (3) name of institution in which work was done; (4) acknowledgments for research support; (5) name and address of the author to whom communications regarding the manuscript should be directed; (6) a short title, not to exceed 40 characters (including spaces), to be used as a running title. The second page should contain an abstract of 200 words or less, summarizing the reason for the study, the methods used, the results, and the major conclusions. Do not include a summary at the end of the paper. The remainder of the paper should be written as concisely as possible. PREPARING AND ILLUSTRATIONS TABLES Tables and illustrations must be cited in order in the text using arabic numerals. All line drawings should be submitted as clear, glossy, black and white photographs. Legible copies may be used with the duplicate manuscripts. Photomicrographs and other photographic illustrations must be submitted in duplicate; copies are not acceptable. Legends for illustrations should be typewritten, double spaced, on a separate sheet, and included at the end of the manuscript. A legend must accompany each illus tration. Contribators will pay all charges involved in processing and printing of color photographs. Figures, especially charts, graphs, and line drawings, are generally reduced in size for publication (consult a recent issue of the journal for examples). To maintain legibility if is important that all numbers, letters, and symbols be large enough originally so that when reduced they will remain at least inch (2 mm) high (i.e., approximately the same size as used for this line of type). Figures not properly prepared will have to be returned to the contributor for revision or will be relettered by the printer and the cost charged to the contributor. Each table should be typed on a separate sheet and appropriately numbered. Legends should be typed on the same sheets as the tables. Tabular ma terial in excess of one and one-half total printed pages may be charged for at approximately $80.00 per page. REFERENCES References should be compiled at the end of the article according to the order of citation in the text. They should be typewritten, double spaced under the heading REFERENCES. Abbreviations for titles of medical periodicals should conform to those used in the latest edition of Index Medicus. (A List of Journals Indexed in Index Medicus -with abbreviations-is obtainable from the Superintendent of Documents, U. S. Government Printing Office, Washington, D.C , at a modest charge.) References to abstracts and Letters to Editors must be identified as such. Inclusive page numbers of references are not required. Personal communications and references to publications in press by authors other than those submitting the paper must be substantiated by a letter from the investigator(s) concerned confirming the data or observations and granting the authors permission to cite the material. EXAMPLES OF REFERENCES Journal article, one author: 1. Beutler E: The effect of methemoglobin formation on sickle cell disease. J Clin Invest 40:1856, 1961 Journal article, two or more authors: 2. Karpafkin S. Charmatz A: Heterogeneity of human platelets. Ill. Glycogen metabolism in platelets of different sizes. Br J Haematol 19:135, 1970 Journal article, in press: 3. O Malley JE, Eisenbera L: The hyperkinetic syndrome. Semin Psychiatry (in press) Complete book: 4. Lillie RD: Histopathologic Technic and Practical Hisfochemistry (ed 3). New York, Blakiston, 1965, p 39 Chapter of book: 5. Moore G, Minowada J: Human hemopoietic cell lines: A progress report, in Fames P (ed): Hemic Cells In Vitro, vol 4. Baltimore, Williams & Wilkins, 1969, p 100 Chapter of book that is part of published meeting: 6. Natvig JB, Kunkel HG, Gedde-DahI T Jr Genetic studies of the heavy chain sub groups at G globulin, in Killander J (ed): Gamma Globulins, Proceedings of the Third Nobel Symposium. New York, Wiley, 1967 Chapter of book that is part of unpublished meeting: 7. Polliak A: A morphologic study of the lympho proliferative lesions induced by excess vitamin A. First Meeting, European Division, International Society of Hematology, Milan, 1971, p 181 Abstract: 8. Curnutte it, Karnovsky ML, Babior BM: Manganese-dependent NADPH oxidation by a particu late preparation from guinea pig granulocytes: An alternative interpretation. Clin Res 23:271A, 1975 (Abstr) Letter to the Editor: 9. Seeler RA Sickle cell anemia monthly varia tions. Blood 47:879, 1976 (Letter) PROOFREADING Contributors are provided with galley proofs and are asked to proofread them for typesetting errors. Important changes in data are allowed, but authors will be charged for excessive alterations in proof. Galley proofs should be returned v,ithin 48 hours. REPRINTS Reprints of articles can be furnished to contributors when ordered in advance of publication. An order form, showing cost of reprints, is sent with proofs. Individuals wishing to obtain reprints of an article that appeared in BLOOD can do so by contacting the author at the address given in the journal. ANNOUNCEMENTS Announcements of meetings, conferences, and the like that are of interest to the readership of BLOOD should be sent to the Editor at least three months before the first day of the month of issue. These items should be as concise as possible. When considered appropriate, they will be published as promptly as possible, subject to the availability of space in the journal.

28 3367R The first inverted microscope designed as an inverted microscope. The new Leitz Diavert#{174}was engineered from the base up to meet the special requirements of inverted microscopy. It is exceptionally stable with a large rectangular base area. The stand will support large or small vessels and photomicrographic equipment, including the Leitz Orthomat#{174} fully automatic camera and the Leicina#{174}Super 8 movie camera for time lapse studies. The large object stage is positioned low so you can see what you are doing while manipulating the specimen. The image moves in the same direction as the specimen. Reason: image-erecting optics. The transmitted light source moves with the stage so it doesn t have to be refocused when you change the specimen plane. Special long-working-distance, brightheld as well as phase objectives, and also long-workingdistance condensers (up to 64mm) are important features. The Diavert is a building block system so you can readily employ all the techniques of light microscopy, including new interference contrast and incident fluorescence accessories. If you own a Leitz Ortholux II research microscope, you can interchange all Ortholux accessories. For information call or write E. Leitz. Inc.. Dept. BL1 Rockleigh, N.J Where most new developments start.

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