TENTH PROGRESS REPORT to the COMMITTEE ON DRUG ADDICTION . of the NATIONAL RESEARCH COUNCIL 1936 United States Public Health Service Hospital University of Michigan University of Virginia Part I, Clinical Studies During the past year studies designed to determine the presence of dependence satiation in some of the new morphine derivatives were continued at the UedePeleS, Hospital, Lex- ington, Kentucky. Certain changes in the clinical evaluation of abstinence were made so that the system now employed is not only completely objective, but reasonably quantitative. This improved system has bean described in a report {to be published) of a study of the effect of "Rossium" treatment during withdrawal. | | There is still no reason to believe that dependence satiation can be Asotinaudance from addiction liability, hence, we still maintain that drugs which will maintain the state of agependence are capable of producing addiction (dependence). By comparison of the mean values of caloric intake, body temperature, respiratory rate, blood pressure, weight, BeMeRe, and blood sugar while on morphine and the new drug under in- vestigation, data on dosage relationships are put on a more sound basiSe ao Alpha=isomorphine, dihydro-alpha-isomorphine, and dihydro-= diacetyl=morphine have been studied and found to possess ad- diction liability. Alpha-isomorphine is of about the same potency as nobehite, while dihydro-alpha-isomorphine and di- hydro=-diacetyl=morphine are about twice as potent as morphine. At the present rate of admissions to this institution it will be possible to progress in these clinical studies at the rate of about one new drug per month, hence, a report on about 12 new drugs should be available at the time of the Fall meet- ings in 193%. Since the bigest tite of the clinical studies, a total of 22 drugs have been made available for investigation. Most of these drugs have not previously been studied in man. in view of the time necessary for the completion of each drug, however, Lt seems imperative to choose only one drug represen- tative of each important structural type, and the compounds planned for study during the coming year have been selected on this basis. These drugs are as follows: Beta chloromorphide Dihydrohydroxycodeinone Dihydrocodeinone enol acetate Tetrahydrothebaine Aminomorphine Dihydrome thy Imorphime thine Me thyldihydromorphinone Ethylmorphine Studies of 3-(1,2,3,4=tetrahydro-isoquinolino+)+4+hy- droxy-1,2,3,4=tetrahydro=-phenanthrene have been started. The data on one of the case following table: a S who received 1i-A are shown in the. j ' | | | | ‘Dates — Mgm, Doses Hour Y¥/L oe P/ce Pu/tr Temp. Pulse Resp. Sleep R? Em/Dof. AM. B.P. WteKgm. Caloric, Degree _ J 10/4/86 B=A:50x2 0-8 ! ! | ' 56,9 52 12 6 1 98/64 63.40 ouee 0 ! 25x2 |B=4 | ! (36.9 55 17 0 : 4en12 Lee oes 37.2 64 18 ee ee gi ee ee = sae . ee po ee ao i 10/5 BeA:50x2 | | i370 70 wo. @t% 1 94/70 68.80 ins i | 25x2 ! | \Bfae TB 12 0 | i | | 3765 66 s7 i sceaiitin acoe-Aegiater- bap ahealiddapbneg cdeuhide tage ibiaakct ih 5 | a ep donde oa — a | ws oe folie © Eo A a 25 | ‘5 7 we 4 gos te | | r eas as 10/7 1l-Ar10 | | 37.0 56 li 8% 3 106/68 == 65482 sag 0 | SoA: 50,25 az 37.5 75 14, om 25 ! : 3747 80 yy. VA iB nae bien cee | eee eee ; papa hi sariaiel ibaa! oe + ph pak SAA ent mere a esas etme 64 ens eam enm stem i | i : 10/8 11-A:15+20 | | 37.1 58 12 4 98/62 62,55 0 | 5-A:25+50 | vi ov | 37,5 67 12 2 he ‘ / : stabi | | | | 37.4 80 20 1 ae a : | morris ecient pees Bl aes mags yee tn on eee 0 ynsrmnenee te ienneenery wo meager vnienmnners atin peng A EST eee emer : 10/9 11-A:25+30 | 137.0 59 14 57 104/62 65418 gay + SeAs254+50 : Vy Ww V1 37.4 71 13 12/2 - : Vi87,.6 68 iB ij é ~ | 10/10 11-A:40,50 | | V BT ,0 61 14 52 106/68 62 84. | | 50+50 Vw Vv! v' 37,6 71 17 0 [a / : /' 1720 ++ . | . | down Mel ee | 10/11 —s-11-A:50,75 iVvwi ww vi A876 17 We lea S28 336/20 60,00 686 +++ | 100+100 iwwi wi vi ¥487,8 100 19 0 ee BS | | ;\Mvi vi Vv; 58,1 = 84 20 0 eo eee _ oe mene | f | - : | ’ | ! 10/12 11-A+100, pee Mets | vi 58,1 76 16 2 VL i0a/78 59,85 852 t+ | 100,100 + iM ov] | W, 88.0 100 20 0 vy & 8 | ee | iv iv vw) vis8&l 80 ~§616 0 ee ee — 7 | bot nh a ee it oars evan | 10/18: 11-A:25,50 wooIM VY vv) Wi 87.9 ge 18 2 “og / 50450 . | wi J vi Or 38.1 . +/P v2 2 104/72 59 627 790 t++ by | __ vi87e9 88k ane, 20 ce _ : a “| . tee mentees Mara crliaiierns ox —Actrceat sam nape «rennin a tw Hn tapneemeenterretmntmen este vicina . j 10/14. 11=A:60,50' ee re A ee 12/, Vv 2 98/70 38 470 921 ++ | 50+50 oe ee ees | vi377 86 jig iz v . ! pce tee tect stiatee il Mo | | 8796 80 Se | rae | : - : 10/15 11=A:50,50 ww 7 | WI37,2 87 15 4 ff | 98/80 58.92 yao . | +50+50 by ; ow | | W{87.5 82 14 */o ft v mouth 7 i | | V SM 88 18 2 F. i 1 senses oe ea ~ “oe | . .é E nf es migpetse target ane — | : ¢ } | f ‘10/16 11-A:50 | MI | | “i872 7 15 3 Ja | 106/68 59.88 : : mgm, per | | WV | Vi 87.5 Bl 14 0 ; Vv : / ete os ! AB9.7 84 18 0 | en '10/17 vi “ Vv) Vy v ot 75 10 4 1 120/76 60,32 2185 ’ bests View ag | 68. 86s. de od ai eth Racine vim aietennhe aia gt ; 7 = re 10/18 keris] eae. 42 124/60 60667 peng 0 ! | 137, CS gd v7 | | Be RD 1 | vy a decteewswdap \aniansitisicsebusperat seer r ee = amas ! ! 7 36.8 84 14 ‘ 2.3% 0 | ! ! ‘ 37.2 82 16 122/68 62. 2722 ! ! | 137.5 86 18 1 fe pote eben ree ataeme Se aN pel gah nen gcd. : Ln grinded ipencenctacaaceske, ie oie — re Le ee ' pin eee ee 4. ON Se 5~Tetrahydroisoquinolino-4=hydroxy=te trahydrophenanthrene In view of Dr. Eddy’s report that in equally effective doses this compound (ll-A) is fifteen times as toxic as morphine, considerable caution must be used in making this study. Thus far it has been found that ll-A, administered in doses up to O.4 gme per day, has no effect on the abstinence syndrome. | In other words, in the doses given, ll-A does not perceptibly support dependence. This is felt to be the most promising lead yet encountered in this cooperative study. It is hoped that it will be possible to administer this drug in more ef- fective dosese Should 11-A continue to show no evidence of addiction liability, the prognosis for the ai ecovers of a drug as analgetic as morphine, but possessing no addiction liability, will become definitely favorable, At present it would seem that there is definite hope in the synthetic field, hence, it is felt that every effort should be exerted to en- courage and expand the researches on synthetic morphine sub- stitutese De 4-A = Morphine Sulfate ll-A = 3=(1,2,3 ,4~Tetrahyaroisoquinolino)=4shydroxy=1, 253554 tetrahydrophenanthrene hydrochloride Dates - as shown Doses = in mgm. subcutaneous except as shown Hours = Three 8=hour periods each day ¥ = yawning L = lacrimation & = sneezing R = rhinorrhea G = gooseflesh Pu = dilated pupils Tr = tremor Temp. = rectal in °c Reap. = rate per minute | a R = Restlessness Sleep = hours observed | | : Hime. = emesis, no, of observed Def. = defecation, no. of observed Be Pe = Ae Me supine Wt = weight, Kem.e, stripped Caloric = total per day Degree = intensity of abstinence Two day period of gtabidisation on onA shown 10/4 and 5 Four day period of transition to lI-A shown 10/6, 7, 8, and 9 Six day period attempted dependence satiation by complete sub- stitution of ll-A for 3A shown 10/10, 11, 12, 13, 14, and 15 Four day period of total abstinence shown. Data show no support of dependence by 1lIl-A in these doses. The period of abstinence following withdrawal of 3=A is quite typical. nn Considerable progress has been made in the establishment of our new laboratories for studies designed to give us in-~ formation on the true nature of drug addictions The biochemi- cal and psychological units have been completed, and it is hoped that the physiological unit will be ready for operation in the near future. The latter unit contains * respiration chamber mounted on a platform scale, a Rein gasometaboligraph, and a gas analysis apparatus. When complete this laboratory will be air-conditioned and will contain a Sauter balance, The studies to be made first center around metabolism, and will include total, carbohydrate, and water metabolism studies with simultaneous psychiatric and psychologic investigations. The psychiatric studies will include electroencephalographic determinations of the effect of morphine at various times. A study of the effect of morphine on the dentition of rats will be undertaken in the near future. Future studics includes Lipid metabolism, acid-base balance, Calcium-phosphorus metabolism, and the effect of morphine on organs (using the Lindberg apparatus)» After the procurement of an electroencephalograph, stud= ies comparing the cerebral effects of morphine with new drugs will be carried out routinely. During the past year it was shown that "Rossium" (a pro- prietary "drug addiction cure" developed by Ostromislensky and marketed by the ChemicoeMedical Corporation) has no demonstrably beneficial effects on the abstinenee syndrome either when administered alone or in combination with the Te therapeutic agents recommended by the manufacturer. The re~ port on this study includes an account of the chemistry of "Rossium" by Dr. Small. A study of Perparin" (a synthetic papaverine derivative ) revealed that it does not possess ad~= diction liability. The desirability of extending our clinical studies to non-= addicted individuals has been emphasized repeatedly. Work of this sort was begun at the Pondville Cancer Hospital, at Wrentham, Massachusetts, early in 1935 and its snoeption and early results were described in our report of a year agoe In order to facilitate the continuation and extension of this work a number of conferences were held in the Spring of this year. These conferences led to the formulation of a report embodying suggestions which it is believed could furnish a systematic basis for this phase of our worke A copy of this report followss | Memorandum Nos 1 Suggestions for the systematic study of the anti-tussic action of codeine and related substances Based upon discussion at the Middlesex Ginter Tuberculosis Sanitorium, June 18, 1936. Those present were Drs. Alton 5S. Pope, Sumner H. Remick, Lowry C. Davenport, C. Ke Himmelsbach, Charles I. Wright and Nathan B. Eddy. Purpose (1) Systematic evaluation of the minimal effec- tive clinical anti-tussic dose of codeine, (2) Determination of the duration of the anti- tussic effect of codeine. (3) Determination of the possible development of tolerance to and dependence upon codeine when administer= Be ed in its minimal effective dose for its anti-tussic effect over a prolonged period of time. (4) Determination of the occurrence of incidene tal effects of codeine in connection with its adminis-= ' tration in single doses or over a prolonged periode (5) Determination of the presence or absence of objective effect on respiratory activity (rate, minute volume) of codeine administered in its minimal effec- tive anti-tussic dose. Method to be determined later, (6) Determination of the presence or absence of analgesic effect in the administration of codeine in its minimal anti-tussic dose, using the method of Seevers or some modification thereof. (Nos. 5 and 6 to be in abeyance at present). (7) Systematic evaluation of another substance in a manner exactly like that outlined for codeine, the first substance to be so evaluated being dihydroiso- codeine. Notes: It was admitted that although the usual procedure was the administration of codeine in dose of 15 to 30 mgm. for the relief of cough we have no exact knowledge of its minimal effective dose or duration of its action, and that for the purpose of this study such exact knowledge is essential, in order that when simi-~ lar information is obtained for a new substance an in- telhigible and sound comparison may be made, Desiderata of the study (1) All anti-tussic administration to be oral. (2) The drug to be made available in sueh a way that neither the nurse, the patient, nor anyone in fact except the person supervising the study (Dr. Davenport) shall know the nature of the substance ad~= ministered or its dose. (3) Observations on the effect of the drug to be made as objective as possible. No. 1 needs no special comment; the reasons for it are cbviouse No. 2 is essential in order to permit the simul- taneous collection of the desired information in re- gard to codeine and another substance (specifically, dihydroisocodeine) uncolored by prejudice or expecta= tion. It was suggested that this end might be attain- ed in this way: Each drug is to be made available in Qe. tablets identical in size and appearance but containing different amounts of drug as follows: Tablet Noe L No drug 2 Codeine, 5 mgme 3 Codeine, 10 mgm, 4 Codeine, 15 mgm. 5 Codeine, 20 mgm. 6 Codeine, 25 mgme 7 Codeine, 30 mgm. 8 Dihydroisocodeine, 5 mgm, 9 Dihydroisocodeine, 10 mgm, LO Dihydroisocodeine, 15 mgm. LL Dihydroisocodeine, 20 mgm. 12 Dihydroisocodeine, 25 mgm. L3 Dihydroisocodeine, 30 mgm. The tablets are to be placed in a series of number- ed bottles (no other label than the number), the series of bottles being greater than the number of tablets, there being several different bottles containing the most used doses to avoid the suspicion of size of dose by the frequent repetition of the same dose number. The key to the doses in the respective bottles is to be known only to Dr. Davenport. Ordering of all anti- tussic administration for the patients included in the study is to be by container number only, neither drug. nor dose is to be specified. It will probably be de~ . sirable to change the key numbers from time to time to avoid giving a clue to drug and dose by frequent repe= tition of the same number. If possible no one at all should be taken into Dr. Davenport’s confidence as to the meaning of the numbers. Ordering of anti-tussic treatment by other members of the staff for other patients than those involved in this study would be made in the usual ways but codeine tablets identical in Size and appearance .with the experimental tablets should be made available for this routine us€e Patients to be used in the anti-tussic study would of course have to be carefully selccted for intelli- gence and cooperativeness as well as for their patho- logical condition and need for cough treatmente They probably should have enough of the plan explained to them to insure their cooperation. Probably better re- sults would be obtained with new patients than with others who have been in the hospital a considerable time and who have had more or less codeine experience. The procedure for determination of minimal effec- tive dose would be as follows: A patient free of codeine and needing cough treatment would be given a LO. blank tablet or the smallest dose of codeine or perhaps each alternately at regular intervals until the observ- er is satisfied that no cough relief is obtained. Then the next Larger dose would be ordered and continued un- til it was determined that it did or did not have an effect on the cough. If necessary one would continue to raise the dose step by step until an effective dose was reached. During this program the occasional order- ing of the blank might facilitate the determination of the effectiveness of the dose and the duration of its effect. For the determination of the presence of effect a number of things were suggested, final determination to depend on collation and interpretation of all of theme 1. Careful counting of respiratory rate, the patient being at rest, at frequent intervals. zee Notes by the nurse on her impressions of the patient’s cough. 3e Notes by the physician in charge, gained by questioning of the patient or otherwise, on his im- pressions of the patient’s coughs 4. Notes by the patient himself ona mes tions naire basis made preferably twice a day. 5e Review of all the data by Dr. Davenporte 6- Dr. Wright suggested the possibility in suit- able patients of obtaining a modified pneumograph record which would record cough objectively. He has demonstrated that such a record is easily obtainable provided that discomfort from the wearing of the pneumograph and the mechanical difficulties in the mak- ing of the record are not insurmountable obstacles. It would be desirable to determine simultaneously the minimal effective doses of codeine and dihydro- isocodeine, but a patient started on codeine should not receive dihydroisocodeine and vice versa until the minimal effective dose of the first drug for that pa= sient has been determined, It might be desirable after the minimal effective dose of either drug has been determined to switch to the other drug, or to determine successively the minimal effective dose of each drug in the same patient. Such a procedure would furnish a slightly different basis of sunmnebeste las After the determination of a minimal effective dose in a patient and acquiring of information in re= gard to the duration of action of that dose in that patient, that dose would be administered regularly to that patient at the interval determined for the dura- tion of its action. Such administration would be con-=- tinued for a prolonged period and observations already outlined for determination of its effect would be con= tinued. From time to time (once a month) administra- tion of drug would be substituted for a 24ehour period by administration of blank tablets to gain an impres- sion of the continued effectiveness of the drug and the possibility of developing dependence on the drug (addiction). The first would be indicated by exacer- bation of the coughj the second by the appearance of some sort of abstinence phenomena. The discussion of the group indicated that the procedures outlined were feasible and that over an ex- tended period they offered the best chance of exact evaluation of the drugs under consideration and the best basis for future study which we could at present devise. The only thing required for putting the plan into operation is the preparation of a series of tablets, uniform in size and appearance, in numbers recommended by the hospital staff. It was understood that the fur- nishing through the Drug Addiction Committee of the Hospital’s entire supply of codeine had already been offered. Memorandum No. 2 Suggestions for the systematic study of the analgesic and other properties of morphine and related substances Based upon discussion at the Pondville Cancer Hospital, June 18, 1936. Those participating were Drs. Alton 5S. Pope, George L. Parker, Raymond E. Militzer, Ce. Ke Himmelsbach, Charles I. Wright and Nathan B,. Eddy. Purpose (1) Systematic evaluation of the minimal effece tive clinical analgesic dose of morphine amd codeine. (2) Determination of the duration of analgesic action of the drug studied. . | (3) Determination of the possible development of tolerance to and dependence upon the drug, administered in its minimal effective dose over a prolonged period of times. | if ‘ ef Pas 3 f bt Mt) dp Mbt Atel kal, SUBSTANCES TESTED (or ready for testing) IN THE CLINIC / ¥ d-A Isocodeine Acid Tartrate / vy 2-& _ Pseudocodeine Hydrochloride / y Soak Morphine Sulfate ( / V 4A Codeine Hydrochloride (/ 5-A Dihydrodesoxymorphine-D Sulfate { (. 6-A Dihydroisocodeine Acid Tartrate Owl oy Dihydroheterocodeine Hydrochloride . - Mptwatamnerphine Hydrochloride ~ th. Molrt futen] . raft U f 9-A Dihydro-alpha-isomorphine Hydrochloride, « | ‘ /* / 10-A Diacetyldihydromorphine Hydrochlordde } ANY. . “ ‘ l1-A Tetrahydroisoquinolino-hydroxy-tetrahydrophenanthrene >> . hydrochloride fo me, 012A Dihydrocodeine A | , yt JV VS-A Beta-chloromorphide Acid Tartrate 1M coud raldes urcdiam | j14-4 Diacetylmorphine iydvoghtoriae ~P"# _ aw | 16-A Dihydrocodeinone Enol Acetate ‘Hydrochloride (Acedicon) | | NV 15-A Dihydrohydroxycodeinone Hydrochloride (Eukodal) | 17-A Codeine Methyl Ether Pd 18-A Dihydromorphine Hydrochloride : egy i, | 19-4 -Monoacetylmorphine Hydrochloride % 20-A Monoacetyldihydromorphine Hydrochloride S) 21-A Dihydrocodeinone Hydrochloride (Dicodide) ‘ 224 Tetrahydrothebaine hydrochloride i ne November 1936 COMMITTEE ON DRUG ADDICTION Annual Meeting November 28, 1936 AGENDA Soientific Presentation a» Dr Himmelsbach. Discussion by Dr. Kolb. be Dr. Eddy c. Dr. Small Executive Session 1. Minutes of last meeting. Be Chairman's Report ~ Patents - Dihydrodesoxymorphine-D, Bow Patent. - Fourneau's Study in France. ~ Chemistry of Opium Alkaloids - Clinical Studies $8. Budget 4. Recommendation with regard to continuation of comnittee. 12. (4) Determination of the occurrence of inciden- tal effects in connection with the administration of single or repeated doses. (5) Systematic evaluation of another substance in a manner exactly like that outlined for morphine or codeine. The first substance to be so evaluated being desocodeine (dihydrodesoxycodeine=D). Notes It was admitted that although the usual procedure was the administration of morphine subcu= taneously in doses of 1/6 to 1/4 grain and of codeine orally in doses of 1/4 to 1/2 grain for the relief of pain, we have no exact knowledge of the minimal ef-= fective analgesic dose or duration of analgesic action of either morphine or codeine, and that for the pur- pose of this study such exact knowledge is essential, in order that when similar information is obtained for a new substance an intelligible and sound comparison may be madee Desiderata of the study (1) Administration may be oral or subcutaneous according to the nature of the druge | (2) The drug should be made available in such a way that neither the nurse, the patient, nor any=- one in fact except the person supervising the study (Dr. Militzer) shall know the nature of the substance administered or its doseée (3) The evaluation of the presence of analgesic action should be made as objective as possible. While it is advisable in connection with expected repeated administration to avoid the subcutaneous route in connection with relief of pain, promptness and intensity of action may outweigh other considera- tions making the subcutaneous route preferable in many CAaSeSe No, 2@ is essential in order to collect the desir- ed data uncolored by prejudice or expectation. It was suggested that this end might be attained for morphine {or other drug to be given subcutaneously) by having the solution made up in such strength that its admins istration can be ordered in doses of 065 ce. or multi- ple thereof, and the solution kept in a bottle marked only with a key number. The meaning of the key is to be known only to Dr. Militzer. The same end might be attained for codeine (or other substance to be given orally) by having the drug made available in tablets LS. identical in size and appearance but containing dif- ferent amounts of drug as follows: Tablet No. No drug. Codeine, 5 mgm. Codeine, 10 mgm. Codeine, 15 mgm. Codeine, 20 mgm, Codeine, 25 mgm, Codeine, 30 mgm. IO OP OF DOH The tablets are to be placed in a series of num- bered bottles and administration ordered by the num- ber of the container onlye Again Dr. Militzer could be the only one knowing the key. Patients to be used in the analgesic study would of course have to be carefully selected for intelli- gence and cooperativeness as well as for their path= ological condition and need for pain relief. They probably should have enough of the plan explained to them to insure their cooperation. Probably better re= sults would be obtained with new patients who have had not more than very casual previous experience of opiate administration. The procedure for the determination of minimal analgesic dose would be as follows: The patient, free of narcotic and needing pain relief would be given a blank injection or a dose of morphine smaller than could be reasonably expected to give any relicf (an initial dose of 2 mgm, is suggested) or perhaps each alternately at regular intervals until the observer is satisfied that no pain relief is obtained. Then the next larger dose (4 mgm.) would be ordered and con- tinued until it was determined that it did or did not have an effect on pain. If necessary one would cone tinue to increase the dose, 2 mgm at a time, step by step, until an effective dose was reached. During this program the occasional ordering of a blank injection might facilitate the determination of the effectiveness of the dose and the duration of its effect, For the determination of the presence of effect a number of things are suggested, final determination to depend on collation and interpretation of all of them, 1. Notes by the nurse on her impression of the patient’s pain. 2. Notes by the physician in charge gained by examining and questioning the patient on his impres=- sion of the patient’s pain and on other possible ef+ 14. fects = pupil, pulse, etc. 36 Notes by the patient himself on a question- naire basis made preferably twice a day. 4. It would be highly desirable to make an ob- jective determination of the presence of analgesic effect by the method of Seevers or some modification thereof. It is realized that this adds somewhat to the time required for the study and on that basis may not be feasible. 5e Review of all the data by Dr. Militzer, For the determination of the analgesic effect of codeine the general procedure would be the same exeept that the start would be made with a blank tablet or a 5 meme codeine tablet. The continuation of the pro- grem would then be like that outlined for morphine, in- creasing the dose as necessary in steps of 5 mgme until it is determined which dose in a particular patient re= lieves paine | | After the determination of a minimal effective dose in a particular patient and the acquiring of in- formation in regard to the duration of analgesic ac- tion of that dose in that patient, that dose would be administered regularly to that patient at the interval determined for the duration of its action. Such ad= ministration would be continued for a prolonged period and observations already outlined for determination of its effect would be continued. From time to time (every 10 days) administration of the drug would be substituted for not less than 12 hours by administration of blank injections or blank tablets to gain an impression of the continued effectiveness of the drug and the possibility of developing dependence on the drug (addiction). The first would be indicated by exacerbation of the pain, the senond by the appearance of some sort of abstinence phenomena, ~ The discussion of the group indicated that the pro- cedures outlined were feasible and that over an extend-= ed period they offered the best chance of exact evalua- tion of the drugs under consideration and the best basis for future study’ which we could at present devise. Mor- phine supplied by the Committee is still on hand at the hospital. For the codeine study it would be necessary to supply a series of tablets like those recommended for the work at the Middlesex Hospital. Requests for narcotic material as recommended in the above report have been forwarded by Dr. Pope and it is prob-= 15. able that studies of the sort outlined will go forward very shortly. In concluding this portion of the report, the inter- est in our work and enthusiasm for cooperation by the clini- | cians concerned should be noted and our appreciation of this cooperation acknowledged. Part Il. Pharmacologic and Chemical Studies. The principal features of the work on phenanthrene and dibenzofuran derivatives of Dr. Mosettig and his co-workers which have been subjected to pharmacological analysis during the past year are as followss 1. Extension of the study of the effect of hydrogena- tion of the nucleus. | 2e Extension of the study of alkylation of amino groups in cyclic compounds and in derivatives containing the amino group in a straight side-chain. ae Comparison of primary, secondary and tertiary aMminese be Comparison of the effect of introduction of dif- ferent alkyl groups. | 3. Effect of changing the position in relation to the © nucleus of an amino group in a straight side-echain3; lengthen-. ing of the side-chain. 4. The effect of acetylation of an hydroxyl in phen= anthrene derivatives. 5e The effect of hydrogenation of the dibenzofuran nucleus. Syme octahydro=- and tetrahydrophenanthrene, in comparison with phenanthrene itself, as well as derivatives of each of these compounds, have been studied and reported previously. Briefly, sym. octahydrophenanthrene, a symmetrical nucleus, 16. is indistinguishable from phenanthrene when administered orally to cats but tetrahydrophenanthrene is more effective than either as a depressant and even exhibits some analgesic action. 9,10-Dihydrophenanthrene, also a symmetrical nucleus, has mow become available and has proven to be even more ef- fective; the ratio of its effective dose to that of tetra- hydrophenanthrene is about 3:4. It has definite analgesic action when administered orally in a dose of 300 mgm. per kilo- grame | All of the derivatives of sym. octahydrophenanthrene _Which were studied exhibited such a degree of local irritant action as to interfere with absorption of an adequate dose after oral administration. These same substances, however, injected intramuscularly were less emetic and had some anal- gesic action. The tetrahydrophenanthrene derivatives were much more active and, while they were more toxic than previous- ly studied derivatives and exhibited some emetic effect and convulsant action, in one of them the margin of safety seemed wide enough to warrant their clinical trial, The analgesic effect of this substance (No, 259, 3+{1,2,3,4~tetrahydroiso- quinolino )-4«hydroxy=1,2,3,4=-tetrahydrophenanthrene hydrochlor= ide) approximates that of pseudocodeines; its effect in ad- dicts when substituted for morphine has already been described in this reporte Five derivatives of 9,10-dihydrophenanthrene comparable to derivatives of phenanthrene itself have been studied. All of these have shown a significant degree of analgesic action, Lt. but unfortunately they have also been very emetic and some of them very convulsant. It is noteworthy that in two instances the convulsant dose for the cat is lower than the analgesic dosee The effectiveness of this group in comparison with the corresponding unhydrogenated vnetiie times derivatives is shown in the following table. All doses are in milligrams per kilogram, of the substance as administered orally to cats. Comparison of derivatives of 9,10-dihydrophenanthrene with corresponding derivatives of unhydrogenated phenanthrene Minimal — Minimal analgesic depressant Convulsant Emetic dose dose dose dose 340. 2/2~(Dimethylamino)-= | 1=hydroxy~ethyl/=9,10-di- None up hydrophenanthrene HCl. 40 40 to 100 25 149. 3-/2-(Dimethylamino)- . l-hydroxy=ethyl/-phenan- None up threne HCl. 60 ole) to 150 00 342. 2~/2=(Diethylemino)= lehydroxy-ethyl/<-9,10-= dihydrophenanthrene HCl. 25 L5 20 20 150. 3-/2-(Diethylamino)-+ | SebdirosyesthyLphensti» threne HCl. 40 25 75 50 344, 2-/2-Piperidino-1- hydroxy-ethyl/=9,10-di- hydrophenanthrene HCl. 20 20 25 20 151. 3~/2-Piperidino-1- hydroxy~e thy1/=phenan~ threne HCl. 50 60 100 60 348. 2-/2-(Diethylamino)-= L-hydroxy-n=-propyl/=+9,10« | dihydrophenanthrene HCl. 350 25 20 20 221. 3+/2-(Diethylamino)+= : l-hydroxy=n=propyl/= NRe Ul & Qa aa co A) tl a im 0 ele 56. 3-(Dimethylamino)=phenanthrene HCl, with BRE ae 115-¢ 3-Amino-phenanthrene,. iy No. 556, NR» = N(CHs). v No. 115, NR» = NH, The dime thylamino~ compounds are not consistently dif- ferent in toxicity and convulsant action from the primary amines but they are less effective analgesics and are slightly less emetic. Of the compounds in which the amino group in a straight sideechain has been alkylated, four pairs are available for comparisons 150. 3/2-(Diethylamino) -l-hydroxy~e thyl/=phenanthrene a HCl, or, KH 49 3-f2~( Dime thylamino )+l-hydroxy-ethy1/=phenan- threne HCl, with E 3-/2—Amino=l=hydroxy-ethyl/-phenanthrene HCl; and Be 3e/2-(Diethylamino)«1-hydroxy=n-propyl/=phenan- threne HCl, or QO | 87. an(Br-( Dime thy lamin) ~1 LoL CT S prece « veces & Ny oo wom 7 a 7} + Anthracene Phenanthrene These figures, however, do not indicate necessarily that anthracene derivatives are useless for our purpose. Only from anthracene analogs with more complex substituents (eee amino alcohol. « side chain) could conclusions be drawn as to whether or not the anthracene nucleus could replace the phenanthrene nucleus in physiologically active compoundse The combined chemical and pharmacological results show rather clearly the direction in which synthetic experiments 266 should proceed in the near future, namelys le Modification of the alcoholic hydroxyl by alkyla- tion or elimination of this group in the more active amino alcohols (e€ege Nos. 150, 259) of the "straight chain" or "cyclic"type, 2, Introduction of a phenolic hydroxyl into amino al- cohols of the aboveementioned type. | 5- Synthesis of amino alcohol derived from asyme-octa= hydrophenanthrene of the type CHOHCH, NK and possibly of the "cyclic" type. 4. Synthesis of amino alcohols derived from 4,5=phenan- thrylene oxide. >; ek ( \ i ) No” 5e Synthesis of condensed ring systems consisting of a phenanthrene nucleus and a 6=membered nitrogen=containing ring. | (a, Yo es. Ye Hi 2 pen, Hef if \ Hf rx y \ "A M-CH, H / po , wy NY Sooo ya Be cteanltl Nec / i % / \ ’ GH 3 ay Sieieaned Y NS ne my on C\ TY | * ; any \xen/ Nay A176 These experiments are well under waye Subsequently the syn thesis of the isomers of the isoquinoline type will be attack- ede 6. The preparation of two morphimethines ( -tetra- hydro= and /3-dihydro-) has been accomplished (C,H 8 -Cc Hy ~ CHOW Morphine (dihydro) (%)Tetrahydro-morphi= Synthetic No. 255 ; methine The morphimethines represént the linking members between morphine or its close relatives and some of our synthetic amino alcohols. They can be obtained only by degradation of morphine derivatives. They are characterized chiefly by their open nitrogen-containing chain. Our studies in the carbazole series now include nine sub- stancess 28. 268 3-Aminocarbazole HCl. oO7. 3-Amino-9=methylecarbazole HCl. sive 6Amino-1,2,35,4-tetrahydrocarbazole S316 Ledminocarbazole HCl. 358-2 l-Amino-9-methyl-carbazole HCl. 2596 5~Amino=9~ethyl-carbazole HCl. 3726 LO