Document M40gKNrdLKQepxn0pN8qOrkr7

R&S 113084 /0000409 BIO-MEDICAL RESEARCH DOCUMENT DESCRIPTION FORM \ 68 69 0 0 0 0 4 0^ Duplicate in all cards: --> ;?9o year as-1961- F;Lle number PRight justify MTymeric only] Author(s), as Last Name FS (No Punctuation) and coden for journal as JAMA preceeded by one blank space 1 20 21 T- f.H- +s 40 41 $ \ 7778 I Uos 1 Sub-Index Code 60 61 62 11 12 13 Title of Report; end with space-hyphen-hyphen-space. Follow with Index Terms, separated from each other with comma-space. Avoid other punctuation; do not abbreviate. 1 :~ :---------------------------------------------------------------------------- oF' Urns / (`h fa/z. /</* -------------- . /C/ B/A77T srr^sx 7^------------------------------ 21 22 23 24 Source (Journal, Vol., Number, Pages, Date) 12 `Lancet. .' X / uo -fo. "O' 61 62 31 32 Brief Sunimary 12 10 SUMMARY: 61 62 ` 61 62 63 64 410 of experiment* wu performed according to the following schedule: --24 hours intramuscular tranylcypromine (20 mg. per kg.); 0 hour intravenous tranylcypromine (10 mg. per kg.)i 1 hour intravenous procyclidinc (5 mg. per kg.); 4 hours intravenous tranylcypromine (10 mg. per kg.). The neuroleptics were injected at different times before the rectal temperature was recorded. Intramuscular administration of o-flupenthixol (0-3 mg. per kg.)a given at -- I hour, did not change the temperature course during the experiment; neither did a-fiupcnthixol decanoatc in oil (10 mg. per kg.) given intramuscularly 3 days before. The following depot neuroleptics were given intramuscularly at --1 hour: a-flupenthixol decanoate (r.p.T.-D, 10 mg. per kg.), fluphenazine decanoatc (F.P.Z.-D, 2-5 mg. per kg.), pipothiazine palmitate (p.rxp, 10 mg. per kg.), and fluspirilene (PJ.L., 2 mg. per kg.). F.P.T.-D did not influence the response to procyclidine, but there was a more striking rise in temperature after the last dose of tranylcypromine. Five out of six rabbits given neuroleptics and only one of the six controls had a tempera ture exceeding 40*C. In the F.P.Z.-D group one of six rabbits died shortly after the administration of procycli dine (40'7'C). Death may have been caused by a cardio vascular effect, since a preliminary experiment in this laboratory demonstrated that such a drug combination may produce dramatic tachycardia. Another animal died in hyperthermia (43-4*C) after tranylcypromine. In the P.P.Z.-P group fatal hyperthermia developed in two of six rabbits (42-9 and 43-7*Q in response to procyclidine. There was a slightly brisker and more pronounced response to the administration of procyclidine in rabbits treated with PAL. compared with the controls and after the last dose of tranylcypromine fatal hyperthermia (44-3-44-5`C) rapidly developed in all rabbits. Thus, in a total of twenty-eight rabbits pretreated with two doses of tranylcypromine, administration of procycli dine resulted in a moderate hyperthermia (temperature not exceeding 41 ^"C) in some animals. After injection of a further dose of tranylcypromine 3 hours after procyclidine, only cases of moderate hyperthermia were recorded, except in animals which had also been treated with a depot neuro leptic preparation on the day of recording. Severe hyper thermia either in response to the administration of pro cyclidine or to the last dose oftranylcypromine was recorded in some of these rabbits. It is remarkable that F.p.t.-o injected 3 days before the experiment did not influence the temperature course, whereas injection of any of the depot preparations 1 hour before appeared to do so. In a period ofa few hours, only minute amounts of active substance could have been released from the intramuscular depot, whereas an amount sufficient to establish neuroleptic effect would have been released after 3 days.11-*2 3 Under certain conditions neuroleptics may possibly aggravate the interaction between antiparkinson drugs and m.a.o.i.3. The reason for this is unknown. However, all three types of drugs may affect dopaminergic neuron systems in the brain. Treatment with an m.a.o.l increases the concentration of dopamine. In addition to the anti cholinergic effect many antiparkinson drugs inhibit dop amine uptake,* leading to an increased amount of dopamine in the synaptic cleft. An imcmeuronal feedback mccha- `rm due to postsynaptic receptor blockade by the neuroleptics is probably not operating, since a receptor blockade can be demonstrated pharmacologically only about 24 hours after injection of a depot neuroleptic.1 Evidence indicating the existence of a feedback control mediated via presynaptic 1. N/msrk, M., Fr,nck, K. F., Fcdcr.cn, V., Boccfc. V., Miller Nielsen, X. Acta Pharmac. tax. 1973, 33, 363. 2. JarcenKn. A.. Krcdricon Ovcre, K., Heiucn. V. Hid. 1971,2*. 339. 3. jortcruen, A., Goctfric, C G. Piychapkanaacalatia, 1972, 27, 1. 6. Fuse, Golducin, M, Uunedehl, A. Li/t Set. 1970, , 811. THE LANCET, AUGUST 30, 1975 A dopamine receptors, has been reported.*-* Minute of the neuroleptics liberated from the depot duri^fthe first few hours may possibly block the presynaptic receptors, resulting in an increased formation of dopamine. Since dopaminergic agonists increase body-temperature in rabbits,' the hyperthermia recorded in the present experi ments might be due to an exaggerated dopamine response. Department of Fturnucolocy ud Toxicology. H. Lundbcck & Co., 7-9 OttilUvci. OK 2300 Copenhagen-Valby, Denmark. V. Pedersen I. Mar.i.ra Nielsen. CHROMOSOMAL AND DOMINANT LETHAL EFFECTS OF VINYL CHLORIDE Six,--Vinyl-chloride monomer (V.CM.) it carcinogenic to rats * and epidemiological evidence has demonstrated its carcinogenicity to man.* It is known that most carcino gens are mutagenic, and therefore evidence of mutagenic effects in man and animals has been sought. In relatively limited studies Funcs-Crsvioto et al.10 and Ducatroan eta!11 have described chromosomal aberrations in man exposed to v.c.m. during the manufacture ofpolyvinyl chloride (p.v.c.). We have examined a larger number of workers and extended the observations to dominant lethal studies in mice exposed to V.C.M, We have studied 80 workers, 56 of whom bad been work ing in the manufacture of p.v.c, and were thus exposed to v.cm.: the remainder were working in plants and labora tories where exposure to v.cm. did not occur. The exposed group consisted of autoclave workers, maintenance workers, and workers associated with the manufacture of .vinyl chloride. Blood samples were taken and lymdftyte cultures prepared using standard Difco kits (Difco J^Hn- tones, Detroit, Michigan, U.SJV.). Lymphocytes'were CHROMOSOMAL ABERRATIONS IN VINYl-CHLORml-EXPOSIO WORKERS ANt> controls not exposcd to VINYL CHLORIDE Exposure category Exposed ,, . Nonexpoted * * No. V* B edit 56 . 24 6-30 3 63 % Cuceti. 1*65 0*46 % C cells 0-38 0-09 cultured for 48 or 72 hours. All slides were coded before scoring to ensure unbiased analyses, and 100 cells from each individual were analysed using the classification of Buckton and Pike.1* Workers who had been exposed to X rays, prolonged drug treatment, or recent viral infections were excluded from the study. The results from 48 and 72 hour cultures were not signifi cantly different and these data have been pooled. The results are given in the accompanying table where it can be seen ttaac there is a significantly increased (p<0-05) percentage of B, Cu, and Cs cells in the exposed workers. These results, which confirm those of the previous authors,10*11 suggest that vinyl chloride has a detectable effect on chromosomal aberrations in man. To check whether any genetic effects could be induced in the germ cells we carried out a dominant lethal study in 5a CtrUaon, A., Kehr, W., Lindquist, M, J. Phantuu, Parit> 1974, f, auppl. 1, 58. 6. Wtiters, J. R., Roth, R. H*7- Pharmaca <xp. 7Tur, 1974,191, 87. 7. Quocfc, R. M., Horirt, A. S<un<*t 1974* J83, 559. 8. Mtlioni, C. L<(cminet G. Emriwu R*f- 1974, 7, 387. 9. Creech, J. L., Johnioo* M* N.J* occup. M*d. 1974, 18, 150,^^ 10. Funes-Crtvioco, P* Ltmbert, B. Lindscen, J., Chrcnhj^HL., Ntunjin, T., Oslcrmmn-Goiktrt, S. La*c*tt 1975, i,^H| 11. Ductimtn, A., Hiftehhortt, 1C, $cUko/T, I. J. Rr7^W75, 31, 163. 12. Buckton, K< E., Pike, M. C /m, 7. Rad, SiW. 1964, 8, 439. THH LANCET, AUGUST 30, 1975 411 R&S 113086 mice. Fifteen male mice per treatment group were exposed to levels of 30 000, 10000, and 3000 p.p.m. of v.c.m. for 6 hours i day on 5 consecutive days, and an examination for dominant lethal effects in two females mated with each male for 8 consecutive weeks was carried out. There was no significant increase in the number of early deaths per implantation compared with a control group exposed to air alone, indicating that V.C.M. does not produce dominant lethal mutations in mice even at these exceptionally high levels. It appears, therefore, that the mutagenic effects of vinyl chloride, expressed as chromosomal aberrations in lymphocytes, do not occur in the germ cells. The reason tor this could well be that active metabolites of vinyl chloride arc responsible for the toxic effects and these do not reach the testis.. The potential danger of mutagenic effects on the fetus via the sperm does not therefore seem to exist. Imperial Chemical Industrie, Limited, Central Toxicology Laboratory, Altkrky Park, Nr. Macclesfield, Cheshire SKI0-4TJ. ' I. F. H. Purchase C. R. Richardson D. Anderson. THYROID-CELL-MEMBRANE ANTIBODIES Sir,--Attention has been drawn ** to an association between various types of thyroid disease and infection with Ytnima enttrocolitUa serotype 3. Lidman et al.* have also shows, using an indirect immunofluorescent technique, that a high percentage of the sera containing agglutinating antibodies to V. enttrocolitUa serotype 3 have antibodies which react with the membrane region of thyrotoxic thyroid epithelial cells. Following beat inactivation of complement, smooth-muscle antibody (s.Ma.) positive sera can be shown served by Bibcrfcld et al,* (see accompanying figure). The 46 sera investigated in this study were' collected over a four-month period. Their selection was simply on the basis of the brightness of the thyroid-membrane fluorescence on initial screening. The indirect-immunofluorescence tech nique used was similar to that described by Beck.* To determine the immunoglobulin dais of the antibodies, specific antisera to G, A, and M were obtained from Wellcome Reagents Ltd, and D and E from Behringwerke AG. As observed by Biberfdd et aL* some thyrotoxic thyroids used as substrates gave no staining of thyroidcell membrane with positive sera and therefore, once a thyrotoxic thyroid waa found suitable, it was used through out the study. The mean age of the patients was 59*2 years (range 18-89); the 46 patients comprised 26 females and 20 males. The clinical diagnoses are shown in table I. TASLS i Clinical diagnosis Thyroid du*au: Thyrotoxicosis Hypothyroidism *. , Unspecified Other dufAMMUfu ditteut: Pernicious anemia .......................... Rheumatoid arthritis Autoimmune hemolytic scuemia Chronic active hepatitis .......................... Alopecia areata MaUfnant diuau .. Vatevlar diwu ,, Inftcrieut diutttt MitttUaiuo*u .. *. No. of patients 12 1 2 6 .1 1 2 t 3 4 2 II TABLE II--ASSOCIATED AUTOANTIBODIES Organ-tpcdfic Thyroid microsomal Gastric parietal celt 4* IS Nou-tfguHptdfic Antinuclear Smooth muscle Mitochondrial Rcticulin 12 11 1 11 * True frequency of thi, antibody could not bo detsauned aince when there ws* bright cytoplasmic fluorescence duo to microso mal antibody this obscured cell-membrane staining. It is evident that some 52% of patients with this particular antibody have dinical autoimmune disease. The mean antibody litre was 1/64 (range 1/8-1/512). The immuno globulin class of the thyroid-membrane antibodies was as follows: G-45, A-34, M-16, D-6, and E-28. The nature and frequency of associated autoantibodies are shown in table n. Uofijcod uedoa of thyrotoxic thyroid dlsployod by ladlroct Imimmoporoxldpso tschalquc. Note the linear staining of epithelial cell membranes, x 440. Like Bibcrfeld et al.* we have observed'that, following heat inactivation of complement, 32 out of 44 sera contain ing smooth-muscle antibody reacted with sectioned thyro toxic cells to produce an identical staining pattern, but this antibody does not show as wide a spectrum of immuno to produce identical staining of thyroid-cell membranes. ** globulin class as that found in the other group and is mainly However, it is clear that this is a different antibody since of the IgG class. Clearly, however, there is some overlap not only can it be removed by absorption with pig stomach since 11 of the unheated sera which were positive for but also it appears to be inhibited by complement.* thyroid-cel 1-membrane antibody also contained s.M.a. We report here our studies on an antibody, found in sera The association between Y. enttrocolitUa serotype 3 and sent to our laboratory for routine autoantibody studies, thyroid-cell-membranc antibody *"* is of interest. Infec which produces an identical staining pattern to that ob-1 * 3 4tion with this particular organism is common in Scandi navia, but this docs not appear to be so in the United 1. Bech, K., Linen. J. H., Hunan, J. M., Ncmp, J. Lanai, 1974, li, 931. 2- Lidman, K., BrikMOn, U,, Fasrseui, A., Norberg, R. Hid, 1974. il, 1449. 3. von BotudoriT, M., Frisian, C. iM. p, 1364. 4, Biberfdd, G., Pagnaua, A., Lanital, R. Clan. exp. Jmmun. 1974.18, 371. 3. Sutton, R. N. Emond, R. T. D., Thomas, D. B., Doniach, D. Hid. 1974, 17, 437. Kingdom.' Of 30 sera (10 positive for thyroid-cell-membrane antibody, 10 positive for smooth-muscle antibody, and 10 negative for all autoantibodies) screened for evidence of infection with this organism none was positive. However, 6. Beck, J. S. Auodtrion of Clinical Pathologiu* Bcoorisbcct, 1974, no. 69. 7. Mair, N. S. Pcnonil communication.