Medical Aspects of Chemical Warfare (2008) - The Black Vault

More documents

Recommendations

Info

Nerve Agentssible for binding nerve agent molecules. Functionally,sufficient excess AChE activity is normally present insynapses so that carbamoylation of 20% to 40% of theenzyme with pyridostigmine does not significantlyimpair neurotransmission.Additionally, it must be recognized that the normalhuman carries excess ChE. Thus, temporary inhibitionof a small portion of ChE is well tolerated by humans,with minimal side effect profiles, as detailed below.When animals are challenged with a lethal doseof nerve agent, AChE activity normally decreasesrapidly, becoming too low to measure. In pyridostigmine-pretreatedanimals with a sufficient quantityof protected, carbamoylated enzyme, spontaneousdecarbamoylation of the enzyme regenerates enoughAChE activity to sustain vital functions, such asneuromuscular transmission to support respiration.Prompt postexposure administration of atropine isstill needed to antagonize ACh excess, and an oximereactivator must also be administered if an excess ofnerve agent remains to attack the newly uncoveredAChE active sites that were protected by pyridostigmine.EfficacyBecause it is impossible to test the rationale inhumans exposed to nerve agents, the US military embarkedupon a series of studies in animal models. Table5-9 summarizes one study using male rhesus monkeys.73 Pretreatment with orally administered, pyridostigmine-inhibitedcirculating red blood cell AChE(RBC-AChE) by 20% to 45%. (Inhibition of RBC-AChEby pyridostigmine is a useful index of its inhibition ofAChE in peripheral synapses). Monkeys that had nopyridostigmine pretreatment were not well protectedfrom soman by the prompt administration of atropineand 2-PAM Cl. The PR of 1.64 in these monkeys is typicalof the most effective known postexposure antidotetherapy in animals not given pretreatment to a somanchallenge. In contrast to this low level of protection,however, the combination of pyridostigmine pretreatmentand prompt postchallenge administration ofatropine and 2-PAM Cl resulted in greatly improvedprotection (PR > 40 when compared with the controlgroup; PR = 24 when compared with the group givenatropine and 2-PAM Cl).Because the number of animals available for somanchallenge at extremely high doses was limited,accurate calculation of a PR was indeterminate in thisexperiment. The PR was well in excess of 40, clearlymeeting the requirement for effectiveness of 5-foldimproved protection. In a later study, four of five rhesusmonkeys receiving pyridostigmine pretreatmentTABLE 5-9EFFECT OF THERAPY ON Median LethalDose IN MONKEYS EXPOSED TO SOMANGroup Mean LD 50(µg/kg) [95% CL]Control (no treatment)Postexposure atropine+ 2-PAM ClPyridostigminepretreatment +postexposureatropine +2-PAM ClMean ProtectiveRatio [95% CL]15.3 [13.7–17.1] NA25.1 [22.0–28.8] 1.64 [1.38–19.5]> 617 > 40**Indeterminate because of small number of subjects; PR relative tothe atropine plus 2-PAM Cl group > 24 (617 ÷ 25.1)2-PAM Cl: 2-pyridine aldoxime methyl chlorideCL: confidence limit (based on a separate slopes model)LD 50: median lethal doseNA: not applicablePR: factor by which the LD 50of a nerve agent challenge is raised(in this experiment, the LD 50for group given therapy divided bythe LD 50for control group)Adapted from: Kluwe WM. Efficacy of pyridostigmine againstsoman intoxication in a primate model. In: Proceedings of the SixthMedical Chemical Defense Bioscience Review. Aberdeen ProvingGround, Md: US Army Medical Research Institute of ChemicalDefense; 1987: 233.and postexposure therapy of atropine and 2-PAM Clsurvived for 48 hours after being challenged with GFat a level 5-fold higher than its LD 50. 247Pyridostigmine pretreatment shows its strongestbenefit, compared with atropine and oxime therapyalone, in animals challenged with soman and tabun,and provides little additional benefit against challengeby sarin or VX. 248–250 Table 5-10 shows the PRs obtainedin animals given atropine and oxime therapy afterchallenge with the five nerve agents with and withoutpyridostigmine pretreatment. As shown, pyridostigminepretreatment is essential for improved survivalafter soman and tabun challenge. With sarin or VX,depending on the animal system studied, pyridostigminecauses either no change or a minor decrease inPRs, which still indicate strong efficacy of atropineand oxime therapy for exposure to these agents. Thedata for GF show no benefit from pyridostigminepretreatment for mice and a small benefit for guineapigs. The only published data on protection of primatesfrom GF show a PR of more than 5 with pyridostigminepretreatment and atropine/oxime therapy, buta control group treated with atropine/oxime alone199
Medical Aspects of Chemical WarfareTABLE 5-10EFFECT OF THERAPY WITH AND WITHOUT PYRIDOSTIGMINE PRETREATMENT ON PROTEC-TIVE RATIOS IN ANIMALS EXPOSED TO NERVE AGENTSProtective RatioNerve Agent Animal Tested Atropine + Oxime Pyridostigmine + Atropine + OximeGA (Tabun) Rabbit 1 2.4 3.9Mouse 2 1.3 1.7/2.1*Guinea pig 2 4.4 7.8/12.1*Rabbit 3 4.2 > 8.5GB (Sarin) Mouse 2 2.1 2.2/2.0*Guinea pig 2 36.4 34.9/23.8*GD (Soman) Mouse 4 1.1 2.5Rat 5 1.2 1.4Guinea pig 6 1.5 6.4/5.0*Guinea pig 7 2.0 2.7/7.1*Guinea pig 8 1.9 4.9Guinea pig 9 1.7 6.8Rabbit 1 1.4 1.5Rabbit 4 2.2 3.1Rabbit 3 1.9 2.8Rhesus monkey 10 1.6 > 40GF Mouse 11 1.4 1.4Guinea pig 11 2.7 3.4Rhesus monkey 12 > 5VX Mouse 2 7.8 6.0/3.9*Rat 5 2.5 2.1Guinea pig 2 58.8 47.1/45.3**Two doses of pyridostigmine were used.(1) Joiner RL, Dill GS, Hobson DW, et al. Task 87-35: Evaluating the Efficacy of Antidote Drug Combinations Against Soman or Tabun Toxicity inthe Rabbit. Columbus, Oh: Battelle Memorial Institute; 1988. (2) Koplovitz I, Harris LW, Anderson DR, Lennox WJ, Stewart JR. Reduction bypyridostigmine pretreatment of the efficacy of atropine and 2-PAM treatment of sarin and VX poisoning in rodents. Fundam Appl Toxicol.1992;18:102–106. (3) Koplovitz I, Stewart JR. A comparison of the efficacy of HI6 and 2-PAM against soman, tabun, sarin, and VX in therabbit. Toxicol Lett. 1994;70:269–279. (4) Sultan WE, Lennox WJ. Comparison of the Efficacy of Various Therapeutic Regimens, With and WithoutPyridostigmine Prophylaxis, for Soman (GD) Poisoning in Mice and Rabbits. Aberdeen Proving Ground, Md: US Army Chemical SystemsLabororatory; 1983. ARCSL Technical Report 83103. (5) Anderson DR, Harris LW, Woodard CL, Lennox WJ. The effect of pyridostigminepretreatment on oxime efficacy against intoxication by soman or VX in rats. Drug Chem Toxicol. 1992;15:285–294. (6) Jones DE, Carter WHJr, Carchman RA. Assessing pyridostigmine efficacy by response surface modeling. Fundam Appl Toxicol. 1985;5:S242–S251. (7) Lennox WJ,Harris LW, Talbot BG, Anderson DR. Relationship between reversible acetylcholinesterase inhibition and efficacy against soman lethality.Life Sci. 1985;37:793–798. (8) Capacio BR, Koplovitz I, Rockwood GA, et al. Drug Interaction Studies of Pyridostigmine with the 5HT3 ReceptorAntagonists Ondansetron and Granisetron in Guinea Pigs. Aberdeen Proving Ground, Md: US Army Medical Research Institute of ChemicalDefense; 1995. USAMRICD Training Report 95-05. AD B204964. (9) Inns RH, Leadbeater L. The efficacy of bispyridinium derivatives in thetreatment of organophosphate poisoning in the guinea pig. J Pharm Pharmacol. 1983;35:427–433. (10) Kluwe WM. Efficacy of pyridostigmineagainst soman intoxication in a primate model. In: Proceedings of the 6th Medical Chemical Defense Bioscience Review. Aberdeen ProvingGround, Md: USAMRICD; 1987: 227–234. (11) Stewart JR, Koplovitz I. The effect of pyridostigmine pretreatment on the efficacy of atropineand oxime treatment of cyclohexylmethylphosphonofluoridate (CMPF) poisoning in rodents. Aberdeen Proving Ground, Md: US ArmyMedical Research Institute of Chemical Defense; 1993. Unpublished manuscript. (12) Koplovitz I, Gresham VC, Dochterman LW, KaminskisA, Stewart JR. Evaluation of the toxicity, pathology, and treatment of cyclohexylmethlyphosphonofluoridate (CMFF) poisoning in rhesusmonkeys. Arch Toxicol. 1992;66:622–628.200
Page 3 and 4:
The Coat of Arms1818Medical Departm
Page 5:
Textbooks of Military MedicinePubli
Page 8 and 9:
MEDICAL ASPECTS o fCHEMICAL WARFARE
Page 10 and 11:
ContentsContributorsForeword by The
Page 12 and 13:
ContributorsMICHAEL ADLER, PhDResea
Page 14 and 15:
DONALD M. MAXWELL, MSResearch Chemi
Page 16 and 17:
ForewordThe US military has been co
Page 18 and 19:
PrefaceA significant concern for th
Page 20:
PrologueThe original edition of Med
Page 23 and 24:
xxii
Page 25 and 26:
Medical Aspects of Chemical Warfare
Page 27 and 28:
Page 29 and 30:
Page 31 and 32:
Page 33 and 34:
Page 35 and 36:
Page 37 and 38:
Page 39 and 40:
Page 41 and 42:
Page 43 and 44:
Page 45 and 46:
Page 47 and 48:
Page 49 and 50:
Page 51 and 52:
Page 53 and 54:
Page 55 and 56:
Page 57 and 58:
Page 59 and 60:
Page 61 and 62:
Page 63 and 64:
Page 65 and 66:
Page 67 and 68:
Page 69 and 70:
Page 71 and 72:
Page 73 and 74:
Page 75 and 76:
Page 77 and 78:
Page 79 and 80:
Page 81 and 82:
Page 83 and 84:
Page 85 and 86:
Page 87 and 88:
Page 89 and 90:
Page 91 and 92:
Page 93 and 94:
Page 95 and 96:
Page 97 and 98:
Page 99 and 100:
Page 101 and 102:
Page 103 and 104:
Page 105 and 106:
Page 107 and 108:
Page 109 and 110:
Page 111 and 112:
Page 113 and 114:
Page 115 and 116:
Page 117 and 118:
Page 119 and 120:
Page 121 and 122:
Page 123 and 124:
Page 125 and 126:
Page 127 and 128:
Page 129 and 130:
Page 131 and 132:
Page 133 and 134:
Page 135 and 136:
Page 137 and 138:
Page 139 and 140:
Page 141 and 142:
Page 143 and 144:
Page 145 and 146:
Page 147 and 148:
Page 149 and 150:
Page 151 and 152:
Page 153 and 154:
Page 155 and 156:
Page 157 and 158:
Page 159 and 160:
Page 161 and 162:
Page 163 and 164:
Page 165 and 166:
Page 167 and 168:
Page 169 and 170:
Page 171 and 172: Medical Aspects of Chemical Warfare
Page 178 and 179: Nerve AgentsChapter 5NERVE AGENTSFR
Page 180 and 181: Nerve AgentsAbout 10,000 to 30,000
Page 182 and 183: Nerve Agentsphorofluoridate (DFP) w
Page 184 and 185: Nerve AgentsFig. 5-2. This schemati
Page 186 and 187: Nerve AgentsExhibit 5-1 continuedis
Page 188 and 189: Nerve Agentsactivity but only 15% t
Page 190 and 191: Nerve AgentsTABLE 5-3CHEMICAL, PHYS
Page 192 and 193: Nerve AgentsTABLE 5-4EFFECTS OF EXP
Page 194 and 195: Nerve Agentsaffecting the other eye
Page 196 and 197: Nerve Agentsmay cause severe rhinor
Page 198 and 199: Nerve Agentsof jerks and tremor.Cen
Page 200 and 201: Nerve Agentsand they were decreased
Page 202 and 203: Nerve Agentsnerve agent toxicity on
Page 204 and 205: Nerve Agentspatient. Decontaminatio
Page 206 and 207: Nerve AgentsFig. 5-5. The Mark I ki
Page 208 and 209: Nerve Agentsadministered intramuscu
Page 210 and 211: Nerve Agentsthat hydroxamine reacti
Page 212 and 213: Nerve AgentsOral administration may
Page 214 and 215: Nerve AgentsTABLE 5-7RECOMMENDED TH
Page 216 and 217: Nerve Agentsimpairment such as whee
Page 218 and 219: Nerve Agentssuboptimal, manner. The
Page 220 and 221: Nerve Agentsthan those who did not.
Page 224 and 225: Nerve Agentsfor comparison was not
Page 226 and 227: Nerve AgentsTABLE 5-11EFFECTS OF PY
Page 228 and 229: Nerve Agentstivity of smooth muscle
Page 230 and 231: Nerve Agents38. Grob D, Lilienthal
Page 232 and 233: Nerve Agents77. McDonough JH, Shih
Page 234 and 235: Nerve Agents117. McLeod CG Jr, Sing
Page 236 and 237: Nerve Agents154. Tryphonas l, Veino
Page 238 and 239: Nerve Agents193. Funckes AJ. Treatm
Page 240 and 241: Nerve Agents235. Suzuki T, Morita H
Page 242: Nerve Agents274. Pellegrini JE, Bak
Page 273 and 274:
Page 275 and 276:
Page 277 and 278:
Page 279 and 280:
Page 281 and 282:
Page 283 and 284:
Page 285 and 286:
Page 287 and 288:
Page 289 and 290:
Page 291 and 292:
Page 293 and 294:
Page 295 and 296:
Page 297 and 298:
Page 299 and 300:
Page 301 and 302:
Page 303 and 304:
Page 305 and 306:
Page 307 and 308:
Page 309 and 310:
Page 311 and 312:
Page 313 and 314:
Page 315 and 316:
Page 317 and 318:
Page 319 and 320:
Page 321 and 322:
Page 323 and 324:
Page 325 and 326:
Page 327 and 328:
Page 329 and 330:
Page 331 and 332:
Page 333 and 334:
Page 335 and 336:
Page 337 and 338:
Page 339 and 340:
Page 341 and 342:
Page 343 and 344:
Page 345 and 346:
Page 347 and 348:
Page 349 and 350:
Page 351 and 352:
Page 353 and 354:
Page 355 and 356:
Page 357 and 358:
Page 359 and 360:
Page 361 and 362:
Page 363 and 364:
Page 365 and 366:
Page 367 and 368:
Page 369 and 370:
Page 371 and 372:
Page 373 and 374:
Page 375 and 376:
PROCESSMedical Aspects of Chemical
Page 377 and 378:
Page 379 and 380:
Page 381 and 382:
Page 383 and 384:
Page 385 and 386:
Page 387 and 388:
Page 389 and 390:
Page 391 and 392:
Page 393 and 394:
Page 395 and 396:
Page 397 and 398:
Page 399 and 400:
Page 401 and 402:
Page 403 and 404:
Page 405 and 406:
Page 407 and 408:
Page 409 and 410:
Page 411 and 412:
Page 413 and 414:
Page 415 and 416:
Page 417 and 418:
Page 419 and 420:
Page 421 and 422:
Page 423 and 424:
Page 425 and 426:
Page 427 and 428:
Page 429 and 430:
Page 431 and 432:
Page 433 and 434:
Page 435 and 436:
Page 437 and 438:
Page 439 and 440:
Page 441 and 442:
Page 443 and 444:
Page 445 and 446:
Page 447 and 448:
Page 449 and 450:
Page 451 and 452:
Page 453 and 454:
Page 455 and 456:
Page 457 and 458:
Page 459 and 460:
Page 461 and 462:
Page 463 and 464:
Page 465 and 466:
Page 467 and 468:
Page 469 and 470:
Page 471 and 472:
Page 473 and 474:
Page 475 and 476:
Page 477 and 478:
Page 479 and 480:
Page 481 and 482:
Page 483 and 484:
Page 485 and 486:
Page 487 and 488:
Page 489 and 490:
Page 491 and 492:
Page 493 and 494:
Page 495 and 496:
Page 497 and 498:
Page 499 and 500:
Page 501 and 502:
Page 503 and 504:
Page 505 and 506:
Page 507 and 508:
Page 509 and 510:
Page 511 and 512:
Page 513 and 514:
Page 515 and 516:
Page 517 and 518:
Page 519 and 520:
Page 521 and 522:
Page 523 and 524:
Page 525 and 526:
Page 527 and 528:
Page 529 and 530:
Page 531 and 532:
Page 534 and 535:
Triage of Chemical CasualtiesChapte
Page 536 and 537:
Triage of Chemical Casualtiesreceiv
Page 538 and 539:
Triage of Chemical Casualtiesentran
Page 540 and 541:
Triage of Chemical Casualtiescatego
Page 542 and 543:
Triage of Chemical CasualtiesIn a f
Page 544 and 545:
Triage of Chemical Casualtiesnose)
Page 546 and 547:
Triage of Chemical CasualtiesWith n
Page 548 and 549:
Triage of Chemical Casualties14. Sa
Page 550 and 551:
Decontamination of Chemical Casualt
Page 552 and 553:
Page 554 and 555:
Page 556 and 557:
Page 558 and 559:
Page 560 and 561:
Page 562 and 563:
Page 564 and 565:
Page 566 and 567:
Page 568 and 569:
Page 570 and 571:
Page 572 and 573:
Page 574 and 575:
Page 576 and 577:
Page 578 and 579:
Page 580:
Page 583 and 584:
Page 585 and 586:
Page 587 and 588:
Page 589 and 590:
Page 591 and 592:
Page 593 and 594:
Page 595 and 596:
Page 597 and 598:
Page 599 and 600:
Page 601 and 602:
Page 603 and 604:
Page 605 and 606:
Page 607 and 608:
Page 609 and 610:
Page 611 and 612:
Page 613 and 614:
Page 615 and 616:
Page 617 and 618:
Page 619 and 620:
Page 621 and 622:
Page 623 and 624:
Page 625 and 626:
Page 627 and 628:
Page 629 and 630:
Page 631 and 632:
Page 633 and 634:
Page 635 and 636:
Page 637 and 638:
Page 639 and 640:
Page 641 and 642:
Page 643 and 644:
Page 645 and 646:
Page 647 and 648:
Page 649 and 650:
Page 651 and 652:
Page 653 and 654:
Page 655 and 656:
Page 657 and 658:
Page 659 and 660:
Page 661 and 662:
Page 663 and 664:
Page 665 and 666:
Page 667 and 668:
Page 669 and 670:
Page 671 and 672:
Page 673 and 674:
Page 675 and 676:
Page 677 and 678:
Page 679 and 680:
Page 681 and 682:
Page 683 and 684:
Page 685 and 686:
Page 687 and 688:
Page 689 and 690:
Page 691 and 692:
Page 693 and 694:
Page 695 and 696:
Page 697 and 698:
Page 699 and 700:
Page 701 and 702:
Page 703 and 704:
Page 705 and 706:
Page 707 and 708:
Page 709 and 710:
Page 711 and 712:
Page 713 and 714:
Page 715 and 716:
Page 717 and 718:
Page 719 and 720:
Page 721 and 722:
Page 723 and 724:
Page 725 and 726:
Page 727 and 728:
Page 729 and 730:
Page 731 and 732:
Page 733 and 734:
Page 735 and 736:
Page 737 and 738:
Page 739 and 740:
Page 741 and 742:
Page 743 and 744:
Page 745 and 746:
Page 747 and 748:
• Analyze using GC-MS with methan
Page 749 and 750:
Page 751 and 752:
Page 753 and 754:
Page 755 and 756:
Page 757 and 758:
Page 759 and 760:
Page 761 and 762:
Page 763 and 764:
Page 765 and 766:
Page 767 and 768:
Page 769 and 770:
Page 771 and 772:
Page 773 and 774:
Page 775 and 776:
Page 777 and 778:
Page 779 and 780:
Page 781 and 782:
Page 783 and 784:
Page 785 and 786:
Page 787 and 788:
Page 789 and 790:
Page 791 and 792:
Page 793 and 794:
Page 795 and 796:
Page 798 and 799:
Abbreviations and AcronymsAbBreviat
Page 800:
Abbreviations and AcronymsPADPRP: p
Page 803 and 804:
Page 805 and 806:
Page 807 and 808:
Page 809 and 810:
Page 811 and 812:
Page 813 and 814:
Page 815 and 816:
Page 817 and 818:
Page 819 and 820:
Page 821 and 822:
Page 823 and 824:
Page 825 and 826:
Page 827 and 828:
Page 829 and 830:
Page 831 and 832:
Page 833 and 834:
Page 835 and 836:
Page 837 and 838:
Page 839 and 840:
Page 841 and 842:
Page 843 and 844:
Page 845:
show all

Medical Aspects of Chemical Warfare (2008) - The Black Vault

Create successful ePaper yourself

Delete template?

Save as template?