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Potentiation of Pyridostigmine Bromide Toxicity in Mice by Selected Adrenergic Agents and Caffeine B

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Potentiation of Pyridostigmine Bromide Toxicity in Mice by Selected Adrenergic Agents and Caffeine B Reprinted from Veterinary and Human Toxicology, Vol.-39, No. 4, August 1997, pp. 214-219 Potentiation of Pyridostigmine Bromide Toxicity in Mice by Selected Adrenergic Agents and Caffeine _ b Leslie A Chaney, Robin H Rockhold, James R Mozingo, J and Arthur S Hume ' Department of Pharmacology and Toxicology, -University of Mississippi Medical Center, Jackson, MS James I Moss V Gainesville, FL ABSTRACT. Pyridostigmine bromide (PB) is a reversible cholinesterase inhibitor used routinely in the treat- ment of myasthenia gravis and recently by the US Army as a prophylactic agent against potential nerve gas attack in the Persian Gulf War. Pyridostigmine has been implicated as one of several possible causative factors associated with Persian Gulf illnesses. To investigate toxic interactions between PB and other drugs, male ICR mice received contralateral ip injections of either a selected adrenergic drug or caffeine, followed I5 min later by PB. Representative isobolograms plotted for each drug interaction illustrate that a B-adreno— ceptor agonist (isoproterenol), selective B2—adrenoceptor ‘agonists (saibutamol, terbutaline), al-and <12- adrenoceptor antagonists (yohimbine, phentolamine, prazosin), ias well as the stimulant caffeine, strongly potentiate the lethal effect of PB. Agents with agonist activity at both u— and B—adrenoceptors (epinephrine, nbrepinephrine) additively increase PB—induced lethality. The potentiation of toxicity between PB and these agents was counteracted by pretreatment with atropine and atropine methyl nitrate. An u2—adrenoceptor agonist (clonidine) and B-adrenoceptor antagonists (propranolol, nadolol, acebutolol) dicl not increase PB-induced lethalities. These data demonstrate a toxic synergism between PB, several commonly used classes of adrenergic agents and caffeine when exposure occurs in different combinations. Future studies into the mechanism(s) of these interactions may bring into question the usage of PB as a protective agent in combat conditions as well as delineate any possible contributions of the drug to Persian Gulf illnesses. Pyridostigmine bromide (PB) is a quaternary oncogene and AChE mRNAs following peripheral dimethyl carbamate that has been used histori- administration of “PB _under conditions ,of cally at relatively high: 'd1oses_.(2‘00-1400 ‘mg/d) stress; ‘Recent investigations Fhave linked treat myasthenia.gravisiga'neur0muscular.dis----# the eXp0su’5I*ii3= ,'PB' and the insect order characterized by skeletal muscle weak- repellent‘"N,N—diethyl#m%toluamidee (DEET) to ness band fatigability_ (l); Since yl986, PBi increased ‘lethality 'in “rats_ (10), chickens has been recommended by the US Army for use (ll), and mice-(12).- In studies of inter- as 21 prophylactic agent.against‘organophos- actions between hydrolytic,enzyme_inhibitors phate (OP) nerve gases (2)., Organophosphates andf DEBT in _German. cockroaches, Moss (13) bind irreversibly to “acetylcholinesterase proposed ‘that DEET - may_ Ihave -linherent (AChE) ~in“ thej'centra1_.(CNS)" and. peripheral adrenergic» activity Pthatr could-_play 21 role (PNS) nervous ‘system "to _prevent _hydrolysis in its toxic interaction with PB. , of acetylcholine (ACh) at sites of choliner- gic transmission;- As a result, ACh accumu- Based, on gthe premise that“ activation} of lates at cholinergic receptor sites, produc- the sympathetic nervous system could be in- ing_ excessive ,parasympathetic 'stimulation volved in an adverse_response to PB, we chose leading tfltimately ix) muscle paralysis and to'. investigate? combinations ;Jof» -PB and death. In. contrast, prophylactic doses of se1eeted~adrenergic agents to probe the pos+ PB (30 zmg, po, tid) reversibly inhibit 305 sibility of an acute_interaction between an 40% of AChE_activit'yi~in__.the PNSfto protect- enhanCed* ;cho1inefgiC' state- and altered it from permanent inactivation by OP chemical adrenergic activity. Several of these agents warfare agents. 'Spontaneous dissociation are commonly prescribed, for ‘the treatment over time restores an adequate level of AChE of asthma and for regulation of blood pres- activity to maintain life, -providing “that sure; (l4)l. .Caffeine‘.Was .also included in atropine and oxime treatments are also admin- this study because of its prevalence in com- istered at the time of exposure (3). It is mon 'stimulatory_ beverages tand fits 'ability assumed that PB -does not cross the blood"- to- increase 'levels are circulating catecho— brain barrier to enter the_CNS,.since it is laminesl(l5). _ V v ' a positivelyqfichargedf agent land‘ therefore should(3); not. .._interfere_ _. -,7.with_cognitive_; -,- ,. functiong . “MATERIALS AND METHODS 'The first usage of PB in a combat situation occurred ‘during _the' _Persian >iGulf ”'War. Chemicals" “ ” ' ' - Between August 1990 and April 1991, approxi- Pyridostigmine ~ bromide, ~(i)—epinephrine mately 700,000‘ US 'troops' were deployed, to hydrochloride, (i)-arterenol bitartrate salt they Persian Gulf where -some _were exposed (norepinephrine), (i)-isoproterenol hydro~ simultaneously, to 2i'variety zit potentially chloride,’ sa1butamol,_ terbutaliney hemisul- toxic insults, including "chemical ’Warfare fate, .yohimbine~ hydrochloride, ;phentolamine agents, toxic fumes,” pesticides, infectious hydrochloride§'Yprazosinu hydrochloride, caf- diseases, multiple. immunizations, chemopro- feine,‘,clonidinej hydrochloride; DL-propra— phylactic agents‘ and psychological stress Anololjgjhydrochloride, "nadolol,"” acebutolol (4). Since returning} fromf:theT war, =an - ihydrochlorideQ<atropine sulfate and atropine estimated 5,000-80,000“ soldiers ‘have com- methyl 'nitrateg'werel purchased from Sigma plained of a persistent array of inexplicable Ch¢mi©31S CS$TB0ui$r=MO)- Z. = " , symptoms- ranging? from 'headache, loss of memory, fatigue, muscle and joint pain,_and Animals ' - V ; ataxia, ‘U3 skin rash, respiratory difficul- t;Ma1e{ICR“mice (20-24 g) were purchased from ties and gastrointestinal disturbances;:(5)-_, Pyridostigmine has been implicated as a pos- Harlan sprague Dawley Inc*(1ndianapolis, IN) sible causative agent linked .to-~these. il- and.$h6used- in vthe_ central animal “facility lnesses based (n1 reports of aeute side ef- which was maintained at 22 i 1 C with a 12- fects which were experienced by a number of h light+dark cycle;- Tap water and laboratory chow vwere provided_ ad llibitum. - Mice were soldiers during the Gulf War (4,6), the queer tionable compliance of troops to the recom- randomly assigned to treatmeni~groups, housed mended dosing regimens (7), lack of knowledge in plastic cages with 6-10 animals/cage, and allowed to acclimate to the animal facility iniregard 1x1 drug interactions-which nnght increase the acute .or chronic toxicity_ of environment for 48‘h before dosing. " the drug" (6)',"‘-‘- and -'t_hfe" unknown ’-respons-e of the human body to the drug under extreme con- ynrug Treatment.‘ _ _.,1 . dit-ions of stress y" co-mpa‘ra'b"_le t‘o“t_h_ose_;. e_n—f ’All drugs were dissolved in distilled water countered in war (4J6).+~ "i 1 q if ' i B P immediately ‘prior "to? each) experiment. _ In- dividual drugs were administered ip at vary- .Enhancement xxf activity Within the sympa- ins doses in a volume of 10 mL]kg body weight thetic V(adrenergic)="nervous'"systemf is ;OnG 1:0 r g-r‘O1.1ps= _;<§:>f” 36-"f-109. .mi"ce; -a'r’id J -thetnumber of of many responses- to fpsychologioal -str6SS$ deathsTwerefrecorded"after.24fh,r-Fixed-doses in addition tQ.other changes in CNS function; of" adrenergic drugs _and* caffeine for_ drug behavioral‘ a1terations,f and. disturbances_ in ii111>eracti'onl 's’tu*die's “Were-‘11se-l‘ected at; refer- the immune, cardiovascular*£uu1 gastrointes- eflcéfi doses (16;l7) and demonstrated to cause tinal systems (8). {Friedman et al (9) showed“ " no“ adverse “effect: ‘ epifiephrifie,' 5 ior 10 that stresS+induced“alteratiens in the blood- ms/ks? B°rePiH@phrine;.713=0r 10-ms/ks; iso- brain barrier may allow PB to act centrally; protéififlfilx 43 mg/R8} saIbutamol, 0.4 tn? 018 as demonstrates-d‘ by 'decr'ea‘s’ed brain ‘ ACh~E ‘»a_c*-*-I mg/hg;Gfterbutaline,=*5‘1mg}kg§' phentolamine,l tivity' and' increased. brain 'leve1si of 1}-fos 1-*m€/kgJ_.PraZ0sin, 2 mg/kg;‘ryohimbine, 1 - Vet Human Toxicol 39 (4) AU9U$i,,1997 * 215 mg/kg; caffeine, 5 mg/kg; clonidine, 1 mg/kg; nnsmrrs propranolo1;§1i5-cu‘ 3 mg/kg; nadolol, 1~or 5 mg/kg; and acebutolo1,7 1..or <5. mg/kg. The 24 in LD5Os and 95%%CL‘fOI_iDdiVidU&1 Single» ip" injections Iof (these ‘agents 'were drugs are reported in Table 1. (The LD50 of administered at 'the.-abover doses to lgroups prazosin‘waspnotrdeterminedvdue.to;so1ubility of— 6-10 animals, (followed. 15 null later» by difficulties; at rsqgh, high. doses.< Instead, a_ single contralateral ip injection of PB an _LD»50_ value of“6"0 mg/kg‘ with 95% CL be- (1, 2 cu‘ 3’mg/kg).- Mice were returned to tween 47—+*77 mg./kgmwas ‘assu-med for prazosin their cages and .0bserved 'continuously for based (xi a report by Noguchi et a1.(20) for 1 h after dosing. 'Number of deaths was re- ip dosing in male ICR mice; “The above data corded after 24.h.“ <‘ 8 I ." .j were used in conjunction with LDSO data de- rived-from the binary mixtures.0f each drug In a separate study, groups of 6-10 animals with PB to plotiisobolograms. r . .,_ were pretreated_with a musqarinic antagonist prior0t0'severalyof*thelabove,drug*combina- In» the- drug (interaction ystudies, .c0ntrol tions.“ Mice were given simultaneous contra- animals that received the selected doses of lateralliplinjections1ofpeitherfatropiner(10 each adrenergic agent or caffeine alone did mg/kg) or atfbpine methyl nitrate (5.4 mg/kg) not __'e-xhibit_-adver.s‘e" effects, ‘except for epine- and "an ‘adrenergic1.ag6nt_ (epinephrine, 15 Phrine and 'norepinePhrine; both Tof. which mg/kg; norepinephrine, 7.3 mg/kg;‘salbutamol, 0.8 mg/kg; yohimb'i.n;e,‘-,_.‘1,,j-Big/kg.)".or c_.a.ff.einIe’ <5 or 10mg/kg>-r@‘11owed .15 min leer by 5?. Si . PB (3 mg/kg), and lethality was recorded over a 24 h period. I .. " ' ‘ " A A . ,dI~‘.\_‘ _ - _ A - ' =. _I1 . \\\\ I . I. ‘,1 3 I ~\\.. -- 1- * " ' ' , ‘~» ~_ .2- it i" ' 2‘... .. -.\\ 0 Data Analysis -;»~ " ~: - I \ 1 ‘ 1__~ \\\.
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