Trihexyphenidyl Enhances Physostigmine Prophylaxis against Soman Poisoning in Guinea Pigs

Trihexyphenidyl Enhances Physostigmine Prophylaxis against SomanPoisoning in Guinea Pigs. LIM, D. K., HOSFCINS, B., and Ho,I. K. (1991). Fundam. Appl. Toxicol. 16, 482–489. Theprotective effects of simultaneous and continuous administrationof physostigmine and trihexyphenidyl against soman-induced toxicitywere studied in guinea pigs. Not only did trihexyphenidyl reducephysostigmine-induced toxicity when it was administered continuouslyto the animals along with physostigmine, the combination affordedgreater protection from soman lethality than did either agentadministered alone. The combination pretreatment also gave betterprotection against soman-induced body weight loss and decreasedwater consumption and attenuated the down-regulation of cholinergicreceptors which occurred when physostigmine alone was used.The onsets of other soman-induced toxicity signs were delayedsignificantly by the combination pretreatment regimen. Theseresults suggest that simultaneous administration of the combinationof physostigmine and trihexyphenidyl may be more useful thanphysostigmine alone as prophylaxis against soman poisoning.     

Protection of Guinea Pigs against Soman Poisoning by Pretreatment withp-Nitrophenyl Phosphoramidates

Severalp-nitrophenyl phosphoramidates with the general formula RO(NH₂)P(O)OC₆H₄-p-NO₂, in which R = CH₂CH₃,CH₂CH₂F, CH₂CHF₂, CH₂CF₃, CH₂CH₂CH₂CH₃, and CH₂CH₂Cl, as well as (NH₂)₂P(O)OC₆H₄-p-NO₂were administered intravenously to guinea pigs as pretreatment compounds for protection against the lethal effects of 1,2,2-trimethylpropyl methylphosphonofluoridate (soman) poisoning. Administration of phosphoramidates at a dose that produces 30% acetylcholinesterase (AChE) inhibition in the blood of atropinized guinea pigs at the moment of soman poisoning increases the subcutaneous LD50 of soman up to almost fivefold depending on which compound was used. A synergistic effect with atropine was observed. Three of these compounds offered a higher degree of protection against soman poisoning than pyridostigmine. Furthermore, the surviving animals pretreated with the two phosphoramidates that provided the highest protective ratio were in a better condition at 24 hr after soman intoxication than those pretreated with pyridostigmine. Due to the limited number of compounds and their different characteristics, it appeared difficult to demonstrate a relationship between the rate of spontaneous reactivation of AChE inhibited by the pretreatment compound and the protection against soman. Nevertheless, the results indicate that a several-fold decrease in the rate of spontaneous reactivation relative to that of pyridostigmine may increase the protective ratio against soman.     

Pharmacokinetic Studies of Intramuscular Midazolam in Guinea Pigs Challenged with Soman

Studies have demonstrated that benzodiazepine compounds are effective at antagonizing seizure activity produced by the organophosphate (OP) cholinesterase inhibitor soman. In this present study we have investigated the pharmacokinetics of midazolam and its associated effects on electroencephalographic (EEG) activity following intramuscular (im) injection to soman‐exposed guinea pigs (Crl:(HA)BR). Prior to experiments, the animals were surgically implanted with EEG leads to monitor seizure activity. For the study, animals were administered the following pretreatment/OP/treatment regimen. Pyridostigmine bromide (0.026 mg/kg, im) was given 30 min prior to soman (56 µg/kg, 2 × LD₅₀; subcutaneously, sc), followed in one minute by atropine sulfate (2 mg/kg, im) and pralidoxime chloride (25 mg/kg, im). All animals receiving this regimen developed seizure activity. Midazolam 0.8 mg/kg, im, was administered 5 min after onset of seizure activity. Based on EEG data, animals were categorized as either seizure‐terminated or seizure not‐terminated at 30 min following anticonvulsant administration. Serial blood samples were collected for the plasma midazolam analysis; the assay was accomplished with a gas chromatograph/mass spectrometer. The mean time to seizure termination was 8.8 ± 1.6 min. The mean time‐plasma concentration data were fit to standard pharmacokinetic models. The following parameter estimates were determined from the model‐fit for seizure terminated and not‐terminated animals respectively: apparent volumes of distribution (Vd) were 1.4 and 1.7 l/kg; area under the time‐concentration curves (AUC), 15,990 and 15,120 ng · min/ml; times to maximal plasma concentration (T_max), 1.66 and 2.91 min and maximal plasma concentrations (C_max) 535.1 and 436.6 ng/ml. These data indicate that im injection of midazolam is effective at terminating ongoing soman‐induced seizure activity. Additionally, the relatively short T_max and latency to seizure termination demonstrate the rapidity of drug absorption and action respectively.     

Acute Inhalation Toxicity of Soman and Sarin in Baboons

Acute Inhalation Toxicity of Soman and Sarin in Baboons. ANZUETO,A., DELEMOS, R. A., SEIDENFELD, J., MOORE, C, HAMIL, H., JOHNSON,D., AND JENKJNSON, S. G. (1990). Fundam. Appl. Toxicol. 14,676–687. Adult baboons (Papio sp.; 8–12 kg) wereanesthetized with sodium pentobarbital (20 mg/kg iv). The animalswere instrumented for measurement of mean blood pressure (MBP),pulmonary artery pressure (PAP), ECG, arterial and mixed venousblood gases, lung volumes, lung pressures, and efferent phrenicnerve activity. Bronchoalveolar lavage (BAL) was performed.Studies were done prior to exposure, at intervals during thefirst 4 hr postexpo-sure, and at 4 and 28 days after exposure.Control animals received a sham exposure to 2-propanol (N =5). Soman (pinacolyl methylphosphonofluoridate) at 13.14 µg/kg(2 x LD50) was vaporized into the upper airway in a second groupof animals (N = 5), and sarin (isopropyl methylphosphonofluoride)30 µg/kg (2 x LD50) was vaporized into a third group ofanimals (N = 4). Controls showed no change in any parametereither immediately after diluent exposure or during the monitoringperiod. Soman and sarin produced a decline in MBP and bradyarrhyth-miasthat were reversed with atropine. Apnea occurred in all soman-and sarin-exposed animals within 5 min postexposure, and wasassociated with absence of phrenic nerve signal. Ventilationwas mechanically supported until the animal could maintain normalarterial blood gases during spontaneous breathing. BAL studiesrevealed an increase in total white cell population and neutrophilsat 4 hr in all three groups. There were signs of impaired hemodynamicsand persistent lung injury for 4 days that resolved by 28 daysafter exposure. In conclusion, inhalation of soman and sarinin the baboon is associated with cardiac arrhythmias, developmentof apnea, and a significant decrease in MBP. Inhalation exposurealso resulted in a persistent influx of neutrophils and hypoxemia.     

Safety of Administration of Human Butyrylcholinesterase and its Conjugates with Soman or VX in Rats

Abstract: We evaluated the effects of conjugated enzyme‐nerve agent product resulting from the inhibition of bioscavenger human serum butyrylcholinesterase (Hu BChE) by nerve agents soman or VX. Rats were trained on a multiple Fixed‐Ratio 32, Extinction 30 sec. (FR32, Ext30) schedule of food reinforcement and then injected (i.m.) with Hu BChE (30 mg/kg), equivalent amounts of Hu BChE–soman conjugate (GDC), Hu BChE–VX conjugate, oxotremorine (OXO) (0.316 mg/kg) or vehicle (n = 8, each group). On the day of injection and on 10 subsequent daily sessions, performance was evaluated on the FR32, Ext30 schedule. Neither conjugates nor Hu BChE produced a performance deficit under the schedule. OXO produced a substantial decrease in responding on the day of administration, with complete recovery observed on subsequent sessions. None of the treatments affected circulating acetylcholinesterase (AChE) activity when evaluated 24–72 hr after injection. The dose of Hu BChE produced a 20,000‐fold increase above baseline in circulating BChE activity. Pathological evaluation of organ systems approximately 2 weeks following administration of conjugates or Hu BChE alone did not show toxicity. Taken together, these results suggest that Hu BChE – nerve agent conjugates produced following bioscavenger protection against nerve agents soman and VX do not appear to be particularly toxic. These results add to the safety assessment of Hu BChE as a bioscavenger countermeasure against nerve agent exposure.     

Attenuation of Benzanthrone Toxicity by Ascorbic Acid in Guinea Pigs

Oral administration of benzanthrone (BA) (50 mg/kg body wt/day)to guinea pigs for 30 days resulted in depletion of ascorbicacid (ASA) in the liver, adrenals, and blood serum and in growthretardation (36%) and an increase (18%) in relative liver weightwhen compared to controls. BA treatment showed a tendency towardnormocytic anemia with a decrease in hemoglobin content, reductionin RBC counts, and lowered packed cell volume. Guinea pigs treatedwith BA showed histopathological changes in liver includingfibrosis, bile duct proliferation, and focal necrosis. Testesshowed marked damage of seminiferous tubules with vacuolar degenerationand irregular and distorted interstitial spaces. BA showed evidenceof patchy glomerular congestion, tubular lesions, and damagedepithelial cells in kidney, while urinary bladders had mildcongestion in lamina propia and submucosa. Hepatic GOT, GPT,and LDH were found to be significantly decreased (17.5–33.5%),whereas activities of these enzymes showed a significant elevationin serum of BA-exposed guinea pigs. BA treatment also led tosignificant decrease of testicular hyaluronidase (29.8%) andLDH (19.8%) and significant depletion of lactic acid content(14.7%). Prior daily oral supplementation with ASA (50 mg/kgbody wt) to BA-administered guinea pigs resulted in marked improvementof histopathological and biochemical changes observed in liver,testis, kidney, and urinary bladder of BA-exposed animals. Theseresults suggest that extra supplementation of ASA could attenuatethe toxic manifestations of BA.     

Acute Lung Injury Following Inhalation Exposure to Nerve Agent VX in Guinea Pigs

A microinstillation technique of inhalation exposure was utilized to assess lung injury following chemical warfare nerve agent VX [methylphosphonothioic acid S-(2-[bis(1-methylethyl)amino]ethyl) O-ethyl ester] exposure in guinea pigs. Animals were anesthetized using Telazol-meditomidine, gently intubated, and VX was aerosolized using a microcatheter placed 2 cm above the bifurcation of the trachea. Different doses (50.4 μg/m³, 70.4 μ g/m^m3, 90.4 μg/m^m3) of VX were administered at 40 pulses/min for 5 min. Dosing of VX was calculated by the volume of aerosol produced per 200 pulses and diluting the agent accordingly. Although the survival rate of animals exposed to different doses of VX was similar to the controls, nearly a 20% weight reduction was observed in exposed animals. After 24 h of recovery, the animals were euthanized and bronchoalveolar lavage (BAL) was performed with oxygen free saline. BAL was centrifuged and separated into BAL fluid (BALF) and BAL cells (BALC) and analyzed for indication of lung injury. The edema by dry/wet weight ratio of the accessory lobe increased 11% in VX-treated animals. BAL cell number was increased in VX-treated animals compared to controls, independent of dosage. Trypan blue viability assay indicated an increase in BAL cell death in 70.4 μg/m^m3 and 90.4 μg/m^m3 VX-exposed animals. Differential cell counting of BALC indicated a decrease in macrophage/monocytes in VX-exposed animals. The total amount of BAL protein increased gradually with the exposed dose of VX and was highest in animals exposed to 90.4 μg/m^m3, indicating that this dose of VX caused lung injury that persisted at 24 h. In addition, histopathology results also suggest that inhalation exposure to VX induces acute lung injury.     

祖师麻止痛喷雾剂对豚鼠的长期毒性研究

目的:观察祖师麻止痛喷雾剂对豚鼠的长期毒性,为临床安全用药提供依据。方法:将50只豚鼠随机分为空白对照组、高剂量完整皮肤组、高剂量破损皮肤组、低剂量完整皮肤组、低剂量破损皮肤组,连续给药4周。随时观察记录其一般情况,用药后做血液学及血液生化指标检查,计算脏器系数并进行组织病理学检查。结果:祖师麻止痛喷雾剂各剂量组未见毒性反应,与空白对照组比较差异均无统计学意义(P>0.05),停药后也未见药物延迟性毒性反应。结论:长期给予豚鼠祖师麻止痛喷雾剂无明显毒性,推论临床拟用剂量安全。     

Dermal Toxicity of Linear Alkylbenzene Sulfonate and Quinalphos in Guinea Pigs

Abstract

Guinea pigs were treated topically at dosage levels of 2.5 mg/kg and 5.0 mg/kg with linear alkylbenzene sulfonate and quinalphos alone and in combination daily for 30 days. In general, the activities of some enzymes, amino nitrogen, glutathione, lipid peroxidation, and histamine showed increases in skin, liver, and kidney. The animals exposed to high doses showed erythema, edema, and hair loss. The treated skin showed hyperkeratinization and infiltration of mononuclear cells, the liver showed hypertrophic hepatocytes, while the kidney showed tubular necrosis and atrophy of the glomerular capsules. The biochemical parameters and histopafhological changes were found to be dose dependent. The study suggests that workers and/or populations exposed simultaneously to the two chemicals are more prone to dermal toxicity.     

Effectiveness of Oral Pyridostigmine Pretreatment and Cholinolytic-Oxime Therapy against Soman Intoxication in Nonhuman Primates

Effectiveness of Oral Pyridostigmine Pretreatment and Cholinolytic-OximeTherapy against Soman Intoxication in Nonhuman Primates, VONBREDOW, J. D., ADAMS, N. L., GROFF, W. A., AND VICK, J. A. (1991).Fundam. Appl. Toxicol. 17, 761–770. Nonhuman primateswhich were fed Mestinon (pyridostigmine) syrup-impregnated foodbiscuits (40 mg per animal) exhibited a reproducible inhibitionof whole blood cholinesterase activity of 40 to 50% for a periodof 1 to 6 hr. Pyridostigmine pretreatment was supplemented bytherapy with two doses of an antidotal combination (A,TM,B)consisting of 0.05 mg/kg atropine, 2.24 mg/kg TMB-4, and 0.4mg/kg benactyzine which assured survival in five of six animalsfollowing three separate exposures to 10 LD50 soman. The protectiveperiod of this oral dose of pyridostigmine supported by A,TM,Btherapy was between and 8 hr. Oral pyridostigmine pretreatmentin combination with atropine therapy (three doses of 0.07 or1.00 mg/kg im) also saved monkeys exposed to 10 LD50 soman;however, the period of recovery was prolonged. Oral pyridostigminepretreatment did not alter the lethality of soman in the absenceof A,TM,B or atropine therapy.     

Acute Inhalation Toxicity of T-2 Mycotoxin in the Rat and Guinea Pig

Acute Inhalation Toxicity of T-2 Mycotoxin in the Rat and GuineaPig. CREASIA, D. A., THURMAN, J. D., WANNEMACHER, R. W., JR.,AND BUNNER, D. L. (1990). Fundam. Appl. Toxicol 14, 54–59.In this study, concentration-response parameters were determinedfor rats and guinea pigs systematically exposed to an aerosolof T-2 toxin. The LC50 for a 10-min exposure to T-2 toxin aerosolwas 0.02 mg T-2/liter air for rats and 0.21 mg T-2/liter airfor guinea pigs. Data from total T-2 deposition in rats andguinea pigs exposed to their respective LC50 aerosol concentrationgave an LD50 of 0.05 mg T-2/kg body weight for the rat and 0.4mg T-2/kg body weight for the guinea pig. These data show thatinhaled T-2 toxin is approximately 20 times more toxic to therat (0.05 mg T-2/kg body wt inhaled vs 1.0 mg T-2/kg body wtip) and at least twice as toxic to the guinea pig (0.4 mg T-2/kgbody wt inhaled vs 1-2 mg T-2/kg body wt ip) than ip administeredT-2 toxin. Histopathologic examination of major organs in boththe rat and guinea pig after respiratory exposure to T-2 toxinindicated that lesions were similar to those described aftersystemic administration of the toxin. Gross and microscopicalterations of respiratory tract tissue after T-2 aerosol exposurewere minimal and could not account for the increase in toxicity.     

Niacinamide Pretreatment Reduces Microvesicle Formation in Hairless Guinea Pigs Cutaneously Exposed to Sulfur Mustard

Niacinamide Pretreatment Reduces Microvesicle Formation in HairlessGuinea Pigs Cutaneously Exposed to Sulfur Mustard. YOURICK,J. J., CLARK, C. R., AND MITCHELTREE. L. W. (1991). Fundam.Appl. Toxicol., 17, 533–;542. It has been proposed thatsulfur mustard (HD) may indirectly activate poly(ADP-ribose)polymerase (PADPRP) by alkylating cellular DNA (Papirmeisteret al. 1985). Activation of PADPRP results in the depletionof cellular NAD⁺, which initiates a series of biochemical processesthat have been proposed to culminate in blister formation. PreventingPADPRP activation and NAD⁺ depletion should inhibit blisterformation. Niacinamide is both an inhibitor of PADPRP and aprecursor for NAD⁺ synthesis. The present study was undertakento determine whether niacinamide can protect against HD-inducedmicrovesication in cutaneously exposed hairless guinea pigs.Each site was exposed to HD for 8 min by means of a vapor cup.Niacinamide (750 mg/kg, ip) given as a 30-mm pretreatment inhibitedmicrovesicle formation by 50% after HD application. However,niacinamide given 2 hr after RD application did not reduce microvesicleformation. There was no benefit when niacinamide was given asboth a pretreatment and treatment when compared to niacinamidegiven only as a pretreatment. The reduction in microvesication24 hr after HD did not correlate with skin NAD⁺ content Niacinamidedid not reduce the degree of erythema or edema. Ballooning degenerationof basal epidermal cells was present in some niacinamide pretreatedHD exposure sites. These results suggest that niacinamide mayonly be effective as a pretreatment compound to reduce the incidenceof HD-induced microvesicle formation. Maintenance of skin NAD⁺content may not be solely responsible for inhibiting microvesicleformation and inhibition of PADPRP may be of greater importance.     

Blood and Bronchoalveolar Lavage Fluid Acetylcholinesterase Levels Following Microinstillation Inhalation Exposure to Sarin in Guinea Pigs

We determined acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibition in the bronchoalveolar lavage fluid (BALF) following inhalation exposure to chemical threat nerve agent (CTNA) sarin. Age- and weight-matched male guinea pigs were exposed to five different doses of sarin (169.3, 338.7, 508, 677.4, and 846.5 mg/m³) using a microinstillation inhalation exposure technique for 4 min. The technique involves aerosolization of the agent in the trachea using a microcatheter with a center hole that delivers the agent and multiple peripheral holes that pumps air to aerosolize the agent at the tip. Animals exposed to higher doses of sarin occasionally developed seizures and succumbed to death within 15 min after exposure. The LCt₅₀ for sarin using the microinstillation technique was determined to be close to 677.4 mg/m³. Ear blood AChE activity showed a dose-dependent inhibition at 15 min postexposure. The inhibition of blood AChE remained constant over 35 and 55 min after sarin exposure indicating that there was no lung depot effect. Cardiac blood AChE and butyrylcholinesterase (BChE) activity in surviving animals euthanized at 24 h postexposure showed a dose-dependent inhibition with an inhibition of 60% at 677.4 and 846.5 mg/m³ sarin exposure. AChE and BChE activity in bronchoalveolar lavage fluid (BALF) showed a slight increase at 338.7 to 677.4 mg/m³ sarin exposure but a marginal inhibition at 169.3 mg/m³. In contrast, the AChE protein levels determined by immunoblotting showed an increase at 169.3 mg/m³ in the BALF. The BALF protein level, a biomarker of lung injury, was increased maximally at 338.7 mg/m³ and that increase was dropped with an increase in the dose of sarin. The BALF protein levels correlated with the AChE and BChE activity. These data suggest that sarin microinstillation inhalation exposure results in respiratory toxicity and lung injury characterized by changes in lavage AChE, BChE, and protein levels.     

Extracellular Hb Enhances Cardiac Toxicity in Endotoxemic Guinea Pigs: Protective Role of Haptoglobin

Endotoxemia plays a major causative role in the myocardial injury and dysfunction associated with sepsis. Extracellular hemoglobin (Hb) has been shown to enhance the pathophysiology of endotoxemia. In the present study, we examined the myocardial pathophysiology in guinea pigs infused with lipopolysaccharide (LPS), a Gram-negative bacterial endotoxin, and purified Hb. We also examined whether the administration of the Hb scavenger haptoglobin (Hp) could protect against the effects observed. Here, we show that Hb infusion following LPS administration, but not either insult alone, increased myocardial iron deposition, heme oxygenase-1 expression, phagocyte activation and infiltration, as well as oxidative DNA damage and apoptosis assessed by 8-hydroxy-2''-deoxyguanosine (8-OHdG) and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) immunostaining, respectively. Co-administration of Hp significantly attenuated the myocardial events induced by the combination of LPS and Hb. These findings may have relevant therapeutic implications for the management of sepsis during concomitant disease or clinical interventions associated with the increased co-exposures to LPS and Hb, such as trauma, surgery or massive blood transfusions.     

Dermal Toxicity of Linear Alkylbenzene Sulfonate,Chromium, and Nickel in Guinea Pigs

Abstract

Guinea pigs were dermally exposed to nickel (Ni) plus chromium (Cr) and Ni plus Cr plus linear alkylbenzene sulfonate (LAS) for 30 days. The exposure resulted in significantly enhanced activities of skin enzymes such as acid phosphatase, β-glucuronidase, lactate dehydrogenase, superoxide dismutase, and tyrosinase. The amino nitrogen, lipid peroxidation, and contents of histamine also increased significantly in skin. The glutathione content decreased while the accumulation of Cr and Ni significantly increased in skin. The alterations were more marked in the Ni plus Cr plus LAS exposed group.     

Butyrylcholinesterase in Guinea Pig Lung Lavage: A Novel Biomarker to Assess Lung Injury Following Inhalation Exposure to Nerve Agent VX

Respiratory disturbances play a central role in chemical warfare nerve agent (CWNA) induced toxicity; they are the starting point of mass casualty and the major cause of death. We developed a microinstillation technique of inhalation exposure to nerve agent VX and assessed lung injury by biochemical analysis of the bronchoalveolar lavage fluid (BALF). Here we demonstrate that normal guinea pig BALF has a significant amount of cholinesterase activity. Treatment with Huperzine A, a specific inhibitor of acetylcholinesterase (AChE), showed that a minor fraction of BALF cholinesterase is AChE. Furthermore, treatment with tetraisopropyl pyrophosphoramide (iso-OMPA), a specific inhibitor of butyrylcholinesterase (BChE), inhibited more than 90% of BChE activity, indicating the predominance of BChE in BALF. A predominance of BChE expression in the lung lavage was seen in both genders. Substrate specific inhibition indicated that nearly 30% of the cholinesterase in lung tissue homogenate is AChE. BALF and lung tissue AChE and BChE activities were strongly inhibited in guinea pigs exposed for 5 min to 70.4 and 90.4 μ g/m³ VX and allowed to recover for 15 min. In contrast, BALF AChE activity was increased 63% and 128% and BChE activity was increased 77% and 88% after 24 h of recovery following 5 min inhalation exposure to 70.4 μ g/m³ and 90.4 μg/m³, respectively. The increase in BALF AChE and BChE activity was dose dependent. Since BChE is synthesized in the liver and present in the plasma, an increase in BALF indicates endothelial barrier injury and leakage of plasma into lung interstitium. Therefore, a measure of increased levels of AChE and BChE in the lung lavage can be used to determine the chronology of barrier damage as well as the extent of lung injury following exposure to chemical warfare nerve agents.     

Assessing the Efficacy of Azaprophen and Physostigmine as a Pretreatment for Soman-Induced Incapacitation in Guinea Pigs by Response-Surface Modeling

Assessing the Efficacy of Azaprophen and Physostigmine as aPretreatment for Soman-lnduced Incapacitation in Guinea Pigsby Response-Surface Modeling. GENNINGS, C, CARTER, W. H., JR.,HARRIS, L. W., CARCHMAN, R. A., CAMPBELL, E. D., BOYLE, R. M.,TALBOT, B. G., AND SOLANA, R. P. (1990). Fundam. Appl. Toxicol.14, 235–242. Physostigmine (PHY) has the advantage overpyridostigmine of minimizing OP-induced incapacitation becauseit penetrates into the CNS. However, physostigmine is behaviorallytoxic at relatively low concentrations. It is anticipated thatthis could be offset by a cholinolytic to prevent behavioraldeficit due to the carbamate pretreatment alone. The therapeuticefficacy of physostigmine/azaprophen pretreatment therapy wasevaluated in soman-challenged guinea pigs. Response surfacemethodology was employed to describe the relationship of thepretreatment combination with duration of incapacitation. Thesignificance of the combination relative to PHY alone was evaluatedin addition to dose combinations that yield optimal time torecovery. Analysis of the fitted response surface indicatedthat combination pretreatment with these compounds significantlyreduces the time to recovery after soman challenge versus pretreatmentwith PHY alone.     

Efficacy Comparison of Scopolamine and Diazepam against Soman-Induced Debilitation in Guinea Pigs

Efficacy Comparison of Scopolamine and Diazepam against Soman-Induced Debilitation in Guinea Pigs. Anderson, D. R., Gennings, C., Carter, W. H. Harris, L. W., Lennox, W. J., Bowersox, S. L., and Solana, R. P. (1994). Fundam. Appl. Toxicol. 22, 588-593.The efficacy of diazepam (DZ) and scopolamine (SCP), in combination with atropine (ATR) + oxime therapy, against soman-induced seizure/convulsive activity and associated brain damage has been demonstrated, but the efficacy of each against the incapacitating effects of soman has not been addressed. Thus, the therapeutic efficacies of SCP (5 doses; 0-0.86 mg/kg) and DZ (5 doses; 0-5 mg/kg), when each was used in conjunction with ATR (3 doses; 0.5-8 mg/kg) + 2-PAM (25 mg/kg) therapy, were compared in groups of pyridostigmine pretreated guinea pigs exposed to 1.6, 2.0, 2.5, or 3.2 LD50s of soman. Response surface methodology was employed to describe the relationship between soman-induced incapacitation and the ATR/DZ or ATR/SCP dosages. Incapacitation was measured by toxicity scores assigned by three graders to test animals at 60 min postsoman. Results show that as the dosage of SCP increased, the mean toxicity scores decreased. Also, within the indicated dose ranges used, the efficacy of SCP was not dependent on the presence of ATR. In contrast, ATR alone was found to be more effective than when combined with DZ at any dose, and indicates that DZ might be temporarily contributing to soman-induced incapacitation. These findings suggest that in guinea pigs. SCP could replace ATR or DZ, or both, as therapy against soman-induced incapacitation.     

Efficacy Comparison of Scopolamine and Diazepam against Soman-lnduced Debilitation in Guinea Pigs

The efficacy of diazepam (DZ) and scopolamine (SCP), in combinationwith atropine (ATR) + oxime therapy, against so-man-inducedseizure/convulsive activity and associated brain damage hasbeen demonstrated, but the efficacy of each against the incapacitatingeffects of soman has not been addressed. Thus, the therapeuticefficacies of SCP (5 doses; 0–0.86 mg/kg) and DZ (5 doses;0–5 mg/kg), when each was used in conjunction with ATR(3 doses; 0.5–8 mg/kg) + 2-PAM (25 mg/kg) therapy, werecompared in groups of pyridostigmine pretreated guinea pigsexposed to 1.6, 2.0, 2.5, or 3.2 LD50s of soman. Response surfacemethodology was employed to describe the relationship betweensoman-induced incapacitation and the ATR/DZ or ATR/SCP dosages.Incapacitation was measured by toxicity scores assigned by threegraders to test animals at 60 min postsoman. Results show thatas the dosage of SCP increased, the mean toxicity scores decreased.Also, within the indicated dose ranges used, the efficacy ofSCP was not dependent on the presence of ATR. In contrast, ATRalone was found to be more effective than when combined withDZ at any dose, and indicates that DZ might be temporarily contributingto soman-induced incapacitation. These findings suggest thatin guinea pigs, SCP could replace ATR or DZ, or both, as therapyagainst soman-induced incapacitation.