Efficacy and Pharmacokinetic/Pharmacodynamic Study of 1,1′-Methylenebis{4-[(hydroxyimino)methyl] pyridinium} Dimethanesulfonate in Guinea Pigs and Rhesus Macaques Exposed to Cyclosarin

2013 ◽  
Vol 32 (4_suppl) ◽  
pp. 108S-117S ◽  
Author(s):  
Jill A. Harvilchuck ◽  
S. Peter Hong ◽  
Jamie S. Richey ◽  
Merrill R. Osheroff ◽  
Jerry D. Johnson
Keyword(s):  
Guinea Pigs ◽  
Rhesus Macaques ◽  
Lethal Dose ◽  
Plasma Concentrations ◽  
Clinical Signs ◽  
Acetylcholinesterase Activity ◽  
Treatment Groups ◽  
Clinically Normal ◽  
Clinical Observations

Male Hartley guinea pigs and male rhesus macaques were used to determine an efficacious dose of 1,1′-methylenebis{4-[(hydroxyimino)methyl] pyridinium} dimethanesulfonate (MMB4 DMS) that would result in 80% survival, 24 hours following a single exposure to cyclosarin (GF). The pharmacokinetic/pharmacodynamic relationship between acetylcholinesterase activity and MMB4 plasma concentrations relative to survival was evaluated. Guinea pigs and non-human primates (NHPs) were concurrently administered MMB4 DMS (guinea pigs: 0, 10, 30, or 40 mg/kg, intramuscular [IM] and NHPs: 0.1, 1, 5, 10, or 20 mg/kg, IM), atropine, and diazepam following a 3 × median lethal dose (LD50) GF challenge. Clinical observations were evaluated using a quality-of-life (QOL) scoring system. All GF-exposed animals exhibited typical signs of nerve agent poisoning immediately following challenge. In guinea pigs, 24-hour survival was 0%, 50%, 90%, and 90% for 0, 10, 30, and 40 mg/kg MMB4 DMS groups, respectively. In addition, nearly all animals surviving to 24 hours were clinically normal, with many in the 30 and 40 mg/kg MMB4 DMS dose group observed as normal by 4 hours post-challenge. In NHPs, survival was 100% for all treatment groups, with all animals noted as clinically normal by 48 hours. Following treatment with atropine/MMB4 DMS/diazepam, NHPs exhibited dose- and temporal-related decreases in incidence and duration of the clinical signs of toxicity. The QOL scores improved with increasing MMB4 DMS dose in both species. The estimated ED80s were 25.5 mg/kg MMB4 DMS (human equivalent dose [HED] of 5.5 mg/kg) and ≤0.1 mg/kg (HED of 0.03 mg/kg) in guinea pigs and NHPs, respectively.

In Vivo Acetylcholinesterase Reactivation in Male Guinea Pigs and Rhesus Macaques Following Cyclosarin Exposure and Treatment With 1,1′-Methylenebis{4-[(hydroxyimino)methyl] pyridinium} Dimethanesulfonate

2013 ◽  
Vol 32 (4_suppl) ◽  
pp. 99S-107S ◽  
Author(s):  
Jill A. Harvilchuck ◽  
S. Peter Hong ◽  
Jamie S. Richey ◽  
Merrill R. Osheroff ◽  
Jerry D. Johnson
Keyword(s):  
Guinea Pigs ◽  
Rhesus Macaques ◽  
Lethal Dose ◽  
Plasma Concentrations ◽  
Pharmacodynamic Modeling ◽  
Post Challenge ◽  
Treatment Groups ◽  
Clinically Normal ◽  
Acetylcholinesterase Reactivation

Acetylcholinesterase (AChE) reactivation studies were conducted in guinea pigs (GPs) and nonhuman primates (NHPs) to determine the 1,1′-methylenebis{4-[(hydroxyimino)methyl] pyridinium} dimethanesulfonate (MMB4 DMS) dose that reactivated at least 20% of blood AChE within 15 minutes following cyclosarin (GF) dosing (used as the criterion for efficacy). Male GPs and male rhesus macaques (NHPs) were pretreated with atropine 15 minutes prior to GF administration (1 × median lethal dose [LD50]) and MMB4 DMS 15 minutes following GF administration. The GP survival was 5 of 8, 8 of 8, 8 of 8, and 6 of 8 for the 0.75, 3.0, 6.0, or 12.0 mg/kg MMB4 DMS treatment groups, respectively. In NHPs, survival was 6 of 6 at 0.5, 1.2, 3.0, or 9.3 mg/kg MMB4 DMS, respectively, 24 hours post-challenge, with the majority of animals noted as clinically normal by 24 hours. Pharmacokinetic/pharmacodynamic modeling revealed that 1.8 mg/kg in GPs or 0.013 mg/kg in NHPs would result in an average 20% reactivation; human equivalent doses were calculated as 0.39 mg/kg (based on GP data) and 0.004 mg/kg (based on NHP data). The model suggested that MMB4 plasma concentrations of 1000 ng/mL and AChE reactivation of 80% would be most effective. Although a 0.5 mg/kg MMB4 DMS dose in NHPs resulted in 100% survival and an average of 78% AChE reactivation, adverse effects associated with GF administration were still observed 24 hours post-challenge (tremors, mydriasis, and weakness were observed in 3 of 6 animals). In comparison, 6 of 6 animals treated with 1.2 mg/kg MMB4 DMS were observed as clinically normal 24 hours post-challenge.

scholarly journals Osteoarthritis in pet guinea pigs: an update on diagnosis, treatment and management

2021 ◽  
Vol 26 (6) ◽  
pp. 100-106
Author(s):  
Emma Keeble
Keyword(s):  
Quality Of Life ◽  
Early Diagnosis ◽  
Guinea Pigs ◽  
Advanced Disease ◽  
Early Stage ◽  
Clinical Signs ◽  
Nutritional Supplements ◽  
Lifestyle Changes ◽  
Early Age

This article reviews the current literature on osteoarthritis in pet and laboratory guinea pigs. The associated clinical signs, diagnosis and treatment of osteoarthritis in pet guinea pigs will be discussed, with options for analgesia detailed. This condition is thought to be common in pet guinea pigs, even from an early age in some genetic lines, although osteoarthritis often goes undiagnosed in this species until advanced disease is present, posing a major welfare concern. Increasing awareness of this condition in veterinary practitioners should aid early diagnosis in pets and help improve their quality of life. Prevention may be possible using oral protective nutritional supplements to slow down the progression of this disease at an early stage. Lifestyle changes are also discussed for the management of this condition in pet guinea pigs.

scholarly journals Pathology and Pathophysiology of Inhalational Anthrax in a Guinea Pig Model

2013 ◽  
Vol 81 (4) ◽  
pp. 1152-1163 ◽  
Author(s):  
Vladimir Savransky ◽  
Daniel C. Sanford ◽  
Emily Syar ◽  
Jamie L. Austin ◽  
Kevin P. Tordoff ◽  
...  
Keyword(s):  
Animal Model ◽  
Guinea Pig ◽  
Lymph Nodes ◽  
Guinea Pigs ◽  
Alternative Model ◽  
Lethal Dose ◽  
Clinical Signs ◽  
Regional Lymph Nodes ◽  
Content Type ◽  
Ames Strain

ABSTRACTNonhuman primates (NHPs) and rabbits are the animal models most commonly used to evaluate the efficacy of medical countermeasures against anthrax in support of licensure under the FDA's “Animal Rule.” However, a need for an alternative animal model may arise in certain cases. The development of such an alternative model requires a thorough understanding of the course and manifestation of experimental anthrax disease induced under controlled conditions in the proposed animal species. The guinea pig, which has been used extensively for anthrax pathogenesis studies and anthrax vaccine potency testing, is a good candidate for such an alternative model. This study was aimed at determining the median lethal dose (LD50) of theBacillus anthracisAmes strain in guinea pigs and investigating the natural history, pathophysiology, and pathology of inhalational anthrax in this animal model following nose-only aerosol exposure. The inhaled LD50of aerosolized Ames strain spores in guinea pigs was determined to be 5.0 × 104spores. Aerosol challenge of guinea pigs resulted in inhalational anthrax with death occurring between 46 and 71 h postchallenge. The first clinical signs appeared as early as 36 h postchallenge. Cardiovascular function declined starting at 20 h postexposure. Hematogenous dissemination of bacteria was observed microscopically in multiple organs and tissues as early as 24 h postchallenge. Other histopathologic findings typical of disseminated anthrax included suppurative (heterophilic) inflammation, edema, fibrin, necrosis, and/or hemorrhage in the spleen, lungs, and regional lymph nodes and lymphocyte depletion and/or lymphocytolysis in the spleen and lymph nodes. This study demonstrated that the course of inhalational anthrax disease and the resulting pathology in guinea pigs are similar to those seen in rabbits and NHPs, as well as in humans.

Influence of parasitism on plasma concentrations of growth hormone, somatomedin-C and somatomedin-binding proteins in calves

1988 ◽  
Vol 116 (2) ◽  
pp. 191-200 ◽  
Author(s):  
T. H. Elsasser ◽  
T. S. Rumsey ◽  
A. C. Hammond ◽  
R. Fayer
Keyword(s):  
Feed Intake ◽  
Binding Proteins ◽  
Binding Protein ◽  
Plasma Concentrations ◽  
Clinical Signs ◽  
Nitrogen Retention ◽  
Protein Patterns ◽  
Somatomedin C ◽  
Treatment Groups ◽  
Ad Libitum

ABSTRACT A parasitic disease model (sarcocystosis) was used to study the effects of infection and associated plane of nutrition on GH and somatomedin-C (SM-C) patterns in plasma, and SM-C binding protein patterns in plasma from 4-month-old male Holstein calves. Calves, matched by age and rate of growth before the experiment, were divided into three treatment groups (n = 7). In the first (control), animals were uninfected and food was available ad libitum; in the second, animals were infected with Sarcocystis cruzi and food was available ad libitum. The third group consisted of uninfected animals pair-fed to the level of feed intake of the infected animals. Blood samples were obtained at various times after infection for analysis of the secretory patterns of GH (day 27 after infection, samples every 10 min for 6 h), SM-C (days 27, 35 and 58 after infection) or binding protein (day 42 after infection). Samples were analysed for GH and SM-C by radioimmunoassay. Relative molecular weights of binding proteins were assessed by elution patterns from gel permeation columns. Clinical signs of infection were manifest abruptly on day 26 after infection. Voluntary feed intakes of infected calves as a per cent of control calves were 18, 46 and 78 on days 27, 35 and 58 after infection respectively. Plasma GH concentrations were lower in infected and pair-fed than in control calves (P < 0·05). Plasma SM-C concentrations were reduced in calves with diminished feed intakes and lower still in infected calves (P < 0·05). Plasma SM-C was positively correlated with nitrogen retention across treatment groups (r = 0·81). Two classes of binding proteins differing in molecular weight were identified. The relative amounts of each binding protein in plasma were reduced during low feed intake with some differences in the endogenous saturation affected by infection. These data suggest that altered growth and metabolism in parasitized calves may arise in part from both nutritional and infection-mediated effects on the regulation of GH, SM-C and SM-C binding proteins. J. Endocr. (1988) 116, 191–200

Comparison of emergence times and quality between isoflurane and sevoflurane in rhesus macaque (Macaca mulatta) undergoing neurosurgical procedure

2017 ◽  
Vol 51 (5) ◽  
pp. 518-525 ◽  
Author(s):  
Henri G M J Bertrand ◽  
Svenja Springer ◽  
Wesley Burnside ◽  
Charlotte Sandersen ◽  
Paul A Flecknell
Keyword(s):  
Rhesus Macaques ◽  
Neurosurgical Procedures ◽  
Mechanically Ventilated ◽  
Treatment Groups ◽  
Sevoflurane Anaesthesia ◽  
Quality Of Recovery ◽  
Quality Profile ◽  
Significant Difference ◽  
Volatile Agents

Volatile agents for anaesthesia are widely used for anaesthetizing laboratory primates, and isoflurane is one of the most frequently used agents. Sevoflurane has been shown to offer a more rapid recovery than isoflurane in a number of species, but no comparisons have been made in non-human primates. This study compared the recovery characteristics of isoflurane and sevoflurane in rhesus macaques undergoing experimental neurosurgery. Twelve primates (7 males and 5 females) were randomly allocated to the treatment groups. They were sedated with ketamine (10 mg/kg) and anaesthesia was induced with propofol (usually 8 mg/kg intravenously [IV]). Anaesthesia was maintained with either sevoflurane (SEVO) (2.2 ± 0.4%) or isoflurane (ISO) (1.2 ± 0.2%) and alfentanil (0.2–0.5 µg/kg/min IV) for 332–592 min. Animals were mechanically ventilated. Meloxicam (0.3 mg/kg) and methylprednisolone infusion (5.4 mg/kg/h) were also administered. Time to extubation after cessation of anaesthesia was significantly shorter with sevoflurane (ISO: 7.0 ± 1.8 min; SEVO: 3.6 ± 1.5; *P = 0.005) as was the time to the animal sitting unaided (ISO: 15.7 ± 8.2 min; SEVO: 7.1 ± 1.7 min; *P = 0.004) . No significant difference in the quality of recovery following isoflurane or sevoflurane anaesthesia was found. In conclusion, isoflurane and sevoflurane are both suitable volatile agents for the maintenance of general anaesthesia in rhesus macaques undergoing experimental neurosurgical procedures. The two volatile agents presented a similar emergence quality profile, however sevoflurane anaesthesia was associated with a faster recovery, offering the possibility of conducting earlier post-operative neurological assessment.

scholarly journals Development of an Inhalational Bacillus anthracis Exposure Therapeutic Model in Cynomolgus Macaques

2012 ◽  
Vol 19 (11) ◽  
pp. 1765-1775 ◽  
Author(s):  
Lisa N. Henning ◽  
Jason E. Comer ◽  
Gregory V. Stark ◽  
Bryan D. Ray ◽  
Kevin P. Tordoff ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Bacillus Anthracis ◽  
Protective Antigen ◽  
Lethal Dose ◽  
Clinical Signs ◽  
Cynomolgus Macaque ◽  
Content Type ◽  
Clinical Observations ◽  
Medical Countermeasures ◽  
Therapeutic Model

ABSTRACTAppropriate animal models are required to test medical countermeasures to bioterrorist threats. To that end, we characterized a nonhuman primate (NHP) inhalational anthrax therapeutic model for use in testing anthrax therapeutic medical countermeasures according to the U.S. Food and Drug Administration Animal Rule. A clinical profile was recorded for each NHP exposed to a lethal dose ofBacillus anthracisAmes spores. Specific diagnostic parameters were detected relatively early in disease progression, i.e., by blood culture (∼37 h postchallenge) and the presence of circulating protective antigen (PA) detected by electrochemiluminescence (ECL) ∼38 h postchallenge, whereas nonspecific clinical signs of disease, i.e., changes in body temperature, hematologic parameters (ca. 52 to 66 h), and clinical observations, were delayed. To determine whether the presentation of antigenemia (PA in the blood) was an appropriate trigger for therapeutic intervention, a monoclonal antibody specific for PA was administered to 12 additional animals after the circulating levels of PA were detected by ECL. Seventy-five percent of the monoclonal antibody-treated animals survived compared to 17% of the untreated controls, suggesting that intervention at the onset of antigenemia is an appropriate treatment trigger for this model. Moreover, the onset of antigenemia correlated with bacteremia, and NHPs were treated in a therapeutic manner. Interestingly, brain lesions were observed by histopathology in the treated nonsurviving animals, whereas this observation was absent from 90% of the nonsurviving untreated animals. Our results support the use of the cynomolgus macaque as an appropriate therapeutic animal model for assessing the efficacy of medical countermeasures developed against anthrax when administered after a confirmation of infection.

scholarly journals Inhalational Botulism in Rhesus Macaques Exposed to Botulinum Neurotoxin Complex Serotypes A1 and B1

2010 ◽  
Vol 17 (9) ◽  
pp. 1293-1304 ◽  
Author(s):  
Daniel C. Sanford ◽  
Roy E. Barnewall ◽  
Michelle L. Vassar ◽  
Nancy Niemuth ◽  
Karen Metcalfe ◽  
...  
Keyword(s):  
Disease Progression ◽  
Dose Response ◽  
Botulinum Neurotoxin ◽  
Rhesus Macaques ◽  
Clinical Chemistry ◽  
Clinical Signs ◽  
Exposure Level ◽  
Clinical Observations ◽  
Aerosol Exposure ◽  
Serotype B

ABSTRACT A recombinant botulinum vaccine (rBV A/B) is being developed for protection against inhalational intoxication with botulinum neurotoxin (BoNT) complex serotype A, subtype A1 (BoNT/A1), and BoNT serotype B, subtype B1 (BoNT/B1). A critical component for evaluating rBV A/B efficacy will be the use of animal models in which the pathophysiology and dose-response relationships following aerosol exposure to well-characterized BoNT are thoroughly understood and documented. This study was designed to estimate inhaled 50% lethal doses (LD50) and to estimate 50% lethal exposure concentrations relative to time (LCt50) in rhesus macaques exposed to well-characterized BoNT/A1 and BoNT/B1. During the course of this study, clinical observations, body weights, clinical hematology results, clinical chemistry results, circulating neurotoxin levels, and telemetric parameters were documented to aid in the understanding of disease progression. The inhaled LD50 and LCt50 for BoNT/A1 and BoNT/B1 in rhesus macaques were determined using well-characterized challenge material. Clinical observations were consistent with the recognized pattern of botulism disease progression. A dose response was demonstrated with regard to the onset of these clinical signs for both BoNT/A1 and BoNT/B1. Dose-related changes in physiologic parameters measured by telemetry were also observed. In contrast, notable changes in body weight, hematology, and clinical chemistry parameters were not observed. Circulating levels of BoNT/B1 were detected in animals exposed to the highest levels of BoNT/B1; however, BoNT/A1 was not detected in the circulation at any aerosol exposure level. The rhesus macaque aerosol challenge model will be used for future evaluations of rBV A/B efficacy against inhalational BoNT/A1 and BoNT/B1 intoxication.

scholarly journals Safety and tolerability of escalating cannabinoid doses in healthy cats

2021 ◽  
pp. 1098612X2110042
Author(s):  
Justyna E Kulpa ◽  
Lina J Paulionis ◽  
Graham ML Eglit ◽  
Dana M Vaughn
Keyword(s):  
Clinical Chemistry ◽  
Clinical Signs ◽  
Medium Chain Triglyceride ◽  
Pharmacokinetic Interaction ◽  
Medical Intervention ◽  
Treatment Groups ◽  
Clinical Observations ◽  
Clinically Significant ◽  
Adult Cats ◽  
Complete Blood Counts

Objectives The aim of this study was to determine the safety and tolerability of escalating doses of orally delivered cannabis oils predominant in cannabidiol (CBD), tetrahydrocannabinol (THC), or both CBD and THC in healthy cats. Methods In this placebo-controlled, blinded study, 20 healthy adult cats were randomized to one of five treatment groups (n = 4 per group): two placebo groups (sunflower oil [SF] or medium-chain triglyceride oil [MCT]), or three plant-derived cannabinoid oil groups (CBD in MCT, THC in MCT or CBD/THC [1.5:1] in SF). Up to 11 escalating doses of each formulation were delivered orally via syringe to fasted subjects, with at least 3 days separating doses. Safety and tolerability were determined from clinical observations, complete blood counts (CBCs) and clinical chemistry. Plasma cannabinoids (CBD, THC) and metabolites (7-COOH-CBD, 11-OH-THC) were assessed. Results Titration to maximum doses of 30.5 mg/kg CBD (CBD oil), 41.5 mg/kg THC (THC oil) or 13.0:8.4 mg/kg CBD:THC (CBD/THC oil) was safely achieved in all subjects. All observed adverse events (AEs) were mild, transient and resolved without medical intervention. Gastrointestinal AEs were more common with formulations containing MCT. Constitutional (lethargy, hypothermia), neurologic (ataxia) and ocular (protrusion membrana nictitans) AEs were more common with oils containing THC (CBD/THC and THC oils). There were no clinically significant changes in CBC or clinical chemistry across treatment groups. Higher plasma levels of the cannabinoids and their metabolites following administration of the CBD/THC combination product are suggestive of a pharmacokinetic interaction. Conclusions and relevance This is the first feline study to explore the safety and tolerability of CBD and THC, alone and in combination, in a controlled research setting. These findings will inform veterinarians of the safety profile of cannabinoids, particularly when considering the potential therapeutic use of CBD in cats or recognizing clinical signs associated with accidental exposure to THC-containing products.

Survival of classic swine fever virus in hams made from the meat of pigs vaccinated with the PAV-250 strain and unvaccinated pigs

2019 ◽  
Vol 10 (3) ◽  
pp. 536-551
Author(s):  
Heidi Amezcua Hempel ◽  
María Salud Rubio Lozano ◽  
Eliseo Manuel Hernández Baumgarten ◽  
Pablo Correa Girón † ◽  
Oscar Torres Ángeles ◽  
...  
Keyword(s):  
Reference Strain ◽  
Clinical Signs ◽  
Classical Swine Fever ◽  
Fever Virus ◽  
Direct Immunofluorescence ◽  
Biometric Analysis ◽  
Treatment Groups ◽  
Group A ◽  
Group B ◽  
Group D

The study was to determine the presence of Classical Swine Fever virus (CSFv), in the meat of vaccinated pigs with the PAV-250 strain and then challenged using the same strain. Five treatment groups were established (each with four pigs). Group A: Pigs thatwere fed with processed hams from negative animals; Group B: Pigs that were fed with processed hams from commercial pigs inoculated with the ALD (reference strain) (titre of 104.0/ml); Group C: Pigs fed with processed hams from pigs infected with the virulent ALD strain (titre of 102.5/ml); Group D: Pigs fed with processed hams from pigs vaccinated with the PAV-250 strain and challenged with the ALD strain (titre of 101.1/ml); and Group E: Pigs fed with processed hams from pigs vaccinated with two doses of the PAV-250 strain and challenged with the ALD strain (negative). Blood samples were taken at d 1, 5, 10, 15 and 20 for biometric analysis. Groups B, C and D manifested clinical signs of CSFv: 40 °C temperature, anorexia, paralysis, vomiting, diarrhea, tremor, hirsute hair and cyanosis. Pigs were slaughtered and necropsies performed to identify lesions in tissues. Results of direct immunofluorescence testing of tissues were positive and the virus was recovered. Under these study conditions, it was found that CSFv resisted the cooking method at 68 °C for 40 min in hams from unvaccinated pigs, and that the virus was able to transmit the disease to healthy unvaccinated pigs, whereas the hams from the vaccinated animals did not transmit the virus.

Method for recording ECG's in unanesthetized guinea pigs

1965 ◽  
Vol 20 (5) ◽  
pp. 1091-1093 ◽  
Author(s):  
Alfred Richtarik ◽  
Thomas A. Woolsey ◽  
Enrique Valdivia
Keyword(s):  
Guinea Pig ◽  
Guinea Pigs ◽  
Standing Posture ◽  
Factors Affecting ◽  
Rapid Succession ◽  
Unanesthetized Animals ◽  
Animal Size ◽  
Four Electrodes

A device for use in recording ECG's from guinea pigs is described. It is constructed of Plexiglas and consists of a base with four electrodes (separated by plastic ridges) on which the animal stands. The animal's activity is restricted by a removable box, the ends and top of which are adjustable to compensate for variations in animal size. The device permits recording of ECG's in rapid succession from quiet, unanesthetized animals in normal standing posture. Results obtained with the method are reported. apparatus for guinea pig ECG; time relations guinea pig ECG; normal ECG, guinea pig; factors affecting quality of ECG recordings from guinea pigs Submitted on October 21, 1964

Sign in / Sign up

Export Citation Format

Share Document