RESUMO
Studies of inhalational melioidosis were undertaken in the common marmoset (Callithrix jacchus). Following exposure to an inhaled challenge with aerosolized Burkholderia pseudomallei, lethal infection was observed in marmosets challenged with doses below 10 cfu; a precise LD(50) determination was not possible. The model was further characterized using a target challenge dose of approximately 10(2) cfu. A separate pathogenesis time-course experiment was also conducted. All animals succumbed, between 27 and 78 h postchallenge. The challenge dose received and the time to the humane endpoint (1 °C below normal body temperature postfever) were correlated. The first indicator of disease was an increased core body temperature (T(c) ), at 22 h postchallenge. This coincided with bacteraemia and bacterial dissemination. Overt clinical signs were first observed 3-5 h later. A sharp decrease (typically within 3-6 h) in the T(c) was observed prior to humanely culling the animals in the lethality study. Pathology was noted in the lung, liver and spleen. Disease progression in the common marmoset appears to be consistent with human infection in terms of bacterial spread, pathology and physiology. The common marmoset can therefore be considered a suitable animal model for further studies of inhalational melioidosis.
Assuntos
Burkholderia pseudomallei , Callithrix , Modelos Animais de Doenças , Melioidose/microbiologia , Melioidose/patologia , Doença Aguda , Administração por Inalação , Animais , Temperatura Corporal/fisiologia , Burkholderia pseudomallei/isolamento & purificação , Progressão da Doença , Feminino , Fígado/microbiologia , Fígado/patologia , Pulmão/microbiologia , Pulmão/patologia , Masculino , Melioidose/fisiopatologia , Baço/microbiologia , Baço/patologia , Fatores de TempoRESUMO
The aim of this study was to compare the pharmacokinetics and efficacy of ciprofloxacin as post-exposure therapy against inhalational anthrax in the common marmoset (Callithrix jacchus) with other non-human primate models in order to determine whether the marmoset is a suitable model to test post-exposure therapies for anthrax. Pharmacokinetic (PK) and efficacy studies with ciprofloxacin were performed in the marmoset. Ciprofloxacin plasma pharmacokinetics were determined in six animals in separate single-dose and multiple-dose studies and were analysed by high-performance liquid chromatography (HPLC). A separate group of marmosets was exposed to ca. 100× the 50% lethal dose (LD(50)) of Bacillus anthracis Ames strain by the airborne route. On Day 5 of a twice-daily dosing regimen of 17.5 mg/kg, the ciprofloxacin half-life (t(1/2)), maximum drug concentration (C(max)) and area under the concentration-time curve (AUC) in marmoset plasma were 1.9 h, 2.1 µg/mL and 7.9 µg/mL/h, respectively. Naïve untreated control animals succumbed to infection by Day 9. All animals treated with ciprofloxacin, started on the day of exposure and continued for 10 days, remained healthy during the treatment period. Two antibiotic-treated animals (33%) died after withdrawal of antibiotic therapy, attributed to the germination of residual spores. In conclusion, in many respects the marmoset appears to respond to B. anthracis in a similar way to the macaque, suggesting that this small non-human primate is an acceptable, practical alternative model for the evaluation of medical countermeasures against respiratory anthrax infection.
Assuntos
Antraz/tratamento farmacológico , Antibacterianos/uso terapêutico , Callithrix , Ciprofloxacina/uso terapêutico , Modelos Animais de Doenças , Exposição por Inalação , Infecções Respiratórias/tratamento farmacológico , Animais , Antraz/microbiologia , Antraz/mortalidade , Antraz/patologia , Antibacterianos/farmacocinética , Antibacterianos/farmacologia , Bacillus anthracis/efeitos dos fármacos , Bacillus anthracis/patogenicidade , Ciprofloxacina/farmacocinética , Ciprofloxacina/farmacologia , Feminino , Humanos , Masculino , Infecções Respiratórias/microbiologia , Infecções Respiratórias/mortalidade , Infecções Respiratórias/patologia , Esporos Bacterianos/efeitos dos fármacosRESUMO
RATIONALE: Exposure of the immature mammalian brain to stress factors, including stress levels of glucocorticoids, either prenatally or postnatally, is regarded as a major regulatory factor in short- and long-term brain function and, in human, as a major aetiological factor in neuropsychiatric disorders. Experimental human studies are not feasible and animal studies are required to demonstrate causality and elucidate mechanisms. A number of studies have been conducted and reviewed in rodents but there are relatively few studies in primates. OBJECTIVES: Here we present an overview of our published studies and some original data on the effects of: (1) prenatal stress on hypothalamic-pituitary-adrenal (HPA) re/activity and hippocampus neuroanatomy in juvenile-adolescent rhesus macaques; (2) prenatal dexamethasone (DEX) on HPA activity, behaviour and prefrontal cortex neuroanatomy in infant-adolescent common marmosets; (3) postnatal daily parental separation stress on HPA re/activity, behaviour, sleep and hippocampus and prefrontal cortex neuroanatomy in infant-adolescent common marmoset. RESULTS: Prenatal stress increased basal cortisol levels and reduced neurogenesis in macaque. Prenatal DEX was without effect on HPA activity and reduced social play and skilled motor behaviour in marmoset. Postnatal social stress increased basal cortisol levels, reduced social play, increased awakening and reduced hippocampal glucocorticoid and mineralocorticoid receptor expression in marmoset. CONCLUSIONS: Perinatal stress-related environmental events exert short- and long-term effects on HPA function, behaviour and brain status in rhesus macaque and common marmoset. The mechanisms mediating the enduring effects remain to be elucidated, with candidates including increased basal HPA function and epigenetic programming.
Assuntos
Dexametasona/farmacologia , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Estresse Psicológico/complicações , Animais , Comportamento Animal/efeitos dos fármacos , Callithrix , Feminino , Glucocorticoides/farmacologia , Hipocampo/metabolismo , Humanos , Sistema Hipotálamo-Hipofisário/metabolismo , Macaca mulatta , Sistema Hipófise-Suprarrenal/metabolismo , Gravidez , Complicações na Gravidez/etiologia , Complicações na Gravidez/fisiopatologiaRESUMO
Pharmacokinetic and efficacy studies with levofloxacin were performed in the common marmoset (Callithrix jacchus) model of inhalational tularemia. Plasma levofloxacin pharmacokinetics were determined in six animals in separate single-dose and multidose studies. Plasma drug concentrations were analyzed using liquid chromatography-tandem mass spectrometry-electrospray ionization. On day 7 of a twice-daily dosing regimen of 40 mg/kg, the levofloxacin half-life, maximum concentration, and area under the curve in marmoset plasma were 2.3 h, 20.9 microg/ml, and 81.4 microg/liter/h, respectively. An efficacy study was undertaken using eight treated and two untreated control animals. Marmosets were challenged with a mean of 1.5 x 10(2) CFU of Francisella tularensis by the airborne route. Treated animals were administered 16.5 mg/kg levofloxacin by mouth twice daily, based on the pharmacokinetic parameters, beginning 24 h after challenge. Control animals had a raised core body temperature by 57 h postchallenge and died from infection by day 5. All of the other animals survived, remained afebrile, and lacked overt clinical signs. No bacteria were recovered from the organs of these animals at postmortem after culling at day 24 postchallenge. In conclusion, postexposure prophylaxis with orally administered levofloxacin was efficacious against acute inhalational tularemia in the common marmoset. The marmoset appears to be an appropriate animal model for the evaluation of postexposure therapies.
Assuntos
Antibacterianos/farmacocinética , Antibacterianos/uso terapêutico , Francisella tularensis/efeitos dos fármacos , Francisella tularensis/patogenicidade , Levofloxacino , Ofloxacino/farmacocinética , Ofloxacino/uso terapêutico , Animais , Antibacterianos/administração & dosagem , Callithrix , Cromatografia Líquida , Esquema de Medicação , Feminino , Masculino , Ofloxacino/administração & dosagem , Espectrometria de Massas por Ionização por Electrospray , Espectrometria de Massas em Tandem , Resultado do Tratamento , Tularemia/tratamento farmacológico , Tularemia/microbiologiaRESUMO
The intracellular Gram-negative pathogen Francisella tularensis is the causative agent of tularaemia and is prevalent in many countries in the northern hemisphere. To determine whether the common marmoset (Callithrix jacchus) would be a suitable non-human primate model of inhalational tularaemia, a pathophysiology study was undertaken. Ten animals were challenged with approximately 10(2) c.f.u. F. tularensis strain SCHU S4 (F. tularensis subsp. tularensis). To look for trends in the infection, pairs of animals were sacrificed at 24 h intervals between 0 and 96 h post-challenge and blood and organs were assessed for bacteriology, pathology and haematological and immunological parameters. The first indication of infection was a raised core temperature at 3 days post-challenge. This coincided with a number of other factors: a rapid increase in the number of bacteria isolated from all organs, more pronounced gross pathology and histopathology, and an increase in the immunological response. As the disease progressed, higher bacterial and cytokine levels were detected. More extensive pathology was observed, with multifocal lesions seen in the lungs, liver and spleen. Disease progression in the common marmoset appears to be consistent with human clinical and pathological features of tularaemia, indicating that this may be a suitable animal model for the investigation of novel medical interventions such as vaccines or therapeutics.
Assuntos
Francisella tularensis/patogenicidade , Pneumonia Bacteriana/microbiologia , Tularemia/microbiologia , Animais , Callithrix , Modelos Animais de Doenças , Progressão da Doença , Suscetibilidade a Doenças , Feminino , Exposição por Inalação , Rim/microbiologia , Contagem de Leucócitos , Fígado/microbiologia , Pulmão/microbiologia , Masculino , Pneumonia Bacteriana/imunologia , Pneumonia Bacteriana/patologia , Baço/microbiologia , Fatores de Tempo , Tularemia/imunologia , Tularemia/patologiaRESUMO
Susceptibility and lethality studies of inhalational tularaemia were undertaken using the common marmoset (Callithrix jacchus) to determine its suitability as a non-human primate model. Pairs of marmosets were exposed to varying challenge doses of Francisella tularensis by the airborne route and monitored for up to 14 days postchallenge (p.c.). Lethal infection was achieved following a retained dose of less than 10 bacterial colony-forming units (CFU). However, precise LD(50) determination was not possible. The model was characterized using a target challenge dose of approximately 100 CFU. Increased core body temperature was the first indicator of disease, at approximately 2.5 days p.c. Overt clinical signs were first observed 12-18 h after the temperature increase. Significantly decreased activity was observed after approximately 3 days. All animals succumbed to infection between 4.5 and 7 days p.c. At postmortem examination, gross pathology was evident in the liver, spleen and lungs of all animals and high bacterial numbers were detected in all the organs assessed. Bacteraemia was demonstrated in all animals postmortem. Histopathological observations included severe suppurative bronchopneumonia, severe multifocal pyogranulomatous hepatitis, splenitis and lymphadenitis. Tularaemia disease progression in the common marmoset therefore appears to be consistent with the disease seen in humans and other animal models. The common marmoset may therefore be considered a suitable model for further studies of inhalational tularaemia.
Assuntos
Francisella tularensis/patogenicidade , Tularemia/patologia , Animais , Callithrix , Contagem de Colônia Microbiana , Modelos Animais de Doenças , Progressão da Doença , Suscetibilidade a Doenças , Feminino , Francisella tularensis/crescimento & desenvolvimento , Francisella tularensis/isolamento & purificação , Exposição por Inalação , Rim/microbiologia , Rim/patologia , Dose Letal Mediana , Fígado/microbiologia , Fígado/patologia , Pulmão/microbiologia , Pulmão/patologia , Masculino , Pneumonia Bacteriana/microbiologia , Pneumonia Bacteriana/patologia , Baço/microbiologia , Baço/patologia , Tularemia/microbiologia , VirulênciaRESUMO
Preface Whenever animals are used in research, minimizing pain and distress and promoting good welfare should be as important an objective as achieving the experimental results. This is important for humanitarian reasons, for good science, for economic reasons and in order to satisfy the broad legal principles in international legislation. It is possible to refine both husbandry and procedures to minimize suffering and improve welfare in a number of ways, and this can be greatly facilitated by ensuring that up-to-date information is readily available. The need to provide such information led the British Veterinary Association Animal Welfare Foundation (BVAAWF), the Fund for the Replacement of Animals in Medical Experiments (FRAME), the Royal Society for the Prevention of Cruelty to Animals (RSPCA) and the Universities Federation for Animal Welfare (UFAW) to establish a Joint Working Group on Refinement (JWGR) in the UK. The chair is Professor David Morton and the secretariat is provided by the RSPCA. This report is the ninth in the JWGR series. The RSPCA is opposed to the use of animals in experiments that cause pain, suffering, distress or lasting harm and together with FRAME has particular concerns about the continued use of non-human primates. The replacement of primate experiments is a primary goal for the RSPCA and FRAME. However, both organizations share with others in the Working Group, the common aim of replacing primate experiments wherever possible, reducing suffering and improving welfare while primate use continues. The reports of the refinement workshops are intended to help achieve these aims. This report produced by the British Veterinary Association Animal Welfare Foundation (BVAAWF)/Fund for the Replacement of Animals in Medical Experiments (FRAME)/Royal Society for the Prevention of Cruelty to Animals (RSPCA)/Universities Federation for Animal Welfare (UFAW) Joint Working Group on Refinement (JWGR) sets out practical guidance on refining the husbandry and care of non-human primates (hereinafter primates) and on minimizing the adverse effects of some common procedures. It provides a valuable resource to help understand the physical, social and behavioural characteristics and needs of individual primates, and is intended to develop and complement the existing literature and legislative guidelines. Topics covered include refinements in housing, husbandry and common procedures such as restraint, identification and sampling, with comprehensive advice on issues such as primate communication, assessing and facilitating primate wellbeing, establishing and maintaining social groups, environmental and nutritional enrichment and animal passports. The most commonly used species are the key focus of this resource, but its information and recommendations are generally applicable to other species, provided that relevant individual species characteristics are taken into account.
Assuntos
Criação de Animais Domésticos/métodos , Primatas , Criação de Animais Domésticos/normas , Bem-Estar do Animal , AnimaisRESUMO
Patent and pathologic infections of the human hookworm Necator americanus were established in the common marmoset (Callithrix jacchus). In a pilot study, a laboratory strain of N. americanus was compared with a fresh field isolate. Pathology was more severe in animals infected with a fresh isolate. In all animals, infection was associated with increased total plasma IgE and production of IgG specific to adult worm excretory/secretory (ES) products. Histamine was released by basophils in response to IgE, ES products, and a recombinant hookworm allergen, calreticulin. The pilot study indicated the potential of this animal model of hookworm infection and led us to investigate the consequences of infecting a further cohort with the fresh field isolate. This second study confirmed our initial findings, that it is possible to investigate the human hookworm N. americanus in a model exhibiting many of the characteristics of the immunology of hookworm infection in its definitive host.
Assuntos
Modelos Animais de Doenças , Infecções por Uncinaria/imunologia , Animais , Callithrix , Feminino , Humanos , Masculino , Projetos PilotoRESUMO
This methodological study was carried out in preparation for a major long term study, also reported in this volume, which was designed to investigate whether the combination of vaccines and pyridostigmine bromide (PB) could have been responsible for adverse signs and symptoms reported by a number of veterans of the 1990/1991 Gulf conflict. In this context, the marmoset has been used to model aspects of the human immune system. The purposes of this methodological study were to select appropriate immunochemical reagents to measure humoral responses induced in marmosets in response to selected health and hygiene and biological warfare vaccines and to initially assess the effects of PB on the responses recorded. Vaccines were administered at 1/5th of a human dose, and also investigated in combination with the nerve agent pretreatment compound PB. PB dosing was selected to induce an inhibition of erythrocyte acetylcholinesterase by 30%. In order to assess the functionality of the immune system, antibody responses to a neo-antigen (keyhole limpet haemocyanin--KLH), administered some 2 months following the completion of the vaccination schedule, were measured. The present study identified appropriate isotyping reporter reagents which cross-reacted with equivalent marmoset immunoglobulins. Robust antibody responses were identified against anthrax protective antigen (PA), whole cell pertussis vaccine and KLH, while weaker responses were measured against cholera and typhoid vaccines. The killed whole cell plague vaccine induced a response which was at the limit of detection of the assay. Coadministered PB had no discernable effect on immunological responses in this study.
Assuntos
Vacinas Bacterianas/farmacologia , Callithrix/imunologia , Inibidores da Colinesterase/farmacologia , Brometo de Piridostigmina/farmacologia , Vacinas Virais/farmacologia , Animais , Formação de Anticorpos , Antígenos de Bactérias/imunologia , Vacinas Bacterianas/efeitos adversos , Feminino , Hemocianinas/imunologia , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Imunoglobulina M/sangue , Imunoglobulina M/imunologia , Masculino , Síndrome do Golfo Pérsico , Vacinas Virais/efeitos adversosRESUMO
Following active service during the 1990/1991 Gulf Conflict, a number of UK and US veterans presented with a diverse range of symptoms, collectively known as Gulf Veterans Illnesses (GVI). The administration of vaccines and/or the pretreatment against possible nerve agent poisoning, pyridostigmine bromide (PB), given to Armed Forces personnel during the Gulf Conflict has been implicated as a possible factor in the aetiology of these illnesses. The possibility that adverse health effects may result from the administration of these vaccines (anthrax, pertussis, plague, yellow fever, polio, typhoid, tetanus, hepatitis B, meningococcal meningitis and cholera) and/or PB, have been investigated over an eighteen month period, in a non-human primate model, the common marmoset. This study reports immunological indices, including leukocyte phenotypes, intracellular cytokines IFN-gamma and IL-4 and antibody responses against vaccine antigens. Using human isotyping reagents previously shown to cross react with marmoset immunoglobulins (ibid) it was shown that marmosets responded strongly against anthrax PA and pertussis and weakly against killed whole cell plague, cholera and typhoid. At the end of the study the immune response to a previously unseen T-cell dependent antigen, keyhole limpet haemocyanin (KLH), was examined in order to determine whether immune function had been compromised by the compounds administered. Statistically equivalent, robust antibody responses were measured against KLH in all treatment groups indicating that the immune system had not been compromised by any of the treatments. In addition, urinary cortisol was measured at key points throughout the study as an index of physiological stress which may have been induced by the treatments. There were no effects of treatment on urinary cortisol secretion. With respect to the other immunological indices measured, there were no statistical differences between the treatment groups during the period of the study.
Assuntos
Callithrix/imunologia , Animais , Antígenos de Bactérias/imunologia , Linfócitos B/imunologia , Vacinas Bacterianas/farmacologia , Inibidores da Colinesterase/farmacologia , Interações Medicamentosas , Feminino , Hemocianinas/imunologia , Hidrocortisona/urina , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Imunoglobulina M/sangue , Imunoglobulina M/imunologia , Interferon gama/imunologia , Interleucina-4/imunologia , Masculino , Monócitos/imunologia , Síndrome do Golfo Pérsico , Brometo de Piridostigmina/farmacologia , Subpopulações de Linfócitos T/imunologia , Linfócitos T/imunologia , Vacinas Virais/farmacologiaRESUMO
BACKGROUND: A non-invasive model has been developed to estimate gaze direction and relative pupil diameter, in minimally restrained rhesus monkeys, to investigate the effects of low doses of ocularly administered cholinergic compounds on visual performance. METHODS: Animals were trained to co-operate with a novel device, which enabled eye movements to be recorded using modified human eye-tracking equipment, and to perform a task which determined visual threshold contrast. Responses were made by gaze transfer under twilight conditions. 4% w/v pilocarpine nitrate was studied to demonstrate the suitability of the model. RESULTS: Pilocarpine induced marked miosis for >3 h which was accompanied by a decrement in task performance. CONCLUSIONS: The method obviates the need for invasive surgery and, as the position of point of gaze can be approximately defined, the approach may have utility in other areas of research involving non-human primates.