Slow Clearance of Acylated, Hybrid Thrombolytic Enzymes

1988 ◽  
Vol 59 (03) ◽  
pp. 421-425 ◽  
Author(s):  
Jeff H Robinson ◽  
Ian Dodd ◽  
Ashiq Esmail ◽  
Harry Ferres ◽  
Barbara Nunn
Keyword(s):  
Half Life ◽  
Guinea Pigs ◽  
Pharmacokinetic Profile ◽  
Plasminogen Activators ◽  
Laboratory Animals ◽  
Small Laboratory ◽  
Active Centre ◽  
A Chain ◽  
Two Hybrid ◽  
Hybrid Enzymes

SummaryTwo hybrid plasminogen activators, plasmin A-chair/t-PA Bchain and plasmin A-chain/u-PA B-chain have been synthestzed and purified in sufficient yield to permit measurement of clearance in small laboratory animals. Each hybrid enzyme was reversibly acylated at the active centre to allow the pharmacokinetic profile to be followed using an activity-based method without interference from plasma inhibitors. The acylated plasmin/u-PA hybrid had a clearance half-life (t½) in guinea pigs of approximately 80 min, whereas acyl u-PA had a t½ of 3 min. The pharmacokinetic profile of the acylated plasmin/t-PA hybrid was measured in guinea pigs, rats and rabbits; the half-lives in all three species were 60–80 min compared to half-lives of acylated, native t-PA that were in the range 0.5–1.0 min. Thus, plasmin A-chaincontaining, acylated hybrid enzymes are cleared some 30- to 100-fold more slowly than the acylated parent activators.

The Use of Active Centre Acylation to Control the Pharmacokinetic Profile of a Recombinant Chimaeric Plasminogen Activator

1993 ◽  
Vol 70 (06) ◽  
pp. 0984-0988 ◽  
Author(s):  
S Wilson ◽  
D W Cronk ◽  
I Dodd ◽  
A F Esmail ◽  
S B Kalindjian ◽  
...  
Keyword(s):  
Plasminogen Activator ◽  
Pharmacokinetic Profile ◽  
Plasminogen Activators ◽  
Active Species ◽  
Bolus Administration ◽  
Clearance Rates ◽  
Active Centre ◽  
Wide Range ◽  
A Chain ◽  
Derivatives Of

SummaryRecombinant hybrid plasminogen activators consisting of the “A” chain of plasminogen linked to the “B” chain of t-PA that are inhibited rapidly by plasma protease inhibitors have recently been described (Robinson et al. Circulation 1992; 86: 548-552). We have now shown that following bolus administration of native hybrid to guinea pigs, fibrinolytic activity was cleared rapidly from the circulation. Active centre acylation appeared to protect the hybrid from inhibition and allowed material to circulate as potentially active species for prolonged periods. Clearance rates of a range of acyl derivatives of the hybrid were 7-35-fold slower than for native hybrid and 20-100-fold slower than for t-PA. Clearance rates were influenced markedly by deacylation rate, such that clearance half-life correlated well with deacylation halflife. We have thus shown that it is feasible to control the pharmacokinetic profile of a recombinant hybrid plasminogen activator over a wide range by selection of an appropriate acyl group for attachment to the active site. Such control is not possible with plasminogen activators that are cleared predominantly by mechanisms other than inhibition.

Neuroleptanalgesic drug combinations in the anaesthetic management of small laboratory animals

1975 ◽  
Vol 9 (3) ◽  
pp. 161-178 ◽  
Author(s):  
C. J. Green
Keyword(s):  
Guinea Pigs ◽  
Anaesthetic Management ◽  
Drug Combinations ◽  
Laboratory Animals ◽  
Small Laboratory ◽  
Fentanyl Citrate

Trials of different drug combinations for use in rabbits, guinea-pigs, rats, hamsters and mice are described in detail and experience over a 5-year period evaluated. Combinations of fentanyl citrate, fluanisone and diazepam provided exceptionally good anaesthesia in each species and were considered superior to other injectable agents.

Interaction of a Plasmin A-Chain/t-PA B-Chain Hybrid Enzyme with Plasma Inhibitors In Vivo and In Vitro

1990 ◽  
Vol 63 (03) ◽  
pp. 459-463 ◽  
Author(s):  
S Wilson ◽  
P Chamberlain ◽  
I Dodd ◽  
A Esmail ◽  
J H Robinson
Keyword(s):  
Guinea Pig ◽  
Plasminogen Activator ◽  
Active Site ◽  
Guinea Pigs ◽  
Fibrinolytic Activity ◽  
Pharmacokinetic Profile ◽  
Inhibitory Mechanisms ◽  
A Chain

SummaryA hybrid plasminogen activator consisting of the “A” chain of plasmin linked to the “B” chain of rt-PA was inhibited in vitro in human and guinea pig plasmas 4 to 5-fold more rapidly than its parent activator, two-chain t-PA. Using zymographic and autoradiographic techniques together with the use of immunodepleted plasma the major inhibitor was identified as aIpha-2-antiplasmin. The pharmacokinetic profile of the hybrid in guinea pigs was determined by two different methods: disappearance of fibrinolytic activity and removal of radiolabelled hybrid from the circulation. Fibrinolytic activity was cleared rapidly via inhibitory mechanisms, whilst radiolabelled material was cleared considerably more slowly due to the formation of hybrid-inhibitor complexes. When the active site of the hybrid was reversibly acylated inhibitory mechanisms were evaded and a prolonged pharmacokinetic profile of activity was observed.

Nasal cavity dimensions in guinea pig and rat measured by acoustic rhinometry and fluid-displacement method

2004 ◽  
Vol 96 (6) ◽  
pp. 2109-2114 ◽  
Author(s):  
Sune P. Straszek ◽  
Ole F. Pedersen
Keyword(s):  
Nasal Cavity ◽  
Guinea Pigs ◽  
Acoustic Rhinometry ◽  
Laboratory Animals ◽  
Small Laboratory ◽  
Acoustic Measurements ◽  
Displacement Method ◽  
Fluid Displacement ◽  
Custom Made

The purpose of the study was to measure nasal passageway dimensions in guinea pigs and rats by use of acoustic rhinometry (AR) and by a previously described fluid-displacement method (FDM) (Straszek SP, Taagehoej F, Graff S, and Pedersen OF. J Appl Physiol 95: 635–642, 2003) to investigate the potential of AR in pharmacological research with these animals. We measured the area-distance relationships by AR of nasal cavities postmortem in five guinea pigs (Duncan Hartley, 400 g) and five rats (Wistar, 250 g) by using custom-made equipment scaled for the purpose. Nosepieces were made from plastic pipette tips and either inserted into or glued onto the nostrils. We used liquid perfluorocarbon in the fluid-displacement study, and it was carried out subsequent to the acoustic measurements. We found for guinea pigs that AR measured a mean volume of 98 mm3 (95–100 mm3) (mean and 95% confidence interval) of the first 2 cm of the cavity. FDM measured a mean volume of 146 mm3 (117–175 mm3), meaning that AR only measured 70% (50–90) of the volume by FDM. For rats, the volume from 0 to 2 cm was 58 mm3 (55–61 mm3) by AR and 73 mm3 (60–87 mm3) by FDM, resulting in AR only measuring 83% (66–100%) of volume by FDM (see Table 2 ). We conclude that absolute nasal cavity dimensions are underestimated by AR in guinea pigs and rats. This does not preclude that relative changes may be correctly measured. In vivo trials with AR using rats have not yet been published. The FDM is possibly the most accurate alternative to AR for measurements of the nasal cavity geometry in small laboratory animals, but it can only be used postmortem.

scholarly journals Air Carriage of Pathogenic and other Organisms

1921 ◽  
Vol 20 (2) ◽  
pp. 173-175
Author(s):  
J. B. Buxton ◽  
H. R. Allen
Keyword(s):  
Direct Current ◽  
Guinea Pigs ◽  
Laboratory Animals ◽  
Small Laboratory

From the foregoing experiments, it may be assumed:(1) That given favourable conditions, such as a direct current of air through a building, organisms derived from animals, their fodder or environment, may be disseminated over distances up to 150 feet from the building.(2) That B. welchii is frequently present in the dust and dirt of buildings in which horses and small laboratory animals (guinea-pigs and rabbits) are housed, and(3) That under suitable conditions, spore-bearing anaerobes such as B.welchii, may be carried with infected dust from such buildings, for a distance of at least 90 feet, and probably considerably further.

Guinea pig lung development: antioxidant enzymes and premature survival in high O2

1987 ◽  
Vol 252 (4) ◽  
pp. R693-R698 ◽  
Author(s):  
I. R. Sosenko ◽  
L. Frank
Keyword(s):  
Guinea Pig ◽  
Guinea Pigs ◽  
Lung Development ◽  
Full Term ◽  
Laboratory Animals ◽  
Small Laboratory ◽  
Term Newborns ◽  
High O2 ◽  
Morphological Maturation ◽  
Better Than

Whereas guinea pigs have advanced prenatal morphological lung development, their surfactant development is not "precocious" compared with other small laboratory animals. To investigate whether maturation of the antioxidant enzyme (AOE) system coincides more closely with surfactant development or with morphological maturation, we assayed fetal guinea pig lungs at gestational days 49-69 for superoxide dismutase, catalase, and glutathione peroxidase activities. We found that elevations in pulmonary AOE occurred in parallel with increases in surfactant during the final 10-15% of gestation. Since newborn guinea pigs behave more like adult animals in their relative intolerance to hyperoxia, we explored whether prematurely delivered guinea pigs would tolerate high O2 exposure better than full-term newborns. We found that prematures have markedly improved hyperoxic tolerance compared with newborns (time at which 50% of animals died in greater than 95% O2, 6.4 days vs. 4.5 days, respectively, P less than 0.05); and (unlike newborns) premature pups are capable of mounting an elevated AOE response to hyperoxic challenge. Thus premature guinea pigs behave more like full-term newborns of other species in respect to hyperoxic tolerance, an additional precocious feature of guinea pig development.

scholarly journals Validation of Сhoice of Laboratory Model for Preclinical Estimation of Medical Protectors Against Bolivian Hemorrhagic Fever

2019 ◽  
Vol 3 (4) ◽  
pp. 319-328
Keyword(s):  
Animal Models ◽  
Guinea Pigs ◽  
Macaca Fascicularis ◽  
Hemorrhagic Fever ◽  
Laboratory Animals ◽  
Laboratory Model ◽  
Small Laboratory ◽  
Quantitative Indices ◽  
Machupo Virus

Th is review is dedicated to the peculiarities of pathogenesis of the experimental Bolivian hemorrhagic fever (BHF) – the disease, caused by Machupo virus (Arenaviridae family). Th e authors come to the conclusion that for carrying out preclinical researches of the medical means of protection (MMP) in vivo on small laboratory animals it is expedient to use guinea pigs, infected with a strain of Chicava or with a variant of Carvallo strain, adapted for these animals. Th e use of guinea pigs as small laboratory animals when studying pathogenesis of the disease caused by Machupo virus allows to carry out statistically reliable defi nition of quantitative indices of an experimental infection and to select medicines for the fi nal stage of preclinical assessment. As arenaviruses block the process of formation of interferon (IFN) in the infected organism, mice, defective by IFN formation, are the perspective animal models for the study of BHF pathogenesis and may be used for the study of attenuated variants of Machupo virus. Th e Javanese macaques (Macaca fascicularis) are the laboratory animals, modeling the pathogenetic manifestations of BHF in humans. Th ey can be used when carrying out the fi nal stages of preclinical assessment of means of medical protection

scholarly journals Some Aspects of Diseases in Small Laboratory Animals. 2. Isolation of Salmonella-like Organisms from the Mesenterial Lymph Node of Guinea Pigs

1960 ◽  
Vol 9 (3) ◽  
pp. 93-102 ◽  
Author(s):  
Kiichi HORIE ◽  
Shotaro OKAZAKI ◽  
Yujiro FUJISAKI ◽  
Junkai IRISAWA ◽  
Yoshio SHIMAZAKI ◽  
...  
Keyword(s):  
Lymph Node ◽  
Guinea Pigs ◽  
Laboratory Animals ◽  
Small Laboratory ◽  
Mesenterial Lymph Node
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