Biomedical subjects

P C Allen

Publications and source records attributed to P C Allen.

60 records · Page 4Linked to original sources

PubMedDate not supplied

Comparisons of the intraocular tissue distribution, pharmacokinetics, and safety of 125I-labeled full-length and Fab antibodies in rhesus monkeys following intravitreal administration.

Access of recombinant proteins to the retina following intravitreal administration is poorly understood. A study was conducted in male Rhesus monkeys (15 to 28 mo of age; 2.8-3.3 kg) in order to compare the intraocular tissue distribution, pharmacokinetics, and safety of 125Iodine (I)-labeled full-length humanized rhuMAb HER2 antibody (148 kD) and of 125I-labeled humanized rhuMAb vascular endothelial growth factor Fab antibody (48.3 kD) following bilateral bolus intravitreal injection on day 0 (5 animals/group). The dose administered to each eye was 25 microg (9-10 microCi) in 50 microl. Animals were euthanatized on day 0 (1 hr postdose) and on days 1, 4, 7, and 14. Safety assessment included direct ophthalmoscopy, intraocular pressure measurements, clinical observations, body weight, and hematology and clinical chemistry panels. Blood and vitreous samples were collected daily (blood only) and at necropsy for pharmacokinetics and analysis for antibodies to the test materials; the ocular tissue distribution of the test material was evaluated by microautoradiography. All animals completed the study. Microautoradiography demonstrated that the full-length antibody did not penetrate the inner limiting membrane of the retina at any of the time points examined. In contrast, the Fab antibody fragment diffused through the neural retina to the retinal pigment epithelial layer at the 1-hr time point and persisted in this location for up to 7 days. Systemic exposure to test material was low but variable: the highest plasma concentration of the full-length antibody was 20.3 ng/ml, whereas plasma concentrations for the Fab antibody remained below the limit of quantitation (i.e., <7.8 ng/ml). An immune response to the test material was not evident in either treatment group. The half-life in vitreous was 5.6 days for the full-length antibody and 3.2 days for the Fab antibody. The shorter intravitreal half-life of the Fab antibody is related to its smaller size and its significant diffusion through the retinal layers. The differences in pharmacokinetics and tissue distribution that are noted between the full-length and Fab antibodies in this study identify potential therapeutic approaches that may be exploited in specific disease conditions.

Animals↗

PubMedDate not supplied

Development of a protective index to rank effectiveness of multiple treatments within an experiment: application to a cross-protection study of several strains of Eimeria maxima and a live vaccine.

Vaccination of chickens with live oocysts has become a more widely used method for controlling avian coccidiosis as resistance to anticoccidial medication increases. However, some coccidia strains are not useful in multispecies vaccines because antigenic variation has made them generally less protective. In order to experimentally test a number of strains for the best cross protection, we have devised an evaluation method using four independently measured variables: weight gain, lesion score, plasma carotenoids, and plasma NO2- + NO3-. These values, when measured at 6 days postchallenge, tend to be significantly correlated. A protective index (PX) is calculated for each chicken using the following algorithm: PX = (Ngain + Ncarotenoids) - (Nsqrls + N[NO2- + NO3-]), where the prefix N indicates values for a variable normalized against a mean of that variable from a control group. Nsqrls values are normalized values of the square roots of lesion scores. The PX can then be treated as a dependent variable. In this study, mean PX values of unchallenged groups cluster around 0. Mean PX values of protected chickens are statistically close to those from unchallenged groups, whereas unprotected chickens have highly negative mean PX values.

Algorithms↗

PubMedDate not supplied

Effect of virginiamycin on serum carotenoid levels and long, segmented, filamentous organisms in broiler chicks.

Virginiamycin (Stafac 20) was mixed with feed at three levels recommended for chickens--5.5, 11, and 22 mg/kg (respectively 5, 10 and 20 g/ton)--and fed to broiler chicks. When fed from 1 day through 2 weeks of age, the drug appeared to retard infection of the lower small intestine by long, segmented, filamentous organisms (LSFOs), and at 2 weeks of age serum carotenoids in treated chicks were significantly higher than levels found in unmedicated chicks. However, as chicks were grown out to 4 and 6 weeks of age, the drug did not completely prevent eventual LSFO infection, even at the highest dose, and mean serum carotenoid levels in treated chicks were not significantly different from levels in control chicks. However, chicks fed at the level of 22 mg/kg had fewer LSFOs. Withdrawal of virginiamycin from treated chicks at 4 weeks of age allowed LSFO infection to occur but did not significantly affect serum carotenoid levels. When the drug was fed for 2 weeks at 22 mg/kg to 2-week-old chicks already infected with LSFOs, the bacteria could no longer be detected, suggesting that virginiamycin may aid the natural decline in LSFO population. Coincident with this treatment, serum carotenoids were higher, but not significantly so. Virginiamycin did not significantly increase the mean body weights of chicks in any of these experiments.

Animals↗

PubMedDate not supplied

The effect of Eimeria acervulina infection on hearts of young broiler chicks.

Hearts from 2-to-3-week-old broiler chicks that were inoculated with 2 X 10(6) sporulated oocysts/bird weighed significantly less than hearts from control chicks at 4 and 7 days postinoculation (PI). However, heart weights of infected chicks expressed as percentage of body weights were not significantly different from those of controls throughout the experiment. Infection also had no significant effect on heart protein content. Cardiac glycogen was significantly increased at 7 days PI but not at 4 days PI. Oxidation of both alpha-ketoglutaric and octanoic acids by mitochondrial preparations from hearts of infected chicks was significantly depressed at 4 days PI compared with controls; at 7 days PI, however, oxidation of octanoic acid was significantly increased, but that of alpha-ketoglutaric acid was not.

Animals↗

PubMedDate not supplied

Physiological responses of chicken gut tissue to infection with Eimeria acervulina.

Although Eimeria acervulina parasitizes primarily the duodenum of chickens, in heavy infections the entire small intestine may become distended. This reaction was measured in terms of length, fresh weight, dry weight, and moisture in relation to time postinfection (PI) and dose. Increases in percent moisture were apparently associated with numbers of infection sites, because higher doses caused increased moisture in the more distal portions of the small intestine. The first gross intestinal response to infection with 2 X 10(6) sporulated oocysts (SO)/bird was an increase in ileal length at 4 days PI. This response was followed by increases in fresh weight and dry weight by 7 days PI. At 7 days PI, inoculation with 10(4) and 10(5) SO/bird was associated not only with increases in fresh and dry weights of ileal segments but with those of jejunal segments as well. Infection with 10(6) SO/bird apparently caused sufficient increases in jejunal infection sites to overcome the hypertrophy or hyperplasia seen at lower doses. At 7 days PI, more mucosal cells could be scraped from ileal segments from infected chicks than from controls. Whole cells, as well as mitochondrial preparations of these cells, oxidized octanoic acid at higher rates than did controls. It is suggested that increased mass and metabolic activity of the more distal portions of the small intestine provide a means for compensatory absorption of nutrients during E. acervulina infection.

Animals↗

PubMedDate not supplied

Genetic influence on nitric oxide production during Eimeria tenella infections in chickens.

Studies were carried out to assess the importance of nitric oxide (NO) production in vivo in resistance to Eimeria tenella infections through treatment of resistant SC and susceptible TK strains of chickens with compounds proven to be effective inhibitors of induced nitric oxide synthase. The SC strain produced higher levels of plasma NO2- + NO3- in response to primary infection than did the TK strain. SC chickens were also more responsive in reduction of NO2- + NO3- levels and increased oocyst output in response to treatments with S-methylisothiourea or NG-methyl-L-arginine (LNMA) during primary infection. However, the SC strain, regardless of drug treatment, consistently yielded higher oocyst output during primary infection, indicating it could be susceptible to a higher parasite burden. On the other hand, the SC strain seemed to develop immunity more rapidly than the TK strain, in that oocyst output was decreased in both untreated and LNMA-treated chicks upon challenge infection compared with that of the TK strain. Oocyst output from both SC and TK strains was further decreased by LNMA treatment during challenge infection rather than increased, suggesting minimal involvement of NO production in the immune response to challenge. These results indicate that NO production during primary E. tenella infection may be only one of several immune responses and may not be the main anticoccidial effector.

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