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Biomedical subjects

J F Young

Publications and source records attributed to J F Young.

At least 73 records · Page 4Linked to original sources
PubMed1990

Developmental toxicity of soman in rats and rabbits.

Soman (GD; phosphonofluoridic acid, methyl-,1,2,2-trimethylpropyl ester) is an organophosphate compound with potent anticholinesterase activity. To determine developmental toxicity, soman was administered orally to CD rats on days 6 through 15 of gestation at dose levels of 0, 37.5, 75, 150, or 165 micrograms/kg/day and to New Zealand White (NZW) rabbits on days 6 through 19 of gestation at dose levels of 0, 2.5, 5, 10, or 15 micrograms/kg/day. At sacrifice, gravid uteri were weighed and examined for number and status of implants. Individual fetal body weights and external, visceral, and skeletal malformations were recorded. Mean maternal weight changes, fetal implantation status/litter, fetal weight, and fetal malformations/litter were compared between dose groups. Monitors for maternal toxicity were net body weight change, treatment weight change, mortality, and clinical signs of toxicity such as lethargy, ataxia, and tremors. Maternal rats and rabbits in the high-dose groups exhibited statistically significant increases in toxicity and mortality when compared to controls. There were no significant dose-related effects among dose groups in the prevalence of postimplantation loss, malformations, or in average body weight of live fetuses per litter. There was no evidence of increased prenatal mortality or fetal toxicity in the CD rat or NZW rabbit following exposure to soman, even at a dose that produced significant maternal toxicity.

Animals↗
PubMed1990

Eliciting principles of hazard identification from experts.

National experts in the field of developmental toxicology were interviewed in order to elicit the principles, or rules-of-thumb, they use in determining if a compound or agent is likely to be a developmental hazard during pregnancy. Several levels of individual and cumulative consensus activity were carried out that resulted in consensus in 71 rules and partial consensus in an additional 24 rules of 145 rules initially elicited. Rules could be divided generically into those affecting the expert's confidence in a piece of scientific evidence and those determining the weight of importance of that evidence in deciding about hazard identification. Topically, the rules also divided into those about the general nature or characteristics of a compound, animal studies testing for an effect of the compound, and human reports about the presence of absence of developmental effects associated with the compound. Several conclusions about the methodology include the following: 1) expert systems must be based on the knowledge of more than one expert; 2) considerable human effort is expended in evaluating the certainty of scientific evidence before combining the evidence for problem solving; 3) how experts use evidence of different degrees of uncertainty in their decisions is a major area that is yet to be determined and that may greatly affect subsequent efforts in artificial intelligence; and 4) knowledge elicitation by interview has limitations but is a workable methodology for medical decision making.

Animal Testing Alternatives↗
PubMed1990

Geographic variation in breast cancer mortality in the United States: a hypothesis involving exposure to solar radiation.

Epidemiologic and laboratory evidence suggests that vitamin D may play a role in reducing breast cancer risk. Lack of exposure to ultraviolet sunlight can increase the prevalence of vitamin D deficiency. This deficiency may place some populations at higher risk for breast cancer. The association between total average annual sunlight energy striking the ground and age-adjusted breast cancer mortality rates in 87 regions of the United States was evaluated. Annual age-adjusted mortality rates for breast cancer varied over a 1.8-fold range, from 17-19 per 100,000 in the South and Southwest United States to 33 per 100,000 in the Northeast; the overall U.S. rate was 27.3 per 100,000. Risk of fatal breast cancer in the major urban areas of the United States was inversely proportional to intensity of local sunlight (r = -0.80, P = 0.0001); multiple regression with stratospheric ozone measurements, r = -0.82, P = 0.0001). Vitamin D from sunlight exposure may be associated with low risk for fatal breast cancer, and differences in ultraviolet light reaching the United States population may account for the striking regional differences in breast cancer mortality. The ecological nature of this study is emphasized, and the possibility that an indirect association with dietary and socioeconomic factors could explain these findings is discussed.

Age Factors↗
PubMed1990

Pharmacokinetics of 2,4,5-T in mice as a function of dose and gestational status.

A pharmacokinetic study was conducted in CD-1 mice with the herbicide 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) as a function of dose (15, 30, 60, and 90 mg/kg, iv) and gestational status (nonpregnant, day 6, 10, 13, and 17 of gestation, and postpartum). Analysis for 2,4,5-T and its metabolites was based on an electron-capture gas-liquid chromatographic method. Pharmacokinetic stimulation of the blood, urine, and feces data from each mouse was performed on an analog-digital hybrid computer system based on a two-compartment model with parallel, first-order elimination kinetics. Data analysis demonstrated dose-independent kinetics for most pharmacokinetic parameters but a gestational status-dependence. There was a tendency, as indicated by an increase in the biologic half-life and AUC and decrease in clearance and total percent recovery, for pregnant animals to eliminate 2,4,5-T more slowly as gestation progressed, resulting in potentially increasing fetal exposure during the later stages of pregnancy.

2,4,5-Trichlorophenoxyacetic Acid↗
PubMed1990

In vivo and perfused liver caffeine kinetics in the rat.

The kinetics of caffeine (1,3,7-TMX) was investigated in male rats given four different doses (1, 2.5, 10 and 25 mg/kg), comparing the patterns found in vivo and after liver perfusion. The same animals were used in both experimental conditions in order to reduce the variability of the caffeine profile. For doses less than 10 mg/kg or mg/L, caffeine blood or perfusate concentrations/time profiles followed first-order kinetics and the elimination rate constant (average 0.013 min-1) and half-life (55 min) were similar for the in vivo and ex vivo conditions. After larger doses (10 and 25 mg/kg or mg/L), kinetics were nonlinear. The area under the blood or medium concentration-time curve increased, but not in proportion to the dose, and modifications of pharmacokinetic parameters were observed, with significant differences for t 1/2 and CL after 10 and 25 mg/kg or mg/L, due to dose-dependent elimination of caffeine at these doses (Km of 8.3 and 7.8 micrograms/ml in vivo and in vitro, respectively). The two different approaches gave close kinetic estimates in vivo and in vitro. Thus, under standardized conditions, the isolated perfused liver technique is a useful tool for studying the kinetics of drugs eliminated by hepatic metabolism.

Animals↗
PubMed1989

A protective monoclonal antibody recognizes an epitope in the carboxyl-terminal cysteine-rich domain in the precursor of the major merozoite surface antigen of the rodent malarial parasite, Plasmodium yoelii.

The 195-kDa major merozoite surface antigen of Plasmodium falciparum (Pf PMMSA) is a potential candidate for the development of a blood-stage malarial vaccine. We have focused on an analogous 230-kDa Ag of the rodent malarial parasite, Plasmodium yoelii, in an effort to study this protein in an experimental model system. Previously we reported the cloning and sequencing of a 2.1-kb portion of the gene encoding the carboxyl-terminal 77 kDa of the Py PMMSA. This region contained the B cell epitope recognized by mAb 302, a mAb shown to protect mice passively against P. yoelii challenge infection. To localize this B cell epitope, we have inserted various restriction fragments of the cloned Py PMMSA sequence into the bacterial expression vector pMG27NSTerm. Recombinant peptides of 74, 40, 34, 17, and 10 kDa have been produced which bear the epitope recognized by mAb 302. The results demonstrate that this B cell epitope is located within the most carboxyl-region of the Py PMMSA which contains a series of ten cysteine residues, also found in the PMMSA of P. falciparum. Further analysis showed that the reduction of disulfide bonds as well as the deletion of CYS-607 of the cloned sequence, resulted in the loss of the expression of this epitope. It is of interest that this epitope does not appear to be a dominant B cell determinant of the Py PMMSA molecule during infection. Inasmuch as this cysteine-rich domain of Py PMMSA displays considerable homology with that of Pf PMMSA, our data suggest that this region of the Pf PMMSA should be considered for inclusion in the development of a blood-stage vaccine.

Amino Acid Sequence↗
PubMed1989

Cell-mediated immune responses to vaccine peptides derived from the circumsporozoite protein of Plasmodium falciparum.

T cell epitopes residing within vaccine candidate peptides have been identified by delayed-type hypersensitivity (DTH) responses in mice. The recombinant sporozoite vaccine candidate, R32tet32, contains at least two T epitopes, one located within the repeat region and another in the tet tail. When C57BL/6 (H-2b) and BALB/c (H-2d) mice were sensitized intradermally with R32tet32 or the truncated protein R32LR emulsified in CFA and challenged 5 days later with R32tet32, only H-2b mice recognized a T epitope located within the major repeat sequence (NANP) and encoded by four or less repeats. H-2d mice responded solely to the T epitope located on the tet tail. Ear swelling was maximal at 48 h and revealed a histologic pattern characteristic of DTH. CD4+ T cell lines derived from immunized animals demonstrated the ability to mediate local DTH, proliferate, and secrete lymphokines in response to stimulation with Ag. High dose i.v. administration of R32tet32 in C57BL/6 and BALB/c mice before intradermal sensitization with R32tet32 revealed that DTH responses were suppressed only in BALB/c mice. Further experiments localized the suppressive determinant to the tet tail. Collectively, these data indicate that DTH may prove to be a useful method to characterize the biologic activity of T epitopes, furthermore they suggest that candidate vaccine peptides should be tested for suppressive activity before inclusion in a vaccine.

Animals↗
PubMed1989

Active immunization against virus infections due to antigenic drift by induction of crossreactive cytotoxic T lymphocytes.

We have examined whether active immunization with c13 protein, a hybrid protein of the first 81 amino acids of the viral NS1 nonstructural protein and the HA2 subunit of A/PR/8 (H1N1) hemagglutinin, could protect BALB/c mice from challenge with A/PR/8 H1 subtype virus. Mice immunized with the c13 protein had a significant reduction of pulmonary virus titers with A/PR/8 (H1) virus, but failed to limit the replication of A/PC (H3) virus, which reflects the in vitro CTL activity of c13 immune spleen cells. We observed that the epitope recognized by HA2 specific CTL, which are induced by a derivative of c13 protein, is highly conserved among H1 and H2 subtype virus strains. This led us to test whether active immunization with c13 protein would also limit pulmonary virus replication in mice infected with the A/TW virus, a virus of the H1 subtype, which was isolated in 1986, and with a virus of the H2 subtype, A/Japan/305/57. Immunized mice had significantly lower lung virus titers than did control mice, and did not possess any neutralizing antibodies to the challenger viruses. These results indicate that active immunization with a fusion protein containing the cross-reactive CTL epitope protects mice from influenza infection by inducing CTL against influenza A H1 and H2 subtype virus strains, which markedly vary in their antibody binding sites on the HA1. The ability to induce active cross-reactive immunization with a fusion protein which contains a highly conserved CTL epitope offers a model for vaccine approaches against viruses which undergo significant variations in their antibody binding sites.

Animals↗
PubMed1989

Workshop on risk assessment in reproductive and developmental toxicology: addressing the assumptions and identifying the research needs.

The risk assessment process is an imprecise procedure aimed at determining a toxicant exposure level with an acceptable risk to the human population. The lack of precision is due to the uncertainties in the assumptions that must be made due to the lack of specific scientific information or knowledge of how to use certain types of data. Unfortunately, every necessary piece of information cannot be obtained for every chemical requiring a risk assessment. In order to better identify and understand some of the assumptions that are made in the risk assessment of reproductive and developmental toxicants, a workshop was organized to specifically define the assumptions underlying the risk assessments for seven specific toxicants (dibromochloropropane, dioxin, glycol ethers, heptachlor, lead, tetrahydrocannabinol, and vitamin A) and to determine the potential research which would reduce the uncertainty associated with making those assumptions. The major assumptions discussed centered around the topics of heterogeneous populations, thresholds, safety factors, exposure assessment, quantitative structure-activity relationships, and mechanisms. This report is the summary of the workshop discussions.

Animals↗
PubMed1989

Pharmacokinetics of doxylamine, a component of Bendectin, in the rhesus monkey.

The elimination of doxylamine and metabolites was determined after iv administration of [14C]doxylamine succinate at 0.7 and 13.3 mg/kg to the adult female rhesus monkey. Although the total recovery of radioactivity was the same for the low- and high-dose studies (90.2%), the rate of plasma elimination of doxylamine and its demethylated metabolite (desmethyldoxylamine) was slower for the high dose group. The 24 hr urinary excretion of doxylamine metabolites, desmethyl- and didesmethyldoxylamine, was significantly increased and the polar doxylamine metabolites were significantly decreased as the iv doxylamine succinate dose was increased. The plasma elimination of gas chromatograph (GC)-detected doxylamine was determined after oral administration of Bendectin (doxylamine succinate and pyridoxine hydrochloride) at 7, 13.3, and 27 mg/kg to adult female rhesus monkeys. As the dose increased, the clearance of doxylamine decreased. A statistically evaluated fit of the oral data to a single-compartment, parallel first-order elimination model and a single-compartment, parallel first- and second-order (Michaelis-Menten) elimination model indicated that the more complex model containing the second-order process was most consistent with the observed elimination data.

Animals↗
PubMed1989

Pharmacokinetics of doxylamine given as Bendectin in the pregnant monkey and baboon.

The object of the present study was to determine the maternal plasma pharmacokinetics of doxylamine (the antihistamine component of Bendectin) following Bendectin administration. Bendectin was administered daily, po, at a dosage approximately 10 times the maximum human therapeutic dosage (7 mg/kg/day) throughout organogenesis (approximately days 22 through 50 of gestation) to three cynomolgus monkeys, four rhesus monkeys, and five baboons. Two pharmacokinetic experiments were performed in each animal, one on the first day of treatment and one on the last day of treatment. Although this study was not designed specifically as a teratologic examination, no morphologic abnormalities were observed when the fetuses were examined on approximately day 100 of gestation. A single-compartment, parallel first- and second-order elimination model was used to analyze the data. Although considerable interindividual variation was evident, no significant differences between species were observed when the half-life for the absorption of doxylamine from the gut or the elimination of doxylamine and metabolites from the plasma were compared. The plasma elimination half-lives and the clearance values were not altered by the 29 days of Bendectin treatment for any of the species. Only the half-life for the absorption of doxylamine in the baboon was reduced by daily dosing with Bendectin, but this did not alter doxylamine elimination. Thus, the pharmacokinetics of doxylamine administered as Bendectin were similar in the three nonhuman primate species examined and were not altered by repeated daily administration.

Animals↗
PubMed1989

Overview of a workshop on quantitative models for developmental toxicity risk assessment.

A workshop was held to discuss potential advancements to improve the precision of risk estimates for developmental toxicity. This paper presents an overview of the discussions at the workshop, focusing on the risk assessment process and science policy considerations important in the use of quantitative models. Some of the pertinent biological considerations are reviewed, particularly those related to the repair capacity of the developing organism and how this affects the concept of a threshold for developmental toxicity effects, as well as the maternal and litter influences on developmental toxicity outcomes. Finally, the current status of use of quantitative approaches is described, possible short-term approaches are discussed, and future research needs in this area are outlined.

Abnormalities, Drug-Induced↗
PubMed1989

Immunization of Saimiri sciureus boliviensis with recombinant vaccines based on the circumsporozoite protein of Plasmodium vivax.

We report a trial in squirrel monkeys of 2 recombinant Plasmodium vivax malaria vaccine candidates based on the circumsporozoite (CS) protein. One recombinant (NSl81V20), produced in Escherichia coli, contains the repeat region of the CS protein. The other (VIVAX-1) recombinant is yeast-derived and contains the entire repeat domain and part of the surrounding N-terminal and C-terminal regions. Both antigens were administered with alum and muramyl tripeptide as adjuvants. No formulations caused toxic side effects. Both antigens, when administered with alum, induced high levels of sporozoite antibodies in all animals. Another group of animals was immunized with irradiated sporozoites alone. Upon challenge, a few immunized animals did not develop detectable parasitemia and others developed parasitemia only after a prolonged prepatent period. Monkeys immunized with irradiated sporozoites had higher levels of antibody but no increased protection. There was no correlation between protection and either antibody level or the in vitro proliferation of lymphocytes in response to the antigens. This is the first time P. vivax sporozoite vaccines have been tested in monkeys with a subsequent sporozoite challenge.

Animals↗
PubMed1988

Oral Salmonella typhimurium vaccine expressing circumsporozoite protein protects against malaria.

Immunization with radiation-attenuated malaria sporozoites induces potent cellular immune responses, but the target antigens are unknown and have not previously been elicited by subunit vaccines prepared from the circumsporozoite (CS) protein. A method is described here for inducing protective cell-mediated immunity to sporozoites by immunization with attenuated Salmonella typhimurium transformed with the Plasmodium berghei CS gene. These transformants constitutively express CS antigens and, when used to immunize mice orally, colonize the liver, induce antigen-specific cell-mediated immunity, and protect mice against sporozoite challenge in the absence of antisporozoite antibodies. These data indicate that the CS protein contains T cell epitopes capable of inducing protective cell-mediated immunity, and emphasize the importance of proper antigen presentation in generating this response. Analogous, orally administered vaccines against human malaria might be feasible.

Animals↗
PubMed1988

HA2 subunit of influenza A H1 and H2 subtype viruses induces a protective cross-reactive cytotoxic T lymphocyte response.

Influenza H1 subtype-specific CTL can be induced by secondary stimulation of a hybrid protein of the first 81 amino acids of the viral NS1 non-structural protein and the HA2 subunit of A/Puerto Rico/8/34(H1N1) hemagglutinin. In addition, a derivative of this protein with 65 amino acids deleted from the N-terminal end of HA2 can also generate H1 subtype-specific CTL in bulk cultures. CTL clones established by stimulation with the derivative protein demonstrated cross-reactive lysis of target cells infected with virus strains of the H1 and H2 subtypes. Cold target competition experiments with CTL clones as effectors demonstrated that the Ag specificity between these two hybrid proteins is identical. Adoptive transfer of the CTL clone significantly reduced virus titers in the lungs of mice infected with the virus strains of the H1 or H2 subtype but not those infected with the H3 subtype virus in vivo, which reflects the in vitro CTL clone activity. These experiments demonstrate that an epitope on the hemagglutinin that is conserved on virus strains of the H1 and H2 subtypes induces a protective CTL response. These results suggest an alternative approach for developing influenza vaccines by using conserved antigenic sites on the hemagglutinin HA2 subunit to avoid the problem of frequent antigenic mutations of the HA1 subunit antibody binding sites.

Animals↗
PubMed1987

Safety and efficacy of a recombinant DNA Plasmodium falciparum sporozoite vaccine.

A recombinant DNA Plasmodium falciparum sporozoite vaccine produced in Escherichia coli (FSV-1) was tested in doses of 10 micrograms to 800 micrograms protein in fifteen volunteers. No serious adverse reactions occurred. Antibodies that reacted with P falciparum sporozoite antigens by enzyme-linked immunoassay developed in twelve of the volunteers. The highest antibody titres induced were similar to those resulting from lifelong natural exposure to sporozoite-infected mosquitoes. Postimmunization serum samples from a majority of volunteers mediated the circumsporozoite (CS) precipitation reaction and inhibited sporozoite invasion of hepatoma cells in vitro. Serum from the three volunteers who received 800 micrograms doses reacted with the surface of sporozoites in an immunofluorescence assay. Six immunised volunteers receiving a fourth dose of FSV-1 and two non-immunised controls were challenged by bites of mosquitoes infected from cultured P falciparum gametocytes. Parasitaemia did not develop in the volunteer with the highest titre of CS antibodies, and parasitaemia was delayed in two other immunised volunteers. This study confirms that human beings can be protected by CS protein subunit vaccines and provides a framework for the further development and testing of more immunogenic sporozoite vaccines.

Adult↗