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At least 739 records · Page 41Linked to original sources
PubMed2003

Hyperhomocysteinemia: genetic determinants and selected mouse models.

Homocysteine, a member of the methionine metabolic pathway, has been implicated in a number of pathologic conditions, including cardiovascular disease and cancer. Although severe hyperhomocysteinemia is found in a number of inborn errors of metabolism, mild hyperhomocysteinemia is of concern because of its prevalence in the general population and its effect on the incidence of disease states. A number of genes and common polymorphisms in these genes have been described that can influence total plasma homocysteine levels. Additionally, the power of mouse genetics has been employed to understand the genetic determinants of total plasma homocysteine levels. This review focuses on common polymorphisms and several relevant mouse models and their role in understanding the control of homocysteine levels.

Adenosine Deaminase↗
PubMed2004

[Effect of methotrexate on the immune response in selected experimental models].

Methotrexate (MTX) is one of the immunosuppressory compounds applied in the prophylaxis and treatment of several diseases, including: rheumatoid arthritis, systemic lupus erythematosus, psoriasis, graft-versus-host disease and, in combination with other drugs, neoplastic diseases. Studies in humans and in animal model, of clinical disease, have demonstrated that MTX diminishes the clinical symptoms of various immunological disorders. MTX, an antagonist of folic acid synthesis, causes apoptosis in activated cells, primarily in the G1 and S phases of the cell cycle. One of its actions, is inhibition of the synthesis or activity of several proinflammatory cytokines. At high doses, MTX is cytotoxic to hemopoietic cells; low doses, however, promote hemopoiesis. MTX also induces the differentiation of monocytic tumor cells, which may explain, in part, its therapeutic effects in the treatment of some disorders. The compound suppresses both cellular and humoral immune response and mitogen-induced lymphocyte proliferation. These effects are dose- and time-dependent. The strongest suppressory activity is exerted when MTX is applied 24 or 48 hours after immunization or mitogen stimulation. Administration of MTX in unfavorable conditions such as stress or other diseases, diminishes its tolerance and increases its toxicity. Side-effects of MTX may be ameliorated by application of pharmacological synthetic agents and plant extracts. In summary, MTX has been an effective agent in suppressing immunological disorders (for 50 years) and is still finding many applications.

Animals↗
PubMedDate not supplied

[Transcription initiation: influence of ionic strength and actinomycin D on the kinetics of the open promoter complex formation between Escherichia coli RNA-polymerase and T7 DNA].

A membrane filter assay has been devised to study the influence of ionic strength (0--150 mM NaCl) and actinomycin D on the kinetics of the open promoter complex formation between E. coli RNA-polymerase and [3H]DNA of T7 phage. The dependence of the complex formation rate upon the ionic strength is non-monotoneus with a maximum at 75--100 mM. The addition of one actinomycin molecule per 200 base pairs decreases the open promoter complex formation rate at ionic strength less than 100 mM. A promoter site selection model including liner diffusional selection is proposed which is in a good agreement with the experimental results obtained.

DNA, Viral↗
PubMedDate not supplied

Factors to consider when selecting animal models for postnatal teratology studies.

This presentation identifies some of the factors which should be considered when choosing a particular animal as a model to predict postnatal teratogenic hazards to man. The developmental pharmacologist-toxicologist must consider in concert the potential interactions of a xenobiotic on the mother, her placenta, her fetus, and her nursing young. Since the physiology of each of these components is in a state of dynamic flux during gestation and/or postnatal development, the critical time at which to expose the mother or her progeny to a chemical will vary widely from species to species and organ to organ. The identification of critical periods during the perinatal period may be quite difficult because the physiological or behavioral changes in the adult organism which signal that perinatal teratogenic effects have occurred are frequently subtle. Much research is still needed on the comparative aspects of maternal, placental, fetal, and neonatal pharmacokinetics and pharmacodynamics. We are not ready to intelligently evaluate large numbers of chemicals as potential postnatal teratogens for man.

Adaptation, Biological↗
PubMed1998

Radiation-activated prodrugs as hypoxia-selective cytotoxins: model studies with nitroarylmethyl quaternary salts.

Bioreductive drugs are designed to be activated by enzymatic reduction in hypoxic regions of tumours, but activation of these drugs is not always fully suppressed by oxygen in normal tissues. A further limitation is that bioreductive drug activation depends on suitable reductases being expressed in the hypoxic zone. This essay proposes an alternative approach in which prodrugs are reduced, and thereby activated, in hypoxic regions by ionizing radiation rather than by enzymes. This strategy is theoretically attractive, but design requirements for such radiation-activated cytotoxins are challenging. In particular, the reducing capacity of radiation at clinically relevant doses is small, which necessitates the development of prodrugs capable of releasing very potent cytotoxins efficiently in hypoxic tissue. It is shown that nitroarylmethyl quaternary (NMQ) salts possess many of the features required of a radiation-activated prodrug. In some heterocyclic NMQ compounds the cytotoxicity of the latent cytotoxic amine effector is suppressed by > 100-fold in the prodrug form, and the effector is released rapidly by fragmentation following reduction by a single electron. Appreciable cytotoxic activation of NMQ prodrugs can be achieved by irradiation at clinically relevant doses in anoxic plasma. Some of the further drug design challenges required to develop a clinical agent based on this approach are outlined.

Animals↗
PubMed1998

Selected animal models: vaginal candidosis, Pneumocystis pneumonia, dermatophytosis and trichosporosis.

A clear understanding of the pathogenesis of fungal disease remains elusive. While technological advances in molecular biology and microbial genetics have provided scientists with major new insights into both microbial virulence factors as well as host susceptibility to infection, there is currently no substitute for animal models in elucidating microbe-host interactions. Animal models are also essential for the evaluation of new antimicrobial agents, including studies of efficacy, adverse reactions and pharmacokinetics. The single most important advance in animal models in the last decade, has been the availability of genetically unique strains of animals as alternative to animals treated with immunosuppressive drugs for use in studies on microbial virulence and host defence mechanisms. These unique strains of test animals also enhance our understanding of the modes of action of antifungal drugs and their metabolism. Some of these advances will be discussed in this symposium.

Animals↗
PubMed2003

Comparing longitudinal binary outcomes in an observational oral health study.

Observational studies continue to be recognized as viable alternatives to randomized trials when making treatment group comparisons, in spite of drawbacks due mainly to selection bias. Sample selection models have been proposed in the economics literature, and more recently in the medical literature, as a method to adjust for selection bias due to observed and unobserved confounders in observational studies. Application of these models has been limited to cross-sectional observational data and to outcomes that are continuous in nature. In this paper we extend application of these models to include longitudinal studies and binary outcomes. We apply a two-stage probit model using GEE to account for correlated longitudinal binary chewing difficulty outcomes. Chewing difficulty was measured every six months during a 24-month period between two groups of subjects: those either receiving or not receiving dental care. Dental care use was measured at six-month intervals as well. Results from our proposed model are compared to results using a standard GEE model that ignores the potential selection bias introduced by unobserved confounders. In this application, accounting for selection bias made a major difference in the substantive conclusions about the outcomes of interest. This is due in part to an adverse selection phenomenon in which those most in need of treatment (and consequently most likely to benefit from it) are actually the ones least likely to seek treatment. Our application of sample selection models to binary longitudinal observational outcome data should serve as impetus for increased utilization of this promising set of models to other health outcomes studies.

Dental Health Services↗
PubMed2001

Population pharmacokinetic modeling and model validation of a spicamycin derivative, KRN5500, in phase 1 study.

PURPOSE: KRN5500, a novel spicamycin derivative, shows the greatest activity against a human tumor xenograft model and the highest therapeutic index among spicamycin derivatives. KRN5500 is currently under clinical development in Japan and the United States. The objective of this study was to develop a population pharmacokinetic model that describes the KRN5500 plasma concentration versus time data. METHODS: Data were collected from 18 patients entered in a phase 1 study. These patients received KRN5500 3-21 mg/m2 as a 2-h infusion. A total of 219 concentration measurements were available. The data were analyzed using the nonlinear mixed effect model (NONMEM) program. In addition, the basic and final population pharmacokinetic models were evaluated using bootstrapping resampling. RESULTS: The basic model selected was a two-compartment model with a combination of additive and constant coefficient of variation error models. The basic model fitted well not only the original data, but also 100 bootstrap replicates generated from the original data set. With regard to the effect of covariates selected by generalized additive modeling analysis, gender (SEX) and performance status were found to be possible determinants of the volume of central compartment by NONMEM analysis. The final regression model for V1 was V1 = theta V1 (1--SEX x theta SEX), where V1 is the typical population value of the volume of central compartment, and SEX = 0 if the patient is male, otherwise SEX = 1. The final model was fitted to the 200 bootstrapped samples. The mean parameter estimates were within 15% of those obtained with the original data set. CONCLUSIONS: The KRN5500 plasma concentration versus time data obtained from the phase 1 study were well described by the population pharmacokinetic model. Further evaluation by bootstrapping showed that the population pharmacokinetic model was stable.

Adult↗
PubMed1993

Temperature-dependent selection in the transmission of mitochondrial DNA in Drosophila.

We previously reported a selective mode of mitochondrial DNA (mtDNA) transmission in mtDNA heteroplasmy that was induced artificially in Drosophila melanogaster; the transmission bias appeared to depend on the particular temperature at which heteroplasmic lines were maintained. Here we report investigations of the temperature-dependent mode of mtDNA transmission in heteroplasmic lines for intra- and interspecific combinations maintained separately at 22.5 degrees C, 25 degrees C and 29 degrees C for 20 generations. We have examined a selection model for mitochondrial transmission, similar to genetic selection in haploid organisms. Changes in the relative proportions of two types of mtDNA fit the expectations from the model well. The intensity of selection estimated as a selection coefficient depends on temperature. Temperature-sensitive processes thus appear to be involved in the transmission and maintenance of mitochondria.

Animals↗
PubMed2000

Kin selection and parasite evolution: higher and lower virulence with hard and soft selection.

Conventional models predict that low genetic relatedness among parasites that coinfect the same host leads to the evolution of high parasite virulence. Such models assume adaptive responses to hard selection only. We show that if soft selection is allowed to operate, low relatedness leads instead to the evolution of low virulence. With both hard and soft selection, low relatedness increases the conflict among coinfecting parasites. Although parasites can only respond to hard selection by evolving higher virulence and overexploiting their host, they can respond to soft selection by evolving other adaptations, such as interference, that prevent overexploitation. Because interference can entail a cost, the host may actually be underexploited, and virulence will decrease as a result of soft selection. Our analysis also shows that responses to soft selection can have a much stronger effect than responses to hard selection. After hard selection has raised virulence to a level that is an evolutionarily stable strategy, the population, as expected, cannot be invaded by more virulent phenotypes that respond only to hard selection. The population remains susceptible to invasion by a less virulent phenotype that responds to soft selection, however. Thus, hard and soft selection are not just alternatives. Rather, soft selection is expected to prevail and often thwart the evolution of virulence in parasites. We review evidence from several parasite systems and find support for soft selection. Most of the examples involve interference mechanisms that indirectly prevent the evolution of higher virulence. We recognize that hard selection for virulence is more difficult to document, but we take our results to suggest that a kin selection model with soft selection may have general applicability.

Adaptation, Physiological↗