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Juvenile hormones (JH), produced by the corpora allata, have an essential role in growth and development, morphogenesis, and reproductive processes of insects. The output of JH and circulating titer are required to be precisely regulated throughout the insect's life in response to developmental requirements and environmental factors. The synthesis of JH must be periodically turned off and on, or finely tuned, in a highly coordinated way. Except for a few key or intensely studied insect species, the control of synthesis of JH by regulatory peptides remains largely undefined and many of the details remain obscure. Several different classes of neuropeptide are believed to be involved in the regulation of corpus allatum function and hence JH output. In different insect species and at different stages of development, these regulatory peptides may include at least three types of inhibitory allatostatins, at least one type of stimulatory allatotropin, and perhaps several other, as yet largely undefined, additional neuropeptides. The details of how each of these peptides acts to affect JH production and their relationship to each other in the coordination of JH synthesis remain to be established. There are several insect orders for which almost nothing is known concerning the regulation of JH synthesis and the peptides that might be involved. Current proteomic and genomic studies are helping to redress this balance but at the same time posing new questions. Other neuropeptides are implicated in the regulation of JH production, and there is new evidence concerning the mode of action of allatotropins. [ABSTRACT FROM AUTHOR]

1. A priori knowledge of the enzyme inhibitory potential of new drug entities and the drug-metabolizing enzymes involved can be used in support of important decisions on the future progress of a drug in clinical development. 2. Important advances in the knowledge of human drug-metabolizing enzymes have largely fuelled the integration of in vitro drug metabolism and clinical drug interaction studies for use in drug development programmes. 3. The likelihood of correctly predicting in vivo drug-drug interactions appears highly dependent on selecting the correct enzyme inhibition model for use in deriving the inhibitor constant (K[sub i]) and correctly determining the available concentration of inhibitor at the active site of the enzyme(s) of interest. 4. The uncertainty and inaccuracy of predicting the extent and duration of in vivo drug interactions currently stems from a lack of definitive models by which to assess likely substrate and inhibitor concentrations at the active site of metabolism. Additional issues contributing to the uncertainty of predicting drug interactions include assumptions of the contribution of presystemic drug extraction and the effect of inhibitors on the processes involved. 5. This review considers the practical aspects of in vitro enzyme inhibition studies and the use of in vitro-in vivo correlation approaches described in the literature to predict in vivo drug-drug interactions. [ABSTRACT FROM AUTHOR]

1. The specific activities of hepatic microsomal cortisol 6 beta-hydroxylase, coumarin 7- hydroxylase, S-mephenytoin 4'-hydroxylase and phenoxazone hydroxylase and the O-dealkylations of seven homologous alkoxyresorufins were <3-fold different between the untreated (UT) cynomolgus monkey and man. 2. Heptoxy- and octoxyresorufin O-dealkylase, S -mephenytoin N-demethylase and dextromethorphan O-demethylase specific activities were >6-fold higher, whereas tolbutamide hydroxylase was almost 5-fold lower in the UT monkey than in man. 3. Phenobarbitone induced (2-6-fold) coumarin 7-hydroxylase, cortisol 6 beta-hydroxylase, S-mephenytoin N-demethylase, phenoxazone hydroxylase and benzyloxyresorufin O-dealkylase activities, but not the O-dealkylations of pentoxyresorufin or other alkoxyresorufins, in monkey. 4. Rifampicin induced (2-3-fold) cortisol 6beta-hydroxylase, S-mephenytoin 4- hydroxylase, S-mephenytoin N-demethylase and tolbutamide hydroxylase activities, the O-dealkylations of methoxy-, ethoxy- and propoxyresorufin and CYP2C- and CYP3A- immunorelated proteins in monkey. 5. Dextromethorphan O -demethylase was significantly reduced by both phenobarbitone and rifampicin treatment in monkey. 6. beta-Naphthoflavone induced (8-39-fold) the O-dealkylations of several alkoxyresorufins, the greatest effect being on propoxyresorufin, but had no effect on the other activities measured in monkey. 7. Constitutive hepatic microsomal CYP2D6-immunorelated proteins were expressed at apparently much higher levels in monkey than in man. [ABSTRACT FROM AUTHOR]

1. The results of molecular modelling of human CYP2C isozymes, CYP2C9 and CYP2C19, are reported based on an alignment with a bacterial form of the enzyme, CYP102. 2. The three-dimensionalstructures of the CYP2C enzymes are consistent with known experimental evidence from site-directed mutagenesis, antibody recognition and regiospecificity of substrate metabolism. 3. The variations in substrate specificity between CYP2C9 and CYP2C19 can be rationalized in terms of single amino acid residue changes within the putative active site region, of which I99H appears to be the most significant. [ABSTRACT FROM AUTHOR]

Abstract: Background: There is in vitro evidence that T cells from allergic patients react to benzylpenicillin‐human serum albumin (BP‐HSA) bioconjugates. Our group has recently shown the existence of naïve CD4+ T cells recognizing BP‐HSA in healthy donors. However, BP‐haptenated peptides from HSA participating in the immunization of allergic patients have never been identified. The purpose of the present study is to identify immunodominant BP‐haptenated peptides from HSA involved in immunization of patients to BP and to refine the frequency calculation of naïve CD4+ T cells recognizing BP. Methods: Co‐cultures were established with CD4+ T cells from non‐allergic donors and mature autologous dendritic cells (DCs) loaded with BP‐HSA or BP‐haptenated peptides from HSA. The CD4+ T‐cell response specific for BP‐HSA or for individual BP‐haptenated peptides was measured using an interferon‐γ (IFN‐γ) ELISpot assay. The frequency of BP‐specific CD4+ T cells was then calculated using the Poisson distribution. BP‐HSA and BP‐haptenated peptides recognition by allergic patients was evaluated on peripheral blood mononuclear cells (PBMCs) using a lymphocyte transformation test (LTT). Results: Results showed that BP‐HSA and BP‐haptenated peptides were recognized by naïve T cells from 15/16 and 13/14 tested healthy donors, respectively. Most donors responded to 3 peptides with BP covalently bound on lysines 159, 212, and 525. Two of these benzylpenicilloylated peptides (lysines 159 and 525) were also found to induce PBMCs proliferation in patients with allergic reaction to penicillins. Conclusion: This study identifies and characterizes for the first time the BP‐haptenated peptides from HSA involved in the immunization of patients to penicillins. [ABSTRACT FROM AUTHOR]

Background Drug hypersensitivity is known to rely on a drug-specific T-cell response. Amplitude of antigen-specific T-cell response is partly controlled by the size of the antigen-specific naïve CD4+ T-cell repertoire, but estimate of this repertoire has never been investigated for allergenic drugs. The purpose of this study was to evaluate the frequency of benzylpenicillin-specific CD4+ T lymphocytes in healthy donors. Methods Co-cultures were established with CD4+ T lymphocytes from healthy donors and mature autologous dendritic cells loaded with benzylpenicillin coupled to human serum albumin. CD4+ T lymphocytes were stimulated once a week for 4 weeks with benzylpenicillin coupled to human serum albumin. The CD4+ T-cell response was measured using an interferon-γ ELISPOT assay. Frequency of benzylpenicillin-specific naive CD4+ T lymphocytes was then calculated using the Poisson distribution law. Results Results showed the presence of benzylpenicillin-specific CD4+ T lymphocytes in 9 of 10 tested healthy donors irrespective of their HLA typing, with a mean frequency of 0.29 cells per million of CD4+ T cells. Experiments performed on naive ( CD45 RA+) and on memory ( CD45 RO+) CD4+ T lymphocytes showed that these benzylpenicillin-specific CD4+ T lymphocytes belonged to the naive T-cell subpopulation. Conclusion This study showed for the first time the existence of naive CD4+ T lymphocytes specific to benzylpenicillin in healthy donors. [ABSTRACT FROM AUTHOR]

This paper considers the impacts of various patterns of differential or excess mortality on the biological and statistical interpretation of 2-year rodent carcinogenicity studies. It provides suggestions on experimental design that are intended to maximize the value of such studies for carcinogenic risk assessment. Specifically, it recommends dose reduction, possibly to the level of dose cessation, when biologically feasible and considers the merits of termination of the entire study as alternatives to the commonly employed strategy of terminating particular dose groups. It then recommends statistical analysis modifications that are appropriate when these suggestions on experimental design are adopted. One of the recommended modifications is a new statistical test to determine whether a dose group exceeds the maximum tolerated dose (MTD) on the basis of mortality. While the authors provide recommendations for the most commonly occurring exigencies, they acknowledge the need for and strongly support the practice of active engagement of the appropriate regulatory agency, e.g., the FDA, prior to any action. [ABSTRACT FROM AUTHOR]

1. In the present study, nine cytochrome P450 enzyme activities in seven species were characterized to allow a practical means of comparing this important metabolic step between various test animals and man. 2. Enzyme activities and kinetic parameters were first determined towards marker substrates for human cytochrome P450 enzymes. Inhibition profiles were then determined with both antibodies directed against various cytochrome P450 enzymes and with chemical inhibitors. 3. Both the enzyme kinetic parameters/enzyme activities, and the inhibition profiles obtained for the animal species were compared with those obtained for human liver microsomes in order to postulate the animal species most similar to man with regard to each individual cytochrome P450 enzyme activity. 4. It was found that, as expected, none of the tested species was similar to man for all the measured P450 enzyme activities, but that in each species only some of the P450 enzyme activities could be considered as similar to man. 5. When it is known which human cytochrome P450 enzymes are involved in the metabolism of a compound, the comparative data presented here can be used for selecting the most suitable species for in vitro and in vivo experiments. [ABSTRACT FROM AUTHOR]