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Primary Response (primary + response)
Selected AbstractsMaintenance of CCL5 mRNA stores by post-effector and memory CD8 T cells is dependent on transcription and is coupled to increased mRNA stabilityEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 10 2006Antoine Marçais Abstract Immunological memory is associated with the display of improved effector functions by cells of the adaptive immune system. The storage of untranslated mRNA coding for the CCL5 chemokine by CD8 memory cells is a new process supporting the immediate display of an effector function. Here, we show that, after induction during the primary response, high CCL5 mRNA levels are specifically preserved in CD8 T cells. We have investigated the mechanisms involved in the long-term maintenance of CCL5 mRNA levels by memory CD8 T cells. We demonstrate that the CCL5 mRNA half-life is increased in memory CD8 T cells and that these cells constitutively transcribe ccl5 gene. By inhibiting ccl5 transcription using IL-4, we demonstrate the essential role of transcription in the maintenance of CCL5 mRNA stores. Finally, we show that these stores are spontaneously reconstituted when the inhibitory signal is removed, indicating that the transcription of ccl5 is a default feature of memory CD8 T cells imprinted in their genetic program. [source] Altered primary CD8+ T,cell response to a modified virus Ankara(MVA)-vectored vaccine in the absence of CD4+ T,cell helpEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 12 2005Marie Abstract T,cell receptor-transgenic F5 mice were used to assess primary CD8+ T,cell responses to a modified virus Ankara (MVA)-vectored vaccine in the absence of CD4+ T,cell help. Naive, CD8-enriched, CFSE-labelled F5 cells were transferred into normal or CD4+ cell-depleted mice and the mice were vaccinated with MVA.HIVA-NP. At different time points during the primary response, F5 cells were re-isolated and analysed on divisional basis for a number of parameters. We demonstrated that the primary CD8+ T,cell response in the absence of CD4+ T,cell help differed from that in normal CD4+ cell-undepleted mice. While in the absence of CD4+ T,cell help, the initial migratory progress from the local response to a systemic one was not grossly affected, the proportion of dying F5 cells during the expansion phase was markedly increased and resulted in an overall smaller expansion and significantly decreased frequency of CD8+ T,cell memory after contraction. T,cells primed without help displayed accelerated proliferation and activation, while expression of interferon-, remained similar. These phenomena were observed in the lymph nodes draining the MVA.HIVA-NP immunization site and were similar, but delayed by 2,3,days in spleen and non-draining lymph nodes. [source] Upregulation of genes orchestrating keratinocyte differentiation, including the novel marker gene ID2, by contact sensitizers in human bulge-derived keratinocytesJOURNAL OF BIOCHEMICAL AND MOLECULAR TOXICOLOGY, Issue 1 2010Yoshie Yoshikawa Abstract In the epidermis, keratinocytes are involved in physical and first-line immune protection of the host. In this study, we analyzed the molecular responses to certain contact sensitizers (2,4-dinitrochlorobenzene and NiSO4) and irritants (sodium dodecyl sulfate and benzalkonium chloride) in cultured human keratinocytes from the bulge region of a plucked hair follicle (bulge-derived keratinocytes [BDKs]) and compared these molecular responses to those with the human monocytic leukemia cell line, THP-1. The BDKs, individually established without invasive biopsies, showed high reactivity to these stimulants. As a primary response to the contact sensitizers, the NRF2-mediated signaling pathway was upregulated in BDKs and THP-1. The expression of IL1B and IL8 genes was not induced by the irritants but by the sensitizers in THP-1. However, the expression of the IL1B and IL8 genes was induced at higher levels by the irritants in BDKs than by the sensitizers. Many genes orchestrating keratinocyte differentiation, including ID2, were significantly upregulated in response to the sensitizers in BDKs but not those in THP-1. The use of the ID2 gene to discriminate between sensitizers and irritants might be effective as a novel marker for application during in vitro sensitization with BDKs. © 2010 Wiley Periodicals, Inc. J Biochem Mol Toxicol 24:10,20, 2010; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jbt.20307 [source] Regulated expression of syndecan-4 in rat calvaria osteoblasts induced by fibroblast growth factor-2JOURNAL OF CELLULAR BIOCHEMISTRY, Issue 2 2007Shu Jun Song Abstract Fibroblast growth factor-2 (FGF2) is a member of a prominent growth factor family that drives proliferation in a wide variety of cell types, including osteoblasts. The binding and signal transduction triggered by these mitogens is dependent on glycosaminoglycan (GAG) sugars, particularly of the heparan sulfate (HS) class. These are secreted in proteoglycan (PG) complexes, some of which become FGF co-receptors. The syndecans, the transmembrane forms of HSPG of which there are four members, act as multifunctional receptors for a variety of ligands involved in cell-extracellular matrix (ECM) adhesion as well as growth factor binding. To understand the role of syndecans in developing osteoblasts, the effects of exogenous FGF2 on syndecan expression were examined using primary rat calvarial osteoblasts. All four syndecan mRNAs were expressed in the osteoblasts, although only syndecan-4 was upregulated by FGF2 treatment in a dose-dependent manner. This upregulation could be abrogated by pretreatment with the protein synthesis inhibitor cycloheximide, suggesting that the upregulation of syndecan-4 by FGF2 is not a primary response. Osteoblast proliferation and mineralization were enhanced by exogenous FGF2 treatment, but could be specifically diminished by anti-syndecan-4 antibody pretreatment. This treatment also blocked FGF2-induced extracellular signal-regulated kinase activation, but not the expression of the bone-specific transcription factor Runx2. These results demonstrate that mitogen-triggered syndecan-4 expression is an intrinsic part of the pathways subtending osteoblast proliferation and mineralization. J. Cell. Biochem. 100: 402,411, 2007. © 2006 Wiley-Liss, Inc. [source] Retinoic acid regulates the expression of PBX1, PBX2, and PBX3 in P19 cells both transcriptionally and post-translationallyJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 1 2004Pu Qin Abstract Pre-B cell leukemia transcription factors (PBXs) are important co-factors for the transcriptional regulation mediated by a number of Hox proteins during embryonic development. It was previously shown that the expression of several Pbx genes is elevated in mouse embryo limb buds and embryonal carcinoma P19 cells upon retinoic acid (RA) treatment although the mechanism of this induction is not well understood. In this report, we demonstrate that PBX1a, PBX1b, PBX2, and PBX3 mRNAs and PBX1/2/3 proteins are induced during endodermal and neuronal differentiation of P19 cells in a RAR-dependent subtype-unspecific manner following RA treatment. The increases in both PBX1 mRNA and PBX3 mRNA levels are secondary responses to RA treatment requiring new proteins synthesis while the increase in PBX2 mRNA is a primary response. The RA-dependent increases in PBX1 mRNA, PBX2 mRNA, and PBX3 mRNA levels are likely to be transcriptionally regulated since the stability of these mRNAs does not change. In addition, the half-lives of PBX1/2/3 proteins are significantly extended by RA treatment. Two possible mechanisms could contribute to the stabilization of PBX proteins: PBX proteins associate with RA-dependent increased levels of MEIS proteins, and RA may decrease the proteasome dependent degradation of PBX proteins. © 2004 Wiley-Liss, Inc. [source] Accurate forecasting of the undecided population in a public opinion pollJOURNAL OF FORECASTING, Issue 6 2002Christopher Monterola Abstract The problem of pollsters is addressed which is to forecast accurately the final answers of the undecided respondents to the primary question in a public opinion poll. The task is viewed as a pattern-recognition problem of correlating the answers of the respondents to the peripheral questions in the survey with their primary answers. The underlying pattern is determined with a supervised artificial neural network that is trained using the peripheral answers of the decided respondents whose primary answers are also known. With peripheral answers as inputs, the trained network outputs the most probable primary response of an undecided respondent. For a poll conducted to determine the approval rating of the (former) Philippine president, J. E. Estrada in December 1999 and March 2000, the trained network predicted with a 95% success rate the direct responses of a test population that consists of 24.57% of the decided population who were excluded in the network training set. For the undecided population (22.67% of December respondents; 23.67% of March respondents), the network predicted a final response distribution that is consistent with the approval/disapproval ratio of the decided population. Copyright © 2002 John Wiley & Sons, Ltd. [source] Third S. S. Ratnam Memorial Lecture 2007.JOURNAL OF OBSTETRICS AND GYNAECOLOGY RESEARCH (ELECTRONIC), Issue 3 2009Ovarian cancer: Is there hope for women? Abstract Ovarian cancer is today the most lethal female cancer with an overall survival of only 49.9%. The currently available screening modalities are disappointing in detecting highly curable early stage ovarian cancer. Natural history of ovarian cancer is unknown; it appears it can develop quickly from normal looking ovaries. Timely referral of women with non-specific symptoms (such as abdominal bloating, pelvic pain) for an ultrasound scan or blood CA125 assessments may help in the early diagnosis. Patients with Stage IA or IB disease with grade 1 tumors have a cure rate of >90%; this is likely to be compromised by laparoscopic surgery. In selected patients fertility preservation with good obstetric outcome is possible. However, the relapse rate in ,high risk' early stage ovarian cancers is 40,45%; adjuvant chemotherapy is needed. Only 20,25% of those with stage III and IV disease are cured. Despite a high primary response (70%) majority (70,75%) will relapse and all are likely to succumb. Optimal debulking surgery followed by adjuvant chemotherapy are needed for stages III and IV disease; the outcome is superior if managed by gynecologic oncologists. Where cost of drugs is an important consideration, an alternative is carboplatin (an affordable and equally effective drug). The role of vaccines needs further study. When relapses occur palliation will be the aim in most instances. Oral contraceptives, breast feeding, tubal sterilization and hysterectomy also have a protective effect. Risk-reducing salpingo-oopherectomy has been suggested in women with BRCA mutations. [source] Principles of pharmacodynamics and their applications in veterinary pharmacologyJOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 6 2004P. LEES Pharmacodynamics (PDs) is the science of drug action on the body or on microorganisms and other parasites within or on the body. It may be studied at many organizational levels , sub-molecular, molecular, cellular, tissue/organ and whole body , using in vivo, ex vivo and in vitro methods and utilizing a wide range of techniques. A few drugs owe their PD properties to some physico-chemical property or action and, in such cases, detailed molecular drug structure plays little or no role in the response elicited. For the great majority of drugs, however, action on the body is crucially dependent on chemical structure, so that a very small change, e.g. substitution of a proton by a methyl group, can markedly alter the potency of the drug, even to the point of loss of activity. In the late 19th century and first half of the 20th century recognition of these facts by Langley, Ehrlich, Dale, Clarke and others provided the foundation for the receptor site hypothesis of drug action. According to these early ideas the drug, in order to elicit its effect, had to first combine with a specific ,target molecule' on either the cell surface or an intracellular organelle. It was soon realized that the ,right' chemical structure was required for drug,target site interaction (and the subsequent pharmacological response). In addition, from this requirement, for specificity of chemical structure requirement, developed not only the modern science of pharmacology but also that of toxicology. In relation to drug actions on microbes and parasites, for example, the early work of Ehrlich led to the introduction of molecules selectively toxic for them and relatively safe for the animal host. In the whole animal drugs may act on many target molecules in many tissues. These actions may lead to primary responses which, in turn, may induce secondary responses, that may either enhance or diminish the primary response. Therefore, it is common to investigate drug pharmacodynamics (PDs) in the first instance at molecular, cellular and tissue levels in vitro, so that the primary effects can be better understood without interference from the complexities involved in whole animal studies. When a drug, hormone or neurotransmitter combines with a target molecule, it is described as a ligand. Ligands are classified into two groups, agonists (which initiate a chain of reactions leading, usually via the release or formation of secondary messengers, to the response) and antagonists (which fail to initiate the transduction pathways but nevertheless compete with agonists for occupancy of receptor sites and thereby inhibit their actions). The parameters which characterize drug receptor interaction are affinity, efficacy, potency and sensitivity, each of which can be elucidated quantitatively for a particular drug acting on a particular receptor in a particular tissue. The most fundamental objective of PDs is to use the derived numerical values for these parameters to classify and sub-classify receptors and to compare and classify drugs on the basis of their affinity, efficacy, potency and sensitivity. This review introduces and summarizes the principles of PDs and illustrates them with examples drawn from both basic and veterinary pharmacology. Drugs acting on adrenoceptors and cardiovascular, non-steroidal anti-inflammatory and antimicrobial drugs are considered briefly to provide a foundation for subsequent reviews in this issue which deal with pharmacokinetic (PK),PD modelling and integration of these drug classes. Drug action on receptors has many features in common with enzyme kinetics and gas adsorption onto surfaces, as defined by Michaelis,Menten and Langmuir absorption equations, respectively. These and other derived equations are outlined in this review. There is, however, no single theory which adequately explains all aspects of drug,receptor interaction. The early ,occupation' and ,rate' theories each explain some, but not all, experimental observations. From these basic theories the operational model and the two-state theory have been developed. For a discussion of more advanced theories see Kenakin (1997). [source] Genome-wide transcriptomic and proteomic analysis of the primary response to phosphate limitation in Streptomyces coelicolor M145 and in a ,phoP mutantPROTEINS: STRUCTURE, FUNCTION AND BIOINFORMATICS, Issue 14 2007Antonio Rodríguez-García Abstract Phosphate limitation in Streptomyces and in other bacteria triggers expression changes of a large number of genes. This response is mediated by the two-component PhoR,PhoP system. A Streptomyces coelicolor ,phoP mutant (lacking phoP) has been obtained by gene replacement. A genome-wide analysis of the primary response to phosphate limitation using transcriptomic and proteomic studies has been made in the parental S. coelicolor M145 and in the ,phoP mutant strains. Statistical analysis of the contrasts between the four sets of data generated (two strains under two phosphate conditions) allowed the classification of all genes into 12 types of profiles. The primary response to phosphate limitation involves upregulation of genes encoding scavenging enzymes needed to obtain phosphate from different phosphorylated organic compounds and overexpression of the high-affinity phosphate transport system pstSCAB. Clear interactions have been found between phosphate metabolism and expression of nitrogen-regulated genes and between phosphate and nitrate respiration genes. PhoP-dependent repressions of antibiotic biosynthesis and of the morphological differentiation genes correlated with the observed ,phoP mutant phenotype. Bioinformatic analysis of the presence of PHO boxes (PhoP-binding sequences) in the upstream regions of PhoP-controlled genes were validated by binding of PhoP, as shown by electrophoretic mobility shift assays. [source] Unmasking of a protective tumor necrosis factor receptor I,mediated signal in the collagen-induced arthritis modelARTHRITIS & RHEUMATISM, Issue 2 2009Cheryll Williams-Skipp Objective To examine the relative importance of tumor necrosis factor receptor I (TNFRI) signaling in the hematopoietic tissue compartment in the progression of collagen-induced arthritis (CIA), a model of rheumatoid arthritis (RA). Methods DBA/1 mice were administered a lethal radiation dose and were then rescued with bone marrow derived from either DBA/1 or TNFRI,/, mice. CIA was then induced, and disease progression was characterized. Results Surprisingly, mice with CIA that received TNFRI,/, donor marrow developed increased disease severity as compared with control mice with CIA. This could not be attributed to an increased primary response to collagen or to the contribution of a non-DBA genetic background. In mice that received TNFRI,/, bone marrow, histologic markers of advanced disease were evident shortly after initiation of the immune response to collagen and long before clinical evidence of disease. Serum TNF, was undetectable, whereas serum interleukin-12 p40 levels were increased, at the end point of the study in mice that received TNFRI,/, bone marrow. Conclusion These data raise the intriguing possibility of the existence of an antiinflammatory, TNFRI-mediated circuit in the hematopoietic compartment. This circuit bears a resemblance to the switch in TNF, function that has been observed during the resolution of bacterial infections. These data suggest that TNFRI-mediated signals in the radioresistant tissues contribute to disease progression, whereas TNFRI-mediated signals in the radiosensitive tissues can contribute to protection from disease. We thus put forward the hypothesis that the degree of response to TNF, blockade in RA is dependent in part on the relative genetic strengths of these 2 pathways. [source] Latent-Model Robustness in Joint Models for a Primary Endpoint and a Longitudinal ProcessBIOMETRICS, Issue 3 2009Xianzheng Huang Summary Joint modeling of a primary response and a longitudinal process via shared random effects is widely used in many areas of application. Likelihood-based inference on joint models requires model specification of the random effects. Inappropriate model specification of random effects can compromise inference. We present methods to diagnose random effect model misspecification of the type that leads to biased inference on joint models. The methods are illustrated via application to simulated data, and by application to data from a study of bone mineral density in perimenopausal women and data from an HIV clinical trial. [source] Incorporating Data Received after a Sequential Trial Has Stopped into the Final Analysis: Implementation and Comparison of MethodsBIOMETRICS, Issue 3 2003Marina Roshini Sooriyarachchi Summary. In a sequential clinical trial, accrual of data on patients often continues after the stopping criterion for the study has been met. This is termed "overrunning." Overrunning occurs mainly when the primary response from each patient is measured after some extended observation period. The objective of this article is to compare two methods of allowing for overrunning. In particular, simulation studies are reported that assess the two procedures in terms of how well they maintain the intended type I error rate. The effect on power resulting from the incorporation of "overrunning data" using the two procedures is evaluated. [source] Post-European settlement response gradients of river sensitivity and recovery across the upper Hunter catchment, AustraliaEARTH SURFACE PROCESSES AND LANDFORMS, Issue 7 2009Kirstie Fryirs Abstract Most analyses of river adjustment have focused on parts of catchments where metamorphosis has occurred. This provides a non-representative view of river responses to human-disturbance. Although many rivers have been subjected to systematic land-use change and disturbance, significant variability is evident in the form, extent and consequences of adjustment. This study documents the catchment-wide distribution of river sensitivity and adjustment in the upper Hunter catchment, New South Wales, Australia in the period since European settlement. The spatial distribution and timing of lateral, vertical and wholesale river adjustments are used to assess river sensitivity to change. The type and pattern of rivers, influenced largely by valley setting, have induced a fragmented pattern of river adjustment in the upper Hunter catchment. Adjustments have been largely non-uniform and localized, reflecting the predominance of bedrock-controlled rivers which have limited capacity to adjust and are resilient to change. Less than 20% of river courses have experienced metamorphosis. Phases of reach-scale geomorphic adjustment to human disturbance are characterized as a gradient of primary, secondary and tertiary responses. In general terms, primary responses such as cutoffs or straightening were followed by secondary responses such as channel expansion. These secondary responses occurred between 50,70 years after initial disturbance. A subsequent tertiary phase of river recovery, denoted as a transition from predominantly erosional to predominantly depositional geomorphic processes such as channel contraction, occurred around 70,120 years after initial disturbance. Such responses are ongoing across much of the upper Hunter catchment. Copyright © 2009 John Wiley & Sons, Ltd. [source] Generating memory with vaccinationEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 8 2009Flora Castellino Abstract The goal of vaccination is to induce long-lasting protective immune memory. Although most vaccines induce good memory responses, the type of memory induced by different vaccines may be considerably different. In addition, memory responses to the same vaccine may be influenced by age, environmental and genetic factors. Results emerging from detailed and integrated profiling of immune-responses to natural infection or vaccination suggest that the type and duration of immune memory are largely determined by the magnitude and complexity of innate immune signals that imprint the acquired immune primary responses. Here we summarize results obtained from analyzing human immune memory responses to different types of vaccines. We will also discuss how extending clinical investigation to events occurring early after vaccination can help identify early predictive markers of protective memory and thus contribute to faster development of better and safer vaccines. [source] Cross-priming of CD8+ T,cells by viral and tumor antigens is a robust phenomenonEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 1 2004Weisan Chen Abstract "Cross-priming" refers to the activation of naive CD8+ T,cells by antigen-presenting cells that have acquired nominal antigens from another cell. The biological relevance of cross-priming of CD8+ T,cells has recently been challenged (Zinkernagel, R. M., Eur. J. Immunol. 2002. 32: 2385,2392), on the basis that responses are weak or poorly quantitated, and the determinants recognized are undefined. Here we show that cross-priming is a robust process that elicits vigorous primary responses to multiple peptides in two well-defined systems. Our findings support the relevance of cross-priming in CD8+ T,cell responses to viruses and tumor cells, and demonstrate that cross-priming elicits CD8+ T,cells to determinants generated by the endogenous processing pathway. [source] CD2+/CD14+ monocytes rapidly differentiate into CD83+ dendritic cellsEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 2 2003Di Pucchio, Tiziana Abstract Since denditric cells (DC) represent the main players linking innate and adaptive immunity, their prompt generation from blood cells would be instrumental for an efficient immune response to infections. Consistent with this, CD2+ monocytes were found to express the DC maturation marker CD83, along with acquisition of high antigen-presenting activity, after a surprisingly short time in culture. This rapid process is associated with expression of IFN-,/, genes and secretion of low levels of pro-inflammatory cytokines. Exposure of monocytes to IFN-,, but not to IL-4, induced persistence of CD2+/CD83+ cells, which were fully competent in stimulating primary responses by naive T cells. These results unravel the natural pathway by which infection-induced signals rapidly transform pre-armed monocytes into active DC. [source] Partial restoration of T-cell function in aged mice by in vitro blockade of the PD-1/,PD-L1 pathwayAGING CELL, Issue 5 2010Celine S. Lages Summary Programmed cell death-1 (PD-1) is a newly characterized negative regulator of immune responses. The interaction of PD-1 with its ligands (PD-L1 and PD-L2) inhibits T-cell proliferation and cytokine production in young mice. Increased PD-1 expression has been described during chronic infections, inducing chronic activation of the immune system to control it. As aging is associated with chronic immune activation, PD-1 may contribute to age-associated T-cell dysfunction. Our data showed the following results in aged mice: (i) the number of PD-1-expressing T cells and the level of expression of PD-Ls was increased on dendritic cell subsets and T cells; (ii) PD-1+ T cells were exhausted effector memory T cells, as shown by their lower level of CD127, CD25 and CD28, as well as their limited proliferative and cytokine-producing capacity; (iii) the expression of PD-1 was up-regulated after T-cell receptor-mediated activation of CD8+ T cells, but not of CD4+ T cells; (iv) blockade of the PD-1/PD-L1 pathway moderately improved the cytokine production of T cells from old mice but did not restore their proliferation; and (v) blockade of the PD-1/PD-L1 pathway did not restore function of PD-1+ T cells; its effect appeared to be exclusively mediated by increased functionality of the PD-1, T cells. Our data thus suggest that blockade of the PD-1/PD-L1 is not likely to be efficient at restoring exhausted T-cell responses in aged hosts, although improving the responses of PD-1, T cells may prove to be a helpful strategy in enhancing primary responses. [source] Principles of pharmacodynamics and their applications in veterinary pharmacologyJOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 6 2004P. LEES Pharmacodynamics (PDs) is the science of drug action on the body or on microorganisms and other parasites within or on the body. It may be studied at many organizational levels , sub-molecular, molecular, cellular, tissue/organ and whole body , using in vivo, ex vivo and in vitro methods and utilizing a wide range of techniques. A few drugs owe their PD properties to some physico-chemical property or action and, in such cases, detailed molecular drug structure plays little or no role in the response elicited. For the great majority of drugs, however, action on the body is crucially dependent on chemical structure, so that a very small change, e.g. substitution of a proton by a methyl group, can markedly alter the potency of the drug, even to the point of loss of activity. In the late 19th century and first half of the 20th century recognition of these facts by Langley, Ehrlich, Dale, Clarke and others provided the foundation for the receptor site hypothesis of drug action. According to these early ideas the drug, in order to elicit its effect, had to first combine with a specific ,target molecule' on either the cell surface or an intracellular organelle. It was soon realized that the ,right' chemical structure was required for drug,target site interaction (and the subsequent pharmacological response). In addition, from this requirement, for specificity of chemical structure requirement, developed not only the modern science of pharmacology but also that of toxicology. In relation to drug actions on microbes and parasites, for example, the early work of Ehrlich led to the introduction of molecules selectively toxic for them and relatively safe for the animal host. In the whole animal drugs may act on many target molecules in many tissues. These actions may lead to primary responses which, in turn, may induce secondary responses, that may either enhance or diminish the primary response. Therefore, it is common to investigate drug pharmacodynamics (PDs) in the first instance at molecular, cellular and tissue levels in vitro, so that the primary effects can be better understood without interference from the complexities involved in whole animal studies. When a drug, hormone or neurotransmitter combines with a target molecule, it is described as a ligand. Ligands are classified into two groups, agonists (which initiate a chain of reactions leading, usually via the release or formation of secondary messengers, to the response) and antagonists (which fail to initiate the transduction pathways but nevertheless compete with agonists for occupancy of receptor sites and thereby inhibit their actions). The parameters which characterize drug receptor interaction are affinity, efficacy, potency and sensitivity, each of which can be elucidated quantitatively for a particular drug acting on a particular receptor in a particular tissue. The most fundamental objective of PDs is to use the derived numerical values for these parameters to classify and sub-classify receptors and to compare and classify drugs on the basis of their affinity, efficacy, potency and sensitivity. This review introduces and summarizes the principles of PDs and illustrates them with examples drawn from both basic and veterinary pharmacology. Drugs acting on adrenoceptors and cardiovascular, non-steroidal anti-inflammatory and antimicrobial drugs are considered briefly to provide a foundation for subsequent reviews in this issue which deal with pharmacokinetic (PK),PD modelling and integration of these drug classes. Drug action on receptors has many features in common with enzyme kinetics and gas adsorption onto surfaces, as defined by Michaelis,Menten and Langmuir absorption equations, respectively. These and other derived equations are outlined in this review. There is, however, no single theory which adequately explains all aspects of drug,receptor interaction. The early ,occupation' and ,rate' theories each explain some, but not all, experimental observations. From these basic theories the operational model and the two-state theory have been developed. For a discussion of more advanced theories see Kenakin (1997). [source] | ||||||||||||||||