The pathologist and toxicologist in pharmaceutical product discovery.
Significant change is occurring in the drug discovery paradigm; many companies are utilizing dedicated groups from the toxicology/ pathology disciplines to support early stage activities. The goal is to improve the efficiency of the discovery process for selecting a successful clinical candidate. Toxicity can be predicted by leveraging molecular techniques via rapid high-throughput, low-resource in vitro and in vivo test systems. Several important activities help create a platform to support rapid development of a new molecular entity. The proceedings of this symposium provide excellent examples of these applied concepts in pharmaceutical research and development. Leading biopharmaceutical companies recognize that a competitive advantage can be maintained via rapid characterization of animal models, the cellular identification of therapeutic targets, and improved sensitivity of efficacy assessment. The participation of the molecular pathologist in this quest is evolving rapidly, as evidenced by the growing number of pathologists that interact with drug discovery organizations. (+info)
PET and drug research and development.
The use of PET to examine the behavioral, therapeutic and toxic properties of drugs and substances of abuse is emerging as a powerful new scientific tool. PET provides a new perspective on drug research by virtue of its ability to directly assess both pharmacokinetic and pharmacodynamic events in humans and in animals. These parameters can be assessed directly in the human body both in healthy volunteers and in patients. Moreover, the new generation of high-resolution, small-animal cameras hold the promise of introducing imaging in the early stages of drug development and make it possible to carry out longitudinal studies in animals and to study genetically altered animals. This places PET in a unique position to contribute significantly to the process of drug development through understanding the molecular mechanisms underlying drug action while addressing some very practical questions such as determining effective drug doses for clinical trials for new drugs, determining the duration of drug action and examining potential drug interactions. (+info)
The pharmacology of gene therapy.
The objective for human gene therapy is to express exogenous DNA at a site in vivo for long enough, and at sufficient levels to produce a therapeutic response. The obstacles to this objective are numerous and include the formulation or packaging of the DNA, in vivo delivery, penetration of biological barriers, DNA elimination within the cell and from the tissue compartments of the whole body, control of product expression and overt toxicity. The current challenge is to resolve each of these obstacles to produce a practical and efficient gene therapy. In doing so, it is vital to understand the disposition of DNA vectors in vivo, and to know how conventional medicines may be used to modulate this disposition and to enhance the therapeutic effect of these vectors. Many of the general concepts of human gene therapy have been reviewed extensively in the literature. This review discusses some of the pharmacological aspects of gene delivery and the fate of vectors in vivo, and then highlights how drugs are being used to modulate gene therapy. (+info)
Is orphan drug status beneficial to tropical disease control? Comparison of the American and future European orphan drug acts.
OBJECTIVES To quantify past outcomes of tropical pharmacology research and development (R & D) and to assess past benefits of the American orphan drug act and potential benefits of the future European orphan drug regulation on tropical diseases. METHODS: This paper presents two analyses: a 1983-97 retrospective study of the United States Orphan Drug Act concerning rare diseases and a prospective study of the European Proposal for a Regulation Concerning Orphan Drugs and its possible impact on tropical diseases. RESULTS: Different programmes have in the past tried to stimulate R & D in this area, but results remain limited. Of 1450 new chemical entities marketed between 1972 and 1997, 13 were specifically for tropical diseases and considered as essential drugs. Between 1983 & 1997, the US Orphan Drug Act approved 837 drugs and marketing of 152 new molecular entities (NMEs). Three NMEs have been designated for malaria and human African trypanosomiasis. Seven others, already commonly used in tropical diseases, received either orphan designation or an orphan approval for another indication. Pharmaceutical companies benefit from the US framework only when the US market exclusivity clause was applicable. Future European orphan drug regulation appears to be similar to the US Orphan Drug Act. CONCLUSION The orphan drug programmes relating to rare diseases have met with some success. Considering tropical diseases rare diseases seems inadequate to boost pharmaceutical R & D. However, some provisions of the European text may be relevant to tropical diseases, admitting the need for a more specific rule for evaluations of this kind of drug and recognizing the existence of 'diseases of exception'. (+info)
A comparison of the direct and reporter antigen popliteal lymph node assay for the detection of immunomodulation by low molecular weight compounds.
The direct popliteal lymph node assay (PLNA) is a predictive test used to detect the immune-stimulating potential of pharmaceuticals and other low molecular weight compounds (LMWCs) with known autoimmunogenic or sensitizing properties. Two limitations in the PLNA are the existence of false negatives and the inability of the assay to provide mechanistic information. Recently the direct PLNA was modified by incorporating reporter antigens (RA), either TNP-Ficoll or TNP-OVA. In the RA-PLNA, immune stimulation is detected by measuring IgM or IgG TNP-specific antibody-forming cells (AFC) using an enzyme-linked immunospot (ELISPOT) assay. The RA-PLNA, when using potent, known autoimmunogenic compounds, may provide greater sensitivity compared to the direct PLNA and might distinguish LMWCs that have intrinsic adjuvant activity from those that create neo-antigens, using TNP-OVA and TNP-Ficoll, respectively. The purpose of this study was to rigorously compare the two assays. Our first objective was to investigate the interlaboratory reproducibility of the RA-PLNA using four autoimmunogenic LMWC models, plus one negative control LMWC. Subsequently, we tested seven LMWCs with known sensitizing properties and compared the results from the direct and modified assay. The test group included LMWCs thought to be mechanistically distinct and similar to compounds typically encountered in preclinical safety assessment. All control and treatment AFC plaques were collected (76 total), pooled, coded to conceal their source, and counted. The interlaboratory reproducibility of the RA-PLNA was demonstrated with the model autoimmunogenic compounds HgCl2, diphenylhydantoin, D-penicillamine, and the negative control compound phenobarbital, by detecting TNP-specific IgM and polyclonal IgG production to both reporter antigens. Additionally, the sensitizing effects of streptozotocin were identified using an IgG2a ELISPOT with both TNP-OVA and TNP-Ficoll. With the extended test group, the sensitizing effects of aniline, a false negative LMWC in the direct PLNA, was not detected in this study when using the direct PLNA. However, there was an increase of IgG1 AFCs using TNP-OVA, when compared to control (508 +/- 113 vs. 12 +/- 4 respectively). Glafenine, diclofenac, and ibuprofen, all associated with drug-induced anaphylaxis in humans, produced significant increases in IgG1 production to TNP-OVA. Of these three LMWCs, only diclofenac, which has been documented to induce neo-antigen formation, was detected with TNP-Ficoll. Hydralazine immunomodulation could be detected only with the direct PLNA although significant increases in IgM were identified with the co-injection of either reporter antigen. Isoniazid and methyldopa consistently produced negative responses in both assays. In summary, this study has demonstrated acceptable interlaboratory reproducibility of the RA-PLNA, using model autoimmunogenic LMWCs. Additionally, it demonstrated that an advantage of the RA-PLNA was that it identified all anaphylactic-associated LMWCs tested, detected the false negative compound aniline, and revealed what is thought to be the mechanism(s) associated with diclofenac-induced immunostimulation. (+info)
Effects of drugs on glucose measurements with handheld glucose meters and a portable glucose analyzer.
Thirty drugs used primarily in critical care and hospital settings were tested in vitro to observe interference on glucose measurements with 6 hand-held glucose meters and a portable glucose analyzer. Paired differences of glucose measurements between drug-spiked samples and unspiked control samples were calculated to determine bias. A criterion of +/- 6 mg/dL was used as the cutoff for interference. Ascorbic acid interfered with the measurements on all glucose devices evaluated. Acetaminophen, dopamine, and mannitol interfered with glucose measurements on some devices. Dose-response relationships help assessment of drug interference in clinical use. High dosages of these drugs may be given to critically ill patients or self-administered by patients without medical supervision. Package inserts for the glucose devices may not provide adequate warning information. Hence, we recommend that clinicians choose glucose devices carefully and interpret results cautiously when glucose measurements are performed during or after drug interventions. (+info)
International union of pharmacology. XXII. Nomenclature for chemokine receptors.
Chemokine receptors comprise a large family of seven transmembrane domain G protein-coupled receptors differentially expressed in diverse cell types. Biological activities have been most clearly defined in leukocytes, where chemokines coordinate development, differentiation, anatomic distribution, trafficking, and effector functions and thereby regulate innate and adaptive immune responses. Pharmacological analysis of chemokine receptors is at an early stage of development. Disease indications have been established in human immunodeficiency virus/acquired immune deficiency syndrome and in Plasmodium vivax malaria, due to exploitation of CCR5 and Duffy, respectively, by the pathogen for cell entry. Additional indications are emerging among inflammatory and immunologically mediated diseases, but selection of targets in this area still remains somewhat speculative. Small molecule antagonists with nanomolar affinity have been reported for 7 of the 18 known chemokine receptors but have not yet been studied in clinical trials. Virally encoded chemokine receptors, as well as chemokine agonists and antagonists, and chemokine scavengers have been identified in medically important poxviruses and herpesviruses, again underscoring the importance of the chemokine system in microbial pathogenesis and possibly identifying specific strategies for modulating chemokine action therapeutically. The purpose of this review is to update current concepts of the biology and pharmacology of the chemokine system, to summarize key information about each chemokine receptor, and to describe a widely accepted receptor nomenclature system, ratified by the International Union of Pharmacology, that is facilitating clear communication in this area. (+info)
Mechanisms mediating substance P-induced contraction in the rat iris in vitro.
PURPOSE: To determine some of the mechanisms by which substance P (SP) induces contraction in the isolated rat iris. METHODS: Rings of rat iris were mounted in a 5-ml organ chamber containing Krebs solution at 37 degrees C under basal tension of 75 mg, and isometric tension was recorded. RESULTS: Substance P produced graded contraction in the rat iris, being approximately 40-fold more potent than carbachol. Peptidase inhibitors (captopril, phosphoramidon, thiorphan) did not affect the SP response. The SP contraction was dependent on external Ca2+ by a mechanism resistant to both nifedipine and omega-conotoxin GVIA. Atropine and tetrodotoxin significantly shifted the SP response to the right (three- and fivefold, respectively). Neither phorbol nor genistein altered the SP-induced contraction, whereas staurosporine caused a weak inhibition. Indomethacin, pyrilamine, guanethidine, 8-37 calcitonin gene-related peptide (CGRP) fragment, and NG-nitro-L-arginine methyl ester had no effect on SP response. All the natural tachykinin agonists caused concentration-dependent contraction in rat iris with similar maximal responses. The NK3 selective agonist senktide caused graded contraction, being approximately 150-fold more active than the NK2 selective agonist [beta-ala] NKA. The NK1 selective agonist SP methyl ester induced a small contraction. The NK3 and NK2 antagonists SR 142801 and SR 48968 shifted the SP response to the right. Schilds plots gave pA2 (negative logarithm of the molar concentration of antagonist causing a twofold rightward displacement of the concentration response curves) values of 9.37 and 7.97 and slopes of 0.70 and 1.02, respectively. CONCLUSIONS: Substance P produces a potent contraction in the isolated rat iris that seems to depend on the neural release of acetylcholine by tetrodotoxin-sensitive mechanisms. Its response relies largely on external Ca2+, through mechanisms independent of activation of L- or N-type Ca2+ channels, and is probably mediated via activation of NK3 and NK2 receptors. (+info)