The Experts below are selected from a list of 318 Experts worldwide ranked by ideXlab platform
David G. Lambert - One of the best experts on this subject based on the ideXlab platform.
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Oxford Medicine Online - Deorphanization of ORL-1/LC132 by Reverse Pharmacology in two landmark studies
Oxford Medicine Online, 2018Co-Authors: Mark F. Bird, David G. LambertAbstract:Deorphanization of ORL-1/LC132 in 1995 by Reverse Pharmacology in two simultaneously published landmark studies added a new member to the opioid family of G-protein coupled receptors. Meunier and Reinscheid used cells expressing recombinant ORL-1 (human) or LC132 (rat) and the presumed intracellular inhibition of cyclic AMP formation to ‘fish’ for endogenous peptide ligands in rat whole-brain and pig hypothalamic extracts. Both studies reported the isolation of a 17-amino-acid peptide, which was named nociceptin and orphanin FQ by the two authors, respectively. The behaviour of the isolated peptide was a complete surprise, as a general hyperalgesia was observed when the peptide was administered at supraspinal sites. We now know that this peptide has, in fact, anti-opioid action, particularly in the medulla. The endogenous peptide exerts a multitude of effects both in the nervous system and, unlike classical opioids, has efficacy in neuropathic pain.
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The nociceptin/orphanin FQ receptor: a target with broad therapeutic potential
Nature Reviews Drug Discovery, 2008Co-Authors: David G. LambertAbstract:Identification of the enigmatic nociceptin/orphanin FQ peptide (N/OFQ) in 1995 represented the first successful use of Reverse Pharmacology and led to deorphanization of the N/OFQ receptor (NOP). Subsequently, the N/OFQ-NOP system has been implicated in a wide range of biological functions, including pain, drug abuse, cardiovascular control and immunity. Although this could be considered a hurdle for the development of pharmaceuticals selective for a specific disease indication, NOP represents a viable drug target. This article describes potential clinical indications and highlights the current status of the very limited number of clinical trials.
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The nociceptin/orphanin FQ receptor: a target with broad therapeutic potential
Nature Reviews Drug Discovery, 2008Co-Authors: David G. LambertAbstract:Identification of the enigmatic nociceptin/orphanin FQ peptide (N/OFQ) in 1995 represented the first successful use of Reverse Pharmacology and led to deorphanization of the N/OFQ receptor (NOP). Subsequently, the N/OFQ–NOP system has been implicated in a wide range of biological functions, including pain, drug abuse, cardiovascular control and immunity. Although this could be considered a hurdle for the development of pharmaceuticals selective for a specific disease indication, NOP represents a viable drug target. This article describes potential clinical indications and highlights the current status of the very limited number of clinical trials. Nociceptin/orphanin FQ (N/OFQ) is the first example of a peptide that was isolated by Reverse Pharmacology. N/OFQ activates a G_i-protein-coupled receptor, NOP, and this peptide–receptor system has been implicated in a diverse range of biological functions including (but not limited to) pain, reward/drug abuse, cardiovascular control and immune function. Many peptide and non-peptide ligands are available. The main chemical classes of the current non-peptides are morphinans (for example, buprenorphine; mixed); aminoquinolines (for example, JTC-801; antagonist); benzimidazopiperidines (for example, J-113397; antagonist); aryl-piperidines (for example, SB-612111; antagonist); and spiropiperidines (for example, Ro64-6198; agonist). Central NOP antagonists have, variably, antinociceptive (supraspinal), and antidepressant effects. Central NOP agonists have anti-opioid (supraspinal), antinociceptive (spinal), anxiolytic effects and produce bradycardia/hypotension. Peripheral NOP agonists have antinociceptive, vasodilatory and aquaretic effects. They also produce bardycardia and hypotension, and inhibit bladder activity. A small number of molecules are in clinical development: ZP120, a peptide in Phase I and II for congestive heart failure, and JTC-801, a non-peptide antagonist in Phase II for pain. In this Review, Lambert describes the physiology and potential clinical applications of nociceptin/orphanin FQ and its receptor. This peptide–receptor system has been implicated in a wide range of biological functions such as pain, drug abuse, cardiovascular control and immunity.
Drissa Diallo - One of the best experts on this subject based on the ideXlab platform.
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Reverse Pharmacology of medicinal plants good luck or efficient method
Planta Medica, 2012Co-Authors: Bertrand Graz, Jacques Falquet, Claudia Simoespires, Amina Haouala, Muriel Cuendet, Philippe Christen, K Ndjoko, Merlin Willcox, Drissa DialloAbstract:Reverse Pharmacology has frequently been advocated in India and China (among other places), as a method based on the search for documented therapeutic effects of plants in ancient texts (Vaidya, 2006). Another definition of Reverse Pharmacology, inspired by ethnopharmacological approaches [Carvalho et al, 1991], begins with a documented outcome as observed by patients. Both approaches will be discussed, the latter in view of our experience with the “success story” of “improved traditional medicines” in Mali [Graz et al. 2011; Willcox et al., 2011]. In this context, the first step was a population-based ethnomedical survey which included patient accounts of recent experiences of the therapeutic itinerary (cure, worsening or adverse events after using traditional preparations) and interviews of traditional medicine practitioners [Diallo et al., 2006]. The traditional preparation based on Argemone mexicana (AM) appeared as the recipe associated with the best outcome among patients with presumed malaria. In subsequent clinical studies (a dose-escalating and a randomized controlled trial) in the village where the AM preparation was used, its safety and clinical efficacy was found non-inferior to the standard imported drug artesunate-amodiaquine in terms of clinical outcomes (need for second-line treatment, incidence of new episodes of malaria) [Willcox et al., 2007; Graz et al., 2010]. Several studies found that AM also has in vitro activity against P. falciparum (Adjobimey et al., 2004; Diallo et al., 2006). In terms of “evidence-based medicine”, AM can now be proposed for pilot introduction in public health programs with careful evaluation of its impact. However, a problem remains: how to check the quality of the plant? Even if three alkaloids (berberine, protopine, allocryptopine) were detected by bio-guided fractionation and showed a significant in vitro activity [Simoes-Pires, 2009], some questions require further investigation. Are these alkaloids solely or even partially responsible for the clinical efficacy? In that case, are these alkaloids metabolized into more or less active compounds? Is there a synergy effect? Several research approaches are being explored in order to answer these questions: early ADME studies, including microsome metabolization and Caco-2 permeability assays; in vitro activity profiling of the alkaloids and metabolites; pre-clinical and clinical pharmacokinetics of the candidate compounds alone and/or after ingestion of the decoction. References: Adjobimey, T., Eday'e, I., Lagnika, L., Gbenou, J., Moudachirou, M., Sanni, A., 2004. C. R. Chimie 7, 1023–1027. Carvalho, L. H., M. G. Brandao, et al. (1991). "Antimalarial activity of crude extracts from Brazilian plants studied in vivo in Plasmodium berghei-infected mice and in vitro against Plasmodium falciparum in culture." Braz J Med Biol Res 24(11): 1113–1123. Diallo, D., Graz, B., Falquet, J., Traore, A.K., Giani, S., Mounkoro, P.P., Berthe, A., Sacko, M., Diakite, C., 2006. Trans. R. Soc. Trop. Med. Hyg. 100, 515–520. Graz, B., Willcox, M. L., Diakite, C., Falquet, J., Dackuo, F., Sidibe, O., Giani, S., Diallo, D., 2010. Trans. R. Soc. Trop. Med. Hyg. 104, no1, 33–41. Graz B, Kitua AY, Malebo HM. To what extent can traditional medicine contribute a complementary or alternative solution to malaria control programmes? Malar J. 2011 Mar 15;10 Suppl 1:S6. [Epub ahead of print]. http://www.malariajournal.com/supplements/10/S1 Simoes-Pires, C. These de doctorat. Universite de Geneve, 2009.– Sc. 4129.–2009/07/27 Vaidya ADB. 2006. Reverse pharmacological correlates of ayurvedic drug actions. Indian J Pharmacol. 38: 311–315 Willcox M. L., Graz, B., Falquet, J., Sidibe, O., Forster, M., Diallo, D., 2007. Trans. R. Soc. Trop. Med. Hyg. 101, 1190–1198. Willcox ML, Graz B, Falquet J, Diakite C, Giani S, Diallo D. A "Reverse Pharmacology" approach for developing an anti-malarial phytomedicine. Malar J. 2011 Mar 15;10 Suppl 1:S8. [Epub ahead of print]
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A “Reverse Pharmacology” approach for developing an anti-malarial phytomedicine
Malaria Journal, 2011Co-Authors: Merlin L Willcox, Bertrand Graz, Jacques Falquet, Chiaka Diakite, Sergio Giani, Drissa DialloAbstract:A “Reverse Pharmacology” approach to developing an anti-malarial phytomedicine was designed and implemented in Mali, resulting in a new standardized herbal anti-malarial after six years of research. The first step was to select a remedy for development, through a retrospective treatment-outcome study. The second step was a dose-escalating clinical trial that showed a dose-response phenomenon and helped select the safest and most efficacious dose. The third step was a randomized controlled trial to compare the phytomedicine to the standard first-line treatment. The last step was to identify active compounds which can be used as markers for standardization and quality control. This example of “Reverse Pharmacology” shows that a standardized phytomedicine can be developed faster and more cheaply than conventional drugs. Even if both approaches are not fully comparable, their efficiency in terms of public health and their complementarity should be thoroughly considered.
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a Reverse Pharmacology approach for developing an anti malarial phytomedicine
Malaria Journal, 2011Co-Authors: Merlin L Willcox, Bertrand Graz, Jacques Falquet, Chiaka Diakite, Sergio Giani, Drissa DialloAbstract:A “Reverse Pharmacology” approach to developing an anti-malarial phytomedicine was designed and implemented in Mali, resulting in a new standardized herbal anti-malarial after six years of research. The first step was to select a remedy for development, through a retrospective treatment-outcome study. The second step was a dose-escalating clinical trial that showed a dose-response phenomenon and helped select the safest and most efficacious dose. The third step was a randomized controlled trial to compare the phytomedicine to the standard first-line treatment. The last step was to identify active compounds which can be used as markers for standardization and quality control. This example of “Reverse Pharmacology” shows that a standardized phytomedicine can be developed faster and more cheaply than conventional drugs. Even if both approaches are not fully comparable, their efficiency in terms of public health and their complementarity should be thoroughly considered.
Ashok D.b. Vaidya - One of the best experts on this subject based on the ideXlab platform.
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Chapter 4 – Reverse Pharmacology
Innovative Approaches in Drug Discovery, 2020Co-Authors: Ashwinikumar Raut, Mukund S Chorghade, Ashok D.b. VaidyaAbstract:The current drug discovery paradigm has a high attrition rate, postmarketing withdrawals, and costly development. Drugs have been emerging serendipitously “from the bedside,” without an organized approach. Drug discovery, at the bedside, is followed in Reverse Pharmacology (RP) by the relevant science of drug development for safety, efficacy, and mechanistic understanding. Such a transdisciplinary structured path can explore the large potential for novel drugs. The phytoactives can be novel scaffolds for new drugs. Ayurveda and other living traditional systems of medicine have a rich reservoir of pharmacotherapeutics. The documented therapeutic experience defines the nature of the drug targets to be studied in vitro and in vivo models. The phytomolecules may lead to newer dimensions of drug actions. Reserpine and Atremisinin exemplify such a potential. The delay in drug discovery can be eliminated by Reverse Pharmacology (RP). A well-structured multisystem and functionally multidisciplinary organization is needed for RP; it also needs an appropriate locus for academic growth, development, and intellectual appeal. A close and continuous collaboration between academia and industry is needed. In the future, RP can differentiate into unique specialities: Ayurvedic pharmacoepidemiology, observational therapeutics, pharmacodynamic methods, advanced pharmacokinetics, and biosynthesis. Early attention to RP is a prerequisite for achieving this. The medical pluralism in India offers observational opportunities for the bedside hits and leads for several unmet medical needs. Such leads can be facilitated by RP as drug discoveries for integrative medicine.
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In vitro growth inhibition study of hydroxyapatite crystals in the presence of selected herbal extract solutions
2019Co-Authors: B. B. Parekh, Ashok D.b. Vaidya, Ashwinikumar Raut, Bhoomika V. Jogiya, Poorvesh M. Vyas, Mihir J. JoshiAbstract:Hydroxyapatite, is the most stable mineral found in body. Hydroxyapatite crystals were grown by the gel technique in the form of periodic Liesegang ring patterns. The size of fine crystalline hydroxyapatite was found in order of microns. The harvested crystals were characterized by Powder X- Ray Diffraction (XRD). Aqueous, alcoholic, hydro-alcoholic extracts of five herbs selected based on Reverse Pharmacology (RP) experiential data of Ayurveda were used for the growth inhibition study of hydroxyapatite crystallites. These extracts were compared with CaCl2 (control) solution to study their effects in terms of the particle size of crystallites, the total diffusion length in the gel column, the number of rings and the spacing between two rings. The inhibition in hydroxyapatite crystal growth by the herbal extracts is reported.
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Urine therapy in Ayurveda: Ancient insights to modern discoveries for cancer regression.
Journal of Ayurveda and Integrative Medicine, 2018Co-Authors: Ashok D.b. VaidyaAbstract:Abstract Investigation of spontaneous regressions (SR) of cancer may explain host mechanisms of control by anticancer substance (A.C.S.). Documented human SR, of bladder cancer after uretero-sigmoidostomy and of uterine leiomyosarcoma after irreparable vesico-vaginal fistula, suggested the presence of A.C.S. in human urine. Animal experiments with urine in rat alveolar carcinoma and in mouse melanoma point to A.C.S. Urine therapy, as cited in Bhrigu-Samhita and used in some cases, needs to be followed up by systematic Reverse Pharmacology and analytical identification of A.C.S.
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chapter 4 Reverse Pharmacology
Innovative Approaches in Drug Discovery#R##N#Ethnopharmacology Systems Biology and Holistic Targeting, 2017Co-Authors: Ashwinikumar Raut, Mukund S Chorghade, Ashok D.b. VaidyaAbstract:The current drug discovery paradigm has a high attrition rate, postmarketing withdrawals, and costly development. Drugs have been emerging serendipitously “from the bedside,” without an organized approach. Drug discovery, at the bedside, is followed in Reverse Pharmacology (RP) by the relevant science of drug development for safety, efficacy, and mechanistic understanding. Such a transdisciplinary structured path can explore the large potential for novel drugs. The phytoactives can be novel scaffolds for new drugs. Ayurveda and other living traditional systems of medicine have a rich reservoir of pharmacotherapeutics. The documented therapeutic experience defines the nature of the drug targets to be studied in vitro and in vivo models. The phytomolecules may lead to newer dimensions of drug actions. Reserpine and Atremisinin exemplify such a potential. The delay in drug discovery can be eliminated by Reverse Pharmacology (RP). A well-structured multisystem and functionally multidisciplinary organization is needed for RP; it also needs an appropriate locus for academic growth, development, and intellectual appeal. A close and continuous collaboration between academia and industry is needed. In the future, RP can differentiate into unique specialities: Ayurvedic pharmacoepidemiology, observational therapeutics, pharmacodynamic methods, advanced pharmacokinetics, and biosynthesis. Early attention to RP is a prerequisite for achieving this. The medical pluralism in India offers observational opportunities for the bedside hits and leads for several unmet medical needs. Such leads can be facilitated by RP as drug discoveries for integrative medicine.
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Antiparasitic and disease-modifying activity of Nyctanthes arbor-tristis Linn. in malaria: An exploratory clinical study
Journal of Ayurveda and Integrative Medicine, 2016Co-Authors: C. S. Godse, Prakash S. Tathed, Sameer S. Talwalkar, Vaidya Ra, Ashok J. Amonkar, Akhil B. Vaidya, Ashok D.b. VaidyaAbstract:Background An unceasing threat of drug resistance continuously poses demand for new antimalarial drugs. A scientific assessment of traditionally used antimalarial plants through Reverse Pharmacology is crucial for a fast track drug discovery. An Ayurvedic plant Nyctanthes arbor-tristis Linn. – (Parijat) is being used in clinical practice and had shown antimalarial activity, with a parasite clearance in 76.6% of 120 patients, in an earlier clinical study.
Bertrand Graz - One of the best experts on this subject based on the ideXlab platform.
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Reverse Pharmacology for developing an anti malarial phytomedicine the example of argemone mexicana
International Journal for Parasitology-Drugs and Drug Resistance, 2014Co-Authors: Claudia Simoespires, Bertrand Graz, Jacques Falquet, Kurt Hostettmann, Amina Haouala, Muriel Cuendet, Philippe ChristenAbstract:Classical Pharmacology has been the basis for the discovery of new chemical entities with therapeutic effects for decades. In natural product research, compounds are generally tested in vivo only after full in vitro characterization. However drug screening using this methodology is expensive, time-consuming and very often inefficient. Reverse Pharmacology, also called bedside-to-bench, is a research approach based on the traditional knowledge and relates to reversing the classical laboratory to clinic pathway to a clinic to laboratory practice. It is a trans-disciplinary approach focused on traditional knowledge, experimental observations and clinical experiences. This paper is an overview of the Reverse Pharmacology approach applied to the decoction of Argemone mexicana, used as an antimalarial traditional medicine in Mali. A. mexicana appeared as the most effective traditional medicine for the treatment of uncomplicated falciparum malaria in Mali, and the clinical efficacy of the decoction was comparable to artesunate–amodiaquine as previously published. Four stages of the Reverse Pharmacology process will be described here with a special emphasis on the results for stage 4. Briefly, allocryptopine, protopine and berberine were isolated through bioguided fractionation, and had their identity confirmed by spectroscopic analysis. The three alkaloids showed antiparasitic activity in vitro, of which allocryptopine and protopine were selective towards Plasmodiumfalciparum. Furthermore, the amount of the three active alkaloids in the decoction was determined by quantitative NMR, and preliminary in vivo assays were conducted. On the basis of these results, the Reverse Pharmacology approach is discussed and further pharmacokinetic studies appear to be necessary in order to determine whether these alkaloids can be considered as phytochemical markers for quality control and standardization of an improved traditional medicine made with this plant.
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Reverse Pharmacology of medicinal plants good luck or efficient method
Planta Medica, 2012Co-Authors: Bertrand Graz, Jacques Falquet, Claudia Simoespires, Amina Haouala, Muriel Cuendet, Philippe Christen, K Ndjoko, Merlin Willcox, Drissa DialloAbstract:Reverse Pharmacology has frequently been advocated in India and China (among other places), as a method based on the search for documented therapeutic effects of plants in ancient texts (Vaidya, 2006). Another definition of Reverse Pharmacology, inspired by ethnopharmacological approaches [Carvalho et al, 1991], begins with a documented outcome as observed by patients. Both approaches will be discussed, the latter in view of our experience with the “success story” of “improved traditional medicines” in Mali [Graz et al. 2011; Willcox et al., 2011]. In this context, the first step was a population-based ethnomedical survey which included patient accounts of recent experiences of the therapeutic itinerary (cure, worsening or adverse events after using traditional preparations) and interviews of traditional medicine practitioners [Diallo et al., 2006]. The traditional preparation based on Argemone mexicana (AM) appeared as the recipe associated with the best outcome among patients with presumed malaria. In subsequent clinical studies (a dose-escalating and a randomized controlled trial) in the village where the AM preparation was used, its safety and clinical efficacy was found non-inferior to the standard imported drug artesunate-amodiaquine in terms of clinical outcomes (need for second-line treatment, incidence of new episodes of malaria) [Willcox et al., 2007; Graz et al., 2010]. Several studies found that AM also has in vitro activity against P. falciparum (Adjobimey et al., 2004; Diallo et al., 2006). In terms of “evidence-based medicine”, AM can now be proposed for pilot introduction in public health programs with careful evaluation of its impact. However, a problem remains: how to check the quality of the plant? Even if three alkaloids (berberine, protopine, allocryptopine) were detected by bio-guided fractionation and showed a significant in vitro activity [Simoes-Pires, 2009], some questions require further investigation. Are these alkaloids solely or even partially responsible for the clinical efficacy? In that case, are these alkaloids metabolized into more or less active compounds? Is there a synergy effect? Several research approaches are being explored in order to answer these questions: early ADME studies, including microsome metabolization and Caco-2 permeability assays; in vitro activity profiling of the alkaloids and metabolites; pre-clinical and clinical pharmacokinetics of the candidate compounds alone and/or after ingestion of the decoction. References: Adjobimey, T., Eday'e, I., Lagnika, L., Gbenou, J., Moudachirou, M., Sanni, A., 2004. C. R. Chimie 7, 1023–1027. Carvalho, L. H., M. G. Brandao, et al. (1991). "Antimalarial activity of crude extracts from Brazilian plants studied in vivo in Plasmodium berghei-infected mice and in vitro against Plasmodium falciparum in culture." Braz J Med Biol Res 24(11): 1113–1123. Diallo, D., Graz, B., Falquet, J., Traore, A.K., Giani, S., Mounkoro, P.P., Berthe, A., Sacko, M., Diakite, C., 2006. Trans. R. Soc. Trop. Med. Hyg. 100, 515–520. Graz, B., Willcox, M. L., Diakite, C., Falquet, J., Dackuo, F., Sidibe, O., Giani, S., Diallo, D., 2010. Trans. R. Soc. Trop. Med. Hyg. 104, no1, 33–41. Graz B, Kitua AY, Malebo HM. To what extent can traditional medicine contribute a complementary or alternative solution to malaria control programmes? Malar J. 2011 Mar 15;10 Suppl 1:S6. [Epub ahead of print]. http://www.malariajournal.com/supplements/10/S1 Simoes-Pires, C. These de doctorat. Universite de Geneve, 2009.– Sc. 4129.–2009/07/27 Vaidya ADB. 2006. Reverse pharmacological correlates of ayurvedic drug actions. Indian J Pharmacol. 38: 311–315 Willcox M. L., Graz, B., Falquet, J., Sidibe, O., Forster, M., Diallo, D., 2007. Trans. R. Soc. Trop. Med. Hyg. 101, 1190–1198. Willcox ML, Graz B, Falquet J, Diakite C, Giani S, Diallo D. A "Reverse Pharmacology" approach for developing an anti-malarial phytomedicine. Malar J. 2011 Mar 15;10 Suppl 1:S8. [Epub ahead of print]
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A “Reverse Pharmacology” approach for developing an anti-malarial phytomedicine
Malaria Journal, 2011Co-Authors: Merlin L Willcox, Bertrand Graz, Jacques Falquet, Chiaka Diakite, Sergio Giani, Drissa DialloAbstract:A “Reverse Pharmacology” approach to developing an anti-malarial phytomedicine was designed and implemented in Mali, resulting in a new standardized herbal anti-malarial after six years of research. The first step was to select a remedy for development, through a retrospective treatment-outcome study. The second step was a dose-escalating clinical trial that showed a dose-response phenomenon and helped select the safest and most efficacious dose. The third step was a randomized controlled trial to compare the phytomedicine to the standard first-line treatment. The last step was to identify active compounds which can be used as markers for standardization and quality control. This example of “Reverse Pharmacology” shows that a standardized phytomedicine can be developed faster and more cheaply than conventional drugs. Even if both approaches are not fully comparable, their efficiency in terms of public health and their complementarity should be thoroughly considered.
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a Reverse Pharmacology approach for developing an anti malarial phytomedicine
Malaria Journal, 2011Co-Authors: Merlin L Willcox, Bertrand Graz, Jacques Falquet, Chiaka Diakite, Sergio Giani, Drissa DialloAbstract:A “Reverse Pharmacology” approach to developing an anti-malarial phytomedicine was designed and implemented in Mali, resulting in a new standardized herbal anti-malarial after six years of research. The first step was to select a remedy for development, through a retrospective treatment-outcome study. The second step was a dose-escalating clinical trial that showed a dose-response phenomenon and helped select the safest and most efficacious dose. The third step was a randomized controlled trial to compare the phytomedicine to the standard first-line treatment. The last step was to identify active compounds which can be used as markers for standardization and quality control. This example of “Reverse Pharmacology” shows that a standardized phytomedicine can be developed faster and more cheaply than conventional drugs. Even if both approaches are not fully comparable, their efficiency in terms of public health and their complementarity should be thoroughly considered.
Jean-claude Meunier - One of the best experts on this subject based on the ideXlab platform.
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Utilizing functional genomics to identify new pain treatments : the example of nociceptin.
American Journal of Pharmacogenomics, 2012Co-Authors: Jean-claude MeunierAbstract:Nociceptin/orphanin FQ (noc/oFQ) is the first novel bioactive substance to have been discovered by the implementation of a functional genomics/Reverse Pharmacology approach. The neuropeptide was indeed identified in brain extracts as the natural ligand of a previously cloned orphan G protein-coupled receptor, the opioid receptor-like 1 (ORL1) receptor.
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Utilizing Functional Genomics to Identify New Pain Treatments
American Journal of Pharmacogenomics, 2003Co-Authors: Jean-claude MeunierAbstract:Nociceptin/orphanin FQ (noc/oFQ) is the first novel bioactive substance to have been discovered by the implementation of a functional genomics/Reverse Pharmacology approach. The neuropeptide was indeed identified in brain extracts as the natural ligand of a previously cloned orphan G protein-coupled receptor, the opioid receptor-like 1 (ORL1) receptor. Since its discovery in 1995, noc/oFQ has been the subject of intensive study to establish its role in normal brain function and its possible involvement in neurophysiopathology. Although the neuropeptide, an inhibitor of neuronal activity, has been found to have a wide spectrum of pharmacological effects in vivo , none has been as intensively investigated as its action on nociception and nociceptive processing. There is now substantial evidence that noc/oFQ has a modulatory role in nociception. However, dependent on the dose and site of injection, and possibly the animal’s genetic background and even psychological status, the peptide has been variously reported to cause allodynia, hyperalgesia, analgesia, and even pain, in rodents. Overall, noc/oFQ tends to facilitate pain when administered supraspinally, and to inhibit it when administered spinally. These opposing effects beg the obvious, yet still unanswered, question as to what would be the net effect on nociception of an ORL1 receptor ligand, agonist or antagonist, able to target supraspinal and spinal sites simultaneously. Owing to the research effort of several drug companies, such ligands, i.e. nonpeptidic, brain-penetrating agonists and antagonists, have recently been produced whose systematic screening in animal models of acute and inflammatory pain may help validate the ORL1 receptor as the target for novel, non-opioid analgesics.
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Molecular neuroendocrinology. Working backwards to find answers.
Nature, 1998Co-Authors: Jean-claude MeunierAbstract:Reverse Pharmacology is a way of identifying biologically active molecules by starting with the receptors to which they bind and, literally, working backwards. One group has gone even further back than this — first they cloned an ‘orphan’ receptor and then they set about looking for its ligand. They identified two peptides that bind this receptor, and have found that these promote the release of prolactin — the hormone that is responsible for lactation.
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nociceptin orphanin fq and the opioid receptor like orl1 receptor
European Journal of Pharmacology, 1997Co-Authors: Jean-claude MeunierAbstract:Abstract Homology cloning and, more recently, the sequencing of whole genomes, have identified many open reading frames encoding proteins of unknown function, in particular putative G protein-coupled membrane receptors. Identification of orphan receptors in this way has marked the advent of `Reverse Pharmacology' to identify the corresponding physiological ligands. This approach has led to the discovery of the ORL1 (Opioid Receptor-Like 1) receptor, and of its natural ligand, nociceptin/orphanin FQ (noc/oFQ), the basic components of a new peptide-based signalling pathway in the nervous sytem. Based on genetic criteria, the ORL1 and opioid receptors belong to the same family, as do noc/oFQ and opioid peptides. The marked structural analogy between the ORL1 and opioid receptors, especially the κ-opioid receptor, and the noc/oFQ and opioid peptides, particularly dynorphin A, is not reflected anatomically since noc/oFQ and opioid peptides appear to be located in separate neuronal circuits. Noc/oFQ triggers the same G protein-mediated signalling pathways as do opioids, however, to produce pharmacological effects that sometimes differ from, and even oppose, those of opioids. Noc/oFQ stimulates an outward K+ current and/or inhibits voltage-gated Ca2+ channels, thereby reducing synaptic efficacy, i.e. neuronal activity. In the rat, noc/oFQ is endowed with supraspinal pronociceptive/anti-opioid properties (it suppresses opioid-mediated analgesia), while convergent electrophysiological and behavioural data indicate that the peptide is a spinal analgesic. Noc/oFQ has not yet been found to precipitate withdrawal in morphine-tolerant rats. Nor does it elicit motivational effects, suggesting it lacks abuse liability. Also, by acting supraspinally, noc/oFQ impairs motor performance, suppresses spatial learning, induces feeding, and regulates basal and stress-induced release of pituitary hormones. Noc/oFQ is also active when administered intravenously, exhibiting potent smooth muscle relaxant, diuretic, and antinatriuretic properties. Last but not least, noc/oFQ appears to regulate stimulated immune function, and to be involved in neuronal differentiation. The discovery of noc/oFQ, a neuropeptide with multiple functions, will certainly improve our knowledge of brain physiology, and may find therapeutic applications, for example in the management of pain or hyponatremic and water-retaining diseases. However, given the wide distribution of noc/oFQ and its receptor, the pharmacological profile of noc/oFQ is likely to be incomplete, and other as yet unknown functions of the peptide remain to be discovered. Most helpful in this respect will be the identification of new ligands of the ORL1 receptor, particularly antagonists. If research on noc/oFQ carries on unabated at the present pace, potentially clinically interesting new compounds could become available in the not too distant future.
