RESUMEN
We define a me-too drug as a pharmacologically active compound that is structurally related to a first-in-class compound, regarded as belonging to the same therapeutic class as the original compound, and used for the same therapeutic purposes, but which may differ in some respects, such as specificity of pharmacological action, adverse reactions profile, or drug-drug interactions. We also offer definitions of related terms, including follow-on drug and first-in-class. The therapeutic advantages of me-too drugs may include improved target specificity, reduced risks of off-target adverse reactions and drug-drug interactions, increased chance of benefit in some patients, and improved drug delivery and pharmacokinetics. Me-too drugs can also demonstrate incremental innovation. Their availability may help in coping with drug shortages. However, they may occasionally cause unexpected adverse reactions that are not class effects. Tricyclic antidepressants, ß-blockers, and statins illustrate the diversity of me-too drugs. Earlier compounds may be as effective as later ones, or more so. Tricyclic antidepressants have similar chemical structures, and compounds introduced after the first-in-class compound (imipramine) mostly offered little in the way of innovative features, but continue to be prescribed. In contrast, me-too ß-blockers introduced after the first-in-class compound, pronethalol, have diverse structures and display several innovative features. Stereoisomers and biosimilars/biobetters provide special examples of me-too drugs. Although many me-too drugs offer no significant advantages over their predecessors, over 60% of the drugs listed on the World Health Organization's essential list are me-toos. Different countries may choose different me-too drugs when constructing essential medicines lists, partly explaining transnational differences between them.
Asunto(s)
Biosimilares Farmacéuticos , Medicamentos Esenciales , Preparaciones Farmacéuticas , Interacciones Farmacológicas , HumanosRESUMEN
We have reviewed pharmaceutical advertisements in every available issue of the British Medical Journal (BMJ) in 12-month periods during 1955/6, 1965/6, 1975/6, and 1985/6. We have determined the amount of advertising, the therapeutic areas covered, and whether adverts reflected the large number of New Chemical Entities (NCEs) launched during that time. For each product we recorded the therapeutic indications, the marketing company, and the number of adverts appearing. The total number of products advertised fell from 340 in 1955/6 to 260 in 1965/6, 70 in 1975/6, and 16 in 1985/6. Advertisement numbers and companies advertising also fell. Antimicrobial drugs and cardiovascular drugs were the top products advertised over the 30 years, with respiratory, analgesic, and gastrointestinal drugs also in the top five. The number of different drugs advertised by individual companies fell from around eight per company in 1955/6 to one or two in 1985/6. There was good concordance between the most advertised therapeutic areas and NCEs entering the market. From the 1950s to the 1980s prescribers were extensively informed about pharmacological advances in therapeutics through BMJ advertisements. Many novel drugs that were advertised proved to be of lasting value. The Medicines Act 1968 introduced product licensing, regulations requiring demonstration of quality, efficacy, and safety, and restrictions on advertising. Subsequently many companies reduced their advertising or stopped altogether. Since advertising influences prescribing, and since antimicrobial drugs were the most commonly advertised products during 1955-86, we speculate that advertising, resulting in excess use, may have, at least partly, driven bacterial drug resistance.
Asunto(s)
Publicidad/historia , Antiinfecciosos/economía , Industria Farmacéutica/economía , Publicaciones Periódicas como Asunto/historia , Publicidad/métodos , Publicidad/estadística & datos numéricos , Antiinfecciosos/historia , Antiinfecciosos/farmacología , Antiinfecciosos/uso terapéutico , Industria Farmacéutica/historia , Prescripciones de Medicamentos/historia , Prescripciones de Medicamentos/estadística & datos numéricos , Farmacorresistencia Bacteriana , Historia del Siglo XX , Humanos , Prescripción Inadecuada/efectos adversos , Prescripción Inadecuada/historia , Difusión de la Información/historia , Difusión de la Información/métodos , Publicaciones Periódicas como Asunto/estadística & datos numéricos , Médicos/estadística & datos numéricos , Medicamentos bajo Prescripción/economía , Medicamentos bajo Prescripción/historia , Medicamentos bajo Prescripción/farmacología , Medicamentos bajo Prescripción/uso terapéutico , Reino UnidoRESUMEN
Nitrones (e.g. α-phenyl-N-tert-butyl nitrone; PBN) are cerebroprotective in experimental stroke. Free radical trapping is their proposed mechanism. As PBN has low radical trapping potency, we tested Sgk1 induction as another possible mechanism. PBN was injected (100 mg/kg, i.p.) into adult male rats and mice. Sgk1 was quantified in cerebral tissue by microarray, quantitative RT-PCR and western analyses. Sgk1+/+ and Sgk1-/- mice were randomized to receive PBN or saline immediately following transient (60 min) occlusion of the middle cerebral artery. Neurological deficit was measured at 24 h and 48 h and infarct volume at 48 h post-occlusion. Following systemic PBN administration, rapid induction of Sgk1 was detected by microarray (at 4 h) and confirmed by RT-PCR and phosphorylation of the Sgk1-specific substrate NDRG1 (at 6 h). PBN-treated Sgk1+/+ mice had lower neurological deficit ( p < 0.01) and infarct volume ( p < 0.01) than saline-treated Sgk1+/+ mice. PBN-treated Sgk1-/- mice did not differ from saline-treated Sgk1-/- mice. Saline-treated Sgk1-/- and Sgk1+/+ mice did not differ. Brain Sgk3:Sgk1 mRNA ratio was 1.0:10.6 in Sgk1+/+ mice. Sgk3 was not augmented in Sgk1-/- mice. We conclude that acute systemic treatment with PBN induces Sgk1 in brain tissue. Sgk1 may play a part in PBN-dependent actions in acute brain ischemia.
Asunto(s)
Óxidos N-Cíclicos/uso terapéutico , Proteínas Inmediatas-Precoces/efectos de los fármacos , Proteínas Serina-Treonina Quinasas/efectos de los fármacos , Animales , Encéfalo/metabolismo , Isquemia Encefálica/tratamiento farmacológico , Óxidos N-Cíclicos/farmacología , Proteínas Inmediatas-Precoces/genética , Proteínas Inmediatas-Precoces/farmacología , Infarto de la Arteria Cerebral Media/tratamiento farmacológico , Masculino , Ratones , Ratones Noqueados , Óxidos de Nitrógeno/farmacología , Óxidos de Nitrógeno/uso terapéutico , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Serina-Treonina Quinasas/farmacología , Ratas , Accidente Cerebrovascular/tratamiento farmacológico , Activación Transcripcional/efectos de los fármacosRESUMEN
BACKGROUND: Many modern pharmaceutical products were launched during 1950-1980, as reflected in advertisements in the British Medical Journal ( BMJ). One of the first therapeutic areas to benefit from novel effective medications was psychiatry. METHODS: We examined BMJ advertising material between 1950 and 1980, including every other issue over six-month periods (October-March) in 1950/1951, 1955/1956, 1957/1958, 1960/1961, 1962/1963, 1965/1966, 1967/1968, 1970/1971, 1972/1973, 1975/1976, 1980/1981. We recorded numbers of adverts for all pharmaceutical products and for psychiatric drugs; we also recorded trade names, generic names and marketing company. RESULTS: Advertising in BMJ peaked in the 1960s and declined markedly in the 1970s. Adverts for psychiatric drugs as a percentage of total pharmaceutical product advertising was broadly similar during 1955-1980, but with peaks in 1960/1961, 1970/1971 and 1975/1976, reflecting the entry of several novel compounds into the market. The peak marketing of antipsychotic drugs, sedatives and anxiolytic drugs was in 1960 and of antidepressants 1970. The time course of the rise of tricyclics and the switch from barbiturates to benzodiazepines can be seen. Drugs for psychiatry rose from ninth (1955/1956) to fourth (1975/1976) in terms of the number of products in the top 10 therapeutic areas. There is no evidence that they were advertised more aggressively (number of adverts/number of products). CONCLUSIONS: The birth of modern psychopharmacology is reflected in th e advertising of psychiatric drugs in BMJ. Many drugs currently used, or their closely related successors, were launched in the early to mid-1960s. This rise in modern pharmaceuticals preceded several other major therapeutic areas.
Asunto(s)
Publicidad/estadística & datos numéricos , Publicaciones Periódicas como Asunto/estadística & datos numéricos , Psicotrópicos , Publicidad/historia , Historia del Siglo XX , Humanos , Publicaciones Periódicas como Asunto/historia , Psicofarmacología/historia , Reino UnidoRESUMEN
AIMS: To examine how pharmaceutical products that were first marketed between 1950 and 1980 were promoted to physicians through advertisements and briefly review advertising regulations and accuracy of the advertisements in the light of modern knowledge. METHODS: We systematically reviewed advertisements promoting drugs for specific therapeutic areas, namely central nervous system disorders (anxiety and sleep disorders, depression, psychoses, and Parkinson's disease), respiratory disorders, cardiovascular disorders, and gastrointestinal disorders. We examined about 800 issues of the British Medical Journal (1950-1980) and about 150 issues of World Medicine (1965-1984). RESULTS: Advertising material was minimally regulated until the mid-1970s. Many drugs were marketed with little preclinical or clinical knowledge and some with the expectation that prescribers would obtain further data. The peak of advertising occurred in parallel with the surge in the release of novel drugs during the 1960s, but declined markedly after the mid-1970s. Advertisements generally contained little useful prescribing information. The period we investigated saw the release of many novel pharmaceuticals in the therapeutic areas we examined, and many (or their class successors) still play important therapeutic roles, including benzodiazepines, tricyclic antidepressants, phenothiazines, levodopa, selective and non-selective ß-adrenoceptor antagonists, thiazide diuretics, ß-adrenoceptor agonists, and histamine H2 receptor antagonists. CONCLUSIONS: Advertising pharmaceuticals in the BMJ and World Medicine in 1950-1980 was poorly regulated and often lacked rigour. However, advertisements were gradually modified in the light of increasing clinical pharmacological knowledge, and they reflect an exciting period for the introduction of many drugs that continue to be of benefit today.
Asunto(s)
Publicidad/historia , Industria Farmacéutica/economía , Comercialización de los Servicios de Salud/historia , Publicaciones Periódicas como Asunto/historia , Publicidad/economía , Publicidad/legislación & jurisprudencia , Publicidad/tendencias , Desarrollo de Medicamentos/economía , Descubrimiento de Drogas/economía , Historia del Siglo XX , Humanos , Comercialización de los Servicios de Salud/legislación & jurisprudencia , Comercialización de los Servicios de Salud/tendencias , Publicaciones Periódicas como Asunto/economía , Publicaciones Periódicas como Asunto/legislación & jurisprudencia , Publicaciones Periódicas como Asunto/tendencias , Farmacología Clínica , Reino UnidoRESUMEN
Administration of caffeine with 3,4-methylenedioxymethamphetamine (MDMA) alters the pharmacological properties of MDMA in rats. The current study examined whether caffeine alters the behavioural and neurochemical effects of mephedrone, which has similar psychoactive effects to MDMA. Rats received either saline, mephedrone (10 mg/kg), caffeine (10 mg/kg) or combined caffeine and mephedrone intraperitoneally twice weekly on consecutive days for three weeks. Locomotor activity (days 1 and 16), novel object discrimination (NOD, day 2), elevated plus maze (EPM) exploration (day 8), rectal temperature changes (day 9) and pre-pulse inhibition (PPI) of acoustic startle response (day 15) were assessed. Seven days after the final injection, brain regions were collected for the measurement of 5-hydroxytryptamine (5-HT), dopamine and their metabolites. Combined caffeine and mephedrone further enhanced the locomotor response observed following either drug administered alone, and converted mephedrone-induced hypothermia to hyperthermia. Co-administration also abolished mephedrone-induced anxiogenic response on the EPM, but had no effect on NOD or PPI. Importantly, no long-term neurotoxicity was detected following repeated mephedrone alone or when co-administered with caffeine. In conclusion, the study suggests a potentially dangerous effect of concomitant caffeine and mephedrone, and highlights the importance of taking polydrug use into consideration when investigating the acute adverse effect profile of popular recreational drugs.
Asunto(s)
Conducta Animal/efectos de los fármacos , Temperatura Corporal/efectos de los fármacos , Cafeína/administración & dosificación , Metanfetamina/análogos & derivados , Síndromes de Neurotoxicidad/etiología , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Discriminación en Psicología/efectos de los fármacos , Dopamina/farmacología , Fiebre/inducido químicamente , Fiebre/metabolismo , Hipotermia/inducido químicamente , Hipotermia/metabolismo , Drogas Ilícitas/farmacología , Locomoción/efectos de los fármacos , Masculino , Metanfetamina/farmacología , N-Metil-3,4-metilenodioxianfetamina/farmacología , Ratas , Reflejo de Sobresalto/efectos de los fármacos , Serotonina/metabolismoRESUMEN
The psychoactive effects of mephedrone are commonly compared with those of 3,4-methylenedioxymethamphetamine, but because of a shorter duration of action, users often employ repeated administration to maintain its psychoactive effects. This study examined the effects of repeated mephedrone administration on locomotor activity, body temperature and striatal dopamine and 5-hydroxytryptamine (5-HT) levels and the role of dopaminergic and serotonergic neurons in these responses. Adult male Lister hooded rats received three injections of vehicle (1 ml/kg, i.p.) or mephedrone HCl (10 mg/kg) at 2 h intervals for radiotelemetry (temperature and activity) or microdialysis (dopamine and 5-HT) measurements. Intracerebroventricular pre-treatment (21 to 28 days earlier) with 5,7-dihydroxytryptamine (150 µg) or 6-hydroxydopamine (300 µg) was used to examine the impact of 5-HT or dopamine depletion on mephedrone-induced changes in temperature and activity. A final study examined the influence of i.p. pre-treatment (-30 min) with the 5-HT1A receptor antagonist WAY-100635 (0.5 mg/kg), 5-HT1B receptor antagonist GR 127935 (3 mg/kg) or the 5-HT7 receptor antagonist SB-258719 (10 mg/kg) on mephedrone-induced changes in locomotor activity and rectal temperature. Mephedrone caused rapid-onset hyperactivity, hypothermia (attenuated on repeat dosing) and increased striatal dopamine and 5-HT release following each injection. Mephedrone-induced hyperactivity was attenuated by 5-HT depletion and 5-HT1B receptor antagonism, whereas the hypothermia was completely abolished by 5-HT depletion and lessened by 5-HT1A receptor antagonism. These findings suggest that stimulation of central 5-HT release and/or inhibition of 5-HT reuptake play a pivotal role in both the hyperlocomotor and hypothermic effects of mephedrone, which are mediated in part via 5-HT1B and 5-HT1A receptors.
Asunto(s)
Temperatura Corporal/efectos de los fármacos , Dopaminérgicos/farmacología , Locomoción/efectos de los fármacos , Metanfetamina/análogos & derivados , Antagonistas de la Serotonina/farmacología , 5,7-Dihidroxitriptamina , Adrenérgicos/farmacología , Análisis de Varianza , Animales , Dopamina/metabolismo , Dopamina/fisiología , Dopaminérgicos/administración & dosificación , Hipercinesia/inducido químicamente , Hipotermia/inducido químicamente , Masculino , Metanfetamina/administración & dosificación , Metanfetamina/farmacología , Neurotoxinas/farmacología , Oxidopamina/farmacología , Ratas , Serotonina/metabolismo , Serotonina/fisiología , Serotoninérgicos/farmacología , Antagonistas de la Serotonina/administración & dosificaciónRESUMEN
The blood-brain barrier (BBB) is essential in the maintenance of brain homeostasis both by preserving normal brain functioning and also by protecting the brain from exposure to a range of potentially harmful substances. This review presents some of the evidence of BBB disruption following exposure to the substituted amphetamines 3,4-methylenedioxymethamphetamine (MDMA, 'ecstasy') and methamphetamine (METH), two drugs of abuse which are widely consumed recreationally by younger sectors of the population. Both MDMA and METH have been shown to produce disruption of the BBB as reflected by IgG extravasation and Evans Blue leakage. In particular, METH decreases the expression of basal lamina proteins associated with an increase in matrix metalloproteinase activity. These changes in BBB integrity appear to be related to MDMA-induced activation of the mitogen-activated protein kinase (MAPK) JNK1/2. The consequences of the disruption in the BBB by these two drugs remain to be established, but there is evidence in the literature that, at least in the case of METH, increased matrix metalloproteinase (MMP) activity may be related to increased behavioural sensitization and reward perhaps because of the modification of the passage of the drug into the CNS. In addition, the high incidence of AIDS-related neurologic disease in METH users may also be related to increased entry into the brain of virally derived neurotoxic products. This article is part of the Special Issue entitled 'CNS Stimulants'.
Asunto(s)
Barrera Hematoencefálica/efectos de los fármacos , Encéfalo/efectos de los fármacos , Estimulantes del Sistema Nervioso Central/farmacología , Metanfetamina/farmacología , N-Metil-3,4-metilenodioxianfetamina/farmacología , Neuroinmunomodulación/efectos de los fármacos , Animales , Barrera Hematoencefálica/metabolismo , Encéfalo/metabolismo , Permeabilidad Capilar/efectos de los fármacos , Permeabilidad Capilar/fisiología , Neuroinmunomodulación/fisiologíaRESUMEN
Despite the publication of a substantial body of preclinical and clinical information on recent recreational drugs such as 3,4-methylenedioxymethamphetamine (MDMA, 'ecstasy') and cathinone compounds such as mephedrone there remains a disturbing lack of consensus as to how dangerous these compounds are to the health of the individual and to society in general. This perspective proposes that use of good pharmacological practice should be mandatory in all preclinical and clinical studies. Its use will assist both translation and reverse translation of information produced in animals and clinical subjects. We propose several basic rules to be followed in all future studies. Preclinical studies should employ pharmacokinetic-pharmacodynamic integration thereby exposing animals to known or calculable drug concentrations. This will provide results relevant to pharmacology rather than toxicology and, crucially, data relevant to human drug use. Full experimental detail should be routinely provided, to allow comparison with other similar work. In clinical studies evidence should be provided that the drug under investigation has been ingested by the subjects being examined, and details given of all other drugs being ingested. Drug-drug interactions are an unavoidable confound but studies of a size that allows reliable statistical evaluation and preferably allows sub-group analysis, particularly by using meta-analysis, should help with this problem. This may require greater collaboration between investigative groups, as routinely occurs during pharmaceutical clinical trials. Other proposals include greater integration of preclinical and clinical scientists in both preclinical and clinical studies and changes in the law regarding Good Manufacturing Process (GMP) sourcing of drug for human studies.
Asunto(s)
Ensayos Clínicos como Asunto/métodos , Evaluación Preclínica de Medicamentos/métodos , Drogas Ilícitas/farmacología , Drogas Ilícitas/farmacocinética , Animales , Interacciones Farmacológicas , HumanosRESUMEN
The Serotonin Club celebrated its silver jubilee in 2012 with a meeting in Montpellier, France. During the past 25 years, great advances have been made in our understanding of the pharmacology of serotonin receptors and the roles of this neurotransmitter in psychiatric disorders. Most of these advances have involved effective collaborations between academic and industrial scientists. In recent years, however, this picture has changed, as many of the major pharmaceutical companies have pulled out of in-house psychopharmacology research into the major psychiatric disorders, despite an increasing worldwide burden of these disorders and a clear need for improved treatment, particularly in terms of improved efficacy. This Viewpoint investigates the reasons for the decline in industrial involvement and makes proposals as to how future academic research on serotonin function in the brain might reawaken industry interest in serotonin-based research. Briefly, academic preclinical scientists need to alter their experimental approach to research into the psychiatric disorders. This will require a move from a single-target approach to understanding the complex neuronal pathways the cause diverse functional and behavioral outputs, using novel technological advances and the development of animal models with enhanced translational values. It is hoped that such an approach will reveal novel drug targets and thus re-engage the pharmaceutical industry in research that will result in improved human health and social well-being.
Asunto(s)
Investigación Biomédica/organización & administración , Industria Farmacéutica/organización & administración , Trastornos Mentales/tratamiento farmacológico , Serotonina/fisiología , Animales , Investigación Biomédica/economía , Modelos Animales de Enfermedad , Descubrimiento de Drogas , Evaluación de Medicamentos/economía , Industria Farmacéutica/economía , Humanos , Relaciones Interprofesionales , Receptores de Serotonina/fisiología , Apoyo a la Investigación como Asunto , Antagonistas de la Serotonina/uso terapéutico , Inhibidores Selectivos de la Recaptación de Serotonina/uso terapéuticoRESUMEN
Historically, much drug discovery and development in psychopharmacology tended to be empirical. However, over the last 20 years it has primarily been target oriented, with synthesis and selection of compounds designed to act at a specific neurochemical site. Such compounds are then examined in functional animal models of disease. There is little evidence that this approach (which we call 'targetophilia') has enhanced the discovery process and some indications that it may have retarded it. A major problem is the weakness of many animal models in mimicking the disease and the lack of appropriate biochemical markers of drug action in animals and patients. In this review we argue that preclinical studies should be conducted as if they were clinical studies in design, analysis, and reporting, and that clinical pharmacologists should be involved at the earliest stages, to help ensure that animal models reflect as closely as possible the clinical disease. In addition, their familiarity with pharmacokinetic-pharmacodynamic integration (PK-PD) would help ensure that appropriate dosing and drug measurement techniques are applied to the discovery process, thereby producing results with relevance to therapeutics. Better integration of experimental and clinical pharmacologists early in the discovery process would allow observations in animals and patients to be quickly exchanged between the two disciplines. This non-linear approach to discovery used to be the way research proceeded, and it resulted in productivity that has never been bettered. It also follows that occasionally 'look-see' studies, a proven technique for drug discovery, deserve to be reintroduced.
Asunto(s)
Diseño de Fármacos , Evaluación Preclínica de Medicamentos/métodos , Neurofarmacología/métodos , Preparaciones Farmacéuticas/administración & dosificación , Ensayos Clínicos como Asunto , Evaluación Preclínica de Medicamentos/normas , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Humanos , Modelos Animales , Neurofarmacología/normasRESUMEN
RATIONALE: 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) produces an acute release of 5-HT in the brain, together with increased locomotion and hyperthermia. OBJECTIVE: This study examined whether the acute functional changes of locomotor activity and body temperature are related to enhanced 5-HT release induced by MDMA. METHODS: We concomitantly measured changes in extraneuronal 5-HT by in vivo brain microdialysis and used radiotelemetry to measure locomotion and body temperature to establish whether any positive correlations occur between these three parameters. 'Binge-type' repeated administration of low doses of MDMA (3 and 6 mg/kg given at 2-h intervals three times) were given to provide drug exposure similar to that experienced by recreational drug users. RESULTS: MDMA induced acute hyperactivity, changes in core body temperature (both hypothermia and hyperthermia) and elevation of hippocampal 5-HT overflow, all of which were dependent on the dose of MDMA administered. The change in locomotor activity and the magnitude of the hyperthermia appeared to be unrelated both to each other and to the magnitude of MDMA-induced 5-HT release. The study also found evidence of long-term disruption of novel object discrimination 2 weeks following "binge-type" repeated MDMA administration. CONCLUSIONS: MDMA-induced 5-HT release in the brain was not responsible for either the hyperthermia or increased locomotor activity that occurred. Since neither dose schedule of MDMA induced a neurotoxic loss of brain 5-HT 2 weeks after its administration, the impairment of recognition memory found in novel object discrimination probably results from other long-term changes yet to be established.
Asunto(s)
Locomoción/efectos de los fármacos , N-Metil-3,4-metilenodioxianfetamina/farmacología , Serotoninérgicos/farmacología , Animales , Temperatura Corporal/efectos de los fármacos , Aprendizaje Discriminativo/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Fiebre/inducido químicamente , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Masculino , Microdiálisis , N-Metil-3,4-metilenodioxianfetamina/administración & dosificación , Ratas , Serotonina/metabolismo , Serotoninérgicos/administración & dosificación , Telemetría/métodosRESUMEN
INTRODUCTION: It has become apparent in recent years that there is a need for a substantial improvement in the processes used to clarify the inter-relationships between a compound's pharmacokinetic (PK) characteristics, its target actions and its safety profile. This is particularly challenging because most of the techniques currently used to obtain meaningful data involve low efficiency animal studies. To maximize the value of such in vivo studies, time and resources need to be better utilized. One way of making major advances is to adopt an integrative approach to designing and analysing in vivo pharmacodynamic (PD) studies. In this paper we address experimental design issues related to maximizing the information content about target engagement. Refined integration of PK and PD (known as 'quantitative pharmacology' or a PKPD approach) is advocated, enabling clarification of the interdependence of a drug's pharmacological properties on its target physiological system(s) and its systemic exposure characteristics. METHODS: Several in vivo pharmacological Case Studies are presented which are used to illustrate the discussion of issues of experimental design. The impact of rate, extent and mode of administration is discussed from a pharmacological viewpoint, and we examine the consequences of temporal differences between concentration and response from the perspective of experimental design. We also consider the importance of differences in plasma protein binding (PPB) on our ability to assess a pharmacodynamic property or safety margin, and examine the usefulness of measuring ex vivo PPB. Finally, we outline the value of implementing a clearly pre-determined, integrated work flow to generate, validate and maximize in vivo PKPD or preclinical disease model data, and summarize the key issues of experimental design. RESULTS AND DISCUSSION: Quantitative pharmacological reasoning focuses on concentration-response and response-time relationships with special emphasis on the impact of drugs on disease (Levy, 1993) and this perspective was written to raise awareness among in vivo scientists as to why PKPD integration is essential in their studies.
Asunto(s)
Farmacocinética , Farmacología/métodos , Animales , Proteínas Sanguíneas/metabolismo , Humanos , Absorción Intestinal , Preparaciones Farmacéuticas/administración & dosificación , Preparaciones Farmacéuticas/metabolismo , Farmacología/normas , Unión Proteica , Receptores de Droga/efectos de los fármacos , Receptores de Droga/metabolismo , Factores de TiempoAsunto(s)
Alucinógenos/administración & dosificación , Alucinógenos/farmacología , N-Metil-3,4-metilenodioxianfetamina/administración & dosificación , N-Metil-3,4-metilenodioxianfetamina/farmacología , Animales , Relación Dosis-Respuesta a Droga , Alucinógenos/farmacocinética , Humanos , N-Metil-3,4-metilenodioxianfetamina/farmacocinética , Ratas , Especificidad de la EspecieRESUMEN
This special issue of Trends in Pharmacological Sciences devoted to serotonin, or 5-hydroxytryptamine (5-HT), celebrates the 21st anniversary of the Serotonin Club, an event also marked by a major international meeting on serotonin held 17-20 July 2008, in Oxford (U.K.).
Asunto(s)
Serotonina/fisiología , Sociedades Científicas/historia , Australia , Historia del Siglo XX , Receptores de Serotonina/clasificación , Receptores de Serotonina/efectos de los fármacos , Serotoninérgicos/farmacología , Terminología como AsuntoRESUMEN
Disodium 2,4-sulphophenyl-N-tert-butylnitrone (NXY-059) is a novel free radical-trapping compound that is neuroprotective in both rodent and primate models of acute ischaemic stroke. Neuroprotection in vitro by NXY-059 has not been reported previously, and we have now investigated whether such an effect can be detected using a simple cell culture model of neurotoxicity. Neuron-like cells of the neuroblastoma-derived clonal cell line N1E-115 were exposed to the free radical-generating agent sodium nitroprusside (SNP), which produced a concentration-dependent reduction in mitochondrial complex II activity 24 h later (EC(50) approximately 100 micromolar). Cell death induced by SNP (100 micromolar), assessed either by an increased proportion of apoptotic nuclear morphology or by mitochondrial complex II activity, was inhibited by a cocktail of known antioxidants (ascorbate, reduced glutathione, and dithiothreitol, all at 100 micromolar) but not by NXY-059 at a concentration known to be neuroprotective in vivo (300 micromolar). Disodium 2,4-sulphophenyl-N-tert-butylnitrone was also without effect on H(2)O(2)-mediated cytotoxicity. These results support recent data suggesting that in vivo NXY-059 probably acts at the neurovascular unit rather than at an intracellular site as a neuroprotective agent.
Asunto(s)
Apoptosis/efectos de los fármacos , Bencenosulfonatos/farmacología , Depuradores de Radicales Libres/farmacología , Peróxido de Hidrógeno/farmacología , Neuronas/metabolismo , Nitroprusiato/farmacología , Oxidantes/farmacología , Animales , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Núcleo Celular/metabolismo , Núcleo Celular/patología , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Complejo II de Transporte de Electrones/antagonistas & inhibidores , Complejo II de Transporte de Electrones/metabolismo , Ratones , Mitocondrias/metabolismo , Mitocondrias/patología , Neuroblastoma/metabolismo , Neuroblastoma/patología , Neuronas/patología , Primates , Accidente Cerebrovascular/tratamiento farmacológico , Accidente Cerebrovascular/metabolismo , Accidente Cerebrovascular/patologíaRESUMEN
The spin trapping ability of the nitrones 2,4-disulphophenyl-N-tert-butyl nitrone (NXY-059), 2-sulphophenyl-N-tert-butyl nitrone (S-PBN) and alpha-phenyl-N-tert-butyl nitrone (PBN) for both hydroxyl and methanol radicals was investigated using electron paramagnetic resonance (EPR) spectroscopy. The radicals of interest were generated in situ in the spectrometer under constant flow conditions in the presence of each nitrone. The spin adducts formed were detected by EPR spectroscopy. This approach allowed for quantitative comparison of the EPR spectra of the spin adducts of each nitrone. The results obtained showed that NXY-059 trapped a greater number of hydroxyl and methanol radicals than the other two nitrones, under the conditions studied.
Asunto(s)
Antioxidantes/química , Bencenosulfonatos/química , Óxidos N-Cíclicos/química , Radicales Libres/análisis , Detección de Spin , Espectroscopía de Resonancia por Spin del Electrón , Espectroscopía de Resonancia MagnéticaRESUMEN
We tested whether glutamate receptor ligands affect oxygen-glucose deprivation-evoked L-glutamate efflux from adult rat cerebrocortical prisms. The uncompetitive NMDA antagonist AR-R15896AR inhibited efflux (IC50 34 microM, 87% maximal inhibition). AMPA/kainate receptor blockade (NBQX, 100 microM) or Group II metabotropic glutamate receptor activation (DCG-IV, 10 microM) inhibited efflux (41%, 67% respectively) but Group I mGluR blockade (CPCCOEt/MPEP, 10 microM) was without effect. These data support a modulatory effect of glutamate receptors on L-glutamate efflux.
Asunto(s)
Corteza Cerebral/metabolismo , Ácido Glutámico/metabolismo , Inhibición Neural/fisiología , Receptores de Glutamato/fisiología , Animales , Corteza Cerebral/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Antagonistas de Aminoácidos Excitadores/farmacología , Femenino , Glucosa/deficiencia , Hipoxia/metabolismo , Técnicas In Vitro , Inhibición Neural/efectos de los fármacos , Piridinas/farmacología , Quinoxalinas/farmacología , Ratas , Ratas Sprague-Dawley , Factores de TiempoRESUMEN
RATIONALE: Evidence suggests that recreational users of (+/-)3,4-methylenedioxymethamphetamine HCl (MDMA, "ecstasy") have cognitive and behavioral deficits and show increased impulsivity consistent with 5-hydroxytryptamine (5-HT) neurotoxicity. MDMA effects on impulsivity in users are difficult to establish being confounded by polydrug use and individual predisposition to impulsivity or behavioral inhibition. OBJECTIVE: We previously observed a long-term anxiolytic effect of a neurotoxic dose of MDMA on elevated plus maze behavior in Dark Agouti (DA) rats while other strains were reported to show anxiogenesis. We have now examined whether MDMA influences impulsivity producing disinhibited behavior interpretable as anxiolysis. METHODS: Impulsivity was measured using an operant visuospatial discrimination procedure. Male DA rats (n = 24) were trained to lever press for food reward in response to a light-stimulus and subsequently required to withhold responding. Correct responses, premature responses, and response latencies were used as measures of accuracy and impulsivity. Trained rats were administered MDMA (5 mg/kg, i.p. at 3-h intervals to a total of three injections). Performance was measured at 3 h and 7, 27, 49, and 80 days posttreatment. RESULTS: There was a short-term effect of MDMA on the percentage of correct responses at 3 h and day 1 with recovery to control levels by days 7-8 and no significant long-term changes up to day 80. There was no effect of MDMA on premature responses on any of the days measured. MDMA reduced cortical 5-HT content (MDMA 363 +/- 14 ng/g and control 440 +/- 10 ng/g tissue). CONCLUSION: These results suggest that impulsivity may not be directly altered by MDMA despite serotonergic neurotoxicity.
Asunto(s)
Inhibidores de Captación Adrenérgica/toxicidad , Conducta Animal/efectos de los fármacos , Alucinógenos/toxicidad , Conducta Impulsiva , N-Metil-3,4-metilenodioxianfetamina/toxicidad , Animales , Sesgo , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Condicionamiento Operante/efectos de los fármacos , Ácido Hidroxiindolacético/metabolismo , Masculino , Ratas , Tiempo de Reacción/efectos de los fármacos , Serotonina/metabolismo , Factores de TiempoRESUMEN
Acute ischaemic stroke is a major health problem with no effective treatments apart from the thrombolytic recombinant tissue plasminogen activator (rt-PA), which must be given within 3h of stroke onset. However, rt-PA increases the risk of symptomatic intracranial haemorrhage and is administered to <5% of stroke patients. New perfusion-enhancing compounds are in development but the risk:benefit ratio remains to be determined. Many neuroprotective drugs have been studied but all those that reached clinical development have failed to demonstrate efficacy. However, adherence to recently published guidelines on preclinical development has resulted in one novel compound (NXY-059) demonstrating efficacy in a Phase III trial, providing encouragement for the validity of the concept of neuroprotection. There are a variety of new neuroprotective compounds in the early stages of investigation and some could prove clinically effective, provided appropriate preclinical development guidelines are observed.