RESUMEN
Decades of focus on selective ion channel blockade has been dismissed as an effective approach to antiarrhythmic drug development. In that context many older antiarrhythmic drugs lacking ion channel selectivity may serve as tools to explore mixed ion channel blockade producing antiarrhythmic activity. This study investigated the non-clinical electrophysiological and antiarrhythmic actions of bisaramil and penticainide using in vitro and in vivo methods. In isolated cardiac myocytes both drugs directly block sodium currents with IC50 values of 13µM (bisaramil) and 60µM (penticainide). Both drugs reduced heart rate but prolonged the P-R, QRS and Q-T intervals of the ECG (due to sodium and potassium channel blockade) in intact rats. They reduced cardiac conduction velocity in isolated rat hearts, increased the threshold currents for capture and fibrillation (indices of sodium channel blockade) and reduced the maximum following frequency as well as prolonged the effective refractory period (indices of potassium channel blockade) of electrically stimulated rat hearts. Both drugs reduced ventricular arrhythmias and eliminated mortality due to VF in ischemic rat hearts. The index of cardiac electrophysiological balance (iCEB) did not change significantly over the dose range evaluated; however, different drug effects resulted when changes in BP and HR were considered. While bisaramil is a more potent sodium channel blocker compared to penticainide, both produce a spectrum of activity against ventricular arrhythmias due to mixed cardiac ion channel blockade. Antiarrhythmic drugs exhibiting mixed ion channel blockade may serve as tools for development of safer mixed ion channel blocking antiarrhythmic drugs.
Asunto(s)
Antiarrítmicos/farmacología , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Clorobencenos/farmacología , Frecuencia Cardíaca/efectos de los fármacos , Bloqueadores de los Canales de Potasio/farmacología , Propilaminas/farmacología , Piridinas/farmacología , Bloqueadores de los Canales de Sodio/farmacología , Animales , Antiarrítmicos/química , Compuestos Bicíclicos Heterocíclicos con Puentes/química , Células Cultivadas , Clorobencenos/química , Relación Dosis-Respuesta a Droga , Frecuencia Cardíaca/fisiología , Masculino , Técnicas de Cultivo de Órganos , Bloqueadores de los Canales de Potasio/química , Canales de Potasio/fisiología , Propilaminas/química , Piridinas/química , Ratas , Ratas Sprague-Dawley , Bloqueadores de los Canales de Sodio/química , Canales de Sodio/fisiologíaRESUMEN
BACKGROUND: RSD921, the R,R enantiomer of the kappa (k) agonist PD117,302, lacks significant activity on opioid receptors. METHODS: The pharmacological and toxicological actions were studied with reference to cardiovascular, cardiac, antiarrhythmic, toxic and local anaesthetic activity. RESULTS: In rats, dogs and baboons, RSD921 dose-dependently reduced blood pressure and heart rate. In a manner consistent with sodium channel blockade it prolonged the PR and QRS intervals of the ECG. Furthermore, in rats and NHP, RSD921 increased the threshold currents for induction of extra-systoles and ventricular fibrillation (VFt), and prolonged effective refractory period (ERP). In rats, RSD921 was protective against arrhythmias induced by electrical stimulation and coronary artery occlusion. Application of RSD921 to voltage-clamped rat cardiac myocytes blocked sodium currents. RSD921 also blocked transient (ito) and sustained (IKsus) outward potassium currents, albeit with reduced potency relative to sodium current blockade. Sodium channel blockade due to RSD921 in myocytes and isolated hearts was enhanced under ischaemic conditions (low pH and high extracellular potassium concentration). When tested on the cardiac, neuronal and skeletal muscle forms of sodium channels expressed in Xenopus laevis oocytes, RSD921 produced equipotent tonic block of sodium currents, enhanced channel block at reduced pH (6.4) and marked use-dependent block of the cardiac isoform. RSD921 had limited but quantifiable effects in subacute toxicology studies in rats and dogs. Pharmacokinetic analyses were performed in baboons. Plasma concentrations producing cardiac actions in vivo after intravenous administration of RSD921 were similar to the concentrations effective in the in vitro assays utilized. CONCLUSIONS: RSD921 primarily blocks sodium currents, and possesses antiarrhythmic and local anaesthetic activity.
Asunto(s)
Anestésicos Locales/farmacología , Antiarrítmicos/farmacología , Arritmias Cardíacas/prevención & control , Frecuencia Cardíaca/efectos de los fármacos , Miocitos Cardíacos/efectos de los fármacos , Pirroles/farmacología , Bloqueadores de los Canales de Sodio/farmacología , Canales de Sodio/efectos de los fármacos , Tiofenos/farmacología , Potenciales de Acción , Administración Intravenosa , Anestésicos Locales/administración & dosificación , Anestésicos Locales/farmacocinética , Anestésicos Locales/toxicidad , Animales , Antiarrítmicos/administración & dosificación , Antiarrítmicos/farmacocinética , Antiarrítmicos/toxicidad , Antihipertensivos/farmacología , Arritmias Cardíacas/etiología , Arritmias Cardíacas/metabolismo , Arritmias Cardíacas/fisiopatología , Presión Sanguínea/efectos de los fármacos , Modelos Animales de Enfermedad , Perros , Relación Dosis-Respuesta a Droga , Femenino , Cobayas , Humanos , Inyecciones Intradérmicas , Preparación de Corazón Aislado , Masculino , Ratones , Miocitos Cardíacos/metabolismo , Conducción Nerviosa/efectos de los fármacos , Umbral del Dolor/efectos de los fármacos , Papio , Ratas , Ratas Sprague-Dawley , Bloqueadores de los Canales de Sodio/administración & dosificación , Bloqueadores de los Canales de Sodio/farmacocinética , Bloqueadores de los Canales de Sodio/toxicidad , Canales de Sodio/metabolismo , Factores de Tiempo , Xenopus laevisRESUMEN
Safety Pharmacology studies are conducted to characterize the confidence by which biologically active new chemical entities (NCE) may be anticipated as safe. Non-clinical safety pharmacology studies aim to detect and characterize potentially undesirable pharmacodynamic activities using an array of in silico, in vitro and in vivo animal models. While a broad spectrum of methodological innovation and advancement of the science occurs within the Safety Pharmacology Society, the society also focuses on partnerships with health authorities and technology providers and facilitates interaction with organizations of common interest such as pharmacology, physiology, neuroscience, cardiology and toxicology. Education remains a primary emphasis for the society through content derived from regional and annual meetings, webinars and publication of its works it seeks to inform the general scientific and regulatory community. In considering the future of safety pharmacology the society has developed a strategy to successfully navigate forward and not be mired in stagnation of the discipline. Strategy can be defined in numerous ways but generally involves establishing and setting goals, determining what actions are needed to achieve those goals, and mobilizing resources within the society to accomplish the actions. The discipline remains in rapid evolution and its coverage is certain to expand to provide better guidance for more systems in the next few years. This overview from the Safety Pharmacology Society will outline the strategic plan from 2016 to 2018 and beyond and provide insight into the future of the discipline which builds upon a previous strategic plan established in 2009.
Asunto(s)
Evaluación Preclínica de Medicamentos/métodos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/prevención & control , Farmacología/métodos , Sociedades Científicas , Animales , Evaluación Preclínica de Medicamentos/normas , Evaluación Preclínica de Medicamentos/tendencias , Humanos , Farmacología/normas , Farmacología/tendencias , Sociedades Científicas/normas , Sociedades Científicas/tendenciasRESUMEN
Each year the Safety Pharmacology Society (SPS) recognizes an investigator who has had a marked impact upon the discipline. The 2016 recipient of the SPS Distinguished Service Award (DSA) was Dr. Craig R. Hassler. Dr. Hassler is one of the founding members of the SPS and has been actively engaged in physiological research for over 46years. Dr. Hassler delivered a talk entitled "My 43Years at Battelle Memorial Institute" to meeting attendees. In this article an overview is provided of the illustrious career of Dr. Hassler along with an account of the numerous animal models that were developed at Battelle under his guidance over the years.
Asunto(s)
Distinciones y Premios , Movilidad Laboral , Personal de Laboratorio/historia , Farmacología/historia , Sociedades Científicas/historia , Animales , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos/historia , Evaluación Preclínica de Medicamentos/métodos , Historia del Siglo XX , Historia del Siglo XXI , HumanosRESUMEN
Animal models of hematopoietic and gastrointestinal acute radiation syndromes (ARS) have been characterized to develop medical countermeasures. Acute radiation-induced decrease of intestinal absorptive function has been correlated to a decrease in the number of intestinal crypt cells resulting from apoptosis and enterocyte mass reduction. Citrulline, a noncoded amino acid, is produced almost exclusively by the enterocytes of the small intestine. Citrullinemia has been identified as a simple, sensitive and suitable biomarker for radiation-induced injury associated with gastrointestinal ARS (GI-ARS). Here we discuss the effect of radiation on plasma citrulline levels in three different species, C57BL/6 mice, Göttingen minipigs and rhesus nonhuman primates (NHPs), measured by liquid chromatography tandem mass spectrometry (LC-MS/MS). The effects of experimental study conditions such as feeding and anesthesia were also examined on plasma citrulline levels in the NHPs. Both the mice and Göttingen minipigs were partial-body irradiated (PBI) with doses from 13-17 Gy and 8-16 Gy, respectively, whereas NHPs were total-body irradiated (TBI) with doses from 6.72-13 Gy. Blood samples were taken at different time points and plasma citrulline levels were measured in the three species at baseline and after irradiation. Basal plasma citrulline concentrations (mean ± SEM) in mice and minipigs were 57.8 ± 2.8 µM and 63.1 ± 2.1 µM, respectively. NHPs showed a basal plasma citrulline concentration of 32.6 ± 0.7 µM, very similar to that of humans (â¼40 µM). Plasma citrulline progressively decreased after irradiation, reaching nadir values between day 3.5 and 7. The onset of citrulline recovery was observed earlier at lower radiation doses, while only partial citrulline recovery was noted at higher radiation doses in minipigs and NHPs, complete recovery was noted in mice at all doses. Plasma citrulline levels in NHPs anesthetized with ketamine and acepromazine significantly decreased by 35.5% (P = 0.0017), compared to unanesthetized NHPs. In the postprandial state, citrulline concentrations in NHPs were slightly but significantly decreased by 12.2% (P = 0.0287). These results suggest that plasma citrulline is affected by experimental conditions such as anesthesia and feeding.
Asunto(s)
Síndrome de Radiación Aguda/sangre , Citrulina/sangre , Enfermedades Gastrointestinales/sangre , Acepromazina/farmacología , Síndrome de Radiación Aguda/complicaciones , Animales , Biomarcadores/sangre , Citrulinemia/complicaciones , Ingestión de Alimentos , Enfermedades Gastrointestinales/complicaciones , Ketamina/farmacología , Ratones , Especificidad de la Especie , Porcinos , Porcinos EnanosRESUMEN
This study characterized the antiarrhythmic effects of the opioid receptor antagonist naloxone in rats subject to electrically induced and ischemic arrhythmias. Naloxone (2, 8 and 32 µmol/kg/min) was examined on heart rate, blood pressure, and the electrocardiogram (EKG) as well as for effectiveness against arrhythmias produced by occlusion of the left anterior descending coronary artery or electrical stimulation of the left ventricle. Naloxone reduced blood pressure at the highest dose tested while heart rate was dose-dependently reduced. Naloxone dose-dependently prolonged the P-R and QRS intervals and increased the RSh amplitude indicative of effects on cardiac sodium (Na) channels. Naloxone prolonged the Q-T interval suggesting a delay in repolarization. Naloxone effects were comparable to the comparator quinidine. Naloxone (32 µmol/kg/min) reduced ventricular fibrillation (VF) incidence to 38% (from 100% in controls). This same dose significantly increased the threshold for induction of ventricular fibrillation (VFt), prolonged the effective refractory period (ERP) and reduced the maximal following frequency (MFF). The patterns of ECG changes, reduction in ischemic arrhythmia (VF) incidence and changes in electrically induced arrhythmia parameters at high doses of naloxone suggest that it directly blocks cardiac Na and potassium (K) ion channels.
Asunto(s)
Antiarrítmicos/uso terapéutico , Arritmias Cardíacas/tratamiento farmacológico , Naloxona/uso terapéutico , Disfunción Ventricular/tratamiento farmacológico , Animales , Presión Sanguínea/efectos de los fármacos , Vasos Coronarios/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Estimulación Eléctrica , Electrocardiografía/efectos de los fármacos , Frecuencia Cardíaca/efectos de los fármacos , Ventrículos Cardíacos , Masculino , Isquemia Miocárdica/tratamiento farmacológico , Isquemia Miocárdica/fisiopatología , Quinidina/farmacología , Ratas , Ratas Sprague-Dawley , Periodo Refractario Electrofisiológico/efectos de los fármacos , Canales de Sodio/efectos de los fármacos , Fibrilación Ventricular/prevención & controlRESUMEN
Almost uniquely in pharmacology, drug safety assessment is driven by the need for elaboration and validation of methods for detecting drug actions. This is the 9th consecutive year that the Journal of Pharmacological and Toxicological Methods (JPTM) has published themed issues arising from the annual meeting of the Safety Pharmacology Society (SPS). The SPS is now past its 10th year as a distinct (from pharmacology to toxicology) discipline that integrates safety pharmacologists from industry with those in academia and the various global regulatory authorities. The themes of the 2011 meeting were (i) the bridging of safety assessment of a new chemical entity (NCE) between all the parties involved, (ii) applied technologies and (iii) translation. This issue of JPTM reflects these themes. The content is informed by the regulatory guidance documents (S7A and S7B) that apply prior to first in human (FIH) studies, which emphasize the importance of seeking model validation. The manuscripts encompass a broad spectrum of safety pharmacology topics including application of state-of-the-art techniques for study conduct and data processing and evaluation. This includes some exciting novel integrated core battery study designs, refinements in hemodynamic assessment, arrhythmia analysis algorithms, and additionally an overview of safety immunopharmacology, and a brief survey discussing similarities and differences in business models that pharmaceutical companies employ in safety pharmacology, together with SPS recommendations on 'best practice' for the conduct of a non-clinical cardiovascular assessment of a NCE.
Asunto(s)
Evaluación Preclínica de Medicamentos/métodos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Farmacología/métodos , Toxicología/métodos , Animales , Animales de Laboratorio , Evaluación Preclínica de Medicamentos/economía , Industria Farmacéutica/economía , Industria Farmacéutica/organización & administración , Humanos , Modelos Organizacionales , Preparaciones Farmacéuticas/economía , Proyectos de Investigación , Medición de Riesgo/métodos , Sociedades Científicas , Pruebas de Toxicidad/métodosRESUMEN
BACKGROUND AND PURPOSE: JNJ-Q2, a novel broad-spectrum fluoroquinolone with anti-methicillin-resistant Staphylococcus aureus activity, was evaluated in a comprehensive set of non-clinical and clinical cardiovascular safety studies. The effect of JNJ-Q2 on different cardiovascular parameters was compared with that of moxifloxacin, sparfloxacin and ofloxacin. Through comparisons with these well-known fluoroquinolones, the importance of effects on compensatory ion channels to the cardiovascular safety of JNJ-Q2 was investigated. EXPERIMENTAL APPROACH: JNJ-Q2 and comparator fluoroquinolones were evaluated in the following models/test systems: hERG-transfected HEK293 cells sodium channel-transfected CHO cells, guinea pig right atria, arterially perfused rabbit left ventricular wedge preparations and in vivo studies in anaesthetized guinea pigs, anaesthetized and conscious telemetered dogs, and a thorough QT study in humans. KEY RESULTS: The trend for effects of JNJ-Q2 on Tp-Te, QT, QRS and PR intervals in the non-clinical models and the plateau in QTc with increasing plasma concentration in humans are consistent with offsetting sodium and calcium channel activities that were observed in the non-clinical studies. These mixed ion channel activities result in the less pronounced or comparable increase in QTc interval for JNJ-Q2 compared with moxifloxacin and sparfloxacin despite its greater in vitro inhibition of I(Kr). CONCLUSIONS AND IMPLICATIONS: Based on the non-clinical and clinical cardiovascular safety assessment, JNJ-Q2 has a safe cardiovascular profile for administration in humans with comparable or reduced potential to prolong QT intervals, compared with moxifloxacin. The results demonstrate the importance of compensatory sodium and calcium channel activity in offsetting potassium channel activity for compounds with a fluoroquinolone core.
Asunto(s)
Antibacterianos/farmacología , Canales de Calcio/fisiología , Fluoroquinolonas/farmacología , Canales de Potasio/fisiología , Canales de Sodio/fisiología , Animales , Antibacterianos/sangre , Función Atrial/efectos de los fármacos , Presión Sanguínea/efectos de los fármacos , Células CHO , Cricetinae , Cricetulus , Estudios Cruzados , Perros , Método Doble Ciego , Femenino , Fluoroquinolonas/sangre , Cobayas , Células HEK293 , Atrios Cardíacos/efectos de los fármacos , Frecuencia Cardíaca/efectos de los fármacos , Ventrículos Cardíacos/efectos de los fármacos , Humanos , Técnicas In Vitro , Síndrome de QT Prolongado/inducido químicamente , Síndrome de QT Prolongado/fisiopatología , Masculino , Staphylococcus aureus Resistente a Meticilina , Conejos , Función Ventricular/efectos de los fármacosRESUMEN
This issue of the Journal of Pharmacological and Toxicological Methods (JPTM) is themed. It is the eighth in a series, arising from the Annual Safety Pharmacology Society (SPS) meeting. The SPS is now in its 10th year as an independent branch of biological sciences (distinct from pharmacology and toxicology) and is the primary forum for driving advances in safety pharmacology. The theme of the meeting and this journal issue is innovation, and the focus is non-clinical safety assessment of new chemical entity (NCEs). The content is informed by regulatory guidance documents (S7A and S7B) prior to first in human (FIH) studies. The manuscripts cover a broad spectrum of safety pharmacology topics from theory to practice, with interrogation of state-of-the-art techniques, and profiling of methods that are in development for safety assessment. Philosophical and strategic issues are addressed, with consideration of the use of novel methods for population pharmacokinetic (PK) analysis, abuse liability, electrocardiogram (ECG) analysis algorithms, in vitro cardiac slice preparations, human pluripotent stem cells, and a brief discussion regarding the assessment of changes in the QRS complex of the ECG indicative of drug-induced blockade of cardiac sodium channels. Safety pharmacology methods continue to evolve.
Asunto(s)
Evaluación Preclínica de Medicamentos/métodos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Evaluación Preclínica de Medicamentos/normas , Humanos , Pruebas de Toxicidad/métodosRESUMEN
The current issue of the Journal of Pharmacological and Toxicological Methods (JPTM) focuses exclusively on safety pharmacology methods. This is the 7th year the Journal has published on this topic. Methods and models that specifically relate to methods relating to the assessment of the safety profile of a new chemical entity (NCE) prior to first in human (FIH) studies are described. Since the Journal started publishing on this topic there has been a major effort by safety pharmacologists, toxicologists and regulatory scientists within Industry (both large and small Pharma as well as Biotechnology companies) and also from Contract Research Organizations (CRO) to publish the surgical details of the non-clinical methods utilized but also provide important details related to standard and non-standard (or integrated) study models and designs. These details from core battery and secondary (or ancillary) drug safety assessment methods used in drug development programs have been the focus of these special issues and have been an attempt to provide validation of methods. Similarly, the safety pharmacology issues of the Journal provide the most relevant forum for scientists to present novel and modified methods with direct applicability to determination of drug safety-directly to the safety pharmacology scientific community. The content of the manuscripts in this issue includes the introduction of additional important surgical methods, novel data capture and data analysis methods, improved study design and effects of positive control compounds with known activity in the model.
Asunto(s)
Evaluación Preclínica de Medicamentos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Proyectos de Investigación , Animales , Biotecnología , Interpretación Estadística de Datos , Humanos , Preparaciones Farmacéuticas , Estudios de Validación como AsuntoRESUMEN
Safety Pharmacology is a rapidly developing discipline that uses the basic principles of pharmacology in a regulatory-driven process to generate data to inform risk/benefit assessment. The aim of Safety Pharmacology is to characterize the pharmacodynamic/pharmacokinetic (PK/PD) relationship of a drug's adverse effects using continuously evolving methodology. Unlike toxicology, Safety Pharmacology includes within its remit a regulatory requirement to predict the risk of rare lethal events. This gives Safety Pharmacology its unique character. The key issues for Safety Pharmacology are detection of an adverse effect liability, projection of the data into safety margin calculation and finally clinical safety monitoring. This article sets out to explain the drivers for Safety Pharmacology so that the wider pharmacology community is better placed to understand the discipline. It concludes with a summary of principles that may help inform future resolution of unmet needs (especially establishing model validation for accurate risk assessment). Subsequent articles in this issue of the journal address specific aspects of Safety Pharmacology to explore the issues of model choice, the burden of proof and to highlight areas of intensive activity (such as testing for drug-induced rare event liability, and the challenge of testing the safety of so-called biologics (antibodies, gene therapy and so on.).
Asunto(s)
Control de Medicamentos y Narcóticos/métodos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Farmacología , Animales , Humanos , Modelos Biológicos , FarmacocinéticaRESUMEN
BACKGROUND AND PURPOSE: Whereas some angiotensin II (Ang II) type 1 receptor blockers (ARBs) produce surmountable antagonism of AT(1) receptors, others such as olmesartan and telmisartan display varying degrees of insurmountability. This study compared the molecular interactions of olmesartan and telmisartan with the human AT(1) receptor, using well characterised in vitro methods and model systems. EXPERIMENTAL APPROACH: CHO-K1 cells that stably express human AT(1) receptors (CHO-hAT(1) cells) were used in several pharmacological studies of olmesartan and telmisartan, including direct radioligand binding and inhibition of Ang II-induced inositol phosphate (IP) accumulation. KEY RESULTS: Both ARBs were found to be competitive antagonists that displayed high affinity, slow dissociation, and a high degree of insurmountability for the AT(1) receptor (the latter greater with olmesartan). Their receptor interactions could be described by a two-step process with the initial formation of a loose complex (IR) and subsequent transformation into a tight binding complex (IR*). In washout experiments, [(3)H] telmisartan dissociated from the receptor with a half-life of 29 min and the Ang II-mediated IP accumulation response was 50% maximally restored within 24 min, whereas values for [(3)H] olmesartan were 72 min and 76 min, respectively. CONCLUSIONS AND IMPLICATIONS: The high degree of insurmountability, slow dissociation, and high affinity of olmesartan for its receptor may relate to its ability to stabilise IR* via the carboxyl group of its imidazole core. In comparison, telmisartan displays a less potent interaction with the receptor.
Asunto(s)
Bencimidazoles/metabolismo , Benzoatos/metabolismo , Imidazoles/metabolismo , Receptor de Angiotensina Tipo 1/metabolismo , Tetrazoles/metabolismo , Angiotensina II/química , Angiotensina II/metabolismo , Angiotensina II/farmacología , Bloqueadores del Receptor Tipo 1 de Angiotensina II/química , Bloqueadores del Receptor Tipo 1 de Angiotensina II/metabolismo , Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacología , Animales , Bencimidazoles/química , Bencimidazoles/farmacología , Benzoatos/química , Benzoatos/farmacología , Células CHO , Cricetinae , Cricetulus , Relación Dosis-Respuesta a Droga , Sinergismo Farmacológico , Humanos , Imidazoles/química , Imidazoles/farmacología , Fosfatos de Inositol/metabolismo , Estructura Molecular , Unión Proteica/efectos de los fármacos , Ensayo de Unión Radioligante/métodos , Receptor de Angiotensina Tipo 1/genética , Telmisartán , Tetrazoles/química , Tetrazoles/farmacología , Factores de Tiempo , TritioRESUMEN
Although it seems unlikely, it has only been 20 years since the US Food and Drug Administration (FDA) approved the first recombinant protein as a therapeutic modality. Unbelievably, an average of slightly more than two approvals per year of monoclonal antibodies (MAbs) and other human protein therapeutics has been achieved by this burgeoning industry 43 recombinant protein therapeutics in the two decades since 1982 (see Table 1), and the pace is increasing.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Enfermedades Cardiovasculares/tratamiento farmacológico , Proteínas Recombinantes/uso terapéutico , Anticuerpos Monoclonales/efectos adversos , Biotecnología , Enfermedades Cardiovasculares/inducido químicamente , Aprobación de Drogas , Diseño de Fármacos , Industria Farmacéutica , Humanos , Ingeniería de Proteínas , Proteínas Recombinantes/efectos adversos , Estados Unidos , United States Food and Drug AdministrationRESUMEN
Controlled activation of the complement system is critical to the host-defense response of the immune system. Activated complement is responsible for the stimulation of a localized protective inflammatory response to either invading microorganisms or foreign molecules (toxins). However, the autologous activation of the complement system can have devastating consequences on many organ systems. This review discusses the various pathways involved in the activation of the complement system and the multiple levels of control established within the body to regulate activation. It also focuses on the role of complement activation in cardiovascular disease, especially myocardial ischemia and reperfusion injury as well as in cardiopulmonary bypass procedures. Lastly, this review also provides a comprehensive overview of both biologically derived proteins and chemically developed inhibitors of the complement system that range from those that are currently in the discovery stage to those that are in clinical development as novel therapeutic agents.
Asunto(s)
Enfermedades Cardiovasculares/tratamiento farmacológico , Proteínas Inactivadoras de Complemento/farmacología , Proteínas del Sistema Complemento/fisiología , Animales , Enfermedades Cardiovasculares/metabolismo , Proteínas Inactivadoras de Complemento/uso terapéutico , Complejo de Ataque a Membrana del Sistema Complemento/fisiología , Vía Clásica del Complemento/efectos de los fármacos , Vía Clásica del Complemento/fisiología , Diseño de Fármacos , Humanos , Lectinas/fisiologíaAsunto(s)
Antiarrítmicos/farmacología , Hemodinámica/efectos de los fármacos , Antagonistas de Heparina/farmacología , Protaminas/farmacología , Anestesia , Animales , Presión Sanguínea/efectos de los fármacos , Electrocardiografía/efectos de los fármacos , Frecuencia Cardíaca/efectos de los fármacos , Canales Iónicos/efectos de los fármacos , Lidocaína/farmacología , Masculino , Ratas , Ratas Sprague-DawleyRESUMEN
Immunex has developed and launched etanercept, a soluble TNF receptor (TNFR) fusion protein, for the treatment of rheumatoid arthritis (RA). It has also been developed for various TNF-mediated conditions such as congestive heart failure, endometriosis and multiple sclerosis. Etanercept has been launched as a second-line agent in the US for the treatment of moderate-to-severe RA and can be used in conjunction with methotrexate in patients unresponsive to methotrexate alone. It is also available in the EU. In 2000, it was in phase III trials for psoriatic arthritis and an NDA filing for this indication was expected for the first half of 2001. In July 2001, the sBLA was filed, and in September 2001, the FDA granted the sBLA Priority Review status. As of January 2001, etanercept was in phase III trials for congestive heart failure, with sNDA filing expected in 2002; however, by March 2001, these had been halted, as it did not appear that statistical significance would be reached for the efficacy endpoints. Further data analysis was being undertaken at this time, before a final decision was taken. In April 2001, Merrill Lynch reported that development for this indication was to be halted. Sales for the drugs first full quarter on the market in 1999 were US $59.7 million. By November 1999 the drug had made sales of US $500 million; Immunex expected the drug to generate over US $2 billion in annual sales by 2004. In September 2000, Merrill Lynch reported that if sales of the drug continued at the present rate then it is likely that demand would temporarily outstrip supply in 2001. Resolution of the supply issue was expected by 2002. Also in September 2000, Merrill Lynch lowered their estimate of sales in 2001 from US $1 billion to $927 million. In the long-term, Merrill Lynch believed that the drug has the potential to exceed US $5 billion in sales in the US. In April 2001, Merrill Lynch predicted that etanercept prescribed for RA would generate sales of US $71 in 2002 rising to US $600 million in 2005. In October 2001, Morgani Stanley reported that Enbrel continues to be the primary source of revenue of Immunex (US $198.1 million). It was also reported that if launched for CHF, an estimated peak year revenue was likely to be US $500 million. The company maintains a website containing additional information about etanercept at http://www.enbrelinfo.com.
Asunto(s)
Antirreumáticos/uso terapéutico , Artritis Reumatoide/tratamiento farmacológico , Inmunoglobulina G/uso terapéutico , Receptores del Factor de Necrosis Tumoral/uso terapéutico , Proteínas Recombinantes de Fusión/efectos adversos , Animales , Antirreumáticos/efectos adversos , Antirreumáticos/metabolismo , Antirreumáticos/farmacología , Antirreumáticos/toxicidad , Ensayos Clínicos Fase I como Asunto , Ensayos Clínicos Fase II como Asunto , Ensayos Clínicos Fase III como Asunto , Etanercept , Humanos , Inmunoglobulina G/efectos adversos , Inmunoglobulina G/metabolismo , Inmunoglobulina G/farmacología , Inmunoglobulina G/toxicidad , Receptores del Factor de Necrosis Tumoral/metabolismo , Proteínas Recombinantes de Fusión/síntesis química , Proteínas Recombinantes de Fusión/metabolismo , Proteínas Recombinantes de Fusión/farmacología , Proteínas Recombinantes de Fusión/uso terapéutico , Proteínas Recombinantes de Fusión/toxicidad , Relación Estructura-ActividadRESUMEN
OBJECTIVES: To determine whether the kappa opioid receptor agonist U-50,488H, a benzacetamide derivative of the cyclo-hexane-1,2-diamine analgesics, may be a useful molecular probe to define the structural requirements of this class of drugs for cardiac sodium channel blockade. ANIMALS AND METHODS: The electrophysiological effects of U-50,488H were compared with those of lidocaine, a clinically used class Ib antiarrhythmic agent, in rat heart sodium currents expressed in Xenopus laevis oocytes by using two-electrode voltage clamp. RESULTS: Both U-50,488H and lidocaine produced a concentration-dependent tonic block of sodium current, but U-50,488H was approximately fourfold more potent than lidocaine. Both drugs produced a hyperpolarizing shift in the voltage dependence of sodium channel inactivation and both delayed recovery from inactivation. Both drugs exhibited use-dependent block, but U-50,488H showed a 1.8-fold increase in potency compared with lidocaine at a high frequency of stimulation (30 Hz). CONCLUSIONS: The more potent tonic and use-dependent block of cardiac sodium channels by U-50,488H suggests that structural features of this molecule may provide it with a greater ability to block the channel. An understanding of these structural features may provide information needed in the development of novel arylacetamide-based antiarrhythmic drugs and insight into possible mechanisms describing channel block, resulting in a highly efficacious antiarrhythmic action in the heart.