ABSTRACT
INTRODUCTION: Frontotemporal lobar degeneration (FTLD) is the most common form of dementia for those under 60 years of age. Increasing numbers of therapeutics targeting FTLD syndromes are being developed. METHODS: In March 2018, the Association for Frontotemporal Degeneration convened the Frontotemporal Degeneration Study Group meeting in Washington, DC, to discuss advances in the clinical science of FTLD. RESULTS: Challenges exist for conducting clinical trials in FTLD. Two of the greatest challenges are (1) the heterogeneity of FTLD syndromes leading to difficulties in efficiently measuring treatment effects and (2) the rarity of FTLD disorders leading to recruitment challenges. DISCUSSION: New personalized endpoints that are clinically meaningful to individuals and their families should be developed. Personalized approaches to analyzing MRI data, development of new fluid biomarkers and wearable technologies will help to improve the power to detect treatment effects in FTLD clinical trials and enable new, clinical trial designs, possibly leveraged from the experience of oncology trials. A computational visualization and analysis platform that can support novel analyses of combined clinical, genetic, imaging, biomarker data with other novel modalities will be critical to the success of these endeavors.
Subject(s)
Biomarkers , Clinical Trials as Topic , Frontotemporal Lobar Degeneration/genetics , Magnetic Resonance Imaging , Atrophy , Congresses as Topic , HumansABSTRACT
Biological, genetic, and clinical evidence provide validation for N-type calcium channels (Ca(V)2.2) as therapeutic targets for chronic pain. A state-dependent Ca(V)2.2 inhibitor may provide an improved therapeutic window over ziconotide, the peptidyl Ca(V)2.2 inhibitor used clinically. Supporting this notion, we recently reported that in preclinical models, the state-dependent Ca(V)2 inhibitor (3R)-5-(3-chloro-4-fluorophenyl)-3-methyl-3-(pyrimidin-5-ylmethyl)-1-(1H-1,2,4-triazol-3-yl)-1,3-dihydro-2H-indol-2-one (TROX-1) has an improved therapeutic window compared with ziconotide. Here we characterize TROX-1 inhibition of Cav2.2 channels in more detail. When channels are biased toward open/inactivated states by depolarizing the membrane potential under voltage-clamp electrophysiology, TROX-1 inhibits Ca(V)2.2 channels with an IC(50) of 0.11 µM. The voltage dependence of Ca(V)2.2 inhibition was examined using automated electrophysiology. TROX-1 IC(50) values were 4.2, 0.90, and 0.36 µM at -110, -90, and -70 mV, respectively. TROX-1 displayed use-dependent inhibition of Ca(V)2.2 with a 10-fold IC(50) separation between first (27 µM) and last (2.7 µM) pulses in a train. In a fluorescence-based calcium influx assay, TROX-1 inhibited Ca(V)2.2 channels with an IC(50) of 9.5 µM under hyperpolarized conditions and 0.69 µM under depolarized conditions. Finally, TROX-1 potency was examined across the Ca(V)2 subfamily. Depolarized IC(50) values were 0.29, 0.19, and 0.28 µM by manual electrophysiology using matched conditions and 1.8, 0.69, and 1.1 µM by calcium influx for Ca(V)2.1, Ca(V)2.2, and Ca(V)2.3, respectively. Together, these in vitro data support the idea that a state-dependent, non-subtype-selective Ca(V)2 channel inhibitor can achieve an improved therapeutic window over the relatively state-independent Ca(V)2.2-selective inhibitor ziconotide in preclinical models of chronic pain.
Subject(s)
Calcium Channel Blockers/chemistry , Calcium Channels, N-Type/drug effects , Indoles/chemistry , Triazoles/chemistry , Calcium Channel Blockers/pharmacology , Cell Line , Humans , Indoles/pharmacology , Inhibitory Concentration 50 , Membrane Potentials/drug effects , Patch-Clamp Techniques , Triazoles/pharmacologyABSTRACT
Voltage-gated calcium channel (Ca(v))2.2 (N-type calcium channels) are key components in nociceptive transmission pathways. Ziconotide, a state-independent peptide inhibitor of Ca(v)2.2 channels, is efficacious in treating refractory pain but exhibits a narrow therapeutic window and must be administered intrathecally. We have discovered an N-triazole oxindole, (3R)-5-(3-chloro-4-fluorophenyl)-3-methyl-3-(pyrimidin-5-ylmethyl)-1-(1H-1,2,4-triazol-3-yl)-1,3-dihydro-2H-indol-2-one (TROX-1), as a small-molecule, state-dependent blocker of Ca(v)2 channels, and we investigated the therapeutic advantages of this compound for analgesia. TROX-1 preferentially inhibited potassium-triggered calcium influx through recombinant Ca(v)2.2 channels under depolarized conditions (IC(50) = 0.27 microM) compared with hyperpolarized conditions (IC(50) > 20 microM). In rat dorsal root ganglion (DRG) neurons, TROX-1 inhibited omega-conotoxin GVIA-sensitive calcium currents (Ca(v)2.2 channel currents), with greater potency under depolarized conditions (IC(50) = 0.4 microM) than under hyperpolarized conditions (IC(50) = 2.6 microM), indicating state-dependent Ca(v)2.2 channel block of native as well as recombinant channels. TROX-1 fully blocked calcium influx mediated by a mixture of Ca(v)2 channels in calcium imaging experiments in rat DRG neurons, indicating additional block of all Ca(v)2 family channels. TROX-1 reversed inflammatory-induced hyperalgesia with maximal effects equivalent to nonsteroidal anti-inflammatory drugs, and it reversed nerve injury-induced allodynia to the same extent as pregabalin and duloxetine. In contrast, no significant reversal of hyperalgesia was observed in Ca(v)2.2 gene-deleted mice. Mild impairment of motor function in the Rotarod test and cardiovascular functions were observed at 20- to 40-fold higher plasma concentrations than required for analgesic activities. TROX-1 demonstrates that an orally available state-dependent Ca(v)2 channel blocker may achieve a therapeutic window suitable for the treatment of chronic pain.
Subject(s)
Analgesics/pharmacology , Calcium Channel Blockers/pharmacology , Calcium Channels, N-Type/physiology , Indoles/pharmacology , Triazoles/pharmacology , Analgesics/adverse effects , Analgesics/pharmacokinetics , Animals , Baroreflex/drug effects , Biological Availability , Calcium Channel Blockers/adverse effects , Calcium Channel Blockers/pharmacokinetics , Calcium Channels, N-Type/genetics , Calcium Channels, R-Type/physiology , Cation Transport Proteins/physiology , Cell Line , Dogs , Ganglia, Spinal/drug effects , Ganglia, Spinal/physiology , Hyperalgesia/drug therapy , Hypotension, Orthostatic/chemically induced , Indoles/adverse effects , Indoles/pharmacokinetics , Male , Mice , Mice, Knockout , Neurons/drug effects , Neurons/physiology , Pain/drug therapy , Pain/etiology , Patch-Clamp Techniques , Rats , Rats, Sprague-Dawley , Triazoles/adverse effects , Triazoles/pharmacokineticsABSTRACT
Voltage gated calcium channels (VGCCs) are well established mediators of pain signals in primary afferent neurons. N-type calcium channels are localized to synaptic nerve terminals in laminae 1 and 2 of the dorsal horn where their opening results in the release of neurotransmitters such as glutamate and substance P. The contribution of N-type channels to the processing of pain signals is regulated by alternate splicing of the N-type channel gene, with unique N-type channel splice variants being expressed in small nociceptive neurons. In contrast, T-type VGCCs of the Ca(v)3.2 subtype are likely localized to nerve endings where they regulate cellular excitability. Consequently, inhibition of N-type and Ca(v)3.2 T-type VGCCs has the propensity to mediate analgesia. T-type channel activity is regulated by redox modulation, and can be inhibited by a novel class of small organic blockers. N-type VGCC activity can be potently inhibited by highly selective peptide toxins that are delivered intrathecally, and the search for small organic blockers with clinical efficacy is ongoing. Here, we provide a brief overview of recent advances in this area, as presented at the Spring Pain Research conference (Grand Cayman, 2008).
Subject(s)
Afferent Pathways/metabolism , Calcium Channels/metabolism , Nervous System/metabolism , Nociceptors/metabolism , Pain/metabolism , Sensory Receptor Cells/metabolism , Afferent Pathways/drug effects , Afferent Pathways/physiopathology , Analgesics/chemistry , Analgesics/pharmacology , Animals , Calcium Channels/drug effects , Calcium Channels/genetics , Ganglia, Spinal/drug effects , Ganglia, Spinal/metabolism , Ganglia, Spinal/physiopathology , Humans , Ion Channel Gating/drug effects , Ion Channel Gating/physiology , Nervous System/drug effects , Nervous System/physiopathology , Nociceptors/drug effects , Pain/drug therapy , Pain/physiopathology , Posterior Horn Cells/drug effects , Posterior Horn Cells/metabolism , Posterior Horn Cells/physiopathology , Sensory Receptor Cells/drug effectsABSTRACT
Central Nervous System (CNS) diseases represent one of the most challenging therapeutic areas for successful drug approvals. Developing quantitative biomarkers as Drug Development Tools (DDTs) can catalyze the path to innovative treatments, and improve the chances of drug approvals. Drug development and healthcare management requires sensitive, reliable, validated, and regulatory accepted biomarkers and endpoints. This review highlights the regulatory paths and considerations for developing DDTs required to advance biomarker and endpoint use in clinical development (e.g., consensus CDISC [Clinical Data Interchange Standards Consortium] data standards, precompetitive sharing of anonymized patient-level data, and continual alignment with regulators). Summarized is the current landscape of biomarkers in a range of CNS diseases including Alzheimer disease, Parkinson Disease, Amyotrophic Lateral Sclerosis, Autism Spectrum Disorders, Depression, Huntington's disease, Multiple Sclerosis and Traumatic Brain Injury. Advancing DDTs for these devastating diseases that are both validated and qualified will require an integrated, cross-consortium approach to accelerate the delivery of innovative CNS therapeutics.
Subject(s)
Biomarkers/analysis , Central Nervous System Diseases/drug therapy , Drug Development , Drug Discovery , Central Nervous System Diseases/metabolism , Drug Development/legislation & jurisprudence , Drug Development/methods , Drug Discovery/legislation & jurisprudence , Drug Discovery/methods , Guidelines as Topic , Humans , United States , United States Food and Drug AdministrationABSTRACT
Neuronal nicotinic acetylcholine receptors (nAChRs) have been a target for drug discovery efforts, primarily for CNS indications, for the past two decades. While nicotine and related natural products have been used for smoking cessation in various formulations (e.g., gum, spray, patches), it was only in 2006 with the launch of varenicline (Chantix) by Pfizer for smoking cessation that a new chemical entity (NCE) originating from a rational medicinal chemistry effort targeting neuronal AChRs was approved. The current overview outlines the chronology of drug discovery efforts in nAChRs from the cloning of the receptor family in the 1980s, to initial research efforts at SIBIA, R.J. Reynolds and Abbott, to the current industry-wide interest in nAChR agonists as novel therapeutics for pain, schizophrenia and Alzheimer's Disease. Key events in the evolution of the nAChR field were the development of high throughput electrophysiological screening tools that provided the means to enable lead optimization efforts in medicinal chemistry and the discovery by John Daly at the NIH of the frog alkaloid, epibatidine, that provided the framework for the discovery of ABT-594, an alpha4beta2 agonist that is 200 times more potent than morphine as an analgesic. Over the next decade, it is anticipated that additional NCEs including antagonists and allosteric modulators (both positive and negative), interacting with various nAChR subtypes, will be advanced to the clinic in areas of high unmet medical need, e.g., pain, neurodegeneration, to provide novel medications with improved efficacy.
Subject(s)
Drug Design , Neurons/drug effects , Receptors, Nicotinic/drug effects , Animals , Cognition/drug effects , Drug Industry , Humans , Pain/drug therapy , Schizophrenia/drug therapy , Smoking CessationABSTRACT
INTRODUCTION: Informed consent forms that restrict the distribution of data and samples have been an impediment to advancing Alzheimer's disease (AD) understandings and treatments. The Coalition Against Major Disease public-private partnership developed concise addenda to responsibly broaden data access of informed consent forms. METHODS: Coalition Against Major Disease members identified key elements for ensuring data and biospecimen access, and patient privacy protection according to applicable US law. Collaboration with the Alzheimer's Association established the understandability and relevance of the addenda with AD patients and Care Partners. RESULTS: Two key findings are (1) patients with dementia and Care Partners were shocked that their data and samples are not broadly shared and (2) with diverse feedback, two concise addenda were created to enable data and sample sharing both within and outside future sponsored studies (see Boxes). DISCUSSION: Increasing the access of valuable anonymized patient-level clinical trial data has the potential to inform the foundational and regulatory science required to deliver innovative treatments for AD.
ABSTRACT
INTRODUCTION: The exceedingly high rate of failed trials in Alzheimer's disease (AD) calls for immediate attention to improve efficiencies and learning from past, ongoing, and future trials. Accurate, highly rigorous standardized data are at the core of meaningful scientific research. Data standards allow for proper integration of clinical data sets and represent the essential foundation for regulatory endorsement of drug development tools. Such tools increase the potential for success and accuracy of trial results. METHODS: The development of the Clinical Data Interchange Standards Consortium (CDISC) AD therapeutic area data standard was a comprehensive collaborative effort by CDISC and Coalition Against Major Diseases, a consortium of the Critical Path Institute. Clinical concepts for AD and mild cognitive impairment were defined and a data standards user guide was created from various sources of input, including data dictionaries used in AD clinical trials and observational studies. RESULTS: A comprehensive collection of AD-specific clinical data standards consisting of clinical outcome measures, leading candidate genes, and cerebrospinal fluid and imaging biomarkers was developed. The AD version 2.0 (V2.0) Therapeutic Area User Guide was developed by diverse experts working with data scientists across multiple consortia through a comprehensive review and revision process. The AD CDISC standard is a publicly available resource to facilitate widespread use and implementation. DISCUSSION: The AD CDISC V2.0 data standard serves as a platform to catalyze reproducible research, data integration, and efficiencies in clinical trials. It allows for the mapping and integration of available data and provides a foundation for future studies, data sharing, and long-term registries in AD. The availability of consensus data standards for AD has the potential to facilitate clinical trial initiation and increase sharing and aggregation of data across observational studies and among clinical trials, thereby improving our understanding of disease progression and treatment.
ABSTRACT
Alzheimer's disease (AD) drug development is burdened with the current requirement to conduct large, lengthy, and costly trials to overcome uncertainty in patient progression and effect size on treatment outcome measures. There is an urgent need for the discovery, development, and implementation of novel, objectively measured biomarkers for AD that would aid selection of the appropriate subpopulation of patients in clinical trials, and presumably, improve the likelihood of successfully evaluating innovative treatment options. Amyloid deposition and tau in the brain, which are most commonly assessed either in cerebrospinal fluid (CSF) or by molecular imaging, are consistently and widely accepted. Nonetheless, a clear gap still exists in the accurate identification of subjects that truly have the hallmarks of AD. The Coalition Against Major Diseases (CAMD), one of 12 consortia of the Critical Path Institute (C-Path), aims to streamline drug development for AD and related dementias by advancing regulatory approved drug development tools for clinical trials through precompetitive data sharing and adoption of consensus clinical data standards. This report focuses on the regulatory process for biomarker qualification, briefly comments on how it contrasts with approval or clearance of companion diagnostics, details the qualifications currently available to the field of AD, and highlights the current challenges facing the landscape of CSF biomarkers qualified as hallmarks of AD. Finally, it recommends actions to accelerate regulatory qualification of CSF biomarkers that would, in turn, improve the efficiency of AD therapeutic development.
Subject(s)
Alzheimer Disease/cerebrospinal fluid , Biomarkers/cerebrospinal fluid , Clinical Trials as Topic , Drug Approval , Drug Discovery , HumansABSTRACT
Importance: It is unclear whether female carriers of the apolipoprotein E (APOE) ε4 allele are at greater risk of developing Alzheimer disease (AD) than men, and the sex-dependent association of mild cognitive impairment (MCI) and APOE has not been established. Objective: To determine how sex and APOE genotype affect the risks for developing MCI and AD. Data Sources: Twenty-seven independent research studies in the Global Alzheimer's Association Interactive Network with data on nearly 58â¯000 participants. Study Selection: Non-Hispanic white individuals with clinical diagnostic and APOE genotype data. Data Extraction and Synthesis: Homogeneous data sets were pooled in case-control analyses, and logistic regression models were used to compute risks. Main Outcomes and Measures: Age-adjusted odds ratios (ORs) and 95% confidence intervals for developing MCI and AD were calculated for men and women across APOE genotypes. Results: Participants were men and women between ages 55 and 85 years. Across data sets most participants were white, and for many participants, racial/ethnic information was either not collected or not known. Men (OR, 3.09; 95% CI, 2.79-3.42) and women (OR, 3.31; CI, 3.03-3.61) with the APOE ε3/ε4 genotype from ages 55 to 85 years did not show a difference in AD risk; however, women had an increased risk compared with men between the ages of 65 and 75 years (women, OR, 4.37; 95% CI, 3.82-5.00; men, OR, 3.14; 95% CI, 2.68-3.67; P = .002). Men with APOE ε3/ε4 had an increased risk of AD compared with men with APOE ε3/ε3. The APOE ε2/ε3 genotype conferred a protective effect on women (OR, 0.51; 95% CI, 0.43-0.61) decreasing their risk of AD more (P value = .01) than men (OR, 0.71; 95% CI, 0.60-0.85). There was no difference between men with APOE ε3/ε4 (OR, 1.55; 95% CI, 1.36-1.76) and women (OR, 1.60; 95% CI, 1.43-1.81) in their risk of developing MCI between the ages of 55 and 85 years, but women had an increased risk between 55 and 70 years (women, OR, 1.43; 95% CI, 1.19-1.73; men, OR, 1.07; 95% CI, 0.87-1.30; P = .05). There were no significant differences between men and women in their risks for converting from MCI to AD between the ages of 55 and 85 years. Individuals with APOE ε4/ε4 showed increased risks vs individuals with ε3/ε4, but no significant differences between men and women with ε4/ε4 were seen. Conclusions and Relevance: Contrary to long-standing views, men and women with the APOE ε3/ε4 genotype have nearly the same odds of developing AD from age 55 to 85 years, but women have an increased risk at younger ages.
Subject(s)
Alzheimer Disease/genetics , Apolipoproteins E/genetics , Sex Characteristics , Aged , Aged, 80 and over , Alzheimer Disease/epidemiology , Case-Control Studies , Databases, Factual/statistics & numerical data , Female , Humans , Logistic Models , Male , Middle Aged , Risk FactorsABSTRACT
Several lines of evidence suggest a link between the alpha7 neuronal nicotinic acetylcholine receptor (nAChR) and brain disorders including schizophrenia, Alzheimer's disease, and traumatic brain injury. The present work describes a novel molecule, 1-(5-chloro-2,4-dimethoxy-phenyl)-3-(5-methyl-isoxazol-3-yl)-urea (PNU-120596), which acts as a powerful positive allosteric modulator of the alpha7 nAChR. Discovered in a high-throughput screen, PNU-120596 increased agonist-evoked calcium flux mediated by an engineered variant of the human alpha7 nAChR. Electrophysiology studies confirmed that PNU-120596 increased peak agonist-evoked currents mediated by wild-type receptors and also demonstrated a pronounced prolongation of the evoked response in the continued presence of agonist. In contrast, PNU-120596 produced no detectable change in currents mediated by alpha4beta2, alpha3beta4, and alpha9alpha10 nAChRs. PNU-120596 increased the channel mean open time of alpha7 nAChRs but had no effect on ion selectivity and relatively little, if any, effect on unitary conductance. When applied to acute hippocampal slices, PNU-120596 increased the frequency of ACh-evoked GABAergic postsynaptic currents measured in pyramidal neurons; this effect was suppressed by TTX, suggesting that PNU-120596 modulated the function of alpha7 nAChRs located on the somatodendritic membrane of hippocampal interneurons. Accordingly, PNU-120596 greatly enhanced the ACh-evoked inward currents in these interneurons. Systemic administration of PNU-120596 to rats improved the auditory gating deficit caused by amphetamine, a model proposed to reflect a circuit level disturbance associated with schizophrenia. Together, these results suggest that PNU-120596 represents a new class of molecule that enhances alpha7 nAChR function and thus has the potential to treat psychiatric and neurological disorders.
Subject(s)
Cholinergic Agonists/chemistry , Cholinergic Agonists/pharmacology , Receptors, Nicotinic/metabolism , Acetylcholine/pharmacology , Acoustic Stimulation/methods , Allosteric Regulation , Amphetamine/pharmacology , Animals , Animals, Newborn , Calcium/metabolism , Cell Line , Central Nervous System Stimulants/pharmacology , Cholinergic Antagonists/pharmacology , Dose-Response Relationship, Drug , Drug Interactions , Electric Stimulation/methods , Epithelial Cells/drug effects , Evoked Potentials, Auditory/drug effects , Hippocampus/cytology , Humans , In Vitro Techniques , Isoxazoles/chemistry , Isoxazoles/pharmacology , Male , Membrane Potentials/drug effects , Membrane Potentials/physiology , Membrane Potentials/radiation effects , Microinjections/methods , Neurons/drug effects , Neurons/physiology , Nicotine/pharmacology , Oocytes , Patch-Clamp Techniques/methods , Phenylurea Compounds/chemistry , Phenylurea Compounds/pharmacology , Protein Subunits/physiology , Rats , Rats, Sprague-Dawley , Tetrodotoxin/metabolism , Time Factors , Xenopus , alpha7 Nicotinic Acetylcholine ReceptorABSTRACT
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]furo[2,3-c]pyridine-5-carboxamide (14, PHA-543,613), a novel agonist of the alpha7 neuronal nicotinic acetylcholine receptor (alpha7 nAChR), has been identified as a potential treatment of cognitive deficits in schizophrenia. Compound 14 is a potent and selective alpha7 nAChR agonist with an excellent in vitro profile. The compound is characterized by rapid brain penetration and high oral bioavailability in rat and demonstrates in vivo efficacy in auditory sensory gating and, in an in vivo model to assess cognitive performance, novel object recognition.
Subject(s)
Bridged Bicyclo Compounds, Heterocyclic/chemical synthesis , Cognition Disorders/drug therapy , Nicotinic Agonists/chemical synthesis , Nootropic Agents/chemical synthesis , Quinuclidines/chemical synthesis , Receptors, Nicotinic/metabolism , Schizophrenia/drug therapy , Animals , Biological Availability , Brain/metabolism , Bridged Bicyclo Compounds, Heterocyclic/chemistry , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Drug Stability , Ether-A-Go-Go Potassium Channels/drug effects , Evoked Potentials, Auditory/drug effects , Humans , In Vitro Techniques , Learning/drug effects , Male , Memory/drug effects , Microsomes, Liver/drug effects , Microsomes, Liver/metabolism , Neurons/drug effects , Neurons/physiology , Nicotinic Agonists/pharmacokinetics , Nicotinic Agonists/pharmacology , Nootropic Agents/pharmacokinetics , Nootropic Agents/pharmacology , Patch-Clamp Techniques , Quinuclidines/chemistry , Quinuclidines/pharmacology , Radioligand Assay , Rats , Rats, Sprague-Dawley , Receptors, Nicotinic/physiology , Recognition, Psychology/drug effects , Stereoisomerism , Structure-Activity Relationship , alpha7 Nicotinic Acetylcholine ReceptorABSTRACT
RATIONALE: One of the common neurochemical features of many drugs of abuse is their ability to directly or indirectly enhance dopaminergic activity in the brain, particularly within the ventral tegmental-nucleus accumbens pathway. Dopaminergic pathways in the frontal and limbic cortex also may be targets for these agents, where pharmacological effects could result in heightened attention and/or support self-administration behavior. OBJECTIVES: The purpose of this study was to determine whether drugs from differing pharmacological classes that exhibit abuse potential would share the ability to counter distractability in the delayed matching task. METHODS: Well trained mature macaques performed a computer-assisted delayed matching-to-sample task which included trials associated with three delay intervals and randomly interspersed task-relevant distractors. Drug regimens included four to five doses and subjects were tested no more than twice per week. RESULTS: All but one of the six compounds (tomoxetine), on average, increased task accuracy for either non-distractor or distractor trials. It was evident that for several compounds, doses required to improve accuracy for non-distractor trials were routinely greater than the doses required to improve accuracy for distractor trials. Data for the individualized Best dose (based upon the subject's optimal level of accuracy during distractor trials) revealed statistically significant distractor-related improvements in task accuracy for the same five compounds. The relative efficacy for reversing distractor-induced decrements in task accuracy was estimated by the level of improvement with respect to baseline: nomifensine (31%)>nicotine (22%) approximately morphine (19%) approximately caffeine (19%) approximately methylphenidate (22%) >tomoxetine (9%). Tomoxetine (noradrenergic preferring) was the only compound that did not produce a significant improvement in accuracy. CONCLUSIONS: These results provide pharmacological support for the concept that attentional mechanisms may play an important role in the "environmental" associative aspects of drug seeking behavior, and as such they may provide the basis for treatment strategies aimed at preventing relapse in detoxified addicts.
Subject(s)
Attention/drug effects , Cognition Disorders/chemically induced , Cognition/drug effects , Substance-Related Disorders/psychology , Animals , Atomoxetine Hydrochloride , Attention/physiology , Caffeine/administration & dosage , Caffeine/pharmacokinetics , Cognition/physiology , Color Perception , Female , Macaca mulatta , Macaca nemestrina , Male , Methylphenidate/administration & dosage , Methylphenidate/pharmacokinetics , Morphine/administration & dosage , Morphine/pharmacokinetics , Neuropsychological Tests , Nicotine/administration & dosage , Nicotine/pharmacokinetics , Nomifensine/administration & dosage , Nomifensine/pharmacokinetics , Photic Stimulation , Propylamines/administration & dosage , Propylamines/pharmacokinetics , Task Performance and AnalysisABSTRACT
Chronic pain is increasingly recognized as a disease and accounts for substantial suffering and disability worldwide. The aging 'baby-boomer' generation is creating a tsunami of elderly patients (>65 years old) for global healthcare systems (between 2010 and 2030). The phenotypic expression of chronic pain in the elderly can be influenced by co-morbid diseases (e.g. diabetes, cancer, depression, Alzheimer's disease, etc.), changes in physiological competency (e.g. drug metabolism/elimination) or cognitive reserve. Will a shift in the drug discovery paradigm be required to improve efficacy, side-effects or positively impact quality of life (QoL) in the elderly with chronic pain? This review highlights a number of potential pitfalls that should be considered when delivering valued pain relief medicines tailored for the elderly.
Subject(s)
Chronic Pain/therapy , Life Expectancy/trends , Pain Management/trends , Age Factors , Aged , Analgesics/therapeutic use , Chronic Pain/diagnosis , Chronic Pain/epidemiology , Humans , Pain Management/methods , Treatment OutcomeSubject(s)
Clinical Trials as Topic/instrumentation , Drug Discovery , Monitoring, Physiologic/instrumentation , Clinical Trials as Topic/methods , Computer Communication Networks , Disease Progression , Drug Monitoring/instrumentation , Humans , Monitoring, Physiologic/methods , Patient Compliance , Patient Outcome Assessment , Remote Sensing Technology/instrumentation , Telemetry/instrumentation , Telemetry/methodsABSTRACT
Most cancer patients will experience moderate to severe pain and/or neuropathy during the course of their disease. Recent improvements in the primary treatment of cancer have increased the life span of cancer patients, but not necessarily their quality of life (QoL). The pain and suffering cancer patients experience may be the result of the tumor itself, or the treatments required to arrest tumor growth and progression. In contrast to the rapid, highly mechanistic, tailored medicine approach used to target and treat the primary tumor burden, the evolution of pain and other supportive treatment approaches for cancer patients have been slow to non-existent. A movement is emerging to use more rational mechanistic approaches to the treatment of pain created by cancer and chemotherapeutics. This review briefly describes the most severe and debilitating symptoms (endophenotypes) from the cancer patient's perspective, the biochemical/neurobiological sequalae associated with tumor growth and therapies designed to arrest tumor progression, and highlights some promising pharmacologic mechanisms that may be used to treat cancer-related pain, sensory neuropathies, and associated endophenotypes. Delivering improved broader spectrum supportive care medicines to cancer patients will fill a significant unmet need and enable them to live productive, fulfilling lives that preserve their overall QoL.
Subject(s)
Analgesics/therapeutic use , Neoplasms/drug therapy , Pain/drug therapy , Animals , Humans , Neoplasms/complications , Neoplasms/physiopathology , Neuroglia/physiology , Pain/etiology , Pain/physiopathology , Quality of LifeABSTRACT
Voltage-gated ion channels are implicated in pain sensation and transmission signaling mechanisms within both peripheral nociceptors and the spinal cord. Genetic knockdown and knockout experiments have shown that specific channel isoforms, including Na(V)1.7 and Na(V)1.8 sodium channels and Ca(V)3.2 T-type calcium channels, play distinct pronociceptive roles. We have rationally designed and synthesized a novel small organic compound (Z123212) that modulates both recombinant and native sodium and calcium channel currents by selectively stabilizing channels in their slow-inactivated state. Slow inactivation of voltage-gated channels can function as a brake during periods of neuronal hyperexcitability, and Z123212 was found to reduce the excitability of both peripheral nociceptors and lamina I/II spinal cord neurons in a state-dependent manner. In vivo experiments demonstrate that oral administration of Z123212 is efficacious in reversing thermal hyperalgesia and tactile allodynia in the rat spinal nerve ligation model of neuropathic pain and also produces acute antinociception in the hot-plate test. At therapeutically relevant concentrations, Z123212 did not cause significant motor or cardiovascular adverse effects. Taken together, the state-dependent inhibition of sodium and calcium channels in both the peripheral and central pain signaling pathways may provide a synergistic mechanism toward the development of a novel class of pain therapeutics.
Subject(s)
Ion Channels/metabolism , Neuralgia/drug therapy , Spinal Nerves/pathology , Acetanilides/chemical synthesis , Acetanilides/chemistry , Acetanilides/pharmacokinetics , Acetanilides/therapeutic use , Acrylates/chemical synthesis , Acrylates/chemistry , Acrylates/pharmacokinetics , Acrylates/therapeutic use , Analysis of Variance , Animals , Animals, Newborn , Biophysics , Calcium Channels, T-Type/genetics , Calcium Channels, T-Type/metabolism , Cell Line, Transformed , Disease Models, Animal , Electric Stimulation , Ganglia, Spinal/pathology , Heart/drug effects , Heart/physiopathology , Humans , Hyperalgesia/drug therapy , Hyperalgesia/pathology , Hyperalgesia/physiopathology , In Vitro Techniques , Ion Channels/genetics , Male , Membrane Transport Modulators/chemical synthesis , Membrane Transport Modulators/chemistry , Membrane Transport Modulators/pharmacokinetics , Membrane Transport Modulators/therapeutic use , NAV1.7 Voltage-Gated Sodium Channel , NAV1.8 Voltage-Gated Sodium Channel , Neural Inhibition/drug effects , Neuralgia/metabolism , Neuralgia/pathology , Pain Measurement/methods , Patch-Clamp Techniques , Piperazines/chemical synthesis , Piperazines/chemistry , Piperazines/pharmacokinetics , Piperazines/therapeutic use , Rabbits , Rats , Rats, Wistar , Sensory Receptor Cells/drug effects , Sensory Receptor Cells/physiology , Sodium Channel Blockers/pharmacology , Sodium Channels/genetics , Sodium Channels/metabolismABSTRACT
Current clinical treatments for neuropathic pain include amitriptyline, a tricyclic antidepressant with mixed pharmacology that is also clinically reported to impair cognitive performance; and gabapentin, a compound that selectively interacts with alpha2delta-1 calcium channel subunits. Since few assessments of cognitive performance have been made in non-human primates with these marketed treatments, the purpose of this study was to determine their relative abilities to alter working memory as measured in mature macaques in their performance of a delayed matching-to-sample task. Four delay intervals of increasing duration provided increasing impairment in task accuracies during vehicle sessions. Administration of clinically relevant doses of amitriptyline significantly decreased task accuracy at the highest dose tested (3mg/kg). Administration of gabapentin increased mean task accuracy, though the effect was not statistically significant until intra-subject variability was reduced by selecting the individual best dose for each animal (which averaged 12.8mg/kg). Most of the effect was obtained during the presentation of long delay trials (18.2% above vehicle). Task improvement was sustained during sessions run 24h after gabapentin administration. In a series that used a task-relevant distractor to determine gabapentin's effect on attention, drug treatment reversed distractor-impaired accuracy during long delay trials (25.4% above vehicle). The selective improvement in long delay accuracy in both paradigms suggests improvement in encoding or retention components of working memory. It is currently unclear whether the ability of acute administration of gabapentin to modestly improve working memory occurs by a mechanism that could be related to its anti-allodynic mechanism of action.
Subject(s)
Amines/pharmacology , Amitriptyline/pharmacology , Analgesics, Non-Narcotic/pharmacology , Analgesics/pharmacology , Cyclohexanecarboxylic Acids/pharmacology , Neuralgia/drug therapy , Psychomotor Performance/drug effects , gamma-Aminobutyric Acid/pharmacology , Amines/therapeutic use , Amitriptyline/therapeutic use , Analgesics/therapeutic use , Analgesics, Non-Narcotic/therapeutic use , Animals , Cyclohexanecarboxylic Acids/therapeutic use , Disease Models, Animal , Dose-Response Relationship, Drug , Female , Gabapentin , Macaca nemestrina , Male , Memory, Short-Term/drug effects , Neuralgia/physiopathology , Neuropsychological Tests , Reaction Time/drug effects , gamma-Aminobutyric Acid/therapeutic useABSTRACT
T-type voltage-gated Ca(2+) channels have been implicated in contributing to a broad variety of human disorders, including pain, epilepsy, sleep disturbances, cardiac arrhythmias, and certain types of cancer. However, potent and selective T-type Ca(2+) channel modulators are not yet available for clinical use. This may in part be due to their unique biophysical properties that have delayed the development of high-throughput screening (HTS) assays for identifying blockers. One notable challenge is that at the normal resting membrane potential (V(m)) of cell lines commonly utilized for drug screening purposes, T-type Ca(2+) channels are largely inactivated and thus cannot be supported by typical formats of functional HTS assays to both evoke and quantify the Ca(2+) channel signal. Here we describe a simple method that can successfully support a fluorescence-based functional assay for compounds that modulate T-type Ca(2+)channels. The assay functions by exploiting the pore-forming properties of gramicidin to control the cellular V(m) in advance of T-type Ca(2+) channel activation. Using selected ionic conditions in the presence of gramicidin, T-type Ca(2+) channels are converted from the unavailable, inactivated state to the available, resting state, where they can be subsequently activated by application of extracellular K(+). The fidelity of the assay has been pharmacologically characterized with sample T-type Ca(2+) channel blockers whose potency has been determined by conventional manual patch-clamp techniques. This method has the potential for applications in high-throughput fluorometric imaging plate reader (FLIPR(R), Molecular Devices, Sunnyvale, CA) formats with cell lines expressing either recombinant or endogenous T-type Ca(2+) channels.
Subject(s)
Calcium Channel Blockers/pharmacology , Calcium Channels, T-Type/drug effects , Algorithms , Calcium Channel Blockers/chemical synthesis , Calcium Channels, L-Type/drug effects , Calcium Channels, L-Type/metabolism , Calcium Channels, R-Type/drug effects , Calcium Channels, R-Type/metabolism , Calcium Channels, T-Type/metabolism , Cation Transport Proteins/drug effects , Cation Transport Proteins/metabolism , Cell Line , DNA, Complementary/biosynthesis , DNA, Complementary/genetics , Drug Evaluation, Preclinical , Electrophysiology , Gramicidin/pharmacology , Humans , Membrane Potentials/drug effects , Patch-Clamp Techniques , Pharmaceutical Solutions , Spectrometry, FluorescenceABSTRACT
This report describes the syntheses and structure-activity relationships of 8-(substituted pyridyl)pyrazolo[1,5-a]-1,3,5-triazine corticotropin releasing factor receptor-1 (CRF(1)) receptor antagonists. These CRF(1) receptor antagonists may be potential anxiolytic or antidepressant drugs. This research resulted in the discovery of compound 13-15, which is a potent, selective CRF(1) antagonist (hCRF(1) IC(50) = 6.1 +/- 0.6 nM) with weak affinity for the CRF-binding protein and biogenic amine receptors. This compound also has a good pharmacokinetic profile in dogs. Analogue 13-15 is orally effective in two rat models of anxiety: the defensive withdrawal (situational anxiety) model and the elevated plus maze test. Analogue 13-15 has been advanced to clinical trials.