ABSTRACT
The 5-hydroxytryptamine (5-HT) (serotonin) 5-HT3 receptor represents a clinical target for antagonists to deliver symptomatic relief to patients with diarrhea-predominant irritable bowel syndrome (IBS-d) or carcinoid syndrome. Unfortunately, this pharmacological strategy can present side effects (e.g., severe constipation). The present study investigates the potential of a novel 5-HT3 receptor partial agonist, CSTI-300, to treat patients with IBS-d and other conditions associated with discomfort from colonic distension, with a predicted reduced side-effect profile. The in vitro and in vivo preclinical pharmacology of the drug CSTI-300 was investigated to explore the potential to treat patients with IBS-d. CSTI-300 displayed selective high affinity for the human and rat 5-HT3 receptor (Ki approximately 2.0 nM) and acted as a partial agonist (approximately 30%-50% intrinsic efficacy) in vitro. In an in vivo model of IBS-d, the rat colon distension model, CSTI-300 displayed dose-dependent efficacy. In addition, oral administration of CSTI-300 to dogs that achieved plasma levels of the drug exceeding the Ki value for the 5-HT3 receptor failed to either evoke emesis or alter the state of feces. Pharmacokinetics for CSTI-300 in rat and dog identified high levels of oral availability with t 1/2 range of 1.6-4.4 hours. The preclinical pharmacology of the lead candidate drug, CSTI-300, supports the potential of this novel drug to offer symptomatic relief to patients with irritable bowel syndrome and carcinoid syndrome with a rationale for a reduced "on-target" side-effect profile relative to 5-HT3 receptor antagonists, such as alosetron. SIGNIFICANCE STATEMENT: There is a lack of effective current treatment for diarrhea-predominant irritable bowel syndrome and carcinoid syndrome, and in both conditions, overactivity of the 5-hydroxytryptamine (5-HT) 5-HT3 receptor is thought to be implicated in the pathophysiology. Because 5-HT3 receptor blockade with antagonists results in significant side effects, we present evidence that treatment with a suitable 5-HT3 receptor partial agonist will alleviate some symptoms associated with these conditions yet, without fully inhibiting the receptor, predict a less pronounced side-effect profile associated with this therapeutic strategy.
Subject(s)
Drug Partial Agonism , Heterocyclic Compounds, 3-Ring/chemistry , Heterocyclic Compounds, 3-Ring/therapeutic use , Irritable Bowel Syndrome/drug therapy , Malignant Carcinoid Syndrome/drug therapy , Serotonin 5-HT3 Receptor Agonists/chemistry , Serotonin 5-HT3 Receptor Agonists/therapeutic use , Animals , Dogs , Dose-Response Relationship, Drug , HEK293 Cells , Humans , Irritable Bowel Syndrome/physiopathology , Male , Malignant Carcinoid Syndrome/physiopathology , Rats , Rats, Sprague-Dawley , Treatment OutcomeABSTRACT
It remains uncertain how perennial grasses with different photosynthetic pathways respond to fire, and how this response varies with stress at the time of burning. Resprouting after fire was examined in relation to experimentally manipulated pre-fire watering frequencies. We asked the following questions: are there response differences to fire between C3 and C4 grasses? And, how does post-fire resprouting vary with pre-fire drought stress? Fifty-two perennial Australian grasses (37 genera, 13 tribes) were studied. Three watering frequencies were applied to simulate increasing drought. Pre-fire tiller number, tiller density, specific leaf area and leaf dry matter content were measured as explanatory variables to assess response. Most species (90%) and individuals (79%) resprouted following experimental burning. C4 grasses had higher probabilities of surviving fire relative to C3 grasses. Responses were not related to phylogeny or tribe. High leaf dry matter content reduced the probability of dying, but also reduced the re-emergence of tillers. Post-fire tiller number increased with increasing drought, regardless of photosynthetic type, suggesting that drought plays a role in the ability of grasses to recover after fire. This has implications for understanding the persistence of species in landscapes where fire management is practiced.
Subject(s)
Droughts , Fires , Poaceae/growth & development , Phylogeny , Regression Analysis , Species Specificity , WaterABSTRACT
Purpose: The anterior vestibule salvaging ('Birdcage') technique may limit orbital implant extrusion following evisceration. Methods: A 10-year retrospective chart review from 2005 to 2015 of individuals who underwent evisceration procedures utilizing the vestibule salvaging technique was performed. Results: A total of 96 patients (61 male; 35 female; average age 64 years; range 17-96 years) underwent evisceration with a technique avoiding anterior scleral relaxing incisions. Three (3.1%) patients had documented extrusion of the silicone implant. Time from evisceration to extrusion ranged from 26 to 372 days. Conclusions: Maintenance of the anterior scleral vestibule during evisceration may decrease extrusion rates after surgery compared with traditional evisceration techniques that utilize anterior relaxing incisions.
Subject(s)
Eye Evisceration , Ophthalmologic Surgical Procedures , Orbital Implants , Postoperative Complications/prevention & control , Sclera/surgery , Silicone Elastomers , Surgical Wound Dehiscence/prevention & control , Adolescent , Adult , Aged , Aged, 80 and over , Female , Humans , Male , Middle Aged , Prosthesis Implantation , Retrospective Studies , Young AdultABSTRACT
The acute and chronic effects of repeated intravitreal antivascular endothelial growth factor (VEGF) injections on intraocular pressure have not been fully characterized, and the development of sustained ocular hypertension could adversely affect patients who are at risk of glaucomatous optic neuropathy. As expected, volume-driven, acute ocular hypertension immediately follows intravitreal injection, but this pressure elevation is generally transient and well tolerated. Several medications have been investigated to limit acute ocular hypertension following anti-VEGF therapy, but the benefits of pretreatment are not conclusive. Chronic, sustained ocular hypertension, distinct from the short-term acute ocular hypertension after each injection, has also been associated with repeated intravitreal anti-VEGF injections. Risk factors for chronic ocular hypertension include the total number of injections, a greater frequency of injection, and preexisting glaucoma. Proposed mechanisms for chronic ocular hypertension include microparticle obstruction, toxic or inflammatory effects on trabecular meshwork, as well as alterations in outflow facility by anti-VEGF agents. Although limiting anti-VEGF therapy could minimize the risk of both acute and chronic ocular hypertension, foregoing anti-VEGF therapy risks progression of various macular diseases with resulting permanent central vision loss. While definitive evidence of damage to the retinal nerve fiber layer is lacking, patients receiving repeated injections should be monitored for ocular hypertension and patients in whom sustained ocular hypertension subsequently developed should be periodically monitored for glaucomatous changes with optic nerve optical coherence tomography and static visual fields.
Subject(s)
Angiogenesis Inhibitors/pharmacology , Intraocular Pressure/drug effects , Ocular Hypertension/chemically induced , Acute Disease , Angiogenesis Inhibitors/adverse effects , Chronic Disease , Humans , Intravitreal Injections , Ocular Hypertension/prevention & control , Risk Assessment , Risk Factors , Vascular Endothelial Growth Factor A/antagonists & inhibitorsABSTRACT
INTRODUCTION: The eye is a target for investigational gene therapy due to the monogenic nature of many inherited retinal and optic nerve degenerations (IRD), its accessibility, tight blood-ocular barrier, the ability to non-invasively monitor for functional and anatomic outcomes, as well as its relative immune privileged state.Vectors currently used in IRD clinical trials include adeno-associated virus (AAV), small single-stranded DNA viruses, and lentivirus, RNA viruses of the retrovirus family. Both can transduce non-dividing cells, but AAV are non-integrating, while lentivirus integrate into the host cell genome, and have a larger transgene capacity. AREAS COVERED: This review covers Leber's congenital amaurosis, choroideremia, retinitis pigmentosa, Usher syndrome, Stargardt disease, Leber's hereditary optic neuropathy, Achromatopsia, and X-linked retinoschisis. EXPERT OPINION: Despite great potential, gene therapy for IRD raises many questions, including the potential for less invasive intravitreal versus subretinal delivery, efficacy, safety, and longevity of response, as well as acceptance of novel study endpoints by regulatory bodies, patients, clinicians, and payers. Also, ultimate adoption of gene therapy for IRD will require widespread genetic screening to identify and diagnose patients based on genotype instead of phenotype.
Subject(s)
Genetic Therapy , Nerve Degeneration/therapy , Choroideremia/pathology , Choroideremia/therapy , Clinical Trials as Topic , Color Vision Defects/pathology , Color Vision Defects/therapy , Dependovirus/genetics , Genetic Vectors/genetics , Genetic Vectors/metabolism , Humans , Lentivirus/genetics , Macular Degeneration/congenital , Macular Degeneration/pathology , Macular Degeneration/therapy , Nerve Degeneration/pathology , Stargardt Disease , Usher Syndromes/pathology , Usher Syndromes/therapy , cis-trans-Isomerases/geneticsSubject(s)
Dacryocystitis/etiology , Lacrimal Duct Obstruction/complications , Mucocele/complications , Nasolacrimal Duct/abnormalities , Acute Disease , Dacryocystitis/diagnosis , Endoscopy , Humans , Infant, Newborn , Lacrimal Duct Obstruction/congenital , Lacrimal Duct Obstruction/diagnosis , Mucocele/congenital , Mucocele/diagnosis , Nasolacrimal Duct/diagnostic imaging , Tomography, X-Ray ComputedABSTRACT
INTRODUCTION: In neovascular age related macular degeneration (nAMD), gene therapy to chronically express anti-vascular endothelial growth factor (VEGF) proteins could ameliorate the treatment burden of chronic intravitreal therapy and improve limited visual outcomes associated with 'real world' undertreatment. Areas covered: In this review, the authors assess the evolution of gene therapy for AMD. Adeno-associated virus (AAV) vectors can transduce retinal pigment epithelium; one such early application was a phase I trial of AAV2-delivered pigment epithelium derived factor gene in advanced nAMD. Subsequently, gene therapy for AMD shifted to the investigation of soluble fms-like tyrosine kinase-1 (sFLT-1), an endogenously expressed VEGF inhibitor, binding and neutralizing VEGF-A. After some disappointing results, research has centered on novel vectors, including optimized AAV2, AAV8 and lentivirus, as well as genes encoding other anti-angiogenic proteins, including ranibizumab, aflibercept, angiostatin and endostatin. Also, gene therapy targeting the complement system is being investigated for geographic atrophy due to non-neovascular AMD. Expert opinion: The success of gene therapy for AMD will depend on the selection of the most appropriate therapeutic protein and its level of chronic expression. Future investigations will center on optimizing vector, promoter and delivery methods, and evaluating the risks of the chronic expression of anti-angiogenic or anti-complement proteins.
Subject(s)
Genetic Therapy , Macular Degeneration/drug therapy , Dependovirus/genetics , Genetic Vectors/genetics , Genetic Vectors/metabolism , Humans , Macular Degeneration/pathology , RNA Interference , RNA, Small Interfering/metabolism , RNA, Small Interfering/therapeutic use , Vascular Endothelial Growth Factor A/antagonists & inhibitors , Vascular Endothelial Growth Factor A/genetics , Vascular Endothelial Growth Factor A/metabolism , Vascular Endothelial Growth Factor Receptor-1/geneticsABSTRACT
INTRODUCTION: In age-related macular degeneration (AMD), stem cells could possibly replace or regenerate disrupted pathologic retinal pigment epithelium (RPE), and produce supportive growth factors and cytokines such as brain-derived neurotrophic factor. Induced pluripotent stem cells (iPSCs)-derived RPE was first subretinally transplanted in a neovascular AMD patient in 2014. Areas covered: Induced PSCs are derived from the introduction of transcription factors to adult cells under specific cell culture conditions, followed by differentiation into RPE cells. Induced PSC-derived RPE cells exhibit ion transport, membrane potential, polarized VEGF secretion and gene expression that is similar to native RPE. Despite having similar in vitro function, morphology, immunostaining and microscopic analysis, it remains to be seen if iPSC-derived RPE can replicate the myriad of in vivo functions, including immunomodulatory effects, of native RPE cells. Historically, adjuvant RPE transplantation during CNV resections were technically difficult and complicated by immune rejection. Autologous iPSCs are hypothesized to reduce the risk of immune rejection, but their production is time-consuming and expensive. Alternatively, allogenic transplantation using human leukocyte antigen (HLA)-matched iPSCs, similar to HLA-matched organ transplantation, is currently being investigated. Expert opinion: Challenges to successful transplantation with iPSCs include surgical technique, a pathologic subretinal microenvironment, possible immune rejection, and complications of immunosuppression.
Subject(s)
Induced Pluripotent Stem Cells/transplantation , Macular Degeneration/therapy , Cell Differentiation , Graft Rejection/prevention & control , HLA Antigens/immunology , Humans , Immunosuppressive Agents/therapeutic use , Macular Degeneration/pathology , Retinal Pigment Epithelium/cytology , Retinal Pigment Epithelium/metabolism , Transcription Factors/genetics , Transcription Factors/metabolismABSTRACT
BACKGROUND: The aim of this study was to evaluate the rate of periocular allergic skin reactions to topical neomycin, polymyxin B, and dexamethasone (NPD) ophthalmic ointment. METHODS: A consecutive patient prospective study was performed. A total of 522 patients who had a procedure involving incision of the periocular skin with subsequent postoperative application of NPD ophthalmic ointment were included. Patients were evaluated for signs of allergy at 1 week postoperatively or prior if the patient had complaints. A periocular allergic reaction was defined as any periocular skin pruritus, erythema, edematous papules, vesicles, or plaques at the site of ointment application beyond that of the typical postprocedure presentation. The patients continued to be monitored for 30 days postoperatively. RESULTS: Of the 522 patients who completed the study, eight (1.5%) had a definitive periocular allergic contact dermatitis to the NPD ophthalmic ointment. Allergic presentation ranged from postoperative day 3 to 14. CONCLUSIONS: The rate of periocular allergic reactions to NPD ophthalmic ointment is significantly lower than reported in the literature for other topical preparations of neomycin and polymyxin B. The low rate of allergy in this study suggests that NPD ophthalmic ointment can safely be applied to the periocular skin with a very minimal risk of inciting an allergic reaction.
ABSTRACT
BACKGROUND/AIMS: Previous studies suggest that vascular abnormalities are involved in the pathogenesis of open-angle glaucoma. This study aims to examine the relationship of baseline retrobulbar blood flow measurements with functional and structural glaucomatous progression in patients with open-angle glaucoma over 4â years. METHODS: In this study, 112 patients with open-angle glaucoma were examined at baseline and 78 with retrobulbar blood flow assessments were followed to 4â years. Colour Doppler imaging was used to evaluate retrobulbar blood flow. Structural disease progression was examined with optical coherence tomography and Heidelberg Retinal Tomography III. Functional disease progression was monitored with automated perimetry using Humphrey visual fields. Mixed-model analysis of covariance was used to test for significance of changes from baseline to 4-year follow-up. Two-sample t tests and χ2 tests were used to test for baseline blood flow differences between patients who progressed and those who did not progress. RESULTS: Patients who progressed structurally had a statistically significant lower baseline mean ophthalmic artery peak systolic velocity (PSV) (p=0.024) and ophthalmic artery end diastolic velocity (EDV) (p=0.012) compared with those who did not progress. Similarly, a lower baseline mean ophthalmic artery PSV (p=0.031) and ophthalmic artery EDV (p=0.005) were associated with patients who progressed functionally compared with those who did not progress after 4â years. CONCLUSIONS: In this study population, lower baseline ophthalmic artery blood flow velocities were associated with simultaneous structural and functional glaucoma progression after 4â years.
Subject(s)
Ciliary Arteries/physiology , Glaucoma, Open-Angle/diagnosis , Glaucoma, Open-Angle/physiopathology , Ophthalmic Artery/physiology , Retinal Artery/physiology , Aged , Blood Flow Velocity/physiology , Disease Progression , Female , Follow-Up Studies , Humans , Intraocular Pressure/physiology , Laser-Doppler Flowmetry , Male , Middle Aged , Nerve Fibers/pathology , Regional Blood Flow/physiology , Retinal Ganglion Cells/pathology , Tomography, Optical Coherence , Visual Field Tests , Visual Fields/physiologyABSTRACT
PURPOSE: To report our experience with protractor myectomy in patients with benign essential blepharospasm who did not respond to serial botulinum toxin injection, and to describe intra- and postoperative techniques that limited skin contracture while also providing excellent functional and cosmetic results. METHODS: The medical records of patients with isolated, benign, essential blepharospasm who underwent protractor myectomy from 2005 to 2008 by a single surgeon were reviewed retrospectively. The technique entailed operating on a single eyelid during each procedure, using a complete en bloc resection of all orbicularis tissue, leaving all eyelid skin intact at the time of surgery, and placing the lid under stretch with Frost suture and applying a pressure dressing for 5-7 days. RESULTS: Data from 28 eyelids in 7 patients were included. Average follow-up was 21.5 months (range, 4-76 months). Of the 28 eyelids, 20 (71.4%) showed postoperative resolution of spasm, with no further need for botulinum toxin injections. In the 8 eyelids requiring further injections, the average time to injection after surgery was 194 days (range, 78-323 days), and the average number of injections was 12 (range, 2-23 injections). All but one eyelid had excellent cosmetic results, without signs of contracture; one eyelid developed postoperative skin contracture following premature removal of the Frost suture and pressure dressing because of concerns over increased intraocular pressure. CONCLUSIONS: In our patient cohort, this modified technique resulted in excellent cosmetic and functional results and limited postoperative skin contracture.
Subject(s)
Blepharospasm/surgery , Contracture/surgery , Eyelids/surgery , Oculomotor Muscles/surgery , Ophthalmologic Surgical Procedures/methods , Postoperative Complications/surgery , Skin Diseases/surgery , Aged , Aged, 80 and over , Contracture/diagnosis , Contracture/etiology , Eyelids/pathology , Female , Follow-Up Studies , Humans , Male , Middle Aged , Ophthalmologic Surgical Procedures/adverse effects , Postoperative Complications/diagnosis , Postoperative Complications/etiology , Reoperation , Retrospective Studies , Skin/pathology , Skin Diseases/diagnosis , Skin Diseases/etiology , Time Factors , Treatment OutcomeABSTRACT
We previously disclosed the discovery of rationally designed N-((1-(4-(propylsulfonyl)piperazin-1-yl)cycloalkyl)methyl)benzamide inhibitors of glycine transporter-1 (GlyT-1), represented by analogues 10 and 11. We describe herein further structure-activity relationship exploration of this series via an optimization strategy that primarily focused on the sulfonamide and benzamide appendages of the scaffold. These efforts led to the identification of advanced leads possessing a desirable balance of excellent in vitro GlyT-1 potency and selectivity, favorable ADME and in vitro pharmacological profiles, and suitable pharmacokinetic and safety characteristics. Representative analogue (+)-67 exhibited robust in vivo activity in the cerebral spinal fluid glycine biomarker model in both rodents and nonhuman primates. Furthermore, rodent microdialysis experiments also demonstrated that oral administration of (+)-67 significantly elevated extracellular glycine levels within the medial prefrontal cortex (mPFC).
Subject(s)
Benzamides/chemistry , Benzamides/pharmacology , Glycine Plasma Membrane Transport Proteins/antagonists & inhibitors , Animals , Benzamides/chemical synthesis , Benzamides/pharmacokinetics , Glycine/cerebrospinal fluid , Glycine/metabolism , Glycine Plasma Membrane Transport Proteins/metabolism , Macaca fascicularis , Male , Methylation , Piperazines/chemical synthesis , Piperazines/chemistry , Piperazines/pharmacokinetics , Piperazines/pharmacology , Rats , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
PURPOSE: To investigate the relationship of changes in ocular blood flow with optic nerve head (ONH) and retinal morphology in open-angle glaucoma (OAG) patients of African versus European descent (ED) over 4 years. MATERIALS AND METHODS: In this study, 112 patients with OAG were examined at baseline, 79 [59 ED, 20 African descent (AD)] of which were followed for 4 years. Retinal capillary blood flow was assessed with Heidelberg retinal flowmetry. Retrobulbar blood flow was measured by color Doppler imaging. Retinal structural changes were examined with optical coherence tomography and Heidelberg retinal tomography-III. Mixed-model analysis of covariance was used to test for the significance of change from baseline to 4-year follow-up, and Pearson correlation coefficients were calculated to evaluate linear associations. RESULTS: In OAG patients of AD, structural changes of the ONH demonstrated a strong association with the end diastolic velocities and resistive indices of the short posterior ciliary arteries over 4 years. In addition, there was a significantly larger increase in the avascular area of the inferior retina in patients of AD, and this reduction in retinal capillaries strongly correlated with a reduction in macular thickness. CONCLUSIONS: Reductions in retinal capillary and retrobulbar blood flow strongly correlated with changes in the ONH and macular thickness over 4 years in OAG patients of AD compared with ED. These data suggest that ocular vascular health may be a more influential contributing factor in the pathophysiology of OAG in patients of AD compared with ED.
Subject(s)
Black People , Glaucoma, Open-Angle/physiopathology , Optic Disk/pathology , Orbit/blood supply , Retinal Ganglion Cells/pathology , Retinal Vessels/physiology , White People , Aged , Blood Flow Velocity/physiology , Capillaries/physiology , Female , Glaucoma, Open-Angle/ethnology , Hemodynamics , Humans , Laser-Doppler Flowmetry , Male , Middle Aged , Regional Blood Flow , Tomography, Optical Coherence , Tonometry, OcularABSTRACT
BACKGROUND: The European Resuscitation Council Guidelines recognise that there is a lack of direct evidence for the effect of age on outcome following cardiopulmonary resuscitation. AIM: To determine the role that advancing age plays in the decision by clinicians to complete a do not attempt cardiopulmonary resuscitation order based on perceived futility. DESIGN: A questionnaire-based trial. Clinicians were randomly assigned to receive one of two versions of a patient case, varying in age but otherwise identical (90 years vs 60 years). Participants were asked to decide whether a do not attempt cardiopulmonary resuscitation form should be completed based on perceived futility for a single patient case. Rates of do not attempt cardiopulmonary resuscitation order were compared between groups. PARTICIPANTS: Consultant physicians, surgeons and anaesthetists from 12 district general hospitals in England. RESULTS: In total, 291 questionnaires were returned. Overall, clinicians were significantly more likely to complete a do not attempt cardiopulmonary resuscitation form for a 90-year-old patient than a 60-year-old patient, when all other factors are equal (67.7% vs 7.4%, p < 0.001). This finding was consistent across speciality and experience level of the consultant. Surgeons were found to be significantly less likely to complete a do not attempt cardiopulmonary resuscitation order in the 90-year-old patient compared to other consultants (46.4% vs 74.1%, p < 0.001). Anaesthetists were more likely than other consultants to complete a do not attempt cardiopulmonary resuscitation order in the 60-year-old patient (17.8% vs 4.3%, p < 0.05). CONCLUSION: Age is a highly significant independent factor in a clinicians' decision to withhold cardiopulmonary resuscitation. We highlight a potential gap between current practice and supporting evidence base.
Subject(s)
Attitude of Health Personnel , Cardiopulmonary Resuscitation , Resuscitation Orders , Adult , Age Factors , Decision Making , England , Female , Humans , Male , Medical Futility , Middle Aged , Specialization/statistics & numerical data , Surveys and QuestionnairesABSTRACT
Clinical development of drugs for CNS disorders can be a challenging and risky endeavor. In this article we look at the steps required to move a preclinical candidate compound into clinical development. We use the case study of ALB-127158(a), an MCH1 antagonist for the treatment of obesity via a central mechanism to highlight the steps needed to move into early clinical development. Preclinical studies demonstrated that the compound produced significant weight loss in rodents. Based on the observation that the weight loss was caused by a reduction in food intake it was possible to build measures of ingestive behavior into the early clinical development plan. Single and multiple ascending dose studies were conducted in normal and overweight volunteers. The compound was safe and well tolerated with good PK characteristics. ALB-127158(a) was shown to have some effects on measures of 'hunger' and 'desire to eat', unfortunately these effects only occurred at doses higher than those predicted from the preclinical studies. A subsequent study looking at compound levels in the cerebrospinal fluid (CSF) suggested lower brain exposure than seen in the preclinical models. Based on this data and the limited efficacy observed it was possible to terminate further progression of this compound for obesity before costly long-term weight loss studies were initiated. However, recent reports have demonstrated that MCH acting via MCH1 receptors located on intestinal epithelial cells may be a critical mediator of inflammatory responses within the gastrointestinal (GI) tract. MCH1 receptor antagonists may therefore have a beneficial effect in disorders such as inflammatory bowel disease (IBD). Based on this evidence a peripherally selective MCH1 receptor antagonist such as ALB-127158(a) may be a potential treatment for IBD. This example demonstrates how using data from the preclinical studies is possible to build decision points into an early clinical development plan that will allow early assessment of potential efficacy and allow timely go/no go decisions.
Subject(s)
Anti-Obesity Agents/therapeutic use , Clinical Trials as Topic , Drug Discovery/standards , Drug Evaluation, Preclinical , Indazoles/therapeutic use , Obesity/drug therapy , Pyridones/therapeutic use , Animals , Humans , Male , Rats , Receptors, Pituitary Hormone/antagonists & inhibitorsABSTRACT
Water temperature is a primary factor affecting the number and kinds of species in a stream. A key step towards including water temperatures in environmental flow assessments is to develop metrics which describe natural variability in a river's thermal regime. This is best achieved using time series analyses, where metrics are defined based either on time series disaggregation, or shapes of regimes defined using agglomerative techniques. The aim of this paper was to refine approaches in setting environmental water temperature guidelines for inclusion in defining environmental flows assessments. Annual water temperature series from 82 sites sampled across 48 rivers (mainstems and tributaries) in ten catchments in the southern Cape region of South Africa were described using 39 metrics based on the magnitude, frequency, duration and timing of thermal events. Sites were classified into thermal groups using their similarity in multivariate temperature regime and variation amongst groups along important temperature gradients examined. Deviation from a natural range of variability using a thermal confidence envelope is a suitable approach for broad evaluation of thermal guidelines. The approach presented can be applied at multiple levels of complexity to assess which elements of a thermal time series fall outside of reference conditions. Further steps in this approach are to link thermal patterns to biotic metrics, and gain a clearer understanding of interactions between flows, temperatures and biota, particularly below impoundments. Research on improving approaches in defining thermal regions is recommended.
Subject(s)
Rivers , Water , Environmental Monitoring/methods , Guidelines as Topic , Seasons , South Africa , TemperatureABSTRACT
Irritable bowel syndrome (IBS) is a functional bowel disorder characterized by abdominal pain, discomfort, and altered bowel habits, which have a significant impact on quality of life for approximately 10-20% of the population. IBS can be divided into three main types IBS-D (diarrhea predominant), IBS-C (constipation predominant), and mixed or alternating IBS. 5-HT(3) receptor antagonism has proved to be an efficacious treatment option for IBS-D. For example, alosetron displays efficacy in the treatment of multiple symptoms, including abdominal pain, discomfort, urgency, stool frequency and consistency. However, significant constipation occurred in approximately 25% of patients, leading to withdrawal of up to 10% of patients in clinical trials. Targeting compounds with partial agonist activity at the 5-HT(3) receptor represents a mechanistic departure from the classic 5-HT(3) receptor antagonist approach and should result in agents that are applicable to a broader array of IBS patient populations. Attenuation of the activity of the ion channel without completely abolishing its function may control or normalize bowel function without leading to a total block associated with severe constipation. We have identified a new class of selective, orally active 5-HT(3) receptor ligands with high 5-HT(3) receptor affinity and low partial agonist activity currently in preclinical development that should offer a significant advantage over existing therapies.
Subject(s)
Irritable Bowel Syndrome/drug therapy , Serotonin 5-HT3 Receptor Agonists/therapeutic use , Humans , Ligand-Gated Ion Channels/drug effects , Receptors, Serotonin, 5-HT3/physiology , Serotonin 5-HT3 Receptor Agonists/pharmacology , Serotonin 5-HT3 Receptor Antagonists/pharmacology , Serotonin 5-HT3 Receptor Antagonists/therapeutic useABSTRACT
The review focuses on the central neuronal circuits involved in energy homeostasis and the opportunities these offer for pharmacological intervention to decrease feeding behaviour and reduce weight. This article is based on the presentation 'New central targets for the treatment of obesity' (Sargent, British Pharmacological society, Clinical Section Symposium, December 2008). Central neuronal substrates controlling weight offer numerous opportunities for pharmacological intervention. These opportunities range from non-specific enhancement of monoamine signalling (triple reuptake inhibitors) to targeting specific monoamine receptor subtypes (5-HT(2c) and 5-HT(6)). The data reviewed suggest that these approaches will lead to weight loss; whether this is sufficient to produce clinically meaningful effect remains to be determined. Combination therapy targeting more than one mechanism may be a means of increasing the magnitude of the response. Preclinical studies also suggest that novel approaches targeting specific neuronal pathways within the hypothalamus, e.g. MCH(1) receptor antagonism, offer an opportunity for weight reduction. However, these approaches are at an early stage and clinical studies will be needed to determine if these novel approaches lead to clinically meaningful weight loss and improvements in co-morbid conditions such as diabetes and cardiovascular disorders.
Subject(s)
Anti-Obesity Agents/therapeutic use , Appetite Depressants/therapeutic use , Energy Metabolism/drug effects , Obesity/drug therapy , Selective Serotonin Reuptake Inhibitors/therapeutic use , Serotonin/metabolism , Weight Loss/drug effects , Anti-Obesity Agents/pharmacology , Body Mass Index , Body Weight , Drug Delivery Systems , Humans , Obesity/metabolismABSTRACT
Clozapine and olanzapine have been shown to acutely stimulate consumption of a fat emulsion (Intralipid) by male Lister hooded rats. We initially investigated the extent of any sex difference in Intralipid hyperphagia associated with olanzapine treatment. We then examined the degree of Intralipid hyperphagia produced by a range of atypical antipsychotic drugs having different associations with human weight gain, and also determined their effects on cocaine-stimulated locomotor activity as a measure of functional dopamine antagonism in vivo. Olanzapine (0.1-1 mg/kg) stimulated Intralipid intake to an equal extent in male and female rats. Quetiapine (10 mg/kg) also stimulated Intralipid intake whereas ziprasidone (0.3-10 mg/kg) or risperidone (0.03-0.3 mg/kg) did not have this effect. All of the compounds, except quetiapine, reduced cocaine-stimulated locomotor activity but the relationship to the degree of Intralipid hyperphagia was variable. Since there was a positive relationship between Intralipid hyperphagia and the reported extent of human body weight gain, we conclude that Intralipid hyperphagia may have predictive value for this drug-associated side effect and is not related to the dopamine antagonist properties of these agents.
Subject(s)
Antipsychotic Agents/pharmacology , Cocaine/pharmacology , Dopamine Uptake Inhibitors/pharmacology , Eating/drug effects , Fat Emulsions, Intravenous/pharmacology , Hyperkinesis/chemically induced , Hyperkinesis/psychology , Animals , Dibenzothiazepines/pharmacology , Dopamine Antagonists/pharmacology , Dose-Response Relationship, Drug , Female , Male , Motor Activity/drug effects , Piperazines/pharmacology , Quetiapine Fumarate , Rats , Risperidone/pharmacology , Thiazoles/pharmacologyABSTRACT
FMPD [6-fluoro-10-[3-(2-methoxyethyl)-4-methyl-piperazin-1-yl]-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene] is a potential novel antipsychotic with high affinity for dopamine D2 (Ki= 6.3 nM), 5-HT(2A) (Ki= 7.3 nM), and 5-HT6 (Ki= 8.0 nM) human recombinant receptors and lower affinity for histamine H1 (Ki= 30 nM) and 5-HT2C (Ki= 102 nM) human recombinant receptors than olanzapine. Oral administration of FMPD increased rat nucleus accumbens 3,4-dihyroxyphenylacetic acid concentrations (ED200 = 6 mg/kg), blocked 5-HT2A agonist-induced increases in rat serum corticosterone levels (ED50= 1.8 mg/kg), and inhibited the ex vivo binding of [125I]SB-258585 [4-iodo-N-[4-methoxy-3-(4-methyl-piperazin-1-yl)-phenyl]-benzenesulfonamide] to striatal 5-HT6 receptors (ED50= 10 mg/kg) but failed to inhibit ex vivo binding of [3H]pyrilamine to hypothalamic histamine H1 receptors at doses of up to 30 mg/kg. In electrophysiology studies, acute administration of FMPD selectively elevated the number of spontaneously active A10 (versus A9) dopamine neurons and chronic administration selectively decreased the number of spontaneously active A10 (versus A9) dopamine neurons. FMPD did not produce catalepsy at doses lower than 25 mg/kg p.o. In Fos-induction studies, FMPD had an atypical antipsychotic profile in the striatum and nucleus accumbens and increased Fos expression in orexin-containing neurons of the hypothalamus. FMPD produced only a transient elevation of prolactin levels. These data indicate that FMPD is an orally available potent antagonist of dopamine D2, 5-HT2A, and 5-HT6 receptors and a weak antagonist of H1 and 5-HT2C receptors. FMPD has the potential to have efficacy in treating schizophrenia and bipolar mania with a low risk of treatment-emergent extrapyramidal symptoms, prolactin elevation, and weight gain. Clinical trials are needed to test these hypotheses.