97 results on '"Jackson HC"'
Search Results
2. Effectiveness of oseltamivir in preventing influenza in household contacts: a randomized controlled trial.
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Welliver R, Monto AS, Carewicz O, Schatteman E, Hassman M, Hedrick J, Jackson HC, Huson L, Ward P, Oxford JS, Oseltamivir Post Exposure Prophylaxis Investigator Group, Welliver, R, Monto, A S, Carewicz, O, Schatteman, E, Hassman, M, Hedrick, J, Jackson, H C, Huson, L, and Ward, P
- Abstract
Context: Influenza virus is easily spread among the household contacts of an infected person, and prevention of influenza in household contacts can control spread of influenza in the community.Objective: To investigate the efficacy of oseltamivir in preventing spread of influenza to household contacts of influenza-infected index cases (ICs).Design and Setting: Randomized, double-blind, placebo-controlled study conducted at 76 centers in North America and Europe during the winter of 1998-1999.Participants: Three hundred seventy-seven ICs, 163 (43%) of whom had laboratory-confirmed influenza infection, and 955 household contacts (aged >/=12 years) of all ICs (415 contacts of influenza-positive ICs).Interventions: Household contacts were randomly assigned by household cluster to take 75 mg of oseltamivir (n = 493) or placebo (n = 462) once daily for 7 days within 48 hours of symptom onset in the IC. The ICs did not receive antiviral treatment.Main Outcome Measure: Clinical influenza in contacts of influenza-positive ICs, confirmed in a laboratory by detection of virus shedding in nose and throat swabs or a 4-fold or greater increase in influenza-specific serum antibody titer between baseline and convalescent serum samples.Results: In contacts of an influenza-positive IC, the overall protective efficacy of oseltamivir against clinical influenza was 89% for individuals (95% confidence interval [CI], 67%-97%; P<.001) and 84% for households (95% CI, 49%-95%; P<.001). In contacts of all ICs, oseltamivir also significantly reduced incidence of clinical influenza, with 89% protective efficacy (95% CI, 71%-96%; P<.001). Viral shedding was inhibited in contacts taking oseltamivir, with 84% protective efficacy (95% CI, 57%-95%; P<.001). All virus isolates from oseltamivir recipients retained sensitivity to the active metabolite. Oseltamivir was well tolerated; gastrointestinal tract effects were reported with similar frequency in oseltamivir (9.3%) and placebo (7.2%) recipients.Conclusion: In our sample, postexposure prophylaxis with oseltamivir, 75 mg once daily for 7 days, protected close contacts of influenza-infected persons against influenza illness, prevented outbreaks within households, and was well tolerated. [ABSTRACT FROM AUTHOR]- Published
- 2001
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3. Time- and glucose-dependent differentiation of 3T3-L1 adipocytes mimics dysfunctional adiposity.
- Author
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Jackson HC, Pheiffer C, Jack B, and Africander D
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- Humans, Mice, Animals, 3T3-L1 Cells, Reactive Oxygen Species metabolism, Adipocytes metabolism, Obesity metabolism, Cell Differentiation genetics, Hypertrophy metabolism, Adiposity, Glucose metabolism
- Abstract
The 3T3-L1 murine adipocyte cell line remains one of the most widely used models to study the mechanisms of obesity and related pathologies. Most studies investigate such mechanisms using mature adipocytes that have been chemically induced to differentiate for 7 days in media containing 25 mM glucose. However, the dysfunctional characteristics commonly observed in obesity including adipocyte hypertrophy, increased expression of inflammatory markers, enhanced production of reactive oxygen species (ROS), increased steroidogenic enzyme expression/activity and production of steroid hormones, are not necessarily mimicked in these cells. The aim of this study was to provide an inexpensive model which represents the well-known characteristics of obesity by manipulating the time of adipocyte differentiation and increasing the concentration of glucose in the cell media. Our results showed a glucose- and time-dependent increase in adipocyte hypertrophy, ROS production and gene expression of the pro-inflammatory cytokine interleukin-6 (IL-6), as well as a time-dependent increase in lipolysis and in the gene expression of the chemokine monocyte chemoattractant protein 1 (MCP1). We also showed that gene expression of the steroidogenic enzymes 11-beta-hydroxysteroid dehydrogenase type 1 (11βHSD1), 17βHSD type 7 and 12, as well as CYP19A1 (aromatase), were significantly higher in the hypertrophic model relative to the control adipocytes differentiated using the conventional method. The increase in 11βHSD1 and 17βHSD12 expression was consistent with the enhanced conversion of cortisone and androstenedione to cortisol and testosterone, respectively. As these characteristics reflect those commonly observed in obesity, hypertrophic 3T3-L1 adipocytes are an appropriate in vitro model to study mechanisms of adipocyte dysfunction in an era where the rise in obesity incidence is a global health concern, and where access to adipose tissue from obese patients are limited., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2023
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4. Metabolic consequences of antipsychotic therapy: preclinical and clinical perspectives on diabetes, diabetic ketoacidosis, and obesity.
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Heal DJ, Gosden J, Jackson HC, Cheetham SC, and Smith SL
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- Animals, Body Weight drug effects, Diabetes Mellitus metabolism, Diabetic Ketoacidosis metabolism, Humans, Insulin-Secreting Cells drug effects, Models, Animal, Obesity metabolism, Antipsychotic Agents adverse effects, Diabetes Mellitus chemically induced, Diabetic Ketoacidosis chemically induced, Obesity chemically induced
- Abstract
Antipsychotic drugs, particularly second-generation antipsychotics (SGAs), have reduced the burden to society of schizophrenia, but many still produce excessive weight gain. A significant number of SGAs also act directly to impair glycemic control causing insulin resistance, impaired glucose tolerance and type 2 diabetes, and also rarely diabetic ketoacidosis (DKA). Schizophrenia itself is almost certainly causal in many endocrine and metabolic disturbances, making this population especially vulnerable to the adverse metabolic consequences of treatment with SGAs. Hence, there is an urgent need for a new generation of antipsychotic drugs that provide efficacy equal to the best of the SGAs without their liability to cause weight gain or type 2 diabetes. In the absence of such safe and effective alternatives to the SGAs, there is a substantial clinical need for the introduction of new antipsychotics without adverse metabolic effects and new antiobesity drugs to combat these metabolic side effects. We discuss the adverse metabolic consequences of schizophrenia, its exacerbation by a lack of social care, and the additional burden placed on patients by their medication. A critical evaluation of the animal models of antipsychotic-induced metabolic disturbances is provided with observations on their strengths and limitations. Finally, we discuss novel antipsychotic drugs with a lower propensity to increase metabolic risk and adjunctive medications to mitigate the adverse metabolic actions of the current generation of antipsychotics.
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- 2012
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5. The utility of animal models to evaluate novel anti-obesity agents.
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Vickers SP, Jackson HC, and Cheetham SC
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- Animals, Anti-Obesity Agents adverse effects, Anti-Obesity Agents therapeutic use, Anti-Obesity Agents toxicity, Appetite Depressants adverse effects, Appetite Depressants pharmacology, Appetite Depressants toxicity, Feeding Behavior physiology, Female, Humans, Male, Obesity epidemiology, Obesity pathology, Obesity physiopathology, Satiety Response drug effects, Time Factors, Anti-Obesity Agents pharmacology, Appetite Depressants therapeutic use, Disease Models, Animal, Obesity drug therapy
- Abstract
The global incidence of obesity continues to rise and is a major driver of morbidity and mortality through cardiovascular and cerebrovascular diseases. Animal models used in the discovery of novel treatments for obesity range from straightforward measures of food intake in lean rodents to long-term studies in animals exhibiting obesity due to the continuous access to diets high in fat. The utility of these animal models can be extended to determine, for example, that weight loss is due to fat loss and/or assess whether beneficial changes in key plasma parameters (e.g. insulin) are evident. In addition, behavioural models such as the behavioural satiety sequence can be used to confirm that a drug treatment has a selective effect on food intake. Typically, animal models have excellent predictive validity whereby drug-induced weight loss in rodents subsequently translates to weight loss in man. However, despite this, at the time of writing orlistat (Europe; USA) remains the only drug currently marketed for the treatment of obesity, with sibutramine having recently been withdrawn from sale globally due to the increased incidence of serious, non-fatal cardiovascular events. While the utility of rodent models in predicting clinical weight loss is detailed, the review also discusses whether animals can be used to predict adverse events such as those seen with recent anti-obesity drugs in the clinic., (© 2011 RenaSci Consultancy Ltd. British Journal of Pharmacology © 2011 The British Pharmacological Society.)
- Published
- 2011
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6. Deorphanization of a G protein-coupled receptor for oleoylethanolamide and its use in the discovery of small-molecule hypophagic agents.
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Overton HA, Babbs AJ, Doel SM, Fyfe MC, Gardner LS, Griffin G, Jackson HC, Procter MJ, Rasamison CM, Tang-Christensen M, Widdowson PS, Williams GM, and Reynet C
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- Animals, Appetite Depressants administration & dosage, Appetite Depressants chemistry, Cyclic AMP metabolism, Diet, Dose-Response Relationship, Drug, Endocannabinoids, Humans, Male, Mice, Molecular Sequence Data, Obesity drug therapy, Oleic Acids administration & dosage, Oleic Acids chemistry, RNA, Messenger genetics, RNA, Messenger metabolism, Rats, Rats, Sprague-Dawley, Rats, Wistar, Receptors, G-Protein-Coupled agonists, Receptors, G-Protein-Coupled genetics, Substrate Specificity, Time Factors, Yeasts metabolism, Appetite Depressants pharmacology, Feeding Behavior drug effects, Oleic Acids metabolism, Oleic Acids pharmacology, Receptors, G-Protein-Coupled metabolism
- Abstract
The endogenous lipid signaling agent oleoylethanolamide (OEA) has recently been described as a peripherally acting agent that reduces food intake and body weight gain in rat feeding models. This paper presents evidence that OEA is an endogenous ligand of the orphan receptor GPR119, a G protein-coupled receptor (GPCR) expressed predominantly in the human and rodent pancreas and gastrointestinal tract and also in rodent brain, suggesting that the reported effects of OEA on food intake may be mediated, at least in part, via the GPR119 receptor. Furthermore, we have used the recombinant receptor to discover novel selective small-molecule GPR119 agonists, typified by PSN632408, which suppress food intake in rats and reduce body weight gain and white adipose tissue deposition upon subchronic oral administration to high-fat-fed rats. GPR119 therefore represents a novel and attractive potential target for the therapy of obesity and related metabolic disorders.
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- 2006
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7. The uptake of a fluorescently labelled antisense oligonucleotide in vitro and in vivo.
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Robinson ES, Nutt DJ, Jackson HC, and Hudson AL
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- Animals, Biological Transport, Cells, Cultured, Drug Administration Routes, Fluorescein administration & dosage, In Vitro Techniques, Male, Oligodeoxyribonucleotides, Antisense administration & dosage, Rats, Rats, Wistar, Cerebral Cortex metabolism, Fluorescein pharmacokinetics, Oligodeoxyribonucleotides, Antisense pharmacokinetics
- Abstract
Antisense oligonucleotides have been used to target a range of different gene products in the CNS including neurotransmitter receptors. Previous studies using antisense oligonucleotides to target the rat alpha(2A/D)-adrenoceptor revealed changes in receptor expression in specific brain areas following i.c.v. administration but no reduction was observed following antisense treatment in primary cortical neurones. In order to resolve these discrepant results, the uptake and distribution of the antisense sequence has been determined. In vivo, the fluorescent signal was detected close to the site of injection (2-3 mm) and on the same side of the brain as the injection. Although the oligonucleotides (ODN) were distributed throughout the CSF, the ODN was not widely distributed within the mid or hindbrain parenchyma. In vitro uptake studies revealed the antisense was poorly taken up into primary cortical neurones but a higher level of fluorescence was detected in a small sub-population of cells. These studies demonstrate that antisense is rapidly taken up into cells in vivo but poorly taken up into primary cortical neurones in culture. These data provide further evidence for the uptake and distribution of antisense oligonucleotides in neuronal tissue in vivo.
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- 2005
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8. Role of picornaviruses in flu-like illnesses of adults enrolled in an oseltamivir treatment study who had no evidence of influenza virus infection.
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Boivin G, Osterhaus AD, Gaudreau A, Jackson HC, Groen J, and Ward P
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- Adolescent, Adult, Aged, Double-Blind Method, Enterovirus classification, Humans, Influenza A virus isolation & purification, Influenza B virus isolation & purification, Middle Aged, Nasopharynx virology, Oseltamivir, RNA, Viral blood, Rhinovirus classification, Acetamides therapeutic use, Antiviral Agents therapeutic use, Enterovirus isolation & purification, Influenza, Human drug therapy, Influenza, Human virology, Picornaviridae Infections virology, Rhinovirus isolation & purification
- Abstract
The primary objective of this study was to determine the role of picornavirus in flu-like episodes (temperature of > or =38.0 degrees C plus one respiratory and one constitutional symptom) among otherwise healthy adults enrolled in a placebo-controlled, double-blind, randomized oseltamivir treatment study. Combined nasal and pharyngeal swabs were collected at baseline for influenza cultures and picornavirus reverse transcription (RT)-PCR. In addition, acute- and convalescent-serum samples were obtained for serological studies of common respiratory pathogens. From a total of 719 subjects enrolled in the clinical trial within 36 h of the onset of symptoms, 475 (66%) had evidence of recent influenza A or B virus infections by means of culture and/or serological testing. Of the 244 remaining patients, 36 (15%) presented a seroconversion for at least one of the common respiratory viruses or atypical pathogens. An RT-PCR assay for the picornavirus 5" noncoding region (NCR) was positive in a subset of 15 (19%) of 78 patients with flu-like illnesses of undetermined etiology. Sequence analysis of the picornavirus 5" NCR amplicons revealed that 14 (93%) of them had greater homology to rhinoviruses, whereas 1 (7%) was related to enteroviruses. Interestingly, median total symptom scores and oral temperatures of picornavirus-positive patients (n = 15) and placebo-treated influenza virus-positive patients (n = 161) were similar over a 3-week period. We conclude that, among the influenza virus-negative preselected cases of this study, rhinoviruses were relatively frequent pathogens associated with important respiratory and systemic symptoms.
- Published
- 2002
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9. Paradoxical effects of a high sucrose diet: high energy intake and reduced body weight gain.
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Goodson S, Halford JC, Jackson HC, and Blundell JE
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- Animals, Dietary Carbohydrates administration & dosage, Dietary Fats administration & dosage, Energy Metabolism, Rats, Dietary Sucrose administration & dosage, Energy Intake, Weight Gain
- Published
- 2001
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10. Behavioural and physiological effects induced by an infusion of antisense to alpha(2D)-adrenoceptors in the rat.
- Author
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Robinson ES, Nutt DJ, Jackson HC, and Hudson AL
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- Animals, Body Temperature drug effects, Body Temperature physiology, Drinking drug effects, Drinking physiology, Eating drug effects, Eating physiology, Grooming physiology, Male, Motor Activity physiology, Pupil drug effects, Pupil physiology, Rats, Rats, Wistar, Receptors, Adrenergic, alpha-2 physiology, Weight Gain drug effects, Weight Gain physiology, Grooming drug effects, Motor Activity drug effects, Oligonucleotides, Antisense pharmacology, Receptors, Adrenergic, alpha-2 drug effects
- Abstract
1. The aim of this study was to investigate the behavioural and physiological effects of an i.c.v. infusion of antisense oligonucleotide to the alpha(2D)-adrenoceptor subtype. Behavioural and physiological parameters were monitored for 2 days before the infusion, throughout the 3-day infusion period and for 3 days following the end of the infusion. 2. The antisense infusion resulted in a significant increase in behavioural activity characterized by increased locomotion and grooming scores. Behavioural activity scores of rats treated with antisense to alpha(2D)-adrenoceptors were significantly higher than those of rats treated with vehicle (H(2)O) or the mismatch toxicity control on day 4 and day 5 and, significantly higher than vehicle controls on day 6. 3. Body weight gain was significantly reduced in the antisense-treated rats at the end of the study compared to the vehicle (34%) and mismatch groups (30%), although daily food and water intakes were not significantly different at any time point. 4. Pupil diameters of rats infused with antisense to alpha(2D)-adrenoceptors were significantly greater than those of animals treated either with vehicle or mismatch oligonucleotide on day 5 of the study. On day 6, the pupil diameters of these animals were still significantly greater than the mismatch group. 5. In conclusion, an i.c.v. infusion of antisense to the alpha(2D)-adrenoceptor induced behavioural activation in rats, increased pupil diameter and reduced total weight gain. These effects were specific to the antisense-treated group and were fully reversed post-infusion.
- Published
- 2000
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11. In vitro and in vivo approaches to the characterization of the alpha2-adrenoceptor.
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Hudson AL, Robinson ES, Lalies MD, Tyacke RJ, Jackson HC, and Nutt DJ
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- Animals, Dopamine metabolism, Idazoxan metabolism, Norepinephrine metabolism, Oligonucleotides, Antisense metabolism, Rabbits, Rats, Thionucleotides metabolism, Adrenergic alpha-Antagonists metabolism, Brain metabolism, Idazoxan analogs & derivatives, Receptors, Adrenergic, alpha-2 metabolism
- Abstract
1. In order to more fully understand the role of the alpha2-adrenoceptor in brain function, a combination of in vitro and in vivo techniques were utilized including radioligand binding, autoradiography, brain microdialysis and antisense oligonucleotides. 2. Binding studies showed the tritiated form of the selective alpha2-adrenoceptor antagonist, RX821002 (methoxy-idazoxan) labelled an apparent single population of sites in rat brain membranes with high affinity (1 nM), for which prazosin had low affinity (1107 nM). Similar studies in rabbit brain membranes found that prazosin and oxymetazoline were able to displace [3H]-RX821002 in a biphasic manner indicating the presence of subtypes of alpha2-adrenoceptors. 3. Receptor autoradiography revealed a distribution of [3H]-RX821002 binding in rat brain consistent with the labelling of all alpha2-adrenoceptor subtypes, namely alpha(2A/D-), alpha2B and alpha2C. 4. In rat, in vivo brain dialysis experiments demonstrated peripherally administered RX821002 elevated basal noradrenaline in frontal cortex and also, although to a lesser extent, in ventral hippocampus. RX821002 was also able to elevate extracellular dopamine in the striatum. 5. A 7-day i.c.v. infusion of an antisense oligonucleotide targeting the alpha(2A/D)-adrenoceptor, resulted in a significant reduction in the autoradiographic density of [3H]-RX821002 binding in specific brain areas, notably the lateral septal nuclei and anterior hypothalamic area. 6. Several years of research by our group has extended our knowledge of the pharmacology and function of the alpha2-adrenoceptor and has provided evidence of the roles of this receptor in the control of monoamine turnover. The successful use of antisense technology to knockdown expression of the alpha(2A/D) subtype provides future opportunities to explore the physiology of this receptor subtype.
- Published
- 1999
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12. Autoradiographical and behavioural effects of a chronic infusion of antisense to the alpha2D-adrenoceptor in the rat.
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Robinson ES, Nutt DJ, Hall L, Jackson HC, and Hudson AL
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- Animals, Autoradiography, Base Sequence, Body Temperature drug effects, Brain metabolism, Brimonidine Tartrate, Idazoxan analogs & derivatives, Idazoxan metabolism, Injections, Intraventricular, Male, Pupil drug effects, Quinoxalines pharmacology, RNA, Antisense pharmacology, Rats, Rats, Wistar, Receptors, Adrenergic, alpha-2 metabolism, Behavior, Animal drug effects, RNA, Antisense administration & dosage, Receptors, Adrenergic, alpha-2 genetics
- Abstract
1. The aims of this study were, firstly to use receptor autoradiography to investigate the effect of antisense oligonucleotides to the alpha2D-adrenoceptor on receptor binding and, secondly to measure behavioural and physiological parameters to determine whether the chronic antisense infusion had any effect on alpha2-adrenoceptor function in vivo. 2. A 3 day infusion of antisense to the alpha2D-adrenoceptor significantly reduced specific [3H]-RX821002 binding in the septum (20 - 30%) and anterior hypothalamic area (20 - 30%). beta-Adrenoceptor expression was unaffected in those brain areas examined, indicating the antisense knockdown was specific to the alpha2-adrenoceptors. 3. On the second day of the infusion, the hypothermic response to UK 14,304 was significantly attenuated in the antisense-treated group compared with both vehicle and mismatch controls. The effect was fully reversible and a similar decrease in body temperature was observed in all the treatment groups 4 days after the end of infusion. 4. During the second day of the infusion, the effects of UK 14,304 on behaviour were reduced in the antisense-treated rats, but were not significantly lower than those of the vehicle and mismatch, UK 14, 304 controls. These trends were not observed 4 days after the end of the infusion. 5. In conclusion, antisense has been shown to selectively knockdown alpha2-adrenoceptor expression in specific brain areas. The consequence of this knockdown is a significant attenuation of UK 14,304-induced hypothermia and a reduction in its sedative actions. These changes were fully reversed 4 days after the end of the infusion.
- Published
- 1999
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13. Sibutramine: a novel anti-obesity drug. A review of the pharmacological evidence to differentiate it from d-amphetamine and d-fenfluramine.
- Author
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Heal DJ, Aspley S, Prow MR, Jackson HC, Martin KF, and Cheetham SC
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- Animals, Biogenic Monoamines metabolism, Cyclobutanes adverse effects, Energy Metabolism drug effects, Humans, Hypertension, Pulmonary chemically induced, Cyclobutanes therapeutic use, Dextroamphetamine, Fenfluramine, Obesity drug therapy, Selective Serotonin Reuptake Inhibitors
- Abstract
Sibutramine (BTS 54 524; N-[1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutyl]-N,N-dimethylamine hydrochloride monohydrate) is a novel 5-HT (serotonin) and noradrenaline reuptake inhibitor (SNRI) anti-obesity drug. Sibutramine reduces the food intake of rodents and this effect is partially or completely reversed by pretreating with 5-HT or noradrenaline antagonists, indicating that both neurotransmitters are involved in sibutramine's hypophagic effect. In addition, fluoxetine and nisoxetine, which are selective reuptake inhibitors of 5-HT and noradrenaline, respectively, have no effect on food intake when given alone, but they profoundly inhibit food intake when given in combination (equivalent to the actions of the SNRI, sibutramine), demonstrating a synergistic interaction of those two monoamines in the control of ingestive behaviour. Sibutramine reduces food intake by enhancing the physiological response of post-ingestive satiety. This reduction of food intake is a CNS-mediated effect because it is induced by intracerebroventricular injection of sibutramine's potently active secondary and primary amine metabolites (BTS 54 354 and BTS 54 505). Sibutramine increases energy expenditure (thermogenesis) in rats. Once again, whilst fluoxetine and nisoxetine have no thermogenic effect when given alone, the combination of these two selective monoamine reuptake inhibitors profoundly enhances thermogenesis, demonstrating a synergistic interaction of 5-HT and noradrenaline neurotransmission in the regulation of energy expenditure. Sibutramine-induced thermogenesis is abolished by administration of a high non-selective dose of atenolol or ICI 118,551 which blocks beta3-adrenoceptors in addition to beta1- and beta2-adrenoceptors, but not by a low dose of atenolol or ICI 118,551 which blocks beta1- and beta2-adrenoceptors, respectively. Glucose utilization studies demonstrate that sibutramine-induced thermogenesis is mediated via selective sympathetic activation of brown adipose tissue, and it is a centrally mediated effect because it is prevented by pretreating the animals with the ganglionic blocker, chlorisondamine. The SNRI mode of action of sibutramine is clearly differentiated from those of the two major classes of anti-obesity drugs, viz, the 5-HT releasing agents, for example, fenfluramine and dexfenfluramine, and the noradrenaline + dopamine-releasing agents, for example, dexamphetamine. In the case of the 5-HT-releasing agents, this mechanism has been linked in animal studies to profound and prolonged depletion and dysfunction of CNS 5-HT neurons. With noradrenaline + dopamine-releasing agents, it is the enhancement of central dopaminergic function which is believed to be responsible for their stimulant, rewarding and reinforcing properties and it is their releasing mechanism which makes them such powerful psychostimulant drugs of abuse. By utilizing noradrenaline and 5-HT for its anti-obesity effects, sibutramine is differentiated from other weight-reducing drugs which act through either 5-HT alone or noradrenaline + dopamine. In addition, sibutramine is further differentiated because it enhances monoamine function by reuptake inhibition, rather than by monoamine release.
- Published
- 1998
14. Isolation and characterisation of an antifungal antibiotic (GR135402) with protein synthesis inhibition.
- Author
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Kinsman OS, Chalk PA, Jackson HC, Middleton RF, Shuttleworth A, Rudd BA, Jones CA, Noble HM, Wildman HG, Dawson MJ, Stylli C, Sidebottom PJ, Lamont B, Lynn S, and Hayes MV
- Subjects
- Animals, Antifungal Agents pharmacology, Aspergillus drug effects, Candida albicans drug effects, Fermentation, Mice, Microbial Sensitivity Tests, Mitosporic Fungi classification, Polycyclic Compounds pharmacology, Protein Synthesis Inhibitors pharmacology, Antifungal Agents chemistry, Antifungal Agents isolation & purification, Mitosporic Fungi chemistry, Polycyclic Compounds chemistry, Polycyclic Compounds isolation & purification, Protein Synthesis Inhibitors chemistry, Protein Synthesis Inhibitors isolation & purification
- Abstract
A novel antifungal antibiotic GR135402 has been isolated from a fermentation broth of Graphium putredinis which inhibited protein synthesis in Candida albicans but not rabbit reticulocytes. The spectrum of activity included C. albicans and Cryptococcus neoformans but not some other Candida species or Aspergillus species. Therapeutic efficacy in a mouse model of systemic candidosis was attained following parenteral dosing.
- Published
- 1998
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15. Comparison of the effects of sibutramine and other monoamine reuptake inhibitors on food intake in the rat.
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Jackson HC, Needham AM, Hutchins LJ, Mazurkiewicz SE, and Heal DJ
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- Animals, Cyclohexanols pharmacology, Fenfluramine pharmacology, Fluoxetine analogs & derivatives, Fluoxetine pharmacology, Male, Obesity drug therapy, Rats, Rats, Sprague-Dawley, Venlafaxine Hydrochloride, Cyclobutanes pharmacology, Eating drug effects, Neurotransmitter Uptake Inhibitors pharmacology
- Abstract
1. The effects of the potent 5-hydroxytryptamine (5-HT) and noradrenaline reuptake inhibitor (serotonin-noradrenaline reuptake inhibitor, SNRI), sibutramine, on the cumulative food intake of freely-feeding male Sprague-Dawley rats during an 8 h dark period were investigated and compared to those of the selective 5-HT reuptake inhibitor (selective serotonin reuptake inhibitor, SSRI), fluoxetine; the selective noradrenaline reuptake inhibitor, nisoxetine; the 5-HT and noradrenaline reuptake inhibitors, venlafaxine and duloxetine; and the 5-HT releaser and 5-HT reuptake inhibitor, (+)-fenfluramine. 2. Sibutramine (3 and 10 mg kg-1, p.o.) and (+)-fenfluramine (1 and 3 mg kg-1, p.o.) produced a significant, dose-dependent decrease in food intake over the 8 h dark period. These responses became apparent within the first 2 h following drug administration. 3. Fluoxetine (3, 10 and 30 mg kg-1, p.o.), and nisoxetine (3, 10 and 30 mg kg-1, p.o.) had no significant effect on food intake during the 8 h dark period. However, a combination of fluoxetine and nisoxetine (30 mg kg-1, p.o., of each) significantly decreased food intake 2 and 8 h after drug administration. 4. Venlafaxine (100 and 300 mg kg-1, p.o.) and duloxetine (30 mg kg-1, p.o.) also significantly decreased food intake in the 2 and 8 h following drug administration. 5. The results of this study demonstrate that inhibition of 5-HT and noradrenaline reuptake by sibutramine, venlafaxine, duloxetine, or by a combination of fluoxetine and nisoxetine, markedly reduces food intake in freely-feeding rats and suggest that this may be a novel approach for the treatment of obesity.
- Published
- 1997
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16. Investigation of the mechanisms underlying the hypophagic effects of the 5-HT and noradrenaline reuptake inhibitor, sibutramine, in the rat.
- Author
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Jackson HC, Bearham MC, Hutchins LJ, Mazurkiewicz SE, Needham AM, and Heal DJ
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- Animals, Idazoxan analogs & derivatives, Idazoxan pharmacology, Male, Metoprolol pharmacology, Prazosin pharmacology, Propanolamines pharmacology, Rats, Rats, Sprague-Dawley, Receptors, Adrenergic, beta drug effects, Receptors, Serotonin drug effects, Adrenergic Uptake Inhibitors pharmacology, Cyclobutanes pharmacology, Eating drug effects, Selective Serotonin Reuptake Inhibitors pharmacology
- Abstract
1. Sibutramine is a novel 5-hydroxytryptamine (5-HT) and noradrenaline reuptake inhibitor (serotonin-noradrenaline reuptake inhibitor, SNRI) which is currently being developed as a treatment for obesity. Sibutramine has been shown to decrease food intake in the rat. In this study we have used a variety of monoamine receptor antagonists to examine the pharmacological mechanisms underlying sibutramine-induced hypophagia. 2. Individually-housed male Sprague-Dawley rats were maintained on reversed phase lighting with free access to food and water. Drugs were administered at 09 h 00 min and food intake was monitored over the following 8 h dark period. 3. Sibutramine (10 mg kg-1, p.o.) produced a significant decrease in food intake during the 8 h following drug administration. This hypophagic response was fully antagonized by the alpha 1-adrenoceptor antagonist, prazosin (0.3 and 1 mg kg-1, i.p.), and partially antagonized by the beta 1-adrenoceptor antagonist, metoprolol (3 and 10 mg kg-1, i.p.) and the 5-HT receptor antagonists, metergoline (non-selective; 0.3 mg kg-1, i.p.); ritanserin (5-HT2A/2C; 0.1 and 0.5 mg kg-1, i.p.) and SB200646 (5-HT2B/2C; 20 and 40 mg kg-1, p.o.). 4. By contrast, the alpha 2-adrenoceptor antagonist, RX821002 (0.3 and 1 mg kg-1, i.p.) and the beta 2-adrenoceptor antagonist, ICI 118,551 (3 and 10 mg kg-1, i.p.) did not reduce the decrease in food intake induced by sibutramine. 5. These results demonstrate that beta 1-adrenoceptors, 5-HT2A/2C-receptors and particularly alpha 1-adrenoceptors, are involved in the effects of sibutramine on food intake and are consistent with the hypothesis that sibutramine-induced hypophagia is related to its ability to inhibit the reuptake of both noradrenaline and 5-HT, with the subsequent activation of a variety of noradrenaline and 5-HT receptor systems.
- Published
- 1997
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17. Antisense oligonucleotides in psychopharmacology and behaviour: promises and pitfalls.
- Author
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Robinson ES, Nutt DJ, Jackson HC, and Hudson AL
- Subjects
- Animals, Behavior, Animal physiology, Brain physiology, Humans, Psychopharmacology, Receptors, Neurotransmitter physiology, Behavior, Animal drug effects, Brain drug effects, Oligonucleotides, Antisense pharmacology, Receptors, Neurotransmitter drug effects
- Abstract
Antisense oligonucleotides are used to study the expression and function of a diverse range of proteins. Areas for which antisense has been used for pharmacological investigation include receptors, neuropeptides and immediate early genes, particularly when specific ligands or markers are not yet available. Antisense oligonucleotides target a specific mRNA and block the expression of the protein by sequence specific hybridization. This technique has not only been shown to be a valuable pharmacological tool but also to have potential therapeutic applications. In this review we discuss the technology behind the technique including developments in methodology employed in antisense experiments. Although antisense provides a novel and highly specific tool, the reliability of the technique and many of the problems associated with antisense experiments are discussed. The main focus of this article is the use of antisense in psychopharmacology to investigate behavioural changes following antisense-mediated inhibition of the expression of specific brain proteins and receptors.
- Published
- 1997
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18. Inhibitory effect of a Pichia anomala killer toxin on the viability of rat-derived Pneumocystis carinii.
- Author
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Jackson HC, Séguy N, Killigin EM, Dei-Cas E, Polonelli L, and Cailliez JC
- Subjects
- Animals, Killer Factors, Yeast, Pneumocystis growth & development, Rats, Mycotoxins pharmacology, Pichia, Pneumocystis drug effects
- Published
- 1996
- Full Text
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19. Anticonvulsant profile of the imidazoquinazolines NNC 14-0185 and NNC 14-0189 in rats and mice.
- Author
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Jackson HC, Hansen HC, Kristiansen M, Suzdak PD, Klitgaard H, Judge ME, and Swedberg MD
- Subjects
- Acoustic Stimulation, Amygdala physiology, Animals, Anticonvulsants antagonists & inhibitors, Bicuculline adverse effects, Carbolines therapeutic use, Clonazepam therapeutic use, Diazepam therapeutic use, Electroshock, Flumazenil pharmacology, GABA Modulators pharmacology, GABA-A Receptor Agonists, Kindling, Neurologic physiology, Male, Mice, Mice, Inbred DBA, Mice, Inbred Strains, Pentylenetetrazole adverse effects, Pentylenetetrazole antagonists & inhibitors, Quinazolines adverse effects, Rats, Rats, Wistar, Seizures chemically induced, Seizures drug therapy, Seizures prevention & control, Anticonvulsants therapeutic use, Quinazolines therapeutic use
- Abstract
The anticonvulsant effects of NNC 14-0185 (3-(3-cyclopropyl-5-isoxazolyl)-6-fluoro-5-morpholino-imidazo[1,5- a] quinazoline) and NNC 14-0189 (3-(5-cyclopropyl-1,2, 4-oxadiazol-3-yl)-7-fluoro-5-(4-methyl-1-piperazinyl)-imidazo[1,5- a] quinazoline) in mice and rats were evaluated and compared with those of diazepam, clonazepam and the novel beta-carboline, abecarnil. Following i.p. administration, NNC 14-0185 and NNC 14-0189 prevented audiogenic seizures in DBA/2 mice and the clonic convulsions induced in mice by pentylenetetrazole, DMCM (methyl 6, 7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate), 3-mercaptopropionic acid and a low dose of bicuculline. NNC 14-0185 and NNC 14-0189 prevented seizures induced by pentylenetetrazole in rats and were also effective anticonvulsants in amygdala-kindled rats. In general, the anticonvulsant potencies of NNC 14-0185 and NNC 14-0189 were comparable to those of the reference benzodiazepines. However, like abecarnil, they were not effective against the seizures induced in mice by maximal electroshock and a high dose of bicuculline. The anticonvulsant effects of NNC 14-0185 and NNC 14-0189 against pentylenetetrazole-induced seizures were apparent within 5 min of i.p. injection and persisted for at least 2 h. These effects appeared to be mediated by benzodiazepine receptors since they were inhibited by concurrent administration of flumazenil. Both NNC 14-0185 and NNC 14-0189 showed greater separation between their anticonvulsant and muscle relaxant effects (measured as impaired rotarod performance) than did diazepam. In this respect, their therapeutic windows were similar (NNC 14-0185) to or better (NNC 14-0189) than that of abecarnil. Tolerance did not develop to the anticonvulsant effects of NNC 14-0185 and NNC 14-0189 over a 4-day test. In comparison, the anticonvulsant effects of diazepam and abecarnil were attenuated by repeated drug administration. Thus, NNC 14-0185 and NNC 14-0189 have a promising anticonvulsant and side-effect profile in comparison with diazepam, clonazepam and abecarnil. The potential use of these compounds in the treatment of epilepsy should be explored further.
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- 1996
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20. Behavioural and anticonvulsant effects of Ca2+ channel toxins in DBA/2 mice.
- Author
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Jackson HC and Scheideler MA
- Subjects
- Acoustic Stimulation, Animals, Behavior, Animal drug effects, Disease Models, Animal, Male, Mice, Mice, Inbred DBA, omega-Agatoxin IVA, omega-Conotoxin GVIA, Calcium Channel Blockers pharmacology, Peptides pharmacology, Seizures prevention & control, Spider Venoms pharmacology, omega-Conotoxins
- Abstract
This study investigated the behavioural and anticonvulsant effects of voltage-sensitive calcium channel blockers in DBA/2 mice. Omega-Conotoxin MVIIC (0.1, 0.3 micrograms ICV/mouse) and omega-agatoxin IVA (0.1, 0.3, 1 micrograms ICV), which act predominantly at P- and/or Q-type calcium channels, prevented clonic and tonic sound-induced seizures in this animal model of reflex epilepsy (ED50 values with 95% confidence limits for protection against clonic sound-induced seizures were 0.09 (0.04-0.36) micrograms ICV and 0.09 (0.05-0.15) micrograms ICV respectively and against tonic seizures 0.07 (0.03-0.16) micrograms ICV and 0.08 (0.04-0.13) micrograms ICV, respectively). The N-type calcium channel antagonists omega-conotoxin GVIA and omega-conotoxin MVIIA were also tested in this model. Omega-Conotoxin GVIA was anticonvulsant in DBA/2 mice, but only at high doses (3 micrograms ICV prevented tonic seizures in 60% of the animals; 10 micrograms ICV prevented clonic seizures in 60% and tonic seizures in 90% of the animals), whereas omega-conotoxin MVIIA did not inhibit sound-induced seizures in doses up to 10 micrograms ICV. Both omega-conotoxin GVIA and omega-conotoxin MVIIA induced an intense shaking syndrome in doses as low as 0.1 microgram ICV, whereas omega-conotoxin MVIIC and omega-agatoxin IVA did not produce shaking at any of the doses examined. Finally, omega-conotoxin GI (0.01-1 microgram ICV) and alpha-conotoxin SI (0.3-30 micrograms ICV), which both act at acetylcholine nicotinic receptors, were not anticonvulsant and did not induce shaking in DBA/2 mice. These results confirm that blockers of N- and P-/Q-type calcium channels produce different behavioural responses in animals. The anticonvulsant effects of omega-conotoxin MVIIC and omega-agatoxin IVA in DBA/2 mice are consistent with reports that P- and/or Q-type calcium channel blockers inhibit the release of excitatory amino acids and are worthy of further exploration.
- Published
- 1996
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21. 6,7-disubstituted 2,4-diaminopteridines: novel inhibitors of Pneumocystis carinii and Toxoplasma gondii dihydrofolate reductase.
- Author
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Jackson HC, Biggadike K, McKilligin E, Kinsman OS, Queener SF, Lane A, and Smith JE
- Subjects
- 4-Aminobenzoic Acid metabolism, Animals, Cell Line, Female, Male, Mice, Rats, Rats, Sprague-Dawley, Structure-Activity Relationship, Folic Acid Antagonists pharmacology, Pneumocystis drug effects, Pteridines pharmacology, Toxoplasma drug effects
- Abstract
Four novel, disubstituted diaminopteridines have been identified which antagonize the uptake of a folate precursor (para-aminobenzoic acid) by rat-derived Pneumocystis carinii maintained in short-term axenic culture at concentrations ranging from 4.5 to 26 microM. The compounds were at least 10 to 100 times more active than trimethoprim in this assay. None of these entities exhibited toxicity to mammalian cell lines at < 100 microM. The same structures also caused significant inhibition of Toxoplasma gondii tachyzoite replication within Madin-Darby bovine kidney cells at concentrations ranging from 0.1 to 10 microM. Three of the structures (GR92754, AH10639, and AH2504) were at least an order of magnitude more potent than the standard anti-T. gondii agent, pyrimethamine. All three entities were also significantly more potent and selective than pyrimethamine as inhibitors of T. gondii dihydrofolate reductase (DHFR), with 50% inhibitory concentrations within the range of 0.018 to 0.033 microM. One of these compounds, 6,7-dibutyl-2,4-diaminopteridine (GR92754), was also a potent and selective inhibitor of P. carinii DHFR (50% inhibitory concentration, 0.082 microM). GR92754 is the first DHFR inhibitor described that exhibits greater potency, selectivity, and intracellular activity against both organisms than any of the DHFR agents used clinically, namely, trimethoprim, pyrimethamine, and trimetrexate. This information could provide the starting point for examination of the pharmacokinetic and therapeutic potential of GR92754 and related chemical entities with animal models.
- Published
- 1996
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22. Discriminative stimulus produced by the imidazoline I2 site ligand, 2 -BFI.
- Author
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Jordan S, Jackson HC, Nutt DJ, and Handley SL
- Abstract
2-(2-Benzofuranyl)-2-imidazoline, RX801077 (2-BFI) which has high affinity for imidazoline I(2) binding sites and very low aflinity for α(2)-adrenoceptors, has been investigated for its ability to produce a discriminative stimulus (cue) in drug-discrimination studies in rats since the existence of such a cue could assist in determining the functionality of I(2) sites. All rats subjected to training proved able to discriminate the training dose of 2-BFI (33 μmol/kg i.p) from saline vehicle and lower (5-14 μmol/kg) doses exhibited dose-dependent substitution. The mixed α(2)-adrenoceptor/I( 2) site ligand idazoxan fully substituted at 40μmol/kg. However, ethoxy idazoxan (11 μmol/kg) and fluparoxan (13 μmol/kg), selective α( 2)-adrenoceptor antagonists, also fully substituted for 2- BFI as did the monoamine oxidase (MAO) inhibitors moclobemide (99 μmol/kg) and pargyline (153 μmol/kg). A lower dose of moclobemide (16 μmol/kg) exhibited partial substitution. The α( 2)-adrenoceptor agonists clonidine (0.1 μmol/kg) and guanabenz (1.4 μmol/kg), and the benzodiazepine diazepam (14 μmol/kg), failed to substitute for 2-BFI indicating cue specificity. However, 2-BFI (14-50 μmol/kg) substituted partially but dose-dependently for clonidine (0.1 μmol/kg) in rats trained to distinguish the latter from saline. Changes in rates of response were independent of the degree of substitution. The observed pattern of drug substitution is consistent with the previously reported ability of 2-BFI to decrease MAO activity and thus increase extracellular monoamines.
- Published
- 1996
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23. Discriminative stimulus properties of ethoxy idazoxan.
- Author
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Jordan S, Jackson HC, Nutt DJ, and Handley SL
- Abstract
The technique of drug discrimination was used to examine the ability of the highly selective α(2)-adrenoceptor antagonist ethoxy idazoxan, which has negligible affinity for α( 1)-adrenoceptors or I(2) imidazoline receptors, to produce an interoceptive discriminable stimulus or cue in rats. Rats were trained to respond on one lever after receiving α-ethoxy idazoxan (2.5 mg/kg, i.p.) and on the opposite lever after saline vehicle. The ethoxy idazoxan cue appeared to be mediated by antagonists of central α(2)-adrenoceptors, on the basis that dose- related substitution was produced by the highly selective α(2)-adrenoceptor antagonists idazoxan (imidazoline), fluparoxan and 1-(2-pyrimidinyl) piperazine (1-PP) (both non-imidazoline) but not by clonidine, which acts as an agonist at this receptor, nor by the peripherally acting α(2)-adrenoceptor antagonist L659,066. However, the α(2)-adrenoceptor antagonists yohimbine and atipamezole showed partial and non-dose-dependent substitution for ethoxy idazoxan over a wide range of doses. 2-BFI [2-(2-benzfuranyl)-2-imidazoline, RX801077], an imidazoline which is highly selective for I(2) imidazoline receptors over α(2)-adrenoceptors, showed dose- dependent substitution for ethoxy idazoxan, although the maximum effect (73% responding on the ethoxy idazoxan lever) fell short of criteria adopted for full substitution. Among other agents which bind to I(2) receptors, only idazoxan and 2-phenyl-2-imidazoline exhibited significant substitution; cirazoline could only be tested at very low doses because it powerfully inhibited responding in general, probably due to its α(1)-adrenoceptor agonist properties. It is suggested that the ability of 2-BFI to substitute partially for ethoxy idazoxan might be due to the ability of both agents to increase extracellular concentrations of noradrenaline.
- Published
- 1995
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24. DNA amplification of a portion of the phosphomannose isomerase (PMI) gene in Pneumocystis carinii-enriched extracts.
- Author
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Chung V, Wakefield AE, Kinsman OS, and Jackson HC
- Subjects
- Amino Acid Sequence, Animals, Gene Amplification, Mannose-6-Phosphate Isomerase classification, Molecular Sequence Data, Opportunistic Infections microbiology, Pneumocystis isolation & purification, Pneumonia, Pneumocystis microbiology, Rats, Rats, Sprague-Dawley, Sequence Homology, Amino Acid, Species Specificity, DNA, Fungal genetics, Genes, Fungal, Mannose-6-Phosphate Isomerase genetics, Pneumocystis enzymology, Pneumocystis genetics
- Published
- 1994
25. Measurement of protein biosynthesis in Pneumocystis carinii to investigate the effects of translation-specific inhibitors.
- Author
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Bishop RL, Jackson HC, and Warhurst DC
- Subjects
- Animals, Antifungal Agents pharmacology, Drug Resistance, Microbial, In Vitro Techniques, Methionine metabolism, Pneumocystis genetics, Protein Biosynthesis drug effects, Protein Precursors metabolism, Rats, Ribosomes drug effects, Ribosomes metabolism, Fungal Proteins biosynthesis, Pneumocystis drug effects, Pneumocystis metabolism, Protein Synthesis Inhibitors pharmacology
- Published
- 1994
26. Evaluation of anti-Pneumocystis agents using flow cytometry.
- Author
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Morley PJ, Dash L, and Jackson HC
- Subjects
- Animals, Candida albicans isolation & purification, Drug Evaluation, Preclinical methods, Evaluation Studies as Topic, In Vitro Techniques, Male, Microbial Sensitivity Tests, Mycology methods, Opportunistic Infections microbiology, Pneumocystis isolation & purification, Pneumonia, Pneumocystis microbiology, Rats, Rats, Sprague-Dawley, Antifungal Agents pharmacology, Flow Cytometry methods, Pneumocystis drug effects
- Published
- 1994
27. (S)-4-carboxy-3-hydroxyphenylglycine, an antagonist of metabotropic glutamate receptor (mGluR) 1a and an agonist of mGluR2, protects against audiogenic seizures in DBA/2 mice.
- Author
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Thomsen C, Klitgaard H, Sheardown M, Jackson HC, Eskesen K, Jacobsen P, Treppendahl S, and Suzdak PD
- Subjects
- Acoustic Stimulation, Animals, Anticonvulsants pharmacology, Cricetinae, Dose-Response Relationship, Drug, Glycine pharmacology, Mice, Mice, Inbred DBA, Receptors, Metabotropic Glutamate classification, Seizures etiology, Glycine analogs & derivatives, Receptors, Metabotropic Glutamate antagonists & inhibitors, Receptors, Metabotropic Glutamate metabolism, Seizures prevention & control
- Abstract
The in vivo anticonvulsant effects and in vitro metabotropic glutamate receptor selectivity of (S)-4-carboxy-3-hydroxy-phenylglycine [(S)-4C3HPG] were examined. Intracerebroventricular injection of (S)-4C3HPG dose-dependently antagonized audiogenic-induced clonic and tonic convulsions in DBA/2 mice with ED50 values of 76 and 110-nmol per mouse, respectively. (S)-4C3HPG dose-dependently inhibited the spontaneously evoked epileptic spikes in a cingulate cortex-corpus callosum slice preparation. (S)-4C3HPG displaced the binding of [3H]glutamate in membranes prepared from baby hamster kidney (BHK) cells expressing the metabotropic glutamate receptor mGluR1a with an EC50 of 5 +/- 1 microM. (S)-4C3HPG dose-dependently antagonized glutamate-stimulated phosphoinositide hydrolysis in BHK cells expressing mGluR1a with an IC50 of 15 +/- 3 microM. (S)-4C3HPG was, however, an agonist at mGluR2 with an EC50 of 21 +/- 4 microM for inhibition of forskolin-stimulated cyclic AMP formation in BHK cells expressing the mGluR2. (S)-4C3HPG had no effects at mGluR4a. These data suggest that the anticonvulsant action of (S)-4C3HPG is mediated by combined antagonism of mGluR1a and agonism of mGluR2. These results suggest the importance of mGluR1a and/or mGluR2 in the control of epileptic activity.
- Published
- 1994
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28. Buprenorphine-cocaine interactions in mice: effect on locomotor activity and hole-dipping behaviour.
- Author
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Jackson HC, Griffin IJ, and Nutt DJ
- Subjects
- Animals, Buprenorphine administration & dosage, Cocaine administration & dosage, Dose-Response Relationship, Drug, Drug Interactions, Male, Mice, Behavior, Animal drug effects, Buprenorphine pharmacology, Cocaine pharmacology, Motor Activity drug effects
- Abstract
The effect of cocaine and the mixed mu-opioid partial agonist/kappa-antagonist buprenorphine on locomotor activity and hole-dipping behaviour was investigated in mice. The drugs were given alone and in combination. Cocaine (7.5, 15, 30 mg kg-1, i.p.) significantly increased locomotion in a dose-related manner in the hour following injection. The two highest doses also increased hole-dipping although this response was not consistently seen. Buprenorphine (0.5, 5 mg kg-1, i.p.) produced an increase in locomotion which occurred 30-60 min after injection but did not alter hole-dipping behaviour. A lower dose (0.05 mg kg-1) had no effect on either parameter. The locomotion induced by cocaine (15 mg kg-1, i.p.) was not modified by buprenorphine (0.05, 0.5, 1, 5 mg kg-1, i.p.; 5 min pretreatment). However, hole-dipping was almost completely abolished in animals given combinations of cocaine and buprenorphine (0.05-5 mg kg-1, i.p.), although neither drug decreased hole-dipping when given alone. This observation, which was not simply due to the emergence of stereotyped behaviour, suggests an interaction between buprenorphine and cocaine.
- Published
- 1993
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29. A single preexposure produces sensitization to the locomotor effects of cocaine in mice.
- Author
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Jackson HC and Nutt DJ
- Subjects
- Animals, Conditioning, Psychological drug effects, Environment, Habituation, Psychophysiologic, Male, Mice, Mice, Inbred Strains, Cocaine pharmacology, Motor Activity drug effects
- Abstract
Sensitization to the locomotor effects of cocaine (10 mg/kg, IP) occurred in mice following preexposure to a single high dose (40 mg/kg, IP) of the drug on the previous day. Behavioral sensitization only occurred under certain experimental conditions; that is, in mice which were injected in a novel environment (i.e., the activity boxes) on day 1 and tested in the same environment on day 2. It did not occur in mice that were fully habituated to the test apparatus on both days of the experiment or in mice that were injected in the home cage on day 1. This model is consistent with studies in rats, and offers the opportunity for further characterization of the processes underlying cocaine sensitization.
- Published
- 1993
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30. Benzodiazepine partial agonists.
- Author
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Jackson HC
- Published
- 1993
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31. Epilepsy europe: glasgow, september 1992.
- Author
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Jackson HC
- Published
- 1993
- Full Text
- View/download PDF
32. Central alpha-2 adrenoceptors are responsible for a clonidine-induced cue in a rat drug discrimination paradigm.
- Author
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Jordan S, Jackson HC, Nutt DJ, and Handley SL
- Subjects
- Adrenergic alpha-2 Receptor Agonists, Adrenergic alpha-2 Receptor Antagonists, Animals, Clonidine antagonists & inhibitors, Conditioning, Operant drug effects, Male, Oxazoles pharmacology, Rats, Reinforcement Schedule, Reward, Rilmenidine, Clonidine pharmacology, Cues, Discrimination, Psychological drug effects, Receptors, Adrenergic, alpha-2 drug effects
- Abstract
Clonidine produces an interoceptive discriminative stimulus or "cue" in rat drug discrimination studies. This cue may be mediated by its alpha-2 adrenoceptor agonist properties and/or its affinity for the non-adrenoceptor imidazoline preferring receptor. Six rats were trained to respond differentially after receiving clonidine (0.02 mg kg-1, IP) or a saline vehicle. The alpha-2 adrenoceptor agonists clonidine, UK14, 304 and rilmenidine, which bind to the imidazoline preferring receptor, and guanabenz which does not, dose-dependently substituted for (i.e. > 80% total responding was clonidine associated) the clonidine-induced cue in doses up to 0.02, 0.16, 1.25 and 0.32 mg kg-1, respectively. Furthermore, the cue was blocked when clonidine was given in combination with 30-min pretreatments of the highly selective alpha-2 adrenoceptor antagonists RX811059 (2.5 mg kg-1) and fluparoxan (3 mg kg-1). Since the clonidine-induced cue was substituted for by guanabenz, which does not act at the imidazoline-preferring receptor, and antagonised by RX811059 and fluparoxan it appears to be mediated by alpha-2 adrenoceptors. Moreover, abolition of the clonidine-induced cue did not occur with the peripherally acting alpha-2 adrenoceptor antagonist L659, 066 suggesting it involves central as opposed to peripheral sites.
- Published
- 1993
- Full Text
- View/download PDF
33. Investigation of the involvement of opioid receptors in the action of anticonvulsants.
- Author
-
Jackson HC and Nutt DJ
- Subjects
- Animals, Anticonvulsants antagonists & inhibitors, Dose-Response Relationship, Drug, Electroshock, Male, Mice, Mice, Inbred Strains, Morphinans pharmacology, Naloxone pharmacology, Phenytoin antagonists & inhibitors, Phenytoin pharmacology, Receptors, Opioid, mu antagonists & inhibitors, Seizures physiopathology, Anticonvulsants pharmacology, Narcotic Antagonists pharmacology, Receptors, Opioid drug effects
- Abstract
This study investigates the possible involvement of opioid receptors in the action of a variety of anticonvulsant agents. The opioid antagonist naloxone (0.3, 1 mg/kg IP) and the selective mu-opioid antagonist cyprodime (3 mg/kg IP) significantly inhibited the increase in electroshock seizure threshold induced by phenytoin (3 mg/kg IP) in mice. The anticonvulsant effects of ethanol (1 g/kg IP) were also significantly antagonised by naloxone (1 mg/kg IP) but not by a 0.3 mg/kg IP dose or by cyprodime (3 mg/kg IP). The results with naloxone were confirmed using higher doses of phenytoin (10 mg/kg IP) and ethanol (1.5 g/kg IP). In contrast to the above findings, naloxone (0.3, 1 mg/kg IP) had no effect on the increase in seizure threshold induced by sodium valproate (200 mg/kg IP) or dizocilpine (MK801, 0.5 mg/kg IP) and paradoxically potentiated the increase in seizure threshold produced by phenobarbitone (15 mg/kg IP); carbamazepine (10 mg/kg IP) and the benzodiazepine agonist loprazolam (1 mg/kg IP), clearly differentiating these compounds from phenytoin and ethanol. These findings suggest that the anticonvulsant effects of phenytoin and ethanol (as assessed by their ability to prevent tonic hindlimb extension in the mouse electroshock model) may be mediated, at least in part, by the release of endogenous opioids and subsequent activation of opioid receptors (mu, in the case of phenytoin, but non-mu, in the case of ethanol) although direct activity at opioid receptors cannot be precluded.
- Published
- 1993
- Full Text
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34. Are 5-HT receptors or beta-adrenoceptors involved in idazoxan-induced food and water intake?
- Author
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Jackson HC and Nutt DJ
- Subjects
- 8-Hydroxy-2-(di-n-propylamino)tetralin antagonists & inhibitors, 8-Hydroxy-2-(di-n-propylamino)tetralin pharmacology, Adrenergic alpha-Antagonists pharmacology, Adrenergic beta-Antagonists pharmacology, Animals, Betaxolol antagonists & inhibitors, Betaxolol pharmacology, Dose-Response Relationship, Drug, Idazoxan, Male, Metergoline antagonists & inhibitors, Metergoline pharmacology, Propanolamines antagonists & inhibitors, Propanolamines pharmacology, Propranolol antagonists & inhibitors, Propranolol pharmacology, Quinolizines antagonists & inhibitors, Quinolizines pharmacology, Rats, Rats, Wistar, Stereoisomerism, Dioxanes pharmacology, Drinking drug effects, Eating drug effects, Receptors, Adrenergic, beta drug effects, Receptors, Serotonin drug effects
- Abstract
Idazoxan (10 mg/kg, i.p.) produces an unexpected increase in food intake in freely-feeding rats which has been linked to its high affinity for non-adrenoceptor idazoxan binding sites. In this study, a dose-related antagonism of idazoxan-induced food intake by the beta-adrenoceptor antagonist (-)-propranolol (5-20 mg/kg, i.p.), which also blocks 5-HT1 (5-hydroxytryptamine1) receptors has been demonstrated. (+)-Propranolol (10, 20 mg/kg, i.p.) did not attenuate idazoxan-induced feeding. (-)-Propranolol (10 mg/kg, i.p.) but not the (+)-enantiomer (10 mg/kg, i.p.) also significantly inhibited the food intake, induced by the 5-HT1A agonist 8-OH-DPAT (0.25 mg/kg, i.p.). Idazoxan-induced feeding was not altered by the selective beta-adrenoceptor antagonists betaxolol (beta 1; 5 mg/kg, i.p.) and ICI 118,551 (beta 2; 5 mg/kg, i.p.) but was potentiated by the 5-HT receptor antagonist metergoline (5 mg/kg, i.p.). The anomalous findings with metergoline may reflect its action at different sub-types of 5-HT receptor. The water intake induced by idazoxan and the peripherally-active alpha 2-adrenoceptor antagonist L-659,066 was also blocked in a stereoselective manner by propranolol (10 mg/kg) but not significantly by either metergoline (5 mg/kg, i.p.), the beta 1-adrenoceptor antagonist betaxolol (5 mg/kg, i.p.) nor by the beta 2-adrenoceptor antagonist ICI 118,551 (5 mg/kg, i.p.). These results suggest that the food intake induced by idazoxan (and perhaps mediated by non-adrenoceptor idazoxan binding sites) may involve the 5-HT system, although further studies, using antagonists acting selectively at the different sub-types of 5-HT receptor, are required to confirm this.(ABSTRACT TRUNCATED AT 250 WORDS)
- Published
- 1992
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35. Effects of benzodiazepine receptor inverse agonists on locomotor activity and exploration in mice.
- Author
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Jackson HC and Nutt DJ
- Subjects
- Animals, Flumazenil pharmacology, Male, Mice, Azepines pharmacology, Azides pharmacology, Benzodiazepines pharmacology, Benzodiazepinones pharmacology, Exploratory Behavior drug effects, Motor Activity drug effects, Receptors, GABA-A drug effects
- Abstract
This study investigates the effects of benzodiazepine receptor inverse agonists on the locomotor and exploratory behaviour of mice when tested in a familiar environment. The weak partial inverse agonist Ro 15-3505 (0.3, 1, 3 mg/kg i.p.) significantly increased locomotion and hole-dipping in habituated mice. However, the more efficacious partial inverse agonists Ro 15-4513 (0.3, 1, 3 mg/kg i.p.) and Ro 19-4603 (0.03, 0.1, 0.3 mg/kg i.p.) had no effect on these parameters. The benzodiazepine receptor antagonist flumazenil (3, 10, 20 mg/kg i.p.) also increased locomotion and hole-dipping in habituated mice, although like Ro 15-3505, these effects were of short duration occurring largely in the first 15 min following injection. Opposite effects were obtained with the partial benzodiazepine agonist Ro 17-1812 (1, 3, 10 mg/kg i.p.) which produced a longer-lasting significant decrease in hole-dipping behaviour in habituated mice without altering locomotion. Finally, in contrast to its effects in habituated animals, Ro 15-3505 (0.3, 1, 3 mg/kg i.p.) did not modify either locomotion or exploration in mice which were tested in a novel environment, showing that the effects of the inverse agonist were state-dependent. This demonstration that, under certain conditions, the weak benzodiazepine receptor inverse agonist Ro 15-3505 and the antagonist flumazenil, produce behavioural activation is in accordance with the work of others suggesting that these classes of compound may increase arousal and may therefore be of some value in treatment of memory disorders.
- Published
- 1992
- Full Text
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36. Endogenous opioids may be involved in idazoxan-induced food intake.
- Author
-
Jackson HC, Griffin IJ, and Nutt DJ
- Subjects
- Animals, Dose-Response Relationship, Drug, Idazoxan, Indoles pharmacology, Male, Morphinans pharmacology, Naloxone pharmacology, Naltrexone pharmacology, Narcotic Antagonists pharmacology, Rats, Rats, Inbred Strains, Adrenergic alpha-Antagonists pharmacology, Dioxanes pharmacology, Eating drug effects, Endorphins physiology
- Abstract
In this study it has been shown that the unexpected increase in food consumption, produced by the alpha 2-adrenoceptor antagonist idazoxan (10 mg/kg, i.p.) in rats, was significantly attenuated by small doses of the opioid antagonist (-)-naloxone (0.1, 1 mg/kg, i.p.) and totally inhibited by a small dose of naltrexone (1 mg/kg, i.p.). On the other hand, idazoxan-induced feeding was not affected by (+)-naloxone (0.1, 1 mg/kg, i.p.), which is inactive at opioid receptors. In addition, idazoxan-induced food consumption was not blocked by the delta-opioid antagonist, naltrindole (0.1, 1 mg/kg, i.p.) nor by the mu/delta-antagonist, RX8008M (16-methyl cyprenorphine; 0.1, 1 mg/kg, i.p.), which clearly discriminates between mu/delta- and kappa-opioid receptor function in vivo. These findings suggest that idazoxan may lead to the release of endogenous opioid peptides, which subsequently stimulate feeding by activation of kappa-, as opposed to mu- or delta-opioid receptors. This response is unlikely to be due to alpha 2-adrenoceptor blockade, since other highly selective alpha 2-adrenoceptor antagonists do not increase food intake and, instead may reflect the high affinity of idazoxan for non-adrenoceptor idazoxan binding sites.
- Published
- 1992
- Full Text
- View/download PDF
37. Attenuation of the behavioural effects of ethanol in mice by des-enkephalin-gamma-endorphin (ORG 5878).
- Author
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Jackson HC, Ramsay E, and Nutt DJ
- Subjects
- Animals, Body Temperature Regulation drug effects, Dose-Response Relationship, Drug, Ethanol pharmacology, Injections, Intraperitoneal, Kindling, Neurologic drug effects, Male, Mice, Mice, Inbred Strains, Sensory Thresholds drug effects, Arousal drug effects, Ethanol antagonists & inhibitors, Motor Activity drug effects, beta-Endorphin pharmacology
- Abstract
This study shows inhibition of the increase in locomotor activity induced by ethanol (2 g/kg i.p.) in mice by a low dose (0.1 mg/kg i.p.) of the non-opioid beta-endorphin fragment ORG 5878 (des-enkephalin-gamma-endorphin). ORG 5878 (0.1 mg/kg i.p.) also significantly antagonised the large increase in electroshock seizure threshold produced by ethanol (1.5 g/kg i.p.). In contrast, the hypothermia induced by ethanol (2 g/kg i.p.) was not altered by ORG 5878 (0.1 mg/kg i.p.). The effects of ORG 5878 showed an abnormal dose-response relationship, in that a high dose (1 mg/kg i.p.) did not significantly suppress any of the behavioural effects of ethanol examined although there was some indication that it attenuated the stimulant action of ethanol. ORG 5878 (0.1, 1 mg/kg i.p.) did not have any intrinsic effects on locomotion, seizure threshold or body temperature in mice. These results are the first demonstration that ORG 5878 may act as an ethanol antagonist in some paradigms.
- Published
- 1992
38. The effects of idazoxan and other alpha 2-adrenoceptor antagonists on urine output in the rat.
- Author
-
Jackson HC, Griffin IJ, Birkett SD, and Nutt DJ
- Subjects
- Animals, Idazoxan, Male, Quinolizines pharmacology, Rats, Rats, Brattleboro, Rats, Wistar, Yohimbine pharmacology, Adrenergic alpha-Antagonists pharmacology, Dioxanes pharmacology, Urodynamics drug effects
- Abstract
1. In normally-hydrated Wistar rats the alpha 2-adrenoceptor antagonist, idazoxan (1, 3, 10 mg kg-1 i.p.), increased urine output during the 6 h following injection. 2. The more selective and specific alpha 2-adrenoceptor antagonist, RX811059 (0.3, 1, 3 mg kg-1 i.p.), and the peripherally-acting alpha 2-adrenoceptor antagonist, L-659,066 (1, 3, 10 mg kg-1 i.p.), had no effect on urine output in normally-hydrated animals. 3. In rats given a 25 ml kg-1 water-load orally, idazoxan (10 mg kg-1, i.p.) produced an initial antidiuretic response which was followed by an increase in urine output which was apparent 4 and 6 h after drug administration. 4. RX811059 (1, 3 mg kg-1 i.p.) and L-659,066 (3, 10 mg kg-1 i.p.) significantly decreased urine output in water-loaded rats in the 2 h after injection. 5. The antidiuretic effects of L-659,066 were attenuated in Brattleboro rats which are deficient in vasopressin; only the highest dose (10 mg kg-1 i.p.) decreased urine output, and this was only a small response in comparison with its virtual abolition of urine output in water-loaded Wistar rats. 6. The results with the selective alpha 2-adrenoceptor antagonists in Wistar and Brattleboro rats suggest that alpha 2-adrenoceptors in the periphery may play a physiological role in the control of water balance through a mechanism which involves vasopressin. 7. The paradoxical diuretic effects of idazoxan contrast with the effects of the other alpha 2-adrenoceptor antagonists and therefore may be attributed to a property of this compound unrelated to alpha 2-adrenoceptor blockade.
- Published
- 1992
- Full Text
- View/download PDF
39. Effect of the cyclopyrrolones suriclone and RP 59037 on body temperature in mice.
- Author
-
Jackson HC, Ramsay E, and Nutt DJ
- Subjects
- Analysis of Variance, Animals, Anti-Anxiety Agents pharmacology, Benzodiazepines pharmacology, Carbolines pharmacology, Drug Interactions, Flumazenil pharmacology, Isoindoles, Male, Mice, Piperazines antagonists & inhibitors, Sulfur Compounds, Body Temperature drug effects, Indoles pharmacology, Naphthyridines pharmacology, Piperazines pharmacology, Receptors, GABA-A drug effects
- Abstract
The effects of the cyclopyrrolones suriclone and RP 59037 on body temperature were investigated in male TO mice. The full agonist suriclone (3, 10, 30 mg/kg i.p.) produced significant hypothermia which was inhibited by concurrent administration of benzodiazepine receptor antagonists of both benzodiazepine (flumazenil; 10 mg/kg i.p.) and beta-carboline (ZK 93426; 3 mg/kg i.p.) structure. The response to suriclone (10 mg/kg i.p.) was also attenuated by benzodiazepine (Ro 17-1812; 10 mg/kg i.p.) and beta-carboline (ZK 91296; 30 mg/kg i.p.) partial agonists - which have no effect on body temperature per se. In contrast with these compounds, the cyclopyrrolone partial agonist RP 59037 (10, 30 mg/kg i.p.) produced significant hypothermia itself (although it was much less efficacious in this respect than the full agonist) and at a dose of 30 mg/kg failed to block the decrease in body temperature induced by suriclone (10 mg/kg i.p.). Thus suriclone acts as a full agonist at benzodiazepine receptors in the body temperature paradigm. RP 59037 possesses some partial agonist properties in this model, however, it appears to have greater intrinsic activity than other partial agonists tested previously.
- Published
- 1992
- Full Text
- View/download PDF
40. The Hennepin County Medical Center's Women's Advocacy Program--sixteen years of service.
- Author
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Jackson HC
- Subjects
- Adult, Consumer Advocacy, Female, Humans, Minnesota, Women's Health Services, Counseling, Crisis Intervention, Spouse Abuse
- Published
- 1992
41. Investigations on the "set-point" theory of benzodiazepine receptor function.
- Author
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Nutt DJ, Smith CF, Bennett R, and Jackson HC
- Subjects
- Animals, Humans, Models, Biological, Receptors, GABA-A drug effects
- Published
- 1992
42. Alpha 2-adrenoceptor antagonists block the stimulant effects of cocaine in mice.
- Author
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Jackson HC, Griffin IJ, and Nutt DJ
- Subjects
- Animals, Idazoxan, Male, Mice, Adrenergic alpha-Antagonists pharmacology, Cocaine antagonists & inhibitors, Dioxanes pharmacology, Motor Activity drug effects
- Abstract
In the present study we have investigated the effects of the alpha 2-adrenoceptor antagonist idazoxan and its 2-ethoxy derivative RX811059 on the locomotor activity induced by cocaine in mice. The stimulant effects of cocaine (15 mg/kg i.p.) were significantly antagonised by idazoxan (3 mg/kg i.p.) and RX811059 (1 mg/kg i.p.) and also initially suppressed by idazoxan (1 mg/kg i.p.) and RX811059 (0.3 mg/kg i.p.). The alpha 2-adrenoceptor antagonists had no effect on locomotion when given alone. These results suggest that noradrenergic mechanisms may play a role in the stimulant effects of cocaine and that alpha 2-adrenoceptor antagonists like idazoxan may be of some benefit in the clinical management of cocaine abuse.
- Published
- 1992
- Full Text
- View/download PDF
43. Strain differences in sensitivity to the hypothermic effects of benzodiazepine receptor ligands in mice.
- Author
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Jackson HC and Nutt DJ
- Subjects
- Analysis of Variance, Animals, Benzodiazepines, Binding Sites, Body Temperature drug effects, Carbolines pharmacology, Male, Mice, Mice, Inbred CBA, Mice, Inbred DBA, Sensitivity and Specificity, Species Specificity, Anti-Anxiety Agents pharmacology, Hypothermia chemically induced, Receptors, GABA-A drug effects
- Abstract
The hypothermic effects of intraperitoneal (IP) administration of the full benzodiazepine agonist loprazolam (1, 10 mg/kg); the partial agonist Ro 17-1812 (1, 10 mg/kg); the benzodiazepine receptor antagonist flumazenil (10, 20 mg/kg); the benzodiazepine inverse agonists Ro 15-4513 (1, 3, 10 mg/kg) and Ro 19-4603 (0.03, 0.1, 0.3 mg/kg) and the beta-carboline inverse agonists FG 7142 (10, 30 mg/kg) and DMCM (1, 3, 10 mg/kg) were investigated in three strains of mice. TO mice were less sensitive than CBA/cA and DBA/2 mice, since only loprazolam and the partial and full beta-carboline inverse agonists FG 7142 and DMCM lowered body temperature in these animals. CBA/cA mice were particularly sensitive to the hypothermic effects of loprazolam and Ro 17-1812, and also responded to the beta-carboline but not the benzo diazepine inverse agonists. In contrast, DBA/2 mice responded with moderate hypothermia to loprazolam, Ro 17-1812, and to the partial inverse agonist Ro 15-4513, and exhibited marked hypothermia in response to the more efficacious benzodiazepine inverse agonist Ro 19-4603 and to FG 7142 and DMCM. Flumazenil did not alter body temperature. DBA/2 mice were also more sensitive to the convulsant activity of inverse agonists than TO mice. CBA/cA mice exhibited enhanced sensitivity to the convulsant, but not the hypothermic, effects of Ro 19-4603, showing dissociation of these responses. The mechanisms underlying the genetic differences in sensitivity of mice to the hypothermic and convulsant action of the different ligands are unknown and warrant further investigation.
- Published
- 1992
- Full Text
- View/download PDF
44. Comparison of the effects of benzodiazepine and beta-carboline inverse agonists on body temperature in mice.
- Author
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Jackson HC and Nutt DJ
- Subjects
- Animals, Azepines pharmacology, Azides pharmacology, Benzodiazepines antagonists & inhibitors, Benzodiazepinones pharmacology, Injections, Intraperitoneal, Male, Mice, Benzodiazepines pharmacology, Body Temperature drug effects, Carbolines pharmacology
- Abstract
The effect of benzodiazepine and beta-carboline inverse agonists on body temperature in mice was investigated using doses shown to be pro-convulsant in other studies. The benzodiazepine partial inverse agonists Ro 15-3505 (0.1-30 mg/kg i.p.), Ro 15-4513 (0.1-10 mg/kg i.p.) and the fuller benzodiazepine inverse agonist Ro 19-4603 (0.03-0.3 mg/kg i.p.) had no effect on rectal temperature. Ro 19-4603 (1 mg/kg i.p.) produced a small hypothermic response. In contrast, the beta-carboline partial and full inverse agonists, FG 7142 (30, 60 mg/kg i.p.) and methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (3, 10 mg/kg i.p.), produced large decreases in body temperature. These differential effects of benzodiazepine and beta-carboline inverse agonists on body temperature may provide further evidence for the existence of benzodiazepine receptor subtypes.
- Published
- 1991
- Full Text
- View/download PDF
45. Detection and quantification of Pneumocystis carinii using a sandwich ELISA.
- Author
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Lane A, Hissey PH, and Jackson HC
- Subjects
- Animals, Antibodies, Fungal isolation & purification, Antigens, Fungal isolation & purification, Detergents, Enzyme-Linked Immunosorbent Assay, Fixatives, Lung microbiology, Pneumocystis growth & development, Rats, Rats, Inbred Strains, Pneumocystis isolation & purification
- Abstract
Antigenic sites on Pneumocystis carinii, the basis for organism enumeration by an enzyme-linked immunosorbent assay (ELISA) were adversely affected by incubation in detergents. However, stronger detergent concentrations were needed to eliminate high levels of non-specific background. Good P. carinii quantification was obtained with low non-specific background when the detergent was used only in the washing steps and not in cell suspension solutions. Formalin fixation of the cells resulted in good ELISA quantification of organism numbers with low non-specific background. No adverse effects were observed using a detergent on fixed cells. Although the system's range of accuracy needs to be expanded, a reduction in the number of organisms in response to the effects of pentamidine in vitro could be demonstrated by ELISA.
- Published
- 1991
46. Exploitation of a 650 bp probe for quantification of Pneumocystis carinii.
- Author
-
Hancock V, Christodoulou C, and Jackson HC
- Subjects
- Animals, Densitometry, Lung microbiology, Rats, Rats, Inbred Strains, DNA Probes, DNA, Fungal isolation & purification, Pneumocystis isolation & purification
- Abstract
Signals obtained from serial dilutions of rat-derived Pneumocystis carinii DNA were used to assess the sensitivity of a 650-bp DNA probe which recognises both cystic and non-cystic forms. Enhanced chemiluminescence was selected as a non-radioactive detection method and signals could be semi-quantitated by scanning densitometry. This technique was used to examine the inhibitory effect of pentamidine in vitro indicating that DNA probes might be useful tools in the search for a novel therapeutic agent.
- Published
- 1991
47. Analysis of the dynamics of Pneumocystis carinii in vitro.
- Author
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Jackson HC, Hancock V, and Elahi N
- Subjects
- Animals, Cell Nucleus, Cells, Cultured, Evaluation Studies as Topic, Lung cytology, Rats, Rats, Inbred Strains, Pneumocystis growth & development
- Abstract
Three culture systems employing mammalian lung cell monolayers were evaluated in terms of their ability to support the replication of primary isolates of rat-derived Pneumocystis carinii. For each system, analysis of variance was used to identify changes in the numbers of P. carinii over time. Significant replication was consistently demonstrated over lung fibroblasts (MRC-5), however, increases perceived in the culture supernatant were clearly influenced by the density of the underlying monolayer.
- Published
- 1991
48. Investigation of the different types of opioid receptor involved in electroconvulsive shock-induced antinociception and catalepsy in the rat.
- Author
-
Jackson HC and Nutt DJ
- Subjects
- Animals, Electroshock, Injections, Intraperitoneal, Male, Rats, Rats, Inbred Strains, Analgesia, Catalepsy etiology, Indoles pharmacology, Morphinans pharmacology, Naltrexone analogs & derivatives, Narcotic Antagonists pharmacology, Receptors, Opioid drug effects
- Abstract
The effects of novel opioid antagonists on the behavioural syndrome induced by electroconvulsive shock (ECS) in rats have been examined and compared with those of the established agent naloxone. A single ECS produced catalepsy and significantly increased tail immersion response times during the 15 min following the seizure. These responses were inhibited by a low dose of naloxone (1 mg kg-1, i.p.) and also by RX8008M (16-methylcyprenorphine; 1 mg kg-1, i.p.) which blocks mu- and delta- but not kappa-opioid receptor function. In comparison, the antinociception and catalepsy induced by ECS was not attenuated by the selective delta-receptor antagonist naltrindole (1 mg kg-1, i.p.). These results suggest that ECS-induced antinociception and catalepsy may be mediated by endogenous opioids acting at mu-opioid receptors and are consistent with biochemical studies showing the release of beta-endorphin in both animals and man following this procedure.
- Published
- 1991
- Full Text
- View/download PDF
49. The effects of idazoxan and other alpha 2-adrenoceptor antagonists on food and water intake in the rat.
- Author
-
Jackson HC, Griffin IJ, and Nutt DJ
- Subjects
- Animals, Dioxanes metabolism, Dose-Response Relationship, Drug, Idazoxan, Male, Quinolizines pharmacology, Rats, Rats, Inbred Strains, Receptors, Drug drug effects, Receptors, Drug metabolism, Adrenergic alpha-Antagonists pharmacology, Dioxanes pharmacology, Drinking drug effects, Eating drug effects
- Abstract
1. Idazoxan (1, 3, 10 mg kg-1, i.p.) produced a significant increase in food and water intake in freely feeding rats during the daylight phase. 2. The more selective and specific alpha 2-adrenoceptor antagonists, RX811059 (0.3, 1, 3 mg kg-1, i.p.) and RX821002 (0.3, 1, 3 mg kg-1, i.p.), did not produce hyperphagia in rats, however, the highest dose produced a significant increase in water intake. 3. The peripherally acting alpha 2-adrenoceptor antagonist, L-659,066 (1, 3, 10 mg kg-1, i.p.), did not affect food intake in the 4 h following injection, but the highest dose (10 mg kg-1), produced a large increase in water intake. 4. These results indicate that alpha 2-adrenoceptor antagonists may increase water intake by a peripherally mediated mechanism. 5. The lack of effect RX811059 and RX821002 on food intake contrasts with the large dose-related increases induced by idazoxan and suggests that the hyperphagic effects of idazoxan are not due to alpha 2-adrenoceptor blockade but may instead reflect its affinity for a non-adrenoceptor site, a property not shared by the other alpha 2-antagonists.
- Published
- 1991
- Full Text
- View/download PDF
50. Anticonvulsant activity of the imidazoline 6,7-benzoidazoxan.
- Author
-
Jackson HC, Ripley TL, Dickinson SL, and Nutt DJ
- Subjects
- Animals, Behavior, Animal drug effects, Bicuculline, Electroshock, Male, Mice, Phenytoin pharmacology, Postural Balance drug effects, Rats, Rats, Inbred Strains, Seizures chemically induced, Seizures prevention & control, Valproic Acid pharmacology, Anticonvulsants pharmacology, Dioxanes pharmacology, Imidazoles pharmacology
- Abstract
The effects of the imidazoline 6,7-benzoidazoxan on seizure threshold were assessed using standard tests of anticonvulsant activity. Benzoidazoxan (10-30 mg/kg i.p.; 100 mg/kg p.o.) prevented tonic, but not clonic, convulsions induced by electroshock in mice. The increase in seizure threshold was of rapid onset, and, although of short duration, was comparable with that obtained using phenytoin and sodium valproate. Moreover, unlike sodium valproate, benzoidazoxan was an efficacious anticonvulsant at doses (20, 30 mg/kg i.p.) which did not impair rotarod performance. The anticonvulsant effects of benzoidazoxan were confirmed using the maximal electroshock test in mice (median effective dose, 13.2 mg/kg i.p.) and rats (anticonvulsant at 30 mg/kg i.p.). In addition, benzoidazoxan (10, 30 mg/kg i.p.) prevented tonic, but not clonic, seizures induced by bicuculline in mice. Thus, the imidazoline benzoidazoxan was found to be a novel anticonvulsant agent against electrically and chemically induced seizures in mice and rats with a profile of action similar to that of phenytoin.
- Published
- 1991
- Full Text
- View/download PDF
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