ALX 111: ALX1-11, parathyroid hormone (1-84) - NPS Allelix,PREOS, PTH,recombinant human parathyroid hormone,rhPTH (1-84)

ALX 111 [parathyroid hormone (1-84) - NPS Allelix, recombinant human parathyroid hormone, rhPTH (1-84), PREOS] is a full-length, recombinant human parathyroid hormone. It has potential as an anti-osteoporotic agent, due to its properties as a bone formation stimulant. This profile has been selected from R&D Insight, a pharmaceutical intelligence database produced by Adis International Ltd. It has been recommended that ALX 111 should be given for 1 to 2 years and may be given in combination with an antiresorptive agent, such as estrogen or a bisphosphonate. In December 1999, Allelix Biopharmaceuticals merged with NPS Pharmaceuticals. This combined company is operating as NPS Pharmaceuticals in the US and as NPS Allelix in Canada. The merger has enabled a phase III study of ALX 111 to begin in the US, Europe and South America. NPS harmaceuticals has signed an agreement with Bio-Imaging Technologies, which will provide all image handling and analysis for this trial. Until 1994, Allelix Biopharmaceuticals and Glaxo in Canada were involved in a joint venture to investigate the efficacy of ALX 111 in osteoporosis. Allelix was subsequently, until September 1998, collaborating with Astra of Sweden in developing ALX 111. Astra had acquired exclusive worldwide rights to ALX 111 and was responsible for development of the agent. However, Astra returned all rights to ALX 111 to Allelix as a result of its merger with Zeneca to form AstraZeneca. In December 1999, Allelix Biopharmaceuticals merged with NPS Pharmaceuticals. This combined company is operating as NPS Pharmaceuticals in the US and as NPS Allelix in Canada. The merger has enabled a phase III study of ALX 111 to begin in the US, Europe and South America. The phase III trial of ALX 111 for the treatment of osteoporosis has completed patient enrolment, and phase II trials have been completed in Canada and the Netherlands. The 18-month, phase III, multicentre, placebo-controlled trial (Treatment of Osteoporosis with Parathyroid Hormone; TOP) has been designed to assess the bone-building and fracture-reducing potential of the drug, and over 2600 postmenopausal women with osteoporosis who have not received previous drug therapy for osteoporosis have been enrolled. Treatment will be completed in September 2003, but more than 75% of patients enrolled in the TOP study have chosen to enrol in an Open Label Extension Study (OLES), which allows for a total treatment period of up to 24 months. NPS Pharmaceuticals has signed an agreement with Bio-Imaging Technologies, which will provide all image handling and analysis for this trial. In September 2002, NPS Pharmaceuticals announced that it has met its patient enrolment target (n > 150) for its POWER (PTH for Osteoporotic Women on Estrogen Replacement) study; a 24-month phase III trial initiated in Europe in November 2001. In this trial, women with osteoporosis receive SC injections of ALX 111 or placebo, in combination with their existing hormone replacement therapies, to test the bone building potential of the drug. In addition to the POWER study, a clinical trial sponsored by the National Institutes of Health (NIH) is being conducted to evaluate the potential of ALX 111 to build bone in combination with another osteoporosis medication. The 'PaTH' study (PTH/alendronate) is designed to assess the effect of various combinations and sequential uses of ALX 111 and Merck's Fosamax, a drug for slowing the loss of bone due to osteoporosis. The PaTH study, initiated in May 2000 and scheduled to conclude in September 2003, involved 238 patients with postmenopausal osteoporosis. It is thought that alendronic acid and ALX 111, when administered in combination, may act in an additive manner to treat osteoporosis because they act in different ways; alendronic acid acts to inhibit resorption and ALX 111 speeds up bone formation and resorption, with a net increase in formation. Results of this study are still being analysed but preliminary results appear to be positive. The effect of ALX 111 on bone cell cultures underare still being analysed but preliminary results appear to be positive. The effect of ALX 111 on bone cell cultures under conditions of microgravity was tested in orbit on the Space Shuttle Columbia, which was launched on 16 January 2003 but did not survive re-entry. This study was one in a series of studies known as 'OSTEO' and had been prepared by researchers from NPS Pharmaceuticals using Millenium Biologix' OSTEO Mini-Lab System. Under space flight conditions, astronauts experience a loss in bone density at a rate up to ten times faster than that of earth-bound patients with osteoporosis, and it was hoped that this study would indicate the mechanism of action of ALX 111 at cellular and genetic levels. The results of these studies were represented by the samples of human bone cells, which were lost during the re-entry tragedy.     

The highs and lows of NPS/“Legal High” use: Qualitative views from a UK online survey

Abstract

Introduction: Novel psychoactive substances (NPS) are rapidly proliferating in the United Kingdom and elsewhere. We lack detailed information on rationales for their use. Methods: Qualitative data from 431 NPS users were collected as part of a 2014 online survey on NPS (n?=?468 NPS users, 704 non-NPS users). These 431 users answered some or all of five open-ended questions on favourite NPS and NPS they would not use and rationales for these assessments. Findings: Respondents were asked to identify and describe favourite NPS. The favourite NPS identified (n?=?258 respondents) mostly had brand names (148). Favourite NPS was associated with a good buzz/feeling, euphoria, enhancing sociability and relaxation. Ease of availability, cheapness and legality of NPS were cited. Achieving a predictable, safe high was important. Adverse NPS experience, including dependency issues both personally or amongst friends was reported by a majority of the 148 who described NPS that they would definitely not take and why, most of these reported having now ceased NPS use. Negative experiences ran from the mildly unpleasant to the persistent, serious and life threatening. Conclusions: Developing new methods of reaching and working with NPS users need timely knowledge of global and local trends in NPS use and effects. These data are of some assistance in expanding such knowledge.     

The Presence of New Psychoactive Substances in a Tor Network Marketplace Environment

Prior research has documented the availability of drugs on many Tor Network websites, with the Internet playing a particularly vital role in the global new psychoactive substances (NPS) market. The primary objective of this research was to document types of NPS for sale on the largest operating Tor site (Agora) over a period of four months. Secondary objectives were to analyze countries and vendors sourcing NPS on Agora. Data from Agora were collected in February and June 2015. The number of total advertisements on Agora increased from 20,742 to 27,431 over the four months, while the number of NPS advertisements increased from 2,205 to 2,271 and the number of vendors increased from 157 to 288. The composition of NPS listings and source countries for NPS advertised on Agora diversified over time. Advertisements for ketamine and unclassified NPS experienced substantial growth, while the availability of phenethylamines decreased. However, phenethylamines remained the most frequently advertised NPS type. China and the U.S. were found to be the top two countries by volume selling NPS on Agora over the fpir months, but the number of countries identified as advertising NPS increased by nearly 43%. The United States housed the most NPS vendors.     

Addictive Processes

Abstract

A growing number of New Psychoactive Substances (NPS) appear yearly on the European market (81 for the first time in 2013, adding to a total of over 350 NPS). Using semi-structured interviews with 25 Dutch experienced recreational drug users, the role of the Internet and friends in gathering and exchanging information about NPS was elaborated. Furthermore, we investigated how NPS were acquired and which aspects make NPS more or less attractive, including their legal status. It appeared that the Internet was an important source of information about NPS in general. Personal experiences with NPS were preferably shared face-to-face with friends, as for privacy reasons users were cautious to post their experiences on web sites and forums. NPS were usually obtained or bought from friends or—to a lesser extent—purchased via the Internet. The preference for a specific NPS depended on the desired effects (mostly stimulant or psychedelic), price (similar to MDMA or amphetamine), duration of effect (preferably around four hours), and setting (at home, at festivals, or in nightlife). Legal status was not relevant for the decision to use NPS. Most NPS are not superior to the already marketed drugs, and do not displace conventional illicit drugs.     

Intranasally Administered Neuropeptide S (NPS) Exerts Anxiolytic Effects Following Internalization Into NPS Receptor-Expressing Neurons

Experiments in rodents revealed neuropeptide S (NPS) to constitute a potential novel treatment option for anxiety diseases such as panic and post-traumatic stress disorder. However, both its cerebral target sites and the molecular underpinnings of NPS-mediated effects still remain elusive. By administration of fluorophore-conjugated NPS, we pinpointed NPS target neurons in distinct regions throughout the entire brain. We demonstrated their functional relevance in the hippocampus. In the CA1 region, NPS modulates synaptic transmission and plasticity. NPS is taken up into NPS receptor-expressing neurons by internalization of the receptor–ligand complex as we confirmed by subsequent cell culture studies. Furthermore, we tracked internalization of intranasally applied NPS at the single-neuron level and additionally demonstrate that it is delivered into the mouse brain without losing its anxiolytic properties. Finally, we show that NPS differentially modulates the expression of proteins of the glutamatergic system involved inter alia in synaptic plasticity. These results not only enlighten the path of NPS in the brain, but also establish a non-invasive method for NPS administration in mice, thus strongly encouraging translation into a novel therapeutic approach for pathological anxiety in humans.     

Nasal application of neuropeptide S reduces anxiety and prolongs memory in rats: social versus non-social effects

Recent studies demonstrated potent behavioral effects of centrally applied neuropeptide S (NPS) in mice and rats. These include increased arousal and wakefulness, facilitation of fear extinction and object memory consolidation and anxiolysis. Here, we compared the effects of NPS on both social and non-social memory, in male rats, and on social preference/social anxiety versus non-social anxiety after either intracerebroventricular (icv) or nasal application. Intranasal application of neuropeptides has been successfully employed to alter behavioral parameters in humans and rodents, but studies concerning nasal application of NPS are lacking so far. First, we confirmed the facilitatory effect of icv NPS (1 nmol) on object discrimination after an inter-exposure interval (IEI) of 240 min. These effects were context-dependent, as icv NPS (1 nmol) did not prolong social memory in a social discrimination paradigm. Second, we confirmed the anxiolytic effect of icv NPS (1 nmol) on the elevated plus-maze, whereas neither icv NPS (1 nmol) nor NPS receptor antagonist (10 nmol) altered social preference/social avoidance behavior. Third, nasal NPS (4-40 nmol applied topically on the rhinarium) facilitated object discrimination in a dose-dependent manner. Also, the anxiolytic effect of NPS on the elevated plus-maze could be confirmed after nasal administration (40 nmol). In contrast, identical doses of subcutaneously injected NPS failed to produce corresponding behavioral effects in both tests. Our findings provide evidence for memory-enhancing and anxiolytic effects of icv NPS in a non-social context. We could further show that these effects are context-specific, as social memory and social preference behavior remained unchanged after icv NPS. The effects of icv NPS were replicated by nasal application of the neuropeptide. Thus, nasal application of NPS seems to be a useful method in rodents for screening for behavioral or physiological effects before more specific and time-consuming, intracerebral methods are employed, and may represent a viable therapeutic approach for NPS treatment of patients with psychiatric illnesses such as anxiety or panic disorders. This article is part of a Special Issue entitled 'Anxiety and Depression'.     

New psychoactive substances (NPS) on cryptomarket fora: An exploratory study of characteristics of forum activity between NPS buyers and vendors

BackgroundThe continual diversification of new psychoactive substances (NPS) circumventing legislation creates a public health and law enforcement challenge, and one particularly challenged by availability on Hidden Web cryptomarkets.MethodsThis is the first study of its kind which aimed to explore and characterise cryptomarket forum members’ views and perspectives on NPS vendors and products within the context of Hidden Web community dynamics. An internal site search was conducted on two cryptomarkets popular with NPS vendors and hosting fora; Alphabay and Valhalla, using the search terms of 40 popular NPS in the seven categories of stimulant/cathinone; GABA activating; hallucinogen, dissociative, cannabinoid, opioid and other/unspecified/uncategorised NPS. 852 identified threads relating to the discussion of these NPS were generated. Following exclusion of duplicates, 138 threads remained. The Empirical Phenomenological Psychological method of data analysis was applied. Four themes and 32 categories emerged.Results120 vendors selling NPS were visible on Alphabay, and 21 on Valhalla. Themes were ‘NPS Cryptomarkets and Crypto-community interest in NPS’; ‘Motives for NPS use’; ‘Indigenous Crypto Community Harm Reduction’; and ‘Cryptomarket Characteristics underpinning NPS trafficking’, with two higher levels of abstraction centring on ‘NPS vendor reputation’ and ‘NPS transactioning for personal use’. NPS cryptomarket characteristics centred on generation of trust, honesty and excellent service. Users appeared well informed, with harm reduction and vendor information exchange central to NPS market dynamics. GABA activating substances appeared most popular in terms of buyer interest on cryptomarkets. Interest in sourcing ‘old favorite’ stimulant and dissociative NPS was evident, alongside the sequential and concurrent poly use of NPS, and use of NPS with illicit drugs such as MDMA.ConclusionContinued monitoring of new trends in NPS within Surface Web and cryptomarkets are warranted. A particular focus on the rising market in prescribed benzodiazepine and Z-hypnotic drugs should be included.     

Investigating the appearance of new psychoactive substances in South Australia using wastewater and forensic data

New psychoactive substances (NPS) have increased in use and popularity worldwide. Wastewater analysis has been successfully applied to evaluate illicit drugs use within a population. However, for NPS, such an approach may be limited due to low doses of NPS combined with their ever‐changing composition and usage. The dynamic nature of the NPS market means use may be opportunistic, infrequent, and with few users. Hence, the use of complementary information sources is recommended to improve the knowledge on NPS consumption. The aim of this study was to investigate the changing landscape of NPS use on a community scale by combining wastewater analysis and forensic toxicology. Forensic analysis provided specific information on NPS prevalence in post‐mortem blood samples in Adelaide, South Australia over five years, while wastewater analysis showed community use over the same period. A qualitative liquid chromatography–‐high resolution mass spectrometry method was initially used to screen the wastewater samples. A total of 24 NPS were found: 6 in wastewater only, 13 in forensic post‐mortem toxicology samples only, and 5 in both. As these results showed the presence of NPS, a targeted method was subsequently employed to quantify levels of these NPS in wastewater. Temporal trends were found in wastewater with distinct tendencies for synthetic cathinones visible over the period studied.     

Neuropeptide S in the basolateral amygdala mediates an adaptive behavioral stress response in a rat model of posttraumatic stress disorder by increasing the expression of BDNF and the neuropeptide YY1 receptor

Neuropeptide S (NPS) is a regulatory peptide that has anxiolytic and arousal-promoting effects in rodents. We used an animal model of posttraumatic stress disorder (PTSD) to assess long-term behavioral effects of a single dose of NPS, microinjected into the basolateral amygdala (BLA) 1 h following exposure to predator-scent stress (PSS). To elucidate the molecular mechanism by which NPS attenuates behavioral stress responses, expression levels of neuropeptide Y (NPY), NPY-Y1 receptor (NPY-Y1R), and brain-derived neurotrophic factor (BDNF) were evaluated in the hippocampus. The behavioral and molecular effects of NPS receptor antagonist (NPS-RA), NPY-Y1R antagonist (NPY-Y1RA), or both administered centrally were evaluated in the same manner. Circulating corticosterone levels were measured at different time points following PSS-exposure. Immediate post-exposure treatment with NPS had a marked protective effect; BLA microinfusion of NPS completely abolished the extreme behavioral response to PSS, restored the decreased expression of BDNF and, unexpectedly, PY-Y1R, but didn't affect the decreased expression of NPY. BLA microinfusion of both NPY-Y1RA and NPS-RA together had an additive effect, which completely prevented the anxiolytic effects of NPS in rats exposed to PSS and disrupted the expression of NPY-Y1R in the hippocampus following NPS infusion. It may therefore be hypothesized that NPS acts, directly or indirectly, on both the NPY-Y1R and NPS receptors and that the cross-talk between NPS and NPY-Y1R may be necessary for the anxiolytic effects of NPS post-exposure. The NPS system might thus contribute to a potential endogenous mechanism underlying the shift towards adaptive behavioral response and thereby might be relevant as a pharmacological target for attenuating stress-related sequelae.     

Intraventricular administration of neuropeptide S has reward-like effects

Neuropeptide S (NPS) is an endogenous brain peptide produced by neurons located in the lower brainstem, and functional studies suggest that NPS has arousing effects. Because its receptors are found in reward-associated regions throughout the brain, we evaluated whether intraventricular NPS injections elicit reward-related effects in rats. Rats increased lever presses that led to intraventricular administration of NPS (0.34–34 pmol per infusion) in a dose dependent manner, with a cue-assisted procedure. Cue-assisted self-administration of NPS was decreased by systemic administration of the dopamine receptor antagonist SCH 23390 (0.025 mg/kg, i.p.) or the hypocretin-1 (orexin-1) receptor antagonist SB 334867 (20 mg/kg, i.p.). In addition, intraventricular NPS injections (1000 pmol) induced conditioned place preference, whereas a lower dose (100 pmol) of NPS induced conditioned place aversion. Finally, NPS injections (100–1000 pmol) acutely facilitated locomotor activity, whereas repeated NPS injections did not lead to locomotor sensitization. Our data suggest that intraventricular NPS injections have reward-like effects in that NPS weakly facilitates seeking and induces positive reinforcement. These effects may depend on intact dopamine and hypocretin systems.     

The risk of violence associated with novel psychoactive substance misuse in patients presenting to acute mental health services

Novel psychoactive substance (NPS) availability is increasing at a phenomenal rate and so is their associated misuse. Currently, the harms associated with NPS misuse are unclear. This report presents the initial findings of a continuing study looking into the impact of NPS misuse on admissions to an acute mental health facility in London. Violence preadmission and violence during admission have been found to be significant in NPS misusers compared to non‐NPS substance misusers. Our findings have important consequences for acute mental health, emergency, and public health services. NPS misusers require specific assessment and risk management to reduce the risk of violence towards others.     

Neuropeptide S Enhances Memory During the Consolidation Phase and Interacts with Noradrenergic Systems in the Brain

Neuropeptide S (NPS) has been shown to promote arousal and anxiolytic-like effects, as well as facilitation of fear extinction. In rodents, NPS receptors (NPSR) are prominently expressed in brain structures involved in learning and memory. Here, we investigate whether exogenous or endogenous NPS signaling can modulate acquisition, consolidation, or recall of emotional, spatial, and contextual memory traces, using two common behavioral paradigms, inhibitory avoidance (IA) and novel object recognition. In the IA paradigm, immediate and delayed post-training central NPS administration dose dependently enhanced memory retention in mice, indicating that NPS may act during the consolidation phase to enhance long-term memory. In contrast, pre-training or pre-test NPS injections were ineffective, suggesting that NPS had no effect on IA memory acquisition or recall. Peripheral administration of a synthetic NPSR antagonist attenuated NPS-induced IA memory enhancement, showing pharmacological specificity. NPS also enhanced hippocampal-dependent non-aversive memory in the novel object recognition task. In contrast, NPSR knockout mice displayed deficits in IA memory, novel object recognition, and novel place or context recognition, suggesting that activity of the endogenous NPS system is required for memory formation. Blockade of adrenergic signaling by propranolol attenuated NPS-induced memory enhancement in the IA task, indicating involvement of central noradrenergic systems. These results provide evidence for a facilitatory role of NPS in long-term memory, independent of memory content, possibly by acting as a salience signal or as an arousal-promoting factor.     

Neuropeptide S: A transmitter system in the brain regulating fear and anxiety

The recently discovered Neuropeptide S (NPS) and its cognate receptor represent a highly interesting system of neuromodulation with unique physiological effects. On one hand, NPS increases wakefulness and arousal. On the other, NPS produces anxiolytic-like effects by acutely reducing fear responses as well as modulating long-term aspects of fear memory, such as attenuation of contextual fear or enhancement of fear extinction. The main sources of NPS in the brain are a few clusters of NPS-producing neurons in the brainstem. NPS binds to a G-protein-coupled receptor that is highly conserved among vertebrates and stimulates mobilization of intracellular Ca²⁺ as well as activation of protein kinases. In synaptic circuits within the amygdala, which are important for processing of acute fear as well as formation and expression of fear memories, NPS causes increased release of the excitatory transmitter glutamate, especially in synaptic contacts to a subset of GABAergic interneurons. Polymorphisms in the human NPS receptor gene have been associated with altered sleep behavior and panic disorder. In conclusion, the NPS system displays a unique physiological profile with respect to the specificity and time course of its actions. These functions could provide interesting opportunities for both basic research and clinical applications.     

Patterns of NPS Use and Risk Reduction in Slovenia

Background: The following study presents factors influencing the decision to use/not to use new psychoactive substances (NPS), various patterns of NPS use, the problems experienced by users, and the methods for reducing the risks associated with NPS use. Objectives: The study seeks to provide an in-depth look into the characteristics of NPS use and support the planning of targeted interventions in the field of NPS. Methods: The study involved 19 in-depth interviews carried out with 25 individuals divided into three subsamples in order to gain insight into the various experiences of NPS users. The interviews were conducted in Slovenia between December 2013 and October 2014. The sample was obtained by using the convenience sampling and snowball sampling methods. Results: The main pattern of NPS use determined by the study concerned synthetic cathinones, specifically 3-MMC, with binge use spanning several days being a prominent feature. The main risks involving NPS use were: mixing various drugs, inappropriate dosing, lack of information prior to use, and the use of unknown substances. Several users spoke about effective strategies for reducing risks, such as obtaining information beforehand, using one's own implements and using only small quantities of unknown substances. Conclusions/Importance: The study revealed various factors based on which users decide to use NPS. Furthermore, users reported a number of problems resulting from NPS use, while risk reduction strategies are employed to a much lesser extent. Based on the results obtained, specific intervention efforts concerning NPS use and targeting specific groups of younger users were designed.     

Pharmacological management of behavioral disturbances in patients with Alzheimer’s disease

ABSTRACT

Neuropsychiatric symptoms (NPS) inevitably occur during the course of Alzheimer’s disease (AD) including psychosis, aggression, and depression. The effectiveness of pharmacological treatments for NPS has been limited because of their lack of efficacy, discontinuation due to undesirable adverse events, or poor adherence. In recent consensus guidelines, non-pharmacological treatments for NPS have been prioritized as first-line management strategies. Pharmacological treatments for severe NPS should be administrated as a second-line approach, and have been suggested to be started at a lower dosage followed by titration to a minimum effective dosage and for a limited time period. However, recent studies have shown that some patients receiving pharmacological treatments do not exhibit treatment efficacy in comparison with placebo. The concurrence of several sub-symptoms in NPS makes it difficult to target one symptom exclusively. Therefore, the current review focuses on a strategy for such refractory NPS in patients with AD. Recent randomized controlled trials have shown that the severity of NPS gradually reduces in a time-dependent manner regardless of active treatments. Therefore, clinicians should consider potential causes of NPS sub-symptoms from multifactorial aspects and select alternative treatments (e.g. neuromodulation or relocation into specialized care units) during the long-term disease course.     

Neuropeptide S attenuates neuropathological, neurochemical and behavioral changes induced by the NMDA receptor antagonist MK-801

Neuropeptide S (NPS) and its cognate receptor were reported to mediate anxiolytic-like and arousal effects. NPS receptors are predominantly expressed in the brain, especially in limbic structures, including amygdala, olfactory nucleus, subiculum and retrosplenial cortex. In contrast, the NPS precursor is expressed in only a few brainstem nuclei where it is co-expressed with various excitatory transmitters, including glutamate. The current study investigates interactions of the NPS system with glutamatergic neurotransmission. It has been suggested that dysfunctions in glutamatergic neurotransmission via N-methyl-d-aspartate (NMDA) receptors might be involved in the pathophysiology of schizophrenia since NMDA receptor antagonists, such as MK-801, have been shown to induce psychotic-like behavior in humans and animal models. Also, MK-801 is known to produce histological changes such as cytoplasmic vacuoles in retrosplenial cortex neurons where NPS receptors are highly expressed. In this study we show that NPS is able to alleviate neuropathological, neurochemical and behavioral changes produced by NMDA receptor antagonists. NPS treatment attenuated MK-801-induced vacuolization in the rat retrosplenial cortex in a dose-dependent manner that can be blocked by an NPS receptor-selective antagonist. NPS also suppressed MK-801-induced increases of extracellular acetylcholine levels in the retrosplenial cortex. In the prepulse inhibition (PPI) assay, animals pretreated with NPS recovered significantly from MK-801-induced disruption of PPI. Our study suggests that NPS may have protective effects against the neurotoxic and behavioral changes produced by NMDA receptor antagonists and that NPS receptor agonists may elicit antipsychotic effects.     

Interactions between Bromobenzene Dose, Glutathione Concentrations, and Organ Toxicities in Single- and Multiple-Treatment Studies

Interactions between Bromobenzene Dose, Glutathione Concentrations,and Organ Toxicities in Single- and Multiple-Treatment Studies.KLUWE, W. M., MARONPOT, R. R., GREENWELL, A., AND HARRINGTON,F. (1984). Fundam. Appl. Toxicol. 4, 1019–1028. A singleoral dose of 4.0 mmol/kg bromobenzene transiently depleted hepaticand renal reduced nonprotein sulfhydryl group (NPS) concentrations,caused hepatocellular necrosis, and increased serum glutamic-pyruvictransaminase activity in male Fischer 344 rats. The depletionof NPS had partially reversed by 24 hr, and NPS concentrationswere approximately twice normal values by 48 hr post-treatmentWhen the effects of single and repeated (once dairy for 2, 4,or 10 days) treatments with 4.0 mmol/kg were compared, it wasapparent that the severity of hepatotoxicity lessened and thepercentage depletions of hepatic and renal NPS concentrationsdecreased with increasing length of bromobenzene treatment Therewere essentially no signs of toxicity following the tenth treatmentwith 4.0 mmol/kg. Single-treatment studies indicated the followingdose-response; 2.0 mmol/kg bromobenzene depleted liver NPS andwas hepatotoxic 0.5 mmol/ kg caused a lesser depletion of liverNPS and was not (overtly) hepatotoxic, and 0.0625 mmol/ kg wasthe maximum dose that did not deplete liver NPS. The responsesto single and multiple (ten) treatments with these representativedoses were compared. Liver injury was observed after a singlebut not after the tenth daily treatment with 2.0 mmol/kg. Boththe single and the tenth administrations of 2.0 mmol/kg depletedhepatic NPS, but the precentage of depletion was greater afterthe first than after the tenth dose. Liver injury was not detectedwith lower dose regimens. The patterns of NPS depletion in liverand kidney were similar after single or muliple (ten) treatments.The minimum NPS concentrations produced, however, were lowerafter single than after multiple treatments. The molar amountsof liver NPS depleted after the tenth treatment appeared tobe equivalent to or greater than those after the first but priorbromobenzene exposure resulted in a higher concentration oftissue NPS being present at the time of the final treatment.Thus, the minimum tissue concentrations of NPS were greaterafter multiple treatments than after single treatments, despitethe loss of equivalent amounts of NPS. It is concluded fromthese studies that repeated treatment produces resistance tobromobenzene hepatotoxicity. This protective adaptation maybe due to a chemically induced increase in liver glutathioneconcentration     

Neuropeptide S is a stimulatory anxiolytic agent: a behavioural study in mice

BACKGROUND AND PURPOSE: Neuropeptide S (NPS) was recently identified as the endogenous ligand of an orphan receptor, now referred to as the NPS receptor. In vivo, NPS produces a unique behavioural profile by increasing wakefulness and exerting anxiolytic-like effects. In the present study, we further evaluated the effects of in vivo supraspinal NPS in mice. EXPERIMENTAL APPROACH: Effects of NPS, injected intracerebroventricularly (i.c.v.), on locomotor activity (LA), righting reflex (RR) recovery and on anxiety states (measured with the elevated plus maze (EPM) and stress-induced hyperthermia (SIH) tests) were assessed in Swiss mice. KEY RESULTS: NPS (0.01-1 nmol per mouse) caused a significant increase in LA in naive mice, in mice habituated to the test cages and in animals sedated with diazepam (5 mg kg(-1)). In the RR assay, NPS dose dependently reduced the proportion of animals losing the RR in response to diazepam (15 mg kg(-1)) and their sleeping time. In the EPM and SIH test, NPS dose dependently evoked anxiolytic-like effects by increasing the time spent by animals in the open arms and reducing the SIH response, respectively. CONCLUSIONS AND IMPLICATIONS: We provide further evidence that NPS acts as a novel modulator of arousal and anxiety-related behaviours by promoting a unique pattern of effects: stimulation associated with anxiolysis. Therefore, NPS receptor ligands may represent innovative drugs for the treatment of sleep and anxiety disorders.