Predrug Baseline Research Articles

Post-SSRI sexual dysfunction: barriers to quantifying incidence and prevalence.

While sexual dysfunction is a well-known side effect of taking selective serotonin reuptake inhibitors (SSRIs), in an undetermined number of patients, sexual function does not return to pre-drug baseline after stopping SSRIs. The condition is known as post-SSRI sexual dysfunction (PSSD) and is characterised most commonly by genital numbness, pleasureless or weak orgasm, loss of libido and erectile dysfunction. This article provides a commentary on the incidence and prevalence of PSSD based on a combination of academic literature as well as clinical and research experience. A number of obstacles to quantifying the occurrence of PSSD are outlined including difficulty in designing a suitable study method. Other contextual obstacles include patient embarrassment at raising sexual concerns, the response of healthcare professionals, inability to stop an antidepressant due to withdrawal issues in a proportion of patients and patient unawareness that their sexual difficulties are linked to prior medication compounded by variability of online information and a lack of information aimed at public education. A definition of PSSD with diagnostic criteria has been published. A MedDRA code for PSSD has also been introduced, but this is yet to be adopted by regulators.

0124 Dextroamphetamine biases the brain towards enhanced spatial selective attention compared over working memory

Abstract Introduction There is a growing trend in the non-medical use of prescription psychostimulant (PStim) in healthy adults One of the main reasons of increased usage of PStim is due to their perceived benefits on the cognitive capacity. However, evidences from empirical studies on healthy adults point to an inconclusive answer. There are various factors which could have contributed to these overall mixed findings. These factors range from differences in drug dosages, individual baseline variability and use of different tasks. However, one of the important factors that previous studies have not considered is the presence possible selective bias of PStim towards a specific cognitive domain over others which may lead to its selective enhancement at the cost of others’ degradation. Methods To study this, we carried out a double blind, placebo-controlled study, with repeated measures design to investigate the differential influence of a stimulant drug (DEX vs PBO) on the cognitive skills of working memory (WM) and spatial selective attentive in the form multiple object tracking (MOT) across a period of a day. We compared the change in the performance of WM and MOT in DEX vs PBO conditions at 1) pre-drug baseline, 2) 75 minutes post-drug (peak concentration), 3) 12 hours post-drug intake (washout). Results First, we found that DEX did not have any overall significant effect on WM performance across a period of day compared to the placebo condition. We also found that MOT performance was rescued by DEX, unlike the placebo condition in which the MOT performance degraded over different testing periods across a wake day period. Importantly, we found that during the peak concentration of DEX in the body MOT performance was significantly superior to that of the WM performance. This superiority of MOT over WM was not present before the drug administration (baseline) and also returned to a level similar to baseline after a gap of 12hours. Conclusion Overall, our study findings suggest that DEX has a favorable bias towards MOT compared to WM and selectively enhances its performance when the brain is required to support both of these two cognitive domains concurrently. Support (If Any)

Tiagabine induced modulation of oscillatory connectivity and activity match PET-derived, canonical GABA-A receptor distributions

As the most abundant inhibitory neurotransmitter in the mammalian brain, γ-aminobutyric acid (GABA) plays a crucial role in shaping the frequency and amplitude of oscillations, which suggests a role for GABA in shaping the topography of functional connectivity and activity. This study explored the effects of pharmacologically blocking the reuptake of GABA (increasing local concentrations) using the GABA transporter 1 (GAT1) blocker, tiagabine (15 mg). In a placebo-controlled crossover design, we collected resting magnetoencephalography (MEG) recordings from 15 healthy individuals prior to, and at 1-, 3- and 5- hours post, administration of tiagabine and placebo. We quantified whole brain activity and functional connectivity in discrete frequency bands. Drug-by-session (2 × 4) analysis of variance in connectivity revealed interaction and main effects. Post-hoc permutation testing of each post-drug recording vs. respective pre-drug baseline revealed consistent reductions of a bilateral occipital network spanning theta, alpha and beta frequencies, across 1- 3- and 5- hour recordings following tiagabine only. The same analysis applied to activity revealed significant increases across frontal regions, coupled with reductions in posterior regions, across delta, theta, alpha and beta frequencies. Crucially, the spatial distribution of tiagabine-induced changes overlap with group-averaged maps of the distribution of GABAA receptors, from flumazenil (FMZ-VT) PET, demonstrating a link between GABA availability, GABAA receptor distribution, and low-frequency network oscillations. Our results indicate that the relationship between PET receptor distributions and MEG effects warrants further exploration, since elucidating the nature of this relationship may uncover electrophysiologically-derived maps of oscillatory activity as sensitive, time-resolved, and targeted receptor-mapping tools for pharmacological imaging.

QT prolongation associated with azithromycin/hydroxychloroquine combination in treatment of COVID-19: a single centre study

Background: The long QT syndrome is characterized by prolongation of QT interval, which may lead to life-threatening cardiac arrhythmias. Objectives were to assess prevalence, quantity and severity of QTc prolongation with combined drugs (azithromycin and hydroxychloroquine) in adults COVID-19 patients treated on these agents at KFSHRC. And to characterize cardiac complications of QTc prolongation with combined drugs.Methods: A retrospective cohort study at KFSH&RC, in Riyadh, Saudi Arabia. Baseline and daily ECG was done until completion of duration as per KFSH&RC guidelines for management of Covid-19, QTc prolongation>500 or increase of at least 60 ms compared with the pre-drug baseline value, or presence of cardiac conductive complications (torsades de pointes). The QTc prolongation was defined as>470 for male and >480 for female as per American Heart Association. A risk score that has been validated by Tisdale et al, for prediction of QT prolongation drug-related in admitted patients in cardiac care unit. The study duration was specified as one month after study approval by Research Ethics committee.Results: A total of 74 patients were included in the study. The patients were distributed according to their risk score for prediction of QT prolongation as the following: low (67/74), medium (6/74), high (1/74). Two patients with medium risk were started on both azithromycin and hydroxychloroquine. one of them his baseline QT was 490, Azithromycin was stopped as QT reached 502. The second patient has QT baseline 471, after starting treatment; QT range was 472-475, hydroxychloroquine was stopped on day 4. None of them had torsades de pointes. Only one patient with low risk, no baseline QT was recorded, but QT was 499 on day three, so hydroxychloroquine was stopped. Repeated ECG showed: QT decreased to 478, no torsades de pointes. Conclusions: In this single centered-retrospective cohort, we noticed that a small percentage of patients developed QT prolongation with the use of this combination. With the increasing the risk of developing QT prolongation the number of the patient who developed the condition increased. We used Tisdale score which is a scoring system Identifying hospitalized patients at risk for QT interval prolongation could lead to interventions to reduce the risk of torsades de pointes validated in May 2013.5 None of our population developed significant cardiac complications of QTc prolongation with combined drugs.

Long-Term Cocaine Self-administration Produces Structural Brain Changes That Correlate With Altered Cognition

BackgroundAn enduring question from cross-sectional clinical studies is whether the structural and functional differences often observed between cocaine users and healthy control subjects result from a history of drug use or instead reflect preexisting differences. To assess causality from drug exposure, true predrug baseline imaging and neurocognitive assessments are needed. MethodsWe addressed this fundamental question of causality using longitudinal anatomical magnetic resonance imaging and neurocognitive assessments in rhesus macaques. Cognitive tasks employed were stimulus reversal learning as a measure of cognitive flexibility/inhibitory control and delayed match to sample as a measure of visual working memory. Time points examined were before and following 12 months of chronic cocaine (n = 8) or water (n = 6) self-administration. A magnetic resonance imaging–only time point was also obtained following 2 years of forced abstinence. ResultsWe identified localized patterns of gray matter density (GMD) changes that were largely concordant with cross-sectional clinical studies. These included decreases in orbitofrontal cortex, insula, amygdala, and temporal cortex. There was also a prominent increase in GMD in the caudate putamen. GMD decreases were significantly correlated with cognitive impairments across individuals only in select cortical regions. Following abstinence, changes in GMD in some regions, including the orbitofrontal cortex, insula, and amygdala, were persistent and thus may play an important role in risk of relapse following extended abstinence. ConclusionsCocaine use is causal in producing regional changes in GMD, and those changes appear to drive cognitive impairments.

Pharmacokinetic and Pharmacodynamic Impacts of Depot Medroxyprogesterone Acetate Use on HIV Pre-exposure Prophylaxis in Women.

Depot medroxyprogesterone acetate (DMPA) is a commonly used contraceptive in areas where use of tenofovir disoproxil fumarate and emtricitabine for HIV pre-exposure prophylaxis (PrEP) is increasing. We aimed to investigate the impact of DMPA on PrEP drug pharmacokinetics and pharmacodynamics in women using PrEP before and after DMPA administration. In this pilot study, 12 HIV-negative women ages 18-45 underwent biological sample collection at 3 time points: before study drug, after 2 weeks of daily PrEP use alone, and after 2 weeks of daily PrEP and concomitant DMPA use. We measured drug and drug metabolites in plasma, peripheral blood mononuclear cells, cervicovaginal fluid, cervical tissue, and rectal fluid after each 2-week course of PrEP. We measured HIV replication ex vivo in genital tissue biopsies and innate anti-HIV activity in cervicovaginal fluid before PrEP and after both courses. We compared drug concentrations after PrEP alone to after PrEP and DMPA in the same participant using Wilcoxon signed-rank tests. We used mixed effects linear regression models to compare pharmacodynamic measures for each participant at predrug baseline, after PrEP alone, and after PrEP and DMPA. We found no significant differences in PrEP drug and drug metabolite concentrations in any compartment during concomitant DMPA use compared with use of PrEP alone, except for a reduction in emtricitabine concentration in cervical tissue. We found no difference in HIV replication in cervical tissue or anti-HIV activity in cervicovaginal fluid during concomitant DMPA and PrEP use compared with during PrEP use alone. Concomitant use of DMPA does not clinically alter pharmacokinetics or pharmacodynamics of PrEP in women. These data support the safety of DMPA use in women using PrEP.

A MEG Study of Acute Arbaclofen (STX-209) Administration.

Several electrophysiological parameters, including the auditory evoked response component M50/M100 latencies and the phase synchrony of transient and steady-state gamma-band oscillations have been implicated as atypical (to various extents) in autism spectrum disorder (ASD). Furthermore, some hypotheses suggest that an underlying neurobiological mechanism for these observations might be atypical local circuit function indexed by atypical levels of inhibitory neurotransmitter, GABA. This study was a randomized, placebo-controlled, double-blind, escalating-dose, acute investigation conducted in 25 14–18 year-old adolescents with ASD. The study assessed the sensitivity of magnetoencephalography (MEG) and MEGAPRESS “GABA” magnetic resonance spectroscopy (MRS) to monitor dose-dependent acute effects, as well as seeking to define properties of the pre-drug “baseline” electrophysiological and GABA signatures that might predict responsiveness to the GABA-B agonist, arbaclofen (STX-209). Overall, GABA levels and gamma-band oscillatory activity showed no acute changes at either low (15 mg) or high (30 mg) dose. Evoked M50 response latency measures tended to shorten (normalize), but there was heterogeneity across the group in M50 latency response, with only a subset of participants (n = 6) showing significant M50 latency shortening, and only at the 15 mg dose. Findings thus suggest that MEG M50 latency measures show acute effects of arbaclofen administration in select individuals, perhaps reflecting effective target engagement. Whether these subjects have a greater trend towards clinical benefit remains to be established. Finally, findings also provide preliminary support for the use of objective electrophysiological measures upon which to base inclusion for optimal enrichment of populations to be included in full-scale clinical trials of arbaclofen.

Effects of AUT00063, a Kv3.1 channel modulator, on noise-induced hyperactivity in the dorsal cochlear nucleus

The purpose of this study was to test whether a Kv3 potassium channel modulator, AUT00063, has therapeutic potential for reversing noise-induced increases in spontaneous neural activity, a state that is widely believed to underlie noise-induced tinnitus. Recordings were conducted in noise exposed and control hamsters from dorsal cochlear nucleus (DCN) fusiform cells before and following intraperitoneal administration of AUT00063 (30 mg/kg). Fusiform cell spontaneous activity was increased in sound-exposed animals, approximating levels that were nearly 50% above those of controls. Administration of AUT00063 resulted in a powerful suppression of this hyperactivity. The first signs of this suppression began 13 min after AUT00063 administration, but activity continued to decline gradually until reaching a floor level which was approximately 60% of pre-drug baseline by 25 min after drug treatment. A similar suppressive effect of AUT00063 was observed in control animals, with onset of suppression first apparent at 13 min post-treatment, but continuing to decline toward a floor level that was 54% of pre-drug baseline and was reached 28 min after drug treatment. In contrast, no suppression of spontaneous activity was observed in animals given similar injections of vehicle (control) solution. The suppressive effect of AUT00063 was achieved without significantly altering heart rate and with minimal effects on response thresholds, supporting the interpretation that the reductions of hyperactivity were not a secondary consequence of a more general physiological suppression of the brain or auditory system. These findings suggest that Kv3 channel modulation may be an effective approach to suppressing spontaneous activity in the auditory system and may provide a future avenue for treatment of tinnitus resulting from exposure to intense sound.

Methylphenidate significantly alters the functional coupling between the prefrontal cortex and dopamine neurons in the ventral tegmental area

Amphetamine-like psychostimulants, including methylphenidate, have been shown to produce two opposing effects on dopamine (DA) neurons: a DA receptor-mediated feedback inhibition and a non-DA receptor-mediated excitation. To test whether the latter effect is mediated through the prefrontal cortex (PFC), we made dual-site recordings from the PFC and ventral tegmental area (VTA). Consistent with previous reports, methylphenidate inhibited VTA DA neurons. The D2 receptor antagonist raclopride completely reversed the inhibition and further increased the activity, particularly bursting, to above pre-drug baseline. This increase in DA cell activity was blocked by the α1 receptor antagonist prazosin, suggesting an effect mediated through α1 receptors. Recordings in the PFC showed that methylphenidate increased PFC UP state duration and shifted the functional coupling between the PFC and DA neurons from negative to positive. The former effect was partially reversed by not only prazosin, but also raclopride, whereas the latter was reversed only by raclopride. These results suggest that methylphenidate increases PFC cell activity through both α1 and D2 receptors. Its effect on PFC-DA cell functional coupling, however, is mediated through D2 receptors. The finding that the latter effect was unaffected by prazosin further suggests that it does not play a significant role in the α1-mediated excitatory effect of methylphenidate on DA neurons. However, the shift in PFC-DA cell functional coupling from negative to positive may significantly alter the relative timing between DA and glutamate release from DA and PFC terminals and thus the synaptic plasticity that depends on DA-glutamate interaction.

In Vivo Detection of CPP-115 Target Engagement in Human Brain

CPP-115, a next-generation γ-amino butyric acid (GABA)-aminotransferase (AT) inhibitor, shows comparable pharmacokinetics, improved safety and tolerability, and a more favorable toxicity profile when compared with vigabatrin. The pharmacodynamic characteristics of CPP-115 remain to be evaluated. The present study employed state-of-the-art proton magnetic resonance spectroscopy techniques to measure changes in brain GABA+ (the composite resonance of GABA, homocarnosine, and macromolecules) concentrations in healthy subjects receiving oral daily doses of CPP-115 or placebo. Six healthy adult males were randomized to receive either single daily 80 mg doses of CPP-115 (n=4) or placebo (n=2) for 6, 10, or 14 days. Metabolite-edited spectra and two-dimensional J-resolved spectroscopy data were acquired from the parietal-occipital cortex and supplementary motor area in all subjects. Four scans were performed in each subject that included a predrug baseline measure, two scans during the dosing timeframe, and a final scan that occurred 1 week after drug cessation. CPP-115 induced robust and significant increases in brain GABA+ concentrations that ranged between 52 and 141% higher than baseline values. Elevated GABA+ concentrations returned to baseline values following drug clearance. Subjects receiving placebo showed no significant changes in GABA+ concentration. CPP-115-induced changes were exclusive to GABA and homocarnosine, and CPP-115 afforded brain GABA+ concentration changes comparable to or greater than previous vigabatrin spectroscopy studies in healthy epilepsy-naive subjects. The return to baseline GABA+ concentration indicates the reversible GABA-AT resynthesis following drug washout. These preliminary data warrant further spectroscopy studies that characterize the acute pharmacodynamic effects of CPP-115 with additional dose-descending measures.

Dysregulated corticostriatal activity in open-field behavior and the head-twitch response induced by the hallucinogen 2,5-dimethoxy-4-iodoamphetamine

The substituted amphetamine, 2,5-dimethoxy-4-iodoamphetamine (DOI), is a hallucinogen that has been used to model a variety of psychiatric conditions. Here, we studied the effect of DOI on neural activity recorded simultaneously in the primary motor cortex (M1) and dorsal striatum of freely behaving FvB/N mice. DOI significantly decreased the firing rate of individually isolated neurons in M1 and dorsal striatum relative to pre-drug baseline. It also induced a bursting pattern of activity by increasing both the number of spikes within a burst and burst duration. In addition, DOI increased coincident firing between simultaneously recorded neuron pairs within the striatum and between M1 and dorsal striatum. Local field potential (LFP) activity also increased in coherence between M1 and dorsal striatum after DOI in the low frequency gamma band (30–50 Hz), while corticostriatal coherence in delta, theta, alpha, and beta activity decreased. We also assessed corticostriatal LFP activity in relation to the DOI-induced head-twitch response (HTR), a readily identifiable behavior used to assess potential treatments for the conditions it models. The HTR was associated with increased delta and decreased theta power in both M1 and dorsal striatum. Together, our results suggest that DOI dysregulates corticostriatal communication and that the HTR is associated with this dysregulation.

Chronic administration of the dopamine D2/3 agonist ropinirole invigorates performance of a rodent slot machine task, potentially indicative of less distractible or compulsive-like gambling behaviour.

Whilst dopamine agonist therapies can successfully manage the symptoms of diseases such as Parkinson's disease (PD), fibromyalgia and restless leg syndrome, they can also cause impulse control and addiction disorders such as gambling disorder (GD). These compulsive behaviours seriously undermine the utility of such treatments. The objective of the study was to model this phenomenon using a rodent slot machine task (rSMT) in order to investigate the neurobiological basis underlying such behavioural changes. Male Long Evans rats were trained to perform the rSMT. The D2-like agonist ropinirole, or saline, was then delivered continuously for 28days via osmotic mini-pump. The effects of ropinirole on baseline rSMT performance, as well as extinction and reinstatement sessions, were determined during this time. Brain samples from key frontostriatal regions implicated in GD and PD were then harvested immediately or after a 4-week washout period during which behaviour returned to pre-drug baseline. Ropinirole invigorated task performance, in that drug treatment resulted in a robust and sustained increase in the number of trials completed. Ex vivo analyses revealed that chronic ropinirole treatment led to a pattern of changes indicative of upregulation within the β-arrestin-AKT-GSK3β intracellular cascade, recently theorised to dominate D2-mediated signalling under hyperdopaminergic conditions, in the dorsal striatum, rather than the canonical PKA-dependent signalling pathway associated with D2 receptor activation. Such findings provide novel insight into the role of dopamine signalling in mediating compulsive-like gambling behaviour and may inform more directed pharmacotherapies for the treatment of both idiopathic and iatrogenic GD.

The upright posture improves plantar stepping and alters responses to serotonergic drugs in spinal rats

Recent studies on the restoration of locomotion after spinal cord injury have employed robotic means of positioning rats above a treadmill such that the animals are held in an upright posture and engage in bipedal locomotor activity. However, the impact of the upright posture alone, which alters hindlimb loading, an important variable in locomotor control, has not been examined. Here we compared the locomotor capabilities of chronic spinal rats when placed in the horizontal and upright postures. Hindlimb locomotor movements induced by exteroceptive stimulation (tail pinching) were monitored with video and EMG recordings. We found that the upright posture alone significantly improved plantar stepping. Locomotor trials using anaesthesia of the paws and air stepping demonstrated that the cutaneous receptors of the paws are responsible for the improved plantar stepping observed when the animals are placed in the upright posture.We also tested the effectiveness of serotonergic drugs that facilitate locomotor activity in spinal rats in both the horizontal and upright postures. Quipazine and (±)-8-hydroxy-2-(dipropylamino)tetralin hydrobromide (8-OH-DPAT) improved locomotion in the horizontal posture but in the upright posture either interfered with or had no effect on plantar walking. Combined treatment with quipazine and 8-OH-DPAT at lower doses dramatically improved locomotor activity in both postures and mitigated the need to activate the locomotor CPG with exteroceptive stimulation. Our results suggest that afferent input from the paw facilitates the spinal CPG for locomotion. These potent effects of afferent input from the paw should be taken into account when interpreting the results obtained with rats in an upright posture and when designing interventions for restoration of locomotion after spinal cord injury.

Effects of Dronabinol, a Non-Selective Cannabinoid Receptor Agonist, on Gastrointestinal and Colonic Transit in Diarrhea-Predominant Irritable Bowel Syndrome

Purpose: Cannabinoid receptors (CBR) are widely expressed on cholinergic neurons in both the central and enteric nervous systems. CBR activation delays gastric emptying in healthy female volunteers. In diarrheapredominant irritable bowel syndrome (IBS-D) patients, CBR activation with dronabinol 5 mg inhibits phasic contractile activity in the left colon [Wong B et al. Gastroenterology 2011;140 (Issue 5, Supplement 1):S-2] without altering high amplitude propagated contractions (HAPC). Nearly 50% of IBS-D patients have accelerated colonic transit. Aim: To compare acute effects of dronabinol, a non-selective CBR agonist, and placebo on colonic transit in IBS-D patients. Methods: We conducted a randomized, double-blind trial in 36 patients with IBS-D by Rome III criteria of oral placebo (n=13), dronabinol 2.5 mg (n=10), or dronabinol 5 mg (n=13) given twice daily (b.i.d.) for 2 consecutive days. A validated scintigraphic method was used to measure gastrointestinal and colonic transit during the 2 days of treatment. We used an intention-to-treat analysis of covariance (ANCOVA) to assess post-drug effects overall and by dronabinol dosage using BMI and the pre-drug baseline colonic geometric center at 24 hours (GC24) as covariates. The primary transit endpoint was post-drug GC24 (on a 0 to 5 scale). Data are reported as covariate-adjusted means ± standard errors. Results: In IBS-D patients, there were no significant overall treatment effects on GC24 (p>0.5) for either dronabinol 2.5 mg b.i.d. (2.69±0.42; p>0.5) or dronabinol 5 mg b.i.d. (3.03±0.34; p>0.5) compared to placebo (3.08±0.36). Dronabinol also had no effect on gastric emptying, or small bowel transit at either dosages compared to placebo in IBS-D. A numerical (non-significant) decrease in ascending colon (AC) emptying t1/2, which correlates with faster colonic transit, was observed with the dronabinol 5 mg b.i.d. dosage (8.9±1.7 hr vs. 11.7±1.9 hr with placebo; p=0.3). Similarly, the numerically greater colonic transit at 48 hours with 5mg dose (4.53±0.27) compared to placebo (4.10±0.29, p=0.3) was not significant. Conclusion: In IBS-D patients, the non-selective CBR agonist, dronabinol 2.5 mg or 5 mg twice daily, did not delay gastrointestinal or colonic transit. The numerically faster colonic emptying with the 5mg dosage is consistent with A.M. Connell's demonstration (Gut 1962;3:342-8) that irregular phasic activity slows colonic transit, since the inhibition of phasic contractility by dronabinol 5 mg dose is associated with a trend to facilitated colonic transit. This study was supported by RO1 DK-079866 award from National Institutes of Health.

Nitrous Oxide Paradoxically Modulates Slow Electroencephalogram Oscillations

Nitrous oxide (N(2)O) is one of the oldest analgesics/adjuvant agents still in use today; however, its effects on the human electroencephalogram (EEG) remain unclear. It has been proposed that N(2)O may enhance higher-frequency EEG activity (often indicative of alert states and cognition) duration sedation. This possibly paradoxical effect has been used to explain the failure of many EEG monitors to capture the effects of N(2)O on patient state during anesthesia. To better understand the poor efficacy of current EEG approaches to monitoring N(2)O action, we quantitatively studied the sole effect of N(2)O on the resting EEG in healthy volunteers using multichannel EEG recordings under noise-minimized laboratory conditions. Healthy male volunteers were administered 20% (n = 10), 40% (n = 10), or 60% (n = 5) inspired N(2)O mixed with oxygen during noise-shielded EEG recordings. N(2)O was administered over a 20-minute period involving a 5-minute equilibration period and 5-minute washout. EEG spectral edge frequency (95%), median power frequency, total power, and band-limited power (δ, , α, β, and γ) were used as quantitative EEG parameters. The changes in these EEG parameters were quantified throughout N(2)O inhalation and compared between predrug baseline, peak drug effect, and washout. Quantification of changes in spectral power during N(2)O inhalation showed only minor changes in estimates of spectral edge and median power frequency, whereas significant reductions in total power were observed at frontal sites during peak gas effect (P = 0.001; mean reduction [95% confidence interval]: 41.90 μV(2) [18.19-65.61 μV(2)]) that rebounded during N(2)O washout. Such changes in total power were driven by shifts in low-frequency power (δ/), which were most elevated at frontal sites. Rather than directly enhancing high-frequency EEG power (β or γ bands), N(2)O seems to preserve the awake features of resting EEG (α band) and suppress power in those bands in which increases are typically associated with sedation/hypnosis (δ and ). These data suggest that N(2)O's suppression of low-frequency EEG power may help to explain previously reported difficulties in attempting to monitor patient state with the EEG during anesthesia involving N(2)O. Because increases in low-frequency power typically indicate increasing anesthesia, N(2)O's suppression of such activity and its rebound during washout would paradoxically influence EEG monitoring parameters. Therefore, correcting for such effects is expected to improve future monitoring methods.

Statins Alter Intracellular Calcium Homeostasis in Malignant Hyperthermia Susceptible Individuals

Statines, HMG-CoA reductase inhibitors, are widely used to treat hypercholesterinemia. These substances are well tolerated, but myotoxic effects have been reported. The exact mechanisms of the induced myotoxicity are unknown but an involvement of intracellular calcium handling is suspected. Individuals susceptible to malignant hyperthermia (MH) have an impaired calcium homeostasis. An in vitro test measuring contracture responses of isolated muscle bundles is used to investigate cellular processes of MH. Aim of this study was to investigate if statins modify the contracture response of isolated muscle bundles from MH susceptible (MHS) and nonsusceptible (MHN) pigs. With approval of the local ethics committee muscle biopsies of 18 MH susceptible and 12 nonsusceptible pigs were performed. Muscle bundles were mounted on an isometric force transducer, preloaded, and electrically stimulated. After establishment of a stable baseline, muscle bundles were exposed to simvastatin, atorvastatin, gemfibrocil, and the pure solvent. Baseline tension was measured and analyzed for changes with P < 0.05 considered to be significant. There were no differences in weight, length, and predrug baseline tension between the groups. Both simvastatin and atorvastatin induced significant contractures in muscle bundles from MHS pigs. Gemfibrocil and the solvent methanol showed no effect. In MHN muscle bundles, none of the tested substances induced a contracture. Statines induce contractures only in MHS muscle bundles. We therefore conclude that the underlying mechanism may be a pathologic influence on intracellular calcium handling that is absent in MHN. A preexisting impairment of the calcium homeostasis seems to be necessary for this behavior because muscle bundles of MHN pigs showed no pathologic reaction. A higher muscle cell vulnerability toward statins is assumed in MHS patients. Statins ought to be used with caution in these individuals. Analogous a diagnostic workup for MH should be considered for patients with statin-induced rhabdomyolyis.

Muscarinic receptor blockade in the ventral tegmental area attenuates cocaine enhancement of laterodorsal tegmentum stimulation‐evoked accumbens dopamine efflux in the mouse

The reinforcing properties of cocaine have been related to increased extracellular concentrations of dopamine in the nucleus accumbens (NAc). M5 muscarinic acetylcholine receptors (mAChRs) on dopamine cells in the ventral tegmental area (VTA) facilitate mesoaccumbens dopamine transmission and are critically involved in mediating natural and drug reinforcement. We investigated the effects of pharmacological blockade of mAChRs in the VTA on cocaine's ability to enhance electrically evoked NAc dopamine efflux. Using fixed potential amperometry together with carbon fiber recording microelectrodes positioned in the NAc core, we quantified dopamine oxidation currents (dopamine efflux) evoked by brief stimulation (15 monophasic pulses at 50 Hz every 30 s) of the laterodorsal tegmentum (LDT) in urethane (1.5 g/kg, i.p.) anesthetized mice. Compared to predrug baseline responses, cocaine (5 or 10 mg/kg, i.p.) dose-dependently enhanced LDT stimulation-evoked NAc dopamine efflux, whereas the nonsubtype selective mAChR antagonist scopolamine (10 microg/0.5 microl) microinfused into the VTA diminished LDT-evoked NAc dopamine efflux. Preinfusion of scopolamine into the VTA diminished the facilitatory actions of cocaine on LDT stimulation-evoked NAc dopamine efflux, and when infused at the peak effect of cocaine attenuated LDT-evoked dopamine efflux to below predrug baseline levels. These findings suggest that LDT cholinergic inputs to dopamine neurons in the VTA, via activation of mAChRs (probably of the M5 subtype), are involved in modulating the facilitatory effects of cocaine on NAc dopamine neurotransmission. They also suggest that the development of antagonists aimed at selectively disrupting M5 receptor function may be valuable in reducing abuse liability of psychostimulants.

S1588 Cirrhotic Patients with TIPS Are At Risk for Medication Induced QT Prolongation

Aim: Cytochrome P450 3A is the most important drug metabolizing enzyme in humans and nearly 40% of its activity is located in the small bowel. We have previously shown that intestinal CYP3A activity is markedly diminished in cirrhotics with transjugular intrahepatic portasystemic shunts (TIPS) and this leads to markedly increased bioavailability of orally administered CYP3A substrates and may lead to adverse effects. We conducted a study to test the hypothesis that oral CYP3A substrates with QT prolonging effect cause abnormal prolongation of QT interval in cirrhotics with TIPS. Methods: 23 subjects (9 controls, 8 cirrhotics with TIPS and 6 cirrhotics without TIPS) participated in this study. Subjects with cirrhosis and TIPSS were matched for age, gender, race and BMI. The mean age ± SD was 52 ± 9 years, 9 females and 6 African American. Oral erythromycin (ERY), a CYP3A substrate known to prolong QT interval in humans, was administered to test the relationship between diminished small bowel CYP3A activity and QT prolongation by oral medications. It was dosed at 500 mg PO BID for 7 days. EKGs (n=32) were obtained from each subject at baseline and after administration of ERY on day 1 and day 7 at scheduled intervals (over 24 hours) on each study day. QT intervals were measured in 3 consecutive beats in two leads and corrected QT interval (QTc) was obtained by fredericia correction and simple regression analysis. Primary outcome measure is maximal QTc change (QTc Max δ) after ERY administration on day 1 and day 7 in comparison to pre-drug administration baseline. The changes in QTc are compared among the three patient groups using ANOVA according to day 1 and day 7. Results: There was no statistically significant difference among the three groups in QTc Max δ following the first dose of ERY (p=0.8) on day 1. However, cirrhotics with TIPS had significantly greater QTc Max δ than other two groups following 7-days of oral ERY administration (p= 0.0271), irrespective of correction formula. Summary: Cirrhotic Patients with TIPS had significantly greater prolongation in QTc following multiple doses of erythromycin than cirrhotics without TIPS. Conclusion: Cirrhotics with TIPS are more prone for adverse events such QT prolongation by oral medications that are metabolized by small bowel CYP3A. The maximal QTc change (mean± SE) (QTc Max δ) milliseconds in each group on day 1 and on day 7 of oral erythromycin 500 mg twice daily.

S1590 Immuno-Allergic (I-a) Manifestations of Drug-Induced Liver Injury (DILI) in the USA. Results from the Prospective Study of the DILI Network

Aim: Cytochrome P450 3A is the most important drug metabolizing enzyme in humans and nearly 40% of its activity is located in the small bowel. We have previously shown that intestinal CYP3A activity is markedly diminished in cirrhotics with transjugular intrahepatic portasystemic shunts (TIPS) and this leads to markedly increased bioavailability of orally administered CYP3A substrates and may lead to adverse effects. We conducted a study to test the hypothesis that oral CYP3A substrates with QT prolonging effect cause abnormal prolongation of QT interval in cirrhotics with TIPS. Methods: 23 subjects (9 controls, 8 cirrhotics with TIPS and 6 cirrhotics without TIPS) participated in this study. Subjects with cirrhosis and TIPSS were matched for age, gender, race and BMI. The mean age ± SD was 52 ± 9 years, 9 females and 6 African American. Oral erythromycin (ERY), a CYP3A substrate known to prolong QT interval in humans, was administered to test the relationship between diminished small bowel CYP3A activity and QT prolongation by oral medications. It was dosed at 500 mg PO BID for 7 days. EKGs (n=32) were obtained from each subject at baseline and after administration of ERY on day 1 and day 7 at scheduled intervals (over 24 hours) on each study day. QT intervals were measured in 3 consecutive beats in two leads and corrected QT interval (QTc) was obtained by fredericia correction and simple regression analysis. Primary outcome measure is maximal QTc change (QTc Max δ) after ERY administration on day 1 and day 7 in comparison to pre-drug administration baseline. The changes in QTc are compared among the three patient groups using ANOVA according to day 1 and day 7. Results: There was no statistically significant difference among the three groups in QTc Max δ following the first dose of ERY (p=0.8) on day 1. However, cirrhotics with TIPS had significantly greater QTc Max δ than other two groups following 7-days of oral ERY administration (p= 0.0271), irrespective of correction formula. Summary: Cirrhotic Patients with TIPS had significantly greater prolongation in QTc following multiple doses of erythromycin than cirrhotics without TIPS. Conclusion: Cirrhotics with TIPS are more prone for adverse events such QT prolongation by oral medications that are metabolized by small bowel CYP3A. The maximal QTc change (mean± SE) (QTc Max δ) milliseconds in each group on day 1 and on day 7 of oral erythromycin 500 mg twice daily.

S1589 Alcohol Promotes HIV Protease Inhibitor-Induced Hepatoxicity By Activating the ER Stress Response in Hepatocytes

Aim: Cytochrome P450 3A is the most important drug metabolizing enzyme in humans and nearly 40% of its activity is located in the small bowel. We have previously shown that intestinal CYP3A activity is markedly diminished in cirrhotics with transjugular intrahepatic portasystemic shunts (TIPS) and this leads to markedly increased bioavailability of orally administered CYP3A substrates and may lead to adverse effects. We conducted a study to test the hypothesis that oral CYP3A substrates with QT prolonging effect cause abnormal prolongation of QT interval in cirrhotics with TIPS. Methods: 23 subjects (9 controls, 8 cirrhotics with TIPS and 6 cirrhotics without TIPS) participated in this study. Subjects with cirrhosis and TIPSS were matched for age, gender, race and BMI. The mean age ± SD was 52 ± 9 years, 9 females and 6 African American. Oral erythromycin (ERY), a CYP3A substrate known to prolong QT interval in humans, was administered to test the relationship between diminished small bowel CYP3A activity and QT prolongation by oral medications. It was dosed at 500 mg PO BID for 7 days. EKGs (n=32) were obtained from each subject at baseline and after administration of ERY on day 1 and day 7 at scheduled intervals (over 24 hours) on each study day. QT intervals were measured in 3 consecutive beats in two leads and corrected QT interval (QTc) was obtained by fredericia correction and simple regression analysis. Primary outcome measure is maximal QTc change (QTc Max δ) after ERY administration on day 1 and day 7 in comparison to pre-drug administration baseline. The changes in QTc are compared among the three patient groups using ANOVA according to day 1 and day 7. Results: There was no statistically significant difference among the three groups in QTc Max δ following the first dose of ERY (p=0.8) on day 1. However, cirrhotics with TIPS had significantly greater QTc Max δ than other two groups following 7-days of oral ERY administration (p= 0.0271), irrespective of correction formula. Summary: Cirrhotic Patients with TIPS had significantly greater prolongation in QTc following multiple doses of erythromycin than cirrhotics without TIPS. Conclusion: Cirrhotics with TIPS are more prone for adverse events such QT prolongation by oral medications that are metabolized by small bowel CYP3A. The maximal QTc change (mean± SE) (QTc Max δ) milliseconds in each group on day 1 and on day 7 of oral erythromycin 500 mg twice daily.