Effect of Anesthesia on Microelectrode Recordings during Deep Brain Stimulation Surgery in Tourette Syndrome Patients.

BACKGROUND: Deep brain stimulation (DBS) is an accepted treatment for patients with medication-resistant Tourette syndrome (TS). Sedation is commonly required during electrode implantation to attenuate anxiety, pain, and severe tics. Anesthetic agents potentially impair the quality of microelectrode recordings (MER). Little is known about the effect of these anesthetics on MER in patients with TS. We describe our experience with different sedative regimens on MER and tic severity in patients with TS. METHODS: The clinical records of all TS patients who underwent DBS surgery between 2010 and 2018 were reviewed. Demographic data, stimulation targets, anesthetic agents, perioperative complications, and MER from each hemisphere were collected and analyzed. Single-unit activity was identified by filtering spiking activity from broadband MER data and principal component analysis with K-means clustering. Vocal and motor tics which caused artifacts in the MER data were manually selected using visual and auditory inspection. RESULTS: Six patients underwent bilateral DBS electrode implantation. In all patients, the target was the anterior internal globus pallidus. Patient comfort and hemodynamic and respiratory stability were maintained with conscious sedation with one or more of the following anesthetic drugs: propofol, midazolam, remifentanil, clonidine, and dexmedetomidine. Good quality MER and clinical testing were obtained in 9 hemispheres of 6 patients. In 3 patients, MER quality was poor on one side. CONCLUSION: Cautiously applied sedative drugs can provide patient comfort, hemodynamic and respiratory stability, and suppress severe tics, with minimal interference with MER.

Ethical, legal, and societal issues and recommendations for controlled and uncontrolled DCD.

This report deals with organ retrieval procedures in both controlled and uncontrolled DCD, looking at the ethical, legal, and psychosocial aspects during the different phases of the process. A recently published report by the UK Donation Ethics Committee (UKDEC) has served as an important reference document to outline the steps in the controlled DCD patient-donor pathway (Academy of Medical Royal Colleges. UK Donation Ethics Committee. An ethical framework for controlled donation after circulatory death. December 2011). For uncontrolled DCD, the UKDEC pathway description was adapted. At the 6th International Conference in Organ Donation held in Paris in 2013, an established expert European Working Group reviewed the UKDEC reports, which were then considered along with the available published literature. Along this pathway, the crucial ethical, legal, and psychosocial aspects have been flagged, and relevant recommendations have been formulated based on a consensus of the working group.

Preclinical profile of BI 224436, a novel HIV-1 non-catalytic-site integrase inhibitor.

BI 224436 is an HIV-1 integrase inhibitor with effective antiviral activity that acts through a mechanism that is distinct from that of integrase strand transfer inhibitors (INSTIs). This 3-quinolineacetic acid derivative series was identified using an enzymatic integrase long terminal repeat (LTR) DNA 3'-processing assay. A combination of medicinal chemistry, parallel synthesis, and structure-guided drug design led to the identification of BI 224436 as a candidate for preclinical profiling. It has antiviral 50% effective concentrations (EC50s) of <15 nM against different HIV-1 laboratory strains and cellular cytotoxicity of >90 µM. BI 224436 also has a low, ∼2.1-fold decrease in antiviral potency in the presence of 50% human serum and, by virtue of a steep dose-response curve slope, exhibits serum-shifted EC95 values ranging between 22 and 75 nM. Passage of virus in the presence of inhibitor selected for either A128T, A128N, or L102F primary resistance substitutions, all mapping to a conserved allosteric pocket on the catalytic core of integrase. BI 224436 also retains full antiviral activity against recombinant viruses encoding INSTI resistance substitutions N155S, Q148H, and E92Q. In drug combination studies performed in cellular antiviral assays, BI 224436 displays an additive effect in combination with most approved antiretrovirals, including INSTIs. BI 224436 has drug-like in vitro absorption, distribution, metabolism, and excretion (ADME) properties, including Caco-2 cell permeability, solubility, and low cytochrome P450 inhibition. It exhibited excellent pharmacokinetic profiles in rat (clearance as a percentage of hepatic flow [CL], 0.7%; bioavailability [F], 54%), monkey (CL, 23%; F, 82%), and dog (CL, 8%; F, 81%). Based on the excellent biological and pharmacokinetic profile, BI 224436 was advanced into phase 1 clinical trials.

Discovery of a novel series of non-nucleoside thumb pocket 2 HCV NS5B polymerase inhibitors.

A novel series of non-nucleoside thumb pocket 2 HCV NS5B polymerase inhibitors were derived from a fragment-based approach using information from X-ray crystallographic analysis of NS5B-inhibitor complexes and iterative rounds of parallel synthesis. Structure-based drug design strategies led to the discovery of potent sub-micromolar inhibitors 11a-c and 12a-c from a weak-binding fragment-like structure 1 as a starting point.

A potassium channel agonist protects hearing function and promotes outer hair cell survival in a mouse model for age-related hearing loss.

Age-related hearing loss (ARHL) is the most common sensory impairment mainly caused by degeneration of sensory hair cells in the cochlea with no causal medical treatment available. Auditory function and sensory hair cell survival critically depend on the Kv7.4 (KCNQ4) channel, a voltage-gated potassium channel expressed in outer hair cells (OHCs), with its impaired function or reduced activity previously associated with ARHL. Here, we investigated the effect of a potent small-molecule Kv7.4 agonist on ARHL in the senescence-accelerated mouse prone 8 (SAMP8) model. For the first time in vivo, we show that Kv7.4 activation can significantly reduce age-related threshold shifts of auditory brainstem responses as well as OHC loss in the SAMP8 model. Pharmacological activation of Kv7.4 thus holds great potential as a therapeutic approach for ARHL as well as other hearing impairments related to Kv7.4 function.

Discovery of a 1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione series of inhibitors of HIV-1 capsid assembly.

The discovery of a 1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione series of inhibitors of HIV-1 capsid assembly is described. Synthesis of analogs of the 1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione hit established structure-activity relationships. Replacement of the enamine functionality of the hit series with either an imidazole or a pyrazole ring led to compounds that inhibited both capsid assembly and reverse transcriptase. Optimization of the bicyclic benzodiazepine scaffold to include a 3-phenyl substituent led to lead compound 48, a pure capsid assembly inhibitor with improved antiviral activity.

Effect of Anesthesia on Microelectrode Recordings During Deep Brain Stimulation Surgery: A Narrative Review.

Deep brain stimulation (DBS) is an effective surgical treatment for patients with various neurological and psychiatric disorders. Clinical improvements rely on careful patient selection and accurate electrode placement. A common method for target localization is intraoperative microelectrode recording (MER). To facilitate MER, DBS surgery is traditionally performed under local or regional anesthesia. However, sedation or general anesthesia is sometimes needed for patients who are unable to tolerate the procedure fully awake because of severe motor symptoms, psychological distress, pain, or other forms of discomfort. The effect of anesthetic drugs on MER is controversial but likely depends on the type and dose of a particular anesthetic agent, underlying disease, and surgical target. In this narrative review, we provide an overview of the current literature on the anesthetic drugs most often used for sedation and anesthesia during DBS surgery, with a focus on their effects on MERs.

Impact of Procedural Sedation on the Clinical Outcome of Microelectrode Recording Guided Deep Brain Stimulation in Patients with Parkinson's Disease.

BACKGROUND: Subthalamic nucleus (STN) deep brain stimulation (DBS) has become a routine treatment of advanced Parkinson's disease (PD). DBS surgery is commonly performed under local anesthesia (LA) to obtain reliable microelectrode recordings. However, procedural sedation and/or analgesia (PSA) is often desirable to improve patient comfort. The impact of PSA in addition to LA on outcome is largely unknown. Therefore, we performed an observational study to assess the effect of PSA compared to LA alone during STN DBS surgery on outcome in PD patients. METHODS: Seventy PD patients (22 under LA, 48 under LA + PSA) scheduled for STN DBS implantation were included. Dexmedetomidine, clonidine or remifentanil were used for PSA. The primary outcome was the change in Movement Disorders Society Unified Parkinson's Disease Rating Score III (MDS-UPDRS III) and levodopa equivalent daily dosage (LEDD) between baseline, one month before surgery, and twelve months postoperatively. Secondary outcome measures were motor function during activities of daily living (MDS-UPDRS II), cognitive alterations and surgical adverse events. Postoperative assessment was conducted in "on" stimulation and "on" medication conditions. RESULTS: At twelve months follow-up, UPDRS III and UPDRS II scores in "on" medication conditions were similar between the LA and PSA groups. The two groups showed a similar LEDD reduction and an equivalent decline in executive function measured by the Stroop Color-Word Test, Trail Making Test-B, and verbal fluency. The incidence of perioperative and postoperative adverse events was similar between groups. CONCLUSION: This study demonstrates that PSA during STN DBS implantation surgery in PD patients was not associated with differences in motor and non-motor outcome after twelve months compared with LA only.

An NS3 protease inhibitor with antiviral effects in humans infected with hepatitis C virus.

Hepatitis C virus (HCV) infection is a serious cause of chronic liver disease worldwide with more than 170 million infected individuals at risk of developing significant morbidity and mortality. Current interferon-based therapies are suboptimal especially in patients infected with HCV genotype 1, and they are poorly tolerated, highlighting the unmet medical need for new therapeutics. The HCV-encoded NS3 protease is essential for viral replication and has long been considered an attractive target for therapeutic intervention in HCV-infected patients. Here we identify a class of specific and potent NS3 protease inhibitors and report the evaluation of BILN 2061, a small molecule inhibitor biologically available through oral ingestion and the first of its class in human trials. Administration of BILN 2061 to patients infected with HCV genotype 1 for 2 days resulted in an impressive reduction of HCV RNA plasma levels, and established proof-of-concept in humans for an HCV NS3 protease inhibitor. Our results further illustrate the potential of the viral-enzyme-targeted drug discovery approach for the development of new HCV therapeutics.

Influence of Anesthesia and Clinical Variables on the Firing Rate, Coefficient of Variation and Multi-Unit Activity of the Subthalamic Nucleus in Patients with Parkinson's Disease.

BACKGROUND: Microelectrode recordings (MER) are used to optimize lead placement during subthalamic nucleus deep brain stimulation (STN-DBS). To obtain reliable MER, surgery is usually performed while patients are awake. Procedural sedation and analgesia (PSA) is often desirable to improve patient comfort, anxiolysis and pain relief. The effect of these agents on MER are largely unknown. The objective of this study was to determine the effects of commonly used PSA agents, dexmedetomidine, clonidine and remifentanil and patient characteristics on MER during DBS surgery. METHODS: Data from 78 patients with Parkinson's disease (PD) who underwent STN-DBS surgery were retrospectively reviewed. The procedures were performed under local anesthesia or under PSA with dexmedetomidine, clonidine or remifentanil. In total, 4082 sites with multi-unit activity (MUA) and 588 with single units were acquired. Single unit firing rates and coefficient of variation (CV), and MUA total power were compared between patient groups. RESULTS: We observed a significant reduction in MUA, an increase of the CV and a trend for reduced firing rate by dexmedetomidine. The effect of dexmedetomidine was dose-dependent for all measures. Remifentanil had no effect on the firing rate but was associated with a significant increase in CV and a decrease in MUA. Clonidine showed no significant effect on firing rate, CV or MUA. In addition to anesthetic effects, MUA and CV were also influenced by patient-dependent variables. CONCLUSION: Our results showed that PSA influenced neuronal properties in the STN and the dexmedetomidine (DEX) effect was dose-dependent. In addition, patient-dependent characteristics also influenced MER.

Assessing the effectiveness of perioperative s-ketamine on new-onset headache after resective epilepsy surgery (ESPAIN-trial): protocol for a randomised, double-blind, placebo-controlled trial.

INTRODUCTION: Effective treatment of new-onset headache after craniotomy, especially anterior temporal lobectomy (ATL) and amygdalohippocampectomy for drug-resistant temporal lobe epilepsy, is a challenge. The current practice, acetaminophen combined with opioids is often reported by patients as insufficient and sometimes accompanied by opioid-related adverse effects. Based on expert opinion, anaesthesiologists therefore frequently consider s-ketamine as add-on therapy. This randomised parallel group design trial compares s-ketamine with a placebo as add on medication to a multimodal pain approach. METHODS AND ANALYSIS: In total 62 adult participants, undergoing ATL for drug resistant epilepsy under general anaesthesia, will be randomised to either receive a 0.25 mg/kg bolus followed by a continuous infusion of 0.1 mg/kg/hour of s-ketamine or placebo (0.9% NaCl) starting before incision and continued for 48 hours as an addition to acetaminophen and opioids administered in a patient-controlled analgesia pump. The primary outcome measure is the cumulative postoperative opioid consumption. Patient recruitment started August 2018 and will end in 2021. Secondary outcome measures are postoperative pain intensity scores, psychological parameters, length of hospital stay and adverse events and will be reassessed at 3 and 6 months after surgery, with a baseline measurement preoperatively. All data are collected by researchers who are blinded to the treatment. The data will be analysed by multivariable linear mixed-effects regression. ETHICS AND DISSEMINATION: Ethical approval has been given by the local medical ethical committee (NL61666.068.17). This study will be conducted in accordance with the Dutch Medical Research Involving Human Subjects Act and the Declaration of Helsinki. The results of this trial will be publicly disclosed and submitted for publication in an international peer-reviewed scientific journal. TRIAL REGISTRATION NUMBER: NTR6480.

Comparison of the diameter, cross-sectional area, and position of the left and right internal jugular vein and carotid artery in adults using ultrasound.

STUDY OBJECTIVE: Central venous access is indicated for transduction of central venous pressure and the administration of inotropes in the perioperative period. The right internal jugular vein (RIJV) is cannulated preferentially over the left internal jugular vein (LIJV). Cannulation of the LIJV is associated with a higher complication rate and a perceived increased level of difficulty when compared with cannulation of the RIJV. Possible explanations for the higher complication rate include a smaller diameter and more anterior position relative to the corresponding carotid artery (CA) of the LIJV compared with the RIJV. In this study, the RIJV and LIJV were examined in mechanically ventilated patients to determine the validity of these possible explanations. DESIGN: A prospective, nonrandomized cohort study. SETTING: The operating room of a major teaching hospital. PATIENTS: One hundred fifty-one patients scheduled for elective heart surgery. INTERVENTION: Ultrasound examination of the RIJV and LIJV at the level of the cricoid cartilage with a 12-MHz linear transducer in 151 anesthetized, mechanically ventilated patients in the Trendelenburg position. MEASUREMENTS AND RESULTS: In 72% of patients, the RIJV was dominant over the LIJV. The diameter and cross-sectional area of the RIJV was larger than the LIJV (P < .001). An anterior position of the LIJV in relation to the left CA was detected more often when compared with the RIJV and right CA (15.1% vs 5.4%, P = .01). CONCLUSION: This study confirms the smaller diameter and increased frequency of anterior positioning relative to the corresponding CA of the LIJV when compared with the RIJV. This validates them as possible explanations for the higher complication rate of LIJV cannulation compared with RIJV cannulation.

Novel 8-substituted dipyridodiazepinone inhibitors with a broad-spectrum of activity against HIV-1 strains resistant to non-nucleoside reverse transcriptase inhibitors.

A series of novel 8-substituted dipyridodiazepinone-based inhibitors were investigated for their antiviral activity against wild type human immunodeficiency virus (HIV-1) and the clinically prevalent K103N/Y181C mutant virus. Our efforts have resulted in a series of benzoic acid analogues that are potent inhibitors of HIV-1 replication against a panel of HIV-1 strains resistant to non-nucleoside reverse transcriptase inhibitors (NNRTIs). Furthermore, the combination of good antiviral potency, a broad spectrum of activity, and an excellent pharmacokinetic profile provides strong justification for the further development of compound (7) as a potential treatment for wild type and NNRTI-resistant HIV-1 infection.

Ethical and legal issues in non-heart-beating organ donation.

Procurement of kidneys and livers from non-heart-beating donors (NHBD) raises ethical and legal issues that need to be considered before wider use of these donors is undertaken. Although NHBDs were used in kidney transplantation as early as the 1960s, retrieval of these organs is not universally accepted today. From a medical point of view, these organs were considered "marginal" because the majority showed delayed or impaired function early after implantation. Legal problems relate to determination of death on cardiopulmonary criteria, the issue of valid consent, and the use of preservation measures. Among ethical issues involved are observance of the dead-donor rule, decisions with respect to resuscitation and withdrawal of life-sustaining treatment, respect for the dying patient and the dead body, and proper guidance of the family. In The Netherlands NHB donation was pioneered by the Maastricht Centre as early as 1981. Today, all seven transplant centers procure and transplant these organs, and NHBDs have become an important source of transplantable kidneys and livers. Recent legislation in The Netherlands also supports NHB donation by allowing the use of organ-preserving measures, even in the absence of family consent. As a result, one of every three kidneys transplanted in The Netherlands in 2004 derives from a NHBD. This article explores Dutch NHBD practice, protocols, and results and compares these data internationally.

Pediatric Deceased Donation-A Report of the Transplantation Society Meeting in Geneva.

The Ethics Committee of The Transplantation Society convened a meeting on pediatric deceased donation of organs in Geneva, Switzerland, on March 21 to 22, 2014. Thirty-four participants from Africa, Asia, the Middle East, Oceania, Europe, and North and South America explored the practical and ethical issues pertaining to pediatric deceased donation and developed recommendations for policy and practice. Their expertise was inclusive of pediatric intensive care, internal medicine, and surgery, nursing, ethics, organ donation and procurement, psychology, law, and sociology. The report of the meeting advocates the routine provision of opportunities for deceased donation by pediatric patients and conveys an international call for the development of evidence-based resources needed to inform provision of best practice care in deceased donation for neonates and children.

Influence of the 5-HT6 receptor on acetylcholine release in the cortex: pharmacological characterization of 4-(2-bromo-6-pyrrolidin-1-ylpyridine-4-sulfonyl)phenylamine, a potent and selective 5-HT6 receptor antagonist.

A small series of aryl pyridyl sulfones has been prepared and investigated for its 5-HT(6) receptor binding properties. Thereof, pyrrolidinyl derivative 11 proved to be a very potent (pK(i) 9) and selective 5-HT(6) receptor antagonist. By means of in vivo microdialysis in the frontal cortex and a passive avoidance paradigm, where 11 reversed a scopolamine induced retention deficit, a functional correlation between 5-HT(6) receptors and cholinergic neurotransmission could be shown, supporting the therapeutic potential of 5-HT(6) receptors in the treatment of cognitive deficits.

Conformation-based restrictions and scaffold replacements in the design of hepatitis C virus polymerase inhibitors: discovery of deleobuvir (BI 207127).

Conformational restrictions of flexible torsion angles were used to guide the identification of new chemotypes of HCV NS5B inhibitors. Sites for rigidification were based on an acquired conformational understanding of compound binding requirements and the roles of substituents in the free and bound states. Chemical bioisosteres of amide bonds were explored to improve cell-based potency. Examples are shown, including the design concept that led to the discovery of the phase III clinical candidate deleobuvir (BI 207127). The structure-based strategies employed have general utility in drug design.