Efficacy of a propofol bolus against placebo to prevent cough at emergence from general anesthesia with desflurane: a randomized controlled trial.

PURPOSE: Emergence from anesthesia is a critical period and cough can result in adverse effects. Propofol inhibits airway reflexes and when infused it reduces cough more than inhalation anesthesia does. We evaluated the effect of a propofol bolus given at emergence on the incidence of coughing following a desflurane-based anesthesia. METHODS: One hundred and fifty-four patients scheduled for elective surgery were prospectively randomized to propofol (0.5 mg·kg-1) or normal saline (NS) administered at the end of the surgery at 1 minimum alveolar concentration (MAC) of desflurane. A "no touch" emergence technique was used until extubation. The primary outcome was the incidence of cough at the discontinuation of desflurane (T0) and reaching a MAC adjusted for age (MACage) of 0.15. Secondary outcomes included incidence and severity of cough until five minutes postextubation (T0-T5), time to extubation, nausea and vomiting, sedation, hemodynamic variations, postoperative hypoventilation, hypoxemia, and sore throat. RESULTS: We could not draw inferences on the incidence of cough between T0 and MACage of 0.15 because only 27/68 (40%) patients in the NS group and 13/73 (18%) patients in the propofol group regained consciousness before reaching a MACage of 0.15. There were no significant differences between the groups in coughing incidence and severity between T0 and T5 (NS group, 57/68 [84%] vs propofol group, 70/73 [96%] ). The mean time to extubation in the propofol group was prolonged by 3 min 27 sec (95% confidence interval, 1 min 7 sec to 4 min 47 sec; P < 0.001) and more vasopressors were used at emergence (P = 0.02). The incidence of respiratory complications, nausea and vomiting, agitation, and sedation were not different between groups. CONCLUSION: In the present trial, a propofol bolus administered at emergence did not reduce the incidence of cough occurring between T0 and T5 following a desflurane-based general anesthesia compared with placebo. TRIAL REGISTRATION: ClinicalTrials.gov (NCT02932397); registered 13 October 2016.

RéSUMé: OBJECTIF: L'émergence de l'anesthésie est une période critique et la toux peut entraîner des effets indésirables. Le propofol inhibe les réflexes des voies aériennes et, lorsqu'il est perfusé, il est plus efficace pour réduire la toux que l'anesthésie inhalée. Nous avons évalué l'effet d'un bolus de propofol administré à l'émergence sur l'incidence de toux après une anesthésie à base de desflurane. MéTHODE: Cent cinquante-quatre patients devant bénéficier d'une chirurgie non urgente ont été randomisés prospectivement à recevoir du propofol (0,5 mg·kg−1) ou une solution physiologique de sérum salé (NS) administrée à la fin de la chirurgie lorsque la concentration alvéolaire minimale (MAC) de desflurane était de 1. Une technique d'émergence « sans contact ¼ a été utilisée jusqu'à l'extubation. Le critère d'évaluation principal était l'incidence de toux à l'arrêt du desflurane (T0) et à l'atteinte d'une MAC ajustée en fonction de l'âge (MACâge) de 0,15. Les critères d'évaluation secondaires comprenaient l'incidence et la gravité de la toux jusqu'à cinq minutes après l'extubation (T0-T5), le délai d'extubation, les nausées et vomissements, la sédation, les variations hémodynamiques, l'hypoventilation postopératoire, l'hypoxémie et les maux de gorge. RéSULTATS: Nous n'avons pas pu tirer de conclusions sur l'incidence de toux entre T0 et à une MACâge de 0,15 parce que seulement 27/68 (40 %) patients du groupe NS et 13/73 (18 %) patients du groupe propofol ont repris conscience avant d'atteindre une MACâge de 0,15. Il n'y avait aucune différence significative entre les groupes dans l'incidence et la gravité de la toux entre T0 et T5 (groupe NS, 57/68 [84 %] vs groupe propofol, 70/73 [96 %]). Le temps moyen d'extubation dans le groupe propofol a été prolongé de 3 min 27 sec (intervalle de confiance à 95 %, 1 min 7 sec à 4 min 47 sec; P < 0,001) et une plus grande quantité de vasopresseurs a été utilisée à l'émergence (P = 0,02). L'incidence de complications respiratoires, de nausées et vomissements, d'agitation, et de sédation n'était pas différente entre les groupes. CONCLUSION: Dans la présente étude, un bolus de propofol administré à l'émergence n'a pas réduit l'incidence de toux survenant entre T0 et T5 après une anesthésie générale à base de desflurane par rapport au placebo. ENREGISTREMENT DE L'éTUDE: ClinicalTrials.gov (NCT02932397); enregistrée le 13 octobre 2016.

Postoperative outcomes in surgical COVID-19 patients: a multicenter cohort study.

BACKGROUND: Data on postoperative outcomes of the COVID-19 patient population is limited. We described COVID-19 patients who underwent a surgery and the pandemic impact on surgical activities. METHODS: We conducted a multicenter cohort study between March 13 and June 192,020. We included all COVID-19 patients who underwent surgery in nine centres of the Province of Québec, the Canadian province most afflicted by the pandemic. We also included concomitant suspected COVID-19 (subsequently confirmed not to have COVID-19) patients and patients who had recovered from it. We collected data on baseline characteristics, postoperative complications and postoperative mortality. Our primary outcome was 30-day mortality. We also collected data on overall surgical activities during this first wave and during the same period in 2019. RESULTS: We included 44 COVID-19 patients, 18 suspected patients, and 18 patients who had recovered from COVID-19 at time of surgery. Among the 44 COVID-19 patients, 31 surgeries (71%) were urgent and 16 (36%) were major. In these patients, pulmonary complications were frequent (25%) and 30-day mortality was high (15.9%). This mortality was higher in patients with symptoms (23.1%) compared to those without symptoms (5.6%), although not statistically significant (p = 0.118). Of the total 22,616 cases performed among participating centres during the study period, only 0.19% had COVID-19 at the time of surgery. Fewer procedures were performed during the study period compared to the same period in 2019 (44,486 cases). CONCLUSION: In this Canadian cohort study, postoperative 30-day mortality in COVID-19 patients undergoing surgery was high (15.9%). Although few surgeries were performed on COVID-19 patients, the pandemic impact on surgical activity volume was important. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04458337 .

Pectoral nerves I block is associated with a significant motor blockade with no dermatomal sensory changes: a prospective volunteer randomized-controlled double-blind study.

PURPOSE: The pectoral nerves (PECS) I block, first described in 2011 for surgery involving the pectoralis muscle, has principally been used for breast cancer surgery. No formal evaluation of its differential motor- and sensory-blocking abilities has been reported. We hypothesize that the PECS I block will produce a motor block of the pectoralis muscles with diminished upper limb adduction strength as measured with a handheld dynamometer. METHODS: We conducted a PECS I block in a randomized placebo-controlled trial in six healthy subjects who received 0.4 mL·kg-1 of 0.9% saline (placebo) on one side and bupivacaine (0.25% with 1:400 000 epinephrine) on the other. We measured both upper limb adduction strength with a dynamometer and sensory skin levels over the thorax. RESULTS: The mean (standard deviation [SD]) adductor strength evaluated before the block was 119.4 (20.7) Newtons (N). After the PECS I block with bupivacaine, the mean (SD) strength of 54.2 (16.3) N was compared with 116.0 (30.4) N in the placebo group (difference in means 61.8 N; 95% confidence interval [CI], 27.8 to 95.8 N; P = 0.005), showing a 54.6% (95% CI, 43.6 to 65.6%) reduction in adductor strength. There was no difference in dermatomal skin sensory testing between the placebo and bupivacaine sides. CONCLUSIONS: This study shows that a PECS I block produces motor blockade as shown by reduced upper limb adductor strength without any overlying dermatomal sensory loss. TRIAL REGISTRATION: www.clinicaltrials.gov (NCT03040167) 2 February 2017.

Anesthetic implications of recreational drug use.

PURPOSE: As the use of recreational drugs increases, the likelihood of an anesthesiologist perioperatively encountering patients using or addicted to these drugs will also increase. PRINCIPAL FINDINGS: Addicted patients may present for anesthetic care in a variety of circumstances in everyday elective surgeries or in acute or life-saving situations, such as emergency Cesarean delivery or trauma surgery. Therefore, it is important for anesthesiologists to know about the most common illicit drugs being used, their clinical presentation and side effects, and the anesthetic options that are beneficial or detrimental to these patients. The most frequently used illicit substances, apart from alcohol and tobacco, are cannabis, cocaine, heroin, prescription opioids, methamphetamine, and hallucinogens. When planning anesthetic care, it is important for anesthesiologists to understand the effects of these agents, including various drug interactions, to predict tolerance to some anesthetic agents, to recognize drug withdrawal signs and symptoms, and to be prepared to manage all these factors in the perioperative period. CONCLUSIONS: For optimal patient care through the perioperative period, it is critical to obtain information about patient drug use and other associated treatment in order to construct an appropriate anesthetic plan, including specific considerations during surgery, emergence, and in the postanesthesia care unit.

Medical cannabis: considerations for the anesthesiologist and pain physician.

PURPOSE: New regulations are in place at the federal and provincial levels in Canada regarding the way medical cannabis is to be controlled. We present them together with guidance for the safe use of medical cannabis and recent clinical trials on cannabis and pain. SOURCE: The new Canadian regulations on the use of medical cannabis, the provincial regulations, and the various cannabis products available from the Canadian Licensed Producers were reviewed from Health Canada, provincial licensing authorities, and the licensed producers website, respectively. Recent clinical trials on cannabis and pain were reviewed from the existing literature. PRINCIPAL FINDINGS: Health Canada has approved a new regulation on medical marijuana/cannabis, the Marihuana for Medical Purposes Regulations: The production of medical cannabis by individuals is illegal. Health Canada, however, has licensed authorized producers across the country, limiting the production to specific licenses of certain cannabis products. There are currently 26 authorized licensed producers from seven Canadian provinces offering more than 200 strains of marijuana. We provide guidance for the safe use of medical cannabis. The recent literature indicates that currently available cannabinoids are modestly effective analgesics that provide a safe, reasonable therapeutic option for managing chronic non-cancer-related pain. CONCLUSION: The science of medical cannabis and the need for education of healthcare professionals and patients require continued effort. Although cannabinoids work to decrease pain, there is still a need to confirm these beneficial effects clinically and to exploit them with acceptable benefit-to-risk ratios.

Postoperative awake paralysis in the intensive care unit after cardiac surgery due to residual neuromuscular blockade: a case report and prospective observational study.

PURPOSE: We report a case of awake paralysis due to residual neuromuscular blockade (NMB) in the intensive care unit (ICU) in a patient following fast-track cardiac surgery. As a result of this case, we performed a prospective quality assurance audit to investigate the incidence of residual paralysis in the ICU in a similar population of cardiac surgery patients. CLINICAL FEATURES AND AUDIT METHODS: A 73-yr-old woman (69 kg) underwent coronary artery bypass surgery under anesthesia induced with intravenous sufentanil 25 µg, midazolam 5 mg, ketamine 25 mg, and rocuronium 100 mg (followed by two additional 50-mg doses during surgery) and maintained with sevoflurane. Postoperatively in the ICU, the patient was initially sedated with propofol (50 mg·hr(-1)) but failed to awaken 90 min after its cessation. As train-of-four neurostimulation showed residual paralysis, she was re-sedated. Neostigmine 3 mg and glycopyrrolate 0.6 mg were administered, and she was extubated 30 min later. During this episode of residual paralysis, the patient was conscious and reported explicit memory of the events. She was discharged on day 7 without psychological distress related to her postoperative awake paralysis. We subsequently performed a prospective audit in 50 consecutive patients to determine the timing of NMB dosing and to quantify the incidence of residual paralysis after fast-track cardiac surgery. RESULTS: Of the 50 patients studied, 24 (48%) had received an NMB during the last hour of surgery and 33 (66%) had evidence of residual paralysis during the immediate postoperative period. CONCLUSION: Postoperative residual paralysis after fast-track cardiac surgery was common in our institution and likely contributed to the reported case of postoperative awake paralysis. We suggest that an NMB not be administered after intubation in fast-track patients. If given, however, it must be well communicated to the ICU team upon ICU admission. We further recommend routine assessment of neuromuscular function before sedation is weaned prior to extubation.

Aza follow-ups to BI 207524, a thumb pocket 1 HCV NS5B polymerase inhibitor. Part 1: Mitigating the genotoxic liability of an aniline metabolite.

A series of heterocyclic aza-analogs of BI 207524 (2), a potent HCV NS5B polymerase thumb pocket 1 inhibitor, was investigated with the goal to reduce the liability associated with the release of a genotoxic aniline metabolite in vivo. Analog 4, containing a 2-aminopyridine aniline isostere that is negative in the Ames test was identified, and was found to provide comparable GT1a/1b potency to 2. Although the cross-species PK profile, poor predicted human liver distribution of analog 4 and allometry principles projected high doses to achieve a strong antiviral response in patients, this work has provided a path forward toward the design of novel thumb pocket 1 NS5B polymerase inhibitors with improved safety profiles.

A prodrug strategy for the oral delivery of a poorly soluble HCV NS5B thumb pocket 1 polymerase inhibitor using self-emulsifying drug delivery systems (SEDDS).

A prodrug approach was developed to address the low oral bioavailability of a poorly soluble (<0.1µg/mL in pH 6.8 buffer) but highly permeable thumb pocket 1 HCV NS5B polymerase inhibitor. Bioconversion rates of structurally diverse prodrug derivatives were evaluated in a panel of in vitro assays using microsomes, from either liver or intestinal tissues, simulated intestinal fluids, simulated gastric fluids or plasma. In vivo bioconversion of promising candidates was evaluated following oral administration to rats. The most successful strategy involved modification of the parent drug carboxylic acid moiety to glycolic amide esters which improved solubility in lipid-based self-emulsifying drug delivery systems (SEDDS). Crystalline prodrug analog 36 (mp 161°C) showed good solubility in individual SEDDS components (up to 80mg/mL) compared to parent 2 (<3mg/mL; mp 267°C) and cross-species bioconversions which correlated with in vitro stability in liver microsomes.

Multi-parameter optimization of aza-follow-ups to BI 207524, a thumb pocket 1 HCV NS5B polymerase inhibitor. Part 2: Impact of lipophilicity on promiscuity and in vivo toxicity.

We describe our efforts to identify analogs of thumb pocket 1 HCV NS5B inhibitor 1 (aza-analog of BI 207524) with improved plasma to liver partitioning and a predicted human half-life consistent with achieving a strong antiviral effect at a reasonable dose in HCV-infected patients. Compounds 3 and 7 were identified that met these criteria but exhibited off-target promiscuity in an in vitro pharmacology screen and in vivo toxicity in rats. High lipophilicity in this class was found to correlate with increased probability for promiscuous behavior and toxicity. The synthesis of an 8×11 matrix of analogs allowed the identification of C3, an inhibitor that displayed comparable potency to 1, improved partitioning to the liver and reduced lipophilicity. Although C3 displayed reduced propensity for in vitro off-target inhibition and the toxicity profile in rats was improved, the predicted human half-life of this compound was short, resulting in unacceptable dosing requirements to maintain a strong antiviral effect in patients.

A Descriptive Analysis of Adverse Event Reports from the Quebec Cannabis Registry.

INTRODUCTION: Published data on the safety of natural medical cannabis (MC) when used in the real-world clinical practice setting are lacking. This study aimed to describe adverse events (AEs) reported across three years following MC initiation. METHODS: The Quebec Cannabis Registry (QCR) was a prospective registry of adults enrolled through participating physicians when they initiated MC between May 2015 and October 2018. Follow-up ended at MC discontinuation, loss to follow-up, three years, or end of data collection (May 2019). Data were collected at baseline and at follow-up visits every three months for the first two years, then once in the third year. Physicians filled adverse event (AE) reports, which were coded using MedDRA® preferred terms (PTs), and descriptive analyses were conducted. RESULTS: A total of 2991 patients were enrolled (mean age 50.9 years, 50.2% females). During follow-up, 108 patients (3.6%) experienced moderate or severe AEs, yielding 111 AE reports (three patients had two reports) and 214 AEs (average 1.9 AEs per report). Mild AEs were recorded as a reason for MC discontinuation for nine patients, but no AE reports were available. The most common PTs for ingested MC (62 reports) were dizziness (12.9%), nausea (11.3%), somnolence (9.7%), and vomiting (8.1%), and for inhaled MC (23 reports), headache (13.0%) was the most common. The most frequent PTs associated with tetrahydrocannabinol (THC)-dominant MC (25 reports) were dizziness and somnolence (12.0% each); for cannabidiol (CBD)-dominant MC (20 reports), vomiting (20.0%) was most common; and dizziness (17.2%), nausea (13.8%), somnolence (10.3%), and headache (8.6%) were the most frequent for balanced MC (58 reports). CONCLUSION: No new safety concerns were identified relative to the published literature, although notable differences in AE profile between modes of administration and cannabinoid content ratios should be considered by health professionals. Further work identifying and managing risk factors for AEs is warranted to maintain a favorable benefit-risk balance for MC.

Structure-based design of novel HCV NS5B thumb pocket 2 allosteric inhibitors with submicromolar gt1 replicon potency: discovery of a quinazolinone chemotype.

We describe the structure-based design of a novel lead chemotype that binds to thumb pocket 2 of HCV NS5B polymerase and inhibits cell-based gt1 subgenomic reporter replicons at sub-micromolar concentrations (EC50<200nM). This new class of potent thumb pocket 2 inhibitors features a 1H-quinazolin-4-one scaffold derived from hybridization of a previously reported, low affinity thiazolone chemotype with our recently described anthranilic acid series. Guided by X-ray structural information, a key NS5B-ligand interaction involving the carboxylate group of anthranilic acid based inhibitors was replaced by a neutral two-point hydrogen bonding interaction between the quinazolinone scaffold and the protein backbone. The in vitro ADME and in vivo rat PK profile of representative analogs are also presented and provide areas for future optimization of this new class of HCV polymerase inhibitors.

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.

Anthranilic acid-based Thumb Pocket 2 HCV NS5B polymerase inhibitors with sub-micromolar potency in the cell-based replicon assay.

Optimization efforts on the anthranilic acid-based Thumb Pocket 2 HCV NS5B polymerase inhibitors 1 and 2 resulted in the identification of multiple structural elements that contributed to improved cell culture potency. The additive effect of these elements resulted in compound 46, an inhibitor with enzymatic (IC50) and cell culture (EC50) potencies of less than 100 nanomolar.

Electrical impedance to detect accidental nerve puncture during ultrasound-guided peripheral nerve blocks.

PURPOSE: The objective of this study was to assess if an increase in electrical impedance was associated with intraneural (sub-epineural) needle tip placement. METHODS: Two electrical impedance measurements were carried out in each of 140 peripheral nerve blocks. The first measurement was performed at a distance of 0.5-1 cm from the nerve trunk (reference value), and the second measurement was performed close to the nerve, either immediately before local anesthetic injection if no nerve puncture was suspected, or immediately before repositioning the needle if nerve puncture was suspected. Nerve puncture was suspected if any one of the following indications was present: pain or paresthesia; motor responses with a minimal stimulating current < 0.4 mA; needle tip observed inside the nerve using ultrasound; nerve swelling after injection of local anesthetic. Electrical impedance variations were compared between the no puncture and the suspected puncture groups. RESULTS: Nerve puncture was suspected in 21 cases. The median variation [quartiles] of electrical impedance was +6.6% [-20; 36%] in the suspected puncture group (n = 21) and -10.0% [-28; 0%] in the no puncture group (n = 119) (P = 0.02). Absolute values of electrical impedance close to the nerve were greater in the suspected puncture group (15.5 kΩ [12.0; 18.0 kΩ]) vs the no puncture group (12.0 kΩ [8.9; 15.1% kΩ]) (P = 0.013). A receiver operating characteristic (ROC) curve was constructed, and the optimal cut-off for impedance was +4.3%. CONCLUSION: A > 4.3% increase in electrical impedance may indicate accidental nerve puncture during peripheral nerve block.

The Quebec Cannabis Registry: Investigating the Safety and Effectiveness of Medical Cannabis.

Objective: To investigate the safety and effectiveness of medical cannabis (MC) in the real-world clinical practice setting. Design: A 4-year prospective noncomparative registry of adult patients who initiated MC for a variety of indications. This paper reports on patients followed for up to 12 months, with interim visits at 3, 6, and 9 months after enrollment. Setting: Public or private outpatient clinics certified to authorize MC in the province of Quebec, Canada. Participants: Overall, 2991 adult (age ≥18 years) patients (mean age 51 years; 50.2% women) were enrolled between May 2015 and October 2018, with the last follow-up ending in May 2019. Interventions/Exposures: Cannabis products (dried, oil, or other) purchased from a Canadian licensed cannabis producer as authorized by physicians. Main Outcome Measures: The primary outcomes were self-reported pain severity, interference and relief (Brief Pain Inventory [BPI]), symptoms using the Revised Edmonton Symptom Assessment System (ESAS-r) and health-related quality of life dimensions (EQ-5D-5L) at baseline and each follow-up visit. The secondary outcomes were self-reported adverse events (AEs) and characteristics of cannabis treatment. Results: All patient-reported outcomes (BPI, ESAS-r, and EQ-5D-5L) showed a statistically significant improvement at 3 months (all p<0.01), which was maintained or further improved (for pain interference, tiredness, and well-being) over the remainder of the 12-month follow-up. Results also revealed clinically significant improvements in pain interference and tiredness, anxiety, and well-being from baseline. There were 79 AE reports (77 patients), 16 met the regulatory definition of seriousness, in which only 8 AEs were certainly or probably related to MC. Conclusions: MC directed by physicians appears to be safe and effective within 3 months of initiation for a variety of medical indications.

Predictors of Pain Reduction Among Fibromyalgia Patients Using Medical Cannabis: A Long-Term Prospective Cohort Study.

OBJECTIVE: Many patients with fibromyalgia (FM) report using cannabis as a strategy to improve pain. Given that pain often co-occurs with symptoms of anxiety and depression (i.e., negative affect) and sleep problems among patients with FM, improvements in these symptoms might indirectly contribute to reductions in pain intensity following cannabis use. The main objective of the study was to examine whether changes in pain intensity following initiation of medical cannabis among patients with FM could be attributed to concurrent changes (i.e., reductions) in negative affect and sleep problems. METHODS: This was a 12-month prospective cohort study among patients with FM (n = 323) initiating medical cannabis under the care of physicians. Patients were assessed at baseline, and follow-up assessment visits occurred every 3 months after initiation of medical cannabis. Patients' levels of pain intensity, negative affect, and sleep problems were assessed across all visits. RESULTS: Multilevel mediation analyses indicated that reductions in patients' levels of pain intensity were partly explained by concurrent reductions in sleep problems and negative affect (both P < 0.001). This remained significant even when accounting for patients' baseline characteristics or changes in medical cannabis directives over time (all P > 0.05). CONCLUSION: Our findings provide preliminary insight into the potential mechanisms of action underlying pain reductions among patients with FM who are using medical cannabis. Given the high attrition rate (i.e., 75%) observed in the present study at 12 months, our findings cannot be generalized to all patients with FM who are using medical cannabis.

From benzimidazole to indole-5-carboxamide Thumb Pocket I inhibitors of HCV NS5B polymerase. Part 1: indole C-2 SAR and discovery of diamide derivatives with nanomolar potency in cell-based subgenomic replicons.

Replacement of the benzimidazole core of allosteric Thumb Pocket 1 HCV NS5B finger loop inhibitors by more lipophilic indole derivatives provided up to 30-fold potency improvements in cell-based subgenomic replicon assays. Optimization of C-2 substitution on the indole core led to the identification of analogs with EC(50)<100 nM and modulated the pharmacokinetic properties of the inhibitors based on preliminary data from in vitro ADME profiles and in vivo rat PK.

Indole 5-carboxamide Thumb Pocket I inhibitors of HCV NS5B polymerase with nanomolar potency in cell-based subgenomic replicons (part 2): central amino acid linker and right-hand-side SAR studies.

In this part 2, new indole 5-carboxamide Thumb Pocket 1 inhibitors of HCV NS5B polymerase are described. Structure-activity relationships (SAR) were explored at the central amino acid linker position and the right-hand-side of the molecule in an attempt to identify molecules with a balanced overall profile of potency (EC(50)<100 nM), physicochemical properties and ADME characteristics.