Klaus Kucher

Translocator protein (18 kD) as target for anxiolytics without benzodiazepine-like side effects.

Keeping Calm Benzodiazepines are the most prescribed anxiolytics and are used by a broad population. However, benzodiazepines can cause unwanted side effects, including sedation, development of tolerance, and withdrawal symptoms after long-term administration. Rupprecht et al. (p. 490; published online 18 June) now find that a translocator protein (18-kD) ligand, XBD173, is a fast-acting anxiolytic agent, both in animals and humans, which lacks the unwanted side effects of benzodiazepines and provides a promising target for novel clinically effective anxiolytic drugs. Possible drug alternative for rapid treatment of anxiety disorders could replace benzodiazepines. Most antianxiety drugs (anxiolytics) work by modulating neurotransmitters in the brain. Benzodiazepines are fast and effective anxiolytic drugs; however, their long-term use is limited by the development of tolerance and withdrawal symptoms. Ligands of the translocator protein [18 kilodaltons (kD)] may promote the synthesis of endogenous neurosteroids, which also exert anxiolytic effects in animal models. Here, we found that the translocator protein (18 kD) ligand XBD173 enhanced γ-aminobutyric acid–mediated neurotransmission and counteracted induced panic attacks in rodents in the absence of sedation and tolerance development. XBD173 also exerted antipanic activity in humans and, in contrast to benzodiazepines, did not cause sedation or withdrawal symptoms. Thus, translocator protein (18 kD) ligands are promising candidates for fast-acting anxiolytic drugs with less severe side effects than benzodiazepines.

Evaluation of the CCK-4 model as a challenge paradigm in a population of healthy volunteers within a proof-of-concept study

RationaleExperimental panic induction with cholecystokinin-tetrapeptide (CCK-4) has been established as a model to study the pathophysiology of panic disorder and might serve as a tool to asses the antipanic potential of novel anxiolytic compounds. However, assessment of CCK-4-induced panic does not follow consistent rules.ObjectivesTo provide a basis for the use of the CCK-4 model in proof-of-concept studies, we investigated CCK-4-induced panic according to different criteria in 85 healthy volunteers who underwent a CCK-4 bolus injection.MethodsWe assessed panicker/non-panicker ratios according to different panic criteria and explored whether differences in cardiovascular and neuroendocrine responses to CCK-4 paralleled subjective panic responses. Subjective panic responses were measured with the Acute Panic Inventory (API) and the Panic Symptom Scale (PSS). Heart rate, blood pressure, adrenocorticotropic hormone (ACTH) and cortisol were assessed concomitantly.ResultsThe API-derived panic rate was 10.6% higher than that derived from the PSS. CCK-4 induced an increase in heart rate, systolic blood pressure and ACTH/cortisol plasma levels, which did not differ between panickers and non-panickers.ConclusionsThe panic criterion applied appears to be of major importance for the panic rate achieved, whereas CCK-4-induced cardiovascular and hormonal alterations are not valuable as an objective “read out”. The CCK-4 challenge might serve as a useful model to study putative anxiolytic effects of novel compounds during the early phase of drug development if the challenge procedure is carried out according to strictly comparable conditions.

Cannabinoid Receptor Agonist 13, a Novel Cannabinoid Agonist: First in Human Pharmacokinetics and Safety

Cannabinoid receptor agonist 13 (CRA13) is a novel cannabinoid (CB) receptor agonist with high affinity and functional activity toward both CB1 and CB2 receptors. This phase I study aimed to evaluate the pharmacokinetics, safety, and tolerability of single oral doses of CRA13. Sixty-three of 69 healthy adult males were randomized in seven cohorts (n = 9) to receive 1 to 80 mg of CRA13 or placebo orally in fasted condition. To investigate the diet effect, an independent group (n = 6) was randomized to receive 40 mg of CRA13 after high-fat and high-calorie breakfast in crossover design with a 2-week washout period. Peak plasma concentration (Cmax) ranged from 7.8 to 467.6 ng/ml (1–80 mg). CRA13 was rapidly absorbed and demonstrated linear pharmacokinetics (1–80 mg). Time to reach Cmax (tmax) was 1.5 to 2 h for all doses in both fasted and fed groups. Administration of 40 mg of CRA13 with food induced approximately 2-fold increase in the Cmax and the area under the concentration-time curve, AUC0 – tz. The apparent elimination half-life (t1/2) was 21 to 36 h and 30 to 41 h for fasted and fed groups, respectively. Dizziness, headache, and nausea were the most frequently reported adverse events (AEs), predominantly at the 40- and 80-mg doses. The incidence of AEs was dose-dependent and mild to moderate. No deaths and serious adverse events were reported. In conclusion, CRA13 was reasonably well tolerated and demonstrated a linear pharmacokinetics over the studied dose range (1–80 mg). Food intake increased CRA13 Cmax and AUC0 – tz by approximately 2-fold, whereas tmax was unaffected.

Dose-dependent suppression of human photoparoxysmal response with the competitive AMPA/kainate receptor antagonist BGG492: Clear PK/PD relationship.

Examine the efficacy of a competitive α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA)/kainate glutamate receptor antagonist, selurampanel (BGG492), in the human photostimulation model.

AQW051, a novel, potent and selective α7 nicotinic ACh receptor partial agonist: pharmacological characterization and phase I evaluation

Activation of the α7 nicotinic ACh receptor (nACh receptor) is considered an attractive target for the treatment of cognitive impairment associated with neurological disorders. Here we describe the novel α7‐nACh receptor agonist AQW051 as a promising drug candidate for this indication.

First-in-Man Intrathecal Application of Neurite Growth-Promoting Anti-Nogo-A Antibodies in Acute Spinal Cord Injury:

Background. Neutralization of central nervous system neurite growth inhibitory factors, for example, Nogo-A, is a promising approach to improving recovery following spinal cord injury (SCI). In animal SCI models, intrathecal delivery of anti-Nogo-A antibodies promoted regenerative neurite growth and functional recovery. Objective. This first-in-man study assessed the feasibility, safety, tolerability, pharmacokinetics, and preliminary efficacy of the human anti-Nogo-A antibody ATI355 following intrathecal administration in patients with acute, complete traumatic paraplegia and tetraplegia. Methods. Patients (N = 52) started treatment 4 to 60 days postinjury. Four consecutive dose-escalation cohorts received 5 to 30 mg/2.5 mL/day continuous intrathecal ATI355 infusion over 24 hours to 28 days. Following pharmacokinetic evaluation, 2 further cohorts received a bolus regimen (6 intrathecal injections of 22.5 and 45 mg/3 mL, respectively, over 4 weeks). Results. ATI355 was well tolerated up to 1-year follow-up. All patients experienced ≥1 adverse events (AEs). The 581 reported AEs were mostly mild and to be expected following acute SCI. Fifteen patients reported 16 serious AEs, none related to ATI355; one bacterial meningitis case was considered related to intrathecal administration. ATI355 serum levels showed dose-dependency, and intersubject cerebrospinal fluid levels were highly variable after infusion and bolus injection. In 1 paraplegic patient, motor scores improved by 8 points. In tetraplegic patients, mean total motor scores increased, with 3/19 gaining >10 points, and 1/19 27 points at Week 48. Conversion from complete to incomplete SCI occurred in 7/19 patients with tetraplegia. Conclusions. ATI335 was well tolerated in humans; efficacy trials using intrathecal antibody administration may be considered in acute SCI.

RESULTS FROM A FIRST-IN-HUMAN STUDY WITH THE BACE INHIBITOR CNP520

Luc Tritsmans, Luc Van Nueten, Niels Andreassen, Sebastiaan Engelborghs, Janssen Research & Development, Beerse, Belgium; 2 Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, M€ olndal, Sweden; Ortho-McNeil Pharmaceutical, Raritan, NJ, USA; Janssen Research & Development, Titusville, NJ, USA; 5 Hospital Mutua de Terrasa, Servicio de Neurologia, Terrassa, Spain; Hospital Universitario La Paz, Madrid, Spain; Hospital Clinico San Carlos, Servicio de Neurologia, Madrid, Spain; Fundaci o ACE, Barcelona, Alzheimer Treatment & Research Center, Barcelona, Spain; 9 Hospital Universitari La Fe Avinguda Abril Martorell, Valencia, Spain; Karolinska Institutet, Stockholm, Sweden; Department of Neurology and Memory Clinic, Hospital Network Antwerp (ZNA) Middelheim and Hoge Beuken, Antwerp, Belgium. Contact e-mail: jstreffe@its.jnj.com

CYP3A but not P-gp plays a relevant role in the in vivo intestinal and hepatic clearance of the delta-specific phosphoinositide-3 kinase inhibitor leniolisib

This study investigated the effect of itraconazole, a strong dual inhibitor of cytochrome P450 (CYP) 3A4 and P‐glycoprotein (P‐gp), on the single dose pharmacokinetics of leniolisib. In order to differentiate the specific contribution of CYP3A from P‐gp, the potential interaction with quinidine, a strong inhibitor of P‐gp but not CYP3A, was studied as well. Using a fixed‐sequence, 3‐way crossover design, 20 healthy male subjects received single oral doses of 10 mg leniolisib during three phases separated by a washout: (1) leniolisib alone, (2) 200 mg itraconazole once daily for 9 days plus leniolisib on day 5, and (3) 300 mg quinidine administered 1 h before and 3 h after leniolisib. Itraconazole increased the leniolisib oral drug exposure (AUCinf) by on average 2.1‐fold, whereas the peak drug concentration (Cmax) was less impacted (1.25‐fold). The terminal elimination half‐life (T1/2) of leniolisib was also increased by ~2‐fold. Neither oral AUCinf nor Cmax or T1/2 was found to be altered by quinidine. These findings suggest that the interaction with itraconazole occurred mainly systemically through inhibition of CYP3A, and corroborate our in vitro findings that leniolisib is neither a sensitive CYP3A substrate nor a relevant in vivo substrate for intestinal or hepatic P‐gp. Assuming itraconazole levels achieved complete inhibition of CYP3A, the fractional contribution of CYP3A to the overall disposition of leniolisib is estimated to be about 50%. The concomitant use of leniolisib with strong inhibitors of CYP3A as well as strong and moderate inducers of CYP3A is best avoided.