A PDE10A inhibitor CPL500036 is a novel agent modulating striatal function devoid of most neuroleptic side-effects.

Background: Phosphodiesterase 10A (PDE10A) is expressed almost exclusively in the striatum and its inhibition is suggested to offer potential treatment in disorders associated with basal ganglia. We evaluated the selectivity, cytotoxicity, genotoxicity, pharmacokinetics and potential adverse effects of a novel PDE10A inhibitor, CPL500036, in vivo. Methods: The potency of CPL500036 was demonstrated by microfluidic technology, and selectivity was investigated in a radioligand binding assay against 44 targets. Cardiotoxicity in vitro was evaluated in human ether-a-go-go related gene (hERG)-potassium channel-overexpressing cells by the patch-clamp method and by assessing key parameters in 3D cardiac spheroids. Cytotoxicity was determined in H1299, HepG2 and SH-SY5Y cell lines. The Ames test was used for genotoxicity analyses. During in vivo studies, CPL500036 was administered by oral gavage. CPL500036 exposure were determined by liquid chromatography-tandem mass spectrometry and plasma protein binding was assessed. The bar test was employed to assess catalepsy. Prolactin and glucose levels in rat blood were measured by ELISAs and glucometers, respectively. Cardiovascular safety in vivo was investigated in dogs using a telemetry method. Results: CPL500036 inhibited PDE10A at an IC50 of 1 nM, and interacted only with the muscarinic M2 receptor as a negative allosteric modulator with an IC50 of 9.2 µM. Despite inhibiting hERG tail current at an IC25 of 3.2 µM, cardiovascular adverse effects were not observed in human cardiac 3D spheroids or in vivo. Cytotoxicity in vitro was observed only at > 60 µM and genotoxicity was not recorded during the Ames test. CPL500036 presented good bioavailability and penetration into the brain. CPL500036 elicited catalepsy at 0.6 mg/kg, but hyperprolactinemia or hyperglycemic effects were not observed in doses up to 3 mg/kg. Conclusion: CPL500036 is a potent, selective and orally bioavailable PDE10A inhibitor with a good safety profile distinct from marketed antipsychotics. CPL500036 may be a compelling drug candidate.

Esketamine inhaled as dry powder: Pharmacokinetic, pharmacodynamic and safety assessment in a preclinical study.

Ketamine and its enantiomer esketamine have gained much attention in recent years as potent, fast-acting agents for the management of treatment-resistant depression. However, an alternative to oral ketamine administration is required to ensure adequate systemic exposure as the drug undergoes extensive first-pass metabolism. We propose dry powder inhalation as a new esketamine delivery route. Here, we examine the pharmacokinetics, pharmacodynamics, toxicology and safety of this novel esketamine administration method. Esketamine (10 mg/kg) and ketamine racemate (20 mg/kg) were administered to rats by dry powder inhalation, intravenous injection or intratracheal instillation and the pharmacokinetics of these treatments were compared. Analyte concentration of ketamine stereoisomers and their metabolites was assessed by LC-MS/MS method. Esketamine showed a clinically relevant pharmacokinetic profile, with high bioavailability (62%) and relatively low maximum concentration peaks. Esketamine exhibited high penetration of the blood-brain barrier, but pharmacodynamic examinations of brain homogenates showed no changes in selected protein phosphorylation or expression analyzed by the immunoblotting method. We conducted GLP-compliant 14-day and 28-day general toxicity studies in rats and dogs, respectively, subjected to dry esketamine powder inhalation. The maximum daily dosages were 46.5 mg/kg and 36.5 mg/kg, respectively. We also performed pharmacological safety studies. Esketamine inhaled as dry powder had an expected safety profile consistent with its known pharmacological action. None of its observed effects were considered toxicologically significant. The pharmacological safety studies confirmed that the observed effects were transient and that inhaled esketamine had a good safety profile. Hence, our preclinical studies demonstrated that dry powder inhalation is a highly efficacious and safe delivery route for esketamine and may be a viable alternative administration route meriting further clinical development.

Fabrication of Microchannels in a Nodeless Antiresonant Hollow-Core Fiber Using Femtosecond Laser Pulses.

In this work, we present femtosecond laser cutting of microchannels in a nodeless antiresonant hollow-core fiber (ARHCF). Due to its ability to guide light in an air core combined with exceptional light-guiding properties, an ARHCF with a relatively non-complex structure has a high application potential for laser-based gas detection. To improve the gas flow into the fiber core, a series of 250 × 30 µm microchannels were reproducibly fabricated in the outer cladding of the ARHCF directly above the gap between the cladding capillaries using a femtosecond laser. The execution time of a single lateral cut for optimal process parameters was 7 min. It has been experimentally shown that the implementation of 25 microchannels introduces low transmission losses of 0.17 dB (<0.01 dB per single microchannel). The flexibility of the process in terms of the length of the performed microchannel was experimentally demonstrated, which confirms the usefulness of the proposed method. Furthermore, the performed experiments have indicated that the maximum bending radius for the ARHCF, with the processed 100 µm long microchannel that did not introduce its breaking, is 15 cm.

Do Small Molecules Activate the TrkB Receptor in the Same Manner as BDNF? Limitations of Published TrkB Low Molecular Agonists and Screening for Novel TrkB Orthosteric Agonists.

TrkB is a tyrosine kinase receptor that is activated upon binding to brain-derived neurotrophic factor (BDNF). To date, the search for low-molecular-weight molecules mimicking BDNF's action has been unsuccessful. Several molecules exerting antidepressive effects in vivo, such as 7,8-DHF, have been suggested to be TrkB agonists. However, more recent publications question this hypothesis. In this study, we developed a set of experimental procedures including the evaluation of direct interactions, dimerization, downstream signaling, and cytoprotection in parallel with physicochemical and ADME methods to verify the pharmacology of 7,8-DHF and other potential reference compounds, and perform screening for novel TrkB agonists. 7,8 DHF bound to TrkB with Kd = 1.3 µM; however, we were not able to observe any other activity against the TrkB receptor in SN56 T48 and differentiated SH-SY5Y cell lines. Moreover, the pharmacokinetic and pharmacodynamic effects of 7,8-DHF at doses of 1 and 50 mg/kg were examined in mice after i.v and oral administration, respectively. The poor pharmacokinetic properties and lack of observed activation of TrkB-dependent signaling in the brain confirmed that 7,8-DHF is not a relevant tool for studying TrkB activation in vivo. The binding profile for 133 molecular targets revealed a significant lack of selectivity of 7,8-DHF, suggesting a distinct functional profile independent of interaction with TrkB. Additionally, a compound library was screened in search of novel low-molecular-weight orthosteric TrkB agonists; however, we were not able to identify reliable drug candidates. Our results suggest that published reference compounds including 7,8-DHF do not activate TrkB, consistent with canonical dogma, which indicates that the reported pharmacological activity of these compounds should be interpreted carefully in a broad functional context.

Antiresonant Hollow-Core Fiber-Based Dual Gas Sensor for Detection of Methane and Carbon Dioxide in the Near- and Mid-Infrared Regions.

In this work, we present for the first time a laser-based dual gas sensor utilizing a silica-based Antiresonant Hollow-Core Fiber (ARHCF) operating in the Near- and Mid-Infrared spectral region. A 1-m-long fiber with an 84-µm diameter air-core was implemented as a low-volume absorption cell in a sensor configuration utilizing the simple and well-known Wavelength Modulation Spectroscopy (WMS) method. The fiber was filled with a mixture of methane (CH4) and carbon dioxide (CO2), and a simultaneous detection of both gases was demonstrated targeting their transitions at 3.334 µm and 1.574 µm, respectively. Due to excellent guidance properties of the fiber and low background noise, the proposed sensor reached a detection limit down to 24 parts-per-billion by volume for CH4 and 144 parts-per-million by volume for CO2. The obtained results confirm the suitability of ARHCF for efficient use in gas sensing applications for over a broad spectral range. Thanks to the demonstrated low loss, such fibers with lengths of over one meter can be used for increasing the laser-gas molecules interaction path, substituting bulk optics-based multipass cells, while delivering required flexibility, compactness, reliability and enhancement in the sensor's sensitivity.

Kagome Hollow Core Fiber-Based Mid-Infrared Dispersion Spectroscopy of Methane at Sub-ppm Levels.

In this paper, we demonstrate the laser-based gas sensing of methane near 3.3 µm inside hollow-core photonic crystal fibers. We exploit a novel anti-resonant Kagome-type hollow-core fiber with a large core diameter (more than 100 µm) which results in gas filling times of less than 10 s for 1.3-m-long fibers. Using a difference frequency generation source and chirped laser dispersion spectroscopy technique, methane sensing with sub-parts-per-million by volume detection limit is performed. The detection of ambient methane is also demonstrated. The presented results indicate the feasibility of using a hollow-core fiber for increasing the path-length and improving the sensitivity of the mid-infrared gas sensors.

Photothermal spectroscopy of CO2 in an intracavity mode-locked fiber laser configuration.

A novel configuration of a photothermal gas sensor is demonstrated. Photothermal-induced gas refractive index (RI) modulation is probed by a simple, mode-locked (ML) ring cavity fiber laser, operating in the 1.55 µm wavelength region. The measured gas sample is placed in an open-path section of the ML laser and the RI variations directly translate to its optical path-length change, which is easily detectable as pulse repetition frequency deviations. Wavelength modulation spectroscopy (WMS) technique was used along with a custom-built FM demodulator simplifying the signal retrieval and acquisition. Normalized noise equivalent coefficient calculated for the sensor was 1 x 10-5 cm-1 W Hz-1/2.

Hollow core fiber-assisted absorption spectroscopy of methane at 3.4 µm.

A laser-based spectrometer exploiting a novel Kagome-type hollow core photonic crystal fiber, which serves as a gas cell is demonstrated. Low attenuation of this silica-based fiber in the 3.4 µm wavelength region enables accessing strong, fundamental transitions of methane, which was used as a target analyte in the presented experiment. With an all-fiber differential frequency generation source combined with wavelength modulation spectroscopy technique detection limit at single parts-per-million by volume level was obtained. These results show potential for developing compact and sensitive Kagome-fiber-based mid-infrared laser spectrometers.

Heterodyne interferometric signal retrieval in photoacoustic spectroscopy.

A new heterodyne interferometric method for optical signal detection in photoacoustic or photothermal spectroscopy is demonstrated and characterized. It relies on using one laser beam for the photoacoustic excitation of the gas sample that creates refractive index changes along the beam path, while another laser beam is used to measure these changes. A heterodyne-based detection of path-length changes is presented that does not require the interferometer to be balanced or stabilized, which significantly simplifies the optical design. We discuss advantages of this new approach to photoacoustic signal detection and the new sensing arrangements that it enables. An open-path photoacoustic spectroscopy of carbon dioxide at 2003 nm and a novel sensing configuration that enables three-dimensional spatial gas distribution measurement are experimentally demonstrated.

Dissipative soliton resonance mode-locked all-polarization-maintaining double clad Er:Yb fiber laser.

Our first demonstration of an all-PM fiber double clad erbium-ytterbium figure-8 laser mode-locked in a dissipative soliton resonance regime is presented. The laser generated µJ-level rectangular-shaped pulses with a maximum average output power of 1 W at 994 kHz repetition rate. The proposed configuration was characterized for two values resonator lengths - 44 and 205 m (total net-dispersion -0.9274 ps2 and -4.3084 ps2, respectively) to verify the possibility of non-complex tailoring of pulse parameters. The long-term stability of the all-PM configuration and self-starting of the mode-locking was experimentally confirmed by exposing the laser to forces of -5G to 7G magnitude on a vibration generator.

Dissipative soliton resonance mode-locked double clad Er:Yb laser at different values of anomalous dispersion.

Emission of an all-fiber, Dissipative Soliton Resonance (DSR) mode-locked, Double-Clad (DC), Erbium-Ytterbium (Er:Yb) laser configuration is investigated under several different values of large anomalous dispersion. The laser was mode-locked by means of Nonlinear Amplifying Loop Mirror (NALM) in a Figure-8 (F8) resonator configuration. The boundaries of anomalous dispersion in which the laser operated in purely DSR regime was experimentally verified by changing the length of passive SMF28 fiber spliced into the NALM. The influence of 6 different values of dispersion (-1.061 ps2 to -10.7 ps2) on the pulse properties is presented and discussed.

Compact all-fiber figure-9 dissipative soliton resonance mode-locked double-clad Er:Yb laser.

The first demonstration of a compact all-fiber figure-9 double-clad erbium-ytterbium laser working in the dissipative soliton resonance (DSR) regime is presented. Mode-locking was achieved using a nonlinear amplifying loop (NALM) resonator configuration. The laser was assembled with an additional 475 m long spool of SMF28 fiber in the NALM loop in order to obtain large net-anomalous cavity dispersion (-10.4 ps2), and therefore ensure that DSR would be the dominant mode-locking mechanism. At maximum pump power (4.78 W) the laser generated rectangular-shaped pulses with 455 ns duration and an average power of 950 mW, which at a repetition frequency of 412 kHz corresponds to a record energy of 2.3 µJ per pulse.

Amplification of noise-like pulses generated from a graphene-based Tm-doped all-fiber laser.

We report on the generation of noise-like pulse (NLP) trains in a Tm-doped fiber laser mode-locked by multilayer graphene saturable absorber. The spectral bandwidth obtained directly from the oscillator exceeds 60 nm, centered at 1950 nm, with 23.5 MHz repetition rate. The pulses were also amplified in a fully fiberized amplifier based on a double-cladding Tm-doped fiber. The system was capable of delivering 1.21 W of average power, which corresponds to 51.5 nJ energy stored in the noise-like bundle. We believe that the presented source might serve as a pump for supercontinuum generation in highly nonlinear fibers.

All-fiber Ho-doped mode-locked oscillator based on a graphene saturable absorber.

In this Letter, we demonstrate a graphene mode-locked, all-fiber Ho-doped fiber laser generating 1.3 nJ energy pulses directly from the oscillator. The graphene used as a saturable absorber was obtained via chemical vapor deposition on copper substrate and immersed in a poly(methyl methacrylate) support. The laser generated ultrashort soliton pulses at 2080 nm with bandwidth up to 6.1 nm. The influence of the output coupling ratio and the SA modulation depth on the mode-locking performance was also investigated.

Ultra-broadband dissipative soliton and noise-like pulse generation from a normal dispersion mode-locked Tm-doped all-fiber laser.

We report generation of ultra-broadband dissipative solitons and noise-like pulses from a simple, fully fiberized mode-locked Tm-doped fiber laser. The oscillator operates in the normal net dispersion regime and is mode-locked via nonlinear polarization evolution. Depending on the cavity dispersion, the laser was capable of generating 60 nm or 100 nm broad dissipative solitons. These are the broadest spectra generated from a normal dispersion mode-locked Tm-doped fiber laser so far. The same oscillator might also operate in the noise-like pulse regime with extremely broad emission spectra (over 300 nm), which also significantly outperforms the previous reports.

Direct comparison of shot-to-shot noise performance of all normal dispersion and anomalous dispersion supercontinuum pumped with sub-picosecond pulse fiber-based laser.

Coherence of supercontinuum sources is critical for applications involving characterization of ultrafast or rarely occurring phenomena. With the demonstrated spectral coverage of supercontinuum extending from near-infrared to over 10 µm in a single nonlinear fiber, there has been a clear push for the bandwidth rather than for attempting to optimize the dynamic properties of the generated spectrum. In this work we provide an experimental assessment of the shot-to-shot noise performance of supercontinuum generation in two types of soft glass photonic crystal fibers. Phase coherence and intensity fluctuations are compared for the cases of an anomalous dispersion-pumped fiber and an all-normal dispersion fiber. With the use of the dispersive Fourier transformation method, we demonstrate that a factor of 100 improvement in signal-to-noise ratio is achieved in the normal-dispersion over anomalous dispersion-pumped fiber for 390 fs long pump pulses. A double-clad design of the photonic lattice of the fiber is further postulated to enable a pump-related seeding mechanism of normal-dispersion supercontinuum broadening under sub-picosecond pumping, which is otherwise known for similar noise characteristics as modulation instability driven, soliton-based spectra.

260 fs and 1 nJ pulse generation from a compact, mode-locked Tm-doped fiber laser.

We report on generation of 260 fs-short pulses with energy of 1.1 nJ from a fully fiberized, monolithic Tm-doped fiber laser system. The design comprises a simple, graphene-based ultrafast oscillator and an integrated all-fiber chirped pulse amplifier (CPA). The system generates 110 mW of average power at 100.25 MHz repetition rate and central wavelength of 1968 nm. This is, to our knowledge, the highest pulse energy generated from a fully fiberized sub-300 fs Tm-doped laser, without the necessity of using grating-based dispersion compensation. Such compact, robust and cost-effective system might serve as a seed source for nonlinear frequency conversion or mid-infrared supercontinuum generation.

Fully-integrated dual-wavelength all-fiber source for mode-locked square-shaped mid-IR pulse generation via DFG in PPLN.

First demonstration of a dissipative soliton resonance (DSR), double-clad (DC) active fiber, mode-locked figure-8 laser (F8L) enabling simultaneous amplification of 1064 nm seed signal is presented. Appropriate design supported peak power clamping (PPC) effect in the laser resonator and enabled easy tuning of the generated, square-shaped pulses from 20 ns to 170 ns. By incorporating a circulator-based isolating element in the directional loop of the laser, record pulse energy of 2.13 µJ was achieved, directly at the output of the resonator. The usability of the unique dual-wavelength design was experimentally put to a test in a difference frequency generation (DFG) setup using periodically poled lithium niobate (PPLN) crystal.

Investigation on pulse shaping in fiber laser hybrid mode-locked by Sb(2)Te(3) saturable absorber.

We report a study on a hybrid mode-locked fiber laser with two saturable absorbers: slow and fast, integrated in a single device. Amorphous antimony telluride (Sb(2)Te(3)) layer was deposited on side-polished fiber to form the slow saturable absorber due to the third order nonlinear susceptibility of Sb(2)Te(3). Additionally, an unsymmetrical design of the device causes polarization-dependent losses and together with polarization controller allows to use a nonlinear polarization evolution to form the artificial fast saturable absorber. Sub-200 fs soliton pulses with 0.27 nJ of pulse energy were generated in the hybrid mode-locked Er-doped fiber laser. Differences in the dynamics of mode-locked laser are further investigated with the use of slow and fast saturable absorbers solely, and compared with the hybrid device. Joint operation of two saturable absorbers enhances the laser performance and stability. The conducted experiments allowed to define roles of each mechanism on the pulse shaping in the laser cavity.

Ultrafast thulium-doped fiber laser mode locked with black phosphorus.

We report, for the first time to our knowledge, the usage of black phosphorus (BP) as a saturable absorber for the mode locking of a thulium-doped fiber laser. We have experimentally shown that BP exhibits saturable absorption in the 2 µm wavelength range and supports ultrashort pulse generation. The saturable absorber was based on mechanically exfoliated BP deposited on a fiber connector tip. The laser was capable of generating 739 fs pulses centered at 1910 nm. Our results show that BP might be considered as a universal broadband saturable absorber that could successfully compete with graphene or other low-dimension nanomaterials.