Spinal cord anaplastic Pilocytic Astrocytoma - two stage resection with elsberg and beer technique. Case report and literature review.

Pilocytic Astrocytomas are generally presenting as WHO grade 1 intracranial masses in the paediatric population with a favourable prognostic. In less common instances they can be found in the spinal cord. There have been rare cases of Anaplastic variants of the Cranial Pilocytic Astrocytomas. We report a rare instance of an adult patient with pilocytic astrocytoma of the cervical cord with anaplastic features. Our patient presented with 6 months history of neck pain and right-hand paraesthesia which partially responded to steroid treatment. MRI of the cervical spine demonstrated marked expansion of the cervical cord with oedema extending cranially to the medulla and caudally to the mid-thoracic cord. Post-gadolinium T1-weighted images showed intense intramedullary enhancement mainly centred at the level of the C3 vertebra. Diffusion Tensor Imaging Tractography showed the central location of the tumour expanding the cord and displacing the tracts circumferentially. Surgical resection was performed in two stages according to the Elsberg and Beer technique that assisted with safe margin tumour debulking. The histological sections revealed a glial lineage tumour with retained ATRX nuclear expression, positive for GFAP, Ki-67 estimated to 10% and a methylation class corresponding to an Anaplastic Pilocytic Astrocytoma. Subsequently, our patient underwent adjuvant radiotherapy and chemotherapy (10 cycles of Temozolamide and 6 cycles of CCNU). Symptomatic progression developed at 18 months from the initial surgery, radiological progression at 34 months and the overall survival was 40 months. We reviewed the literature and found only four other cases with similar histology.

Posterior cervical foraminotomy versus anterior cervical discectomy for Cervical Brachialgia: the FORVAD RCT.

Background: Posterior cervical foraminotomy and anterior cervical discectomy are routinely used operations to treat cervical brachialgia, although definitive evidence supporting superiority of either is lacking. Objective: The primary objective was to investigate whether or not posterior cervical foraminotomy is superior to anterior cervical discectomy in improving clinical outcome. Design: This was a Phase III, unblinded, prospective, United Kingdom multicentre, parallel-group, individually randomised controlled superiority trial comparing posterior cervical foraminotomy with anterior cervical discectomy. A rapid qualitative study was conducted during the close-down phase, involving remote semistructured interviews with trial participants and health-care professionals. Setting: National Health Service trusts. Participants: Patients with symptomatic unilateral cervical brachialgia for at least 6 weeks. Interventions: Participants were randomised to receive posterior cervical foraminotomy or anterior cervical discectomy. Allocation was not blinded to participants, medical staff or trial staff. Health-care use from providing the initial surgical intervention to hospital discharge was measured and valued using national cost data. Main outcome measures: The primary outcome measure was clinical outcome, as measured by patient-reported Neck Disability Index score 52 weeks post operation. Secondary outcome measures included complications, reoperations and restricted American Spinal Injury Association score over 6 weeks post operation, and patient-reported Eating Assessment Tool-10 items, Glasgow-Edinburgh Throat Scale, Voice Handicap Index-10 items, PainDETECT and Numerical Rating Scales for neck and upper-limb pain over 52 weeks post operation. Results: The target recruitment was 252 participants. Owing to slow accrual, the trial closed after randomising 23 participants from 11 hospitals. The qualitative substudy found that there was support and enthusiasm for the posterior cervical FORaminotomy Versus Anterior cervical Discectomy in the treatment of cervical brachialgia trial and randomised clinical trials in this area. However, clinical equipoise appears to have been an issue for sites and individual surgeons. Randomisation on the day of surgery and processes for screening and approaching participants were also crucial factors in some centres. The median Neck Disability Index scores at baseline (pre surgery) and at 52 weeks was 44.0 (interquartile range 36.0-62.0 weeks) and 25.3 weeks (interquartile range 20.0-42.0 weeks), respectively, in the posterior cervical foraminotomy group (n = 14), and 35.6 weeks (interquartile range 34.0-44.0 weeks) and 45.0 weeks (interquartile range 20.0-57.0 weeks), respectively, in the anterior cervical discectomy group (n = 9). Scores appeared to reduce (i.e. improve) in the posterior cervical foraminotomy group, but not in the anterior cervical discectomy group. The median Eating Assessment Tool-10 items score for swallowing was higher (worse) after anterior cervical discectomy (13.5) than after posterior cervical foraminotomy (0) on day 1, but not at other time points, whereas the median Glasgow-Edinburgh Throat Scale score for globus was higher (worse) after anterior cervical discectomy (15, 7, 6, 6, 2, 2.5) than after posterior cervical foraminotomy (3, 0, 0, 0.5, 0, 0) at all postoperative time points. Five postoperative complications occurred within 6 weeks of surgery, all after anterior cervical discectomy. Neck pain was more severe on day 1 following posterior cervical foraminotomy (Numerical Rating Scale - Neck Pain score 8.5) than at the same time point after anterior cervical discectomy (Numerical Rating Scale - Neck Pain score 7.0). The median health-care costs of providing initial surgical intervention were £2610 for posterior cervical foraminotomy and £4411 for anterior cervical discectomy. Conclusions: The data suggest that posterior cervical foraminotomy is associated with better outcomes, fewer complications and lower costs, but the trial recruited slowly and closed early. Consequently, the trial is underpowered and definitive conclusions cannot be drawn. Recruitment was impaired by lack of individual equipoise and by concern about randomising on the day of surgery. A large prospective multicentre trial comparing anterior cervical discectomy and posterior cervical foraminotomy in the treatment of cervical brachialgia is still required. Trial registration: This trial is registered as ISRCTN10133661. Funding: This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 27, No. 21. See the NIHR Journals Library website for further project information.

Cervical brachialgia is pain that starts in the neck and passes down into the arm. Although most people with cervical brachialgia recover quickly, in some patients pain persists, and in 15% of patients pain is so severe that they are unable to work. In the posterior cervical FORaminotomy Versus Anterior cervical Discectomy in the treatment of cervical brachialgia trial, we investigated two neck surgeries used to treat this problem: posterior cervical foraminotomy (surgery from the back of the neck) and anterior cervical discectomy (surgery from the front of the neck). This trial aimed to find out if one of them is better than the other at relieving pain and more cost-effective for the National Health Service. We assessed patients' quality of life 1 year after their surgery and how their pain changed over the course of the year. We also measured the number of complications patients had in the first 6 weeks after their operation. Recruitment was slow and so the trial was stopped early, after only 23 patients from 11 hospitals had been randomly allocated to the two surgery groups. We had planned to recruit 252 participants to the trial; the number of participants we were able to recruit in practice was too small to enable us to determine which surgery is better at relieving pain. To find out why the trial had struggled to recruit, we asked hospital staff and participants about their experiences. We found that hospital staff sometimes struggled to organise everything needed to randomise patients on the day of surgery. Some staff also found it difficult to randomise patients as they had an opinion on which surgery they thought the patient should receive. The data collected in the trial will still be useful to help design future research. Finding out which surgery is better at relieving pain remains important, and the data we have collected will support answering this question in future.

Discovery and Optimization of Potent and Orally Available CTP Synthetase Inhibitors for Use in Treatment of Diseases Driven by Aberrant Immune Cell Proliferation.

Herein, we report the discovery of a first-in-class chemotype 2-(alkylsulfonamido)thiazol-4-yl)acetamides that act as pan-selective inhibitors of cytidine 5'-triphosphate synthetase (CTPS1/2), critical enzymes in the de novo pyrimidine synthesis pathway. Weak inhibitors identified from a high-throughput screening of 240K compounds have been optimized to a potent, orally active agent, compound 27, which has shown significant pharmacological responses at 10 mg/kg dose BID in a well-established animal model of inflammation.

Unconscious Influences on "Free Will" Movement Initiation: Slow-wave Brain Stimulation and the Readiness Potential.

A central objective in the study of volition has been to identify how changes in neural activity relate to voluntary-"free will"-movement. The readiness potential (RP) is observed in the EEG as a slow-building signal that precedes action onset. Many consider the RP as a marker of an underlying preparatory process for initiating voluntary movement. However, the RP may emerge from ongoing slow-wave brain oscillations that influence the timing of movement initiation in a phase-dependent manner. Transcranial alternating current stimulation (tACS) enables brain oscillations to be entrained at the frequency of stimulation. We delivered tACS at a slow-wave frequency over frontocentral motor areas while participants (n = 30) performed a simple, self-paced button press task. During the active tACS condition, participants showed a tendency to initiate actions in the phase of the tACS cycle that corresponded to increased negative potentials across the frontocentral motor region. Comparisons of premovement EEG activity observed over frontocentral and central scalp electrodes showed earlier onset and increased amplitude of RPs from active stimulation compared with sham stimulation. This suggests that movement-related activity in the brain can be modulated by the delivery of weak, nonconsciously perceptible alternating currents over frontocentral motor regions. We present novel findings that support existing theories, which suggest the timing of voluntary movement is influenced by the phase of slow-changing oscillating brain states.

Anterolateral thoracic approach for thoracic discectomy using pedicle marking and 3D intraoperative imaging system.

Thoracic disc herniation (TDH) is a rare occurrence comprising of only 0.25-0.75% of all herniated discs in any region. Limitations in direct visualization remains a surgical challenge for complete and safe resection of TDH. In this case report, we describe the use of a 3D intraoperative imaging system (O-arm system TM) coupled with percutaneous pedicle markers placed under fluoroscopic guidance to circumvent the current limitations in visualisation for a patient with a giant calcified TDH using an anterolateral approach. There was an improvement in overall visualisation and ease of procedure, leading to a successful surgery. Post-op, there was a significant improvement in the motor power of the patient.

Effects of Slow Oscillatory Transcranial Alternating Current Stimulation on Motor Cortical Excitability Assessed by Transcranial Magnetic Stimulation.

Converging evidence suggests that transcranial alternating current stimulation (tACS) may entrain endogenous neural oscillations to match the frequency and phase of the exogenously applied current and this entrainment may outlast the stimulation (although only for a few oscillatory cycles following the cessation of stimulation). However, observing entrainment in the electroencephalograph (EEG) during stimulation is extremely difficult due to the presence of complex tACS artifacts. The present study assessed entrainment to slow oscillatory (SO) tACS by measuring motor cortical excitability across different oscillatory phases during (i.e., online) and outlasting (i.e., offline) stimulation. 30 healthy participants received 60 trials of intermittent SO tACS (0.75 Hz; 16 s on/off interleaved) at an intensity of 2 mA peak-to-peak. Motor cortical excitability was assessed using transcranial magnetic stimulation (TMS) of the hand region of the primary motor cortex (M1HAND) to induce motor evoked potentials (MEPs) in the contralateral thumb. MEPs were acquired at four time-points within each trial - early online, late online, early offline, and late offline - as well as at the start and end of the overall stimulation period (to probe longer-lasting aftereffects of tACS). A significant increase in MEP amplitude was observed from pre- to post-tACS (paired-sample t-test; t29 = 2.64, P = 0.013, d = 0.48) and from the first to the last tACS block (t29 = -2.93, P = 0.02, d = 0.54). However, no phase-dependent modulation of excitability was observed. Therefore, although SO tACS had a facilitatory effect on motor cortical excitability that outlasted stimulation, there was no evidence supporting entrainment of endogenous oscillations as the underlying mechanism.

Gamma coherence mediates interhemispheric integration during multiple object tracking.

Our ability to track the paths of multiple visual objects moving between the hemifields requires effective integration of information between the two cerebral hemispheres. Coherent neural oscillations in the gamma band (35-70 Hz) are hypothesized to drive this information transfer. Here we manipulated the need for interhemispheric integration using a novel multiple object tracking (MOT) task in which stimuli either moved between the two visual hemifields, requiring interhemispheric integration, or moved within separate visual hemifields. We used electroencephalography (EEG) to measure interhemispheric coherence during the task. Human observers (21 women; 20 men) were poorer at tracking objects between versus within hemifields, reflecting a cost of interhemispheric integration. Critically, gamma coherence was greater in trials requiring interhemispheric integration, particularly between sensors over parieto-occipital areas. In approximately half of the participants, the observed cost of integration was associated with a failure of the cerebral hemispheres to become coherent in the gamma band. Moreover, individual differences in this integration cost correlated with endogenous gamma coherence at these same sensors, although with generally opposing relationships for the real and imaginary part of coherence. The real part (capturing synchronization with a near-zero phase lag) benefited between-hemifield tracking; imaginary coherence was detrimental. Finally, instantaneous phase coherence over the tracking period uniquely predicted between-hemifield tracking performance, suggesting that effective integration benefits from sustained interhemispheric synchronization. Our results show that gamma coherence mediates interhemispheric integration during MOT and add to a growing body of work demonstrating that coherence drives communication across cortically distributed neural networks.NEW & NOTEWORTHY Using a multiple object tracking paradigm, we were able to manipulate the need for interhemispheric integration on a per-trial basis, while also having an objective measure of integration efficacy (i.e., tracking performance). We show that tracking performance reflects a cost of integration, which correlates with individual differences in interhemispheric EEG coherence. Gamma coherence appears to uniquely benefit between-hemifield tracking, predicting performance both across participants and across trials.

Rapid recalibration of temporal order judgements: Response bias accounts for contradictory results.

Recent history influences subsequent perception, decision-making and motor behaviours. In this article, we address a discrepancy in the effects of recent sensory history on the perceived timing of auditory and visual stimuli. In the synchrony judgement (SJ) task, similar timing relationships in consecutive trials seem more synchronous (i.e. less like the repeated temporal order). This effect is known as rapid recalibration and is consistent with a negative perceptual aftereffect. Interestingly, the opposite is found in the temporal order judgement (TOJ) task (positive rapid recalibration). We aimed to determine whether a simple bias to repeat judgements on consecutive trials (choice-repetition bias) could account for the discrepant results in these tasks. Preliminary simulations and analyses indicated that a choice-repetition bias could produce apparently positive rapid recalibration in the TOJ and not the SJ task. Our first experiment revealed no evidence of rapid recalibration of TOJs, but negative rapid recalibration of associated confidence. This suggests that timing perception was rapidly recalibrated, but that the negative recalibration effect was obfuscated by a positive bias effect. In our second experiment, we experimentally mitigated the choice-repetition bias effect and found negative rapid recalibration of TOJs. We therefore conclude that timing perception is negatively rapidly recalibrated, and this is observed consistently across timing tasks. These results contribute to a growing body of evidence that indicates multisensory perception is constantly undergoing recalibration, such that perceptual synchrony is maintained. This work also demonstrates that participants' task responses reflect judgements that are contaminated by independent biases of perception and decision-making.

Current challenges: the ups and downs of tACS.

The non-invasive delivery of electric currents through the scalp (transcranial electrical stimulation) is a popular tool for neuromodulation, mostly due to its highly adaptable nature (waveform, montage) and tolerability at low intensities (< 2 mA). Applied rhythmically, transcranial alternating current stimulation (tACS) may entrain neural oscillations in a frequency- and phase-specific manner, providing a causal perspective on brain-behaviour relationships. While the past decade has seen many behavioural and electrophysiological effects of tACS that suggest entrainment-mediated effects in the brain, it has been difficult to reconcile such reports with the weak intracranial field strengths (< 1 V/m) achievable at conventional intensities. In this review, we first describe the ongoing challenges faced by users of tACS. We outline the biophysics of electrical brain stimulation and the factors that contribute to the weak field intensities achievable in the brain. Since the applied current predominantly shunts through the scalp-stimulating the nerves that innervate it-the plausibility of transcutaneous (rather than transcranial) effects of tACS is also discussed. In examining the effects of tACS on brain activity, the complex problem of salvaging electrophysiological recordings from artefacts of tACS is described. Nevertheless, these challenges by no means mark the rise and fall of tACS: the second part of this review outlines the recent advancements in the field. We describe some ways in which artefacts of tACS may be better managed using high-frequency protocols, and describe innovative methods for current interactions within the brain that offer either dynamic or more focal current distributions while also minimising transcutaneous effects.

Derivatisation of parthenolide to address chemoresistant chronic lymphocytic leukaemia.

Parthenolide is a natural product that exhibits anti-leukaemic activity, however, its clinical use is limited by its poor bioavailability. It may be extracted from feverfew and protocols for growing, extracting and derivatising it are reported. A novel parthenolide derivative with good bioavailability and pharmacological properties was identified through a screening cascade based on in vitro anti-leukaemic activity and calculated "drug-likeness" properties, in vitro and in vivo pharmacokinetics studies and hERG liability testing. In vitro studies showed the most promising derivative to have comparable anti-leukaemic activity to DMAPT, a previously described parthenolide derivative. The newly identified compound was shown to have pro-oxidant activity and in silico molecular docking studies indicate a prodrug mode of action. A synthesis scheme is presented for the production of amine 7 used in the generation of 5f.

Comparison of clinical outcomes in anterior cervical discectomy versus foraminotomy for brachialgia.

AIM: The choice between anterior cervical discectomy & fusion (ACD) or posterior cervical foraminotomy (PCF) for the treatment of cervical brachialgia is controversial. This study aimes to compare clinical outcomes between these two operative inteventions for brachialgia. METHODS: Retrospective review of prospectively collected data was performed. Patients receiving a primary ACD or PCF to treat brachialgia, in a single tertiary neurosurgical unit were included. Surgical details, and patient reported outcomes (COMI-Neck questionnaire) were extracted from a prospectively maintained spinal procedure database. Minimum clinically important difference (MCID) was defined as a change in COMI score of -2 at 12 months. The student t-test, Chi-square test, and linear regression were used to compare groups. RESULTS: Between June 2011 ad February 2016 there were 634 ACD procedures (Median age 49; 321 Male), and 54 PCF procedures (Median age 50; 37 Male) perfomed for brachialgia. Age, ASA and pre-operative COMI were similar between the groups (p > .05). Complete outcome data was recorded at twelve months in 312 ACD and 36 PCF patients. Both ACD and PCF were associated with an improvement in COMI at 3 and 12 months (all p < .01). Mean change in COMI at 3 months was -2.38 for ACD, versus -2.31 for PCF (p = .88); at twelve months it was -2.94 for ACD, versus -2.67 for PCF (p = .55). MCID was seen in 59% of ACD cases, versus 58% of PCF cases at twelve months (p = .91). CONCLUSION: There was no significant difference between outcomes in the ACD and PCF groups. This is supportive of published literature. The proposed multicenter RCTs may inform further.

No Evidence for Phase-Specific Effects of 40 Hz HD-tACS on Multiple Object Tracking.

Phase synchronization drives connectivity between neural oscillators, providing a flexible mechanism through which information can be effectively and selectively routed between task-relevant cortical areas. The ability to keep track of objects moving between the left and right visual hemifields, for example, requires the integration of information between the two cerebral hemispheres. Both animal and human studies have suggested that coherent (or phase-locked) gamma oscillations (30-80 Hz) might underlie this ability. While most human evidence has been strictly correlational, high-density transcranial alternating current stimulation (HD-tACS) has been used to manipulate ongoing interhemispheric gamma phase relationships. Previous research showed that 40 Hz tACS delivered bilaterally over human motion complex could bias the perception of a bistable ambiguous motion stimulus (Helfrich et al., 2014). Specifically, this work showed that in-phase (0° offset) stimulation boosted endogenous interhemispheric gamma coherence and biased perception toward the horizontal (whereby visual tokens moved between visual hemifields-requiring interhemispheric integration). By contrast, anti-phase (180° offset) stimulation decreased interhemispheric gamma coherence and biased perception toward the vertical (whereby tokens moved within separate visual hemifields). Here we devised a multiple object tracking arena comprised of four quadrants whereby discrete objects moved either entirely within the left and right visual hemifields, or could cross freely between visual hemifields, thus requiring interhemispheric integration. Using the same HD-tACS montages as Helfrich et al. (2014), we found no phase-specific effect of 40 Hz stimulation on overall tracking performance. While tracking performance was generally lower during between-hemifield trials (presumably reflecting a cost of integration), this difference was unchanged by in- vs. anti-phase stimulation. Our null results could be due to a failure to reliably modulate coherence in our study, or that our task does not rely as heavily on this network of coherent gamma oscillations as other visual integration paradigms.

Evaluation of pyrrolidine and pyrazolone derivatives as inhibitors of trypanosomal phosphodiesterase B1 (TbrPDEB1).

Human African trypanosomiasis (HAT) is a parasitic disease, caused by the protozoan pathogen Trypanosoma brucei, which affects thousands every year and which is in need of new therapeutics. Herein we report the synthesis and assessment of a series of pyrrolidine and pyrazolone derivatives of human phosphodiesterase 4 (hPDE4) inhibitors for the assessment of their activity against the trypanosomal phosphodiesterase TbrPDEB1. The synthesized compounds showed weak potency against TbrPDEB1.

Repurposing human PDE4 inhibitors for neglected tropical diseases. Evaluation of analogs of the human PDE4 inhibitor GSK-256066 as inhibitors of PDEB1 of Trypanosoma brucei.

Cyclic nucleotide phosphodiesterases (PDEs) have been identified as important enzyme targets for drug development in both humans and Trypanosoma brucei, the causative agent of human African trypanosomiasis. With this in mind, we recently reported the profiling of a range of human phosphodiesterase inhibitors, showing that human PDE4 inhibitors tend to display the best potency against the trypanosomal phosphodiesterase TbrPDEB1. Among these was GSK-256066, a potent inhibitor of human PDE4 and a weak inhibitor of TbrPDEB1. In this report, we describe the results of a structure-activity relationship study of this chemotype, leading to the discovery of analogs with improved potency against TbrPDEB1 and micromolar inhibition of T. brucei cellular growth. We rationalize the potency trends via molecular docking of the new inhibitors into a recently reported apo structure of TbrPDEB1. The studies in this article will inform future efforts in repurposing human PDE inhibitors as antitrypanosomal agents.

Repurposing human PDE4 inhibitors for neglected tropical diseases: design, synthesis and evaluation of cilomilast analogues as Trypanosoma brucei PDEB1 inhibitors.

A medicinal chemistry exploration of the human phosphodiesterase 4 (hPDE4) inhibitor cilomilast (1) was undertaken in order to identify inhibitors of phosphodiesterase B1 of Trypanosoma brucei (TbrPDEB1). T. brucei is the parasite which causes African sleeping sickness, a neglected tropical disease that affects thousands each year, and TbrPDEB1 has been shown to be an essential target of therapeutic relevance. Noting that 1 is a weak inhibitor of TbrPDEB1, we report the design and synthesis of analogs of this compound, culminating in 12b, a sub-micromolar inhibitor of TbrPDEB1 that shows modest inhibition of T. brucei proliferation.

Synthesis and assessment of catechol diether compounds as inhibitors of trypanosomal phosphodiesterase B1 (TbrPDEB1).

Human African trypanosomiasis (HAT) is a parasitic neglected tropical disease that affects 10,000 patients each year. Current treatments are sub-optimal, and the disease is fatal if not treated. Herein, we report our continuing efforts to repurpose the human phosphodiesterase 4 (hPDE4) inhibitor piclamilast to target trypanosomal phosphodiesterase TbrPDEB1. We prepared a range of substituted heterocyclic replacements for the 4-amino-3,5-dichloro-pyridine headgroup of piclamilast, and found that these compounds exhibited weak inhibitory activity of TbrPDEB1.

Synthesis and evaluation of human phosphodiesterases (PDE) 5 inhibitor analogs as trypanosomal PDE inhibitors. Part 2. Tadalafil analogs.

In this Letter we describe our ongoing target repurposing efforts focused on discovery of inhibitors of the essential trypanosomal phosphodiesterase TbrPDEB1. This enzyme has been implicated in virulence of Trypanosoma brucei, the causative agent of human African trypanosomiasis (HAT). We outline the synthesis and biological evaluation of analogs of tadalafil, a human PDE5 inhibitor currently utilized for treatment of erectile dysfunction, and report that these analogs are weak inhibitors of TbrPDEB1.

Synthesis and evaluation of human phosphodiesterases (PDE) 5 inhibitor analogs as trypanosomal PDE inhibitors. Part 1. Sildenafil analogs.

Parasitic diseases, such as African sleeping sickness, have a significant impact on the health and well-being in the poorest regions of the world. Pragmatic drug discovery efforts are needed to find new therapeutic agents. In this Letter we describe target repurposing efforts focused on trypanosomal phosphodiesterases. We outline the synthesis and biological evaluation of analogs of sildenafil (1), a human PDE5 inhibitor, for activities against trypanosomal PDEB1 (TbrPDEB1). We find that, while low potency analogs can be prepared, this chemical class is a sub-optimal starting point for further development of TbrPDE inhibitors.

Pharmacological validation of Trypanosoma brucei phosphodiesterases B1 and B2 as druggable targets for African sleeping sickness.

Neglected tropical disease drug discovery requires application of pragmatic and efficient methods for development of new therapeutic agents. In this report, we describe our target repurposing efforts for the essential phosphodiesterase (PDE) enzymes TbrPDEB1 and TbrPDEB2 of Trypanosoma brucei , the causative agent for human African trypanosomiasis (HAT). We describe protein expression and purification, assay development, and benchmark screening of a collection of 20 established human PDE inhibitors. We disclose that the human PDE4 inhibitor piclamilast, and some of its analogues, show modest inhibition of TbrPDEB1 and B2 and quickly kill the bloodstream form of the subspecies T. brucei brucei . We also report the development of a homology model of TbrPDEB1 that is useful for understanding the compound-enzyme interactions and for comparing the parasitic and human enzymes. Our profiling and early medicinal chemistry results strongly suggest that human PDE4 chemotypes represent a better starting point for optimization of TbrPDEB inhibitors than those that target any other human PDEs.