Parsaclisib Is a Next-Generation Phosphoinositide 3-Kinase δ Inhibitor with Reduced Hepatotoxicity and Potent Antitumor and Immunomodulatory Activities in Models of B-Cell Malignancy.

The clinical use of first-generation phosphoinositide 3-kinase (PI3K)δ inhibitors in B-cell malignancies is hampered by hepatotoxicity, requiring dose reduction, treatment interruption, and/or discontinuation of therapy. In addition, potential molecular mechanisms by which resistance to this class of drugs occurs have not been investigated. Parsaclisib (INCB050465) is a potent and selective next-generation PI3Kδ inhibitor that differs in structure from first-generation PI3Kδ inhibitors and has shown encouraging anti-B-cell tumor activity and reduced hepatotoxicity in phase 1/2 clinical studies. Here, we present preclinical data demonstrating parsaclisib as a potent inhibitor of PI3Kδ with over 1000-fold selectivity against other class 1 PI3K isozymes. Parsaclisib directly blocks PI3K signaling-mediated cell proliferation in B-cell lines in vitro and in vivo and indirectly controls tumor growth by lessening immunosuppression through regulatory T-cell inhibition in a syngeneic lymphoma model. Diffuse large B-cell lymphoma cell lines overexpressing MYC were insensitive to proliferation blockade via PI3Kδ signaling inhibition by parsaclisib, but their proliferative activities were reduced by suppression of MYC gene transcription. Molecular structure analysis of the first- and next-generation PI3Kδ inhibitors combined with clinical observation suggests that hepatotoxicity seen with the first-generation inhibitors could result from a structure-related off-target effect. Parsaclisib is currently being evaluated in multiple phase 2 clinical trials as a therapy against various hematologic malignancies of B-cell origin (NCT03126019, NCT02998476, NCT03235544, NCT03144674, and NCT02018861). SIGNIFICANCE STATEMENT: The preclinical properties described here provide the mechanism of action and support clinical investigations of parsaclisib as a therapy for B-cell malignancies. MYC overexpression was identified as a resistance mechanism to parsaclisib in DLBCL cells, which may be useful in guiding further translational studies for the selection of patients with DLBCL who might benefit from PI3Kδ inhibitor treatment in future trials. Hepatotoxicity associated with first-generation PI3Kδ inhibitors may be an off-target effect of that class of compounds.

INCB040093 Is a Novel PI3Kδ Inhibitor for the Treatment of B Cell Lymphoid Malignancies.

Phosphatidylinositol 3-kinase delta (PI3Kδ) is a critical signaling molecule in B cells and is considered a target for development of therapies against various B cell malignancies. INCB040093 is a novel PI3Kδ small-molecule inhibitor and has demonstrated promising efficacy in patients with Hodgkin's lymphoma in clinical studies. In this study, we disclose the chemical structure and the preclinical activity of the compound. In biochemical assays, INCB040093 potently inhibits the PI3Kδ kinase, with 74- to >900-fold selectivity against other PI3K family members. In vitro and ex vivo studies using primary B cells, cell lines from B cell malignancies, and human whole blood show that INCB040093 inhibits PI3Kδ-mediated functions, including cell signaling and proliferation. INCB040093 has no significant effect on the growth of nonlymphoid cell lines and was less potent in assays that measure human T and natural killer cell proliferation and neutrophil and monocyte functions, suggesting that the impact of INCB040093 on the human immune system will likely be restricted to B cells. INCB040093 inhibits the production of macrophage-inflammatory protein-1ß (MIP-1beta) and tumor necrosis factor-ß (TNF-beta) from a B cell line, suggesting a potential effect on the tumor microenvironment. In vivo, INCB040093 demonstrates single-agent activity in inhibiting tumor growth and potentiates the antitumor growth effect of the clinically relevant chemotherapeutic agent, bendamustine, in the Pfeiffer cell xenograft model of non-Hodgkin's lymphoma. INCB040093 has a favorable exposure profile in rats and an acceptable safety margin in rats and dogs. Taken together, data presented in this report support the potential utility of orally administered INCB040093 in the treatment of B cell malignancies.

The Role of Non-invasive Testing in Evaluation and Diagnosis of Pediatric Lower Urinary Tract Dysfunction.

PURPOSE OF REVIEW: The symptoms of lower urinary tract dysfunction (LUTD) including urinary incontinence, frequency, and urgency are among the most common reasons children are referred to pediatric urologists. Despite this, the workup for LUTD is often time consuming and a source of frustration for patients, parents, and clinicians alike. In the current review, we summarize the important role non-invasive testing plays in the diagnosis and management of children with LUTD and to show how use of these tests can help avoid the need for more invasive testing in the majority of children. RECENT FINDINGS: Non-invasive tests such urine studies, uroflowmetry ± simultaneous electromyography, assessment of post-void residual, renal/bladder ultrasound, and pelvic ultrasound when used appropriately can provide valuable information to facilitate decision making during the evaluation of children with LUTD. While these tests should be employed prior to more invasive testing such as urodynamic studies, they can often act as a surrogate for the more invasive tests. Non-invasive tests can help us in our goal of improving diagnostic ability to better classify the child's LUTD into an actual condition which allows targeted treatment in the hope of better outcomes and more satisfied patients and families.

Roles of UGT, P450, and Gut Microbiota in the Metabolism of Epacadostat in Humans.

Epacadostat (EPA, INCB024360) is a first-in-class, orally active, investigational drug targeting the enzyme indoleamine 2,3-dioxygenase 1 (IDO1). In Phase I studies, EPA has demonstrated promising clinical activity when used in combination with checkpoint modulators. When the metabolism of EPA was investigated in humans, three major, IDO1-inactive, circulating plasma metabolites were detected and characterized: M9, a direct O-glucuronide of EPA; M11, an amidine; and M12, N-dealkylated M11. Glucuronidation of EPA to form M9 is the dominant metabolic pathway, and in vitro, this metabolite is formed by UGT1A9. However, negligible quantities of M11 and M12 were detected when EPA was incubated with a panel of human microsomes from multiple tissues, hepatocytes, recombinant human cytochrome P450s (P450s), and non-P450 enzymatic systems. Given the reductive nature of M11 formation and the inability to define its source, the role of gut microbiota was investigated. Analysis of plasma from mice dosed with EPA following pretreatment with either antibiotic (ciprofloxacin) to inhibit gut bacteria or 1-aminobenzotriazole (ABT) to systemically inhibit P450s demonstrated that gut microbiota is responsible for the formation of M11. Incubations of EPA in human feces confirmed the role of gut bacteria in the formation of M11. Further, incubations of M11 with recombinant P450s showed that M12 is formed via N-dealkylation of M11 by CYP3A4, CYP2C19, and CYP1A2. Thus, in humans three major plasma metabolites of EPA were characterized: two primary metabolites, M9 and M11, formed directly from EPA via UGT1A9 and gut microbiota, respectively, and M12 formed as a secondary metabolite via P450s from M11.

Breathing changes following mini-implant-supported maxillary skeletal expander treatment in late adolescent or adult patients : Assessment of objective and subjective functional breathing changes.

PURPOSE: The aim of this study was to assess objective and subjective breathing changes in adult patients who underwent maxillary skeletal expansion with the mini-implant-supported maxillary skeletal expander (MSE). METHODS: Twenty-nine patients (mean age 18.1 ± 4.3 years) who underwent expansion using the MSE were compared pre- and posttreatment and with a control group (mean age 19.9 ± 2.6 years) to assess objective and subjective functional breathing changes. Objective measurements of the airway including peak nasal inspiratory flow (PNIF) and peak oral inspiratory flow (POIF) were measured utilizing the In-Check medical device (Clement Clarke, Harlow, United Kingdom). Patients reported subjective breathing assessment utilizing the visual analog scale (VAS). Intragroup comparisons were performed with Wilcoxon tests and intergroup comparison with Mann-Whitney U tests. Spearman correlation coefficients were calculated among the studied variables (P < 0.05). RESULTS: Following MSE treatment, there were significantly higher values for PNIF total (P < 0.0001), PNIF right (P < 0.0001), PNIF left (P < 0.0001), and POIF (P < 0.01) compared to pretreatment and control group results. Also, patients reported a significant decrease in troubled breathing as measured by the VAS for breathing through the right nostril (P < 0.01), left nostril (P < 0.001), and both nostrils (P < 0.01). Comparing the objective and subjective variables for both the pre-MSE or post-MSE groups, the results indicated no significant correlation between total PNIF and total VAS. However, the values had significant correlations between PNIF and VAS on each side when the patients were asked to block one nostril. CONCLUSIONS: Objective functional breathing measurements were increased immediately after treatment with MSE. Subjective functional breathing measurements changes were significantly higher after MSE treatment and compared with the control group. MSE presents a nonsurgical alternative to achieving orthopedic expansion in adult patients which may provide a benefit for patients with nasal airway obstruction.

Long-term effects of maxillary skeletal expander treatment on functional breathing.

Objective: : To investigate the long-term effects of maxillary skeletal expander (MSE) treatment on functional breathing. Objective: measures of breathing, the peak nasal inspiratory flow (PNIF), and peak oral inspiratory flow (POIF), and subjective measures of breathing, the visual analog scale (VAS) and nasal obstruction symptom evaluation (NOSE) survey, were used to investigate the long-term effects of MSE in functional breathing. Seventeen patients, mean age 19.4 ± 3.9 years treated at the UCLA Orthodontics Clinic were assessed on their functional breathing at 3 timepoints: pre-expansion (T0), post-expansion (T1), and post-orthodontic treatment (T2). Results: : Immediately after expansion (T1), all the objective functional breathing values were significantly increased in comparison to T0 (P < 0.05). The VAS total, VAS right and VAS left were significantly lower at T1 in comparison to T0 (P < 0.05). At 26.8 ± 3.9 months after MSE expansion (T2), PNIF total, PNIF right, PNIF left, and POIF were significantly higher when compared to T0 (P < 0.05). Also, VAS total, VAS right and VAS left were significantly lower at T2 when compared to T0 (P < 0.05). Additionally, there was a positive correlation between PNIF and the magnitude of expansion at anterior nasal spine and zygomaticomaxillary point (ZMA). There was a positive correlation between total VAS and the magnitude of expansion at the ZMA. There were no significant changes for the NOSE subjective breathing measurement at all time comparisons. Conclusions: : Overall, MSE treatment produces an increased objective and subjective airway improvement that continues to remain stable in the long-term post expansion.

Short pelvic floor electromyographic lag time: a novel noninvasive approach to document detrusor overactivity in children with lower urinary tract symptoms.

PURPOSE: Noninvasive uroflow with simultaneous electromyography can measure electromyographic lag time, ie the interval between the start of pelvic floor relaxation and the start of urine flow (normally 2 to 6 seconds). Intuitively one would expect that in patients experiencing urgency secondary to detrusor overactivity the lag time would be short or even a negative value. We studied whether short electromyographic lag time on uroflow with electromyography actually correlates with documented detrusor overactivity on urodynamics. MATERIALS AND METHODS: We reviewed 2 separate and distinct cohorts of 50 neurologically and anatomically normal children with persistent lower urinary tract symptoms who were evaluated by uroflow with simultaneous electromyography and videourodynamics. Group 1 consisted of 30 boys and 20 girls (mean age 7.8 years, range 4 to 19) selected based on electromyographic lag time of 0 seconds or less on screening uroflow with electromyography who subsequently underwent videourodynamics. Group 2 consisted of 14 boys and 36 girls (median age 8.4 years, range 5 to 18) selected based on the presence of detrusor overactivity on videourodynamics whose screening uroflow with electromyography was then reviewed. Correlations between short electromyographic lag time and videourodynamically proved detrusor overactivity were analyzed. RESULTS: For group 1 urodynamics confirmed the presence of detrusor overactivity in all patients with an electromyographic lag time of 0 seconds or less. For group 2 mean ± SD electromyographic lag time was 0.1 ± 1.7 seconds, and 35 patients (70%) with urodynamically proved detrusor overactivity had a lag time of 0 seconds or less. CONCLUSIONS: In patients with lower urinary tract symptoms an electromyographic lag time of 0 seconds or less is 100% predictive of detrusor overactivity. This short electromyographic lag time has 100% specificity and 70% sensitivity for diagnosing detrusor overactivity (88% if less than 2 seconds). Thus, diagnosing the presence or absence of detrusor overactivity in most children with lower urinary tract symptoms and a quiet pelvic floor during voiding can be done reliably via uroflow with simultaneous electromyography.

Dysfunctional elimination syndromes--how closely linked are constipation and encopresis with specific lower urinary tract conditions?

PURPOSE: It is recognized that there is a strong association between bladder and bowel dysfunction. We determined the association of constipation and/or encopresis with specific lower urinary tract conditions. MATERIALS AND METHODS: We reviewed our database of children with lower urinary tract dysfunction and divided cases into 3 categories of bowel dysfunction (constipation, encopresis and constipation plus encopresis) and 4 lower urinary tract conditions (dysfunctional voiding, idiopathic detrusor overactivity disorder, detrusor underutilization disorder and primary bladder neck dysfunction). Associations between bowel dysfunction types and each lower urinary tract condition were determined. RESULTS: Of 163 males and 205 females with a mean age of 8.5 years constipation was the most common bowel dysfunction (27%). Although encopresis is generally thought to reflect underlying constipation, only half of children with encopresis in this series had constipation. Dysfunctional voiding was associated with the highest incidence of bowel dysfunction. All but 1 patient with encopresis had associated urgency and detrusor overactivity, and the encopresis resolved in 75% of patients after initiation of anticholinergic therapy. Constipation was significantly more common in girls (27%) than in boys (11%, p <0.01), while encopresis was more common in boys (9%) than in girls (3%, p = 0.02), likely reflecting the higher incidence of dysfunctional voiding in girls and idiopathic detrusor overactivity disorder in boys. CONCLUSIONS: Active bowel dysfunction was seen in half of the children with a lower urinary tract condition. Constipation was more common in patients with dysfunctional voiding, while encopresis was significantly increased in those with idiopathic detrusor overactivity disorder and in those with dysfunctional voiding, severe urgency and detrusor overactivity. Anticholinergics, despite their constipating effect, given for treatment of detrusor overactivity resolved encopresis in most children with this bowel dysfunction.

Prevalence of urinary tract infection and vesicoureteral reflux in children with lower urinary tract dysfunction.

PURPOSE: Lower urinary tract dysfunction is a common pediatric urological problem that is often associated with urinary tract infection. We determined the prevalence of a urinary tract infection history in children with lower urinary tract dysfunction and its association, if any, with gender, bowel dysfunction, vesicoureteral reflux and specific lower urinary tract conditions. MATERIALS AND METHODS: We retrospectively reviewed the charts of children diagnosed with and treated for lower urinary tract dysfunction, noting a history of urinary tract infection with or without fever, gender, bowel dysfunction and vesicoureteral reflux in association with specific lower urinary tract conditions. RESULTS: Of the 257 boys and 366 girls with a mean age of 9.1 years 207 (33%) had a urinary tract infection history, including 88 with at least 1 febrile infection. A total of 64 patients underwent voiding cystourethrogram/videourodynamics, which revealed reflux in 44 (69%). In 119 of the 207 patients all infections were afebrile and 18 underwent voiding cystourethrogram/videourodynamics, which revealed reflux in 5 (28%). A urinary tract infection history was noted in 53% of girls but only 5% of boys (p <0.001). Patients with detrusor underutilization disorder were statistically more likely to present with an infection history than patients with idiopathic detrusor overactivity disorder or primary bladder neck dysfunction (each p <0.01). CONCLUSIONS: Females with lower urinary tract dysfunction have a much higher urinary tract infection incidence than males. This association was most often noted for lower urinary tract conditions in which urinary stasis occurs, including detrusor underutilization disorder and dysfunctional voiding. Reflux was found in most girls with a history of febrile infections. Since reflux was identified in more than a quarter of girls with only afebrile infections who were evaluated for reflux, it may be reasonable to perform voiding cystourethrogram or videourodynamics in some of them to identify reflux.

Outcomes of targeted treatment for vesicoureteral reflux in children with nonneurogenic lower urinary tract dysfunction.

PURPOSE: There is a known association between nonneurogenic lower urinary tract conditions and vesicoureteral reflux. Whether reflux is secondary to the lower urinary tract condition or coincidental is controversial. We determined the rate of reflux resolution in patients with lower urinary tract dysfunction using targeted treatment for the underlying condition. MATERIALS AND METHODS: Patients diagnosed and treated for a lower urinary tract condition who had concomitant vesicoureteral reflux at or near the time of diagnosis were included. Patients underwent targeted treatment and antibiotic prophylaxis, and reflux was monitored with voiding cystourethrography or videourodynamics. RESULTS: Vesicoureteral reflux was identified in 58 ureters in 36 females and 5 males with a mean age of 6.2 years. After a mean of 3.1 years of treatment reflux resolved with targeted treatment in 26 of 58 ureters (45%). All of these patients had a history of urinary tract infections before starting targeted treatment. Resolution rates of vesicoureteral reflux were similar for all reflux grades. Resolution or significant improvement of reflux was greater in the ureters of patients with dysfunctional voiding (70%) compared to those with idiopathic detrusor overactivity disorder (38%) or detrusor underutilization (40%). CONCLUSIONS: Vesicoureteral reflux associated with lower urinary tract conditions resolved with targeted treatment and antibiotic prophylaxis in 45% of ureters. Unlike the resolution rates reported in patients with reflux without a coexisting lower urinary tract condition, we found that there were no differences in resolution rates among grades I to V reflux in patients with lower urinary tract conditions. Patients with dysfunctional voiding had the most improvement and greatest resolution of reflux. Additionally grade V reflux resolved in some patients.

Can staccato and interrupted/fractionated uroflow patterns alone correctly identify the underlying lower urinary tract condition?

PURPOSE: Worldwide, uroflowmetry without simultaneous electromyography is often the only testing performed during the initial assessment of children with lower urinary tract symptoms. Various alterations in uroflow pattern are thought to indicate particular types of lower urinary tract conditions, specifically staccato uroflow indicating dysfunctional voiding and intermittent/fractionated uroflow indicating detrusor underactivity. We determined how reliable uroflow pattern alone is as a surrogate for simultaneously measured pelvic floor electromyography activity during voiding, and how well staccato and interrupted uroflow actually correlate with the diagnoses they are presumed to represent. MATERIALS AND METHODS: We reviewed uroflow/electromyography studies performed during the initial evaluation of 388 consecutive neurologically and anatomically normal patients with persistent lower urinary tract symptoms. We identified those with staccato, interrupted/fractionated and mixed uroflow based on current International Children's Continence Society guidelines. RESULTS: A total of 69 girls (58.5%) and 49 boys (41.5%) met inclusion criteria. Staccato uroflow was noted in 60 patients, interrupted/fractionated uroflow in 28 and a combination in 30. An active electromyography during voiding confirmed the diagnosis of dysfunctional voiding in 33.3% of patients with staccato, 46.4% with interrupted/fractionated and 50% with mixed uroflow patterns. CONCLUSIONS: Diagnoses based on uroflow pattern appearance without simultaneous electromyography to support them can be misleading, and reliance on uroflow pattern alone can lead to overdiagnoses of dysfunctional voiding and detrusor underactivity. When assessing patients with uroflow, an accompanying simultaneous pelvic floor electromyography is of utmost importance for improving diagnostic accuracy and thereby allowing for the most appropriate therapy.

Efficacy of the JAK2 inhibitor INCB16562 in a murine model of MPLW515L-induced thrombocytosis and myelofibrosis.

The discovery of JAK2 and MPL mutations in patients with myeloproliferative neoplasms (MPNs) provided important insight into the genetic basis of these disorders and led to the development of JAK2 kinase inhibitors for MPN therapy. Although recent studies have shown that JAK2 kinase inhibitors demonstrate efficacy in a JAK2V617F murine bone marrow transplantation model, the effects of JAK2 inhibitors on MPLW515L-mediated myeloproliferation have not been investigated. In this report, we describe the in vitro and in vivo effects of INCB16562, a small-molecule JAK2 inhibitor. INCB16562 inhibited proliferation and signaling in cell lines transformed by JAK2 and MPL mutations. Compared with vehicle treatment, INCB16562 treatment improved survival, normalized white blood cell counts and platelet counts, and markedly reduced extramedullary hematopoeisis and bone marrow fibrosis. We observed inhibition of STAT3 and STAT5 phosphorylation in vivo consistent with potent inhibition of JAK-STAT signaling. These data suggest JAK2 inhibitor therapy may be of value in the treatment of JAK2V617F-negative MPNs. However, we did not observe a decrease in the size of the malignant clone in the bone marrow of treated mice at the end of therapy, which suggests that JAK2 inhibitor therapy, by itself, was not curative in this MPN model.

Selective inhibition of IDO1 effectively regulates mediators of antitumor immunity.

Indoleamine 2,3-dioxygenase-1 (IDO1; IDO) mediates oxidative cleavage of tryptophan, an amino acid essential for cell proliferation and survival. IDO1 inhibition is proposed to have therapeutic potential in immunodeficiency-associated abnormalities, including cancer. Here, we describe INCB024360, a novel IDO1 inhibitor, and investigate its roles in regulating various immune cells and therapeutic potential as an anticancer agent. In cellular assays, INCB024360 selectively inhibits human IDO1 with IC(50) values of approximately 10nM, demonstrating little activity against other related enzymes such as IDO2 or tryptophan 2,3-dioxygenase (TDO). In coculture systems of human allogeneic lymphocytes with dendritic cells (DCs) or tumor cells, INCB024360 inhibition of IDO1 promotes T and natural killer (NK)-cell growth, increases IFN-gamma production, and reduces conversion to regulatory T (T(reg))-like cells. IDO1 induction triggers DC apoptosis, whereas INCB024360 reverses this and increases the number of CD86(high) DCs, potentially representing a novel mechanism by which IDO1 inhibition activates T cells. Furthermore, IDO1 regulation differs in DCs versus tumor cells. Consistent with its effects in vitro, administration of INCB024360 to tumor-bearing mice significantly inhibits tumor growth in a lymphocyte-dependent manner. Analysis of plasma kynurenine/tryptophan levels in patients with cancer affirms that the IDO pathway is activated in multiple tumor types. Collectively, the data suggest that selective inhibition of IDO1 may represent an attractive cancer therapeutic strategy via up-regulation of cellular immunity.

Synthesis and structure-activity relationships of pyrido[3,2-b]pyrazin-3(4H)-ones and pteridin-7(8H)-ones as corticotropin-releasing factor-1 receptor antagonists.

Pyrido[3,2-b]pyrazin-3(4H)-ones and pteridin-7(8H)-ones were evaluated as corticotropin-releasing factor-1 receptor antagonists. The synthesis, SAR studies and pharmacokinetic evaluation of these analogs are described herein.

Simplifying the diagnosis of 4 common voiding conditions using uroflow/electromyography, electromyography lag time and voiding history.

PURPOSE: Noninvasive uroflowmetry with simultaneous electromyography is useful to triage cases of lower urinary tract symptoms into 4 urodynamically defined conditions, especially when incorporating short and long electromyography lag times in the analysis. We determined the prevalence of these 4 conditions at a single referral institution and the usefulness of uroflowmetry with simultaneous electromyography and electromyography lag time to confirm the diagnosis, guide treatment and monitor response. MATERIALS AND METHODS: We retrospectively reviewed the records of 100 consecutive normal children who presented with persistent lower urinary tract symptoms, underwent uroflowmetry with electromyography as part of the initial evaluation and were diagnosed with 1 of 4 conditions based on certain uroflowmetry/electromyography features. The conditions included 1) dysfunctional voiding--active pelvic floor electromyography during voiding with or without staccato flow, 2a) idiopathic detrusor overactivity disorder-A--a quiet pelvic floor during voiding and shortened lag time (less than 2 seconds), 2b) idiopathic detrusor overactivity disorder-B--a quiet pelvic floor with a normal lag time, 3) detrusor underutilization disorder--volitionally deferred voiding with expanded bladder capacity but a quiet pelvic floor, and 4) primary bladder neck dysfunction--prolonged lag time (greater than 6 seconds) and a depressed, right shifted uroflowmetry curve with a quiet pelvic floor during voiding. Treatment was tailored to the underlying condition in each patient. RESULTS: The group consisted of 50 males and 50 females with a mean age of 8 years (range 3 to 18). Dysfunctional voiding was more common in females (p <0.05) while idiopathic detrusor overactivity disorder-B and primary bladder neck dysfunction were more common in males (p <0.01). With treatment uroflowmetry parameters normalized for all types. Electromyography lag time increased in idiopathic detrusor overactivity disorder-A cases and decreased in primary bladder neck dysfunction cases. CONCLUSIONS: Noninvasive uroflowmetry with simultaneous electromyography offers an excellent alternative to invasive urodynamics to diagnose 4 urodynamically defined conditions. It identifies the most appropriate therapy for the specific condition and objectively monitors the treatment response.

Synthesis and in vivo evaluation of cyclic diaminopropane BACE-1 inhibitors.

The synthesis, evaluation, and structure-activity relationships of a set of related constrained diaminopropane inhibitors of BACE-1 are described. The full in vivo profile of an optimized inhibitor in both normal and P-gp deficient mice is compared with data generated in normal rats.

Nonneurogenic voiding disorders in children and adolescents: clinical and videourodynamic findings in 4 specific conditions.

PURPOSE: We determined if there were any unique findings regarding specific clinical manifestations and videourodynamics among our patients with nonneurogenic voiding disorders. MATERIALS AND METHODS: A cohort of 237 normal children with lower urinary tract symptoms were evaluated by videourodynamics and uroflow/electromyogram, and divided into 4 groups based on the specific urodynamic findings 1) dysfunctional voiding (active electromyogram during voiding with or without detrusor overactivity), 2) idiopathic detrusor overactivity disorder (detrusor overactivity on urodynamics but quiet electromyogram during voiding), 3) detrusor underutilization disorder (willful infrequent but otherwise normal voiding) and 4) primary bladder neck dysfunction. Association of lower urinary tract symptoms, urinary tract infection, vesicoureteral reflux and abnormal urodynamic parameters within each condition was compared. RESULTS: The only strong correlation between a particular symptom and a specific condition was between hesitancy and primary bladder neck dysfunction. Urgency was reported to some degree with all 4 conditions. The most common abnormal urodynamic finding was detrusor overactivity, which was seen in 91% of patients with dysfunctional voiding. The highest detrusor pressures were seen in dysfunctional voiding during voiding and in idiopathic detrusor overactivity disorder during detrusor overactivity. Vesicoureteral reflux was seen in a third of children with dysfunctional voiding or idiopathic detrusor overactivity disorder, in all 8 boys with a history of urinary tract infection and in 51% of patients with febrile or recurrent urinary tract infections with lower urinary tract symptoms when not infected. Bilateral vesicoureteral reflux and bowel dysfunction were most common in dysfunctional voiding. CONCLUSIONS: On objective urodynamic assessment pediatric nonneurogenic voiding dysfunction can essentially be divided into 4 specific conditions. These conditions have distinct urodynamic features that distinguish them from each other, as opposed to their clinical features (particularly lower urinary tract symptoms), which frequently overlap and are not as defining as they are often presumed to be.

Primary bladder neck dysfunction in children and adolescents III: results of long-term alpha-blocker therapy.

PURPOSE: Primary bladder neck dysfunction is a nonneurogenic voiding disorder frequently overlooked in pediatrics. The diagnosis classically is made by videourodynamics but can also be made with noninvasive uroflow studies with pelvic floor electromyography. We report our long-term results using alpha-blocker therapy in patients with primary bladder neck dysfunction. MATERIALS AND METHODS: We reviewed 51 neurologically normal children (mean age 11.6 years, range 3.5 to 17.8) meeting criteria for primary bladder neck dysfunction who underwent alpha-blocker therapy for at least 1 year. All patients were symptomatic with abnormal flow parameters and an electromyogram lag time of 6 seconds or more on initial uroflow/electromyography. Pretreatment and on-treatment uroflow/electromyogram studies were performed in all patients. Average and maximum uroflow rates, electromyogram lag times and post-void residual volumes were compared. RESULTS: After a mean followup of 46.2 months (range 12 to 124) mean average and maximum uroflow rates improved from 7.0 to 12.4 cc per second and from 12.4 to 20.3 cc per second, respectively, while mean electromyogram lag time decreased from 30.8 to 5.8 seconds (all p <0.01). Of the patients 85% reported subjective symptomatic relief. A total of 15 patients (29%) stopped alpha-blocker therapy for various reasons, none related to side effects. Repeat off-treatment uroflow/electromyogram studies showed that measured parameters reverted to pretreatment values (all p <0.05). Eight of these 15 patients eventually resumed alpha-blocker therapy, while only 3 remained asymptomatic off of the alpha-blocker. CONCLUSIONS: alpha-Blocker therapy continues to benefit children with primary bladder neck dysfunction even after 3 years of treatment. Few patients can come off of alpha-blocker therapy without returning to their pretreatment state, suggesting the condition is likely chronic in most patients.