The discovery of UK-369003, a novel PDE5 inhibitor with the potential for oral bioavailability and dose-proportional pharmacokinetics.

This paper describes our recent efforts to design and synthesise potent and selective PDE5 inhibitors and the use of in vitro predictors of clearance, absorption and permeability to maximise the potential for dose-proportional pharmacokinetics and good oral bioavailability in man. Optimisation of the preclinical profile resulted in the identification of UK-369003 (19a) and its nomination as a clinical candidate. The clinical pharmacokinetic and safety profile has enabled us to progress the compound to test its efficacy in patients with lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH) and a paper describing its efficacy has recently been published.

Part 3: Design and synthesis of proline-derived α2δ ligands.

A potent series of substituted (2S,4S)-benzylproline α(2)δ ligands have been designed from the readily available starting material (2S,4R)-hydroxy-L-proline. The ligands have improved pharmacokinetic profile over the (4S)-phenoxyproline derivatives described previously and have potential for development as oral agents for the treatment of neuropathic pain. Compound 16 has been progressed to clinical development.

Part 2: Design, synthesis and evaluation of hydroxyproline-derived α2δ ligands.

Conformational constraint has been used to design a potent series of α(2)δ ligands derived from the readily available starting material (2S,4R)-hydroxy-l-proline. The ligands have improved physicochemistry and potency compared to their linear counterparts (described in our earlier publication) and the lead compound has been progressed to clinical development.

Impact of a parenting program in a high-risk, multi-ethnic community: the PALS trial.

BACKGROUND: Parenting programs have been shown to work when delivered to motivated ethnic majority parents in demonstration projects, but comparatively little is known about their impact when delivered to high-risk, multi-ethnic populations by routine local services. METHODS: The Primary Age Learning Skills (PALS) trial was a randomized controlled trial of an evidence-based parenting-group program that targeted the parent-child relationship and child literacy. Parents of 174 children were selected from a population of 672 5- and 6-year-olds attending four primary schools in a high-risk, ethnically diverse, inner-city area. Eighty-eight children were allocated to the Incredible Years preventive program plus a shortened six-week version of the SPOKES literacy program, delivered by local services; 86 to usual community services; 152/174 (87%) of families were successfully followed up. Parent-child relationship quality and child behavior were measured using direct observation and parent interview; child reading was assessed psychometrically. RESULTS: Two-thirds (58/89) of those offered the parenting program attended at least one session, with similar enrollment rates across the Black African, African-Caribbean, White-British and Other ethnic groups. Mean attendance was four relationship-building sessions and one literacy-development session. Satisfaction questionnaires were completed by 43/58 starters; 93% said they were well or extremely satisfied, with equally high rates across ethnic groups. At follow-up after one year, those allocated to the intervention showed significant improvements in the parent-child relationship on observation and at interview compared to controls; effects were similar across all ethnic groups. However, child behavior problems and reading did not improve. The cost was £1,343 ($2,100) per child. CONCLUSIONS: Programs can be organized to be engaging and effective in improving parenting among high-risk, multi-ethnic communities, which is of considerable value. To also be cost-effective in achieving child changes may require a set-up that enables parents to attend more sessions and/or an exclusive focus on children with clinically significant behavior problems.

Randomised controlled trial of parent groups for child antisocial behaviour targeting multiple risk factors: the SPOKES project.

BACKGROUND: There is a pressing need for cost-effective population-based interventions to tackle early-onset antisocial behaviour. As this is determined by many factors, it would seem logical to devise interventions that address several influences while using an efficient means of delivery. The aim of this trial was to change four risk factors that predict poor outcome: ineffective parenting, conduct problems, attention deficit/hyperactivity disorder (ADHD) symptoms, and low reading ability. METHODS: A randomised controlled trial was carried out in eight schools in London, England. Nine hundred and thirty-six (936) 6-year-old children were screened for antisocial behaviour, then parents of 112 high scorers were randomised to parenting groups held in schools or control; 109 were followed up a year later. The intervention lasted 28 weeks and was novel as it had components to address both child behaviour (through the Incredible Years programme) and child literacy (through a new 'SPOKES' programme to help parents read with their children). Fidelity of implementation was emphasised by careful training of therapists and weekly supervision. Controls received an information helpline. Assessment of conduct problems was by parent interview, parenting by direct observation and child reading by psychometric testing. RESULTS: At follow-up parents allocated to the intervention used play, praise and rewards, and time out more often than controls, and harsh discipline less; effect sizes ranged from .31 to .59 sd (p-values .046 to .005). Compared to control children, whose behaviour didn't change, intervention children's conduct problems reduced by .52sd, (p < .001), dropping from the 80th to the 61st percentile; oppositional-defiant disorder (ODD) halved from 60% to 31% (p = .003). ADHD symptoms reduced by .44sd (p = .002), and reading age improved by six months (.36sd, p = .027). Teacher-rated behaviour didn't change. The programme cost pound2,380 ($3,800) per child. CONCLUSIONS: Effective population-based early intervention to improve the functioning of with antisocial behaviour is practically feasible by targeting multiple risk factors and emphasising implementation fidelity.

Urine screening for clients with learning disabilities.

This article describes a study carried out to explore how common urinary tract infections are among adults with learning disabilities who use continence products. The study also evaluated the use of a product to assist urine sample collection with this client group.

Is Hybridization a Source of Adaptive Venom Variation in Rattlesnakes? A Test, Using a Crotalus scutulatus × viridis Hybrid Zone in Southwestern New Mexico.

Venomous snakes often display extensive variation in venom composition both between and within species. However, the mechanisms underlying the distribution of different toxins and venom types among populations and taxa remain insufficiently known. Rattlesnakes (Crotalus, Sistrurus) display extreme inter- and intraspecific variation in venom composition, centered particularly on the presence or absence of presynaptically neurotoxic phospholipases A2 such as Mojave toxin (MTX). Interspecific hybridization has been invoked as a mechanism to explain the distribution of these toxins across rattlesnakes, with the implicit assumption that they are adaptively advantageous. Here, we test the potential of adaptive hybridization as a mechanism for venom evolution by assessing the distribution of genes encoding the acidic and basic subunits of Mojave toxin across a hybrid zone between MTX-positive Crotalus scutulatus and MTX-negative C. viridis in southwestern New Mexico, USA. Analyses of morphology, mitochondrial and single copy-nuclear genes document extensive admixture within a narrow hybrid zone. The genes encoding the two MTX subunits are strictly linked, and found in most hybrids and backcrossed individuals, but not in C. viridis away from the hybrid zone. Presence of the genes is invariably associated with presence of the corresponding toxin in the venom. We conclude that introgression of highly lethal neurotoxins through hybridization is not necessarily favored by natural selection in rattlesnakes, and that even extensive hybridization may not lead to introgression of these genes into another species.

Highly potent and selective zwitterionic agonists of the delta-opioid receptor. Part 1.

A series of zwitterionic delta-opioid agonists, with targeted physicochemistry, as a strategy to limit potential for CNS exposure, were prepared. These agents were found to possess exquisite potency and selectivity over mu and kappa-opiate activity. Furthermore, analogue 3a was found to display restricted CNS exposure, as evidenced by its inactivity in a rodent hyperlocomotion assay of central opiate activity. Dog pharmacokinetic studies on 3a indicated encouraging oral bioavailability.