A second generation of N-substituted 3alpha-[bis(4'-fluorophenyl)methoxy]-tropanes (GA 1-69, JHW 005 and JHW 013) binds with high affinity to the dopamine transporter (DAT) and are highly selective toward DAT compared to muscarinic receptor binding (M1). The objective of this study was to characterize brain distribution, pharmacokinetics, and pharmacodynamics [extracellular brain dopamine (DA) levels] of three novel N-substituted benztropine (BZT) analogs in male Sprague-Dawley rats. The BZT analogs displayed a higher distribution (Vd = 8.69-34.3 vs. 0.9 L/kg) along with longer elimination (t l/2: 4.1-5.4 vs. 0.5 h) than previously reported for cocaine. Brain-to-plasma partition coefficients were 1.3-2.5 vs. 2.1 for cocaine. The effect of the BZT analogs on extracellular brain (DA) levels ranged from minimal effects (GA 1-69) to several fold elevation (approximately 850% of basal DA for JHW 013) at the highest dose evaluated. PK/PD analysis of exposure-response data resulted in lower IC50 values for the BZT analogs compared to cocaine indicating their higher potency to inhibit DA reuptake (0.1-0.3 vs. 0.7 mg/L). These BZT analogs possess significantly different PK and PD profiles as compared to cocaine suggesting that further evaluation as cocaine abuse therapeutics is warranted.

BACKGROUND: Juvenile idiopathic arthritis (JIA) is the most common rheumatic disease in children. Children with JIA are at risk of inflammation of the uvea in the eye (uveitis). Overall, 20% to 25% of paediatric uveitis is associated with JIA. Major risk factors for development of uveitis in JIA are oligoarticular pattern of arthritis, an age at onset of arthritis of less than seven years of age, and antinuclear antibody positivity. In the initial stages of mild to moderate inflammation the uveitis is asymptomatic. This has led to current practice of screening all children with JIA for uveitis. Approximately 12% to 38% of patients with JIA develop uveitis in seven years following onset of arthritis. In 30% to 50% of children with JIA-associated uveitis structural complications are present at diagnosis. Furthermore about 50% to 75% of those with severe uveitis will eventually develop visual impairment secondary to ocular complications such as cataract and glaucoma. Defining the severity of inflammation and structural complications in uveitis patients is now possible following Standardised Uveitis Nomenclature (SUN) guidelines, and modified to incorporate the consensus of end point and outcome criteria into the design of randomised trials. Despite current screening and therapeutic options (pre-biologics) 10% to 15% of children with JIA-associated uveitis may develop bilateral visual impairment and certified legally blind. To date, there remains no controlled trial evidence of benefits of biologic therapy.

METHODS/DESIGN: This study will randomise 154 patients aged 2 to 18 years with active JIA-associated uveitis (despite methotrexate (MTX) treatment for at least 12 weeks). All participants will be treated for 18 months, with follow up of 3 years from randomisation (continuing on MTX throughout). All participants will receive a stable dose of MTX and in addition either adalimumab (20 mg/0.8 ml for patients<30 kg or 40 mg/0.8 ml for patients weighing 30 kg or more, subcutaneous (s/c) injection every 2 weeks based on body weight), or placebo (0.8 ml as appropriate according to body weight) s/c injection every 2 weeks.

DISCUSSION: This is the first randomised controlled trial that will assess the clinical effectiveness, safety and cost effectiveness of adalimumab in combination with methotrexate for the treatment of juvenile idiopathic arthritis associated uveitis.

TRIAL REGISTRATION: ISRCTN10065623.

Psoriasis, recently considered a systemic inflammatory disease, is associated with increased
cardiovascular morbidity and mortality. Inflammation can affect left ventricular function via
multiple mechanisms.
Objective Our aim was to determine the usefulness of using the relatively new tissue Doppler imaging
(TDI) in detecting left ventricular (LV) function abnormalities which may be underestimated
by conventional Doppler echocardiography (DE) in psoriasis patients.
Methods Thirty young patients with psoriasis (mean age36.9±9.2 yrs), without cardiovascular risk
factors or clinically evident cardiovascular disease and 30 healthy age and sex-matched
controls were subjected to DE and TDI. High-sensitivity C-reactive protein (hs-CRP), serum
homocysteine (Hcys) were also measured.
Results The serum hs-CRP and Hcys levels were significantly higher in patients compared to controls
(10.6±5.2 vs. 1.1±0.6mg/dl and 21.8±13.4 vs. 13.6±6.0μmol/l; both p <0.0001; respectively).
As regards DE, there was no statistically significant difference in LV dimensions, ejection
fraction, mitral Doppler flow E, A wave peak velocities, E/A ratio, or isovolumic relaxation time
(IVRT). As regards TDI, the peak systolic annular velocity (S), the early peak e’ and the late
peak a’ diastolic annular velocities were significantly lower in patients compared to controls
(9.6±1.6 vs. 10.9±1.0cm/sec; p <0.007; 12.6±2.6 vs. 14.6±1.2cm/sec; p <0.001 and 10.1±2.3 vs.
12.5±2.2cm/sec; p <0.002; respectively). The TDI derived IVCT and IVRT were significantly
prolonged in patients compared to controls (78.9±15.3 vs. 68.8±9.5msec; p <0.01 and 83.6±17.8
vs. 69.2±6.1msec; p <0.001 respectively). Significant negative correlations between hs-CRP
(r= -0.47; p= 0.017), Hcys (r= -0.61; p= 0.001) levels and e’ peak velocity, and between Hcys
level and S peak velocity (r= -0.52; p= 0.008) and a significant positive correlation between Hcys
level and TDI derived IVRT (r= 0.48; p= 0.014) were noted in patients.
Conclusions Mitral annular systolic and diastolic abnormalities detected by TDI, in patients with psoriasis
may be a useful marker for early heart failure in this group of patients.

Background In subjects with coronary artery disease (CAD), the angina induced by initial exercise is
attenuated with re-exercise after a brief rest. This warm-up phenomenon believed to be due
to ischemic preconditioning is related to the opening of cardiac ATP-sensitive K channels (K
ATP). Blockers of these K ATP channels such as the sulphonylurea drugs can lead to loss of
ischemic preconditioning.
Objective This study aimed to examine the effects of three different sulfonylureas: glibenclamide,
gliclazide and glimepiride, on the warm-up phenomenon by analyzing the results of 2
consecutive exercise tests in diabetic patients with coronary artery disease (CAD).
Methods Forty patients with chronic stable angina: 30 patients having type 2 diabetes mellitus (DM)
and 10 non diabetic patients (group D) were enrolled in the study. The DM patients were
divided into 3 groups according to the type of sulfonylurea drug they are receiving: Group
A (glibenclamide), Group B (gliclazide) and group C (glimepiride). All the patients were
subjected to 2 consecutive exercise tests with a 15-minute recovery period between the 2 tests..
Results There was no significant increase in peak heart rate, systolic blood pressure and rate pressure
product during test 2 compared to test 1 in groups B, C and D but not in group A patients. There
was a statistically significant increase in the time to onset of chest pain (p <0.007 for B, C and
p <0.005 for D), time to onset of 1 mm ST segment depression (p <0.007 for B, C and p <0.03 for
D) and exercise duration (p <0.01 for B; p <0.008 for C and p <0.02 for D) in test 2 compared to
test 1 in groups B, C and D but not in group A. There was also a significant decrease in time to ST
segment recovery to baseline in test 2 compared to test 1 in groups B,C and D (p <0.005 in the 3
groups) but not in group A.
Conclusions Glibenclamide, but not gliclazide or glimepiride abolished the warm-up phenomenon, the
clinical counterpart of ischemic preconditioning in type 2 DM patients with CAD.