Unexpectedly high affinity of a novel histamine H(3) receptor antagonist, GSK239512, in vivo in human brain, determined using PET.

BACKGROUND AND PURPOSE: This study aimed to investigate the relationship between the plasma concentration (PK) of the novel histamine H3 receptor antagonist, GSK239512, and the brain occupancy of H(3) receptors (RO) in healthy human volunteers. EXPERIMENTAL APPROACH: PET scans were obtained after i.v. administration of the H(3) -specific radioligand [(11) C]GSK189254. Each subject was scanned before and after single oral doses of GSK239512, at 4 and 24 h after dose. PET data were analysed by compartmental analysis, and regional RO estimates were obtained by graphical analysis of changes in the total volumes of distribution of the radioligand, followed by a correction for occupancy by the high affinity radioligand. The PK/RO relationship was analysed by a population-modelling approach, using the average PK of GSK239512 during each scan. KEY RESULTS: Following administration of GSK239512, there was a reduction in the brain uptake of [(11) C]GSK189254 in all regions, including cerebellum. RO at 4 h was higher than at 24 h, and the PK/RO model estimated a PK associated with 50% of RO of 0.0068 ng·mL(-1) . This corresponds to a free concentration of 4.50 × 10(-12 ) M (pK = 11.3). CONCLUSIONS AND IMPLICATIONS: The affinity of GSK239512 for brain H3 receptors in humans in vivo is much higher than that expected from studies in vitro, and higher than that observed in PET studies in pigs. The study illustrates the utility of carrying out PET studies in humans early in drug development, providing accurate quantification of GSK239512 RO in vivo as a function of time and dose.

Multifocal electroretinography changes in patients on ethambutol therapy.

PURPOSE: To evaluate the multifocal electroretinography (mfERG) changes in patients on ethambutol therapy. METHODS: A cross-sectional observational study of 17 visually asymptomatic patients receiving antituberculosis therapy with ethambutol. Patients underwent complete ophthalmic examination and mfERG recordings. The first-order mfERG N1 and P1 response amplitudes and implicit times of six concentric rings were analysed and compared with 17 normal age-similar controls. Correlation analyses were performed between the patients' mfERG parameters with parameters of ethambutol usage (daily dose of ethambutol per body weight, duration of ethambutol therapy, cumulative dose of ethambutol, and cumulative dose of ethambutol per body weight). RESULTS: The mean duration of ethambutol therapy was 3.6 months (range: 2-9 months) and the mean daily dose per body weight was 13.2 mg/kg/day. Analysis of response amplitude measures showed no significant difference in the mfERG N1 and P1 response amplitudes between the ethambutol and control groups at all ring eccentricities (P>0.05). For implicit times, there were significant delays in the mfERG P1 implicit times of rings 4-6 in the ethambutol group compared with controls (P=0.012 to P=0.041). Correlation analyses showed no significant correlation between the mfERG and ethambutol parameters (P>0.05). CONCLUSIONS: The mfERG findings suggested that visually asymptomatic patients receiving ethambutol therapy might have localized mild electrophysiological changes involving the peripheral macula. These changes might be related to localized alteration of metabolism or physiological changes associated with ethambutol therapy.

Safety enhanced photodynamic therapy with half dose verteporfin for chronic central serous chorioretinopathy: a short term pilot study.

AIM: To evaluate short term safety of an enhanced photodynamic therapy (PDT) protocol with half dose verteporfin for treating chronic central serous chorioretinopathy (CSC). METHODS: 20 eyes of 18 patients with symptomatic chronic CSC underwent PDT using 3 mg/m2 verteporfin. Verteporfin was infused over 8 minutes followed by indocyanine green angiography guided laser application 2 minutes later. Serial optical coherence tomography (OCT) and multifocal electroretinography (mfERG) recordings were performed before PDT, at 4 days, 2 weeks, and 1 month after PDT. The best corrected visual acuity (BCVA), OCT central retinal thickness, and mean mfERG response amplitudes and peak latencies were compared longitudinally. Subgroup analysis was further performed for eyes with or without pigment epithelial detachment (PED). RESULTS: At 1 month after PDT, the median BCVA improved from 20/40 to 20/30 (p = 0.001). The mean central retinal thickness also reduced from 276 microm to 158 microm (p < 0.001) and 17 (85%) eyes had complete resolution of serous retinal detachment and/or PED. MfERG showed no significant changes in the mean N1 and P1 response amplitude and latency for all eyes. Subgroup analysis demonstrated that eyes without PED had a significant increase in the mean central mfERG P1 response amplitude with reduction in P1 peak latency at 1 month post-PDT. For eyes with PED, transient reduction in the mean central P1 response amplitude was observed at 4 days post-PDT. CONCLUSIONS: The modified safety enhanced PDT protocol with half dose verteporfin appeared to be a beneficial treatment option for patients with chronic CSC, especially in eyes without serous PED. Further controlled study is warranted to demonstrate the long term safety and efficacy of this treatment option.

Myopia progression among preschool Chinese children in Hong Kong.

INTRODUCTION: Myopia is the most common eye disorder especially in Asia. However, the information on myopic progression and ocular growth among preschool children, who undergo rapid changes, is limited. The aim of this study was to determine the prevalence, incidence of myopia and myopic progression among preschool children in Hong Kong. MATERIALS AND METHODS: A kindergarten was randomly chosen in Hong Kong, China. Preschool children aged 2 to 6 years attending the selected kindergarten were invited to participate. One hundred and eight children completed the 5-year cohort study. Refractive error and axial ocular dimensions were the main outcome measures. RESULTS: A total of 255 preschool children with a mean age of 4.96 (SD, 0.90) years were examined in the initial examination. Only 4.6% children had myopia of at least -0.50 D. The prevalence of myopia increased almost 10-fold to 43.5% after 5 years in the final examination. The annual incidence of myopia was 8.2%. The mean increase in axial length was 1.72 mm (SD, 0.80 mm) over the 5-year period (P < 0.001). The lens thickness decreased significantly from 3.80 mm (SD, 0.37 mm) to 3.74 mm (SD, 0.51 mm) whereas the vitreous chamber depth increased significantly from 15.01 mm (SD, 0.68 mm) to 16.42 mm (SD, 0.88 mm) (both P < 0.001). Children who were younger or were less hypermetropic at the initial examination was having greater myopic progression (P = 0.015, P < 0.001 respectively). CONCLUSION: This is the first prospective study to investigate the myopic progression and ocular growth among preschool children. Hong Kong has a high prevalence of myopia even in preschool children. They also experience a significant myopic shift and ocular growth. Further studies on the prevention of myopic development or progression should be targeted on this population.