Amino acid immunoreactivity in normal human retina and after brachytherapy

We localised amino acids in the mid‐peripheral aged human retina and a retina that had undergone radiation treatment 10 years earlier. The distribution pattern of glutamate, γ‐amino butyric acid (GABA), glycine, glutamine and taurine, reflected patterns established in the primate retina. The retina that had undergone radiation exposure displayed both anatomical and neurochemical remodelling. The proximal retina comprised around 40 to 45 per cent of the total retina and neuronal kinesis and aberrant neuronal projections were also present. Amino acid neurochemistry was strikingly different with Müller cells displaying GABA loading, glycinergic neurons displaced and displaying a very high level of glycine labelling. We conclude that radiation exposure triggered these changes in the human retina and likely reflects general remodelling of structure and function following ischaemic damage to endothelial cells.     

Management of hepatitis B virus in HIV-positive patients

High rates of coinfection with human immunodeficiency virus-1 (HIV) and the hepatitis B virus (HBV) are commonly found in at risk populations due to their shared parenteral route of transmission. Although the increasingly widespread use of highly active antiretroviral therapy (HAART) has prolonged survival for those with HIV, it has also increased the potential for morbidity and mortality from other diseases and opportunistic infections. Liver-related illness is a leading cause of morbidity and mortality in those infected with HIV and HBV is responsible for a vast proportion of this, especially in regions of high HBV prevalence. HIV/HBV coinfected patients may exhibit atypical serological markers of HBV infection, hindering appropriate diagnosis. They may experience faster progression to cirrhosis, decompensation, and hepatocellular carcinoma than HBV-monoinfected patients. Rates of response to vaccine against HBV are abrogated in those with HIV, facilitating the spread of the virus. Treatment of HBV must be monitored for resistance, although newer agents appear to have less risk of resistance development. Moreover, treatment of HIV with antivirals must be monitored closely for liver toxicity. Because liver damage with HBV occurs via the immune response to the virus, liver damage is possible with HAART-mediated immune reconstitution. Although liver transplant is not commonly undertaken in HIV-positive patients, centers undertaking transplantation report improved survival and low rates of HBV recurrence.     

Robust anti-arrhythmic efficacy of verapamil and flunarizine against dofetilide-induced TdP arrhythmias is based upon a shared and a different mode of action

BACKGROUND AND PURPOSE

The high predisposition to Torsade de Pointes (TdP) in dogs with chronic AV-block (CAVB) is well documented. The anti-arrhythmic efficacy and mode of action of Ca²⁺ channel antagonists, flunarizine and verapamil against TdP were investigated.

EXPERIMENTAL APPROACH

Mongrel dogs with CAVB were selected based on the inducibility of TdP with dofetilide. The effects of flunarizine and verapamil were assessed after TdP and in different experiments to prevent dofetilide-induced TdP. Electrocardiogram and ventricular monophasic action potentials were recorded. Electrophysiological parameters and short-term variability of repolarization (STV) were determined. In vitro, flunarizine and verapamil were added to determine their effect on (i) dofetilide-induced early after depolarizations (EADs) in canine ventricular myocytes (VM); (ii) diastolic Ca²⁺ sparks in RyR2^R4496+/+ mouse myocytes; and (iii) peak and late I_Na in SCN5A-HEK 293 cells.

KEY RESULTS

Dofetilide increased STV prior to TdP and in VM prior to EADs. Both flunarizine and verapamil completely suppressed TdP and reversed STV to baseline values. Complete prevention of TdP was achieved with both drugs, accompanied by the prevention of an increase in STV. Suppression of EADs was confirmed after flunarizine. Only flunarizine blocked late I_Na. Ca²⁺ sparks were reduced with verapamil.

CONCLUSIONS AND IMPLICATIONS

Robust anti-arrhythmic efficacy was seen with both Ca²⁺ channel antagonists. Their divergent electrophysiological actions may be related to different additional effects of the two drugs.     

Interaction between anandamide and sphingosine-1-phosphate in mediating vasorelaxation in rat coronary artery

Background and purpose:

This study establishes a pharmacokinetic/pharmacodynamic (PK/PD) model to describe the time course and in vivo mechanisms of action of the antinociceptive effects of lumiracoxib, evaluated by the thermal hyperalgesia test in rats.

Experimental approach:

Female Wistar fasted rats were injected s.c. with saline or carrageenan in the right hind paw, followed by either 0, 1, 3, 10 or 30 mg·kg⁻¹ of oral lumiracoxib at the time of carrageenan injection (experiment I), or 0, 10 or 30 mg·kg⁻¹ oral lumiracoxib at 4 h after carrageenan injection (experiment II). Antihyperalgesic responses were measured as latency time (LT) to a thermal stimulus. PK/PD modelling of the antinociceptive response was performed using the population approach with NONMEM VI.

Results:

A two-compartment model described the plasma disposition. A first-order model, including lag time and decreased relative bioavailability as a function of the dose, described the absorption process. The response model was: LT=LT₀/(1 +MED). LT₀ is the baseline response, and MED represents the level of inflammatory mediators. The time course of MED was assumed to be equivalent to the predicted profile of COX-2 activity and was modelled according to an indirect response model with a time variant synthesis rate. Drug effects were described as a reversible inhibition of the COX-2 activity. The in vivo estimate of the dissociation equilibrium constant of the COX-2-lumiracoxib complex was 0.24 µg·mL⁻¹.

Conclusions:

The model developed appropriately described the time course of pharmacological responses to lumiracoxib, in terms of its mechanism of action and pharmacokinetics.     

输液中注射用头孢米诺钠的稳定性

1材料和方法 1.1材料日本岛津10-Arp高效液相色谱仪,C18柱(5 μm,4.6 mm×150 mm),PHS-3C型pH计(上海雷磁仪器厂);注射用头孢米诺钠(南昌立健药业有限公司,批号:20040701),50 g/L葡萄糖注射液(四川科伦大制药有限公司,批号:040912-091),100 g/L葡萄糖注射液(湖南科伦大制药有限公司,批号:040710-07),9 g/L氯化钠注射液(湖南科伦大制药有限公司,批号:040926-06),葡萄糖氯化钠注射液(湖南科伦大制药有限公司,批号:040929-06),甲硝唑注射液(安徽双鹤药业有限公司,批号:040926-2E);甲醇、冰醋酸、四氢呋喃均为分析纯.