Pyridazines,LVII: Synthesis and Cyclocondensation Reactions of (2-Aminophenyl)-(4-pyridazinyl)-ketone,a New Diaza Isoster of 2-Aminobenzophenone

A convenient approach to the new 2-aminobenzophenone analogue 4 is reported. Condensation reactions of 4 with ortho esters or amide acetals, respectively, followed by intramolecular cyclisations were found to provide smooth access to (4-pyridazinyl)-substituted quinolines 10, 13a,b , and the quinazoline derivative 15 .     

The Effect of Antiepileptic Drugs on Cognition: Patient Perceived Cognitive Problems of Topiramate versus Levetiracetam in Clinical Practice

Summary:  Introduction: Neurocognitive complaints may interfere with long-term antiepileptic drug (AED) treatment and are an important issue in clinical practice. Most data about drug-induced cognitive problems are derived from highly controlled short-term clinical trials. We analyzed such cognitive complaints for the two most commonly used AEDs in a clinical setting using patient perceived problems as primary outcome measure.
Method: All patients of the epilepsy center Kempenhaeghe that received topiramate (TPM) or levetiracetam (LEV) from the introduction to mid 2004 were analyzed using a medical information system, an automated medical file. Patients were analyzed after 6, 12, and 18 months of treatment.
Results: Four hundred and two patients used either TPM (n = 260) or LEV (n = 142); 18 months retention showed a statistically significant difference, revealing 15% more patients that continued LEV compared to TPM: 18 months retention 46% for TPM and 61% for LEV [F (1.400) = 3.313, p = 0.043]. Neurocognitive complaints accounted for a significant number of drug discontinuations and especially the high frequency of neurocognitive complaints in the first period of TPM treatment appeared to be significant different from LEV [F(2,547) = 3.192, p = 0.042]. In the remaining patients, the difference in neurocognitive complaints was not statistically significant.
Conclusion: cognitive complaints are common in TPM treatment and frequently lead to drug withdrawal. The impact of LEV on cognitive function is only mild. This leads to a much higher (15%) drug discontinuation rate for TPM compared to LEV.     

Gliotoxin non-selectively induces apoptosis in fibrotic and normal livers.

BACKGROUND: Liver fibrosis is the common response to chronic liver injury, ultimately leading to cirrhosis. Several lines of evidence indicate that inducing apoptosis of hepatic stellate cells (HSC) may lead to regression of liver fibrosis. Recently, it was shown that gliotoxin (GTX) induces apoptosis of HSC. However, the clinical use of GTX may be limited because of the lack of cell and tissue specificity, causing a high risk of potentially severe adverse effects. The aim of this study, therefore, was to study the effect of GTX on different cells of the liver. METHODS: We used normal and fibrotic precision-cut rat liver slices to study the effect of GTX on the various resident liver cell types. In these slices, the complex cell-cell interactions are preserved, which closely mimics the in vivo situation. RESULTS: GTX exhibited a potent apoptosis-inducing activity in these slices. Both immunohistochemical stainings and real-time mRNA techniques showed that this apoptosis-inducing effect was seen in HSC. However, Kupffer cells and liver endothelial cells were also affected by GTX, whereas hepatocytes were only mildly affected. CONCLUSIONS: This study indicates that the apoptosis-inducing strategy to treat liver fibrosis has high potential, but it will be necessary to develop an HSC-specific therapy to prevent adverse effects.     

The role of insurance data in setting priorities for netball injury prevention strategies

The aim of this study was to investigate insurance records for a one-year period to determine the injury frequencies and costs associated with different age groups in netball. The insurance records for all netball claims made during 1999 in Victoria were obtained from the insurer and entered into a database. The overall injury rate was 9.49 injuries per 1000 players, with 829 claims for injuries filed with the insurance company. Of all injuries claimed for, 85.3% were to the lower limb, 8.7% to the upper limb, 3.1% to the spine/torso and 2.9% to the head and face. Lower limb injuries accounted for 85.4% of costs, upper limb injuries 10.7% and head/neck/torso injuries 3.9% of total injury costs. Knee injuries accounted for 56.9% of total costs, with ankle and calf/Achilles injuries costing 12.7 and 11.8% of total costs, respectively. Injury prevention strategies should therefore be directed to three main injuries taking into account costs and incidence. These injuries were: ankle sprains, knee ligament sprains and Achilles tendon strains. Specifically, the prevention program for Achilles injuries should be directed to the >25 years age groups.     

Systemic angioendotheliomatosis of the lung

Systemic angioendotheliomatosis is a very rare malignant disease characterized by intravascular neoplastic proliferation of reticuloendothelial cells. According to the clinical features three different types of prognostic value can be distinguished: Exclusive skin involvement; Progressive skin lesions disseminating to internal organs; Aggressive and lethal type affecting primarily internal organs. Until now about 60 cases of systemic angioendotheliomatosis have been reported in the literature. Here we describe the first well-documented case with almost isolated lung involvement. The presentation of morphologic and clinical signs and differential-diagnostic considerations are followed by a critical review of the literature.