Synthesis of Thiazolotriazine Derivatives and Their Antinociceptive Effects in Mice

A series of 2-(4-arylpiperazin-1-yl-methyl)-4-methyl-1-oxo-5,6,8,8a-tetrahydro-thiazolo[3,4-d] [1,2,4]triazines was prepared and tested for antinociceptive activity. The compounds were prepared by the Mannich reaction from the corresponding 2-unsubstituted thiazolotriazines. When administered intraperitoneally most were found to have potent analgesic activity in the mouse during tests of phenylbenzoquinone-induced abdominal constriction; ED50 values (doses resulting in half the maximum effect) ranged from 10 to 87 mg kg^?1. Derivatives with a 3-chloro- or 4-fluorophenylpiperazinylmethyl side-chain in the 2-position of the bicyclic system were, when administered intraperitoneally at doses greater than 25 mg kg^?1, also effective in the hot-plate test without associated sedative effects. The compounds have a large therapeutic index; intraperitoneal LD50 values (doses which result in the death of half the animals) were > 700 mg kg^?1. Naloxone attenuated the analgesic activity of the 3-chloro derivative, suggesting the participation of μ-receptors in the antinociceptive effects of this drug. In addition, a non-opioid mechanism, probably related to enhancement of the release of 5-hydroxytryptamine and noradrenaline, or inhibition of the neuronal re-uptake of these compounds, has been evinced to explain the analgesic properties of the 3-chloro or 4-fluoro derivatives. These results provide evidence for the involvement of noradrenergic and 5-hydroxytryptaminergic pathways in the analgesic activity of 3 and 4. Because of their potential effectiveness, the 3-chloro- or 4-fluorophenylpiperazinylmethyl derivatives might be suitable for treatment of a wide variety of painful conditions and could be attractive reserve agents for patients dissatisfied with opioids.     

Duplex-Doppler assessment of cirrhosis in patients with chronic compensated liver disease

Portal venous flow velocity (PFV) was measured with duplex-Doppler equipment in 50 normal subjects and in 117 patients with suspected chronic liver disease who showed no evidence of decompensation such as ascites, hepatic encephalopathy, jaundice or oesophageal bleeding. All the patients underwent percutaneous liver biopsy which demonstrated non-cirrhotic liver disease in 58 cases (CH-patients: steatosis 8, persistent chronic hepatitis 8, active chronic hepatitis 42) and liver cirrhosis in the other 59 cases (LC-patients). The normal subjects and the CH-patients had similar values of max-PFV and mean-PFV (max-PFV 26.7±3.2 and 25.7±3.4 cm/s respectively; mean-PFV 22.9±2.8 and 22.4±3.8 cm/s respectively). The LC-patients’ values (max-PFV 19.3±3.5; mean-PFV 16.9±2.9) were significantly lower than those of the normal subjects (P<0.001) and of the CH-patients (P<0.001). Considering the normal max-PFV to be in the range 20–33.1 cm/s (mean±2 s.d. of the normal subjects, 95% confidence limits), max-PFV was reduced in 0/50 normal subjects, 1/58 CH-patients and 39/59 LC-patients (66.1% sensitivity; 98.2% specificity). In conclusion, the duplex-Doppler measurement of PFV is of great interest in the diagnostic study of patients with suspected chronic compensated liver disease and in the early diagnosis of cirrhosis. A low max-PFV is a reliable pointer to liver cirrhosis, whereas a normal max-PFV indicates a non-cirrhotic liver disease but is less probative. Each centre should standardize normal PFV values in order to establish their own threshold value for diagnosing liver cirrhosis.     

p53 OVEREXPRESSION AND HUMAN PAPILLOMAVIRUS INFECTION IN TRANSITIONAL CELL CARCINOMA OF THE URINARY BLADDER: CORRELATION WITH HISTOLOGICAL PARAMETERS

Seventy-nine transitional cell carcinomas (TCCs) of the urinary bladder (25 grade 1, 22 grade 2, and 32 grade 3 tumours) were examined for p53 overexpression by immunohistochemistry with a monoclonal antibody and for human papillomavirus (HPV) infection by the polymerase chain reaction (PCR). Positive immunostaining for p53 was detected in 40·5 per cent of the cases; the percentage of positive cases was significantly lower in low-grade (G1 and G2) TCCs than in high-grade (G3) tumours (10·6 per cent vs. 84·4 per cent; P <0·0001). The overall rate of HPV infection was 32·9 per cent; 20·3 per cent of the cases were positive for HPV 16, 3·8 per cent for HPV 18, and 8·9 per cent for both. Consensus primers as well as type-specific primers for HPV types 6, 11, and 33 failed to detect any additional case with HPV infection. The prevalence of HPV 16 and/or HPV 18 infection was significantly higher in low-grade than in high-grade tumours (44·7 per cent vs. 15·6 per cent; P =0·0061). p53-positive cases were more common among papillary, deeply infiltrating tumours, and HPV-positive cases among papillary, non-infiltrating lesions. According to these data, p53 overexpression and HPV 16/18 infection are common findings in bladder TCC and there appears to be an inverse correlation of p53 overexpression and of HPV infection with tumour aggressiveness. The possibility of different molecular pathways in superficial low-grade and in invasive high-grade tumours is suggested.     

Antibodies against Echinococcus multilocularis alkaline phosphatase as markers for the specific diagnosis and the serological monitoring of Alveolar echinococcosis

The immunological properties of the purified alkaline phosphatase (pAP) of Echinococcus multilocularis metacestodes have been investigated using alveolar echinococcosis (AE) patient sera in ELISA tests. A comparative study was done with EmC-Ag (crude antigen) and pAP-Ag (purified antigen). When the parasite purified enzyme pAP was used as antigen, the specificity of the ELISA was markedly increased since it reached 100% without any decrease of its sensitivity (100%). The serologic follow-up of AE patients was conducted during several months with these two antigens in three categories of patients: cured, stabilized and aggravated. There was a good correlation between clinical and serologic data when the pAP was used as antigen in ELISA tests. The anti-pAP antibodies titres did change more rapidly than anti-EmC antibodies titres when a recurrence occurred. Modifications of the anti-pAP antibodies levels were also observed during the patient's therapy: mebendazole, albendazole and Isoprinosine^®. These results suggest that pAP-Ag should be used for the diagnosis and the follow-up of AE patients.