Multicentric evaluation of the DiaMed enzyme-linked immunosorbent assay malaria antibody test for screening of blood donors for malaria.

BACKGROUND: The risk of malaria transmission by blood transfusion is critical due to extensive travel from endemic areas to non-endemic areas. An enzyme-linked immunosorbent assay (ELISA) malaria antibody test has been developed that is claimed to perform better than the immunofluorescence assay test (IFAT). The assay contains antigens to both Plasmodium falciparum and Plasmodium vivax. A multicentre study was performed to evaluate the appropriateness of replacing the IFAT by the new ELISA test. MATERIAL AND METHODS: Nine French blood banks participated in this multicentre study. Two panels of samples were evaluated. The first included 4163 samples from healthy donors and was used to calculate clinical specificity of the assay. The second involved 10,995 samples, either collected retrospectively or prospectively from malaria-risk donors , was used to assess the comparative performance of the ELISA and IFAT. Discordant samples were further tested using an in-house IFAT and also tested for presence of Plasmodium DNA by polymerase chain reaction. RESULTS: The ELISA showed a clinical specificity of 99.02%. In the malaria-risk blood donors groups, the retrospective group showed a concordance rate of 92.6% (k = 0.90), while the prospective group showed a concordance rate of 97% (k = 0.46). After confirming the discordant sample results by an in-house IFAT, the k index increased to 0.81. None of the discordant samples was shown to contain Plasmodium DNA. CONCLUSION: The performance of the ELISA test in this study has confirmed its potential as a new screening test for use in blood banks, as an alternative to the IFAT in prevention of transfusion-transmitted malaria in non-endemic countries.

Absorption and intestinal metabolism of SDZ-RAD and rapamycin in rats.

The new immunosuppressive agent, SDZ-RAD, and its analog rapamycin were examined for intestinal absorption, metabolism, and bioavailability in Wistar rats. Intestinal first-pass metabolism studies from rat jejunum showed that at 0.5 mg of SDZ-RAD/kg rat, 50% of the parent compound was metabolized in the intestinal mucosa, and this decreased to around 30% when SDZ-RAD was increased to 5.0 mg/kg rat. Results for rapamycin at the low dose were similar to those for SDZ-RAD, but at the higher dose only 1 to 14% of the total rapamycin absorbed was metabolized by the intestine. After i.v. administration of 1 mg/kg SDZ-RAD or rapamycin, the area under the concentration curve (AUC) for rapamycin was twice that of SDZ-RAD, resulting in a systemic clearance of 6.2 ml/min and 3.0 ml/min for SDZ-RAD and rapamycin, respectively. However, the AUC for oral absorption was similar for the two compounds: 140 and 172 ng*h/ml for SDZ-RAD and rapamycin, respectively. Because blood clearance was faster for SDZ-RAD after i.v. administration, the absolute oral bioavailability for SDZ-RAD was 16% compared with 10% for rapamycin. Overall, the data suggest that intestinal first pass is a major site of metabolism for SDZ-RAD and rapamycin and that intestinal absorption of SDZ-RAD was much faster than that of rapamycin. This allowed it to counteract the combined actions of faster systemic clearance and increased intestinal metabolism, resulting in comparable absolute exposure when given orally. Also, the coadministration of cyclosporin A with SDZ-RAD was shown to dramatically increase blood AUCs for SDZ-RAD, probably through saturating intestinal metabolism mechanisms.

Effect of the P-glycoprotein inhibitor, SDZ PSC 833, on the blood and brain pharmacokinetics of colchicine.

The effect of the multidrug resistance-reversing agent, SDZ PSC 833, on blood and brain pharmacokinetics of a P-glycoprotein substrate, colchicine, was investigated using simultaneous blood and brain microdialysis in freely moving rats. The use of microdialysis for pharmacokinetic studies was validated by comparing the blood concentrations of colchicine obtained by microdialysis with those obtained by direct blood sampling. The rats received either SDZ PSC 833 (2.3 mg/kg i.v. bolus followed by 16.7 microg/min/kg i.v. infusion during all the experiment) and colchicine (1 mg/kg i.v. bolus followed by 12.5 microg/min/kg i.v. infusion during 2 hours) or colchicine alone (the same dosage with SDZ PSC 833 vehicle). The SDZ PSC 833 treatment resulted in important modifications of colchicine blood pharmacokinetics: the unbound colchicine blood concentration at steady-state was enhanced from 149.6 +/- 9.9 to 333.5 +/- 81.7 ng/ml indicating a two-fold decrease in colchicine clearance. Moreover the coadministration of SDZ PSC 833 increased the brain penetration of colchicine by a factor of 10, at least. This enhancement could not be exactly assessed because the brain dialysate concentrations of control group were below the limit of detection. Nevertheless, the large increase of colchicine brain penetration is consistent with the hypothesis that SDZ PSC 833 is able to inhibit the P-glycoprotein pump present at the blood-brain barrier.

Dose-dependent brain penetration of SDZ PSC 833, a novel multidrug resistance-reversing cyclosporin, in rats.

This study quantitatively assessed the brain penetration of a potent P-glycoprotein inhibitor, SDZ PSC 833, and its effect on the blood-brain barrier (BBB) permeability (PS) of an anticancer agent, vincristine. At lower doses of SDZ PSC 833 the brain penetration, defined as the brain-to-blood partition coefficient (Kp), was very low in spite of the high lipophilicity of this compound. At higher doses, however, the brain penetration of SDZ PSC 833 was markedly increased. Since the blood pharmacokinetics of SDZ PSC 833 proved to be linear in the dose range studied, these results demonstrated a dose-dependent brain passage of SDZ PSC 833. The brain passage of cyclosporin A was also found to be dose-dependent. However, the potency of SDZ PSC 833 in inhibiting the efflux mechanism at the BBB was higher than that of cyclosporin A since 10 times higher doses of cyclosporin A were required to obtain the same Kp values recorded for SDZ PSC 833. Moreover, the coadministration of SDZ PSC 833 increased the brain penetration of cyclosporin A, whereas the latter did not modify that of SDZ PSC 833. The increase in SDZ PSC 833 and vincristine PS values observed at high blood levels of SDZ PSC 833 are consistent with the hypothesis of a saturation of the P-glycoprotein pump present at the BBB. The involvement of P-glycoprotein in the brain passage of SDZ PSC 833 could be of great significance for clinical application of the drug in the treatment of brain cancers when it is given in combination with anticancer agents.

[Single-lobe Caroli's disease. Anatomoclinical aspects. Diagnostic and therapeutic procedure. Apropos of 3 personal cases and 101 cases in the literature]. / La maladie de Caroli unilobaire. Aspects anatomocliniques. Démarche diagnostique et thérapeutique. A propos de 3 observations personnelles et de 101 observations de la littérature.

On the basis of 3 personal cases of single-lobe Caroli's disease and of 101 cases in the literature, the authors have observed that biliary-type pain was the most constant presenting symptom (85%), in association with fever (72%), while angiocholitis was observed in only 44% of all cases. The preoperative diagnosis of the disease and of the hepatic and extrahepatic lesions is aided by the noninvasive techniques of morphological exploration such as ultrasound and computed tomography, which must be proposed in first intention as they clearly demonstrate the cystic nature of the intrahepatic lesions, the associated biliary lesions [choledochal cyst (30%), lithiasis (37%)]. However, the cystobiliary communication and the definition of the type of biliary dilatation can be demonstrated only by transhepatic percutaneous cholangiography, endoscopic retrograde cholangiography, the injection of a contrast medium with biliary elimination, and quite often by intraoperative cholangiography only. The 4 types of single-lobe Caroli's disease distinguished by the authors, ie: type I: racemose biliary dilatation, type II: digitiform biliary dilatation, type III: large cystic biliary dilatation, type IV: choledochal cyst associated to the intrahepatic biliary disease, require a particular surgical treatment, which must also take account of the operative risks and of all the associated lesions (lithiasis, choledochal cyst, congenital hepatic fibrosis (5 cases), neoplastic degeneration (8 cases)]. External biliary bypass no longer has any use for treatment as it constantly fails. First-intention hepatic resection is the ideal treatment is all anatomical forms of single-lobe Caroli's disease as it treats all the hepatic lesions with no mortality. It is therefore indicated whenever the general conditions do not produce an excessive risk, when the controlateral liver is normal and when resection will not injure the bile duct of the remaining liver. If an associated choledochal cyst is present, it must be resected at the same time. Hepatic resection also is the best second surgery to propose when the other methods have failed. Hepaticojejunal anastomosis is the therapeutic solution every time hepatic resection cannot be performed.