Intra-arterial thrombolysis for perioperative stroke after open heart surgery

Recent major surgery is an exclusion criterion for thrombolysis. Six patients with acute ischemic stroke underwent intra-arterial thrombolysis after recent open heart surgery without clinically significant bleeding complications, although one patient developed a small, asymptomatic cerebellar hemorrhage. Intra-arterial thrombolysis may be an option for patients with cerebral embolism in the perioperative period.     

A study on the role of the family and other risk factors in HCV transmission

Background/aims: To understand the intrafamilial transmission and the existing risk factors related to HCV infection in subjects confirmed anti-HCV positive, their sexual partners and household contacts in Friuli, North-East Italy. Methods: We enrolled all the subjects that were consecutively identified as HCV positive during routine laboratory testing in six health districts and their household contacts. From each subject we obtained a blood sample, demographic data and a medical history including the existence of risk factors for HCV. Antibodies to HCV were detected employing a commercially available second-generation enzyme immunoassay (EIA); positive serum specimens were retested using a second-generation recombinant immunoblot assay (RIBA-2). Results: We recruited 743 subjects, 229 first subjects identified as HCV positive and 514 household contacts. There were no statistically significant differences in positivity among household contacts. Analysing intracouple transmission we found no significant differences by gender in couples both with and without parenteral risk factors. We found, both with univariate and multivariate analysis, as statistically significant risk factors in all the subjects: age older than 60, blood transfusions (particularly those performed before 1984), surgical procedures such as abortion and/or uterine curettage, history of HBV infection, intravenous drug use, and tattooing. Conclusions: Our results stress the low relevance of sexual transmission in the intrafamilial context, the importance of abortion and/or uterine curettage, the important role of blood transfusions in the past, a higher prevalence of HCV infection within a household of a HCV positive member compared to all other existing data in the area.     

Halofantrine metabolism in microsomes in man: major role of CYP 3A4 and CYP 3A5.

We have clarified the contribution of the different enzymes involved in the N-debutylation of halofantrine in liver microsomes in man. The effect of ketoconazole and cytochrome P450 (CYP) 3A substrates on halofantrine metabolism has also been studied. The antimalarial drug halofantrine is metabolized into one major metabolite, N-debutylhalofantrine. In microsomes from nine livers from man, N-debutylation of halofantrine was highly variable with apparent Michaelis-Menten constant V(max) and K(m) values of 215+/-172 pmol min(-1) mg(-1) and 48+/-26 micromol L(-1), respectively, (mean+/-standard deviation). Formation of N-debutylhalofantrine was cytochrome P450 (CYP)-mediated. Studies using selective inhibitors of individual CYPs revealed the role of CYP 3As in the formation of N-debutylhalofantrine. alpha-Naphthoflavone, a CYP 3A activator, increased metabolite formation. In microsomes from 12 livers from man the rate of N-debutylation of halofantrine correlated strongly with CYP 3A4 relative levels (P = 0.002) and less strongly, but significantly, with CYP 2C8 levels (P = 0.025). To characterize CYP-mediated metabolism of halofantrine further, incubations were performed with yeast microsomes expressing specific CYP 3A4, CYP 3A5, CYP 2D6, CYP 2C8 and CYP 2C19 from man. The rate of formation of N-debutylhalofantrine was six- and twelvefold with CYP 3A4 than with CYP 3A5 and CYP 2C8, respectively. CYP 2D6 and CYP 2C19 did not mediate the N-debutylation of halofantrine, but, because in-vivo CYP 2C8 is present at lower concentrations than CYP 3A in the liver in man, the involvement of CYP 3As would be predominant. Diltiazem, erythromycin, nifedipine and cyclosporin (CYP 3A substrates) inhibited halofantrine metabolism. Similarly, ketoconazole inhibited, non-competitively, formation of N-debutylhalofantrine with an inhibition constant, K(i), of 0.05 microM. The theoretical percentage inhibition of halofantrine metabolism in-vivo by ketoconazole was estimated to be 99%. These results indicate that both CYP 3A4 and CYP 3A5 metabolize halofantrine, with major involvement of CYP 3A4. In-vivo, the other CYPs have a minor role only. Moreover, strong inhibition, and consequently increased halofantrine cardiotoxicity, might occur with the association of ketoconazole or other CYP 3A4 substrates.     

The effect of antibiotic resistance on the outcome of three 1-week triple therapies against Helicobacter pylori

BACKGROUND: Resistance of Helicobacter pylori to antibiotics may be a major reason for treatment failure. AIM: To evaluate the effect of primary H. pylori resistance to antibiotics on the cure rates of three anti-H. pylori 1-week triple therapies. METHODS: One hundred and sixteen consecutive patients diagnosed H. pylori-positive by gastric histology, rapid urease test and culture were enrolled. Activity of tested antibiotics was determined by means of the E-test. Patients were treated for 7 days with: (i) pantoprazole 40 mg o.d. plus amoxycillin 1 g b.d. and metronidazole 250 mg q.d.s. (PAM); (ii) pantoprazole 40 mg o.d. plus clarithromycin 250 mg b.d. and metronidazole 250 mg q.d.s. (PCM); or (iii) pantoprazole 40 mg o.d. plus amoxycillin 1 g b.d. and clarithromycin 250 mg b.d. (PAC). Two months after completion of therapy, endoscopy and gastric biopsies were repeated. RESULTS: Primary resistance rates to metronidazole, clarithromycin and amoxycillin were 17.2, 6.9 and 0%, respectively. Overall H. pylori cure rates expressed as intention-to-treat and per protocol analyses were, respectively, 79% and 86% with PAM, 82% and 89% with PCM, and 85% and 85% with PAC. Significantly lower cure rates were observed in metronidazole-resistant patients treated with PAM (56% vs. 96%, P = 0.01) or PCM (50% vs. 97%, P = 0.01). A trend towards lower H. pylori cure rates was observed in clarithromycin-resistant patients treated with PCM (67% vs. 91%, P = 0.74) or PAC (50% vs. 87%, P = 0.68). CONCLUSION: Primary resistance to metronidazole influences the H. pylori cure rate of anti-H. pylori proton pump inhibitor-based triple therapies which include this antibiotic. A similar trend exists for primary clarithromycin resistance.     

Intravenous digital subtraction angiography: an index of collateral cerebral blood flow in internal carotid artery occlusion

The objective of this investigation was to correlate Xenon-133 inhalation rCBF measurements with the pattern of cortical arterial filling on intravenous DSA in 18 patients with unilateral internal carotid artery occlusion. Of 9 patients showing symmetrical filling of hemispheric cortical arteries, none showed an inter-hemispheric difference in rCBF ( delta Fg) greater than 10ml/100gm/min. Of 9 patients showing delayed cortical opacification ipsilateral to the internal artery occlusion, 3 showed a delta Fg greater than 10ml/100gm/min, 3 showed a delta Fg in the 7-10ml/100gm/min range, and 3 had a delta Fg less than 7ml/100gm/min. All patients with asymmetric abnormalities in the rCBF profile had the delayed pattern of cortical filling on DSA. The presence of symmetrical hemispheric opacification of cortical arteries on DSA indicates adequate interhemispheric redistribution of rCBF and patent inter-hemispheric collateral channels, but not necessarily normal cerebral blood flow. The presence of delayed cortical arterial opacification on the side of internal carotid artery occlusion does not necessarily imply significant inter-hemispheric rCBF differences, nor does it rule out a normal rCBF. The presence of bilateral reduction of rCBF and symmetrical cortical artery filling on DSA may represent an "interhemispheric steal".     

Concomitant radiotherapy with mitomycin C and bleomycin compared with radiotherapy alone in inoperable head and neck cancer: final report

Purpose: To compare the efficacy of concomitant irradiation with mitomycin C and bleomycin in patients with inoperable head and neck carcinoma with radiotherapy alone.

Methods and materials: Between March 1991 and December 1993, 64 patients with inoperable head and neck carcinoma (41 with oropharyngeal site) were randomized to radiotherapy alone (group A) or radiotherapy combined with simultaneous application of mitomycin C and bleomycin (group B). In both groups patients were irradiated five times weekly with 2 Gy to a total dose of 66–70 Gy. The planned concomitant treatment in group B was: bleomycin 5 units twice a week IM, total dose 70 units, mitomycin C 15 mg/m² IV after delivery of 10 Gy, and 10 mg/m² IV on the last day of radiotherapy. To enhance the effect of these two drugs, patients received also nicotinamide, chlorpromazine, and dicoumarol.

Because significantly better results were achieved in arm B for patients with inoperable oropharyngeal carcinoma, the study was closed and such patients were after December 1993 routinely treated with the combined therapy (as in arm B). Until October 1996, we treated and followed up 48 such consecutive patients.

Results: Median follow-up of our study patients is 42 months. Complete remission (CR) rate in group A was 31% and in group B 59% (p = 0.04); disease-free survival (DFS) in group A was 8% and in group B 37% (P = 0.01); and overall survival (OS) was 7% in group A and 26% in group B (p = 0.08). CR rate for patients with oropharyngeal carcinoma was 29% in group A (N = 21) and 75% in group B (N = 20) (p = 0.007); DFS in group A was 10% and in group B 48% (p = 0.001); and the OS was 10% in group A and 38% in group B (p = 0.019). In patients with inoperable oropharyngeal carcinoma treated after December 1993, complete remission was achieved in 32/48 (67%, 95% CI: 52%–80%). DFS at the median follow-up of 14 months was 60% (95% CI 43–77%) and OS 58% (95% CI 42–74%).

Conclusion: From the results of our study it seems that the concomitant treatment significantly improves CR rate, DFS, and OS in patients with inoperable oropharyngeal carcinoma in comparison with radiotherapy alone.