First-pass effects of verapamil on the intestinal absorption and liver disposition of fexofenadine in the porcine model.

The aim of this study in pigs was to investigate the local pharmacokinetics of fexofenadine in the intestine and liver by using the pig as a model for drug transport in the entero-hepatobiliary system. A parallel group design included seven pigs (10-12 weeks, 22.2-29.5 kg) in three groups (G1, G2, G3), and a jejunal single-pass perfusion combined with sampling from the bile duct and the portal, hepatic, and superior caval veins was performed. Fexofenadine was perfused through the jejunal segment alone (G1: 120 mg/l, total dose 24 mg) or with two different verapamil doses (G2: 175 mg/l, total dose 35 mg; and G3: 1000 mg/l, total dose 200 mg). The animals were fully anesthetized and monitored throughout the experiment. Fexofenadine had a low liver extraction (E(H); mean +/- S.E.M.), and the given doses of verapamil did not affect the E(H) (0.13 +/- 0.04, 0.16 +/- 0.03, and 0.12 +/- 0.02 for G1, G2, and G3, respectively) or biliary clearance. The E(H) for verapamil and antipyrine agreed well with human in vivo data. Verapamil did not increase the intestinal absorption of fexofenadine, even though the jejunal permeability of fexofenadine, verapamil, and antipyrine showed a tendency to increase in G2. This combined perfusion and hepatobiliary sampling method showed that verapamil did not affect the transport of fexofenadine in the intestine or liver. In this model the E(H) values for both verapamil and antipyrine were similar to the corresponding values in vivo in humans.     

Determinants of symptom interval in childhood cancer.

The duration of symptoms before diagnosis (lag time) was defined for 184 of 236 children diagnosed as having a malignancy at the Royal Hospital for Sick Children, Edinburgh for the time period January 1982 until December 1990. The natural logarithm of the lag time was correlated with age, gender, diagnostic group, white cell count in acute leukaemia, clinical stage of disease in solid tumours, and event free survival. Age was significantly associated with lag time, older children presenting later. In the diagnostic groups, mean lag time ranged from 2.8 weeks in nephroblastoma to 13.3 weeks for brain tumours. Diagnostic group was predictive for lag time after adjustment for age, with for example, a significantly longer lag time for those with brain tumours. However lag time was not predictive of event free survival and it is likely that lag time has other major determinants. When compared with previous studies, there also appears to be a regional variation in lag time for diagnostic groups. It seems likely that this is a reflection of geographical difference in the structure of health systems and is therefore yet another important determinant.     

Pulmonary Function in Survivors of Wilms' Tumor

The respiratory status of 47 patients surviving childhood Wilms' tumor was studied. The group that had receivedflnnk irradiation (which impinges on the lower lung) (n - 17) had a sisnijGantly lower mean percent predicted for forced expiratory volume in one second, residual volume, and total lung capaci(v when compared to those who had received no irradiation (n - 23). Those patients who had received whole-lung irradiation (n - 3) had sisnijicantly lower transfn. foctor for carbon monoxide and gas transfer per unit lung volume whm compared to the nonirradiated group (n - 23). There was no sipiftiant dimue in the prevalence of respiratory symptoms between the three groups. Patients receiving any form of radiotherapy for Wilms' tumor may have abnormulities o f pulmonary function and should have pulmonary function tests performed as part o f their long-tmn follow-up.     

Muscle membrane polarisation after provocative tests, and after cooling: the normal CMAP changes to be expected.

OBJECTIVE: To know the range of changes of compound muscle action potentials (CMAPs) in the muscles innervated by the ulnar nerve after diverse provocative tests, 14 healthy patients were studied with the same protocol. METHODS: CMAPs were measured at rest, just after a short exercise test (SET), during short 5 and 10c/s repetitive nerve stimulation (RNS) trains, at approximately 32 and approximately 20 degrees C. RESULTS: At 32 degrees C, the SET induced a significant but transient enlargement of the CMAPs (amplitude increased by 8.3%, duration decreased by 9%) that was only partially reproduced by RNS trains, except for a significant shortening of the CMAPs at 10c/s. At 20 degrees C without exercise, CMAPs increased significantly by approximately 30% in amplitude, duration and area, and after the SET the inverse of what has been seen at 32 degrees C was observed (amplitude decreased by 1.7% and duration increased by 9%). RNS at 20 degrees C produced a marked interpatient heterogeneity except for a significant shortening of the CMAPs at 10c/s. In one pure autonomic failure patient, the infusion of norepinephrine induced potentiation of the responses at rest and a decrease in the expected changes after provocative tests. CONCLUSIONS: CMAP amplitude and duration are significantly modified just after the SET at 32 degrees C, at rest at 20 degrees C and after RNS at 10c/s but not at 5c/s. Although providing indirect evidence, these findings indicate that provocative tests make the muscle membrane hyperexcitable by the way of a direct influence on the electrical events and by an indirect local catecholamine spillover.     

Results of Medical Research Council Childhood Leukaemia Trial UKALL VIII (Report to the Medical Research Council on behalf of the Working Party on Leukaemia in Childhood)

During the 1970s, despite apparently similar treatment, the prognosis for children with lymphoblastic leukaemia (ALL) improved more in some countries, notably the United States and West Germany, than in others. To find out why, the first phase of the United Kingdom (UK) Medical Research Council (MRC) childhood ALL trial, UKALL VIII, was designed to see whether similar results to the United States Children's Cancer Study Group (CCSG) could be obtained in the U.K. using an identical protocol (CCG 162). Protocol 162 was one of a series of regimens devised by the American Children's Cancer Study Group in the 1970s and was used specifically for their average risk patients (all children with ALL with an initial white cell count up to 50 x 10(9)/l except those aged 3-6 years with white cell counts under 10 x 10(9)/l). One arm (1A) of their study was adopted by the MRC for all children in the U.K. aged 0-14 years with confirmed ALL. Eight hundred and twenty-nine consecutive patients were entered between 1980 and 1984. The first 199 patients formed a single arm study as per the original protocol 162 (arm 1A), but the subsequent 630 children were randomized to receive or not two doses of daunorubicin on the first 2 d of induction. This randomization was an attempt to answer the important question as to whether event-free survival was influenced by the use of four rather than three induction agents. A second randomization between 2 and 3 years continuing therapy was also introduced at this stage as it had been by the CCSG in their protocol. With a minimum follow up period of more than 5 years, disease-free survival for the whole group is 55%, a considerable improvement on all previous UKALL trials. Results for patients directly comparable with those in CCSG 162 ('average risk' patients) and their American counterparts were similar. Daunorubicin was associated with more early deaths but improved disease-free survival for those achieving remission. More children relapsed who stopped treatment after 2 years than those who continued for 3, but this was balanced by increased treatment mortality in the third year. The fact that for UKALL VIII the results were similar to those of the CCSG suggests that previous MRC protocols were not sufficiently sustained and intensive, particularly during the maintenance phase of treatment.(ABSTRACT TRUNCATED AT 400 WORDS)     

Modulation of experimental autoimmunity: treatment of adjuvant arthritis by immunization with a recombinant vaccinia virus.

Live recombinant vaccinia viruses, expressing antigens from pathogenic microorganisms, are studied for their use as vaccines designed for the protection against infectious diseases. Infections with these vaccinia virus recombinants, expressing proteins or epitopes from viruses, parasites, or bacteria, have resulted in the development of specific neutralizing antibodies or cytotoxic T lymphocytes. Here, we describe the generation of a recombinant vaccinia virus expressing the mycobacterial 65-kDa heat shock protein (HSP65). A vaccinia recombinant virus was constructed by placing the gene for the Mycobacterium bovis BCG HSP65 under control of a vaccinia virus promoter and inserting this mycobacterial gene in the thymidine kinase locus of the vaccinia virus genome. Mycobacterial HSP65 is a critical antigen in the autoimmune model of adjuvant arthritis induced in Lewis rats by the immunization with Mycobacterium tuberculosis. We report the induction of immunity directed to this mycobacterial HSP65 by testing for the presence of specific antibodies and T-cell proliferation. Furthermore, induction of such immunity resulted in a reduction of arthritis severity when given to rats before or, even more interestingly, during development of arthritis. Disease reduction was not found after administration of HSP65 in the absence of vaccinia virus as a vector when given during arthritis development. Therefore, recombinant vaccinia virus may offer new prospectives for specific intervention in autoimmunity.     

Multiple forms of genes in pyelonephritogenic Escherichia coli encoding adhesins binding globoseries glycolipid receptors.

Earlier studies have shown that the majority of Escherichia coli isolates from urinary tract infections which possess a D-mannose-resistant adhesin contain gene sequences homologous to the pap pilus gene sequences encoded on the recombinant plasmid pRHU845. In this report, several E. coli isolates from urinary tract infections were examined to determined the arrangement of pap-related sequences. Copies of gene sequences homologous to the entire pap operon were found to exist at multiple sites in the chromosomes of some strains. The position of the pap operon(s) with respect to adjacent sequences was also found to be variable.     

Stress proteins as inducers and targets of regulatory T cells in arthritis

Immunization with microbial or mammalian stress proteins or heat-shock proteins in models of experimental autoimmunity has been observed to lead to increased disease resistance. Furthermore, such immunization has been proposed to result in the induction and expansion of T cells that suppress disease upon transfer. Comparisons of microbial heat-shock proteins with other conserved immunogenic proteins of bacterial origin have indicated a unique capacity for heat-shock proteins to induce a regulatory phenotype in T cells, such as reflected by the production of IL10. Also, studies in children with chronic arthritis have indicated that T-cell responses to heat-shock proteins are associated with a benign course of the disease and with remission. Furthermore, in patients, heat-shock-protein-(HSP-) activated T cells were shown to display regulatory phenotypes consistent with CD4+ CD25+ T regulatory cells.