Plasma concentrations and bioavailability of propranolol by oral, rectal, and intravenous administration in man

Eight normal male volunteers received 80 mg doses of propranolol by the oral and rectal routes and 2.2 mg by intravenous administration in a crossover fashion. Plasma concentrations of propranolol were measured by a gas chromatographic method using an electron capture detector. Individual subject concentration-time data were analysed and results indicated that the data fit a two compartment model with first order absorption. An approximately two-fold higher plasma propranolol concentration was observed after rectal administration as compared with oral dosing. Statistical analysis of the difference in the total AUCs indicates a significantly higher bioavailability of propranolol administered by the rectal route. The reduced bioavailability after oral administration indicates a substantial first pass effect but that it is possible to bypass the liver, at least partially, by giving the drug rectally to man.     

Trends in cancer mortality sex ratios in Europe, 1950-1989.

A study was carried out to analyse trends in cancer mortality sex differentials. This study compared age-standardized sex ratio values for mortality from 18 cancers (or groups of cancers), and total cancer mortality over the period 1950-1989 in 24 European countries, for 4 age groups (all ages, 20-44 years, 45-64 years, and 65 years and over). For lung cancer and other tobacco-related neoplasms, appreciable rises in sex ratio values were observed until the late 1970s, particularly in Southern and Eastern Europe, before levelling off in recent years, particularly among the younger age groups. In the late 1980s, the range of variation in overall age-standardized sex ratios for lung cancer was between 2 and 3 in the United Kingdom and in Nordic countries, and around or over 10 in Southern Europe. In young adults, the decline in sex ratio values observed in Denmark and Sweden (unity), and in other Nordic countries and in the United Kingdom (around or below 2) reflects a levelling of lung cancer in young males and an increase in young females. This clearly indicates that young women are a priority target group for smoking control interventions in Europe. Appreciable cohort effects were also observed for stomach cancer: rises in sex ratio values were greater in, or restricted to, middle- and older age groups, whereas in the young there was some tendency towards a levelling in sex differentials. The overall sex ratio values for stomach cancer were around 2 in most areas of Europe in the late 1980s. For intestinal cancer, sex ratio values showed some tendency to rise, reaching a level of 1.3-1.7 in the late 1980s; steady rises were also registered in sex ratio values for melanoma (skin cancer), reaching 1.5-1.8 in the late 1980s in most countries. These upward trends which were minor or inconsistent at younger ages in several countries became progressively stronger with advancing age. Sex ratio values were below unity for cancers of the gallbladder and the thyroid. Sex ratio values tended to rise also for leukaemia (from 1.2-1.5 to 1.5-1.7), but showed no noticeable trend for lymphomas or myeloma. The overall sex ratio values for total cancer mortality in the 1950s were between 1.2 and 1.4 in most European countries. Thereafter, they rose appreciably in several countries, reaching 1.9 in Czechoslovakia, Italy and Poland, and 2.3 in France.(ABSTRACT TRUNCATED AT 400 WORDS)     

The checkpoint protein Ddc2, functionally related to S. pombe Rad26, interacts with Mec1 and is regulated by Mec1-dependent phosphorylation in budding yeast

DDC2 is a novel component of the DNA integrity checkpoint pathway, which is required for proper checkpoint response to DNA damage and to incomplete DNA replication. Moreover, Ddc2 overproduction causes sensitivity to DNA-damaging agents and checkpoint defects. Ddc2 physically interacts with Mec1 and undergoes Mec1-dependent phosphorylation both in vitro and in vivo. The phosphorylation of Ddc2 takes place in late S phase and in G(2) phase during an unperturbed cell cycle and is further increased in response to DNA damage. Because Ddc2 phosphorylation does not require any other known tested checkpoint factors but Mec1, the Ddc2-Mec1 complex might respond to the presence of some DNA structures independently of the other known checkpoint proteins. Our findings suggest that Ddc2 may be the functional homolog of Schizosaccharomyces pombe Rad26, strengthening the hypothesis that the mechanisms leading to checkpoint activation are conserved throughout evolution.     

Good Safety Profile and Efficacy of Leucocyte Interferon-α in Combination with Oral Ribavirin in Treatment-Naive Patients with Chronic Hepatitis C

Background: The differential tolerability profile of various interferon (IFN)-α preparations used in combination with ribavirin for the treatment of chronic hepatitis C needs to be elucidated. Approximately 8% of patients receiving recombinant IFNα-2b plus ribavirin discontinue treatment because of adverse events. Human leucocyte IFNα is deemed to have a better safety profile than recombinant IFNα. We therefore compared the safety profile and efficacy of ribavirin combined with leucocyte IFNα or with recombinant IFNα-2b in treatment-naive patients with chronic hepatitis C. Study design: We randomised 423 patients to either leucocyte IFNα 3MU three times weekly plus ribavirin (210 patients) or the same dose of recombinant IFNα-2b plus ribavirin (213 patients). Patients were treated for 24 weeks and followed-up for a further 48 weeks. The primary endpoint was the safety profile of the two therapies; the secondary endpoint was the rate of sustained response. Results: In patients receiving leucocyte IFNα, the total number of adverse events was lower than in the group receiving recombinant IFNα (259 vs 441 patients), and the percentage of patients discontinuing treatment because of adverse events or laboratory abnormalities was significantly reduced (4% vs 11%; p = 0.013). Sustained response was observed in 47% of patients receiving leucocyte IFNα plus ribavirin and in 44% of patients receiving IFNα-2b plus ribavirin. Conclusions: Both therapeutic regimens were effective in inducing a sustained response in naive patients. However, the safety profile of leucocyte IFNα plus ribavirin was more favourable than that observed with the administration of recombinant IFNα-2b plus ribavirin, suggesting that leucocyte IFNα may be an alternative option in patients with reduced tolerability to other IFNs.     

Immunological changes among workers occupationally exposed to styrene

The functional status of the immune system was investigated in a group of 71 workers exposed to styrene and in 65 control subjects, recruited according to the same selection criteria and comparable as to sex, age, and confounding variables. Air and biological monitoring were used to characterize styrene exposure (median of the main urinary metabolites in the next-morning spot samples: 106 mg/g creatinine). Phenotypic analysis of peripheral blood lymphocytes (PBL) by automated flow cytometry revealed a reduced proportion of T lymphocyte subsets (CD3⁺, CD4⁺ and CD4⁺45⁺), with no changes in CD8⁺, and a higher proportion of B lymphocytes (CD19⁺) among styrene-exposed workers. The exposed workers showed a higher proportion of activation markers, namely DR and interleukin-2 receptors (CD25). Immunoglobulin subclasses were comparable in the two groups. An increased prevalence of abnormally low values was apparent for CD2⁺, CD3⁺, CD4⁺, CD4⁺45⁺ and CD11b subsets among workers exposed to styrene, whereas CD19⁺, DR⁺ and CD25⁺ showed an increased prevalence of abnormally high values. Natural killer-related phenotypes (CD56⁺, CD56+16⁺, and CD56⁺16^–) were more expressed among styrene workers, with average increase of 30%. However, the frequency distribution of the lytic activity of natural killer cells against K-562 target cells was shifted towards lower values in the exposed workers as compared to control subjects. Dose-response relationships between indices of internal dose and prevalence of abnormal values were detectable for T lymphocyte subsets, NK phenotypes, and activation markers. These findings suggest that moderate exposure to styrene is associated with an altered distribution of lymphocyte subsets. The decreased proportion of T lymphocytes, mainly of T helper-inducer cells, could hamper regulatory functions, thus suggesting a negative modulation by styrene exposure. Since a proper balance between immunocycte subsets is important for immunological responses, such changes should be regarded as adverse effects.     

Neurotoxicity in operating room personnel working with gaseous and nongaseous anesthesia

Occupational exposure to high concentrations of anesthetic gases (more than 500 ppm of nitrous oxide and more than 15 ppm of halothane and enflurane) can cause neurobehavioral effects in operating room personnel. Factors such as stress and work organization play an additional role in reducing performance capacities. It is still unclear whether these conditions may become the predominant factor in behavioral impairment when exposure to anesthetic gases is reduced; in addition, we wished to ascertain the extent of neurobehavioral and neuroendocrine effects at relatively low levels of exposure to such gases. Therefore the same group of 30 operating room personnel was examined with neurobehavioral tests during gaseous and nongaseous anesthesia. In this way, the neuropsychological performance was examined under the same stress conditions, but with different exposure levels to anesthetic gases. Serum cortisol was measured as an additional biological stress indicator. Prolactin secretion was examined to study possible interference of anesthetic gases with the dopaminergic system. The results were compared with those in a control group of 20 hospital workers from other departments, with similar characteristics in respect of age, sex, and education. During work with gaseous anesthesia, average airborne concentrations (geometric mean) of nitrous oxide were 50.9 ppm (SD 20.8) on the first day of the working week and 54.2 ppm (SD 22.1) on the last day of the working week, whereas average urinary nitrous oxide (geometric mean) were 21.54 g/l on the first day of the working week and 25.67 g/l on the last day of the working week. The operating room workers showed slower reaction times at the end of the week with gaseous anesthesia, compared with workers using nongaseous anesthesia and the control group. At the same time they also showed increased secretion of prolactin, whereas cortisol remained unchanged. Therefore, it can be concluded that lower levels of exposure to anesthetic gases (and not only high exposure levels) cause an impairment of neurobehavioral performance, with the action of stress being less relevant. The mechanism of anesthetics' neurotoxic action seems to be related to interference with the dopaminergic system.     

The recent decline in gallbladder cancer mortality in Europe.

Mortality from gallbladder cancer has been traditionally high in Eastern Europe, and lower in northern countries. Trends in 18 European countries, including the European Union (EU) and selected Eastern European countries, have been updated using official death certification data abstracted from the WHO database over the period 1980-1999. In the EU, age-standardized rates declined by about 30% between the late 1980s and 1999 to reach 1.8/100 000 for women, and by about 10% to reach 1.4/100 000 for men. In the Czech Republic and Hungary, rates for women were over 6/100 000 until the early 1990s, and declined by about 25% thereafter. For males, gallbladder cancer mortality showed no consistent trend, with rates over 3/100 000. Thus, a high mortality area from gallbladder cancer is still evident for both sexes in Central and Eastern Europe. The trends in mortality from gallbladder cancer are probably influenced by changes in risk factor exposure, such as diet, nutrition or tobacco, but essentially reflect more widespread and earlier adoption of cholecystectomy in the EU, since gallstones are the major risk factor for gallbladder cancer. The data also indicate the scope for further improvement of the management of gallbladder disease in Eastern Europe.     

Prevalence of carpal tunnel syndrome in workers executing complex tasks with the upper extremities

In 50 female workers of a manufacturing plant employed on the assembly line of metal and plastic products with cloth covering, we found a high prevalence of Carpal Tunnel Syndrome (16 cases, 32%, 5 of whom had already undergone surgical treatment). The subjects with positive diagnosis of Carpal Tunnel Syndrome also had a longer occupational exposure to repetitive movements, compared to the other subjects. Among the subjects with this disorder, the length of exposure was also significantly associated with the reported symptoms and the extension threshold measured on the 2nd finger of the dominant hand. Ergonomic assessment of the assembly lines revealed high-frequency repetitive movements and application of force, with insufficient rest intervals.     

Lung cancer mortality in European women: recent trends and perspectives

Background: Lung cancer mortality in men has been decliningsince the late 1980s in most European countries. In women, althoughrates are still appreciably lower than those for men, steadyupward trends have been observed in most countries. To quantifythe current and future lung cancer epidemic in European women,trends in lung cancer mortality in women over the last fourdecades were analyzed, with specific focus on the young. Patients and methods: Age-standardized (world standard) lungcancer mortality rates per 100 000 women—at all ages,and truncated 35–64 and 20–44 years—were derivedfrom the WHO for the European Union (EU) as a whole and for33 separate European countries. Joinpoint regression analysiswas used to identify points where a significant change in trendsoccurred. Results: In the EU overall, female lung cancer mortality ratesrose by 23.8% between 1980–1981 and 1990–1991 (from7.8 to 9.6/100 000), and by 16.1% thereafter, to reach the valueof 11.2/100 000 in 2000–2001. Increases were smaller inthe last decade in several countries. Only in England and Wales,Latvia, Lithuania, Russia and Ukraine did female lung cancermortality show a decrease over the last decade. In several Europeancountries, a decline in lung cancer mortality in young women(20–44 years) was observed over the last decade. Conclusions: Although female lung cancer mortality is stillincreasing in most European countries, the more favorable trendsin young women over recent calendar years suggest that if effectiveinterventions to control tobacco smoking in women are implemented,the lung cancer epidemic in European women will not reach thelevels observed in the USA. Key words: Europe, lung cancer, mortality, trends, women