PHARMACOKINETICS AND MULTIPLE PEAKING OF ACEBUTOLOL ENANTIOMERS IN RATS

Acebutolol (AC) is a chiral β-blocker which is extensively metabolized to an active, chiral metabolite, diacetolol (DC). Similar to some other β-adrenoceptors, AC exhibits multiple peaks in plasma concentration–time curves after oral doses to humans. We examined the suitability of the rat as an animal model and studied the effect of various factors including the route of administration, food, and bile on the pharmacokinetics of AC enantiomers. Pharmacokinetics of AC were delineated after oral (fed and fasted), iv, and ip doses, and after oral and iv doses, to intact and bile-duct-ligated female Sprague–Dawley rats, respectively. The possibility of intestinal metabolism or saturable absorption was studied in vitro using everted rat gut. Multiple peaks were present but only after oral doses independent of food intake, suggestive of gastrointestinal tract involvement. Oral absorption of AC enantiomers was incomplete as bioavailability was lower after oral (R, 0·59; S, 0·63) as compared to ip (R, 0·86; S, 0·84) doses. Food reduced bioavailability by 60%. A 250-fold increase in the dose did not alter the absorption kinetics of AC through the everted gut, ruling out the possibility of saturable absorption. No intestinal metabolism was detected in vitro. Enterohepatic recirculation cannot be responsible as ligation of the bile duct did not alter the pattern or route dependence of the multiple peaking. The rat appears to be a suitable animal model; a bile- and food-independent erratic absorption is probably responsible for the observed multiple peaking of AC. © 1997 John Wiley & Sons, Ltd.     

Favorable Influences of Imuthiol on Mouse Reproduction and Immune System of Offspring

ABSTRACT: A physiological immature immune system in newborns is a common feature frequently associated with increased susceptibility to infections. The properties of imuthiol (purified sodium diethyldithiocarbamate), an agent specifically active on the T-cell lineage, and virtually devoid of toxicity for man or animals, encouraged us to determine whether imuthiol administered to the dams could increase the immune capability of offspring without altering fecundability and birth rate. Experiments performed either in histocompatible or histoincompatible mating systems, show that chronic administration of imuthiol prior to mating and/or during pregnancy stimulated newborn mice to increased T-cell-dependent responses, without altering birth rates and growth curves in progenies. The data suggest that imuthiol has no teratogenicity or deleterious influences on mouse gametes, and might be useful to prevent immunodepression-associated infections in newborns.     

EFFECT OF FREQUENT SUN EXPOSURE ON BACTERIAL COLONIZATION OF SKIN

The bacteria colonizing the surface of the skin of a group of frequent sunbathers and a group of infrequent sunbathers were surveyed. Frequent sunbathing does not greatly affect the total number of organisms on the skin, but does tend to increase the proportion of bacteria containing carotenoid pigments.     

Sleep EEG alterations: effects of pulsed magnetic fields versus pulse‐modulated radio frequency electromagnetic fields

Studies have repeatedly shown that electroencephalographic power during sleep is enhanced in the spindle frequency range following radio frequency electromagnetic field exposures pulse‐modulated with fundamental frequency components of 2, 8, 14 or 217 Hz and combinations of these. However, signals used in previous studies also had significant harmonic components above 20 Hz. The current study aimed: (i) to determine if modulation components above 20 Hz, in combination with radio frequency, are necessary to alter the electroencephalogram; and (ii) to test the demodulation hypothesis, if the same effects occur after magnetic field exposure with the same pulse sequence used in the pulse‐modulated radio frequency exposure. In a randomized double‐blind crossover design, 25 young healthy men were exposed at weekly intervals to three different conditions for 30 min before sleep. Cognitive tasks were also performed during exposure. The conditions were a 2‐Hz pulse‐modulated radio frequency field, a 2‐Hz pulsed magnetic field, and sham. Radio frequency exposure increased electroencephalogram power in the spindle frequency range. Furthermore, delta and theta activity (non‐rapid eye movement sleep), and alpha and delta activity (rapid eye movement sleep) were affected following both exposure conditions. No effect on sleep architecture and no clear impact of exposure on cognition was observed. These results demonstrate that both pulse‐modulated radio frequency and pulsed magnetic fields affect brain physiology, and the presence of significant frequency components above 20 Hz are not fundamental for these effects to occur. Because responses were not identical for all exposures, the study does not support the hypothesis that effects of radio frequency exposure are based on demodulation of the signal only.     

How susceptible is the Antwerp female population to mammographic screening?

The benefit of organized screening has been demonstrated forbreast cancer as well as for cervical cancer. As far as breastcancer screening is concerned, there are several recommendationsmade by the European Union that its member states should offermammographic screening every 2 years to all women between 50and 70 years before the year 2000. In Belgium, it is very easyfor a woman to obtain mammography from a private radiologistwho is not taking part In an organized screening for breastcancer. One of the important items before starting an organizedbreast cancer screening programme is to get a clear idea ofthe screening status that already exists, its determinants andthe willingness of the women to be screened. For this reason,a study In Antwerp was performed by means of an extensive questionnaire.Five hundred randomly selected Antwerp women between 46 and70 years of age were interviewed in their homes. The resultsof this study indicate that the Antwerp female population inthe age group for which screening turned out to be valuable(50–70 years of age) can be described as ‘susceptibleto mammographic screening’.     

The relative importance of the X-linked FCP locus and β-globin haplotypes in determining haemoglobin F levels: a study of SS patients homozygous for βS haplotypes

Five factors have been hypothesized to influence the 20-fold variation in fetal haemoglobin (Hb F) levels in sickle cell anaemia (SS): age sex, α-globin gene number, β-globin haplotype, and the X-linked F-cell production locus (FCP) that regulates the production of Hb F containing erythrocytes (F cells). We analysed the association of these factors with Hb F levels in 112 SS patients living in France who are homozygous for the three common African β-globin haplotypes (Benin, Bantu or Central African Republic and Senegal). We found that: (1) FCP accounts for about 40% of the overall variation in Hb F levels, (2) when the FCP influence is removed, β-globin haplotype is associated with 14% of the remaining Hb F variation, and (3) the other factors have little influence. Comparison with our previous study of SS individuals in Jamaica leads to the following conclusions: (1) the X-linked FCP locus is a major determinant of Hb F levels in SS disease, (2) factors linked to the β-globin haplotype have only a small effect on the variation in Hb F levels, in either the homozygous or heterozygous state, and (3) approximately half of the variation in Hb F levels still remains to be explained.     

Cross–reactive antigenic determinants present on different Plasmodium falciparum blood–stage antigens

A gene encoding a previously undescribed antigen of Plasmodium falciparum has been isolated from a genomic expression library by use of a pool of human immune sera. Northern blot analysis indicated that the gene is expressed at the late stages of the intra-erythrocytic cycle. This antigen, 332, contains a series of degenerated amino acid repeats. Human antibodies affinity-purified on the 332 recombinant antigen reacted with a family of parasite proteins that are products of different genes. We identified antigens 11.1 and Pf155-RESA as members of this family and confirmed, using a human monoclonal antibody, the presence of cross-reacting determinants. The sequences of these antigens also share some structural homologies. The significance of this family of blood-stage antigens is discussed.     

The epithelial changes associated with squamous cell carcinoma of the vulva: a review of the clinical, histological and viral findings in 78 women

Summary. Seventy-eight excised specimens of squamous cell carcinoma of the vulva were reviewed retrospectively for the presence of lichen sclerosus or vulvar intraepithelial neoplasia (VTN) at sites proximal to the tumour or more distant. Lichen sclerosus was evident in 61% and VIN alone in 31%. VIN III (differentiated) was associated with over 50% of the specimens with lichen sclerosus. HPV 16 was found in six of the 11 VIN lesions, investigated but in none of the six with lichen sclerosus.     

Reduction of Energy Required for Defibrillation by Delivering Shocks in Orthogonal Directions in the Dog

Reduction of energy required to defibrillate (ERD) seems to represent a necessary condition for intensive development of implantable defibrillator, so as for minimization of cardiac and pulmonary damages provoked by high energy transthoracic defibrillation electric shocks. The present work describes a defibrillation method using shocks delivered in orthogonal directions and separated by a 100 ms delay. Defibrillation threshold measured with classical unidirectional shocks on 30 dogs has been found to be 286.8 ± 22.2 joules. In the same animals, defibrillation threshold measured by use of orthogonal shocks has been found to be 101.4 ± 14.9 joules. We conclude that this crossed shocks method leads to a substantial reduction of ERD (64%).