Effect of ponsinomycin on cyclosporin pharmacokinetics

Summary The influence of treatment with ponsinomycin, a new macrolide antibiotic, on the pharmacokinetics of cyclosporin A has been studied in 10 renal transplant patients. The pharmacokinetics of cyclosporin A was investigated at steady state, before and during treatment with ponsinomycin.On average, the blood levels of cyclosporin A were doubled by the macrolide, possibly due to a decrease in elimination or/and to an increase in absorption.Ponsinomycin should be use very carefully in patients treated with cyclosporin A.     

Onset and development of cyclosporin A effects on lymphocytes of cardiac patients before heart transplantation

The effects of cyclosporin A (CSA) in low dosage (4 mg/kg/24 h i.v.) were studied in 17 patients awaiting heart transplantation. The lymphocyte subsets were typed, enumerated, and their proliferation measured before CSA perfusion, after infusion (over 24 h), and then again after two further 24 h intervals (T0 h, T24 h, T48 h, and T72 h). No significant change was found in T or B enumerations although lymphocyte function was markedly modified. For all 17 patients, there was a significant decrease in lymphocyte proliferation that was, however, re-established after 72 h for 14 of the patients, but not for the remaining 3. Inhibition of the proliferative response was found to occur rapidly, to be potent although rapidly reversible in most cases, while yet subject to wide interindividual variability. These four features suggest that (a) CSA in fixed doses may later the balance between helper and suppressor cells in varying degrees according to the patient, and that (b) CSA given immediately or shortly after heart transplantation could be beneficial.     

A multicentre double-blind comparison of hydroxyzine, buspirone and placebo in patients with generalized anxiety disorder

The efficacy of hydroxyzine and buspirone, controlled by placebo, was investigated in a double-blind, parallel group, multicentre study conducted in France and the UK. A total of 244 patients with generalised anxiety disorder in primary care was allocated randomly to treatments with hydroxyzine (12.5 mg morning and mid-day, 25 mg evening), buspirone (5 mg morning and mid-day, 10 mg evening) or placebo (three capsules/day) for 4 weeks, preceded by a 1-week single-blind placebo run-in and followed by 1-week single-blind placebo administration. Rating scales were applied on days -7,0,7,14,12,28 and 35. Seventy percent of the patients were female; the average age was 41 ± 11 years, and the mean Hamilton Anxiety Score at day 0 was 26.5 ± 4.2. Only 31 of the 244 patients dropped out, but equally in the three groups. Intention-to-treat LOCF analyses on the primary variable showed a significant difference only between hydroxyzine and placebo with respect to improvement on the Hamilton Anxiety Scale (10.75 versus 7.23 points, respectively). Secondary variables such as CGI and self-ratings (HAD scale) showed both hydroxyzine and buspirone to be more efficacious than placebo. Thus, hydroxyzine is a useful treatment for GAD. Received: 26 January 1998/Final version: 15 May 1998     

Cranial sutures and craniometric points detected on MRI

The main goal of the study was to determine on MRI the cranial sutures, the craniometric points and craniometric measurements, and to correlate these results with classical anthropometric measurements. For this purpose, we reviewed 150 cerebral MRI examinations considered as normal (Caucasian population aged 2049 years). For each examination we individualized 11 craniometric landmarks (Glabella, Bregma, Lambda, Opisthocranion, Opisthion, Basion, Inion, Porion, Infra-orbital, Eurion) and three measurements. Measurements were also calculated independently on 498 dry crania (Microscribe 3-DX digitizer). To validate the MRI procedure, we measured four dry crania by MRI and with compass or digital caliper gauges. Cranial sutures always appeared without signal (black), whatever the MRI sequence used, and they are better visualized with a 5 mm slice thickness (compact bone overlapping). Slice dynamic analysis and multiplanar reformatting allowed the detection of all craniometric points, some of these being more difficult to detect than others (Porion, Infra-orbital). The measurements determined by these points were as follows: VertexBasion height=135.66±6.56 mm; EurionEurion width=141.17±5.19 mm; GlabellaOpisthocranion length=181.94±6.40 mm. On the midline T1-weighted sagittal image, all median craniometric landmarks can be individualized and the GlabellaOpisthocranion length, VertexBasion height and parenchyma indices can be calculated. Craniometric points and measurements between these points can be estimated with a standard cerebral MRI examination, with results that are similar to anthropometric data.     

Antifungal coating by biofunctionalized polyelectrolyte multilayered films

The surface of medical devices is a common site of bacterial and fungal adhesion, first step to the constitution of a resistant biofilm leading frequently to chronic infections. In order to prevent such complications, several physical and chemical modifications of the device surface have been proposed. Here, we experiment a new type of topical antifungal coating using the layer-by-layer technique. The nanometric multilayer film obtained by this technique is functionalized by the insertion of a chromogranin A-derived antifungal peptide (CGA 47-66, chromofungin). We show that the embedded peptide keeps its antifungal activity by interacting with the fungal membrane and penetrating into the cell. In vitro studies demonstrate that such an antifungal coating is able to inhibit the growth of yeast Candida albicans by 65% and completely stop the proliferation of filamentous fungus Neurospora crassa. The cytotoxicity of such a coating was also assessed by growing human gingival fibroblasts at its surface. Finally, the antifungal coating of poly(methylmethacrylate), a widely used material for biomedical devices, is successfully tested in an in vivo oral candidiasis rat model. Taken together, these results assessed the functionalized multilayer films containing a new potent antifungal non-toxic peptide, as a novel and promising technique for local antifungal protection.     

Hormonal responses to training and its tapering off in competitive swimmers: relationships with performance

During a winter training season, the effects of 12 weeks of intense training and 4 weeks of tapering off (taper) on plasma hormone concentrations and competition performance were investigated in a group of highly trained swimmers (n = 8). Blood samples were collected and the swimmers performed their speciality in competition at weeks 10 (mid-season), 22 (pre-taper) and 26 (post-taper). No statistically significant changes were observed in the concentrations of total testosterone (TT), non-sex hormone binding globulin-boundtestosterone (NSBT), cortisol (C), luteinising hormone, thyroid stimulating hormone, triiodothyronine, thyroxine plasma catecholamines, creatine kinase and ammonia during training and taper. Mid-season NSBT: C ratio and the amount of training were statistically related (r = 0.82,P < 0.05). Competition performance slightly declined during intense training [0.52 (SD 2.51) %, NS] and improved during taper [2.32 (SD 1.69)%,P < 0.01]. Changes in performance during training and taper correlated with changes in ratios TT: C (r = 0.86,P < 0.01andr = 0.81,P < 0.05, respectively) and NSBT: C (r = 0.77,P < 0.05 andr = 0.76,P < 0.05, respectively). In summary, these results showed that the monitored plasma hormones and metabolic indices were unaltered by 12 weeks of intense training and 4 weeks of taper. The TT: C and NSBT: C ratios, however, appeared to be effective markers of the swimmers' performance capacities throughout the training season.     

Autoradiographic quantitation and anatomical mapping of GTP sensitive-galanin receptors in the guinea pig central nervous system

Galanin is a 29-amino acid peptide widely distributed in the mammalian central nervous system. Galanin receptors in the guinea pig brain were visualized using [¹²⁵I]galanin by in vitro receptor quantitative autoradiography. Scatchard analysis of [¹²⁵I]galanin binding to slide-mounted sections revealed saturable binding to a single class of high affinity receptors with a K_D of approximately 1 nM. Specific [¹²⁵I]galanin binding sites were detected in a large number of brain areas (concentration range: from non detectable to 99.32 fmol/mg of tissular proteins). The anatomical mapping revealed high densities essentially in the telencephalon (e.g. lateral septal nuclei, amygdala, hippocampal dentate gyrus) and the diencephalon (e.g. the anterodorsal and medial habenular thalamic nuclei, the paraventricular, dorsomedian and median mammillary hypothalamic nuclei, the posterior lobe of the pituitary). Addition of Mg²⁺ and GTP increased binding in some areas such as the zona incerta, the median eminence and the arcuate nucleus, and decreased it in other areas such as the amygdala, the hippocampus and the mammillary nuclei. This regional heterogeneity in the effect of Mg²⁺ and GTP can be interpreted as: (1) different rates of galanin receptor occupancy by endogenous peptide; (2) a differential coupling of GTP binding proteins to galanin receptors in the brain structures; and (3) a different nature of receptors. At any rate, this study provides evidence for a specific GTP-sensitive galanin receptor in guinea pig brain with an extensive distribution suggesting various physiological implications. Comparison with studies performed in several mammals shows that the overall distribution of galanin receptors is well preserved among species. These data suggest that galanin may posses similar functional properties in the different species tested so far. Nevertheless, very distinct differences were found in some areas like the cortex, the hippocampus and the pituitary.     

Absence of Correlation Between Delayed-Type Hypersensitivity and Protection in Experimental Systemic Candidiasis in Immunized Mice

We found that in mice which had been immunized intraperitoneally with 2 × 10⁸ heat-killed Candida albicans cells there was a striking temporal relationship between resistance to systemic challenge with 10⁶ living C. albicans cells and a number of measurable cellular parameters of the host response. These included the emergence of delayed-type hypersensitivity and the development of granulocytosis. Since it had been shown in previous work that granulocytosis was associated with an increase in resistance when nonspecific immunostimulation was used, we performed experiments to induce delayed-type hypersensitivity without any measurable modification of the granulocyte population. Adoptive transfer of delayed-type hypersensitivity with spleen cells from immune and resistant donor mice did not produce any increase in resistance in normal recipients. When separate groups of mice were immunized intraperitoneally or subcutaneously with varying doses of heat-killed C. albicans, we found that doses of less than 10⁸ cells did induce significant delayed-type hypersensitivity without any increase in granulocytosis. In such mice, as well as in animals pretreated with immunomodulators before immunization with heat-killed C. albicans, the presence of cell-mediated immunity, as measured by the delayed-type hypersensitivity test, was not associated with an increase in resistance against systemic candidiasis. On the contrary, the results suggested that cell-mediated immunity was associated with an increase in the susceptibility of these mice. The same effect on candidiasis susceptibility was observed when animals were immunized with heat-killed filamentous C. albicans.     

Prevalence and characterization of a binary toxin (actin-specific ADP-ribosyltransferase) from Clostridium difficile

In addition to the two large clostridial cytotoxins (TcdA and TcdB), some strains of Clostridium difficile also produce an actin-specific ADP-ribosyltransferase, called binary toxin CDT. We used a PCR method and Southern blotting for the detection of genes encoding the enzymatic (CDTa) and binding (CDTb) components of the binary toxin in 369 strains isolated from patients with suspected C. difficile-associated diarrhea or colitis. Twenty-two strains (a prevalence of 6%) harbored both genes. When binary toxin production was assessed by Western blotting, 19 of the 22 strains reacted with antisera against the iota toxin of C. perfringens (anti-Ia and anti-Ib). Additionally, binary toxin activity, detected by the ADP-ribosyltransferase assay, was present in only 17 of the 22 strains. Subsequently, all 22 binary toxin-positive strains were tested for the production of toxins TcdA and TcdB, toxinotyped, and characterized by serogrouping, PCR ribotyping, arbitrarily primed PCR, and pulsed-field gel electrophoresis. All binary toxin-positive strains also produced TcdB and/or TcdA. However, they had significant changes in the tcdA and tcdB genes and belonged to variant toxinotypes III, IV, V, VII, IX, and XIII. We could differentiate 16 profiles by using typing methods, indicating that most of the binary toxin-positive strains were unrelated.