Oral contraception does not alter single dose saquinavir pharmacokinetics in women

AIMS: Women experience more adverse drug reactions (ADR) to antiretroviral therapy than men. This may be attributed to higher plasma concentrations of protease inhibitors due to pharmacokinetic interactions with hormonal preparations. Thus, in the present study we aimed to investigate the influence of oral contraceptives (OC) on the pharmacokinetics of the protease inhibitor saquinavir. METHODS: Saquinavir was administered in a hard gelatin capsule formulation (Invirase) to rule out confounding by pharmaceutical aids of the more frequently used soft gelatin capsule. After an overnight fast, eight healthy female participants ingested a single oral dose of 600 mg saquinavir immediately before and after the 19th dose of a combined, low dose OC (0.03 mg ethinylestradiol, 0.075 mg gestodene) in a prospective, fixed sequence study design. The first saquinavir application was scheduled on day 1, 2, or 3 of the individual menstrual cycle. Plasma concentrations of saquinavir and relative concentrations of its M2&M3-hydroxy metabolites were determined by LC/MS/MS for 48 h. RESULTS: Intake of OC resulted in a significant decrease in morning serum concentrations (before intake of OC, compared to day 19 of OC therapy) of 17beta-estradiol by -23.4 pg ml-1 (57%, 95%CI: -76% to -37.4%); progesterone by -0.25 ng ml-1 (33%, 95%CI: -45.3% to -21.5%); follicle-stimulating hormone by -4.06 U l-1 (82%, 95%CI: -96.5% to -67.7%); and luteinizing hormone by -3.49 U l-1 (74%, 95%CI: -93 to -54.6%). Conversely, sexual hormone binding globulin serum concentrations increased by 83.6 nmol l-1 (205%, 95%CI: 32.2% to 377%). Pharmacokinetic parameters of saquinavir (AUC, Cmax, tmax, t1/2, CLR) were not affected by OC, nor was the relative metabolic ratio of saquinavir/M2&M3-hydroxy saquinavir. Furthermore, there was no association of serum hormone concentrations or MDR1-polymorphisms (C3435T and G2677T) with pharmacokinetic parameters of saquinavir. CONCLUSIONS: There was no effect of OC on saquinavir pharmacokinetics. Thus, pharmacokinetic interactions of synthetic sexual steroids with saquinavir are not likely to account for the increased ADR to antiretroviral therapy seen in women.     

Evidence-based medicine: its effect on treatment recommendations as illustrated by the changing role of postmastectomy irradiation to treat breast cancer

PURPOSE: To illustrate the effect that the quality of evidence has on clinical practice, we examined how the role of radiotherapy in treating breast cancer has changed over the years as the quality of evidence evolved from anecdotal evidence based on expert opinion to randomized clinical trials and meta-analyses. METHODS: We searched the medical literature for key randomized studies and meta-analyses that have influenced the clinical use of postmastectomy irradiation since the first randomized trials in breast cancer in the 1950s. We discuss how clinical practice changed based on the outcomes of these trials, and then discuss the quality of those trials based on the criteria currently used to assess evidence from randomized trials (CONSORT) and meta-analysis (QUORUM). RESULTS: Evidence published from the early trials and meta-analyses on the role of postmastectomy irradiation had a strong effect on clinical practice. Examination of these studies, however, continues to show significant flaws in trial design that, by today's evidence-based standards, would not meet standards of quality. CONCLUSION: The quality of evidence has a strong effect on shaping clinical practice and needs to be continually assessed. Current guidelines developed to critique both individual randomized trials and meta-analyses are helping to establish high standards for trial design and interpretation. Evidence from older trials that were not guided by well-developed guidelines need to be reviewed, particularly when results from those trials are continually updated and used to generate evidence on which to base current clinical practice.     

Relation of left ventricular thickness to age and gender in hypertrophic cardiomyopathy

Left ventricular (LV) wall thickening is the most consistent clinical marker of hypertrophic cardiomyopathy (HC), and characteristically increases substantially during adolescence. In this study, we used 2-dimensional echocardiography to develop a cross-sectional profile of LV wall thicknesses in adult patients with HC. We studied a regional community-based cohort of 239 consecutively enrolled patients (aged 18 to 91 years). On average, maximum LV wall thickness decreased relative to increasing age (p = 0.007) within 4 age groups: 22.8 +/- 5.1 mm (18 to 39 years) to 22.1 +/- 5.1 mm (40 to 59 years) to 21.1 +/- 3.7 mm (60 to 74 years) to 20.8 +/- 3.6 mm (>or=75 years). The LV thickness index (summation of wall thicknesses in all 4 segments) also decreased with age (p = 0.017): 63.0 +/- 12.2 mm to 59.8 +/- 11.9 mm to 58.3 +/- 10.4 mm to 57.9 +/- 9.8 mm. Decreasing magnitude of LV hypertrophy was independently associated with increasing age, but not with other relevant disease variables, such as symptoms and outflow obstruction. However, when separated by gender, this inverse relation between age and LV wall thickness was statistically significant only for women (p = 0.007). In conclusion, in an unselected HC cohort, cross-sectional analysis showed a modest but statistically significant inverse relation between age and LV hypertrophy that was largely gender-specific for women. This association constitutes another facet of the natural history of this complex and heterogenous disease and may reflect disproportionate occurrence of premature death in young patients with HC with marked hypertrophy or possibly gradual LV remodeling.     

Periodontal bacteria in adult twins

BACKGROUND: Both environmental and genetic factors are known to influence clinical measures of periodontal disease. The purpose of this study was to determine whether genetic factors similarly influence the presence of specific periodontal bacteria in subgingival plaque. METHODS: Reared-together and reared-apart monozygous (MZ) and dizygous (DZ) adult twins were examined clinically. Demographic and behavioral information was obtained from each subject by questionnaire. Subgingival plaque samples were obtained from the index teeth, and the presence of P. intermedia, P. gingivalis, A. actinomycetemcomitans, E. corrodens, and F. nucleatum was determined using an immunoassay. RESULTS: Microbiological and clinical data were available for 169 twin pairs. The subject-based prevalences of the bacteria in the twin groups ranged from 11% for Porphyromonas gingivalis to 40% for F. nucleatum. For all species examined, the concordance rates were not significantly different (P > 0.05) between MZ and DZ twin groups. These findings were apparent despite similar smoking histories, self-reported oral hygiene practices, and antibiotic use in the twin groups. Furthermore, MZ twins reared together were not more similar than MZ reared-apart twins with respect to any bacterial species examined. CONCLUSIONS: These findings suggest that in a population with access to routine dental care, any effects that host genes and the early family environment have on the presence of specific bacteria in subgingival plaque are not apparent in adulthood. Most twins with disease in this study had early periodontitis. Results from this study may not necessarily be extrapolated to more advanced disease states.     

Inhibition of P-glycoprotein by newer antidepressants

Pharmacokinetic drug-drug interactions often occur at the level of P-glycoprotein (Pgp). To study possible interactions caused by the newer antidepressants we investigated citalopram, fluoxetine, fluvoxamine, paroxetine, reboxetine, sertraline, and venlafaxine and their major metabolites desmethylcitalopram, norfluoxetine, paroxetine-metabolite (paroxetine-M), desmethylsertraline, N-desmethylvenlafaxine, and O-desmethylvenlafaxine for their ability to inhibit Pgp. Pgp inhibition was studied by a fluorometric assay using calcein-acetoxymethylester as Pgp substrate and two different cell systems: L-MDR1 cells (model for human Pgp) and primary porcine brain capillary endothelial cells (pBCECs, model for the blood-brain barrier). Both cell systems proved to be suitable for the evaluation of Pgp inhibitory potency of drugs. All antidepressants tested except O-desmethylvenlafaxine showed Pgp inhibitory activity with sertraline, desmethylsertraline, and paroxetine being the most potent, comparable with the well known Pgp inhibitor quinidine. In L-MDR1 cells fluoxetine, norfluoxetine, fluvoxamine, reboxetine, and paroxetine-M revealed intermediate Pgp inhibition and citalopram, desmethylcitalopram, venlafaxine, and N-desmethylvenlafaxine were only weak inhibitors. The ranking order was similar in pBCECs. The fact that some of the compounds tested exert Pgp inhibitor effects at similar concentrations as quinidine suggests that pharmacokinetic drug-drug interactions between the newer antidepressants and Pgp substrates should now be thoroughly studied in vivo.     

Salt and peroxide compared with conventional oral hygiene. III. Patient compliance and acceptance

This study was undertaken to evaluate patient compliance with, and acceptance of, a salt and peroxide oral hygiene regimen compared with conventional oral hygiene regimens without or with the use of phase-contrast microscope viewing of subgingival plaque over a period of 2 years. A total of 231 subjects with early to moderate periodontitis were randomly divided into four groups. All groups were repeatedly instructed and motivated in their respective regimens. Subjects also received scaling and root planing using clinical and microbial criteria. Compliance with, and acceptance of, the two oral hygiene regimens were determined at the end of the study using a structured self-administered questionnaire. Results indicated that 74% and 58% (P less than or equal to 0.01) of subjects in the conventional and salt/peroxide groups, respectively, used their assigned regimen 4 to 7 days a week during the entire study. More than half of the subjects (54%) using each of the oral hygiene regimens indicated that they flossed once daily. Inconvenience was cited by 23% of the conventional and 43% of the salt/peroxide groups (P less than or equal to 0.01) as the main reason for not using their regimens. Twenty-three per cent of conventional group and 14% of salt/peroxide group indicated that shared their oral hygiene supplies with others. Eighty per cent and 57% (P less than or equal to 0.01) of the conventional and salt/peroxide groups, respectively, stated that they liked their regimens. Ninety-six per cent of all subjects felt that their regimen helped their periodontal status.(ABSTRACT TRUNCATED AT 250 WORDS)     

Evaluation of a Supervised Adapted Physical Activity Program Associated or Not with Oral Supplementation with Arginine and Leucine in Subjects with Obesity and Metabolic Syndrome: A Randomized Controlled Trial

Background: In patients with obesity and metabolic syndrome (MetS), lifestyle interventions combining diet, in particular, and physical exercise are recommended as the first line treatment. Previous studies have suggested that leucine or arginine supplementation may have beneficial effects on the body composition or insulin sensitivity and endothelial function, respectively. We thus conducted a randomized controlled study to evaluate the effects of a supervised adapted physical activity program associated or not with oral supplementation with leucine and arginine in MetS-complicated patients with obesity. Methods: Seventy-nine patients with obesity and MetS were randomized in four groups: patients receiving arginine and leucine supplementation (ALs group, n = 20), patients on a supervised adapted physical activity program (APA group, n = 20), patients combining ALs and APA (ALs+APA group, n = 20), and a control group (n = 19). After the baseline evaluation (m0), patients received ALs and/or followed the APA program for 6 months (m6). Body composition, MetS parameters, lipid and glucose metabolism markers, inflammatory markers, and a cardiopulmonary exercise test (CPET) were assessed at m0, m6, and after a 3-month wash-out period (m9). Results: After 6 months of intervention, we did not observe variable changes in body weight, body composition, lipid and glucose metabolism markers, inflammatory parameters, or quality of life scores between the four groups. However, during the CPET, the maximal power (Pmax and Ppeak), power, and O₂ consumption at the ventilatory threshold (P(VT) and O₂(VT)) were improved in the APA and ALs+APA groups (p < 0.05), as well as the forced vital capacity (FVC). Between m6 and m9, a gain in fat mass was only observed in patients in the APA and ALs+APA groups. Conclusion: In our randomized controlled trial, arginine and leucine supplementation failed to improve MetS in patients with obesity, as did the supervised adapted physical activity program and the combination of both. Only the cardiorespiratory parameters were improved by exercise training.     

Influence of periodontal bacteria and disease status on Vβ expression in T cells

Some bacterial antigens such as S. aureus enterotoxins can selectively stimulate T cells that express specific Vβ genes of the T cell antigen receptor (TCR). The purpose of this study was to investigate whether or not periodontal bacteria could similarly alter the expression of Vβ families within the TCR complex. Peripheral blood mononuclear cells (PBMNCs) were isolated from 12 patients with early onset periodontitis and 11 periodontally-healthy controls. PBMNCs were incubated in media alone, or co-cultured for 48 h with heat-inactivated A. actinomycetemcomitans, P. gingivalis, and P. intermedia. Expression of five Vβ families (Vαβ2, Vβ5, Vβ6, Vβ8, and Vβ12) was determined by use of monoclonal antibodies. Mean unstimulated expression of Vαβ2 and Vβ8 was significantly higher (p<0.05) in patients than healthy controls. Co-culture with the three bacteria resulted in significant changes (increases or decreases) in Vβ expression in 27% of the trials. There were no significant differences in the number or direction of changes in samples from patients and controls. When compared to unstimulated controls, 18 significant increases but no decreases in the percentage of cell expressing Vαβ2, Vβ5, or Vβ6 were noted following co-culture with P. intermedia. Overall, co-culture with P. intermedia significantly (p<0.05) upregulated expression of the five Vβ families studied. These data suggest that periodontal bacteria may alter Vβ expression within the T cell receptor complex.     

Prevalence of periodontal pathogens with varying metabolic control of diabetes mellitus

Abstract. The purpose of this study was to determine the prevalence of 5 periodontal pathogens in individuals with diabetes mellitus. Subjects ( n = 107) 20–70 years of age with type 1 ( n = 60) or 2 ( n = 47) diabetes mellitus were studied for the occurrence of the periodontal pathogens A. actinomycetemcomitans, F. nude-alum, E. corrodens, P. gingivalis and P. intermedia. Subgingival plaque was sampled in each subject from a single site exhibiting the greatest inflammation. The evaluation of selected periodontal bacterial pathogens was based on an immunoassay utilizing bacterial specific monoclonal antibodies. 35% of the sites harbored P. gingivalis , 28% F. nucleatum and 21% E. corrodens. A. actinomycetemcomitans and P. intermedia were found in less than 10% of the sites. Subjects for whom the probing depth at the sampled site was 4 mm were more often found to have detectable pathogens than those with a probing depth 3 mm. Diabetic factors such as duration, type and metabolic control of the disease had no statistically significant effect on the prevalence of these bacteria.     

Development and application of immunochromatographic tests for the detection of staphylococcal enterotoxin E

Two rapid immunochromatographic assay formats for the detection of Staphylococcus aureus enterotoxin serotype E (SEE) were developed. For both tests, polyclonal antibodies against SEE were immobilized on a membrane strip representing the test zone, while second anti‐SEE antibodies conjugated to dyed latex particles were employed as markers in sandwich immunoassay. In a two‐step test format, sample and labelled antibodies were preincubated prior to immunochromatography, whereas in a one‐step test the labelled antibodies were integrated in the test pad and activated by addition of the sample solution. In the presence of SEE in a sample solution, colour development at the antibody‐coated zone occured within 20 min. The visual detection limits for SEE in buffer solution were at 5 ng ml^?1 (two‐step test) and at 10 ng ml^?1 (one‐step test), respectively. Both assays were specific for SEE and showed no cross‐reaction with serotype A, B, C, and D enterotoxins. When the two‐step test format was used for the identification of SEE in S. aureus culture broth, the detection limit was found to be 10 ng ml^?1. Culture supernatants of 10 enterotoxigenic strains of S. aureus were analysed with the immunochromatographic two‐step test and with a microtitre plate enzyme immunoassay (EIA) test kit for enterotoxins A‐E. Results obtained by the immunochromatographic test (presence or absence of SEE) were in excellent agreement with those of the microtitre EIA.