Phase II study of docetaxel in patients with epithelial ovarian carcinoma refractory to platinum.

We analyzed the efficacy and toxicity of docetaxel in patients with ovarian cancer who failed previous chemotherapy with platinum. Fifty-five patients with measurable ovarian cancer were entered in this Phase II study at The University of Texas M. D. Anderson Cancer Center. Treatment consisted of 100 mg/m2 docetaxel given i.v. every 3 weeks. Because of hypersensitivity reactions, premedication with steroids and antihistamine was initiated during the study. Twenty-two (40%) patients responded (there were 3 complete responders and 19 partial responders). Twenty-one (38%) patients had stable disease. The median survival was 10 months. The main toxicity was neutropenia (98% of patients), with 13 episodes of neutropenic fever. Cumulative fluid retention was the main reason for dose modification and required a combination of diuretics and steroids for palliation. Other side effects were alopecia (100%); anemia (87%); dermatitis (67%); gastrointestinal disorders (53%); stomatitis (49%); neurotoxicity (45%); excessive lacrimation (33%); and hypersensitivity reactions (11%), which in one case were life threatening (loss of consciousness, fluid resuscitation). Docetaxel as a single agent proved to be active in heavily pretreated ovarian cancer patients but is associated with significant side effects. Objective toxicity consisted mainly of neutropenia and fluid retention. Neutropenia was dose limiting and required therapy with granulocyte colony-stimulating factor. Fluid retention was improved but not eliminated by diuretics and corticosteroids. Additional studies of docetaxel in ovarian carcinoma are indicated to define the activity in relation to paclitaxel and in platinum combination therapy.

In vitro study of biofilm formation and effectiveness of antimicrobial treatment on various dental material surfaces.

Elevated proportions of Candida albicans in biofilms formed on dentures are associated with stomatitis whereas Streptococcus mutans accumulation on restorative materials can cause secondary caries. Candida albicans, S. mutans, saliva-derived and C. albicans/saliva-derived mixed biofilms were grown on different materials including acrylic denture, porcelain, hydroxyapatite (HA), and polystyrene. The resulting biomass was analysed by three-dimensional image quantification and assessment of colony-forming units. The efficacy of biofilm treatment with a dissolved denture cleansing tablet (Polident(®)) was also evaluated by colony counting. Biofilms formed on HA exhibited the most striking differences in biomass accumulation: biofilms comprising salivary bacteria accrued the highest total biomass whereas C. albicans biofilm formation was greatly reduced on the HA surface compared with other materials, including the acrylic denture surface. These results substantiate clinical findings that acrylic dentures can comprise a reservoir for C. albicans, which renders patients more susceptible to C. albicans infections and stomatitis. Additionally, treatment efficacy of the same type of biofilms varied significantly depending on the surface. Although single-species biofilms formed on polystyrene surfaces exhibited the highest susceptibility to the treatment, the most surviving cells were recovered from HA surfaces for all types of biofilms tested. This study demonstrates that the nature of a surface influences biofilm characteristics including biomass accumulation and susceptibility to antimicrobial treatments. Such treatments should therefore be evaluated on the surfaces colonized by the target pathogen(s).

Determination of the in situ bactericidal activity of an essential oil mouthrinse using a vital stain method.

BACKGROUND: Recent research has indicated that bacteria within a biofilm may undergo changes in susceptibility to antimicrobial agents when compared to planktonic forms. This study was conducted to determine the bactericidal effect of an essential oil-containing mouthrinse (Listerine Antiseptic) on dental plaque bacteria in situ. METHODS: 1-day-old plaque in 17 subjects was sampled at baseline from the buccal surfaces of diagonally contralateral maxillary and mandibular bicuspids and 1st molars. Subjects were then randomly assigned either an essential oil mouthrinse or a sterile saline negative control and rinsed under supervision with 20 ml for 30 s. 30 min later, plaque was sampled from the remaining contralateral posterior teeth. Subjects repeated these procedures with their respective alternate rinse after 1 week. Pooled plaque samples from each subject at each sampling period were stained with a commercially-available fluorescent stain which fluoresces live and dead bacteria green and red, respectively. The stained plaque specimens were analyzed using computerized image analysis. A separate in vitro study was conducted to determine the relationship between the % red stain per sample and bacterial viability. RESULTS: Analysis of vital stained plaque specimens indicated that following rinsing with the essential oil mouthrinse, 78.7% of bacteria were dead compared to 27.9% following rinsing with the negative control (p<0.001). The in vitro findings demonstrated that the % red stain per sample is reflective of actual bacterial kill. CONCLUSIONS: This study confirms the findings of previous in vitro and in vivo studies which demonstrated the essential oil mouthrinse to have significant biocidal activity against oral micro-organisms. These studies all support the primacy of a bactericidal mechanism in producing the plaque and gingivitis reductions observed in numerous clinical trials conducted on the essential oil mouthrinse.

Comparative antimicrobial activity of an essential oil and an amine fluoride/stannous fluoride mouthrinse in vitro.

Although laboratory studies are not necessarily predictive of clinical activity; they can help to elucidate mechanisms underlying clinical activity when the latter has been established. In a recent clinical study, an essential oil mouthrinse (Listerine Antiseptic) was shown to be significantly more effective than an amine fluoride/stannous fluoride mouthrinse (Meridol) in inhibiting supragingival plaque formation. This paper reports the results of laboratory studies comparing the antimicrobial effectiveness of these 2 mouthrinses using a kill kinetics assay and a plaque biofilm kill assay. In both assays, the essential oil mouthrinse was considerably more effective than the amine fluoride/stannous fluoride mouthrinse. These findings are consistent with the results of the clinical trial and may help to explain the observed differences in clinical activity.

Relations between visceral and behavioral function in men at bedrest.

Multiple physiological measurements as well as a self-assessment of arousal was made in eight men on the first, third, and fifth days of bedrest. On the third day, additional measurements of performance on memory and dexterity tasks were made. Univariate analysis did not reveal any physiological variable to either predict subsequent performance well or to co-vary acutely with it; however, self-rating scores did prove to be useful predictors of subsequent performance. Principal components analysis suggested an "alertness" factor comprised of physiological measures as well as self-ratings which helped in predicting better performance. Although the individual patterns of correlations between variable on each of the three test days was variable, even more variability between subjects was found on the performance testing day. We believe this effect of behavioral activation may be due to the injection of common, slow temporal trends into many of the different data sets.

Defective brown adipose oxygen consumption in obese Zucker rats.

The thermogenic capacity and morphologic characteristics of interscapular brown adipose tissue (IBAT) were assessed in 3- to 4-mo-old male, lean and obese Zucker rats. Pads from obese rats were threefold heavier and contained similar numbers of cells but an average of 50% fewer multilocular cells than pads from lean rats and 40% less mitochondrial protein per pad. The maximal number of beta-adrenoreceptor binding sites, as assessed by [125I]iodocyanopindolol binding to isolated brown adipocytes from obese rats was 50% of that in lean rats on a per cell and per pad basis. Basal and norepinephrine (NE)-stimulated in vitro oxygen consumption in isolated brown adipocytes from lean rats correlated directly with the proportion of mutilocular cells present. This correlation was not seen in cells from obese rats that had a 50% decrease in their basal respiratory rates and could not be further stimulated by excess NE or fatty acid. Electron micrographs of IBAT from obese rats revealed distorted mitochondrial shapes and cristae patterns and the presence of numerous inclusion bodies. Because NE-stimulated lipolysis had previously been shown to be normal in the obese Zucker rat, these data suggest that defective BAT thermogenesis in the obese rat is due to an inability of mitochondria to utilize free fatty acids for the production of enhanced oxygen consumption.

Effects of diet and obesity on brown adipose metabolism.

The effect of diet-induced obesity on interscapular brown adipose tissue (IBAT) was assessed after feeding male Sprague-Dawley rats a high-fat diet for 3-5 mo beginning at 3 mo of age. IBAT pads in 6-mo-old obese rats were heavier (22%), had more lipid (71%), and larger unilocular cells (38%) than chow-fed controls. Mitochondrial morphology, beta-adrenergic receptor binding ([ 125I]iodocyanopindolol), and norepinephrine-stimulated lipolysis were similar in IBAT from obese and control rats. When 8-mo-old chow-fed rats were switched to the high-fat diet for 7-14 days, IBAT pads became hypercellular without cell hypertrophy and with a 70% increase in norepinephrine-induced lipolysis. However, when 8-mo-old obese rats that had been on the high-fat diet for 5 mo were switched to chow for 3 days, IBAT cellularity was unchanged, but norepinephrine-induced lipolysis was increased 70%. Therefore, in lean and obese 6- to 8-mo-old rats, short-term dietary manipulation led to metabolic activation, whereas chronic diet-induced obesity on a stable diet was associated with a return of IBAT metabolism to control levels.

A trial of lobaplatin (D-19466) in platinum-resistant ovarian cancer.

Long-term survival in epithelial ovarian cancer remains problematic despite multimodality therapy. A fundamental difficulty is the development of tumor resistance to platinum compounds. Analogs have been developed that demonstrate activity in platinum-resistant cell lines both in vitro and in vivo. Lobaplatin (D-19466), a third-generation compound, demonstrates significant activity in carboplatin and cisplatin-resistant cell lines. Lobaplatin was given to 17 assessable patients with platinum-refractory ovarian cancer. The drug was initially administered at a dose of 50 mg/m2 but was later reduced to 40 mg/m2 because of excessive thrombocytopenia. Nine patients required red cell transfusions during therapy. Cycles were repeated every 21-35 days (median cycle length 28 days). No objective responses were observed. Lobaplatin has no activity in platinum-resistant epithelial ovarian cancer.