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Irrigation volume determines the efficacy of "rectal washout".

PURPOSE: Rectal stump washout has been recommended to prevent implantation of exfoliated malignant cells in the anastomosis after anterior resection for rectal cancer. The aim of this study was to investigate its efficacy, particularly the extent to which the volume of irrigation fluid might influence the efficacy of tumor cell elimination and whether tumor characteristics might influence the result. METHODS: The study comprised 30 consecutive patients operated on by anterior resection for rectal cancer. After cross-clamping the rectum below the tumor, a washout sample was collected for examination after every incremental 500 ml of saline irrigation up to 2 liters. The presence of shed cancer cells was correlated with the washout volume and tumor characteristics. RESULTS: Cancer cells were found in 29 of 30 patients (97 percent) in the first sample of irrigation fluid and decreased gradually in frequency and number with increasing irrigation volumes. No cancer cells were demonstrated after 1.5 liters of irrigation in patients with tumor below the peritoneal reflection, whereas cancer cells were still present in one-fourth of the patients with tumor located above the peritoneal reflection. Finally, only a small number of cancer cells was confirmed in one patient after 2 liters of irrigation. CONCLUSIONS: The irrigation volume determined the efficacy of rectal washout. With our method, 1 1/2 liters of saline irrigation appears to clear contents from cancer cells in patients with tumors below the peritoneal reflection whereas at least 2 liters is recommended for patients with tumor above the peritoneal reflection.

Adult↗

Electrocardiographic determinants of efficacy of 8-Joule shocks for ablation of the atrioventricular node.

Factors determining the success of a single, low-energy, direct current-shock to achieve chronic complete heart block were studied in a consecutive group of 14 patients. A shock of 8 J was delivered by a modified device (Sirecust BS1, Siemens). If the first shock did not produce persistent complete block, multiple shocks were given. Standard 6 French U.S.C.I. catheters were used for all procedures. Chronic complete heart block was achieved with a single shock in six cases (43%; Group I); in eight others multiple shocks were needed (Group II). Neither polarity of the bipolar and of the distal His bundle recording nor the presence of sinus rhythm before the first shock were important factors to predict the outcome. The amplitude of the first recording of the bipolar His electrogram was 225 +/- 55 microV in Group I and 138 +/- 105 microV in Group II (P = 0.029). The duration of the HV interval before the first shock was 55 +/- 12 ms in Group I and 45 +/- 11 ms in Group II (NS). It is concluded that complete permanent heart block can be achieved with a single 8-J shock in 43% of the patients. The long-term success (follow-up at least 1 month, with a range of 1 to 8) of a single 8-J shock is predicted by a large amplitude of the bipolar and distal unipolar His bundle deflection, but not by its polarity or the HV interval.

Adult↗

Evaluation of two methods of determining the efficacies of two alcohol-based hand rubs for surgical hand antisepsis.

The antimicrobial efficacies of preparations for surgical hand antisepsis can be determined according to a European standard (prEN 12791 [EN]) and a U.S. standard (tentative final monograph for health care antiseptic drug products [TFM]). The U.S. method differs in the product application mode (hands and lower forearms, versus hands only in EN), the number of applications (11 over 5 days, versus a single application in EN), the sampling times (0, 3, and 6 h after application, versus 0 and 3 h in EN), the sampling methods (glove juice versus fingertip sampling in EN), and the outcome requirements (absolute bacterial reduction factor [RF], versus noninferiority to reference treatment in EN). We have studied the efficacies of two hand rubs according to both methods. One hand rub was based on 80% ethanol and applied for 2 min, and the other one was based on 45% propan-2-ol, 30% propan-1-ol, and 0.2% mecetronium etilsulfate and applied for 1.5 min. The ethanol-based hand rub was equally effective as the 3-min reference disinfection of prEN 12791 in both the immediate (RFs, 2.97 +/- 0.89 versus 2.92 +/- 1.03, respectively) and sustained (RFs, 2.20 +/- 1.07 versus 2.47 +/- 1.25, respectively) effects. According to TFM, the immediate effects were 2.99 log10 (day 1), 3.00 log10 (day 2), and 3.43 log10 (day 5), and bacterial counts were still below baseline after 6 h. The propanol-based hand rub was even more effective than the reference disinfection of prEN 12791 in both the immediate (RFs, 2.35 +/- 0.99 versus 1.86 +/- 0.87, respectively) and sustained (RFs, 2.17 +/- 1.00 versus 1.50 +/- 1.26, respectively) effects. According to TFM, the immediate effects were 2.82 log10 (day 1), 3.29 log10 (day 2), and 3.25 log10 (day 5), and bacterial counts were still below baseline after 6 h. Some formulations have been reported to meet the efficacy requirements of one of the methods but not those of the other. That is why we conclude that, despite our results, meeting the efficacy requirements of one test method does not allow the claim that the requirements of the other test method are also met.

Disinfectants↗

The MMP-9 expression determined the efficacy of postoperative adjuvant chemotherapy using oral fluoropyrimidines in stage II or III colorectal cancer.

BACKGROUND: The aim of this study was to determine any correlation between the efficacy of postoperative adjuvant chemotherapy using oral fluoropyrimidines and the matrix metalloproteinase 9 (MMP-9) expression in primary colorectal cancer tissues. PATIENTS AND METHODS: The data on 307 patients with colorectal cancer at stage II or III, who underwent potentially curative resection with lymphadenectomy, were reviewed. Of these, 188 received postoperative administration of oral fluoropyrimidines such as UFT and 5'-DFUR (chemotherapy group), while the other 119 patients underwent surgery alone (surgery-alone group). Immunostaining for MMP-9 was performed using surgical specimens of all 307 primary tumors and 18 recurrent tumors. RESULTS: Overall, MMP-9 was positively expressed in the primary tumor in 44% of patients. Multivariate analysis revealed that the MMP-9 expression was a worse prognostic factor with a second highest hazard ratio for recurrence. The disease-free survival rate in the chemotherapy group was significantly higher than that in the surgery-alone group. However, no significant difference in disease-free survival rate between the two groups was found in patients with a tumor positive for MMP-9. There was a strong positive correlation of MMP-9 expression between the primary tumors and the recurrent liver or lung tumors. CONCLUSIONS: The efficacy of postoperative adjuvant chemotherapy using oral fluoropyrimidines such as UFT and 5'-DFUR may not be as great for patients with a tumor positive for MMP-9 having a greater risk to postoperative recurrence.

Administration, Oral↗

The expression of vascular endothelial growth factor determines the efficacy of post-operative adjuvant chemotherapy using oral fluoropyrimidines in stage II or III colorectal cancer.

The aim of this study was to determine any correlation between the efficacy of post-operative adjuvant chemotherapy using oral fluoropyrimidines and the vascular endothelial growth factor (VEGF) expression in primary colorectal cancer tissues. The data were reviewed retrospectively on 342 patients with colorectal cancer at stage II or III, who underwent potentially curative resection between 1988 and 1998. Of these, 225 received post-operative administration of oral fluoropyrimidines such as UFT and 5'-DFUR, while the other 117 patients underwent surgery alone. Immunostaining for VEGF was performed using colorectal tumours. Overall, VEGF was positively expressed in primary tumour cells in 48% of patients. The disease-free survival rate and the overall survival rate in the chemotherapy group were higher than those in the surgery-alone group, although not significantly. However, the disease-free survival rate and the overall survival rate were similar between the two groups in patients with a tumour positive for VEGF. Multivariate analysis revealed that the VEGF expression was an independent factor for post-operative recurrence, and the VEGF expression and post-operative adjuvant chemotherapy were an independent factor for overall survival, in addition to the lymph node metastasis and the venous invasion. In conclusion, the efficacy of post-operative adjuvant chemotherapy using oral fluoropyrimidines may not be as great for patients with a tumour positive for VEGF having a greater risk of post-operative recurrence. The results support further investigation on efficacy of molecular targeting therapy for VEGF in combination with oral fluoropyrimidines as post-operative adjuvant therapy in colorectal cancer positive for VEGF.

Administration, Oral↗

Chorionic plate vascular anatomy determines the efficacy of amnioreduction therapy for twin-twin transfusion syndrome.

The objective of the study was to determine whether vascular anatomy of monochorial placenta influences the therapeutic efficacy of serial amnioreduction in chronic mid-trimester twin-twin transfusion syndrome (TTTS). Twenty-six consecutive monochorial pregnancies complicated by TTTS and treated by serial amnioreduction were studied. The placental anastomoses were delineated postnatally by perfusion studies. Amniotic fluid index, amniotic fluid pressure, number of amnioreductions, interval between amnioreduction, and neonatal outcome were correlated with the presence or absence of superficial anastomotic channels and type of cord insertion. Placentae were divided into two groups according to the presence (n = 9) and absence (n = 14) of superficial anastomosis. Gestational age at diagnosis, delivery, percentage discordance in estimated birth weight were comparable in the two groups. The amniotic fluid index, liquor volume removed, and amniotic pressure at first amnioreduction were also comparable between groups. In the group without superficial arterio-arterial/veno-venous (AA/VV) anastomoses, amnioreduction was required more often (P < 0.05). Perinatal mortality in terms of intrauterine deaths (IUD) and neonatal death was more common in the group without AA/VV anastomotic channels (P < 0.05). There was no difference in incidence of velamentous/marginal cord insertion between the two groups. TTTS lacking superficial AA or VV anastomosis are more likely to require frequent amnioreduction and are associated with increased perinatal mortality and morbidity, whereas the presence of such shunts was associated with increased therapeutic efficacy of amnioreduction and a more favourable prognosis.

Chorion↗

Techniques for determining the efficacy of treatment of osteoporosis.

Each of the presently available noninvasive methods used to determine the nature and degree of changes in skeletal mass has significant advantages and limitations. Dual photon absorptiometric techniques generally have a very low radiation dose. They are also less expensive to construct than other systems. However, they provide information only on a highly localized portion of the axial skeleton. Computed tomography offers significant potential advantages over other techniques, but requires further work for the solution of inherent technical problems. Similarly, considerable additional work is required for the Compton scattering technique; the technical problems associated with this are even more formidable. Neutron activation analysis permits the direct in vivo measurement of total calcium content of the body and hence, skeletal mass. However, while there is vast clinical and research experience with partial body and total body neutron activation, the techniques are generally not routinely available for application in clinical centers. The question as to whether DPA of the spine, or total body calcium measurement best reflects changes in bone mass after therapy has not been resolved.

Bone and Bones↗

Barbiturate shift as a tool for determination of efficacy of benzodiazepine-receptor ligands.

The change in benzodiazepine(BZ)-receptor affinity for selected BZ receptor ligands, induced by pentobarbital at 30 degrees C in the presence of 200 mM NaCl (barbiturate shift) was investigated. The affinity for benzodiazepines (e.g. flunitrazepam) was increased approximately two-fold by the presence of pentobarbital (1 mM) whereas the affinity for convulsive BZ-receptor ligands (e.g. DMCM ) was reduced approximately two-fold. The affinity for BZ-receptor antagonists (e.g. Ro 15-1788) was unaltered by pentobarbital. The results obtained suggest that barbiturate shifts have predictive value in determining the pharmacological efficacies of BZ-receptor ligands. However, compounds such as CL 218.872 and ZK 93423 would not have been recognized as agonists, notwithstanding their clear agonistic profile in pharmacological tests.

Animals↗

Suppressing unwanted memories: where there is a will, there is a way?

Research suggests that suppressing unwanted thoughts, generally, is an ineffective thought control strategy, because suppression attempts oftentimes fail, and, furthermore, result in a paradoxical increase of unwanted thoughts, later on. The present study sought to investigate whether manipulated expectations about suppression efficacy determine actual effects of suppression attempts. To test this hypothesis, participants listened to an audiotaped story, and were subsequently appointed to one of four conditions: a no-instruction-control (n = 20), suppression (n = 20), suppression-works (n = 20; participants were told that suppression generally is a fruitful strategy), or suppression-does-not-work (n = 25; participants were told that suppression primarily has paradoxical effects) condition. Two hours later, participants' memories of the story were tested, and several metamemory questions were answered. Induced expectations actually determined the perceived efficacy of suppression attempts, as well as thought frequency, although perceived or actual accuracy of recollections was not affected by the instructions.

Adolescent↗

Efficacy of a milbemycin oxime-praziquantel combination product against adult and immature stages of Toxocara cati in cats and kittens after induced infection.

Two studies were performed to examine the efficacy of milbemycin oxime against fourth-stage larvae or adults of Toxocara cati. In the study to determine efficacy against fourth-stage larvae, 20 domestic shorthair cats were inoculated with 500 embryonated eggs. Four weeks after inoculation, the animals were allocated to two groups, and cats in one group were treated with medicated tablets containing 4 mg milbemycin oxime and 10mg praziquantel (MILBEMAX) and cats in the other group with placebo tablets. Seven days after treatment the animals were euthanatized and necropsied for worm counting. The number of worms found was significantly (p=0.0002) lower in cats treated with medicated tablets than in cats treated with placebo tablets. The reduction in the number of worms was 96.53%. In the study to determine efficacy against mature adult worms, 13 kittens were inoculated with T. cati embryonated eggs. On day 45 after inoculation and after the infection had been confirmed through faecal examinations for 11 out of the 13 animals, the 11 infected animals were allocated to two groups and treated as in the first study. Seven days after treatment, all animals were euthanatized and necropsied for worm counting. The number of worms found was significantly (p=0.0043) lower in kittens treated with medicated tablets than in kittens treated with placebo tablets. The reduction in the number of worms was 95.90%. No adverse effects were recorded during either study. It is concluded that the milbemycin oxime-praziquantel tablets that were used are efficacious for the control of T. cati infections in cats.

Aging↗

Mechanistic model of G-protein signal transduction. Determinants of efficacy and effect of precoupled receptors.

Tissue-specific characteristics (e.g. receptor number) and agonist-specific characteristics (e.g. agonist binding kinetics) play roles in determining cellular response. The roles that these characteristics play are quantified by models of signal transduction. We examined signal transduction through G-protein-linked receptors, using a model based on the collision coupling model but including interconverting receptor states and the precoupling of receptors with G-proteins prior to the addition of agonist. Reaction and diffusion of molecules within the plasma membrane were simulated using Monte Carlo techniques. The G-protein activation produced by our model was compared with that produced by the collision coupling model. We quantitatively examined how the parameters characteristic of the tissue and agonist determine the midpoint and maximal response of the dose-response curve. Activation through agonist binding to precoupled receptors can produce significantly higher activation rates than does collision coupling. Tissue and agonist characteristics have qualitatively similar effects but quantitatively distinct effects on activation for the two models. Using standard experimental techniques, it may be possible to exploit these differences to determine the mechanism of G-protein activation in a specific cell system. A quantitative comparison of model predictions with published data on the beta-adrenergic receptor system (Stickle D and Barber R, Mole Pharmacol 40: 276-288, 1991) also is presented.

Animals↗

Zinc ion availability--the determinant of efficacy in zinc lozenge treatment of common colds.

This is a re-analysis of reports from 1984 to 1992 of double-blind, placebo-controlled, clinical trials of zinc lozenges in the treatment of common colds. This re-analysis was performed to test the hypothesis that major variations in daily zinc ion availability (ZIA) between chemically different lozenge formulations caused differing results in these clinical trials. Solution chemistry computations determined the bioavailability of Zn2+ ions at physiological pH from the lozenges used in these clinical trails. ZIA was derived from Fick's laws of diffusion in a bio-electric field. Lozenges that released Zn2+ ions at physiological pH (positive ZIAs) shortened colds. Lozenges that released negatively charged zinc species at physiological pH (negative ZIAs) lengthened colds. Lozenges having a zero ZIA had no effect on common colds. Lozenges with ZIA = 100 shortened colds by 7 days while ZIA = -55 lozenges lengthened colds by 4.4 days. A linear dose-response relationship exists between ZIAs of zinc lozenges and changes in duration of common colds. It is concluded that: prospective efficacy of zinc lozenges can be predicted based upon readily determined ZIA factors and ZIAs; chemically different zinc lozenge formulations having greatly different ZIAs resulted in greatly differing results in clinical trials; mast cell granule-derived Zn2+ ions are the foundation of the primary immune system; and high ZIA zinc acetate lozenges are beneficial for common colds.

Biological Availability↗

Using thrombelastography to determine the efficacy of the platelet glycoprotein IIb/IIIa antagonist, roxifiban, on platelet/fibrin-mediated clot dynamics in humans.

The effect of platelet glycoprotein IIb/IIIa antagonists on the dynamics of platelet/fibrin clot formation and strength was determined using thrombelastography (TEG) under conditions of recalcification or tissue factor addition. In the present investigation, the effect of roxifiban (class I) on ex vivo clot dynamics using recalcified blood was tested in normal, healthy volunteers (n = 7) dosed with 1 mg BID roxifiban for 9 days. Roxifiban inhibited platelet aggregation induced by 20 mumol/l adenosine diphosphate by 60-90% but did not significantly affect any of the TEG parameters either at peak, trough, or subtrough drug levels. Addition of 30 nmol/l roxifiban free acid (XV459; which is ineffective by itself to modify TEG parameters) to human blood obtained from roxifiban-treated subjects resulted in 45-60% (P < 0.01) inhibition of clot strength (maximum amplitude), 90-100% (P < 0.01) inhibition of initial kinetic of clot development (angle alpha), and 50-70% (P < 0.01) inhibition of early clot initiation (K). These data suggest that a subthreshold blood level of 40-50 nmol/l roxifiban active form was achieved in those subjects, as estimated from an in vitro calibration with XV459. These data indicate (not studied) that roxifiban, at a targeted clinical dosing regimen, failed to achieve sufficient exposure to modulate platelet-mediated clot retraction.

Amidines↗

Photodynamic therapy with hypericin in a mouse P388 tumor model: vascular effects determine the efficacy.

Hypericin, a polycyclic quinone obtained from plants of the Hypericum genus, exhibits strong photodynamic antitumor effects. In the present study, PDT efficacy of hypericin under different conditions was compared in a P388 mouse tumor model. Plasma and tumor drug measurements and assessment of vascular damage by fluorescein dye exclusion were performed to determine the relative contributions of vascular effects and direct tumor cytotoxicity. Furthermore, the influence of modifying tumor oxygenation on PDT effect was also evaluated. Study of PDT efficacy and tissue distribution revealed that PDT efficacy was more dependent on plasma concentration than tumor drug level. Fluorescein dye exclusion indicated the complete microvascular occlusion in the tumor and surrounding skin immediately after effective PDT treatments, while only a limited vascular occulation was observed after non-effective PDT treatment. It was found that neither tumor hypoxia induced by hydralazine nor increasing tumor oxygenation achieved by nicotinamide could significantly affect the effectiveness of various PDT protocols. These results suggest that tumor vasculature damage might be the primary mechanism of hypericin-mediated PDT effect. The existence of this potent secondary vascular effect is likely to account for the inability of tumor oxygenation modifiers to affect tumor response after PDT with hypericin.

Animals↗

The use of respiratory quotient to determine the efficacy of nutrition support regimens.

Respiratory quotient (RQ) is an indicator of fuel utilization. This study examined the RQs of patients receiving intensive nutrition support to assess the frequency with which net fat synthesis occurred, as determined by RQs greater than 1.0. One hundred twelve RQs were calculated from data obtained using indirect calorimetry. Seventy-four measurements were made while patients were receiving parenteral nutrition--55 with glucose and amino acid (GAAPN) and 19 with glucose, fat, and amino acid (GFAAPN). Thirty-eight measurements were made while patients were receiving either oral or nasoenterally administered carbohydrate, fat, and protein in the form of standard hospital diets or liquid defined formula diets (CFPEN). The mean RQ of the GAAPN patients was significantly higher than those of both the GFAAPN and the CFPEN patients. RQs were greater than 1.0 in a significantly greater number of the GAAPN patients than the GFAAPN or CFPEN patients. The route of nutrient intake did not influence energy nutrient utilization, as determined by RQ. This study suggests that nutrition support regimens containing fat, in addition to carbohydrate and protein, are more efficiently utilized to meet the energy requirements of hospitalized patients than are regimens containing only glucose and amino acid.

Calorimetry, Indirect↗

Ro 15-4513 binding to GABAA receptors: subunit composition determines ligand efficacy.

The bidirectional modulation of ligand binding to benzodiazepine receptors (BzR) by GABA (the "GABA shift") has been widely used to predict ligand efficacy. The present study examined the effects of GABA and muscimol on [3H]Ro 15-4513 binding to "diazepam-insensitive" (DI) and "diazepam-sensitive" (DS) BzR. Neither GABA nor muscimol significantly altered [3H]Ro 15-4513 binding to DI in cerebellum, while both compounds inhibit [3H]Ro 15-4513 binding to cerebellar DS in a concentration-dependent fashion. The maximum reductions in [3H]Ro 15-4513 binding to cerebral cortical and hippocampal membranes elicited by GABA were comparable to those obtained in cerebellar DS, but significantly less than obtained with the full inverse agonist [3H]3-carbomethoxy-beta-carboline. The qualitatively different effect of GABAmimetics on [3H]Ro 15-4513 binding to DS and DI is not species specific since identical effects were obtained in rat and mouse brain. Based on previously established criteria, Ro 15-4513 can be classified as a "GABA-neutral" (antagonist) ligand at DI and "GABA negative" (inverse agonist) at other BzR. These findings suggest that GABAA receptor subunit composition determines not only ligand affinity but also ligand efficacy.

Animals↗

Opioid peptide receptor studies. 14. Stereochemistry determines agonist efficacy and intrinsic efficacy in the [(35)S]GTP-gamma-S functional binding assay.

Previous data obtained with the cloned rat mu opioid receptor demonstrated that stereochemistry affects the four parameters of the ligand-receptor interaction: potency (ED(50)), efficacy (maximal stimulation), intrinsic efficacy (effect as a function of receptor occupation), and binding affinity. This study evaluated the activities of structurally diverse opioid receptor ligands in the [(35)S]GTP-gamma-S binding assay, comparing the relationship between receptor binding, activation, efficacy, and intrinsic efficacy. The data, obtained with cloned rat mu receptors, demonstrated that an analgetic, (-)-5-m-hydroxyphenyl-2-methylmorphan (NIH8508), and its (+)-isomer (NIH8509), behave as partial agonists, but had different intrinsic efficacy in the [(35)S]GTP-gamma-S binding assay. Replacement of the methyl group with the phenethyl group on the piperidine nitrogen of NIH8508 and NIH8509 [(1R,5S)-AH019 and (1S, 5R)-AH019] increased affinity for the mu receptor and eliminated any agonist effect, supporting the hypothesis that certain structural features make these compounds antagonists. These study also show that all of the fully efficacious mu agonists studied here had high levels of intrinsic efficacy, producing a 50% response at about 10% receptor occupancy. Comparison of the binding K(i) in competitively inhibiting [(125)I]IOXY binding to the functional K(i) for opioid antagonists [K(i)(IOXY)/K(i)(GTP-gamma-S)] provides more detailed evidence that the [(35)S]GTP-gamma-S binding assay can be used to reliably determine apparent functional antagonist K(i) values in addition to agonist ED(50), efficacy and intrinsic efficacy.

Analgesics, Opioid↗

Standardization of a method to determine the efficacy of sanitizers in inactivating human pathogenic microorganisms on raw fruits and vegetables.

The efficacy of sanitizers in killing human pathogenic microorganisms on a wide range of whole and fresh-cut fruits and vegetables has been studied extensively. Numerous challenge studies to determine the effects of storage conditions on survival and growth of pathogens on raw produce have also been reported. Results of these studies are often difficult to assess because of the lack of sufficient reporting of methods or, comparatively, because of variations in procedures for preparing and applying inocula to produce, conditions for treatment and storage, and procedures for enumerating pathogens. There is a need for a standard method to accurately determine the presence and populations of pathogenic microorganisms on produce. The adoption of standard, well-characterized reference strains would benefit a comparative assessment of a basic method among laboratories. A single protocol will not be suitable for all fruits and vegetables. Modifications of a basic method will be necessary to achieve maximum recovery of pathogens on various types of produce subjected to different sanitizer or storage treatments. This article discusses parameters that must be considered in the course of developing a basic standard method against which these modifications could be made.

Anti-Bacterial Agents↗