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Biomedical subjects

M P Meredith

Publications and source records attributed to M P Meredith.

16 recordsLinked to original sources
PubMed2004

Statistical validation of surrogate endpoints: is bone density a valid surrogate for fracture?

In the treatment of osteoporosis using anti-resorptive agents there has been increasing interest in quantifying the relationship between fracture endpoints and surrogates such as bone mineral density (BMD) or bone turnover markers. Statistical methodology constitutes a critical component of assessing surrogate validity. Depending on study designs, data resources, and statistical methods used for analyses, one has to use caution when interpreting results from different analyses, especially when results are disparate. For example, analyses based on individual patient data reported that only a limited proportion of the anti-fracture efficacy was explained by BMD increases for agents such as alendronate, risedronate and raloxifene. Analyses employing meta-regression based on summary statistics, however, indicated that most of the anti-fracture benefits were due to improvements in BMD. In this paper, we review definitions of surrogate endpoints and requirements for their statistical validation. We evaluate whether BMD meets these requirements as a possible surrogate for fracture. Our review indicates that the actual BMD value is correlated with fracture risk and thus BMD is useful in identifying patients that might need treatment. There is limited evidence to support BMD increase with anti-resorptive agents as a reliable substitute for fracture risk reduction. Strengths and limitations for various statistical methods are discussed.

Biomarkers↗
PubMed2001

A method to assess the proportion of treatment effect explained by a surrogate endpoint.

Randomized clinical trials are the standard for evaluating new drugs, devices and procedures. Traditional clinical trials entail not only considerable expense, but require considerable time to complete. The use of surrogate endpoints constitutes an effort to control cost and completion time for clinical trials. We propose a method to quantify the proportion of treatment effect explained by a surrogate endpoint based on a general model setting which includes the commonly used linear, logistic and Cox regression models. The interpretation of this quantitative measure is facilitated by graphical displays. To reduce the variability associated with the estimate, a meta-analytic approach is proposed based on random effects models. An example using real clinical trial data is given to illustrate the proposed procedures.

Biometry↗
PubMed1998

Coordinate production of PGE2 and IL-1 beta in the gingival crevicular fluid of adults with periodontitis: its relationship to alveolar bone loss and disruption by twice daily treatment with ketorolac tromethamine oral rinse.

The inflammatory mediators prostaglandin E2 (PGE2) and interleukin-1 beta (IL-1 beta) play critical roles in the inflammatory process leading to alveolar bone and connective tissue loss in periodontal disease. Data from a previously published 6-month clinical study demonstrated that twice daily use of 0.1% ketorolac tromethamine oral rinse prevented alveolar bone loss in adults with periodontitis. We further analyzed data from this study to examine the relationship between PGE2. IL-1 beta and bone loss. Patient mean PGE2 and IL-1 beta levels in gingival crevicular fluid (M-GCF) measured throughout the course of the study were directly compared to the maximum amount of alveolar bone height loss observed at a single study site in each patient. The maximum amount of bone loss measured was chosen for the analysis since the pattern of bone loss was clearly episodic in nature. A statistically significant correlation (r = 0.73, p = 0.001) exists between M-GCF PGE2 concentration and the maximum amount of bone height lost at individual patient study sites. The correlation between M-GCF IL-1 beta concentration and maximum bone height lost is also statistically significant (r = 0.66, p = 0.005). Over the 6-month duration of the study, both PGE2 and IL-1 beta were coordinately expressed in the placebo treatment group as reflected in the significant correlation between M-GCF concentrations of the 2 mediators (r = 0.81, p < 0.001). Treatment of patients with 0.1% ketorolac tromethamine twice daily for 6 months resulted in reductions of PGE2 in GCF and a negligible correlation between M-GCF PGE2 and M-GCF IL-1 beta (r = 0.42, p = 0.088). This lack of a strong association between the 2 mediators in the ketorolac treatment group provides a direct biochemical readout of the anti-inflammatory efficacy of ketorolac tromethamine oral rinse in patients with periodontitis. Further studies are warranted to determine the full diagnostic potential of M-GCF levels of PGE2 and IL-1 beta for predicting risk of alveolar bone loss in patients with periodontitis and monitoring periodontal therapy effectiveness.

Adult↗
PubMed1996

Evaluation of ketorolac concentrations in plasma and gingival crevicular fluid following topical treatment with oral rinses and dentifrices.

Two clinical studies were conducted to determine the relative amounts of ketorolac detectable locally in the gingival crevicular fluid (GCF) and systemically in plasma after oral, topical drug administration. The rinse study compared topical administration of three concentrations of ketorolac tromethamine (0.1%, 0.5%, and 0.01%) in oral rinse formulations administered topically and a perorally administered capsule (10 mg), and the dentifrice study compared two concentrations of ketorolac in dentifrice formulations (0.15% and 1.0%) with a 0.1% oral rinse, all treatments administered topically. The dose-corrected systemic availability of the three oral rinses evaluated in the rinse study relative to the peroral capsule was about 15%. However, the ratios of the observed maximum GCF ketorolac concentration to maximum plasma ketorolac concentration ranged from 22 to 49, compared to less than 1 for the peroral ketorolac capsule. Using this ratio as an estimate of the ability of a treatment to target the drug to the gingival tissue, these data indicate that the ketorolac oral rinses achieved greater delivery of drug to the gingival tissue (presumed site of action for periodontitis) with a lower systemic drug load than peroral administration of a ketorolac capsule. The dose-corrected relative systemic bioavailabilities for the dentifrice treatments with respect to the 0.1% rinse in the dentifrice study were 59.2% and 86.4% for the 1.0% and 0.15% dentifrices, respectively, indicating that significantly less ketorolac was systemically available from the two dentifrices relative to the oral rinse. The relative bioavailabilities of ketorolac in the GCF after dosing with the dentifrice formulations with respect to the rinse were 89.1% for the 1.0% dentifrice and 19.7% for the 0.15% dentifrice. Thus, the 1.0% dentifrice appears to provide statistically equivalent levels of ketorolac to the gingival tissue as the 0.1% oral rinse with significantly less systemic exposure. The T1/2 of ketorolac in the GCF was about 0.5 h for all three treatments, which is significantly less than the plasma half-life of about 5.3 h. These data suggest that GCF levels of ketorolac should remain above the IC50 for PGE2-stimulated IL-1 bone resorption for about 7 h following treatment, assuming continuation of the first-order elimination observed over the first two postdosing hours. We conclude that oral rinses and dentifrices are effective and preferred vehicles for administration of ketorolac for use in treatment of periodontitis.

Administration, Topical↗
PubMed1996

Efficacy of quantitative digital subtraction radiography using radiographs exposed in a multicenter trial.

Digital subtraction radiography (DSR) has been shown to be a sensitive and specific method for the detection of small bony changes in periodontitis. The purpose of this study was to perform a multicenter validation of the DSR in human subjects. Seventeen subjects were enrolled at 3 centers. Feather-edged hydroxyapatite chips (approximately 1, 7 and 10 mg) were used to simulate osseous lesions. Bilateral radiographs were taken with and without chips. Geometry was standardized using a cephalostat and the order of radiographs was determined using a randomization plan. Radiographs were subtracted, lesions isolated, and quantified at a single center without knowledge of the randomization code or location of the chips used in each subject. The overall sensitivity and specificity in detecting 1 mg changes was 87.8% and 100%, respectively. Sensitivity and specificity in detecting 7 mg and 10 mg chips was 100%. A strong linear relationship between actual lesion mass and calculated mass was observed (R2 = 0.94, slope = 0.98, p < 0.0001). No significant differences were observed by center. These data indicate that the DSR is a valid technique for the assessment of alveolar bone changes in multicenter trials.

Adult↗
PubMed1995

Interspecies scaling of tebufelone pharmacokinetic data and application to preclinical toxicology.

PURPOSE: Retrospective application of allometric scaling techniques to tebufelone, a nonsteroidal antiinflammatory agent, in order to better understand the systemic exposure relationships between the doses administered to the species used in toxicology studies and the doses given to human subjects and patients in clinical studies. METHODS: Non-compartmental estimates of tebufelone's total body volume of distribution during the terminal phase (Vz) and clearance (CL) obtained from intravenous dosing to rat, monkey, dog, and human were allometrically scaled to body weight, and body weight and brain weight, respectively. AUCs determined from single or multiple dose pharmacokinetic studies and from preclinical toxicology studies were plotted versus dose adjusted for bioavailability and divided by allometrically scaled clearance to produce an allometric relationship suggesting a non-linear increase in AUC with dose across the four species. RESULTS: Segmental linear regression analysis of this relationship indicates a change point associated with an AUC of approximately 2,300 ng-hr/mL. Elevations in serum levels of various liver enzymes or associated signs of hepatic toxicity occur in some, but not all of the animals exposed for more than three weeks in repeat dosing studies at the actual dose that this represents. CONCLUSIONS: The analysis suggests that doses producing tebufelone plasma levels above a certain threshold AUC and duration of exposure to parent tebufelone are associated with increased risks of hepatic effects. Whether this is because metabolic shifts occur at these doses cannot be determined from these data.

Administration, Oral↗
PubMed1995

A comparison of topical ketorolac, systemic flurbiprofen, and placebo for the inhibition of bone loss in adult periodontitis.

Systemic non-steroidal anti-inflammatory drugs (NSAIDs) have been shown to reduce alveolar bone loss in periodontitis. This study assesses the efficacy of a topical NSAID rinse, containing ketorolac tromethamine as the active agent. Adult periodontitis patients (n = 55) were studied in this 6-month randomized, double blind, parallel, placebo and positive-controlled study. Each patient had a least 3 sites at high risk for bone loss as assessed by low dose bone scan. Groups, balanced for gender, were assigned to one of three regimens: bid ketorolac rinse (0.1%) with placebo capsule; 50 mg bid flurbiprofen capsule (positive control) with placebo rinse; or bid placebo rinse and capsule. Prophylaxes were provided every 3 months. Monthly examinations assessed safety, gingival condition, and gingival crevicular fluid PGE2. Standardized radiographs were taken at baseline and at 3 and 6 months for digital subtraction radiography. A significant loss in bone height was observed during the study period in the placebo group (-0.63 +/- 0.11; P < 0.001), but not in the flurbiprofen (-0.10 +/- 0.12; P = 0.40) or ketorolac rinse (+0.20 +/- 0.11 mm; P = 0.07) groups. Nested ANOVA revealed that ketorolac and flurbiprofen groups had less bone loss (P < 0.01) and reduced gingival crevicular fluid PGE2 levels (P < 0.03) compared to placebo. ANOVA suggests (P = 0.06) that ketorolac rinse preserved more alveolar bone than systemic flurbiprofen at the dose regimens utilized. These data indicate that ketorolac rinse may be beneficial in the treatment of adult periodontitis.

Adult↗
PubMed1994

Improving the sensitivity of in vitro skin penetration experiments.

The institution of a readily-implemented sample screening and data handling procedure for in vitro skin penetration studies yields substantial improvements in sensitivity for distinguishing between formulations, treatments, penetrants, etc. The procedure involves four steps: 1) prescreen the tissue samples to determine their intrinsic permeability; 2) apply treatments using a randomized complete block (RCB) design, with blocking by tissue permeability; 3) apply a variance-stabilizing transformation to the penetration data, followed by outlier testing; and 4) analyze the transformed data according to an RCB analysis of variance, using tissue permeability as the blocking variable. For penetration studies in which high sample variability is a concern, the above procedure commonly yields a sensitivity advantage of several-fold versus alternative methods of comparison.

Humans↗
PubMed1992

Acclimatization to hypoxia alters cerebral convective and diffusive O2 delivery.

Ventilatory acclimatization (VA) to hypoxia alters cerebrovascular responses to arterial blood gas perturbations. For example, after VA, cerebral blood flow (CBF) is elevated, at a given arterial CO2 tension (PaCO2), compared to CBF before VA. This experiment examined the effects of VA to 72 h of normobaric hypoxia [arterial O2 tension (PaO2) approx. 40 mmHg, O2 saturation in arterial blood approx. 50%] on total and regional cerebrovascular resistance (CVR and rCVR) and cerebral O2 extraction fraction (OEF) in 32 conscious sheep. Four different O2-CO2 gas combinations were sequentially administered to each sheep before and after VA. CVR and rCVR were calculated from CBF (radiolabeled microspheres) and arterial and cerebral downstream pressures; OEF was calculated from arterial and cerebral venous O2 contents. After VA, during hyperoxia, CVR and rCVR tended to be lower during both hypocapnia and hypercapnia. During hypoxia, although CVR and rCVR were slightly less during hypocapnia, CVR and rCVR during hypercapnia were surprisingly increased. The post-VA increases in mean CVR and mean rCVR during hypoxic gas combinations differed from the post-VA decreases during hyperoxic gas combinations (0.04 less than or equal to P less than or equal to 0.11). In contrast, although VA decreased OEF during three of four gas combinations (P less than or equal to 0.003), there was a greater mean post-VA decrease in OEF during hypercapnic gas combinations than during hypocapnic gas combinations (P = 0.025); decreases in OEF were correlated with decreases in cerebral O2 consumption. The post-VA CVR responses may reflect altered neurocirculatory control by the arterial chemoreflex; the OEF responses suggest relative cerebral hyperperfusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Acclimatization↗
PubMed1991

Antipyretic activity of tebufelone (NE-11740) in man.

Tebufelone (formerly NE-11740) is a member of the new class of di-tert-butyl-phenol anti-inflammatory agents. It has previously been reported that this new agent has potent analgesic, antipyretic, and anti-inflammatory effects using in vitro, in vivo, and ex vivo experimental models. A randomized, active- and placebo- controlled double-blinded study in 120 healthy males, 20 to 55 years old, was conducted to clinically assess tebufelone's antipyretic activity. Subjects received a single peroral dose of placebo, 650 mg aspirin (ASA), or tebufelone at doses of 25, 50, 100, or 200 mg. Thirty minutes later, E. coli endotoxin (2 ng/kg) was administered intravenously. Oral temperatures were recorded at 15 minute intervals from 30 minutes post dosing to 8 hours post endotoxin administration. Areas under the temperature curves (AUCs), adjusted for baseline, were significantly lower than placebo for ASA and all but the 25 mg tebufelone groups. An AUC dose-response equation estimates 60 mg tebufelone as equivalent to 650 mg ASA, with 50 mg tebufelone not significantly greater than 650 mg ASA. Side effects, attributable to the endotoxin, included mild flu-like symptoms and were worse in the placebo group and the non-efficacious 25 mg tebufelone group. Doses of 100 and 200 mg tebufelone had onset characteristics indistinguishable from 650 mg ASA, whereas 50 mg tebufelone showed significantly slower onset while suppressing temperature for a longer period than ASA. These results provide an important early demonstration of tebufelone's biological activity in man.

Adult↗
PubMed1991

Intracranial pressures and O2 extraction in conscious sheep during 72 h of hypoxia.

High-altitude cerebral edema may occur within several days after a rapid ascent to altitude. However, the mechanisms that produce this potentially lethal condition are unclear. This experiment assessed systemic arterial and intracranial pressures (n = 22) and cerebral blood flow per unit cerebral O2 consumption (Qc/cVo2) and cerebral O2 extraction fraction (cEo2) (n = 9) in conscious sheep before and during 72 h of normobaric hypoxia (arterial O2 tension approximately 40 mmHg, oxygen saturation in arterial blood approximately 50%). Qc/cVo2 and cEo2 were calculated from systemic arterial and cerebral venous O2 contents. Wet-to-dry brain weight ratios were calculated during normoxia (n = 4) or after 72 h of hypoxia (n = 5) in additional sheep. Intracranial pressures did not change during hypoxia (+ 1.3 to +1.8 mmHg, P = 1.0); however, estimated intracranial capillary hydrostatic pressure may have increased 1-20 mmHg depending on the arterial-to-downstream resistance ratio. During the 72 h of hypoxia, Qc/cVO2 doubled (P = 0.02) and cEo2 tended to decrease (5% absolute, P = 1.0). Regional wet-to-dry brain weight ratios after 72 h of hypoxia were 4-13% greater than their respective ratios during normoxia (0.001 less than P less than or equal to 0.05); indirect evidence suggests that this increased brain water content was extravascular. The sheep may be an appropriate model for the further study of high-altitude cerebral edema.

Animals↗
PubMed1989

CO2 reactivity and heterogeneity of cerebral blood flow in ischemic, border zone, and normal cortex.

Regional arterial CO2 tension (PaCO2) reactivity of cerebral blood flow (CBF) and the effect of PaCO2 on the spatial and temporal heterogeneity of CBF were investigated by using autoradiographically determined CBF in the rat middle cerebral artery occlusion model after a 2-h period under pentobarbital anesthesia to clarify the relation between PaCO2 reactivity, CBF heterogeneity, and the temporal cycling of CBF. PaCO2 was adjusted to one of four levels. CBF was determined in four cortical areas and white matter using the tissue fractionation of [14C]iodoantipyrine [( 14C]IAP) in combination with vessel mapping using in vivo 4% thioflavine S. Specific PaCO2 reactivity and CBF were normal in the nonischemic cortex, normal, although slightly depressed, in the border zone far from the ischemic core area, and depressed in the border zone adjacent to the ischemic core area (P less than 0.001) and the ischemic core (P less than 0.001). In normocapnic and hypocapnic animals, CBF heterogeneity in the form of regularly spaced CBF columns perpendicular to the cortical surface was observed in the nonischemic hemisphere but was absent in the ischemic core area. In hypercapnic rats, flow columns were present in the ischemic core areas and border zones but were absent on the nonischemic side. There was a highly significant interaction (P less than 0.0001) in observer-determined heterogeneity grades between PaCO2 level and each of three areas, normal, border zone, and ischemic core. In normal cortex, comparison of the thioflavine S-stained vessels with the flow columns provided evidence supporting the concept of capillary recruitment and cycling as a mode of normal cerebral blood flow control. The presence of flow columns in severely ischemic areas in hypercapnic animals indicates that a short period of high PaCO2 transiently augments microregional flow and could enhance the delivery of a therapeutic agent to these microregions of the ischemic core. The regional analysis of PaCO2 reactivity suggests an index of future tissue viability.

Animals↗
PubMed1986

Effect of pregnancy on the immune response of cattle to a Brucella vaccine.

An experiment was performed to determine whether humoral- or cell-mediated immune responses of cattle to a Brucella abortus vaccine were influenced by the stage of gestation. Heifers were vaccinated 2 mth before and 2 mth after breeding with cell envelopes of B. abortus in an oil adjuvant containing trehalose dimycolate and muramyl dipeptide. Control groups received adjuvant alone or no vaccine. Following breeding, vaccinated animals were divided into pregnant and nonpregnant subgroups. Immune responses to two outer membrane proteins were measured at monthly intervals by ELISA and lymphocyte blastogenesis tests. Skin tests were performed during the ninth month of gestation. Vaccination induced sustained immune responses, but few differences were detected between pregnant and non-pregnant animals. The relative increase in IgA antibodies to group 3 protein in nonpregnant heifers exceeded that in pregnant heifers during months 4 and 6 of gestation (P less than 0.05). Dermal hypersensitivity, measured by changes in double skin thickness, was significantly greater in nonpregnant heifers to porin (P less than 0.01) and group 3 (P less than 0.05) antigens at 24 h post-injection, but no significant differences in skin thicknesses or in the nature of the lesions were observed at 48 h. Animals which received adjuvant alone demonstrated negligible responses. Pregnancy had no significant effect on the responses of lymphocytes to phytohemagglutinin (PHA) or Concanavalin A (Con A). However, plasmas from nonvaccinated pregnant heifers taken during the sixth and seventh (but not eight or ninth) months of pregnancy decreased responses of normal donor cells to PHA and Con A when compared with those in autologous plasma (P less than 0.05).

Animals↗
PubMed1985

Effects of exercise on riboflavin requirements: biological validation in weight reducing women.

The present study was designed to evaluate our previous estimates for riboflavin requirement, 0.96 mg/1000 kcal during nonexercise and 1.16 mg/1000 kcal during exercise in overweight women. Two groups of 6 weight reducing women consumed either 1.16 mg riboflavin/1000 kcal (HR) or 0.96 mg/1000 kcal (MR). The study was two, 3 period by 2 treatment (exercise or nonexercise) crossover designs, one design at each level of riboflavin. Erythrocyte glutathione reductase activity coefficients (AC) significantly increased in both groups from 1.16 +/- .02 to 1.20 +/- .03 in group HR and from 1.31 +/- .04 to 1.36 +/- .02 in the MR group during nonexercise and exercise, respectively. ACs increased in the HR group due to an increase in total enzyme activity while ACs increased in the MR group due to a decrease in basal enzyme activity reflecting decreased flavin availability. There were no differences in aerobic capacity, weight loss, nor change in lean body mass between the two groups. Thus, 0.96 mg/1000 kcal was not adequate during either nonexercise or exercise periods while the 1.16 mg/1000 kcal was adequate.

Adult↗
PubMed1983

Immune response to porin in cattle immunized with whole cell, outer membrane, and outer membrane protein antigens of Brucella abortus combined with trehalose dimycolate and muramyl dipeptide adjuvants.

The immune response of cattle to nonliving vaccines derived from Brucella abortus rough strain 45/20 was studied. Vaccines contained trehalose dimycolate and a derivative of muramyl dipeptide. N-acetylmuramyl-L-alpha-aminobutyryl-D-isoglutamine. A factorial experiment was designed to test the effects of type of antigen, quantity of antigen, and quantity of mineral oil on the immune response to porin. Muramyl dipeptide was kept constant at 5 mg per dose, and 1 part of trehalose dimycolate was incorporated for two parts of dry matter. Over a 10-week period, blastogenesis responses to porin were largest in cattle immunized with outer membranes; the highest antibody titers to the porin-lipopolysaccharide complex were achieved by immunization with detergent-extracted outer membrane proteins. There was no advantage in the use of 25, rather than 5, mg of any of the antigens, but antibody responses were improved by increasing the quantity of oil from 0.6 to 1.8 ml per dose. In other animals, blastogenesis and antibody responses were sustained at high levels longer than 3 months after two vaccinations with outer membrane proteins. Intradermal injection of porin evoked inflammatory reactions histologically consistent with delayed-type hypersensitivity. Cross-reactions in cases of delayed-type hypersensitivity occurred with porin derived from a smooth strain of B. abortus but were less extensive than in the blastogenesis test. The magnitude of the delayed-type hypersensitivity and blastogenesis responses induced by vaccination exceeded those observed after natural or experimental infections. No ill effects were observed after vaccination. These findings provide a basis for the use of trehalose dimycolate and muramyl dipeptide adjuvants in evaluating nonviable vaccines for bovine brucellosis.

Acetylmuramyl-Alanyl-Isoglutamine↗