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PubMed1999

The Range of Impaired Functioning Tool (LIFE-RIFT): a brief measure of functional impairment.

BACKGROUND: The literature documents that functional impairment is associated with affective disorders. Nevertheless, the choice among thorough, yet brief, well-validated assessments of functional impairment is limited. The objective of this study was to evaluate the psychometric properties of a brief scale of functional impairment, the Range of Impaired Functioning Tool (LIFE-RIFT). METHOD: The study sample included subjects who presented with major depressive disorder at intake into the NIMH Collaborative Depression Study (CDS). The LIFE-RIFT is composed of items that are included in the Longitudinal Interval Follow-up Evaluation (LIFE). The reliability and validity were examined using data from LIFE-RIFT assessments conducted at four points in time: 6, 12, 18 and 24 months after intake into the CDS. RESULTS: Cross-sectional one factor models accounted for the covariance structure among the four scale items. A longitudinal factor model, with an invariant factor structure over time, also fitted the data well and indicated that the scale items are measures of one construct, namely functional impairment. The internal consistency reliability of the scale was supported with alpha coefficients ranging from 0.81 to 0.83. The inter-rater reliability intraclass correlation coefficient (ICC) was 0.94. Mixed-effect linear regression models showed that those in episode were significantly more impaired than those in recovery. Furthermore, in analyses of predictive validity, impairment was positively associated with subsequent recurrence and negatively associated with subsequent recovery. CONCLUSIONS: This psychometric evaluation provides empirical support for the reliability and validity of the LIFE-RIFT, a brief measure of functional impairment.

Activities of Daily Living↗
PubMed2003

Population pharmacokinetics of oxaliplatin in patients with metastatic cancer.

Our aim was to develop a population pharmacokinetic model of ultrafilterable oxaliplatin in metastatic cancer patients. Oxaliplatin was administered by 2- or 4-h infusions, 50, 65, 75, 85, 100 or 130 mg/m2 to 56 patients. Blood samples were collected over 28 h. Plasma concentrations of ultrafilterable oxaliplatin were determined by flameless atomic absorption spectrophotometry. Population pharmacokinetic analysis was performed using a non-linear mixed-effects modeling method. Ultrafilterable oxaliplatin concentration-time profiles showed a secondary peak or a shoulder aspect post-infusion, attributed to the existence of an enterohepatic recirculation (EHR). They were best described by a two-compartment model incorporating an EHR component. Plasma clearance (CL) was related positively to body weight (BW) and negatively to serum creatinine (SCr), and was greater in male patients than in female patients. This covariate modeling resulted in a decrease in the interindividual variability for CL from 104 to 62%. The central distribution volume (V1) and inter-compartmental clearance (Q) were related to BW. Typical population estimates of CL, central distribution volume (V1), input rate constant into gallbladder (k1B) and lag time for drug reabsorption (TLAG) were 14.1 or 8.5 l/h (male or female patients), 24.9 l, 1.8 h-1 and 2.0 h, respectively. The final pharmacokinetic model was validated using 200 bootstrap samples of the original data. We conclude that a two-compartment with EHR model adequately described ultrafilterable oxaliplatin pharmacokinetics, explaining a secondary transient increase in concentration. This study identified combined-covariate-effects ultrafilterable oxaliplatin clearance, supporting dose adjustment of oxaliplatin based on BW, gender and corrected for SCr level, if drug exposure is thought to be related to therapeutic or toxic issues.

Adult↗
PubMed2003

Temporal changes in cytokine expression of foals during the first month of life.

Foals are uniquely susceptible to a wide variety of opportunistic infections normally associated with immunodeficiencies. Little is understood about the immune system of foals during the neonatal period. An apparent age-related susceptibility predisposes neonatal foals to infectious diseases and hinders therapeutic and preventative interventions for these diseases. Cytokine expression is correlated with the type of immune response as well as the severity of a disease. In this study, we measured foal peripheral blood mononuclear cell (PBMC)-specific mRNA cytokine expression from 72 foals from three different farms during the first 4 weeks of life. Interleukin-1alpha (IL-1alpha), IL-1beta, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p35, IL-12p40, interferon-gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha), and transforming growth factor-beta1 (TGF-beta1) were cloned and transcribed in vitro to generate antisense probes for ribonuclease protection assays. Using linear mixed-effect models, we determined that IFN-gamma, TGF-beta1, and IL-1alpha increased significantly (P<0.05) with age.

Age Factors↗
PubMed2004

Therapeutic strategies using the aromatase inhibitor letrozole and tamoxifen in a breast cancer model.

BACKGROUND: The antiestrogen tamoxifen has potent activity against estrogen receptor-positive breast cancer, but two nonsteroidal aromatase inhibitors, letrozole and anastrozole, show considerable advantages over tamoxifen with respect to patient survival and tolerability. To determine the optimal way to use letrozole and tamoxifen, we studied their effects on a breast tumor xenograft model, MCF-7Ca, that is responsive to both antiestrogens and aromatase inhibitors. METHODS: Female ovariectomized BALB/c athymic nude mice carrying xenograft tumors were treated daily subcutaneously with one of the following first-line therapies for varying durations: no drug (control), tamoxifen (100 microg/day) alone, letrozole (10 microg/day) alone, both drugs at the same time, or alternating 4-week courses of each drug (beginning with a course of tamoxifen or beginning with a course of letrozole). Tumor volumes and weights were estimated using linear mixed-effects models. The time to tumor doubling was calculated, and tumor weights in the treatment groups were compared, with adjustments for multiple comparisons being made with either Tukey's or Dunnett's procedure. Second-line therapies (with tamoxifen, letrozole, or fulvestrant) were initiated when tumors doubled in size under first-line therapies. All statistical tests were two-sided. RESULTS: The times for doubling of tumor volume were as follows: control, 3-4 weeks; tamoxifen alone, 16 weeks; tamoxifen alternating with letrozole, 17-18 weeks; tamoxifen plus letrozole, 18 weeks; letrozole alternating with tamoxifen, 22 weeks; letrozole alone, 34 weeks. First-line treatment with letrozole was superior to treatment with tamoxifen alone or with the two drugs combined (at week 16, both P<.001). Alternating tamoxifen and letrozole and alternating letrozole and tamoxifen were also not as effective as letrozole alone (at week 16, P =.002 and P<.001, respectively). Tumors progressing on tamoxifen remained sensitive to second-line therapy with letrozole compared with those remaining on tamoxifen at the end of treatment (week 28, P<.001), whereas tumors progressing on letrozole were unaffected by second-line treatment with the antiestrogens tamoxifen or fulvestrant. CONCLUSIONS: First-line letrozole therapy extends time for tumor progression in this model relative to the other treatment regimens tested. However, further studies are needed to determine the most effective second-line therapy for tumors that progress on letrozole.

Animals↗
PubMed2004

Modeling facial movement: I. A dynamic analysis of differences based on skeletal characteristics.

PURPOSE: To introduce a novel approach to analyze and model facial movements; and to quantify variations in facial movement caused by the extent of skeletal differences between the maxilla and mandible and the middle to lower facial heights. The hypothesis was that there are differences in facial movement related to the underlying facial skeleton which may be explained by the shape of the face rather than the pattern of movement. PATIENTS AND METHODS: The study sample consisted of 43 subjects (23 men, 20 women) with a mean age of 18.5 years (SD = 11.90). Measures of the facial skeletal differences were made from lateral cephalometric radiographs, and subjects were classified as Class I and Class II, and normal to decreased lower anterior face height, respectively. Facial movements were recorded by a video-based tracking system. Descriptive and inferential statistics were performed on principal component scores generated from the movement data. A linear mixed-effects model was used to test for significant differences in movement among the different skeletal types. RESULTS: A dynamic modeling of facial movements was described that has numerous potential clinical applications. Also, differences in movement were found during the lip purse movement. Specifically, skeletal Class I individuals showed greater forward and upward movement during lip purse compared with individuals with severe skeletal Class II who moved their lips straight forward with less magnitude of movement. CONCLUSION: For most of the movements, apart from the lip purse, differences in motion were explained by static facial shape.

Adolescent↗
PubMed2004

The effect of temperature, humidity and peak inspiratory nasal flow on olfactory thresholds.

Temperature, humidity and nasal peak inspiratory flow rate (PIFR) are potential variables in the quantitative measurement of olfactory thresholds in the clinic. To date, these variables have not been properly evaluated with respect to olfactory perception, and therefore the aim of this study was to determine their effect on the thresholds. These variables were measured on 10 occasions in 10 subjects over a 10-week period. The results obtained were then subjected to statistical analysis using a linear mixed-effect model. This demonstrated that olfactory thresholds are sufficiently independent of room temperature, peak humidity and nasal PIFR in a routine outpatient clinic environment in normal subjects, with no evidence of any statistically significant influence by these variables.

Adult↗
PubMed2004

Modeling facial movement: II. A dynamic analysis of differences caused by orthognathic surgery.

PURPOSE: The purpose of this study was to determine the facial movement characteristics of patients who underwent orthognathic surgery. The specific aims were to determine the presurgery versus postsurgery differences in facial movements; to determine whether the presurgery facial movements were similar among patients with different dentofacial deformities; and to determine whether patients have a more similar post- than presurgery dentofacial morphology and soft tissue movement. The hypothesis was that there are differences between the pre- and postsurgery facial movements. PATIENTS AND METHODS: The sample consisted of 19 patients (11 women, 8 men) with a mean age of 20.6 years (SD +/- 8.34). Facial movement and lateral cephalometric data were collected at presurgery, and at 6 and 12 months postsurgery. Measures of the facial skeletal differences were made from lateral cephalometric radiographs and facial movements were recorded by a video-based tracking system. Descriptive and inferential statistics were performed on principal component scores generated from the movement data. A linear mixed-effects model was used to test for significant differences in movement. RESULTS: Differences were found between the presurgery and 12-month postsurgery visits for the instructed smile, lip purse, eye closure, grimace, and mouth opening movements as well as the natural smile. Also, there were significant differences at presurgery among the dentofacial groups for the lip purse movement but no differences were found at postsurgery for any of the movements. CONCLUSION: These findings suggest that facial movements are effected by skeletal malocclusion and orthognathic surgical procedures.

Adult↗
PubMed2002

Cyclosporin A in blood and brain tissue following intra-carotid injections in normal and stroke-induced rats.

Administration of Cyclosporin A (CsA) to rats undergoing reversible global or focal ischemia has been demonstrated to be variably neuroprotective. As CsA does not readily cross the blood-brain barrier, the variability may be due to differences in bioavailability of CsA to the ischemic brain. We have, therefore, quantitated CsA levels in blood and brain following intra-carotid injection in rats undergoing permanent right middle cerebral artery (MCA) occlusion using a three-vessel model of focal cerebral ischemia. After 30 min of three-vessel occlusion, CsA (10 mg/kg) was injected into the left external carotid artery followed by reversal of the left common carotid artery occlusion. At various times post-injection, blood samples were collected from the vena cava and samples of ischemic or sham-operated cortex were obtained for CsA quantitation by tandem mass spectrometry. Pharmacokinetic parameters were determined using non-linear mixed-effects modeling. CsA areas under the curve between normal and stroke-induced rats were not significantly different in blood (18355 vs. 19405 ng x h/ml, NS) or in brain tissue (15664 vs. 14931 ng x h/g, NS). These results demonstrate that intra-carotid injection of CsA results in high levels in brain (brain-blood ratio from 0.5 to 1). No significant differences in blood and brain exposure were observed between normal and stroke-induced rats. Therefore, reduced cerebral blood flow in the ischemic territory did not limit CsA availability to the cortex. In addition, CsA intra-carotid administration was neuroprotective following 24 h recovery as there was a significant decrease in the infarct area of the affected hemisphere compared to saline injected rats as estimated by TTC staining of viable tissue.

Animals↗
PubMed1999

Modelling long-term persistence of hepatitis B antibodies after vaccination.

Antibody response to hepatitis B vaccination was measured in 97 institutionalized, mentally handicapped patients after a 0-, 1-, 6-month vaccination schedule. Two groups were formed at month 7 according to the antibody response, which determined whether they needed an additional vaccine dose at month 12, to achieve an antibody titre of 100 IU/liter. All residents were followed up yearly for the first 5 years, after which, they received another booster dose. Another blood sample was taken 11 years after the start of the program. A linear mixed-regression model was used to analyze the data. Random and fixed effects were included to determine the generally known risk factors and the still unknown individual characteristics that influence the titre of hepatitis B surface antibodies (anti-HBs). The mean anti-HBs titre was a function of time, type of mental retardation (Down's syndrome or other types of mental retardation), the use of antiepileptic drugs, and the additional booster at month 12. The immediate and vigorous response of the immune system to booster vaccination shows that the immunologic memory is good after primary vaccination. For the maintenance of protection, the recommendation for mentally retarded patients in institutions is vaccination of all seronegative residents as well as new entrants, after which, no additional boosters will be necessary.

Anticonvulsants↗
PubMed2006

Towards a noninvasive method for determination of patient-specific wall strength distribution in abdominal aortic aneurysms.

The spatial distributions of both wall stress and wall strength are required to accurately evaluate the rupture potential for an individual abdominal aortic aneurysm (AAA). The purpose of this study was to develop a statistical model to non-invasively estimate the distribution of AAA wall strength. Seven parameters--namely age, gender, family history of AAA, smoking status, AAA size, local diameter, and local intraluminal thrombus (ILT) thickness--were either directly measured or recorded from the patients hospital chart. Wall strength values corresponding to these predictor variables were calculated from the tensile testing of surgically procured AAA wall specimens. Backwards-stepwise regression techniques were used to identify and eliminate insignificant predictors for wall strength. Linear mixed-effects modeling was used to derive a final statistical model for AAA wall strength, from which 95% confidence intervals on the model parameters were formed. The final statistical model for AAA wall strength consisted of the following variables: sex, family history, ILT thickness, and normalized transverse diameter. Demonstrative application of the model revealed a unique, complex wall strength distribution, with strength values ranging from 56 N/cm2 to 133 N/cm2. A four-parameter statistical model for the noninvasive estimation of patient-specific AAA wall strength distribution has been successfully developed. The currently developed model represents a first attempt towards the noninvasive assessment of AAA wall strength. Coupling this model with our stress analysis technique may provide a more accurate means to estimate patient-specific rupture potential of AAA.

Aging↗
PubMed2004

The time-dependent distribution of phosphorylated intermediates in native sarcoplasmic reticulum Ca2+-ATPase from skeletal muscle is not compatible with a linear kinetic model.

Quenched-flow mixing was used to characterize the kinetic behavior of the intermediate reactions of the skeletal muscle sarcoplasmic reticulum (SR) Ca-ATPase (SERCA1) at 2 and 21 degrees C. At 2 degrees C, phosphorylation of SR Ca-ATPase with 100 microM ATP labeled one-half of the catalytic sites with a biphasic time dependence [Mahaney, J. E., Froehlich, J. P., and Thomas, D. D. (1995) Biochemistry 34, 4864-4879]. Chasing the phosphoenzyme (EP) with 1.66 mM ADP 10 ms after the start of phosphorylation revealed mostly ADP-insensitive E2P (95% of EP(total)), consistent with its rapid formation from ADP-sensitive E1P. The consecutive relationship of the phosphorylated intermediates predicts a decrease in the proportion of E1P ([E1P]/[EP(total)]) with increasing phosphorylation time. Instead, after 10 ms the proportion of E1P increased and that of E2P decreased until they reached a constant 1:1 stoichiometry ([E1P]:[E2P] approximately 1). At 21 degrees C, phosphorylation displayed a transient overshoot associated with an inorganic phosphate (P(i)) burst, reflecting increased turnover of E2P at the higher temperature. The P(i) burst exceeded the decay of the EP overshoot, suggesting that rephosphorylation of the enzyme occurs before the recycling step (E2 --> E1). This behavior and the reversed order of accumulation of phosphorylated intermediates at 2 degrees C are not compatible with the conventional linear consecutive reaction mechanism: E1 + ATP --> E1.ATP --> E1P + ADP --> E2P --> E2.P(i) --> E1 + P(i). Solubilization of the Ca-ATPase into monomers using the nonionic detergent C(12)E(8) gave a pattern of phosphorylation in which E1P and E2P behave like consecutive intermediates. Kinetic modeling of the C(12)E(8)-solubilized SR Ca-ATPase showed that it behaves according to the conventional Ca-ATPase reaction mechanism, consistent with monomeric catalytic function. We conclude that the nonconforming features of native SERCA1 arise from oligomeric protein conformational interactions that constrain the subunits to a staggered or out-of-phase mode of operation.

Adenosine Diphosphate↗
PubMed2001

Changes in time-trends of nutrient intake from fortified and non-fortified food in German children and adolescents--15 year results of the DONALD study. Dortmund Nutritional and Anthropometric Longitudinally Designed Study.

BACKGROUND: Although fortified products have played an increasing role in food marketing since the 1980s in Germany, data as to the consumption of fortified food is sparse. AIM OF THE STUDY: To assess long-term data on changes in fortified food supply or consumption patterns, nutrient intake, and time trends in the DONALD Study (Dortmund Nutritional and Anthropometric Longitudinally Designed Study). METHODS: Between 1985 and 2000 consumption of nutrient intake (total and from fortified foods) was evaluated and time trends in energy and nutrient intake were assessed on the basis of 3-day weighed dietary records (n = 4193) of 2-14 year-old males (n = 383) and females (n = 404) enrolled in the DONALD Study. Nutrient intake was expressed as percentage of the current German recommendations. Food products were defined as fortified if enriched with at least one of the following nutrients: Vitamin A or provitamin A carotenoids (summarised as Vitamin A), Vitamins E, B1, B2, B6, C, niacin, folate, calcium or iron. Nutrient supplements and medicine were excluded from this evaluation. Time trends were analysed using linear and non-linear regression models (PROC MIXED, SAS 6.12). RESULTS: In percent of German references [3], non-fortified food contributed to folate intake by 20-30%, to Vitamin E by about 40%, to Vitamin B1 by 50-65%, to Vitamin A, C, B2, calcium, iron by about 65-95%, and to Vitamin B6 and niacin intake by 100% and more. Fortified food alone provided no more than 5% of calcium intake, about 10-20% of iron, Vitamin A and folate intake, up to 40-50% of Vitamin C, B1, B2, E, niacin and up to 80% of Vitamin B6 intake. During the 15 year period of the DONALD Study with total food, we only found a significant linear time trend for Vitamin C, whereas significant non-linear time trends were found for calcium, Vitamin E, B1, B2, B6, niacin and folate. In the latter there was a uniform increase until 1994 and a decrease thereafter. For iron and Vitamin A no significant time trend could be identified. Only iron and Vitamin A intake from fortified food showed a significant linear time trend. All other nutrients studied here gave significant non-linear time trends. Nutrient intake with fortified food reached maximum values between 1994 and 1996 followed by a decrease thereafter. CONCLUSIONS: Signs of changing food consumption patterns were found, pointing to an almost uniform decrease of nutrient intake since 1994/96 in our population of German children and adolescents. This could be an alarming indicator of a slight but unpreferable tendency to eat energydense, nutrient-poor foods.

Adolescent↗
PubMed2001

Evaluation of clinical and clinical chemical parameters in periparturient cows.

Certain blood parameters and clinical symptoms have been connected with milk fever and a hypocalcemic condition in the cow. The present study intended to establish a mutual connection between relevant blood parameters and potentially valuable background information about the cow and its observed clinical symptoms at calving. Two veterinarians were summoned within 12 h of parturition of 201 cows, distributed among 41 Danish commercial herds. Cows were at different parity levels (2 to 10) and breeds and management differed broadly among herds. A blood sample was taken from the vena jugularis or the tail vein and was subsequently analyzed in the laboratory. Furthermore, 13 different clinical symptoms were recorded as categorical data. We investigated associations among the data obtained. We assessed an interpretative model for actual blood calcium level with blood parameters and background knowledge of the animals. We established a path analysis using background knowledge, blood parameters, and results of clinical examinations to uncover causal connections among the variables. Twenty-six percent of the animals were diagnosed as having milk fever and subsequent blood analyses revealed a high frequency of hypocalcemia within the general range from 0.69 to 2.73 mmol of Ca per liter. Rectal temperature, inorganic blood phosphate, and potassium were all directly correlated with blood calcium, while glucose, lactate, and magnesium were inversely associated with calcium. Blood osteocalcin was significantly lower in hypocalcemic animals, indicating that de novo synthesis of bone was arrested during hypocalcemia. A mixed effect linear interpretative model explained 75% of the variation in blood calcium. Clinical symptoms like mood, appetite, muscle shivering, rumen motility, and paresis were individually correlated with blood calcium and were thereby predictive of hypocalcemia. The path analysis showed the central role of calcium in affecting the clinical symptoms. However, several other factors contributed to hypocalcemia.

Animals↗
PubMed2004

Tonotopic organization of the human auditory cortex probed with frequency-modulated tones.

Using neuromagnetic source imaging, we investigated tonotopic representation and direction sensitivity in the auditory cortex of humans (N = 15). For this purpose, source analysis was undertaken at every single sampling point during the presentation of a frequency-modulated tone (FM) sweeping slowly downward or upward across periods of 3 s duration. Stimuli were selected to target response properties of the central part of the primary auditory cortical field, which has been shown to exhibit sensitivity to distinct FM-sound features as compared to the ventral and dorsal part. Linear mixed-effects model statistics confirm tonotopic gradients in medial-lateral and anterior-posterior directions. The high resolution provided by this method revealed that the relationship between frequency and spatial location of the responding neural tissue is nonlinear. The idea that neurons specifically sensitive to the employed sound characteristics (slow, downward modulation) were activated is supported by the fact that the upward sweep of identical duration produced a different pattern of functional organisation.

Acoustic Stimulation↗
PubMed2000

Rank power of metrics used to assess QTc interval prolongation by clinical trial simulation.

Monte Carlo simulation was used to assess the type I error rate and rank order of power for six different metrics using linear mixed-effect models, including two variables recommended by the European Agency for the Evaluation of Medicinal Products (EMEA) in the analysis of QTc interval data. The metrics analyzed were maximal change in QTc interval from baseline, maximal QTc interval, area under the QTc interval-time curve (AUC), average QTc interval, maximal QTc interval with baseline QTc interval as covariate, and AUC with baseline QTc interval as covariate. Two dosing regimens were studied: multiple-dose oral and multiple-dose continuous intravenous infusion. Both regimens were designed to produce similar maximal plasma concentrations, albeit with the infusion regimen maintaining maximal plasma concentrations for a longer period of time. The ability of the metrics to detect a drug effect was examined, assuming drug effect followed either an Emax or linear model. All statistics had a type I error rate near the nominal value. Regardless of pharmacokinetic or pharmacodynamic model, AUC with baseline QTc interval as a covariate had greater power than any other metric examined. The simulations also suggest that mean QTc interval data not be used.

Administration, Oral↗
PubMed2006

A population pharmacokinetic/pharmacodynamic analysis of regadenoson, an adenosine A2A-receptor agonist, in healthy male volunteers.

OBJECTIVES: The aims of this study were to investigate the safety, tolerability, pharmacokinetics and pharmacodynamics of regadenoson (CVT-3146) in healthy, male volunteers. METHODS: Thirty-six healthy, male volunteers aged 18-50 years were included in this randomised, double-blind, crossover, placebo-controlled study to evaluate single intravenous bolus doses of regadenoson that ranged from 0.1 to 30.0 micro g/kg. Subjects received one dose of regadenoson or placebo on successive days while supine, then the same dose of regadenoson or placebo on successive days while standing. As part of the safety evaluation, vital signs and adverse events were monitored and recorded throughout the course of the study in all subjects. Up to 20 plasma samples were collected for regadenoson concentration determination within the 24 hours after each supine dosage. All urine was collected during the 24-hour time period post-dose and an aliquot was used for the determination of the regadenoson concentration. Heart rate and blood pressure were recorded at many of the same timepoints that the samples for the pharmacokinetic analysis were taken. A non linear mixed-effect modelling approach, using the software NONMEM, was utilised in modelling the plasma and urine concentration-time profiles and temporal changes in heart rate after regadenoson administration in the supine position. The influences of several covariates, including bodyweight, body mass index and age, on pharmacokinetic model parameters were investigated. RESULTS: Adverse events were more prevalent at regadenoson doses above 3 micro g/kg, and the increase in the occurrence of adverse events was dose-related. Most of the adverse events were related to vasodilation and an increase in heart rate and were generally of mild to moderate severity. Based on the severity and frequency of adverse events, the maximum tolerated doses of regadenoson were deemed to be 10 micro g/kg in the standing position and 20 micro g/kg in the supine position. The pharmacokinetics of regadenoson were successfully described by a three-compartment model with linear clearance. Following intravenous bolus dose administration, regadenoson was rapidly distributed throughout the body, followed by relatively slower elimination (terminal elimination half-life of approximately 2 hours). The clearance was estimated to be 37.8 L/h, with renal excretion accounting for approximately 58% of the total elimination. The volume of distribution of the central compartment and the volume of distribution at steady state were estimated to be 11.5L and 78.7L, respectively. Individual pharmacokinetic parameter estimates were fixed in the pharmacodynamic model, where changes in heart rate were related to plasma drug concentrations using a Michaelis-Menten model. The maximum heart rate increase (Emax) and plasma regadenoson concentration causing a 50% increase in the maximum heart rate (EC50) were estimated to be 76 beats per minute and 12.3 ng/mL, respectively. None of the tested covariates was found to be correlated with any of the pharmacokinetic model parameters. CONCLUSIONS: The pharmacokinetics and the effects of regadenoson on heart rate were successfully described using pharmacokinetic/pharmacodynamic modelling. The lack of a correlation between the model estimates and various baseline patient demographics supports unit-based dose administration of regadenoson.

Adenosine A2 Receptor Agonists↗
PubMed2004

Clinical ototoxicity of teicoplanin.

No strong evidence of ototoxicity of teicoplanin can be found in the literature, possibly because of conservative definitions of ototoxicity. We performed audiometry over time to compare the ototoxicity of teicoplanin with that of cloxacillin as a non-ototoxic standard. The data were analyzed with a linear mixed-effects model. The hearing thresholds of 12 patients who were treated with teicoplanin for severe staphylococcal infections showed a slight but significant increase over time, whereas the thresholds of 5 patients treated with cloxacillin decreased significantly during treatment. This improvement in hearing with cloxacillin may be attributed to improvement of the clinical condition. This outcome implies that previous reports that suggest a lack of ototoxicity of teicoplanin potentially underestimate the risk and should be interpreted accordingly.

Anti-Bacterial Agents↗
PubMed2005

Evaluation of recombinant human bone morphogenetic protein-2 on the repair of alveolar ridge defects in baboons.

BACKGROUND: The objective of this study was to evaluate alveolar ridge augmentation following surgical implantation of recombinant human bone morphogenetic protein-2 (rhBMP-2) using two novel space-providing carrier technologies in the baboon (Papio anubis) model. METHODS: Standardized alveolar ridge defects ( approximately 15 x 8 x 5 mm) were surgically produced in maxillary and mandibular edentulous areas in four baboons. The defect sites were implanted with rhBMP-2 (0.4 mg/mL) in a tricalcium phosphate/hydroxyapatite/ absorbable collagen sponge composite (TCP/HA/ACS) or calcium phosphate cement (alpha-BSM). Control treatments were TCP/HA/ACS and ?-BSM without rhBMP-2 and sham surgery. Stainless steel pins were placed at the mid-apical and coronal level of the defect sites to provide landmarks for clinical measurements pre- and post-implantation. Impressions were obtained pre- and postimplantation to determine changes in alveolar ridge volume. Radiographic registrations were obtained pre- and post-implantation. Block sections of the defect sites were harvested at week 16 postimplantation and processed for histometric analysis including new bone area and bone density. Statistical comparisons between treatments were made using a mixed effect generalized linear model using least squares estimation. RESULTS: The carrier systems without rhBMP-2 provided a modest ridge augmentation. The addition of rhBMP-2 resulted in an almost 2-fold increase in alveolar ridge width, including a greater percentage of trabecular bone and a higher bone density compared to controls (P < or =0.05) without significant differences between the two rhBMP-2 protocols. CONCLUSIONS: TCP/HA/ACS and alphaBSM appear to be suitable carrier technologies for rhBMP-2. Alveolar augmentation procedures using either technology combined with rhBMP-2, rather than stand-alone therapies, may provide clinically relevant augmentation of alveolar ridge defects for placement of endosseous dental implants.

Absorbable Implants↗