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Selected AbstractsMoxonidine improves glycaemic control in mildly hypertensive, overweight patients: a comparison with metforminDIABETES OBESITY & METABOLISM, Issue 4 2006Irina Chazova Aim:, To compare the effects of moxonidine and metformin on glycaemic control in patients with impaired glucose tolerance and signs of the metabolic syndrome. Methods:, A multicentre, prospective, randomized, open-label study design was adopted with blinded endpoint evaluation. Patients ,40 years old, with impaired glucose tolerance (or diabetes mellitus treated with diet alone) and a body mass index (BMI) of at least 27 kg/m2 were treated twice daily with moxonidine 0.2 mg or metformin 500 mg for 16 weeks. Oral glucose tolerance test (OGTT) was performed at baseline and end-of-study; plasma insulin and plasma glucose levels were measured at 0, 60, 120 and 180 min after administration. Results:, With regard to effects on insulin [mean area under the curve (AUC) for insulin], the primary efficacy endpoint of the study, both drugs did not show equivalence. On the contrary, in the per protocol (PP) population, moxonidine statistically significantly (p = 0.025) decreased the AUC for insulin from baseline in the PP population; for metformin, the treatment effect on insulin was a small, net increase resulting in a statistically significant between-group difference of 16.2% (95% CI = 0.1,35.0). The change in mean insulin AUC was most marked in the subgroup of patients with higher sympathetic activity (heart rate >80 bpm). Mean fasting plasma glucose (FPG) levels and HbA1c levels were largely unchanged by moxonidine treatment but significantly decreased by metformin treatment. The difference between the groups was 14.7% (p = 0.0523) in the intent-to-treat (ITT) sample. By study end, both treatments had significantly increased the Matsuda Insulin Sensitivity Index (ISI) from baseline to a comparable extent: moxonidine by reducing plasma insulin after a glucose challenge, metformin by reducing FPG. BMI fell significantly in both groups and blood pressure normalized; both drugs were well tolerated. Conclusions:, Moxonidine improved insulin sensitivity in response to glucose challenge in patients with evidence of metabolic syndrome. This improvement resulted from a reduction in plasma insulin levels and was most marked in patients with high sympathetic drive at baseline. By enhancing insulin sensitivity, moxonidine treatment may help prevent the development of diabetes and thereby ameliorate the risk for cardiovascular disease. [source] Glibenclamide improves postprandial hypertriglyceridaemia in Type 2 diabetic patients by reducing chylomicrons but not the very low-density lipoprotein subfraction levelsDIABETIC MEDICINE, Issue 10 2001I. Skrapari Abstract Aim, There are scarce data dealing with the degree of postprandial lipaemia after sulphonylurea administration. The aim of this study was to examine the effect of acute glibenclamide administration on postprandial lipaemia in Type 2 diabetic patients. Methods, Eight randomly selected Type 2 diabetic individuals, aged 43,65 years (mean, 54 years), who had never received any anti-diabetic drug, were included in the study. Each patient was given a 485 kcal mixed meal (45% fat, 40% carbohydrate and 15% protein) twice on separate days after an overnight fast: once with placebo and once with 5 mg glibenclamide, per os, in a random order. The two tests were performed with an interval of 7 days. Venous blood samples were drawn just before and 2 h, 4 h and 6 h after meal consumption. Total triglyceride levels in plasma, in chylomicrons (CM), in CM-deficient plasma, in very low-density lipoprotein (VLDL) subfractions (VLDL-1, VLDL-2) and in intermediate-density lipoprotein (IDL) were determined. Free fatty acid (FFA) and total cholesterol levels in plasma, as well as high-density lipoprotein (HDL) cholesterol and low-density lipoprotein (LDL) cholesterol levels in CM-deficient plasma, were also measured. Finally, serum glucose, insulin and C-peptide concentrations were measured in each sample. Results, As expected there was a significant decrease in postprandial glycaemia after glibenclamide administration compared to placebo (mean area under the curve values: AUC = 53.3 ± 18.2 and 69.1 ± 21.6 mm/h, P = 0.00009). In addition, the mean AUC values of insulin and C-peptide were significantly greater after drug administration. The AUC values of total plasma triglyceride and of CM triglyceride following glibenclamide administration were significantly lower compared to placebo, while the AUC values of postprandial triglyceride in CM-deficient plasma and of postprandial triglyceride in VLDL-1, VLDL-2 and IDL were not different after drug administration compared to placebo. Finally, no significant differences were noted in the AUC values of total cholesterol, LDL cholesterol, HDL cholesterol and plasma FFA levels after glibenclamide administration. Conclusions, These results demonstrate that glibenclamide administration improves postprandial hypertriglyceridaemia acutely by reducing postprandial triglycerides of intestinal origin. Diabet. Med. 18, 781,785 (2001) [source] Landslide inventories and their statistical propertiesEARTH SURFACE PROCESSES AND LANDFORMS, Issue 6 2004Bruce D. Malamud Abstract Landslides are generally associated with a trigger, such as an earthquake, a rapid snowmelt or a large storm. The landslide event can include a single landslide or many thousands. The frequency,area (or volume) distribution of a landslide event quanti,es the number of landslides that occur at different sizes. We examine three well-documented landslide events, from Italy, Guatemala and the USA, each with a different triggering mechanism, and ,nd that the landslide areas for all three are well approximated by the same three-parameter inverse-gamma distribution. For small landslide areas this distribution has an exponential ,roll-over' and for medium and large landslide areas decays as a power-law with exponent -2·40. One implication of this landslide distribution is that the mean area of landslides in the distribution is independent of the size of the event. We also introduce a landslide-event magnitude scale mL = log(NLT), with NLT the total number of landslides associated with a trigger. If a landslide-event inventory is incomplete (i.e. smaller landslides are not included), the partial inventory can be compared with our landslide probability distribution, and the corresponding landslide-event magnitude inferred. This technique can be applied to inventories of historical landslides, inferring the total number of landslides that occurred over geologic time, and how many of these have been erased by erosion, vegetation, and human activity. We have also considered three rockfall-dominated inventories, and ,nd that the frequency,size distributions differ substantially from those associated with other landslide types. We suggest that our proposed frequency,size distribution for landslides (excluding rockfalls) will be useful in quantifying the severity of landslide events and the contribution of landslides to erosion. Copyright © 2004 John Wiley & Sons, Ltd. [source] CLINICAL STUDY: Effect of saquinavir/ritonavir (1000/100 mg bid) on the pharmacokinetics of methadone in opiate-dependent HIV-negative patients on stable methadone maintenance therapyADDICTION BIOLOGY, Issue 3 2009Candice Jamois ABSTRACT This study was performed to determine the effect of two protease inhibitors, saquinavir (SQV, oral 1000 mg bid) boosted by ritonavir (RTV, oral 100 mg bid), on pharmacokinetics (PK) of methadone in opiate-dependent HIV-negative patients on stable methadone maintenance therapy. This was a two-center, open-label, one-sequence cross-over, multiple-dose study in 13 HIV-negative patients who were on stable methadone therapy (oral, 60,120 mg qd). All patients continued methadone treatment on days 2,15. All patients received SQV/RTV in combination with methadone from days 2,15. PK of methadone was assessed on day 1 (alone) and on day 15 when methadone treatment was combined with SQV/RTV at steady state. Twelve patients completed the study. Median age, body weight and height were 50 years (range: 24,54 years), 80 kg (range: 57,97 kg) and 174 cm (range: 163,189 cm), respectively. All patients were Caucasian, and 11 were smokers. Median methadone dose was 85 mg qd. Geometric mean area under curve of the plasma concentration-time curve over 24 hour dosing interval (AUC0,24 hour) ratio of methadone with and without SQV/RTV was 0.81% (90% confidence interval: 71,91%). There was no significant plasma protein-binding displacement of methadone by SQV/RTV. The combination of SQV/RTV and methadone was well tolerated. There were no clinically significant adverse events or significant changes in laboratory parameters, electrocardiograms or vital signs. The 19% decrease in R-methadone AUC0,24 hour in the presence of SQV/RTV was not clinically relevant. There appears to be no need for methadone dose adjustment when methadone (60,120 mg qd) and SQV/RTV (1000/100 mg bid) are coadministered. [source] Interleukin-1 gene polymorphisms and experimental gingivitisJOURNAL OF CLINICAL PERIODONTOLOGY, Issue 2 2003Søren Jepsen Abstract Background: Recently, an association between the severity of periodontitis and specific variations in the interleukin-1 (IL1) , and , genes has been demonstrated. Aim: The purpose of this study was to evaluate the relationship of the IL1 genotype to the development of experimental gingivitis. Materials and Methods: Twenty young adult subjects presenting with healthy gingival conditions participated after giving their informed consent. The group included 10 risk genotype positive (P+) and 10 risk genotype negative (P,) individuals. The IL1 genotypes were determined on DNA samples from peripheral blood using PCR-RFLP analyses for the IL1, and IL1, polymorphisms. Experimental gingivitis was allowed to develop in two posterior sextants per subject. Bleeding on probing (BOP%) and gingival crevicular fluid volume (GCF) were assessed at baseline and days 2, 7, 9, 14, 16 and 21. The day 21 results for BOP and GCF as well as the rate of increase of these parameters , mean area under the curve (AUC) and mean increase per day (slope) , were evaluated using risk analyses for IL1 genotype, smoking status and gender. Results: Experimental gingivitis developed with a gradual increase in BOP scores and GCF values (expressed as Periotron units=PU) from baseline to day 21 (BOP, P+: 0.5 to 26.0%; P,: 1.0 to 28.1%; GCF, P+: 36.8 to 138.5 PU, P,: 43.1 to 143.4 PU). No significant risk was associated with P+ and P, for day 21 results, AUC or slope. Conclusion: The results of this study failed to provide evidence that the IL1 risk genotype was associated with higher GCF volume and percentage BOP during the development of experimental gingivitis. Zusammenfassung Hintergrund: Kürzlich ist eine Beziehung zwischen dem Schweregrad von Parodontitis und speziellen Varianten der Interleukin-1 (IL1),- und -,-Gene gezeigt worden. Zielsetzung: Untersuchung des Zusammenhanges zwischen dem ILl-Genotyp und der Entwicklung einer experimentellen Gingivitis. Material und Methoden: 20 junge Erwachsene mit gesunden parodontalen Verhältnissen, von denen 10 für den Risikogenotyp positiv (P+) und 10 negativ (P-) waren, nahmen an der Studie teil, nachdem sie ihr Einverständnis dazu gegeben hatten. Die IL1 -Genotypen wurden aus DNS-Proben aus peripherem Blut mittels PCR-RFLP-Analyse auf ILl,- und IL1/,-Polymorphismen untersucht. In 2 Seitenzahnsextanten ließ jeder Proband eine experimentelle Gingivitis entwickeln. Bluten auf Sondieren (BOP%) und Sulkiksfiüssigkeitsvolumen (SFV) wurden zu Beginn der Studie und nach 2, 7, 9, 14, 16 und 21 Tagen bestimmt. Sowohl die Ergebnisse für BOP und SFV an Tag 21 als auch die Zunahme dieser Werte , mittlere Fläche unter der Kurve (AUC) und mittlere Zunahme pro Tag (Steigung) , wurden mittels Risikoanalyse fur IL1 -Genotyp, Rauchen und Gescnlecht bestimmt. Ergebnisse: Die experimentelle Gingivitis entwickelte sich mit einem stetigen Anstieg der BOP- und SFV-Werte (ausgedrückt als Periotroneinheiten=PU) vom Beginn der Studie bis zum 21. Tag (BOP, P+: 0,5% to 26,0%, P-: 1,0% to 28,1%; GCF, P+: 36,8 to 138,5 PU, P-: 43,1 to 143,4 PU). Mit P+und P- war kein signifikantes Risiko für die Werte am 21. Tag, die AUC oder die Steigung verbunden. Schlussfolgerung: Die Ergebnisse dieser Studie konnten keine Beziehung zwischen dem IL1 -Risikogenotype und erhöhtem SFV bzw. Anteil von Stellen mit BOP in % während der Entwicklung einer experimentellen Gingivitis zeigen. Résumé Contexte: Récemment, une association entre la sévérité de la parodontite et des variations spéifiques des gènes codant pour l'interleukin-1 (IL1) , et , a été démontrée. But: Cette étude se propose d'évaluer la relation entre le génotype IL1 dans le developpment de la gingivite expérimentale. Méthods: 20 jeunes sujets adultes présentant une bonne santé gingivale ont participé cette étude après consentement éclairé. Dans ce groupe, il y avait 10 individus à risque positif (P+) et 10 individus à génotype de risque négatif (P,). génotypes lL1 furent déterminés sur des échantillons d'ADN prélevés du sang périphérique par analyse en PCR-RFLP pour les polymorphismes d' IL1, et IL1,. On a laissé se développer une gingivite expérimentale sur 2 sextants postérieurs chez chaque sujet. Le saignement au sondage (BOP%) et le volume de fluide gingival (GCF) furent notes au départ et aux jours 2, 7, 9, 14, 16, et 21. Au vingt et unième jour, les résultats pour BOP et GCF ainsi que le taux d'augmentation de ces paramètres- La surface moyenne sous la courbe (AUC) et l'augmentation moyenne par jour (pente) - furent évalués par analyses du risque pour les génotypes IL1, le tabagisme et le sexe. Résultats: gingivite expérimentale se développa avec une augmentation graduelle des et scores de BOP et des valeurs de GCF (exprimées en unités Periotron=PU) du début de l'étude jusqu'au jour 21 (BOP, P+: 0.5%à 26.0%, P-: 1.0%à 28.1%; GCF, P+: 36.8 à 43.1 à 143.4 PU). Aucun risque significatif ne fut associe avec P+et P-ats à 21 jours, AUC ou la pente. Conclusion: -es résultats de cette étude n'ont pas pu donner de preuves d'associations entre le génotype de risque IL1 et un volume accru de GCF et le % BOP lors du t d'une gingivite expérimentale. [source] Use of topical misoprostol to reduce radiation-induced mucositis: Results of a randomized, double-blind, placebo-controlled trialJOURNAL OF MEDICAL IMAGING AND RADIATION ONCOLOGY, Issue 5 2006MJ Veness Summary Radiation-induced mucositis is an acute reaction of the mucosa of patients undergoing head and neck radiotherapy. It can have debilitating and dose-limiting consequences. There is no consensus on an accepted intervention that significantly reduces its severity. Misoprostol is a synthetic prostaglandin E1 analogue, with properties of a mucosal cytoprotectant. We designed a randomized, double-blind, placebo-controlled trial of misoprostol in patients with head and neck cancer. The aim of this study was to determine if topical misoprostol was effective in reducing the severity of radiation-induced mucositis in patients receiving radical dose radiotherapy. The effect of this intervention on a patient's general well-being was also investigated. The primary end-point of the study was the incidence of Radiation Therapy Oncology Group grade 3 mucositis. Between 1999 and 2002, 83 patients were recruited into the study at Westmead and Nepean Hospitals, Sydney. Forty-two patients were randomized to receive misoprostol and 41 to receive a placebo. Most patients received radiotherapy in the adjuvant setting (52 of the 83) and had either an oral cavity (42 of the 83) or an oropharyngeal (16 of the 83) cancer. We could not identify any significant difference in the incidence of severe mucositis based on whether patients were allocated to receive misoprostol or placebo. There was no significant difference in the mean area under the mucositis curve (13.2 vs 16.6; P = 0.1). Patients allocated to misoprostol did report slightly increased soreness (7.6 vs 6.9; P = 0.04) and a greater use of analgesics. However, this difference did not translate into a worse feeling of general well-being as measured by a simple visual analogue scale (5.8 vs 5.2; P = 0.3). In conclusion, we were unable to identify a reduction in radiation-induced mucositis in patients receiving misoprostol. There is a paucity of high-level evidence on potentially useful interventions and a continued need for new and innovative research, incorporating quality-of-life measurements, in patients experiencing radiation-induced mucositis. [source] Cardiovascular Actions of Orexin-A in the Rat Subfornical OrganJOURNAL OF NEUROENDOCRINOLOGY, Issue 1 2007P. M. Smith Orexin-A is a neuropeptide, primarily produced in the lateral hypothalamic/perifornical hypothalamus. Orexin receptors and immunoreactive neuronal fibres are widely distributed throughout the brain, suggesting integrative neurotransmitter roles in a variety of physiological systems. Intracerebroventricular injections of orexin-A increase blood pressure and stimulate drinking, and the subfornical organ (SFO), a circumventricular structure implicated in autonomic control, is a potential site at which orexin may act to exert these effects. We have therefore used microinjection techniques to examine the effects of orexin-A administered directly into the SFO on blood pressure and heart rate in urethane anaesthetised male Sprague-Dawley rats. Orexin-A microinjection (50 fmol) into the SFO caused site-specific decreases in blood pressure (SFO: mean area under curve (AUC) = ,681.7 ± 46.8 mmHg*s, n = 22 versus non-SFO: 63.68 ± 54.69 mmHg*s, n = 15, P < 0.001), and heart rate (SFO: mean AUC = ,26.7 ± 2.8 beats, n = 22, versus non-SFO: mean AUC = 1.62 ± 2.1 beats, n = 15, P < 0.001). Vagotomy did not alter the hypotensive or bradycardic responses elicited by orexin-A microinjection. Prior ,-adrenoceptor blockade with phenoxybenzamine (1 mg/kg, i.v.) masked the orexin-A induced blood pressure (mean AUC = ,122.6 ± 17.6 mmHg*s, n = 4, P < 0.01 paired t-test) and heart rate (mean AUC = ,6.7 ± 1.7 beats, n = 4, P < 0.05, paired test) response. The orexin-A induced heart rate response was attenuated when ,-adrenoceptors were blocked with propranolol (1 mg/kg, i.v.; mean AUC = 0.6 ± 2.8 beats, n = 5, P < 0.01 paired t-test). These studies demonstrate that microinjection of orexin-A into the SFO causes site specific decreases in blood pressure and heart rate which is mediated by a reduction in sympathetic tone. [source] Ultrasonographic Reference Values for Assessing the Normal Median Nerve in AdultsJOURNAL OF NEUROIMAGING, Issue 1 2009Michael S. Cartwright MD ABSTRACT BACKGROUND AND PURPOSE Several studies have evaluated the cross-sectional area of the median nerve at the wrist, but none have examined other sites along the median nerve. Nerve enlargement has been demonstrated in entrapment, hereditary and acquired neuropathies, as well as with intraneural masses, and cross-sectional area reference values at sites along the nerve will help in the evaluation of these conditions. In addition, muscle intrusion into the carpal tunnel has been implicated in carpal tunnel syndrome, but the normal amount of muscle intrusion has not been quantified. METHODS Fifty asymptomatic volunteers (100 arms) were evaluated to determine the mean cross-sectional area of the median nerve at 6 sites and the mean amount of muscle intruding into the carpal tunnel. RESULTS The cross-sectional area of the nerve was consistent along its course (7.5 to 9.8 mm2). The amount of muscle within the carpal tunnel varied greatly, with the mean area of flexor digitorum being 15.5 mm2 and lumbricals 13.5 mm2. CONCLUSIONS These reference values are necessary for advancing the field of neuromuscular ultrasound, because they facilitate studies of the median nerve in conditions such as entrapment, hereditary neuropathy, acquired neuropathy, and intraneural masses. [source] Pharmacokinetics of gamithromycin in cattle with comparison of plasma and lung tissue concentrations and plasma antibacterial activityJOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 3 2010R. A. HUANG Huang, R. A., Letendre, L. T., Banav, N., Fischer, J., Somerville, B. Pharmacokinetics of gamithromycin in cattle with comparison of plasma and lung tissue concentrations and plasma antibacterial activity. J. vet. Pharmacol. Therap.33, 227,237. The pharmacokinetics (PK) and dose proportionality of gamithromycin (ZACTRAN®), a novel azalide, after a single intravenous (i.v.) dose of 3 mg/kg or subcutaneous (s.c.) injection at 3, 6 and 9 mg/kg body weight were studied in 13 male castrate and 13 female Angus cattle. Following i.v. administration, the mean area under the curve extrapolated to infinity (AUCinf) was 4.28 ± 0.536 ,g·h/mL, and mean elimination half-life (t1/2) was 44.9 ± 4.67 h, with a large volume of distribution (Vss) of 24.9 ± 2.99 L/kg and a high clearance rate (Clobs) of 712 ± 95.7 mL/h/kg. For cattle treated with s.c. injection of 3, 6 or 9 mg/kg, mean AUCinf values were 4.55 ± 0.690, 9.42 ± 1.11 and 12.2 ± 1.13 ,g·h/mL, respectively, and the mean elimination half-lives (t1/2) were 51.2 ± 6.10, 50.8 ± 3.80 and 58.5 ± 5.50 h. Gamithromycin was well absorbed and fully bioavailable (97.6,112%) after s.c. administration. No statistically significant (, = 0.05) gender differences in the AUCInf or elimination half-life values were observed. Dose proportionality was established based on AUCInf over the range of 0.5 to 1.5 times of the recommended dosage of 6 mg/kg of body weight. Further investigations were conducted to assess plasma PK, lung/plasma concentration ratios and plasma antibacterial activity using 36 cattle. The average maximum gamithromycin concentration measured in whole lung homogenate was 18 500 ng/g at first sampling time of 1 day (,24 h) after treatment. The ratios of lung to plasma concentration were 265, 410, 329 and 247 at 1, 5, 10 and 15 days postdose. The lung AUCinf was 194 times higher than the corresponding plasma AUCinf. The apparent elimination half-life for gamithromycin in lung was 90.4 h (,4 days). Antibacterial activity was observed with plasma collected at 6 h postdose with a corresponding average gamithromycin plasma concentration of 261 ng/mL. In vitro plasma protein binding in bovine plasma was determined to be 26.0 ± 0.60% bound over a range of 0.1,3.0 ,g/mL of gamithromycin. The dose proportionality of AUC, high bioavailability, rapid and extensive distribution to lung tissue and low level of plasma protein binding are beneficial PK parameters for an antimicrobial drug used for the treatment and prevention of bovine respiratory disease. [source] Does Erectile Tissue Angioarchitecture Modify with Aging?THE JOURNAL OF SEXUAL MEDICINE, Issue 4 2008An Immunohistological, Morphometric Approach ABSTRACT Introduction., Erectile dysfunction is a common problem in aged men; however, which vascular cavernosal alterations occur with age progression remain unclarified. Aim., Using cavernosal tissue from rats of various ages, we aimed to thoroughly assess erectile vascular-associated morphologic, immunohistological, and morphometric alterations during aging. Methods., Male Wistar rats were divided according to age in groups of 2, 6, 12, 18, 24 months old (N = 5). Cavernosal tissue of all groups was collected and processed for morphologic evaluation, immunodetection of ,-smooth muscle actin and von Willebrand factor and morphometric quantification of vascular and smooth muscle cell (SMC) areas. Main Outcome Measures., The morphometric assessment of age-related alterations in cavernosal vascular and SMCs using the ImageJ image-processing program. Results., Morphologic and immunohistological evaluation showed a similar structure of erectile tissue among all age groups, divided in two cavernosal bodies containing numerous sinusoidal vascular spaces surrounded by SMCs. Additionally, we observed a reduction of SMC content and an increase in the caliber of vascular spaces, with aging. This was confirmed by the morphometric quantification of the vascular and SMC areas (mean area ×103 µm2 ± ×103 standard error). Two-month-old animals had a mean vascular area of 4.21 ± 0.51, approximately 3.5-fold less than the 6-month-old group. The differences increased when comparing the youngest groups with the 12-, 18-, and 24-month-old animals, with mean measurements of 18.99 ± 1.91, 25.23 ± 2.76, and 26.34 ± 2.97. Conversely, SMC areas progressively decreased between 2- and 6-month-old animals, from 6.75 ± 0.90 to 6.38 ± 1.24. The elderly 12-, 18-, and 24-month-old groups presented an approximated 1.5-fold reduction on SMCs area, showed by the respective measurements of 4.11 ± 0.50, 4.01 ± 0.35, and 4.02 ± 0.44. Conclusions., We demonstrated that cavernosal angioarchitecture was modified with aging. The decrease in SMCs and the considerable enlargement of vascular lumens may limit the basic function of penile vascular tree in the elderly. Costa C, and Vendeira P. Does erectile tissue angioarchitecture modify with aging? An immunohistological and morphometric approach. J Sex Med 2008;5:833,840. [source] Grapefruit Juice Enhances the Exposure to Oral OxycodoneBASIC AND CLINICAL PHARMACOLOGY & TOXICOLOGY, Issue 4 2010Tuija H. Nieminen The objective of this study was to examine the effect of grapefruit juice on the pharmacokinetics and pharmacodynamics of oral oxycodone in a randomized cross-over study with two phases at an interval of 4 weeks. Twelve healthy volunteers ingested 200 ml of grapefruit juice or water t.i.d. for 5 days. An oral dose of oxycodone hydrochloride 10 mg was administered on day 4. Oxycodone, noroxycodone, oxymorphone and noroxymorphone concentrations were analysed from the plasma samples for 48 hr and behavioural and analgesic effects were recorded for 12 hr. Grapefruit juice increased the mean area under the oxycodone concentration,time curve (AUC0,,) by 1.7-fold (p < 0.001), the peak plasma concentration by 1.5-fold (p < 0.001) and the half-life of oxycodone by 1.2-fold (p < 0.001) as compared to the water. The metabolite-to-parent AUC0,, ratios (AUCm/AUCp) of noroxycodone and noroxymorphone decreased by 44% (p < 0.001) and 45% (p < 0.001), respectively. Oxymorphone AUC0,, increased by 1.6-fold (p < 0.01) after grapefruit juice, but the AUCm/AUCp remained unchanged. Pharmacodynamic changes were modest and only self-reported performance significantly impaired after grapefruit juice. Analgesic effects were not influenced. Grapefruit juice inhibited the CYP3A4-mediated first-pass metabolism of oxycodone, decreased the formation of noroxycodone and noroxymorphone and increased that of oxymorphone. We conclude that dietary consumption of grapefruit products may increase the concentrations and effects of oxycodone in clinical use. [source] Liquid chromatographic,mass spectrometry analysis and pharmacokinetic studies of a novel rabeprazole formulation, sterile powder for injection, in dogs and ratsBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 4 2007Feng Shao Abstract Rabeprazole is among the most potent proton pump inhibitors (PPI) identified to date and it has been demonstrated that it is effective in such diseases as gastroesophageal reflux disease (GERD), duodenal ulcer and gastric ulcer. There is currently interest in developing a new formulation: rabeprazole sterile powder for injection (RSPI). This investigation was conducted to evaluate the preclinical pharmacokinetics of RSPI in rats and at the same time a comparative study was carried out in dogs between RSPI and Pariet® tablets using liquid chromatographic,mass spectrometry analysis. The liquid chromatographic,mass spectrometry method was first conducted and validated as being specific, and having accuracy, precision, sensitivity and a satisfactory recovery. After intravenous administration of RSPI (i.v.: 2, 6 and 18 mg/kg) to rats, no significant dose-dependency was found in the CL (4.20,5.72 l/h/kg), Varead (0.94,1.32 l/kg), dose-normalized AUC (197.20,245.82 µg/l*h based on 1 mg/kg) and t1/2 (p>0.05). In the dog, a randomized, open-label, crossover experiment was carried out to show that the mean area under the plasma concentration-time curve (AUC0,,) after i.v. administration of RSPI was at least four times larger than that following oral administration of Pariet® tablet at an equivalent dose but the elimination half-life of these two formulation was similar (p>0.05). The results showed that the pharmacokinetics of RSPI was linear (r2 = 0.98) in the dose range 2,18 mg/kg and the RSPI had a much higher AUC0,, and similar t1/2 values compared with the enteric-coated tablet. Copyright © 2007 John Wiley & Sons, Ltd. [source] Pharmacokinetics of sildenafil after single oral doses in healthy male subjects: absolute bioavailability, food effects and dose proportionalityBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 2002Donald J. Nichols Aims, To determine the absolute bioavailability, dose proportionality and the effects of food on the pharmacokinetics of single oral doses of sildenafil citrate. Methods, Three open-label, randomized crossover studies were conducted in healthy male subjects. Absolute bioavailability was determined by comparing pharmacokinetic data after administration of single oral and intravenous 50-mg doses of sildenafil (n=12 subjects). Food effects were examined by comparing pharmacokinetic data for sildenafil and its primary circulating metabolite, UK-103,320, after administration of a single oral 100-mg dose in the fasted and fed states (n=34 subjects). Dose proportionality was assessed from pharmacokinetic data obtained after administration of four single oral doses of sildenafil (25, 50, 100 and 200 mg) to 32 subjects. The safety and tolerability of sildenafil were also assessed in all of these studies. Results, The calculated absolute oral bioavailability of sildenafil was 41% (90% CI: 36,47). Food slowed the rate of absorption, delaying mean tmax by approximately 1 h and reducing Cmax by 29% (90% CI: 19,38). Systemic exposure, as assessed by the mean area under the plasma concentration,time curve (AUC), was reduced by 11% (90% CI: 6,16). These food effects were not considered to be of clinical significance. There was statistical evidence of nonproportionality in Cmax and AUC over the dose range 25,200 mg. However the degree of nonproportionality was small, with predicted increases in Cmax and AUC of 2.2- and 2.1-fold, respectively, for a doubling in dose, and was thought to be clinically nonsignificant. Sildenafil was well tolerated in the three studies; the majority of adverse events were mild and transient. Conclusions, Sildenafil had a mean absolute bioavailability of 41%. Food caused small reductions in the rate and extent of systemic exposure; these reductions are unlikely to be of clinical significance. Across the dose range of 25,200 mg, systemic exposure increased in a slightly greater than dose-proportional manner. [source] A radiologic and histologic study of the os peroneum: Prevalence, morphology, and relationship to degenerative joint disease of the foot and ankle in a cadaveric sampleCLINICAL ANATOMY, Issue 6 2009C. Muehleman Abstract The present study investigated the prevalence of an os peroneum (OP, a sesamoid bone) in a cadaveric sample and its relationship to the shape of the cuboid tuberosity, and cartilage degeneration at the cuboid tuberosity and in regional joints within the foot (first metatarsophalangeal and calcaneocuboid) and ankle. The fibularis longus tendon of 33 embalmed human cadavers (mean age 81 years) were obtained from the anatomy laboratory. Nineteen of 64 tendons (30%) displayed an OP both radiographically and histologically. The os peronei ranged in size from small spicules to prominent masses: mean area 2.48 mm2 (left) and 2.70 mm2 (right). Histologically, the os peronei were cancellous bone, the largest occupying most of the tendon at the point of contact with the cuboid tuberosity. Fibrocartilage was present at their borders, merging with dense regular fibrous tissue and peritenon. The talocrural, calcaneocuboid, and first metatarsophalangeal joints were examined for cartilage integrity and osteophytes based on an earlier suggestion that there may be an association between degenerative joint disease and endochondral bone formation. There was no statistical correlation between presence of an OP with any of the following parameters: age, gender, body size, cartilage degeneration, or osteophytes within any of the joints examined. Therefore, the presence of an OP does not appear to be associated with increased endochondral ossification or degenerative joint disease. This study does not preclude the possibility that sesamoid bone formation may be associated with biomechanical functions within the foot; thus, future studies may be warranted. Clin. Anat. 22:747,754, 2009. © 2009 Wiley-Liss, Inc. [source] Optimal prophylactic dosage and disposition of micafungin in living donor liver recipientsCLINICAL TRANSPLANTATION, Issue 6 2004Satoshi Kishino Abstract:, Micafungin, a new candin antifungal drug, has a good safety profile and a significant therapeutic effect against Candida and Aspergillus. Little is known, however, about the optimal prophylactic dosage and the disposition of micafungin in liver transplant recipients, or about the effect of continuous venovenous hemodialysis (CVVH) on the pharmacokinetics of micafungin. Six living donor liver transplant patients were enrolled in this study. The mean Cmax and Cmin (trough) values of micafungin in plasma were 6.31 ± 1.08 and 1.65 ± 0.54 ,g/mL, respectively. The mean elimination half-life (t1/2) and mean area under the curve up to 12 h post-dosing (AUC 0,12 h) were 13.63 ± 2.77 h and 50.04 ± 6.48 ,g·h/mL, respectively. The concentrations of micafungin at the inlet and outlet of the dialyzer were very similar. The mean (±SD) ratio of micafungin concentrations at the inlet and outlet of the dialyzer (coutlet/cinlet) and the clearance of micafungin were 0.96 ± 0.04 and 0.054 ± 0.04 mL/min/kg, respectively. The amount in the ultrafiltrate was 1.0 mg. Micafungin effectively prevents systemic fungal infection in patients who have undergone liver transplantation. No significant differences were observed in the disposition of micafungin in recipients, and the therapeutic drug level can be achieved by administration of micafungin at a dosage of 40,50 mg/d. The CVVH had little effect on micafungin kinetics, and no dose adjustment or modification of dosing interval was needed during CVVH. [source] Evaluation of the effectiveness of an early peripheral burning strategy in controlling wild fires in north-western ZimbabweAFRICAN JOURNAL OF ECOLOGY, Issue 4 2009Isaac Mapaure Abstract A review of the occurrence of wild fires in Sengwa Wildlife Research Area (SWRA), Zimbabwe, is presented for the period 1965,1993. The effectiveness and desirability of early burning of peripheral areas introduced in 1979 are evaluated. More than 75% of wild fires occurred between July and October, 48.6% of which originated from communal lands. Early burning of peripheral areas led to significant reductions in extent of areas burnt, from annual mean areas of 115 km2 (1965,1978) to 11 km2 (1979,1993) because of effective control of fires, which originated from communal lands. Some areas did not burn at all after 1979, and the overall probability of burning dropped from 0.484 to 0.187. Whilst it may be desirable to keep fires out of SWRA in the short term, fuel build-ups increase the fire hazard resulting in negative consequences on biodiversity in the long term. Consideration should be given to combine peripheral burning with low-intensity prescribed burning of selected blocks to keep a semblance of natural fire regimes to ensure the maintenance of biodiversity while simultaneously reducing the fire-hazard. An integrated fire management plan should be put in place for SWRA. Résumé Ici est passée en revue l'occurrence de feux sauvages dans l'Aire de recherche sur la faune sauvage de Sengwa (SWRA), au Zimbabwe, pour la période 1965,1993. L'efficacité et l'opportunité des feux précoces des zones périphériques, introduits en 1979, sont aussi évaluées. Plus de 75% des feux sauvages avaient lieu entre juillet et octobre, dont 48,6% trouvaient leur origine dans des terres communales. Le brûlage précoce des zones périphériques a conduit à des réductions significatives des superficies brûlées, qui sont passées d'une moyenne annuelle de 115 km2 (1965,1978) à 11 km2 (1979,1993) grâce au contrôle efficace des feux qui commençaient dans les terres communales. Certaines zones n'avaient pas brûlé du tout depuis 1979, et la probabilité globale de brûler a chuté de 0,484 à 0,187. S'il est, à court terme, souhaitable de préserver la SWRA contre les feux, l'accumulation de matières combustibles augmente les risques de feux qui pourraient avoir, à long terme, des conséquences négatives sur la biodiversité. Il faudrait envisager de combiner les feux en périphérie avec des feux programmés, de faible intensité, de certains blocs sélectionnés, pour conserver un semblant de régime naturel de feux et ainsi garantir le maintien de la biodiversité tout en réduisant les risques de feux. Il faudrait instaurer un plan de gestion des feux pour la SWRA. [source] | ||||||||||||||||||||||