Smoking among young people in the MWHB Region in 1997 and 2002.
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Adolescent↗
Biomedical subjects
H Cowley
Publications and source records attributed to H Cowley.
Cilomilast (Ariflo) does not potentiate the cardiovascular effects of inhaled salbutamol.
We investigated the safety and potential pharmacodynamic interactions arising from the co-administration of inhaled beta(2)-agonist salbutamol and cilomilast (Ariflo), a new oral phosphodiesterase 4 inhibitor for the treatment of chronic obstructive pulmonary disease and asthma. This was a randomised, double-blind, placebo-controlled, multiple-dose, three-period crossover study involving non-smoking volunteers between the ages of 18 and 50 years. Volunteers were randomly assigned to receive cilomilast plus nebulised salbutamol, cilomilast plus nebulised placebo or placebo plus nebulised salbutamol. Each volunteer received cilomilast (10 mg twice daily) or placebo for 5 days. On day 5, the morning dose of cilomilast or placebo was followed 1 h later with a single dose of nebulised salbutamol (2.5 mg) or placebo. Primary variables were average change from pre- to 1.5 h post-salbutamol or placebo inhalation in blood pressure, pulse rate, 12-lead ECG and total number of heartbeats measured by 4-h Holter ECG. Thirteen volunteers completed the study. There was no evidence of a clinically important pharmacodynamic interaction between cilomilast and salbutamol in healthy volunteers. Both agents were well tolerated. In conclusion, the pharmacodynamic effects associated with salbutamol inhalation were unaffected by co-administration of cilomilast.
3',5'-Cyclic-AMP Phosphodiesterases↗
Catastrophic failures of freezing bags for cellular therapy products: description, cause, and consequences.
BACKGROUND: Container integrity is critical for maintaining sterility of cryopreserved cellular therapy products. We investigated a series of catastrophic bag failures, first noticed in early 2001. METHODS: Process records were reviewed for all PBPC and lymphocyte products cryopreserved in bags from January 2000 through April 2002. Patient charts were also reviewed. RESULTS: One thousand two hundred and four bags were removed from storage for infusion to 261 patients. All products had been cryopreserved in Cryocyte poly(ethylene co-vinyl acetate) (EVA) bags in either 10% DMSO or 5% DMSO and 6% pentastarch. Product volumes were 25-75 mL, and bags were stored with overwrap bags in a liquid nitrogen tank. From January 2000 to April 2001, failure occurred in 10 of 599 (1.7%) bags. From May 2001 to April 2002, 58 of 605 (9.6%) bags failed, typically with extensive fractures that were visible before thaw. Of the 58 that failed, 24 were salvaged by aseptic methods and infused to patients under antibiotic coverage; 10 of those 24 (42%) had positive bacterial cultures. Bag failures were not related to product type, cryoprotectant solution, liquid versus vapor storage, or freezer location. Failures were linked to use of four Cryocyte bag lots manufactured in 2000 and 2001. After replacing these lots with a 1999 Cryocyte lot and with KryoSafe polyfluoroethylene polyfluoropropylene (FEP) bags, no more failures occurred in 75 and 102 bags, respectively, thawed through April 2002. DISCUSSION: High rates of bag failure were associated with four Cryocyte bag lots. No serious adverse patient effects occurred, but bag failures led to microbial contamination, increased product preparation time, increased antibiotic use, and increased resource expenditure to replace products.
Adolescent↗
Differential occupancy of somatodendritic and postsynaptic 5HT(1A) receptors by pindolol: a dose-occupancy study with [11C]WAY 100635 and positron emission tomography in humans.
Augmentation of selective serotonin reuptake inhibitors (SSRIs) therapy by the 5-HT(1A) receptor agent pindolol may reduce the delay between initiation of antidepressant treatment and clinical response. This hypothesis is based on the ability of pindolol to block 5-HT(1A) autoreceptors in the dorsal raphe nuclei (DRN) and to potentiate the increase in 5-HT transmission induced by SSRIs. However, placebo-controlled clinical studies of pindolol augmentation of antidepressant therapy have reported inconsistent results. Here, we evaluated the occupancy of 5-HT(1A) receptors during treatment with pindolol controlled release (CR) in nine healthy volunteers with Positron Emission Tomography and [11C]WAY 100635. Subjects were studied four times: at baseline, following one week of pindolol CR 7.5 mg/day (4 and 10 hrs post dose), and following one dose of pindolol CR 30 mg(4 hrs post dose). Occupancy of the DRN was 40 +/- 29% on scan 2, 38 +/- 26% on scan 3, and 64 +/- 15% on scan 4. The average occupancy in all other regions was significantly lower at each doses (18 +/- 5% on scan 2, 12 +/- 3% on scan 3, and 42 +/- 4% on scan 4). These results suggest that the blockade in the DRN reached in clinical studies (7.5 mg/day) might be too low and variable to consistently augment the therapeutic effect of SSRIs. However, these data indicate that pindolol exhibits in vivo selectivity for the DRN 5-HT(1A) autoreceptors. As DRN selectivity is desirable for potentiation of 5-HT function, this observation represents an important proof of concept for the development of 5-HT(1A) agents in this application.
Adult↗
An overview of the pharmacokinetics of cilomilast (Ariflo), a new, orally active phosphodiesterase 4 inhibitor, in healthy young and elderly volunteers.
The oral pharmacokinetics of cilomilast (Ariflo) were investigated in five separate studies in healthy volunteers. Cilomilast was rapidly absorbed, and pharmacokinetics were dose proportional after single and repeat dosing. The elimination half-life was 7 to 8 hours; accordingly, steady state was reached on the 3rd day of dosing. The degree of accumulation following repeat twice-daily dosing was predictable from the data following a single dose. Although systemic exposure (AUC) was, on average, 21% higher in elderly (65-84 years) compared with young subjects, values for Cmax and t(1/2) were similar, and no difference in tolerability was noted. Single and repeat doses of cilomilast up to and including 15 mg (dosed before or taken between meals) were well tolerated. Dosing with food reduced the rate of absorption without affecting total bioavailability. Hence, tolerability was optimal in the fed state; repeat doses up to and including 30 mg twice daily aftermeals were well tolerated following dose titration.
3',5'-Cyclic-AMP Phosphodiesterases↗
Positron emission tomography study of pindolol occupancy of 5-HT(1A) receptors in humans: preliminary analyses.
Preclinical studies in rodents suggest that augmentation of serotonin reuptake inhibitors (SSRIs) therapy by the 5-hydroxytryptamine(1A) (5-HT(1A)) receptor agent pindolol might reduce the delay between initiation of treatment and antidepressant response. This hypothesis is based on the ability of pindolol to potentiate the increase in serotonin (5-HT) transmission induced by SSRIs, an effect achieved by blockade of the 5-HT(1A) autoreceptors in the dorsal raphe nuclei (DRN). However, placebo-controlled clinical studies of pindolol augmentation of antidepressant therapy have reported inconsistent results. Here, we evaluated the occupancy of 5-HT(1A) receptors following treatment with controlled release pindolol in nine healthy volunteers with positron-emission tomography (PET). Each subject was studied four times: at baseline (scan 1), following 1 week of oral administration of pindolol CR (7.5 mg/day) at peak level, 4 h after the dose (scan 2), and at 10 h following the dose (scan 3), and following one dose of pindolol CR (30 mg) (at peak level, 4 h) (scan 4). Pindolol occupancy of 5-HT(1A) receptors was evaluated in the DRN and cortical regions as the decrease in binding potential (BP) of the radiolabelled selective 5-HT(1A) antagonist [carbonyl-(11)C]WAY-100635 or [carbonyl-(11)C] N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridyl)cyclohexa necarboxamide abbreviated as [(11)C]WAY-100635. Pindolol dose-dependently decreased [(11)C]WAY-100635 BP. Combining all the regions, occupancy was 20 +/- 8% at scan 2, 14 +/- 8% at scan 3, and 44 +/- 8% at scan 4. The results of this study suggest that at doses used in clinical studies of augmentation of the SSRI effect by pindolol (2.5 mg t.i.d.), the occupancy of 5-HT(1A) receptors is moderate and highly variable between subjects. This factor might explain the variable results obtained in clinical studies. On the other hand, at each dose tested, pindolol occupancy of 5-HT(1A) receptors was higher in the DRN compared to cortical regions, demonstrating a significant in vivo selectivity for DRN 5-HT(1A) autoreceptors relative to cortico-limbic postsynaptic receptors. This selectivity is necessary for the potentiation of 5-HT transmission, and this finding represents an important proof of concept in the development of 5-HT(1A) agents for this application. Early evaluation of new drugs with PET imaging will enable rapid screening of compounds based on DRN selectivity and more appropriate determination of doses for clinical trials.
Adult↗
Absorption, disposition, and metabolism of rosiglitazone, a potent thiazolidinedione insulin sensitizer, in humans.
Rosiglitazone is a potent peroxisome proliferator-activated receptor gamma agonist that decreases hyperglycemia by reducing insulin resistance in patients with type 2 diabetes mellitus. The disposition of (14)C-labeled rosiglitazone was determined after oral and i.v. dosing of rosiglitazone solution, and the disposition of nonradiolabeled rosiglitazone was determined after oral dosing of tablets in this open-label, three-part, semirandomized, crossover study. The absorption of rosiglitazone was rapid and essentially complete, with absolute bioavailability estimated to be approximately 99% after oral tablet dosing and approximately 95% after oral solution dosing, and clearance was primarily metabolic. The time to maximal concentration of radioactivity and the elimination half-life for two metabolites in plasma were significantly longer than for rosiglitazone itself (4-6 h versus 0. 5-1 h, and ca. 5 days versus 3-7 h). Radioactivity was excreted primarily via the urine ( approximately 65%) and was excreted similarly after oral and i.v. dosing. The major routes of metabolism were N-demethylation and hydroxylation with subsequent conjugation, of which neither was affected by the route of drug administration. The major metabolites, those of intermediate importance, and nearly all of the trace metabolites in humans have been identified previously in preclinical studies. Rosiglitazone was well tolerated in all formulations.
Adult↗
Biotinylation modifies red cell antigens.
BACKGROUND: Chemical biotinylation of red cell membranes may be useful for several clinical applications, including red cell survival studies. STUDY DESIGN AND METHODS: To examine the possible effects of biotinylation on red cell antigens, standard hemagglutination assays were performed on matched sets of control and biotinylated red cells. The red cells were biotinylated at a final concentration of 2.0 pg of sulfo-N-hydroxysuccinimide-biotin per cell, and antigen-negative cells were directly compared to antigen-positive cells when possible. The hemagglutination assays were graded in a blinded fashion. Forty-one red cell antigens from 21 of the 23 established blood group systems were tested. RESULTS: Hemagglutination based upon antibody binding to A, A1, M, N, S, s, P1, D, C, E, c, e, C(w), Lu(b), K, k, Kp(b), Le(a), Le(b), Fy(a), Fy(b), Jk(a), Jk(b), Di(a), Wr(a), Wr(b), Yt(a), Xg(a), Sc1, Do(b), Co(a), Ch, H, Ge2, Cr(a), Kn(a), I, and P was not affected by biotinylation. Unexpectedly, the hemagglutination of Di(b+) and LW(a+) red cells was blocked after biotinylation. Conversely, MH04 monoclonal anti-A agglutinated red cells expressing B only after biotinylation. BIRMA-1 monoclonal anti-A and polyclonal anti-A from sera did not agglutinate the biotinylated B red cells. CONCLUSION: Biotinylation of human red cells specifically modified their antigenicity, as measured by standard hemagglutination assays.
Biotinylation↗
An ophthalmic review of cerebral palsy in Queensland 1980.
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Adolescent↗