Isotropic model of fractional transport in two-dimensional bounded domains.

A two-dimensional fractional Laplacian operator is derived and used to model nonlocal, nondiffusive transport. This integro-differential operator appears in the long-wavelength, fluid description of quantities undergoing non-Brownian random walks without characteristic length scale. To study bounded domains, a mask function is introduced that modifies the kernel in the fractional Laplacian and removes singularities at the boundary. Green's function solutions to the fractional diffusion equation are presented for the unbounded domain and compared to the one-dimensional Cartesian approximations. A time-implicit numerical integration scheme is presented to study fractional diffusion in a circular disk with azimuthal symmetry. Numerical studies of steady-state reveal temperature profiles in which the heat flux and temperature gradient are in the same direction, i.e., uphill transport. The response to off-axis heating, scaling of confinement time with system size, and propagation of cold pulses are investigated.

Nasal retention of budesonide and fluticasone in man: formation of airway mucosal budesonide-esters in vivo.

AIMS: The efficacy of topical glucocorticosteroids in rhinitis and asthma is likely to depend on drug retention in the airway mucosa. With fluticasone propionate, retention may be achieved exclusively by lipophilicity, whereas for budesonide an additional possibility may be provided by its ability to form fatty acid esters in the airway mucosa that release the active drug. The aim of the present study was to determine the nasal mucosal retention of budesonide and fluticasone propionate, and the occurrence of budesonide-esters (budesonide-oleate, budesonide-palmitate) in the nasal mucosa. METHODS: In the present study, involving 24 healthy subjects, we have examined nasal mucosal drug retention of single doses of topical budesonide (256 microg) and fluticasone propionate (200 microg). Treatments were given consecutively and the administration sequence was randomised. Subjects were randomised into four parallel groups and two nasal biopsies were taken from each subject, i.e. before and at 2 h, at 2 and 6 h, at 6 and 24 h, or before and at 24 h after drug administration, resulting in 12 biopsies/time point. The measurement of unesterified budesonide, budesonide-oleate, budesonide-palmitate, and fluticasone propionate was based on microwave extraction procedures combined with liquid-chromatography/tandem mass-spectrometry. RESULTS: Neither of the analytes was detected in samples taken before glucocorticosteroid administration. After administration, unesterified budesonide, budesonide-esters, and fluticasone propionate were detected in the tissue from 23, 20, and 19 subjects, respectively. The mean tissue levels of budesonide at 2 and 6 h were 1051 and 176 pmol g(-1); the mean levels of fluticasone propionate at these time points were 237 and 10 pmol g(-1). The dose-corrected budesonide/fluticasone propionate tissue concentration ratios were 3.5 (P = 0.07) and 13.7 (P < 0.0002), respectively. At 24 h, budesonide and fluticasone propionate were detected in 8/12 and 3/12 of the biopsies, respectively. CONCLUSIONS: The present study demonstrates the formation of budesonide-esters in the human nasal mucosa in vivo, and that budesonide is retained in the nasal mucosa to a greater extent than fluticasone propionate. It is suggested that the formation of budesonide-esters and their subsequent release of budesonide contributes to an extended retention of budesonide in the airway mucosa.

Serotonin autoreceptor function and antidepressant drug action.

This article briefly summarizes, within the context of a brief review of the relevant literature, the outcome of our recent rat microdialysis studies on (1) the relative importance of serotonin (5-HT)1A versus 5-HT1B autoreceptors in the mechanism of action of 5-HT reuptake blocking agents, including putative regional differences in this regard, and (2) autoreceptor responsiveness following chronic SSRI administration. First, our data are consistent with the primacy of 5-HT1A autoreceptors in restraining the elevation of 5-HT levels induced by SSRIs, whereas nerve terminal 5-HT1B autoreceptors appear to have an accessory role in this regard. Second, there is an important interplay between cell body and nerve terminal 5-HT autoreceptors, and recent findings suggest that this interplay may potentially be exploited to obtain regionally preferential effects on 5-HT neurotransmission in the central nervous system, even upon systemic drug administration. In particular, emerging data suggest that somatodendritic 5-HT1A autoreceptor- and nerve terminal 5-HT1B autoreceptor-mediated feedback may be relatively more important in the control of 5-HT output in dorsal raphe-frontal cortex and median raphe-dorsal hippocampus systems, respectively. Third, 5-HT autoreceptors evidently retain the capability to limit the 5-HT transmission-promoting effect of SSRIs after chronic treatment. Thus, although the responsiveness of these sites is probably somewhat reduced, residual autoreceptor capacity still remains an effective restraint on large increases in extracellular 5-HT, even after prolonged treatment. If a further increase in extracellular 5-HT is crucial to the remission of depression in patients responding only partially to prolonged administration of antidepressants, then sustained adjunctive treatment with autoreceptor-blocking drugs may consequently prove useful in the long term.

The role of 5-HT1A autoreceptors and alpha1-adrenoceptors in the modulation of 5-HT release--III. Clozapine and the novel putative antipsychotic S 16924.

Clozapine and the novel putative, antipsychotic S 16924 ((1-(benzodioxane-5-yl)-3-[3-(4-fluorophenacyl)pyrrolidine]-1-o xapropane HCl) share significant affinity for alpha1-adrenoceptors and 5-HT1A autoreceptors in vitro and display an 'atypical' behavioural profile in in vivo models used for detecting potential neuroleptic effects. In the present study, in vivo microdialysis was used to examine the effect of clozapine and S 16924 on 5-HT overflow in the rat ventral hippocampus, and to assess the relative role of putative alpha1-adrenoceptor antagonist and 5-HT1A autoreceptor agonist properties of the drugs in this regard. S 16924 (0.1-3 mg/kg, s.c.) reduced dialysate 5-HT in a dose- and time-dependent fashion by maximally approximately 70% from baseline 40-60 min after injection. Clozapine (0.1-10 mg/kg, s.c.) reduced 5-HT overflow in the same manner, with a maximum effect of approximately 60% from baseline, obtained after 60-80 min. The 5-HT decrease elicited by S 16924 (1.0 mg/kg, s.c.) was significantly, though only partially, antagonized by pretreatment with the selective 5-HT1A receptor antagonist WAY 100635 (0.3 mg/kg, s.c.). The selective alpha1-adrenoceptor agonist cirazoline (0.02 mg/kg, i.p.) alone did not significantly attenuate the effect of S 16924 (1.0 mg/kg, s.c.) on 5-HT overflow. Combined treatment with both WAY 100635 and cirazoline, however, totally reversed the 5-HT-suppressing effect of S 16924 (1.0 mg/kg, s.c.). By comparison, when given separately, neither WAY 100635 (0.3 mg/kg, s.c.) nor cirazoline (0.02 mg/kg, i.p.) antagonized the clozapine (0.3 mg/kg, s.c.)-induced decrease of 5-HT in ventral hippocampus dialysates. In the presence of both WAY 100635 and cirazoline, the response to this dose of clozapine was however significantly, though modestly, attenuated. In contrast, the WAY 100635/cirazoline combination failed to antagonise the 5-HT decrease resulting from a higher dose (3.0 mg/kg, s.c.) of clozapine. We conclude that both alpha1-adrenoceptor antagonist and 5-HT1A receptor agonist properties of clozapine and S 16924 contribute to the 5-HT release-reducing action of these drugs. Whereas these factors apparently explain the effect of S 16924 fully, additional mechanism(s) appear to be involved in the case of clozapine. With regard to the interplay between alpha1-adrenoceptor and 5-HT1A (auto)receptor mechanisms in the control of 5-HT release in the rat forebrain, the present data suggest that an excitation mediated by the former is outweighed by the simultaneous activation of the latter-inhibitory-receptors.

Effect of grapefruit juice on urinary 6 beta-hydroxycortisol/cortisol excretion.

1. The aim of the present study was to evaluate the effect of grapefruit juice on urinary 6 beta-hydroxycortisol and cortisol excretion in healthy subjects. 2. The ratio of 6 beta-hydroxycortisol/cortisol was significantly decreased (P = 0.036) in the 0-4 h fraction of urine after ingestion of grapefruit juice, but not in the 4-24 h fraction (P = 0.218) or for the compiled data, fraction 0-24 h (P = 0.114). 3. These results indicate that endogenous cortisol metabolism may not only be of hepatic origin, but may also be dependent on the metabolic capacity of cytochrome P450 IIIA (CYP3A) in the gut mucosa. 4. This finding may cast further doubts of the usefulness of the 6 beta-hydroxycortisol/cortisol ratio as an indicator of hepatic CYP3A activity.

Colcemid resistance in murine SEWA cells: non-Pgy gene amplification at low levels of resistance and preferential Pgy2 gene amplification at high levels of resistance.

Mammalian cell lines often become multidrug-resistant to cytotoxic drugs by amplification and/or overexpression of the P-glycoprotein (Pgy) genes. However, several malignant cell lines seem to acquire low levels of drug resistance by non-P-glycoprotein mediated mechanisms. We report here on cytogenetical signs of non-Pgy gene amplification in murine SEWA cells during the early steps of selection in Colcemid (COL). In line TC13COL0.01, rare cells exhibited a homogeneously staining region (HSR) distally in chromosome 16. As the COL-concentration was raised the HSR-chromosome was retained and, in addition, the cells developed numerous double minutes (DMs). The DMs, but not the HSR, contained amplified Pgy genes. The HSR may correspond to amplified heat shock protein 70 (Hsp70) genes, detected by Southern analysis. A second low-level COL-resistant line, TC13D70.01, contained DMs but showed no amplification of Pgy, Hsp70, Hsp90, alpha- or beta-tubulin genes. In higher COL-concentration, P-glycoprotein mediated drug resistance was induced. In contrast to actinomycin D-resistant SEWA cells, in which higher amplification levels of Pgy1 than of Pgy2 are regularly present, the COL-resistant lines showed a preference for Pgy2 gene amplification. These results are in line with the suggestion that the murine Pgy1 and Pgy2 genes have overlapping but distinct drug specificities.

Drug-specific rearrangements of chromosome 12 in hydroxyurea-resistant mouse SEWA cells: support for chromosomal breakage model of gene amplification.

In order to investigate whether specific, nonrandom chromosome rearrangements were involved in the induction of hydroxyurea (HU) resistance in mouse SEWA cells, we undertook detailed cytogenetic analyses of three independently selected lines during the long-term treatment with HU. We found that cells with trisomy 12 had selective advantage during early steps of HU treatment. Subsequently, numerous rearrangements of chromosome 12 took place in each of the HU-resistant cell lines. More specifically, the proximal end of chromosome 12 (band A3) was frequently involved in breaks and fusions generating multicentric marker chromosomes. In situ hybridization showed that the functional Rrm2 gene was located in this particular region of chromosome 12. Furthermore, amplification and rearrangements of the structural gene Rrm2 were detected both at the chromosomal and at the molecular level. As discussed, the results of the cytogenetic analyses support the chromosomal breakage model of gene amplification.

Benthic macroinvertebrate community structure in 20 streams of varying pH and humic content.

The structure of stream benthic macroinvertebrate communities in relation to pH and humic content was studied in 20 second and third-order forest streams in southern Sweden. Streams varied in pH from 4.2 to 8.0, and in humic content from a colour of 5 to 1200 mg Pt litre(-1). There was a positive relationship between pH and species richness, with a discontinuity occurring at pH approximately 5.7. At pH > 5.7, species richness decreased with increasing colour. At pH < 5.7 there was a positive correlation between species richness and humic concentration up to a colour of about 200-300 mg Pt litre(-1). this may be explained by high concentrations, 0.4-0.9 mg litre(-1), of labile monomeric Al occurring in the low coloured acid streams. In streams with a colour > 200 mg Pt litre(-1) labile monomeric Al was less than 0.2 mg litre(-1). There was no significant change in species richness above this threshold, but a shift in species composition towards a dominance of Plecoptera and Chironomidae. This threshold model seems to explain the observed differences in stream benthic community structure better than a simple linear relationship with pH or humic content.

Intratumor distribution of capillary permeability surface area product (PS) correlated to tumor vascular space and blood flow.

The intratumor distribution of the capillary permeability surface area product (PS) correlated to the intratumor distribution of vascular space and of blood flow was studied by labeled albumin in a transplantable rat fibrosarcoma. A wide heterogeneity in intratumor distribution of PS was found. The tumor PS values were not significantly correlated to tumor vascular space or to blood flow values. This might suggest that intravascularly administered drugs could reach a comparative high intratissue concentration also in less vascularized tumor areas.