21.
Bergman, Ebba, et al.
(författare)
Pharmacokinetics of gefitinib in humans : the influence of gastrointestinal factors
2007
Ingår i: International Journal of Pharmaceutics. - : Elsevier BV. - 0378-5173 .- 1873-3476. ; 341:1-2, s. 134-142
Tidskriftsartikel (refereegranskat) abstract
Purpose To investigate whether differences in plasma pharmacokinetic profiles of gefitinib between healthy subjects having normal (N; t1/2 > 20 h) and altered (A; t1/2 < 20 h) pharmacokinetic (PK) profiles might be explained by inter-individual variability in gastric emptying and/or precipitation/dissolution of gefitinib in the proximal small intestine. Methods One hundred healthy male subjects were screened to enable identification of subjects with the two PK profiles. Twenty five subjects from the screening were subsequently enrolled in an intubation study where a 250 mg gefitinib dispersion preparation (IRESSA®, AstraZeneca) was administered directly into the stomach. Intestinal fluid samples were withdrawn continuously for 180 min post-dose using the Loc-I-Gut catheter positioned in the jejunum. The crystalline form of gefitinib was determined using Raman microscopy. Results There were no differences between normal and altered subjects with regard to gastric emptying or the precipitation/dissolution of gefitinib in jejunal fluid. Due to difficulties in crystalline identification in the jejunal fluid samples, only the same crystalline form as the dosed form was identified. Conclusions There was no pronounced difference in gastric emptying, precipitation and re-dissolution of gefitinib in proximal human jejunum between normal and altered subjects. Other mechanism(s) are also likely to be important in explaining the inter-individual differences in plasma exposure to gefitinib, such as polymorphism in various metabolic enzymes and/or transport proteins. However, the difference between altered and normal subjects cannot be easily explained and it is likely a multifactorial explanation including low jejunal pH, increased expression of enzymatic and transporter activity and rapid small intestine transit.
22.
Bergström, Christel, et al.
(författare)
Poorly soluble marketed drugs display solvation limited solubility
2007
Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 50:23, s. 5858-5862
Tidskriftsartikel (refereegranskat) abstract
We determined the intrinsic aqueous solubility of 15 poorly soluble drugs with solubilities ranging from 2.9 nM to 1.1 μM. We then analyzed the data from a physicochemical perspective, using experimentally determined solid-state properties and easily interpretable two-dimensional molecular descriptors, to better understand the factors underlying poor solubility. The analysis shows that poorly soluble drugs that have reached the market are solubility limited by solvation rather than by their solid state.
23.
Bergström, Lars Magnus
(författare)
Bending energetics of tablet-shaped micelles : A novel approach to rationalize micellar systems
2007
Ingår i: ChemPhysChem. - : Wiley. - 1439-4235 .- 1439-7641. ; 8:3, s. 462-472
Tidskriftsartikel (refereegranskat) abstract
A novel approach to rationalize micellar systems is expounded in which the structural behaviour of tablet-shaped micelles is theoretically investigated as a function of the three bending elasticity constants: spontaneous curvature (H-0), bending rigidity (k(c)), and saddle-splay constant (k(c)). As a result, experimentally accessible micellar properties, such as aggregation number, length-to-width ratio, and polydispersity, may be relation to the different bending elasticity constants. Is it demonstrated that discrete micelles or connected cylinders form when H-0 > 1/4 xi where xi is the thickness of a surfacant monolayer, whereas various bilayer structures are expected to predominate when H-0 > 1/4 xi. Our theory predicts, in agreement with experiments, a transition from discrete globular (tablet-shaped) micelles to a phase of ordered, or disordered, connected cylinders above a critital surfactant concentration. Moreover, a novel explanation for the mechanism of growth, from small globular to long rodlike or wormlike micelles, follows as a consequence from the theory. In accordance, polydiperse elongated micelles (large length-to-width ratio) for as the bending rigidity is lowered, approaching the critical point at k(c) - 0, whereas monodisperse globular micelles (small length-to-width ratio) are expected to be present at larg k(c) values. The spontaneous curvature mainly determines the width of tablet-shaped or ribbonlike micelles, or the radius of dislike micelles, whereas the saddle-splay constant primarily influences the size but not the shape of the micelles.
24.
25.
Birgner, Carolina, et al.
(författare)
Altered extracellular levels of DOPAC and HVA in the rat nucleus accumbens shell in response to sub-chronic nandrolone administration and a subsequent amphetamine challenge
2007
Ingår i: Neuroscience Letters. - : Elsevier BV. - 0304-3940 .- 1872-7972. ; 412:2, s. 168-172
Tidskriftsartikel (refereegranskat) abstract
Associated with acts of violence and polydrug use, abuse of anabolic androgenic steroids (AAS) is an increasing problem in society. The aim of the present study was to elucidate whether sub-chronic treatment with the AAS nandrolone decanoate affects dopamine release and dopamine metabolism in the rat nucleus accumbens shell, before and after an amphetamine challenge. Male Sprague–Dawley rats received daily i.m. injections of nandrolone decanoate (15 mg/kg) or vehicle for 14 days. On day 15, the animals were anaesthetized and a microdialysis probe was implanted into the nucleus accumbens shell. Extracellular fluid was collected 1 h before and 3 h after a single amphetamine injection (5 mg/kg). The samples were then analyzed regarding the content of dopamine, and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), using HPLC with electrochemical detection. Two weeks of nandrolone decanoate administration caused a significant decrease of the basal DOPAC and HVA levels, which remained low during the first hour following the amphetamine challenge. Dopamine levels did not differ significantly between groups, neither after the nandrolone pre-treatment nor the amphetamine challenge. In conclusion, these novel findings indicate that AAS alter the metabolism of dopamine in a brain region involved in the development of drug dependence.
26.
Björkman, Sven E., et al.
(författare)
In vivo recovery of factor VIII and factor IX : intra- and interindividual variance in a clinical setting
2007
Ingår i: Haemophilia. - : Wiley. - 1351-8216 .- 1365-2516. ; 13:1, s. 2-8
Tidskriftsartikel (refereegranskat) abstract
In vivo recovery (IVR) is traditionally used as a parameter to characterize the pharmacokinetic properties of coagulation factors. It has also been suggested that dosing of factor VIII (FVIII) and factor IX (FIX) can be adjusted according to the need of the individual patient, based on an individually determined IVR value. This approach, however, requires that the individual IVR value is more reliably representative for the patient than the mean value in the population, i.e. that there is less variance within than between the individuals. The aim of this investigation was to compare intra- and interindividual variance in IVR (as U dL−1 per U kg−1) for FVIII and plasma-derived FIX in a cohort of non-bleeding patients with haemophilia. The data were collected retrospectively from six clinical studies, yielding 297 IVR determinations in 50 patients with haemophilia A and 93 determinations in 13 patients with haemophilia B. For FVIII, the mean variance within patients exceeded the between-patient variance. Thus, an individually determined IVR value is apparently no more informative than an average, or population, value for the dosing of FVIII. There was no apparent relationship between IVR and age of the patient (1.5–67 years). For FIX, the mean variance within patients was lower than the between-patient variance, and there was a significant positive relationship between IVR and age (13–69 years). From these data, it seems probable that using an individual IVR confers little advantage in comparison to using an age-specific population mean value. Dose tailoring of coagulation factor treatment has been applied successfully after determination of the entire single-dose curve of FVIII:C or FIX:C in the patient and calculation of the relevant pharmacokinetic parameters. However, the findings presented here do not support the assumption that dosing of FVIII or FIX can be individualized on the basis of a clinically determined IVR value.
27.
Blessborn, Daniel, et al.
(författare)
Development and validation of an automated solid-phase extraction and liquid chromatographic method for determination of lumefantrine in capillary blood on sampling paper
2007
Ingår i: Journal of Pharmaceutical and Biomedical Analysis. - : Elsevier BV. - 0731-7085 .- 1873-264X. ; 45:2, s. 282-287
Tidskriftsartikel (refereegranskat) abstract
A bioanalytical method for the determination of lumefantrine in 100 μl blood applied onto sampling paper, by solid-phase extraction and liquid chromatography, has been developed and validated. Whatman 31 ET Chr sampling paper was pre-treated with 0.75 M tartaric acid before sampling capillary blood to enable a high recovery of lumefantrine. Lumefantrine was extracted from the sampling paper, then further purified using solid-phase extraction and finally quantified with HPLC. The between-day variation was below 10% over the range 0.4-25 μM. The lower limit of quantification was 0.25 μM in 100 μl capillary blood. No decrease in lumefantrine concentration in dried blood spot is seen after 4 months storage at 22 °C. The method was also evaluated in field samples from patients in Tanzania after treatment with lumefantrine/artemether. Lumefantrine could be estimated accurately enough to assess bioavailability and treatment compliance on day 7 (i.e. 4 days after the last dose) after a standard regimen with the lumefantrine/artemether combination.
28.
Bohlin, Lars, et al.
(författare)
Modern pharmacognosy : Connecting biology and chemistry
2007
Ingår i: Pure and Applied Chemistry. - : Walter de Gruyter GmbH. - 0033-4545 .- 1365-3075. ; 79:4, s. 763-774
Tidskriftsartikel (refereegranskat) abstract
In many countries today, the number of students selecting chemistry for higher studies is decreasing. At the same time, interest in the environmental aspects of chemistry, green chemistry, and sustainable use of natural products is increasing among the young generation of students. By modernizing and renewing a venerable proven science, pharmacognosy would have a strategic position to connect biology and chemistry. This multidisciplinary subject is important for discovery of novel and unique molecules with drug potential, and for revealing unknown targets, by studying evolutionary structure-activity optimization in nature. In this paper, the overall aim and strategies of our research are presented and exemplified by three different research projects. Natural products are involved in scientific issues important for a sustainable society, and a multidisciplinary subject such as pharmacognosy can, therefore, be useful in increasing future interest in both chemistry and biology.
29.
Borrebaeck, Carl, et al.
(författare)
Progress in miniaturisation of proteon arrays - a step closer to high-density nanoarrays
2007
Ingår i: Drug Discovery Today. - : Elsevier BV. - 1878-5832 .- 1359-6446. ; 12:19-20, s. 813-819
Forskningsöversikt (refereegranskat) abstract
Protein microarrays is a technology with great promise for high-throughput proteomics. Designing high-performance protein microarrays for global proteome analysis has, however, turned out to be challenging. To this end, major efforts are under way to design novel array formats capable of harboring the tremendous range of probes required to target complex proteomes composed of more than 10 000 analytes. By adopting nanotechnology, the first generation of miniaturized nanoarrays has recently emerged, which opens up new avenues for global proteome analysis and disease proteomics. This review describes the progress and key issues in designing miniaturized protein arrays.
30.
