| 1. |
- Ashton, M, et al.
(författare)
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Quantitative in vivo and in vitro sex differences in artemisinin metabolism in rat
- 1999
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Ingår i: Xenobiotica. - : Informa UK Limited. - 0049-8254 .- 1366-5928. ; 29:2, s. 195-204
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Tidskriftsartikel (refereegranskat)abstract
- 1. The pharmacokinetics of the antimalarial compound artemisinin were compared in the male and female Sprague-Dawley rat after single dose i.v. (20 mg.kg(-1)) or i.p. (50 mg.kg(-1)) administration of an emulsion formulation. 2. Plasma clearance of artemisinin was 12.0 (95 % confidence interval: 10.4, 13.0) l.h(-1).kg(-1) in the male rat and 10.6 (95% CI: 7.5, 15.0) I.h(-1).kg(-1) in the female rat suggesting high hepatic extraction in combination with erythrocyte uptake or clearance. Artemisinin half-life was similar to 0.5 h after both routes of administration in both sexes. Values for plasma clearance and half-lives did not statistically differ between the sexes. 3. After i.p. administration artemisinin AUCs were 2-fold higher in the female compared with male rat (p < 0.001). Artemisinin disappearance was 3.9-fold greater in microsomes from male compared with female livers and it was inhibited in male microsomes by goat or rabbit serum containing antibodies against CYP2C11 and CYP3A2 but not CYP2B1 or CYP2E1. 4. The unbound fraction of artemisinin in plasma was lower (p < 0.001) in plasma obtained from the male (8.8+/-2.0%) compared with the female rat (11.7+/-2.2%). 5. The possibility of a marked sex difference, dependent on the route of administration, has to be taken into account in the design and interpretation of toxicological studies of artemisinin in this species.
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| 2. |
- Ejlertsson, Jörgen, et al.
(författare)
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Anaerobic degradation of xenobiotics by organisms from munical solid waste under landfilling conditions
- 1995
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Ingår i: Antonie van Leeuwenhoek. International Journal of General and Molecular Microbiology. - 0003-6072 .- 1572-9699. ; 69:1, s. 67-74
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Tidskriftsartikel (refereegranskat)abstract
- The potential for biological transformation of 23 xenobiotic compounds by microorganisms in municipal solid waste (MSW) samples from a laboratory scale landfill reactor was studied. In addition the influence of these xenobiotic compounds on methanogenesis was investigated. All R11, 1,1 dichloroethylene, 2,4,6 trichlorophenol, dimethyl phthalate, phenol, benzoate and phthalic acid added were completely transformed during the period of incubation (> 100 days). Parts of the initially added perchloroethylene, trichloroethylene, R12, R114, diethyl phthalate, dibutyl phthalate and benzylbutyl phthalate were transformed. Methanogenesis from acetate was completely inhibited in the presence of 2,5 dichlorophenol, whereas 2,4,6 trichlorophenol and R11 showed an initial inhibition, whenafter methane formation recovered. No transformation or effect on the anaerobic microflora occurred for R13, R22, R114, 3 chlorobenzoate, 2,4,6 trichlorobenzoate, bis(2 ethyl)hexyl phthalate, diisodecyl phthalate and dinonyl phthalate. The results indicate a limited potential for degradation, of the compounds tested, by microorganisms developing in a methanogenic landfill environment as compared with other anaerobic habitats such as sewage digestor sludge and sediments.
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| 3. |
- Hassan, M, et al.
(författare)
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A mechanism-based pharmacokinetic-enzyme model for cyclophosphamide autoinduction in breast cancer patients
- 1999
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Ingår i: British Journal of Clinical Pharmacology. - 0306-5251 .- 1365-2125. ; 48:5, s. 669-677
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Tidskriftsartikel (refereegranskat)abstract
- Aims This study investigated the pharmacokinetics of cyclophosphamide (CP) and its main metabolite 4-hydroxycyclophosphamide (4-OH-CP) in patients with breast cancer undergoing high dose chemotherapy prior to autologous stem cell transplantation. An enzyme turn-over model was also developed to study the time course of cyclophosphamide induction. Methods Fourteen patients received a combination of CP (6 g m(-2)), thiotepum (500 mg m(-2)) and carboplatin (800 mg m(-2)) as a 96 h infusion. Plasma concentrations of CP and 4-OH-CP were determined with h.p.l.c. and a pharmacokinetic and enzyme turn-over model applied to data using NONMEM. Results CP plasma concentrations were described by a two-compartment model with a noninducible and an inducible pathway, the latter forming 4-OH-CP. In the final enzyme model, CP affects the amount of enzymes by increasing the enzyme production rate. CP concentrations decreased during the infusion with no subsequent change in 4-OH-CP concentrations. CP inducible and noninducible clearance were estimated to 1.76 1 h(-1) (90% C.I. 0.92-2.58) and 1.14 1 h(-1) (0.31-1.85), respectively. The induction resulted in an approximately doubled CP clearance through the inducible pathway at the end of treatment. The model predicted the enzyme turn-over half-life to be 24 h. Conclusions The presented mechanism-based enzyme induction model where the pharmacokinetics of the inducer and the enzyme pool counterbalance each other successfully described CP autoinduction. It is reasonable to believe that CP affects its own elimination by increasing the enzyme production rate and thereby increasing the amount of enzyme by which CP is eliminated.
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| 4. |
- Mihara, K, et al.
(författare)
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Stereospecific analysis of omeprazole supports artemisinin as a potent inducer of CYP2C19
- 1999
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Ingår i: Fundamental & Clinical Pharmacology. - 0767-3981 .- 1472-8206. ; 13:6, s. 671-675
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Tidskriftsartikel (refereegranskat)abstract
- The purpose of the study was to determine the enantiomer pharmacokinetics of omeprazole and 5-hydroxy-omeprazole before and after administration of the antimalarial artemisinin to confirm artemisinin's ability to induce CYP2C19. Nine healthy male Vietnamese subjects were given a single 20 mg dose of omeprazole orally 1 week before (day -7) artemisinin administration. Artemisinin was then given orally (500 mg) for 7 days (days 1-7). On days 1 and 7, a single 20 mg dose of omeprazole was coadministered with artemisinin. After a washout period of 6 days, a single 20 mg dose of omeprazole was again administered together with a single 500 mg of artemisinin (day 14). Stereoselective pharmacokinetics of omeprazole and 5-hydroxyomeprazole was determined on days of omeprazole administration. Seven days of artemisinin administration significantly decreased the AUC of both omeprazole enantiomers (day 7), compared with day 1 (P < 0.001). All values were normalized after the washout period. Artemisinin increased the AUC ratio of R-5-hydroxyomeprazole/R-omeprazole significantly (P < 0.01) on day 7. The AUC ratio of omeprazole sulphone/S-omeprazole did not differ between study days. Artemisinin decreased the AUC of S-omeprazole to the same extent as that of R-omeprazole in extensive CYP2C19 metabolizers, suggesting that artemisinin induces a different enzyme in addition to CYP2C19. These results support and strengthen earlier findings that artemisinin induces CYP2C19 as well as at least one enzyme other than CYP3A4.
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| 5. |
- Nettelbladt, Per, et al.
(författare)
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The social network of patients with schizoaffective disorder as compared to patients with diabetes and to healthy individuals
- 1995
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Ingår i: Social Science and Medicine. - 0277-9536. ; 41:6, s. 901-907
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Tidskriftsartikel (refereegranskat)abstract
- The social network was evaluated by means of the self-rating scale 'Interview Schedule for Social Interaction' (ISSI) and semi-structured interviews in married patients with a DSM-III diagnosis of schizoaffective disorder (N = 17, partners, N = 16), married patients with diabetes (N = 10, partners, N = 10) and in married healthy individuals (N = 8, partners, N = 8). The two latter groups were comparison control groups matched for sex and age to the patients with a schizoaffective disorder. The scores on the ISSI and its subscales for the groups were compatible to those found in other Swedish studies. Patients with a schizoaffective disorder both experienced that they had less access to (AVAT) and were less satisfied with their deep emotional relations (ADAT). The same patients had a higher level of neuroticism as compared to the rest. The patients with a schizoaffective disorder had less often than the patients with diabetes been informed about their disease. Moreover, the partners to the patients with a schizoaffective disorder had not been informed about the disease and experienced that they had fewer social contacts (AVSI). A challenge for the professional network in psychiatry is to improve the information and education to families in which one member is struck by a schizoaffective disorder.
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| 6. |
- Nilsson, Ulrika K., et al.
(författare)
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Different proliferative responses of Gi/o-protein-coupled receptors in human myometrial smooth muscle cells: a possible role of calcium
- 1998
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Ingår i: Journal of Molecular Neuroscience. - 0895-8696 .- 1559-1166. ; 11:1, s. 11-21
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Tidskriftsartikel (refereegranskat)abstract
- The majority of studies investigating the proliferative effect of Gi/o-protein-coupled receptor agonists are performed in recombinant receptor systems or cell lines. In these systems the relative stoichiometry of receptors compared to other cell components might be changed, which may lead to anomalies in cellular responses in contrast to natural occurring systems. In the present study, we have used primary cultures of smooth muscle cells (SMCs) isolated from human myometrium to characterize the proliferative effects of agonists binding to two different G protein-coupled receptors. Treatment of quiescent SMCs with lysophosphatidic acid (LPA) and noradrenaline resulted in significant increases in [3H]thymidine incorporation. However, LPA was almost four times more effective than noradrenaline in this respect. The proliferative effects of the agonists could be completely blocked by pertussis toxin, indicating that the response are mediated through Gi/o-proteins. The selective α2-adrenergic receptor (α2-AR) antagonist yohimbine dose-dependently reduced the effect of noradrenaline suggesting that the proliferative response was mediated through α2-ARs. The proliferative effects induced by LPA and noradrenaline was markedly reduced in SMCs treated with the tyrosine kinase inhibitor genistein and the cAMP elevating compound forskolin. However, LPA but not noradrenaline induced rapid rises in the cytosolic free Ca2+ concentration [Ca2+]i. The ability to increase Ca2+ might be one explanation why LPA produce a more pronounced proliferative response than noradrenaline in primary cultures of human myometrial SMCs.
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| 7. |
- Pettersson, Ulrika, 1970-
(författare)
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Bone mass in the young athlete
- 1999
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Bone mass and bone size accumulate during childhood and adolescence and peak in the twenties. The obtained peak bone mass has been suggested to be a major determinant of bone mass even in the very elderly. Although, genetic factors are the main determinants, environmental and lifestyle factors also play a crucial role in modulating maximal bone mass. Assessing these lifestyle factors would be of great importance for the intervention strategies against osteoporosis. The first aim of this thesis was to compare the bone mass and bone size in male and female young adults on a high level of physical activity with males or females on a low level of physical activity. Furthermore, it also aimed to investigate the influence of pubertal maturity, menstrual disturbances, and different body constitutional factors on bone mass and size during adolescence and young adulthood. The female activity groups consisted of cross-county skiers, soccer players, and rope skippers. Compared to their age-matched inactive controls, all these athletic groups demonstrated a significantly higher bone mineral density (BMD) at those sites subjected to the sport-specific loading. Rope-skipping, a very high impact activity was associated with a higher bone size, preferentially in the lower extremity, suggesting an effect of weight-bearing activity also on bone geometry. The effect of menstrual disturbances was evaluated in a group of long-distance runners, where amenorrheic runners had significantly lower BMD in both trabecular and also cortical bone in the lower extremity compared to eumenorrheic runners, suggesting that weight-bearing activity cannot compensate for the shortfall of reduced estrogen levels. The male activity groups consisted of ice hockey players and badminton players. Compared to their age-matched controls, both athletic groups demonstrated a significantly higher BMD at those sites subjected to the sport-specific loading. Especially badminton was associated with a high BMD, suggesting that physical activity, including jumps in unusual directions has a great osteogenic potential. The main determinants of BMD in both male and females were, except for type of physical activity, activity, muscle strength, height, and different body constitutional factors. However, the relationships with muscle strength and body constitution were somewhat weaker in the athletic groups, especially in the males, indicating that impact forces may be of greater importance in regulating bone mass in highly trained athletes. Yet bone size was largely determined by parameters related to body size and less strongly to physical activity. In a prospective study on adolescent boys, the changes in bone mass during late puberty were mainly accounted for by growth and development, including height and pubertal maturation, and less to physical activity level. Thus, the osteogenic effect from physical activity seems to be of importance for bone mass achievement predominantly before late puberty.
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| 8. |
- Ringdahl, Ulrika, et al.
(författare)
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Molecular co-operation between protein PAM and streptokinase for plasmin acquisition by Streptococcus pyogenes.
- 1998
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Ingår i: Journal of Biological Chemistry. - 1083-351X. ; 273:11, s. 6424-6430
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Tidskriftsartikel (refereegranskat)abstract
- Bacterial surface-associated plasmin formation is believed to contribute to invasion, although the underlying molecular mechanisms are poorly understood. To define the components necessary for plasmin generation on group A streptococci we used strain AP53 which exposes an M-like protein ("PAM") that contains a plasminogen-binding sequence with two 13-amino acid residues long tandem repeats (a1 and a2). Utilizing an Escherichia coli-streptococcal shuttle vector, we replaced a 29-residue long sequence segment of Arp4, an M-like protein that does not bind plasminogen, with a single (a1) or the combined a1a2 repeats of PAM. When expressed in E. coli, the purified chimeric Arp/PAM proteins both bound plasminogen, as well as plasmin, and when used to transform group A streptococcal strains lacking the plasminogen-binding ability, transformants with the Arp/PAM constructs efficiently bound plasminogen. Moreover, when grown in the presence of plasminogen, both Arp/PAM- and PAM-expressing streptococci acquired surface-bound plasmin. In contrast, plasminogen activation failed to occur on PAM- and Arp/PAM-expressing streptococci carrying an inactivated streptokinase gene: this block was overcome by exogenous streptokinase. Together, these results provide evidence for an unusual co-operation between a surface-bound protein, PAM, and a secreted protein, streptokinase, resulting in bacterial acquisition of a host protease that is likely to spur parasite invasion of host tissues.
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| 9. |
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| 10. |
- Svensson, Ulrika S H, et al.
(författare)
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Artemisinin induces omeprazole metabolism in human beings
- 1998
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Ingår i: Clinical Pharmacology and Therapeutics. - 0009-9236 .- 1532-6535. ; 64, s. 160-
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Tidskriftsartikel (refereegranskat)abstract
- Objective: This study investigated whether time-dependent artemisinin pharmacokinetics correlated to CYP3A4 or CYP2C19 activity in vivo. Methods: Artemisinin (two oral doses per day of 250 mg) was given to nine healthy Vietnamese subjects for 7 days (day 1 to day 7), Single 20 mg doses of omeprazole were given orally on day -7, day 1, and day 7, Single doses of artemisinin and omeprazole were given in combination on day 14 after a 6-day washout period. The pharmacokinetics of artemisinin, omeprazole, hydroxyomeprazole, and omeprazole sulfone were evaluated on days -7, 1, 7, and 14, On the same days urine was collected for the determination of 6 beta-hydroxycortisol and cortisol excretion. Results: Areas under plasma concentration-time curves (AUC) for artemisinin and omeprazole decreased on day 7 to 20% (95% confidence intervals, 13%, 28%) and 35% (25%, 46%), respectively, compared with values on day 1, AUC ratios for hydroxyomeprazole/omeprazole increased 2.2-fold (1,7, 2.7) on day 7 compared with values on day 1, Al values were normalized at day 14, There were no significant changes in the omeprazole sulfone/omeprazole ratio or in the 6 beta-hydroxycortisol/cortisol ratio between the study days. In one subject found to have poor CYP2C19 metabolization, the elimination of omeprazole increased after artemisinin exposure, with no change in the hydroxyomeprazole/omeprazole AUC ratio. Conclusion: Artemisinin did not alter CYP3A4 activity, whereas an increase in CYP2C19 activity was observed. The increased elimination of omeprazole in both poor and extensive CYP2C19 metabolizers suggests artemisinin induces both CYP2C19 and another enzyme.
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| 11. |
- Svensson, Ulrika S H, et al.
(författare)
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High in situ rat intestinal permeability of artemisinin unaffected by multiple dosing and with no evidence of P-glycoprotein involvement
- 1999
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Ingår i: Drug Metabolism And Disposition. - 0090-9556 .- 1521-009X. ; 27:2, s. 227-232
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Tidskriftsartikel (refereegranskat)abstract
- The objective of this study was to investigate whether the decrease in artemisinin bioavailability after repeated oral dosing in humans can be a result of increased efflux of artemisinin by P-glycoprotein or decreased membrane transport at the intestinal barrier, The effective jejunal permeability (P-eff) of artemisinin was investigated using an in situ rat perfusion model. Fifty-four rats were randomized to one of three treatment arms: no pretreatment, pretreatment with artemisinin emulsion for 5 days (60 mg/kg/day, p.o.), or pretreatment with emulsion vehicle for 5 days, The rats within each treatment arm were randomized further to be jejunally perfused with either low (500 ng/ml) or high (5000 ng/ml) artemisinin concentration or low artemisinin concentration plus the P-glycoprotein inhibitor R,S-verapamil (400 mu g/ml). Perfusate samples were assayed for content of artemisinin, R,S-verapamil, and perfusion viability markers. Artemisinin P-eff was 1,44 +/- 0.38, 1.17 +/- 0.32, and 1.71 +/- 0.29 (.10(-4), cm/s) in rats receiving no pretreatment and perfused with low, high, or low artemisinin concentration plus verapamil, respectively. Multiple oral dosing of artemisinin did not affect the jejunal permeability of artemisinin, R,S-verapamil P-eff was similar in artemisinin-pretreated rats (1.09 +/- 0.54.10(-4), cm/s) and rats pretreated with only vehicle (1.07 +/- 0.37.10(-4), cm/s), The decrease in artemisinin bioavailability after multiple oral dosing in human is probably not a result of changes in P-glycoprotein expression or general intestinal transport. It seems more likely attributed to increased hepatocellular activity. Furthermore, artemisinin exhibits high jejunal permeability and is neither a substrate nor inducer of P-glycoprotein.
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| 12. |
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| 13. |
- Svensson, Ulrika S H, et al.
(författare)
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Identification of the human cytochrome P450 enzymes involved in the in vitro metabolism of artemisinin
- 1999
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Ingår i: British Journal of Clinical Pharmacology. - 0306-5251 .- 1365-2125. ; 48:4, s. 528-535
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Tidskriftsartikel (refereegranskat)abstract
- Aims The study aimed to identify the specific human cytochrome P450 (CYP450) enzymes involved in the metabolism of artermisinin. Methods Microsomes from human B-lymphoblastoid cell lines transformed with individual CYP450 cDNAs were investigated for their capacity to metabolize artemisinin. The effect on artemisinin metabolism in human liver microsomes by chemical inhibitors selective for individual forms of CYP450 was investigated. The relative contribution of individual CYP450 isoenzymes to artemisinin metabolism in human liver microsomes was evaluated with a tree-based regression model of: artemisinin disappearance rate and specific CYP450 activities. Results The involvement of CYP2B6 in artermisinin metabolism was demonstrated by metabolism of artemisinin by recombinant CYP2B6, inhibition of artemisinin disappearance in human liver microsomes by orphenadrine (76%) and primary inclusion of CYP2B6 in the tree-based regression model. Recombinant CYP3A4 was catalytically competent in metabolizing artemisinin, although the rate was 10% of that for recombinant CYP2B6. The tree-based regression model suggested CYP3A4 to be of importance in individuals with low CYP2B6 expression. Even though ketoconazole inhibited artemisinin metabolism in human liver microsomes by 46%, incubation with ketoconazole together with orphenadrine did not increase the inhibition of artemisinin metabolism compared to orphenadrine alone. Troleandomycin failed to inhibit artemisinin metabolism. The rate of artemisinin metabolism in recombinant CYP2A6 was 15% of that for recombinant CYP2B6. The inhibition of artemisinin metabolism in human liver microsomes by 8-methoxypsoralen (a CYP2A6 inhibitor)was 82% but CYP2A6 activity was not included in the regression tree. Conclusions Artemisinin metabolism in human liver microsomes is mediated primarily by CYP2B6 with probable secondary contribution of CYP3A4 in individuals with low CYP2B6 expression. The contribution of CYP2A6 to artemisinin metabolism is likely of minor importance.
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| 14. |
- Zuccarello, Guido, et al.
(författare)
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HIV-1 protease inhibitors based on acyclic carbohydrates
- 1998
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Ingår i: Journal of Organic Chemistry. - : American Chemical Society (ACS). - 0022-3263 .- 1520-6904. ; 63:15, s. 4898-4906
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Tidskriftsartikel (refereegranskat)abstract
- A series of acyclic C2-symmetric HIV protease inhibitors readily accessible from D-mannitol have been developed. Several of the compounds synthesized showed significant in vitro activity against HIV-1 protease.
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