51.
52.
Mukonzo, Jackson K, et al.
(författare)
A novel polymorphism in ABCB1 gene, CYP2B6*6 and sex predict single-dose efavirenz population pharmacokinetics in Ugandans.
2009
Ingår i: British journal of clinical pharmacology. - : Wiley. - 1365-2125 .- 0306-5251. ; 68:5, s. 690-9
Tidskriftsartikel (refereegranskat) abstract
AIMS: Efavirenz exhibits pharmacokinetic variability causing varied clinical response. The aim was to develop an integrated population pharmacokinetic/pharmacogenetic model and investigate the impact of genetic variations, sex, demographic and biochemical variables on single-dose efavirenz pharmacokinetics among Ugandan subjects, using NONMEM. METHODS: Efavirenz plasma concentrations (n = 402) from 121 healthy subjects were quantified by high-performance liquid chromatography. Subjects were genotyped for 30 single nucleotide polymorphisms (SNPs), of which six were novel SNPs in CYP2B6, CYP3A5 and ABCB1. The efavirenz pharmacokinetics was described by a two-compartment model with zero- followed by first-order absorption. RESULTS: Apparent oral clearance (95% confidence interval) was 4 l h l(-1) (3.5, 4.5) in extensive metabolizers. In the final model, incorporating multiple covariates, statistical significance was found only for CYP2B6*6 and CYP2B6*11 on apparent oral clearance as well as ABCB1 (rs3842) on the relative bioavailability. Subjects homozygous for CYP2B6*6 (G516T, A785G) and *11 displayed 21 and 20% lower apparent oral clearance, respectively. Efavirenz relative bioavailability was 26% higher in subjects homozygous for ABCB1 (rs3842). The apparent peripheral volume of distribution was twofold higher in women compared with men. CONCLUSIONS: The model identified the four factors CYP2B6*6, CYP2B6*11, a novel variant allele in ABCB1 (rs3842) and sex as major predictors of efavirenz plasma exposure in a healthy Ugandan population after single-dose administration. Use of mixed-effects modelling allowed the analysis and integration of multiple pharmacogenetic and demographic covariates in a pharmacokinetic population model.
53.
Mörck, Catarina, 1972, et al.
(författare)
Statins inhibit protein lipidation and induce the unfolded protein response in the non-sterol producing nematode Caenorhabditis elegans
2009
Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 106:43, s. 18285-90
Tidskriftsartikel (refereegranskat) abstract
Statins are compounds prescribed to lower blood cholesterol in millions of patients worldwide. They act by inhibiting HMG-CoA reductase, the rate-limiting enzyme in the mevalonate pathway that leads to the synthesis of farnesyl pyrophosphate, a precursor for cholesterol synthesis and the source of lipid moieties for protein prenylation. The nematode Caenorhabditis elegans possesses a mevalonate pathway that lacks the branch leading to cholesterol synthesis, and thus represents an ideal organism to specifically study the noncholesterol roles of the pathway. Inhibiting HMG-CoA reductase in C. elegans using statins or RNAi leads to developmental arrest and loss of membrane association of a GFP-based prenylation reporter. The unfolded protein response (UPR) is also strongly activated, suggesting that impaired prenylation of small GTPases leads to the accumulation of unfolded proteins and ER stress. UPR induction was also observed upon pharmacological inhibition of farnesyl transferases or RNAi inhibition of a specific isoprenoid transferase (M57.2) and found to be dependent on both ire-1 and xbp-1 but not on pek-1 or atf-6, which are all known regulators of the UPR. The lipid stores and fatty acid composition were unaffected in statin-treated worms, even though they showed reduced staining with Nile red. We conclude that inhibitors of HMG-CoA reductase or of farnesyl transferases induce the UPR by inhibiting the prenylation of M57.2 substrates, resulting in developmental arrest in C. elegans. These results provide a mechanism for the pleiotropic effects of statins and suggest that statins could be used clinically where UPR activation may be of therapeutic benefit.
54.
Unga, Johan, 1976, et al.
(författare)
Relating solubility data of parabens in liquid PEG 400 to the behaviour of PEG 4000-parabens solid dispersions
2009
Ingår i: European journal of pharmaceutics and biopharmaceutics. - : Elsevier BV. - 0939-6411 .- 1873-3441. ; 73:2, s. 260-268
Tidskriftsartikel (refereegranskat) abstract
The solid state behaviour of polyethylene glycol 4000 (PEG 4000) and dispersions of a homologous series of parabens (methyl- (MP), ethyl- (EP), propyl- (PP) and butyl- (BP)) were examined and compared to the paraben solubility in liquid PEG 400. Dispersions were prepared by co-melting different amounts of paraben (5-80% (w/w)) and PEG 4000 and were studied using a combination of differential scanning calorimetry (DSC) and small and wide angle X-ray diffraction (SAXD/WAXD). Depending on the concentration of parabens in the dispersions, DSC showed melting peaks from folded and unfolded forms of PEG, a eutectic melting and melting of pure parabens. The fraction of folded PEG increased and the melting temperatures of both PEG forms decreased with increasing paraben content. In an apparent phase diagram of PP-PEG dispersions a eutectic mixture appeared above 5% PP. In addition, a melting peak corresponding to the paraben appeared for dispersion containing more than 60% PP. Similar phase diagrams were shown for the other parabens. The SAXD data and a 1D correlation function analysis revealed that MP and BP were incorporated into the amorphous domains of the lamellae of solid PEG to a higher degree than EP and PP. In addition, the lamellae thickness of PEG and the fraction of amorphous domains increased more for MP and BP compared to EP and PP. BP showed the highest solubility of the parabens followed by MP, EP and PP in both liquid and solid PEG. Furthermore, the thickness of the amorphous domains of the PEG in the different parabens-PEG dispersions could be correlated to the solubility in liquid PEG 400.
55.
Wallin, Johan E., et al.
(författare)
A tool for neutrophil guided dose adaptation in chemotherapy
2009
Ingår i: Computer Methods and Programs in Biomedicine. - : Elsevier BV. - 0169-2607 .- 1872-7565. ; 93:3, s. 283-291
Tidskriftsartikel (refereegranskat) abstract
Chemotherapy dosing in anticancer treatment is a balancing act between achieving concentrations that are effective towards the malignancy and that result in acceptable side-effects. Neutropenia is one major side-effect of many antitumor agents, and is related to an increased risk of infection. A model capable of describing the time-course of myelosuppression from administered drug could be used in individual dose selection. In this paper we describe the transfer of a previously developed semi-mechanistic model for myelosuppression from NONMEM to a dosing tool in MS Excel, with etoposide as an example. The tool proved capable to solve a differential equation system describing the pharmacokinetics and pharmacodynamics, with estimation performance comparable to NONMEM. In the dosing tool the user provides neutrophil measures from a previous treatment course and request for the dose that results in a desired nadir in the upcoming course through a Bayesian estimation procedure.
56.
Krigsman, Kristin, et al.
(författare)
Refill non-adherence to repeat prescriptions leads to treatment gaps or to high extra costs.
2007
Ingår i: Pharmacy World & Science. - : Springer Netherlands. - 0928-1231 .- 1573-739X. ; 29:1, s. 19-24
Tidskriftsartikel (refereegranskat) abstract
OBJECTIVE: To determine the nature and extent of undersupply and the economic consequences of oversupply of medication among non-adherent patients. METHODS: This study used copies of repeat prescriptions (= multiple dispensations), collected during 1 week in 2002 at 16 Swedish community pharmacies. For patients with a refill adherence below 80%, treatment gaps were defined as the number of days they had no drug available. The cost of drug oversupply (i.e., refill adherence > 120%) was calculated from the prices of the drug packages dispensed. RESULTS: The number of collected repeat prescriptions was 3,636. The median of treatment gaps among patients with a refill adherence below 80% was 53 days per 90-100 days treatment period and the corresponding median for oversupply was 40 days. The cost of oversupply for exempt patients (i.e., patients who have paid 1,800 SEK (Euro 196; US$ 243) per year for medicines) was 32,000 SEK (Euro 3,500; US$ 4,300) higher than for non-exempt patients. An extrapolation to all Sweden indicates that exemption from charges leads to an additional oversupply of about 142 million SEK (Euro 15 million; US$ 19 million) per year above that of non-exempt patients. CONCLUSION: Both undersupply and oversupply of prescribed medicines are common in Sweden. Patients with a refill adherence below 80% seem to have less than half of the prescribed treatment available. Oversupply or drug stockpiling occurs more frequently among exempt than among non-exempt patients, and this oversupply leads to high unnecessary costs.
57.
Andersen, Grethe, et al.
(författare)
Quantitative measurement of the levels of melanocortin receptor subtype 1, 2, 3 and 5 and pro-opio-melanocortin peptide gene expression in subsets of human peripheral blood leucocytes
2005
Ingår i: Scandinavian Journal of Immunology. - Oxford : Wiley. - 0300-9475 .- 1365-3083. ; 61:3, s. 279-284
Tidskriftsartikel (refereegranskat) abstract
Levels of the melanocortin receptor (MCR) 1, 2, 3 and 5 subtypes and pro-opio-melanocortin (POMC) protein mRNA were measured by the real-time quantitative reverse transcriptase polymerase chain reaction method in CD4+ T helper (Th) cells, CD8+ T cytotoxic cells, CD19+ B cells, CD56+ natural killer (NK) cells, CD14+ monocytes and CD15+ granulocytes from healthy donors. We found high levels of all of the MC1, 2, 3 and 5R subtype mRNA in Th cells and moderate levels in NK cells, monocytes and granulocytes. POMC peptide mRNA was found in all examined leucocyte subsets, but only low levels were present in granulocytes. Our findings suggest a co-ordinating role for MCR subtypes and their naturally occurring ligands in the co-operation between innate and adaptive immunity. Moreover, our findings are compatible with earlier finding of MCR-mediated tolerance induction in Th cells.
58.
59.
Kadi, Fawzi
(författare)
Cellular and molecular mechanisms responsible for the action of testosterone on human skeletal muscle : a basis for illegal performance enhancement
2008
Ingår i: British Journal of Pharmacology. - Basingstoke : Nature Publ. Group. - 0007-1188 .- 1476-5381. ; 154:3, s. 522-528
Tidskriftsartikel (refereegranskat) abstract
The popularity of testosterone among drug users is due to its powerful effects on muscle strength and mass. Important mechanisms behind the myotrophic effects of testosterone were uncovered both in athletes using steroids for several years and in short-term controlled studies. Both long-term and short-term steroid usage accentuates the degree of fibre hypertrophy in human skeletal muscle by enhancing protein synthesis. A mechanism by which testosterone facilitates the hypertrophy of muscle fibres is the activation of satellite cells and the promotion of myonuclear accretion when existing myonuclei become unable to sustain further enhancement of protein synthesis. Interestingly, long-term steroid usage also enhances the frequency of fibres with centrally located myonuclei, which implies the occurrence of a high regenerative activity. Under the action of testosterone, some daughter cells generated by satellite cell proliferation may escape differentiation and return to quiescence, which help to replenish the satellite cell reserve pool. However, whether long-term steroid usage induces adverse effects of satellite cells remains unknown. Testosterone might also favour the commitment of pluripotent precursor cells into myotubes and inhibit adipogenic differentiation. The effects of testosterone on skeletal muscle are thought to be mediated via androgen receptors expressed in myonuclei and satellite cells. Some evidence also suggests the existence of an androgen-receptor-independent pathway. Clearly, testosterone abuse is associated with an intense recruitment of multiple myogenic pathways. This provides an unfair advantage over non-drug users. The long-term consequences on the regenerative capacity of skeletal muscle are unknown.
60.
Abu-Bakar, A'edah, et al.
(författare)
Regulation of CYP2A5 gene by the transcription factor nuclear factor (erythroid-derived 2)-like 2
2007
Ingår i: Drug Metabolism And Disposition. - : American Society for Pharmacology & Experimental Therapeutics (ASPET). - 0090-9556 .- 1521-009X. ; 35:5, s. 787-794
Tidskriftsartikel (refereegranskat) abstract
We have previously shown that cadmium, a metal that alters cellular redox status, induces CYP2A5 expression in nuclear factor (erythroid-derived 2)-like 2 wild-type (Nrf2(-/-)) mice but not in the knockout (Nrf2(-/-)) mice. In the present studies, the potential role of Nrf2 in cadmium-mediated regulation of Cyp2a5 gene was investigated in mouse primary hepatocytes. Cadmium chloride (CdCl2) caused a time-dependent induction of the CYP2A5 at mRNA, protein, and activity levels, with a substantial increase observed within 3 h of exposure. Immunoblotting showed cadmium-dependent nuclear accumulation of Nrf2 within 1 h of exposure. Cotransfection of mouse primary hepatocytes with Cyp2a5 promoter-luciferase reporter plasmids and Nrf2 expression plasmid resulted in a 3-fold activation of Cyp2a5 promoter-mediated transcription relative to the control. Deletion analysis of the promoter localized the Nrf2 responsive region to an area from -2656 to -2339 base pair. Computer-based sequence analysis identified two putative stress response elements (StRE) within the region at positions -2514 to -2505 and -2386 to -2377. Chromatin immunoprecipitation and electrophoretic mobility shift assays showed that interaction of the more proximal StRE with Nrf2 was stimulated by CdCl2. Finally, site-directed mutagenesis of the proximal StRE in Cyp2a5 promoter-luciferase reporter plasmids abolished Nrf2 mediated induction. Collectively, the results indicate that Nrf2 activates Cyp2a5 transcription by directly binding to the StRE in the 5'-flanking region of the gene. This acknowledges Cyp2a5 as the first phase I xenobiotic-metabolizing gene identified under the control of the StRE-Nrf2 pathway with a potential role in adaptive response to cellular stress.
