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  • 3651. Zhang, Weihua
    et al.
    Jernerén, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap. Dept. of Pharmacology, University of Oxford.
    Lehne, Benjamin C
    Chen, Ming-Huei
    Luben, Robert N
    Johnston, Carole
    Elshorbagy, Amany
    Eppinga, Ruben N
    Scott, William R
    Adeyeye, Elizabeth
    Scott, James
    Böger, Rainer H
    Khaw, Kay-Tee
    van der Harst, Pim
    Wareham, Nicholas J
    Vasan, Ramachandran S
    Chambers, John C
    Refsum, Helga
    Kooner, Jaspal S
    Genome-wide association reveals that common genetic variation in the kallikrein-kinin system is associated with serum L-arginine levels.2016Inngår i: Thrombosis and haemostasis, ISSN 2567-689X, Vol. 116, nr 6, s. 1041-1049Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    ). Together these two loci explain 7 % of the total variance in serum L-arginine concentrations. The associations at both loci were replicated in independent cohorts with plasma L-arginine measurements (p<0.004). The two sentinel SNPs are in nearly complete LD with the nonsynonymous SNP rs3733402 at KLKB1 and the 5'-UTR SNP rs1801020 at F12, respectively. SNPs at both loci are associated with blood pressure. Our findings provide new insight into the genetic regulation of L-arginine and its potential relationship with cardiovascular risk.

  • 3652.
    Zhang, Xiaoqun
    et al.
    Karolinska Institutet, Institutionen för fysiologi och farmakologi.
    Andren, Per E
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, MMS, medicinsk masspektrometri.
    Chergui, Karima
    Karolinska Institutet, Institutionen för fysiologi och farmakologi.
    Svenningsson, Per
    Karolinska Institutet, Institutionen för fysiologi och farmakologi.
    Neurokinin B/NK3 receptors exert feedback inhibition on L-DOPA actions in the 6-OHDA lesion rat model of Parkinson's disease2008Inngår i: Neuropharmacology, ISSN 0028-3908, E-ISSN 1873-7064, Vol. 54, nr 7, s. 1143-1152Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Neurokinin B (NKB) and substance P (SP) act via NK(3) and NK(1) receptors. Using the unilateral 6-hydroxydopamine (6-OHDA) lesion rat model of Parkinson's disease (PD), it was found that chronic, but not acute, administration of L-DOPA increases striatal NKB expression in the dopamine-depleted hemisphere. In contrast, both acute and chronic administrations of L-DOPA restore reduced levels of SP mRNA. Co-treatment with the NK(3) receptor antagonist, SB222200, and L-DOPA increased contralateral rotations compared to L-DOPA alone in L-DOPA primed rats. The NK(3)R agonist, senktide, increased the phosphorylation of tyrosine hydroxylase (TH) at Ser(19)-TH, a CaMKII site, and of Thr(286)-CaMKII in striatal slices. Senktide had no effect on P-Ser(31)-TH, a MAPK site, but reduced P-Ser(217/221)-MEK. Amperometry demonstrated that senktide increased evoked dopamine release. SB222200 blocked the effects of senktide. In striatal slices prepared from 6-OHDA-lesioned rats repeatedly treated with L-DOPA, senktide no longer increased P-Thr(286)-CaMKII, suggesting a role of NK(3)R on dopamine terminals under normal conditions. SB222200 increased P-Ser(217/221)-MEK only in dopamine-depleted slices, indicating an increased NK(3)R tone under Parkinsonism conditions. Altogether, these data demonstrate a differential regulation of NKB and SP by L-DOPA in an animal model of PD and indicate a unique role of NKB in long-term effects of L-DOPA. Behavioural, biochemical and amperometric data indicate that NKB/NK(3)R signalling stimulates dopamine transmission at the presynaptic site, but inhibits it at the postsynaptic site. The inhibitory influence of NKB/NK(3)R on dopamine transmission dominates in an animal model of PD and provides a feedback inhibition on actions mediated via L-DOPA.

  • 3653.
    Zhang, Xiaoqun
    et al.
    Karolinska Institutet, Institutionen för fysiologi och farmakologi.
    Andren, Per E
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, MMS, medicinsk masspektrometri.
    Greengard, Paul
    The Rockefeller University, Laboratory of Molecular and Cellular Neuroscience.
    Svenningsson, Per
    Karolinska Institutet, Institutionen för fysiologi och farmakologi.
    Evidence for a role of the 5-HT1B receptor and its adaptor protein, p11, in L-DOPA treatment of an animal model of Parkinsonism2008Inngår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 105, nr 6, s. 2163-2168Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Parkinson's disease (PD) is characterized by a progressive degeneration of substantia nigra dopaminergic neurons projecting to the striatum. Restoration of dopamine transmission by L-DOPA relieves symptoms of PD but causes prominent side effects. There is a strong serotonin innervation of the striatum by serotonergic neurons that remains relatively preserved in PD. The study of this innervation has been largely neglected. Here, we demonstrate that chronic L-DOPA administration to 6-OHDA-lesioned rodents increases, via D1 receptors, the levels of the 5-HT1B receptor and its adaptor protein, p11, in dopamine-denervated striatonigral neurons. Using unilaterally 6-OHDA-lesioned p11 WT and KO mice, it was found that administration of a selective 5-HT1B receptor agonist, CP94253, inhibited L-DOPA-induced rotational behavior and abnormal involuntary movements in a p11-dependent manner. These data reveal an L-DOPA-induced negative-feedback mechanism, whereby the serotonin system may influence the symptomatology of Parkinsonism.

  • 3654. Zhang, Xiaoqun
    et al.
    Andrén, Per E.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Glennon, Richard A.
    Svenningsson, Per
    Distribution, Level, Pharmacology, Regulation, and Signaling of 5-HT6 Receptors in Rats and Marmosets With Special Reference to an Experimental Model of Parkinsonism2011Inngår i: Journal of Comparative Neurology, ISSN 0021-9967, E-ISSN 1096-9861, Vol. 519, nr 9, s. 1815-1827Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Serotonin 5-HT6 receptors have been implicated in the regulation of cognition, locomotion, and mood, but the elucidation of their functions is complicated by conflicting data using various animal models. Here, a systematic evaluation showed that autoradiographic binding with the selective 5-HT6 receptor antagonist [I-125]SB-258585 was similar in marmosets and rats. In both species, [I-125]SB-258585 binding was enriched in the caudate-putamen. Various recently developed agonists and antagonists toward 5-HT6 receptors exhibited similarities in their abilities to displace [I-125]SB-258585 binding in marmosets and rats. The rank order of pEC50 values were as follows: (+) EMDT-CR = EMD386088 > MS-245 = 5-HT > EMDT >>(-)EMDT-CR; and (+)EMDT-CR = EMD386088 > 5-HT = MS-245 = EMDT >>(-)EMDT-CR, in marmosets and rats, respectively. Unilateral 6-hydroxydopamine lesioning of dopaminergic axons caused a significant decrease of [I-125]SB-258585 binding in the caudate-putamen of both marmosets and rats. Nonetheless, acute administration of the 5-HT6 receptor agonist EMDT to unilaterally 6-hydroxydopamine-lesioned rats, caused an induction of egr-1, homer, and enkephalin mRNAs in the dopamine-depleted hemisphere, indicating a supersensitization of 5-HT6 receptors following dopamine depletion. In conclusion, this study provides evidence for significant similarities in the distribution, level, pharmacology, and regulation of 5-HT6 receptors between rats and marmosets.

  • 3655. Zhang, Xiaoqun
    et al.
    Andrén, Per E.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, MMS, medicinsk masspektrometri.
    Svenningsson, Per
    Changes on 5-HT2 receptor mRNAs in striatum and subthalamic nucleus in Parkinson's disease model2007Inngår i: Physiology and Behavior, ISSN 0031-9384, E-ISSN 1873-507X, Vol. 92, nr 1-2, s. 29-33Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Changes on 5-HT2 receptor mRNAs in striatum and subthalamic nucleus in Parkinson's disease model. PHYSIOL. BEHAV. 00(0), 000-000, 2006. Abnormal interactions between the serotonin and dopamine systems may underlie the high prevalence of non-motor complications in Parkinson's disease (PD). Here, we demonstrate that the genes encoding serotonin 5-HT2A and 5-HT2C receptors are differently regulated by dopamine in the 6-hydroxydopamine (6-OHDA) rat model of PD. Nigrostriatal cell loss causes an up-regulation of 5-HT2AR mRNA, but a down-regulation of 5-HT2CR mRNA, in striatum. Repeated injections with L-DOPA/benserazide reverse the effect of 6-OHDA lesioning on 5-HT2AR, but not on 5-HT2CR, gene expression. Neither 6-OHDA-lesioning nor L-DOPA/benserazide treatment had any effect on 5-HT2AR mRNA in cortex or on 5-HT2CR mRNA in nucleus subthalamicus. These data suggest that the regulation of 5-HT2AR in striatum, in the 6-OHDA rat model of PD, is mainly dependent upon alterations in dopamine levels. 5-HT2CR, on the other hand, are regulated by nigrostriatal cell loss and by the accompanied reduction of factor(s), other than dopamine, that are normally co-expressed with dopamine. The apparent imbalance between 5-HT2AR and 5-HT2CR levels in this PD model indicates a potential role for these receptors in the pathophysiology of neuropsychiatric symptoms, such as depression and L-DOPA-induced hallucinations, which are co-morbid with PD. The fact that 5-HT2CR are differentially regulated as compared to 5-HT2AR to alterations in the dopamine tone predicts that pharmacological manipulations at 5-HT2CR, but not at 5-HT2AR, will result in similar effects in PD patients whether they are treated or not with dopamine replacement.

  • 3656.
    Zhang, Xiaoqun
    et al.
    Karolinska Institutet, Institutionen för fysiologi och farmakologi .
    Andrén, Per E.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, MMS, medicinsk masspektrometri.
    Svenningsson, Per
    Karolinska Institutet, Institutionen för fysiologi och farmakologi.
    Repeated l-DOPA treatment increases c-fos and BDNF mRNAs in the subthalamic nucleus in the 6-OHDA rat model of Parkinson's disease2006Inngår i: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 1095, s. 207-210Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The subthalamic nucleus and the striatum are input regions of the basal ganglia. This study used the unilateral 6-OHDA rat model of Parkinson's disease to examine effects of l-DOPA on the expression of c-fos and BDNF mRNAs in these nuclei. Dopamine depletion per se did not affect c-fos or BDNF. Both a single and repeated injections of l-DOPA induced c-fos, but not BDNF, in the dopamine-depleted striatum. However, repeated l-DOPA treatment increased c-fos and BDNF in the dopamine-depleted subthalamic nucleus. These molecular adaptations may reflect changes in neuronal plasticity that underlie some therapeutic actions and/or side effects of l-DOPA in Parkinson's disease.

  • 3657.
    Zhang, Xiaoqun
    et al.
    Karolinska Univ Hosp, Karolinska Inst, Ctr Mol Med L8 01, Sect Translat Neuropharmacol,Dept Clin Neurosci, Stockholm, Sweden..
    Mantas, Ioannis
    Karolinska Univ Hosp, Karolinska Inst, Ctr Mol Med L8 01, Sect Translat Neuropharmacol,Dept Clin Neurosci, Stockholm, Sweden..
    Alvarsson, Alexandra
    Karolinska Univ Hosp, Karolinska Inst, Ctr Mol Med L8 01, Sect Translat Neuropharmacol,Dept Clin Neurosci, Stockholm, Sweden..
    Yoshitake, Takashi
    Karolinska Inst, Dept Physiol & Pharmacol, Sect Pharmacol Neurochem, Solna, Sweden..
    Shariatgorji, Mohammadreza
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap. Uppsala universitet, Science for Life Laboratory, SciLifeLab. Biomolecular Mass Spectrometry Imaging, National Resource for Mass Spectrometry Imaging, Uppsala, Sweden.
    Pereira, Marcela
    Karolinska Univ Hosp, Karolinska Inst, Ctr Mol Med L8 01, Sect Translat Neuropharmacol,Dept Clin Neurosci, Stockholm, Sweden..
    Nilsson, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap. Uppsala universitet, Science for Life Laboratory, SciLifeLab. Biomol Mass Spectrometry Imaging, Natl Resource Mass Spectrometry Imaging, Uppsala, Sweden..
    Kehr, Jan
    Karolinska Inst, Dept Physiol & Pharmacol, Sect Pharmacol Neurochem, Solna, Sweden..
    Andrén, Per E.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap. Uppsala universitet, Science for Life Laboratory, SciLifeLab. Biomol Mass Spectrometry Imaging, Natl Resource Mass Spectrometry Imaging, Uppsala, Sweden..
    Millan, Mark J.
    Ctr Rech Croissy, Ctr Therapeut Innovat CNS, Inst Rech Servier, Paris, France..
    Chergui, Karima
    Karolinska Inst, Dept Physiol & Pharmacol, Sect Mol Neurophysiol, Solna, Sweden..
    Svenningsson, Per
    Karolinska Univ Hosp, Karolinska Inst, Ctr Mol Med L8 01, Sect Translat Neuropharmacol,Dept Clin Neurosci, Stockholm, Sweden..
    Striatal Tyrosine Hydroxylase Is Stimulated via TAAR1 by 3-Iodothyronamine, But Not by Tyramine or beta-Phenylethylamine2018Inngår i: Frontiers in Pharmacology, ISSN 1663-9812, E-ISSN 1663-9812, Vol. 9, artikkel-id 166Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The trace amine-associated receptor 1 (TAAR1) is expressed by dopaminergic neurons, but the precise influence of trace amines upon their functional activity remains to be fully characterized. Here, we examined the regulation of tyrosine hydroxylase (TH) by tyramine and beta-phenylethylamine (beta-PEA) compared to 3-iodothyronamine (T(1)AM). Immunoblotting and amperometry were performed in dorsal striatal slices from wildtype (WT) and TAAR1 knockout (KO) mice. T(1)AM increased TH phosphorylation at both Ser(19) and Ser(40), actions that should promote functional activity of TH. Indeed, HPLC data revealed higher rates of L-dihydroxyphenylalanine (DOPA) accumulation in WT animals treated with T(1)AM after the administration of a DOPA decarboxylase inhibitor. These effects were abolished both in TAAR1 KO mice and by the TAAR1 antagonist, EPPTB. Further, they were specific inasmuch as Ser(845) phosphorylation of the post-synaptic GluA1 AMPAR subunit was unaffected. The effects of T1AM on TH phosphorylation at both Ser(19) (CamKII-targeted), and Ser40 (PKA-phosphorylated) were inhibited by KN-92 and H-89, inhibitors of CamKII and PKA respectively. Conversely, there was no effect of an EPAC analog, 8-CPT-2Me-cAMP, on TH phosphorylation. In line with these data, T(1)AM increased evoked striatal dopamine release in TAAR1 WT mice, an action blunted in TAAR1 KO mice and by EPPTB. Mass spectrometry imaging revealed no endogenous T(1)AM in the brain, but detected T(1)AM in several brain areas upon systemic administration in both WT and TAAR1 KO mice. In contrast to T1AM, tyramine decreased the phosphorylation of Ser40-TH, while increasing Ser(845)-GluA1 phosphorylation, actions that were not blocked in TAAR1 KO mice. Likewise, beta-PEA reduced Ser(40)-TH and tended to promote Ser845-GluA1 phosphorylation. The D-1 receptor antagonist SCH23390 blocked tyramine-induced Ser(845)-GluA1 phosphorylation, but had no effect on tyramine-or beta-PEA-induced Ser(40)-TH phosphorylation. In conclusion, by intracellular cascades involving CaMKII and PKA, T(1)AM, but not tyramine and beta-PEA, acts via TAAR1 to promote the phosphorylation and functional activity of TH in the dorsal striatum, supporting a modulatory influence on dopamine transmission.

  • 3658. Zhang, Xiaozhe
    et al.
    Petruzziello, Filomena
    Zani, Fabio
    Fouillen, Laetitia
    Andrén, Per E.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Solinas, Giovanni
    Rainer, Gregor
    High Identification Rates of Endogenous Neuropeptides from Mouse Brain2012Inngår i: Journal of Proteome Research, ISSN 1535-3893, E-ISSN 1535-3907, Vol. 11, nr 5, s. 2819-2827Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Mass spectrometry-based neuropeptidomics is one of the most powerful approaches for identification of endogenous neuropeptides in the brain. Until now, however, the identification rate of neuropeptides in neuropeptidomics is relatively low and this severely restricts insights into their biological function. In the present study, we developed a high accuracy mass spectrometry-based approach to enhance the identification rates of neuropeptides from brain tissue. Our integrated approach used mixing on column for loading aqueous and organic extracts to reduce the loss of peptides during sample treatment and used charge state-directed tandem mass spectrometry to increase the number of peptides subjected to high mass accuracy fragmentation. This approach allowed 206 peptides on average to be identified from a single mouse brain sample that was prepared using 15 mu L of solutions per 1 mg of tissue. In total, we identified more than 500 endogenous peptides from mouse hypothalamus and whole brain samples. Our identification rate is about two to four times higher compared to previously reported studies conducted on mice or other species. The hydrophobic peptides, such as neuropeptide Y and galanin, could be presented and detected with hydrophilic peptides in the same LC-MS run, allowing a high coverage of peptide characterization over an organism. This will advance our understanding of the roles of diverse peptides and their links in the brain functions.

  • 3659.
    ZHANG, YAQING
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    A comparison between nonlinear mixed-effect methods and naïve pooled data methods in population pharmacokinetic model selection2018Independent thesis Advanced level (degree of Master (Two Years)), 80 poäng / 120 hpOppgave
    Abstract [en]

    Objective: Nonlinear mixed-effect (NLME) modeling is the gold standard for the construction of population PK (PPK) models. However, naïve pooled data (NPD) methods may be more robust, are more invariant to model parameterization and often less time-consuming due to the structural simplicity of the method. These advantages may facilitate NLME model selection. This study aims to compare the performance between NLME and NPD in terms of PPK model selection based on NONMEM 7.3.

    Method: NLME and NPD were compared for 13 previously developed PPK models which based on real data. Each developed model was structurally divided into five components, which contained an absorption delay model (oral administration model), absorption kinetic model, distribution model, elimination model and covariate model. For the 13 original models, 56 test models were generated by changing one of the components iteratively. The test models and original models were fitted to the corresponding real data using both NLME and NPD methods, followed by the calculation of the difference of objective function value (ΔOFV) between each test model and its related original model, for NLME and NPD separately (the OFV of test models minus original models). The best model was then selected for each comparison according to the theoretically expected 95% quantile of the χ2 distribution with degrees of freedom equal to the difference in the number of estimated parameters in component changes. In a second step, simulation studies were performed to test the sensitivity of the NLME and NPD methods to identifying different model structures. A ‘full’ PPK model with 2-compartment distribution kinetics, non-linear elimination and a transit-compartment first-order absorption model was used to simulate relatively densely sampled data. By varying parameters in the ‘full’ model, characteristics of the model could be emphasized or hidden. Relevant reduced models (one-compartment, linear elimination, no transit-compartment, zero order absorption) as well as the ‘full’ model were then fitted to the simulated data and the ability of the NPD and NLME methods to detect the true ‘full’ model were compared using ΔOFV, as in the real data examples.

    Results: In the comparison of real data the model selection of the two methods was consistent for 48 out of 56 test models. 5 out of 8 exceptions in this comparison occurred when the test model and original model differed in the distribution model, and 3 out of 8 differed in the elimination model, which indicated that the difference might exist in the selection of the distribution model and elimination model between NLME and NPD. For the simulation study, NLME and NPD show the same model selection inclination, however, the ΔOFV of NPD were invariably lower than ΔOFV of NLME, which implied that NPD is less powerful in model selection compared to NLME.

  • 3660. Zhong, Jia
    et al.
    Karlsson, Oskar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap. Center for Molecular Medicine, Department of Clinical Neuroscience, Karolinska Institutet, 171 77 Stockholm, Sweden.
    Wang, Guan
    Li, Jun
    Guo, Yichen
    Lin, Xinyi
    Zemplenyi, Michele
    Sanchez-Guerra, Marco
    Trevisi, Letizia
    Urch, Bruce
    Speck, Mary
    Liang, Liming
    Coull, Brent A
    Koutrakis, Petros
    Silverman, Frances
    Gold, Diane R
    Wu, Tangchun
    Baccarelli, Andrea A
    B vitamins attenuate the epigenetic effects of ambient fine particles in a pilot human intervention trial2017Inngår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 114, nr 13, s. 3503-3508Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Acute exposure to fine particle (PM2.5) induces DNA methylation changes implicated in inflammation and oxidative stress. We conducted a crossover trial to determine whether B-vitamin supplementation averts such changes. Ten healthy adults blindly received a 2-h, controlled-exposure experiment to sham under placebo, PM2.5 (250 μg/m(3)) under placebo, and PM2.5 (250 μg/m(3)) under B-vitamin supplementation (2.5 mg/d folic acid, 50 mg/d vitamin B6, and 1 mg/d vitamin B12), respectively. We profiled epigenome-wide methylation before and after each experiment using the Infinium HumanMethylation450 BeadChip in peripheral CD4(+) T-helper cells. PM2.5 induced methylation changes in genes involved in mitochondrial oxidative energy metabolism. B-vitamin supplementation prevented these changes. Likewise, PM2.5 depleted 11.1% [95% confidence interval (CI), 0.4%, 21.7%; P = 0.04] of mitochondrial DNA content compared with sham, and B-vitamin supplementation attenuated the PM2.5 effect by 102% (Pinteraction = 0.01). Our study indicates that individual-level prevention may be used to complement regulations and control potential mechanistic pathways underlying the adverse PM2.5 effects, with possible significant public health benefit in areas with frequent PM2.5 peaks.

  • 3661.
    Zhou, Q
    et al.
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Frandberg, PA
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Kindlundh, AM
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Le Greves, P
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Nyberg, F
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Substance P(1-7) affects the expression of dopamine D2 receptor mRNA inmale rat brain during morphine withdrawal.2003Inngår i: Peptides, Vol. 24, s. 147-Artikkel i tidsskrift (Fagfellevurdert)
  • 3662.
    Zhou, Q
    et al.
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Frändberg, P-A
    Kindlundh, A
    Le Grevès, P
    Nyberg, F
    The substance P aminoterminal metabolite SP(1-7) affects the expression of the dopamine D2 receptor gene transcript in male rat frontal cortex and nucleus accumbens during morphine withdrawalArtikkel i tidsskrift (Fagfellevurdert)
  • 3663.
    Zhou, Q
    et al.
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Karlsson, K
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Liu, Z
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Johansson, P
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    LeGreves, M
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Kiriu, A
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Nyberg:, F
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Substance P endopeptidase-like activity is altered in various regions of the rat central nervous system during morphine tolerance and withdrawal2001Inngår i: Neuropharmacology, Vol. 41, s. 246-Artikkel i tidsskrift (Fagfellevurdert)
  • 3664.
    Zhou, Q
    et al.
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Karlsson, K
    Liu, Z
    Johansson, P
    Thornvall-Le Grevès, M
    Kiuru, A
    Nyberg, F
    Substance P endopeptidase-like activity is altered in various regions of the rat central nervous system during morphine tolerance and withdrawal2001Inngår i: Neuropharmacology, Vol. 41, s. 246-253Artikkel i tidsskrift (Fagfellevurdert)
  • 3665.
    Zhou, Q
    et al.
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Le Greves, P
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Ragnar, F
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Nyberg, F
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Intracerebroventricular injection of the N-terminal substance P fragment SP(1-7) regulates the expression of the N-methyl-D-aspartate receptor NR1,NR2A and NR2B subunit mRNAs in the rat brain2000Inngår i: Neurosci Lett, Vol. 291, s. 109-Artikkel i tidsskrift (Fagfellevurdert)
  • 3666.
    Zhou, Q
    et al.
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Le Grevès, P
    Ragnar, F
    Nyberg, F
    Intracerebroventricular injection of the N-terminal substance P (SP) fragment SP1-7 regulates the expression of the N-methyl-D-aspartate receptor NR1, NR2A and NR2B subunit mRNAs in the rat brain2000Inngår i: Neurosci Lett, Vol. 291, s. 109-112Artikkel i tidsskrift (Fagfellevurdert)
  • 3667.
    Zhou, Q
    et al.
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Liu, Z
    Ray, A
    Huang, W
    Karlsson, K
    Nyberg, F
    Alteration in the brain content of substance P (1-7) during withdrawal in morphine-dependent rats1998Inngår i: Neuropharmacology, Vol. 37, s. 1545-1552Artikkel i tidsskrift (Fagfellevurdert)
  • 3668.
    Zhou, Q
    et al.
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Liu, Z
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Ray, A
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Huang, W
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Karlsson, K
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Nyberg, F
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Alteration in the brain content of substance P (1-7) during withdrawal inmorphine-dependent rats.1998Inngår i: Neuropharmacology, Vol. 37, s. 1545-Artikkel i tidsskrift (Fagfellevurdert)
  • 3669.
    Zhou, Q
    et al.
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Liu, ZR
    Ray, A
    Huang, W
    Karlsson, K
    Nyberg, F
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Alteration in the brain content of substance P (1-7) during withdrawal in morphine-dependent rats1998Inngår i: NEUROPHARMACOLOGY, ISSN 0028-3908, Vol. 37, nr 12, s. 1545-1552Artikkel i tidsskrift (Annet vitenskapelig)
    Abstract [en]

    Previous studies have shown that substance P (SP) may modulate the abstinence reaction to opioid withdrawal. Its N-terminal fragment SP1-7 may inhibit the intensity of the withdrawal reactions in morphine dependent mice, This study was designed to determi

  • 3670.
    Zhou, Q
    et al.
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Nyberg, F
    Injection of substance P (SP) N-terminal fragment SP1-7 into the ventral tegmental area modulates the levels of nucleus accumbens dopamine and DOPAC in male rats during morphine withdrawalArtikkel i tidsskrift (Fagfellevurdert)
  • 3671.
    Zhou, Q
    et al.
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Nyberg, F
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Injection of substance P (SP) N-terminal fragment SP(1-7) into the ventraltegmental area modulates the levels of nucleus accumbens dopamine anddihydroxyphenylacetic acid in male rats during morphine withdrawal.2002Inngår i: Neurosci Lett, Vol. 320, s. 117-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The levels of beta-endorphin and Met-enkephalin-Arg-Phe (MEAP) immunoreactivity in various brain regions (including amygdala, cortex, hippocampus, hypothalmus, nucleus accumbens, pituitary and ventral tegmental area) were studied in male rats subjected to

  • 3672.
    Zhou, Qin
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    The Impact of Substance P (SP) N-Terminal Metabolite SP1-7 in Opioid Tolerance and Withdrawal2001Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    The heptapeptide SP1-7, a metabolite of the neuroactive peptide substance P (SP), is suggested to play a role in opioid addiction and memory function. These two dimensions are known to involve dopamine and glutamate transmissions mediated through dopamine receptors and N-methyl-D- aspartate (NNMA) receptors, respectively. Research on interactions between SP1-7 and these two neurotransmitter systems may therefore be of importance to increase our understanding of the mechanisms behind opioid tolerance and dependence as well as memory processes. New knowledge in this area may lead to the discovery of new therapeutic routes for treatment of opioid addiction and other neuropsychiatric disorders, as well.

    Studies described in this thesis include investigation of adaptive changes during morphine tolerance and withdrawal in brain levels of SP1-7 and in the activity of substance P endopeptidase (SPE), an enzyme responsible for the generation of this fragment. In morphine tolerant and abstinent rats, the SP1-7 level and SPE activity were significantly increased in discrete areas of the brain, which are crucial for the development of opioid tolerance and dependence. Furthermore, significant correlations between the SPE activity and some morphine withdrawal signs were observed. This finding was indicative of an endogenous modulatory mechanism involving both the enzyme and its active peptide product.

    The effects of SP1-7 on the expression of morphine withdrawal and its interaction with dopaminergic pathways were examined in this thesis by behavioural tests, microdialysis as well as Northern blot and autoradiography techniques. Pre-treatment of morphine dependent rats with SP1-7 was found to stimulate dopamine release in nucleus accumbens and to inhibit the intensity of withdrawal behaviours. It was further shown to regulate both the dopamine D2 receptor gene transcript and the density of dopamine receptor proteins in mesolimbic dopamine pathways, confirming an interaction between SP1-7 and the dopamine system.

    The influence of SP1-7 on glutamate transmission was investigated in morphine naive rats. The expression of the gene transcripts of the NMDA receptor subunits NR1, NR2A and NR2B was regulated in several brain regions involved in opioid withdrawal reactions and memory functions. The result is consistent with a possible decrease glutamate transmission in these areas.

    It was concluded that SP1-7 may function as an endogenous modulator of the expression of opioid withdrawal by influencing both dopaminergic and glutamatergic transmission.

    Fulltekst (pdf)
    FULLTEXT01
  • 3673.
    Zhou, Qin
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Carlsson, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Botros, Milad
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Fransson, Rebecca
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi.
    Sandström, Anja
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi.
    Gordh, Torsten
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Hallberg, Mattias
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Nyberg, Fred
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    The C-terminal amidated analogue of the Substance P (SP) fragment SP (1-7) attenuates the expression of naloxone- precipitated withdrawal in morphine dependent rats2009Inngår i: Peptides, ISSN 0196-9781, E-ISSN 1873-5169, Vol. 30, nr 12, s. 2418-2422Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We previously demonstrated that intracerebroventricular (i.c.v.) administration of the substance P (SP) aminoterminal fragment SP(1-7) attenuates the expression of morphine withdrawal in the male rat. In this study we have used a synthetic analogue of this peptide, i.e. the SP(1-7) amide showing higher binding potency than the native heptapeptide, in a similar experimental set-up. Thus, Wistar male rats were made tolerant to morphine by daily injections of the opiate during 8 days. Following peptide administration (i.c.v.) and a subsequent naloxone challenge a variety of physical syndromes of withdrawal were recorded. We observed that the SP(1-7) amide potently and dose-dependently reduced several signs of reaction to morphine withdrawal. Interestingly, the effect of the peptide amide was significantly attenuated by the addition of the sigma agonist (+)-SKF-10047. We conclude that the SP(1-7) amide mimics the effect of the native SP fragment and that the mechanisms for its action involve a sigma receptor site.

  • 3674.
    Zhou, Qin
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Carlsson, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Hallberg, Mathias
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Nyberg, Fred
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Substance P N-terminal fragment SP(1-7) attenuates chronic morphine tolerance and affects dynorphin B and nociceptin in rats2011Inngår i: Peptides, ISSN 0196-9781, E-ISSN 1873-5169, Vol. 32, nr 8, s. 1661-1665Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The N-terminal substance P fragment SP(1-7) is known to modulate hyperalgesia and opioid withdrawal in animal models. This study examined the effects of intraperitoneal (i.p.) injections of SP(1-7) on chronic morphine tolerance and on the levels of dynorphin B (DYN B) and nociceptin/orphanin FQ(N/OFQ) in various brain areas of male Sprague Dawley rats. Morphine tolerance was induced by subcutaneous injections of the opioid (10 mg/kg) twice daily for 7 days. SP(1-7) injected i.p. (185 nmol/kg) 30 min prior to morphine reduced the development of morphine tolerance. Immunoreactive (it) DYN B and N/OFQ peptide levels were measured in several areas of the central nervous system. Levels of ir DYN B in rats treated with SP(1-7) and morphine were decreased in the nucleus accumbens. substantia nigra and ventral tegmental area and increased in the frontal cortex. The ir N/OFQ levels were increased in the periaqueductal gray and decreased in the nucleus accumbens. Since the concentration profiles of the two peptides were altered by SP(1-7) in the areas that are implicated in the modulation of opioid tolerance and analgesia, it is suggested that DYN B and N/OFQ systems may be involved in the effects of SP(1-7) on opioid tolerance.

  • 3675.
    Zhou, Qin
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Kindlundh, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Hallberg, Mathias
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Nyberg, Fred
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    The substance P (SP) heptapeptide fragment SP1-7 alters the density of dopamine receptors in rat brain mesocorticolimbic structures during morphine withdrawal2004Inngår i: Peptides, ISSN 0196-9781, E-ISSN 1873-5169, Vol. 25, nr 11, s. 1951-1957Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The aminoterminal fragment of substance P (SP), SP(1-7), has been suggested to modulate the expression of opiate tolerance and withdrawal behaviors in rodents. However, the mechanism of this effect is not yet clarified. Using a rat model we have previously demonstrated that SP(1-7) affects dopamine transmission and the expression of the dopamine D2-receptor gene transcript in the nucleus accumbens during naloxone precipitated morphine withdrawal. In the present study, we have applied autoradiography to investigate the effect of the heptapeptide on the binding of dopamine D1- and D2-receptors in mesocorticolimbic brain areas of male rats during morphine withdrawal. Morphine dependent animals were treated with an injection of SP(1-7) into the ventral tegmental area prior to naloxone challenge. The result indicated that the SP fragment elicited a significant decrease in specific binding to D1-like receptors in the caudate putamen, nucleus accumbens shell, nucleus accumbens core, substantia nigra and medial globus pallidus. Radioligand binding to dopamine D2-like receptors was also altered by SP(1-7). The heptapeptide induced a decreased density of these sites in the ventral tegmental area but an increased binding in the substantia nigra and the frontal cortex. The observed alterations in the D1- and D2-like receptor density could reflect activations in dopamine pathways associated with the above-mentioned brain regions. The result provides further evidence for the modulatory effect of SP(1-7) on dopamine systems during opioid withdrawal, suggesting the possible role for the heptapeptide to regulate morphine withdrawal reactions.

  • 3676.
    Zindrou, S
    et al.
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Dao, LD
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Xuyen, PT
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Dung, NP
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Sy, ND
    Skold, O
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Swedberg, G
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Rapid detection of pyrimethamine susceptibility of Plasmodium falciparumby restriction endonuclease digestion of the dihydrofolate reductase gene.1996Inngår i: Am J Trop Med Hyg, Vol. 54, s. 185-Artikkel i tidsskrift (Fagfellevurdert)
  • 3677.
    Zingmark, Per-Henrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Models for Ordered Categorical Pharmacodynamic Data2005Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    In drug development clinical trials are designed to investigate whether a new treatment is safe and has the desired effect on the disease in the target patient population. Categorical endpoints, for example different ranking scales or grading of adverse events, are commonly used to measure effects in the trials.

    Pharmacokinetic/Pharmacodynamic (PK/PD) models are used to describe the plasma concentration of a drug over time and its relationship to the effect studied. The models are utilized both in drug development and in discussions with drug regulating authorities. Methods for incorporation of ordered categorical data in PK/PD models were studied using a non-linear mixed effects modelling approach as implemented in the software NONMEM. The traditionally used proportional odds model was used for analysis of a 6-grade sedation scale in acute stroke patients and for analysis of a T-cell receptor expression in patients with Multiple Sclerosis, where the results also were compared with an analysis of the data on a continuous scale. Modifications of the proportional odds model were developed to enable analysis of a spontaneously reported side-effect and to analyze situations where the scale used is heterogeneous or where the drug affects the different scores in the scale in a non-proportional way. The new models were compared with the proportional odds model and were shown to give better predictive performances in the analyzed situations.

    The results in this thesis show that categorical data obtained in clinical trials with different design and different categorical endpoints successfully can be incorporated in PK/PD models. The models developed can also be applied to analyses of other ordered categorical scales than those presented.

    Fulltekst (pdf)
    FULLTEXT01
  • 3678.
    Zingmark, Per-Henrik
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Edenius, Charlotte
    Karlsson, Mats O.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmakokinetik och läkemedelsterapi.
    Pharmacokinetic/pharmacodynamic models for the depletion of Vβ5.2/5.3 T cells by the monoclonal antibody ATM-027 in patients with multiple sclerosis, as measured by FACS2004Inngår i: British Journal of Clinical Pharmacology, ISSN 0306-5251, E-ISSN 1365-2125, Vol. 58, nr 4, s. 378-389Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    AIMS:

    (i) To model the effects of the monoclonal antibody ATM-027 on the number of target cells and on the receptor density on the cell surface as measured by Fluorescence Activated Cell Sorter analysis, (ii) to investigate the effects of categorizing a continuous scale, and (iii) to simulate a phase II trial from phase I data in order to evaluate the predictive performance of the model by comparison with the actual trial results.

    METHODS:

    Based on the data from one phase I and one phase II study in multiple sclerosis (MS) patients, models were developed to characterize the pharmacokinetics and pharmacodynamics of the monoclonal antibody ATM-027 and its effects on Vbeta5.2/5.3+ T cells. The pharmacodynamic variables were the number of target T cells and the expression of its receptor. The latter was modelled in both a categorical and continuous way. The modelling was performed with a nonlinear mixed effects approach using the software NONMEM. The joint continuous models were used to simulate the phase II trial from the phase I data.

    RESULTS:

    The pharmacokinetics of ATM-027 were characterized by a two-compartment model with a total volume of distribution of 5.9 litres and a terminal half-life of 22.3 days (phase II parameter estimates) in the typical patient. Continuous receptor expression was modelled using an inhibitory sigmoidal Emax-model. Similar results from the phase I and phase II data were obtained, and EC50 was estimated to be 138 and 148 microg litre(-1), respectively. Categorical receptor expression was modelled using a proportional odds model, and the EC50 values obtained were highly correlated with those from the continuous model. The numbers of target T cells were also modelled and treatment with ATM-027 decreased the number of cells to 25.7% and 28.9% of their baseline values in the phase I and II trials, respectively. EC50s for the decrease in the number of T cells were 83 microg litre(-1) and 307 microg litre(-1), respectively. Simulations of the phase II trial from the phase I models gave good predictions of the dosing regimens administered in the phase II study.

    CONCLUSION:

    All aspects of effects of the monoclonal antibody ATM-027 on Vbeta5.2/5.3+ T cells were modelled and the phase II trial was simulated from phase I data. The effects of categorizing a continuous scale were also evaluated.

  • 3679.
    Zingmark, Per-Henrik
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Ekblom, Marianne
    Odergren, Tomas
    Ashwood, Tim
    Lyden, Patrick
    Karlsson, Mats O.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Jonsson, E. Niclas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Population pharmacokinetics of clomethiazole and its effect on the natural course of sedation in acute stroke patients2003Inngår i: British Journal of Clinical Pharmacology, ISSN 0306-5251, E-ISSN 1365-2125, Vol. 56, nr 2, s. 173-183Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    AIMS

    This analysis was performed to investigate the population pharmacokinetics of clomethiazole and its effect on the natural course of sedation in acute stroke patients using a nonlinear mixed effects modelling approach.

    METHODS

    One thousand five hundred and forty-six acute stroke patients (774 on active treatment) from 166 centres were included in three randomized, double-blind, placebo-controlled phase III efficacy and safety studies. A total dose of 68 mg kg(-1) clomethiazole edisilate was given as a three-phase i.v.-infusion over 24 h. Three blood samples were drawn from all patients to characterize the pharmacokinetics. Sedation was monitored throughout the entire treatment period and the degree of sedation was measured on a discrete ordinal scale with six levels. Models were fitted to the data using the software NONMEM.

    RESULTS

    Clomethiazole was characterized by a two-compartment pharmacokinetic model with interindividual variability in all structural parameters. For a patient weighing 75 kg, the average CL, V1, Q, and V2 was estimated to be 52.7 l h(-1), 82.5 l, 167 l h(-1) and 335 l, respectively. The interindividual variability in CL, V1, Q and V2 was estimated to be 48%, 53%, 42% and 54%, respectively. Increasing body weight and concomitant administration of liver enzyme inducing drugs were found to increase clearance (by 0.5 l h(-1) kg(-1) and 40%, respectively). Increasing weight also increased the volume of distribution (1.1 l kg(-1) for V1 and 4.7 l kg(-1) for V2). A six-category proportional odds model with a component including the natural course of sedation following placebo administration, a drug component (present or absent) and an interindividual variability component described the degree of sedation. Stroke severity as measured on the NIH-stroke scale on admission and drug treatment were the most important predictors of sedation, but a nonlinear increase in sedation with increasing age was also found. Increasing body weight increased the sedative drug effect.

    CONCLUSIONS

    The pharmacokinetics of clomethiazole were characterized in acute stroke patients and the analysis excluded several possible covariates of interest in drug development. The time course of sedation could be quantitatively described during the first 24 h following an acute stroke in the presence or absence of clomethiazole treatment.

  • 3680.
    Zingmark, Per-Henrik
    et al.
    AstraZeneca R & D Södertälje, Sweden.
    Ekblom, Marianne
    Odergren, Tomas
    Ashwood, Tim
    Lyden, Patrick
    Karlsson, Mats O
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmakokinetik och läkemedelsterapi.
    Jonsson, E Niclas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmakokinetik och läkemedelsterapi.
    Population pharmacokinetics of clomethiazole and its effect on the natural course of sedation in acute stroke patients2003Inngår i: British Journal of Clinical Pharmacology, ISSN 0306-5251, E-ISSN 1365-2125, Vol. 56, nr 2, s. 173-183Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    AIMS: This analysis was performed to investigate the population pharmacokinetics of clomethiazole and its effect on the natural course of sedation in acute stroke patients using a nonlinear mixed effects modelling approach. METHODS: One thousand five hundred and forty-six acute stroke patients (774 on active treatment) from 166 centres were included in three randomized, double-blind, placebo-controlled phase III efficacy and safety studies. A total dose of 68 mg kg(-1) clomethiazole edisilate was given as a three-phase i.v.-infusion over 24 h. Three blood samples were drawn from all patients to characterize the pharmacokinetics. Sedation was monitored throughout the entire treatment period and the degree of sedation was measured on a discrete ordinal scale with six levels. Models were fitted to the data using the software NONMEM. RESULTS: Clomethiazole was characterized by a two-compartment pharmacokinetic model with interindividual variability in all structural parameters. For a patient weighing 75 kg, the average CL, V1, Q, and V2 was estimated to be 52.7 l h(-1), 82.5 l, 167 l h(-1) and 335 l, respectively. The interindividual variability in CL, V1, Q and V2 was estimated to be 48%, 53%, 42% and 54%, respectively. Increasing body weight and concomitant administration of liver enzyme inducing drugs were found to increase clearance (by 0.5 l h(-1) kg(-1) and 40%, respectively). Increasing weight also increased the volume of distribution (1.1 l kg(-1) for V1 and 4.7 l kg(-1) for V2). A six-category proportional odds model with a component including the natural course of sedation following placebo administration, a drug component (present or absent) and an interindividual variability component described the degree of sedation. Stroke severity as measured on the NIH-stroke scale on admission and drug treatment were the most important predictors of sedation, but a nonlinear increase in sedation with increasing age was also found. Increasing body weight increased the sedative drug effect. CONCLUSIONS: The pharmacokinetics of clomethiazole were characterized in acute stroke patients and the analysis excluded several possible covariates of interest in drug development. The time course of sedation could be quantitatively described during the first 24 h following an acute stroke in the presence or absence of clomethiazole treatment.

  • 3681.
    Zingmark, Per-Henrik
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Kjellsson, Maria C.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Jonsson, E. Niclas
    Karlsson, Mats O.
    Comparing the differential drug effect model to the proportional odds modelManuskript (Annet vitenskapelig)
  • 3682.
    Zingmark, Per-Henrik
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Kågedal, Matts
    Karlsson, Mats O
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Modelling a spontaneously reported side effect by use of a Markov mixed-effects model.2005Inngår i: Journal of Pharmacokinetics and Pharmacodynamics, ISSN 1567-567X, E-ISSN 1573-8744, Vol. 32, nr 2, s. 261-281Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Aims: To present a method for analyzing side-effect data where change in severity is spontaneouslyreported during the experiment. Methods: A clinical study in 12 healthy volunteers aimed toinvestigate the concentration-response characteristics of a CNS-specific side-effect was conducted.After an open session where the subjects experienced the side-effect and where the individualpharmacokinetic parameters were evaluated they were randomized to a sequence of three differentinfusion rates of the drug in a double-blinded crossover way. The infusion rates were individualizedto achieve the same target concentration in all subjects and different drug input rates wereselected to mimic absorption profiles from different formulations. The occurrence of the specificside-effect and any subsequent change in severity was self-reported by the subjects. Severity wasrecorded as 0 = no side-effect, 1 = mild side-effect and 2 = moderate or severe side-effect.Results: The side-effect data were analyzed using a mixed-effects model for ordered categoricaldata with and without Markov elements. The former model estimated the probability of having acertain side-effect score conditioned on the preceding observation and drug exposure. The observednumbers of transitions between scores were from 0 ->1: 24, from 0 ->2: 11, from 1 ->2: 23, from2 ->1: 1, from 2 ->0: 32 and from 1 ->0: 2. The side-effect model consisted of an effect-compartmentmodel with a tolerance compartment. The predictive performance of the Markov model wasinvestigated by a posterior predictive check (PPC), where 100 datasets were simulated from thefinal model. Average number of the different transitions from the PPC was from 0 ->1: 26, from0 ->2: 11, from 1 ->2: 25, from 2 ->1: 1, from 2 ->0: 35 and from 1 ->0: 1. A similar PPCfor the model without Markov elements was at considerable disparity with the data. Conclusion:This approach of incorporating Markov elements in an analysis of spontaneously reported categoricalside-effect data could adequately predict the observed side-effect time course and could beconsidered in analyses of categorical data where dependence between observations is an issue.

  • 3683.
    Zingmark, PH
    et al.
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Edenius, C
    Karlsson, MO
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Pharmacokinetic/pharmacodynamic models for the depletion of Vbeta5.2/5.3 T cells by the monoclonal antibody ATM-027 in patients with multiple sclerosis, as measured by FACS.2004Inngår i: Br J Clin Pharmacol., Vol. 58, nr 4, s. 378-89Artikkel i tidsskrift (Fagfellevurdert)
  • 3684.
    Zoriyatkhah, Soheila
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Does testosterone suppress dopamine in nucleus accumbens during decision making?2015Independent thesis Advanced level (degree of Master (Two Years)), 20 poäng / 30 hpOppgave
    Abstract [en]

    Introduction: Anabolic-androgenic steroids (AAS) are derivates from the hormone testosterone and are mainly used to enhance muscle mass and athletic performance. There are some negative behavioral effects associated with AAS abuse such as increased aggression and physical risk taking. The nucleus accumbens (Acb) is a region of the mesolimbic dopamine system involved in reward, motivated behavior and decision making. Testosterone may influence risk taking and decision making behavior by altering dopamine function in Acb.

    Aim: The aim was to investigate whether the hormone testosterone affects dopamine (DA) levels in nucleus accumbens during decision making in male rats.

    Materials and Methods: Eight male Long Evans rats were treated with high dose testosterone (7.5 mg/kg) or vehicle (control group). They were tested daily on a probability discounting task where they chose between a small, certain reward (1 pellet delivered 100% of the time) and a large, uncertain reward (4 pellets) delivered with decreasing probability within the blocks (100, 75, 50, 25 and 0%). When choice performance was stable they underwent surgery to implant a cannula in the Acb. After recovery, microdialysis was performed on behaving rats with the aim of measuring DA levels in Acb during decision making.

    Results: In probability discounting there was a significant effect of drug on selection of the large reward, with testosterone-treated rats choosing the large reward less compared to the controls. The results for dopamine levels in Acb are still preliminary. We anticipate that dopamine correlates with risk taking as confirmed in previous studies.

    Conclusions: Testosterone decreases risk taking in probability discounting. However, the question of testosterone's effect on Acb DA during decision making cannot be answered at this time.

  • 3685.
    Zufan, Araya
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Tang, Wanjin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Wikvall, Kjell
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Hormonal regulation of the human sterol 27-hydroxylase gene (CYP27A1)2003Inngår i: Biochemical Journal, ISSN 0264-6021, E-ISSN 1470-8728, Vol. 372, nr Part 2, s. 529-534Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The nucleotide sequence data reported in this paper will appear in EMBL Nucleotide Sequence Database under the accession number AJ 544720. The mitochondrial sterol 27-hydroxylase (CYP27A1) is a multifunctional cytochrome P450 enzyme that catalyses important hydroxylations in the biosynthesis of bile acids and bioactivation of vitamin D(3). Previous results [Babiker, Andersson, Lund, Xiu, Deeb, Reshef, Leitersdorf, Diczfalusy and Bj örkhem (1997) J. Biol. Chem. 272, 26253-26261] suggest that CYP27A1 plays an important role in cholesterol homoeostasis and affects atherogenesis. In the present study, the regulation of the human CYP27A1 gene by growth hormone (GH), insulin-like growth factor-1 (IGF-1), dexamethasone, thyroid hormones and PMA was studied. HepG2 cells were transfected transiently with luciferase reporter gene constructs containing DNA fragments flanking the 5'-region of the human CYP27A1 gene. GH, IGF-1 and dexamethasone increased the promoter activity by 2-3-fold, whereas thyroxine (T(4)) and PMA repressed the activity significantly when measured with luciferase activity expressed in the cells. The endogenous CYP27A1 enzyme activity in the cells was stimulated by GH, IGF-1 and dexamethasone, whereas T(4) and PMA inhibited the activity. Experiments with progressive deletion/luciferase reporter gene constructs indicated that the response elements for GH may be localized in a region upstream to position -1094 bp. The putative response elements for dexamethasone were mapped to positions between -792 and -1095 bp. The -451 bp fragment of the human CYP27A1 gene was found to confer the activation by IGF-1, and the inhibition by T(4) and PMA. Results of the present study suggest that CYP27A1 is regulated in human cells by hormones and signal-transduction pathways.

  • 3686. Zusman, Oren
    et al.
    Avni, Tomer
    Leibovici, Leonard
    Adler, Amos
    Friberg, Lena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Stergiopoulou, Theodouli
    Carmeli, Yehuda
    Paul, Mical
    Systematic Review and Meta-Analysis of In Vitro Synergy of Polymyxins and Carbapenems2013Inngår i: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 57, nr 10, s. 5104-5111Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    Our objective was to examine the evidence of in vitro synergy of polymyxin-carbapenem combination therapy against Gram-negative bacteria (GNB). A systematic review and meta-analysis were performed. All studies examining in vitro interactions of antibiotic combinations consisting of any carbapenem with colistin or polymyxin B against any GNB were used. A broad search was conducted with no language, date, or publication status restrictions. Synergy rates, defined as a fractional inhibitory concentration index of <= 0.5 or a >2-log reduction in CFU, were pooled separately for time-kill, checkerboard, and Etest methods in a mixed-effect meta-analysis of rates. We examined whether the synergy rate depended on the testing method, type of antibiotic, bacteria, and resistance to carbapenems. Pooled rates with 95% confidence intervals (CI) are shown. Thirty-nine published studies and 15 conference proceeding were included, reporting on 246 different tests on 1,054 bacterial isolates. In time-kill studies, combination therapy showed synergy rates of 77% (95% CI, 64 to 87%) for Acinetobacter baumannii, 44% (95% CI, 30 to 59%) for Klebsiella pneumoniae, and 50% (95% CI, 30 to 69%) for Pseudomonas aeruginosa, with low antagonism rates for all. Doripenem showed high synergy rates for all three bacteria. For A. baumannii, meropenem was more synergistic than imipenem, whereas for P. aeruginosa the opposite was true. Checkerboard and Etest studies generally reported lower synergy rates than time-kill studies. The use of combination therapy led to less resistance development in vitro. The combination of a carbapenem with a polymyxin against GNB, especially A. baumannii, is supported in vitro by high synergy rates, with low antagonism and less resistance development. These findings should be examined in clinical studies.

  • 3687. Zvada, Simbarashe P.
    et al.
    Denti, Paolo
    Donald, Peter R.
    Schaaf, H. Simon
    Thee, Stephanie
    Seddon, James A.
    Seifart, Heiner I.
    Smith, Peter J.
    McIlleron, Helen M.
    Simonsson, Ulrika S. H.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Population pharmacokinetics of rifampicin, pyrazinamide and isoniazid in children with tuberculosis: in silico evaluation of currently recommended doses2014Inngår i: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 69, nr 5, s. 1339-1349Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    To describe the population pharmacokinetics of rifampicin, pyrazinamide and isoniazid in children and evaluate the adequacy of steady-state exposures. We used previously published data for 76 South African children with tuberculosis to describe the population pharmacokinetics of rifampicin, pyrazinamide and isoniazid. Monte Carlo simulations were used to predict steady-state exposures in children following doses in fixed-dose combination tablets in accordance with the revised guidelines. Reference exposures were derived from an ethnically similar adult population with tuberculosis taking currently recommended doses. The final models included allometric scaling of clearance and volume of distribution using body weight. Maturation was included for clearance of isoniazid and clearance and absorption transit time of rifampicin. For a 2-year-old child weighing 12.5 kg, the estimated typical oral clearances of rifampicin and pyrazinamide were 8.15 and 1.08 L/h, respectively. Isoniazid typical oral clearance (adjusted for bioavailability) was predicted to be 4.44, 11.6 and 14.6 L/h for slow, intermediate and fast acetylators, respectively. Higher oral clearance values in intermediate and fast acetylators also resulted from 23 lower bioavailability compared with slow acetylators. Simulations based on our models suggest that with the new WHO dosing guidelines and utilizing available paediatric fixed-dose combinations, children will receive adequate rifampicin exposures when compared with adults, but with a larger degree of variability. However, pyrazinamide and isoniazid exposures in many children will be lower than in adults. Further studies are needed to confirm these findings in children administered the revised dosages and to optimize pragmatic approaches to dosing.

  • 3688. Zvada, Simbarashe P.
    et al.
    Denti, Paolo
    Geldenhuys, Hennie
    Meredith, Sandra
    van As, Danelle
    Hatherill, Mark
    Hanekom, Willem
    Wiesner, Lubbe
    Simonsson, Ulrika S. H.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Jindani, Amina
    Harrison, Thomas
    McIlleron, Helen M.
    Moxifloxacin Population Pharmacokinetics in Patients with Pulmonary Tuberculosis and the Effect of Intermittent High-Dose Rifapentine2012Inngår i: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 56, nr 8, s. 4471-4473Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We described the population pharmacokinetics of moxifloxacin and the effect of high-dose intermittent rifapentine in patients with pulmonary tuberculosis who were randomized to a continuation-phase regimen of 400 mg moxifloxacin and 900 mg rifapentine twice weekly or 400 mg moxifloxacin and 1,200 mg rifapentine once weekly. A two-compartment model with transit absorption best described moxifloxacin pharmacokinetics. Although rifapentine increased the clearance of moxifloxacin by 8% during antituberculosis treatment compared to that after treatment completion without rifapentine, it did not result in a clinically significant change in moxifloxacin exposure.

  • 3689. Zvada, Simbarashe P.
    et al.
    Denti, Paolo
    Sirgel, Frederick A.
    Chigutsa, Emmanuel
    Hatherill, Mark
    Charalambous, Salome
    Mungofa, Stanley
    Wiesner, Lubbe
    Simonsson, Ulrika S. H.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Jindani, Amina
    Harrison, Thomas
    McIlleron, Helen M.
    Moxifloxacin Population Pharmacokinetics and Model-Based Comparison of Efficacy between Moxifloxacin and Ofloxacin in African Patients2014Inngår i: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 58, nr 1, s. 503-510Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Pharmacokinetic exposure and the MIC of fluoroquinolones are important determinants of their efficacy against Mycobacterium tuberculosis. Population modeling was used to describe the steady-state plasma pharmacokinetics of moxifloxacin in 241 tuberculosis (TB) patients in southern Africa. Monte Carlo simulations were applied to obtain the area under the unbound concentration-time curve from 0 to 24 h (fAUC(0-24)) after daily doses of 400 mg or 800 mg moxifloxacin and 800 mg ofloxacin. The MIC distributions of ofloxacin and moxifloxacin were determined for 197 drug-resistant clinical isolates of Mycobacterium tuberculosis. For a specific MIC, the probability of target attainment (PTA) was determined for target fAUC(0-24)/MIC ratios of >= 53 and >= 100. The PTAs were combined with the MIC distributions to calculate the cumulative fraction of response (CFR) for multidrug-resistant (MDR) Mycobacterium tuberculosis strains. Even with the less stringent target ratio of >= 53, moxifloxacin at 400 mg and ofloxacin at 800 mg achieved CFRs of only 84% and 58% for multidrug-resistant isolates with resistance to an injectable drug, while the 800-mg moxifloxacin dose achieved a CFR of 98%. Using a target ratio of >= 100 for multidrug-resistant strains (without resistance to injectable agents or fluoroquinolones), the CFR was 88% for moxifloxacin and only 43% for ofloxacin, and the higher dose of 800 mg moxifloxacin was needed to achieve a CFR target of >90%. Our results indicate that moxifloxacin is more efficacious than ofloxacin in the treatment of MDR-TB. Further studies should determine the optimal pharmacodynamic target for moxifloxacin in a multidrug regimen and clarify safety issues when it is administered at higher doses.

  • 3690. Zvada, Simbarashe P.
    et al.
    van der Walt, Jan-Stefan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Smith, Peter J.
    Fourie, P. Bernard
    Roscigno, Giorgio
    Mitchison, Denis
    Simonsson, Ulrika S H
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    McIlleron, Helen M.
    Effects of Four Different Meal Types on the Population Pharmacokinetics of Single-Dose Rifapentine in Healthy Male Volunteers2010Inngår i: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 54, nr 8, s. 3390-3394Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Rifapentine and its primary metabolite, 25-desacetyl rifapentine, are active against mycobacterium tuberculosis. The objectives of this study were to describe the population pharmacokinetics of rifapentine and 25-desacetyl rifapentine in fasting and fed states. Thirty-five male healthy volunteers were enrolled in an open-label, randomized, sequential, five-way crossover study. Participants received a single 900-mg dose of rifapentine after meals with high fat (meal A), bulk and low fat (meal B), bulk and high fat (meal C), high fluid and low fat (meal D), or 200 ml of water (meal E). Venous blood samples were collected over 72 h after each rifapentine dose, and plasma was analyzed for rifapentine and 25-desacetyl rifapentine using high-performance liquid chromatography. Pharmacokinetic data were analyzed by nonlinear mixed-effect modeling using NONMEM. Compared with the fasting state, meal A had the greatest effect on rifapentine oral bioavailability, increasing it by 86%. Meals B, C, and D resulted in 33%, 46%, and 49% increases in rifapentine oral bioavailability, respectively. Similar trends were observed for 25-desacetyl rifapentine. As meal behavior has a substantial impact on rifapentine exposure, it should be considered in the evaluation of optimal dosing approaches.

  • 3691.
    Zyoud, Maha
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Kartläggning av läkemedelsbehandlingen vidhypertoni i primärvården i Stockholms läns landsting2013Independent thesis Advanced level (degree of Master (One Year)), 20 poäng / 30 hpOppgave
  • 3692.
    Äbelö, Angela
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmakokinetik och läkemedelsterapi.
    Pharmacodynamic Modelling of Irreversible and Reversible Gastric Proton Pump Inhibitors2003Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Acid related diseases like GERD, duodenal-and gastric ulcers and H. Pylori-positive peptic ulcer disease are primarily managed by reducing gastric acidity. Irreversible proton pump inhibitors (PPIs) inhibit gastric acid secretion effectively throughout the day by irreversibly inhibiting the gastric proton pump, H+, K+-ATPase, in the parietal cells. Reversible gastric proton pump inhibitors are under development, but have not yet reached clinical use.

    The pharmacokinetic/pharmacodynamic (PK/PD) relationships of these compounds are nonlinear, with a delay in the effect-time profile compared to the plasma concentration-time course. PK/PD-modelling was used to characterize and quantify the pharmacological effect with regard to onset, intensity and duration of effect. Models based on functional data, that discriminate between drug-and system-specific parameters, were developed.

    In general, the plasma concentration-time course for each individual was approximated by linear interpolation between time-points and served as input into the pharmacodynamic models. A turnover model of irreversible inhibition of gastric acid secretion by omeprazole in the dog described the data well. The model was challenged and found to be robust under different experimental conditions. This model could predict the effect following different exposure of omeprazole and following different histamine provocation. Different fitting approaches (naïve pooling, standard two-stage and nonlinear mixed effects modelling) were compared and resulted in similar parameter estimates. For the reversible inhibitors, a kinetic binding model was finally selected. With a binding model the delay in the effect-time profile is explained by prolonged binding to the enzyme.

    Use of these results in drug development can be helpful with regard to selection of drugs for further development and to predict the first clinical dose.

    Fulltekst (pdf)
    FULLTEXT01
  • 3693. Äbelö, Angela
    et al.
    Andersson, Magdalena
    Holmberg, Ann Aurell
    Karlsson, Mats O.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Application of a combined effect compartment and binding model for gastric acid inhibition of AR-HO47108: a potassium competitive acid blocker, and its active metabolite AR-HO47116 in the dog2006Inngår i: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 29, nr 2, s. 91-101Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The effect of AR-HO47108, a potassium competitive acid blocker, and its active metabolite AR-HO47116 was studied in Heidenhain pouch dogs following administration of single oral and intravenous doses of the two compounds. The histamine-stimulated acid secretion was measured in different periods after dose up to 24 h. All data obtained in the different studies was pooled and analyzed by non-linear mixed effects modelling.

    It was found that there is a delay between the plasma concentration-time peak and the maximum inhibitory effect and that the effect persisted longer than anticipated from the plasma concentration half-lives of the compounds. in addition, it was found that the peak effect was reached earlier at higher doses. The effect data was well described by a combined effect compartment and binding model and both distribution to the biophase i.e. the canaliculus of the parietal cell and a rate limiting binding interaction between drug and enzyme appear to contribute to the observed delay. in addition, a secretion rate dependent washout from the biophase may contribute. Furthermore, because the parent compound and metabolite bind to the same enzyme, the effect is determined by competition between the two for the same enzyme.

    The metabolite was found to be less potent than the parent compound, with K-d values of the combined model of 125 and 11.2 nM for the metabolite and parent compound, respectively. However, the metabolite is generated in high concentrations that rapidly exceed the concentration of parent compound after oral administration of parent compound, and this together with its longer plasma half-life will make its contribution to -the overall effect increase with time and slightly prolong the duration of the effect.

  • 3694.
    Äbelö, Angela
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmakokinetik och läkemedelsterapi.
    Eriksson, Ulf G
    Karlsson, Mats O.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmakokinetik och läkemedelsterapi.
    Larsson, Håkan
    Gabrielsson, Johan
    A turnover model of irreversible inhibition of gastric acid secretion by omeprazole in the dog2000Inngår i: Journal of Pharmacology and Experimental Therapeutics, ISSN 0022-3565, E-ISSN 1521-0103, Vol. 295, nr 2, s. 662-669Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    A turnover model for irreversible inhibition of gastric acid secretion by omeprazole in gastric fistula dogs was developed using data from studies with both short- and long-term measurement periods. In the short-term experiments, after stimulation of acid secretion with histamine, the dogs were infused i.v. with omeprazole and acid secretion was measured for 5 h. Dose and infusion times were varied to produce different concentration-time profiles and schedule dependence in the inhibitory effect of omeprazole was observed. In the long-term experiments, dogs were given single intraduodenal doses, which inhibited the acid secretion for several days. Combining the short-term and long-term data allowed the observation of a biphasic recovery of acid secretion that was described by the turnover model. Second order association rate constants (k(ome)) for the covalent binding of omeprazole to H(+),K(+)-ATPase were estimated to 11 and 3.0 l/micromol/h for the i.v. and intraduodenal experiments, respectively. The apparent turnover rate constant of the enzyme (k(out)) was 0.013 h(-1) and the corresponding half-life of inhibition of acid secretory capacity was 54 h. The potency, calculated as k(out) over k(ome), was 4.3 and 1.2 nM for the intraduodenal and i.v. doses, respectively. Allometric scaling of the model resulted in trustworthy predictions for observations previously done in humans. The model predicted a good correlation between maximal inhibitory effect and exposure (area under the plasma concentration curve). The time dependence in this relation was also predicted by the model.

  • 3695.
    Äbelö, Angela
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmakokinetik och läkemedelsterapi.
    Gabrielsson, Johan
    Holstein, Björn
    Eriksson, Ulf G
    Holmberg, Johan
    Karlsson, Mats O.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmakokinetik och läkemedelsterapi.
    Pharmacodynamic modelling of reversible gastric acid pump inhibition in dog and man2001Inngår i: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 14, nr 4, s. 339-346Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    H 335/25, a 4-amino quinoline, belongs to a new class of reversible gastric acid pump inhibitors. A potential advantage of such drugs over the irreversible proton pump inhibitors (PPIs) is better control over the effect-time profile. Dose escalation studies were performed to characterize the effect on acid secretion in dogs (n=24) and healthy male subjects (n=12). The effect-time profile was delayed compared to the concentration-time profile. A model-based approach, using non-linear mixed effects modelling, was applied to quantify and elucidate the mechanism for the delayed effect. Three different models were investigated: (1) a slow equilibration preceding the formation of drug-enzyme complex, modelled by an effect-compartment, (2) a slow equilibration between free drug, free enzyme and drug-enzyme complex, described by a kinetic binding model, and (3) a delay between enzyme inhibition and the measured response, described by an indirect response model. Model 2 was shown to be superior to models 1 and 3, for both dog and human data. The dissociation rate constant, k(off), was estimated to be 0.85 and 0.88 h and the calculated equilibration constant, K(d), was 160 and 250 nM in dog and man, respectively. Simulations of the predicted time-course of the effect beyond the 4-5-h observation period was similar for the three models.

  • 3696.
    Äbelö, Angela
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmakokinetik och läkemedelsterapi.
    Holstein, Björn
    Andersson, Magdalena
    Karlsson, Mats O
    Application of a combined effect-compartment and binding model for gastric acid inhibition of AR-HO47108, a reversible gastric acid proton pump inhibitor, and its active metabolite AR-HO47116, in the dogManuskript (Annet vitenskapelig)
  • 3697. Äbelö, Angela
    et al.
    Holstein, Björn
    Eriksson, Ulf G.
    Gabrielsson, Johan
    Karlsson, Mats O.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Gastric acid secretion in the dog: a mechanism-based pharmacodynamic model for histamine stimulation and irreversible inhibition by omeprazole2002Inngår i: Journal of Pharmacokinetics and Pharmacodynamics, ISSN 1567-567X, E-ISSN 1573-8744, Vol. 29, nr 4, s. 365-382Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    A mechanism-based pharmacodynamic model was used to describe the inhibitory effect by omeprazole on gastric acid secretion measured after histamine stimulation in the dog. The model identifies parameters that are related to the physiological system, the histamine stimulation, and the irreversible effect of omeprazole on the H+, K(+)-ATPase enzyme. Four different experiments with omeprazole (Exps. 1-4) and two placebo experiments were performed in each of the four Heidenhain pouch dogs used. For placebo and experiments 1-3, saline or omeprazole 0.81 mumol/kg was infused during 3 hr with measurements of histamine-stimulated gastric acid secretion in two periods of 3.5-6.5 hr, one period starting just before the omeprazole infusion and a second later period up to 29 hr post infusion. In experiment 4, 0.18 mumol/kg of omeprazole was infused for 22.5 min and gastric juice was collected for 5 hr post infusion. The response data was well described by the model. Similar parameter estimates were obtained by three different analysis methods; naïve pooling, two-stage method and nonlinear mixed effects modeling. The elimination rate constant for the H+, K(+)-ATPase enzyme, kout, was estimated to be 0.040 hr-1, corresponding to a half-life of about 17 hr. This rate constant determines the duration of omeprazole inhibition after long-term exposure. For short-term omeprazole exposure the duration is determined by the rate constant for transfer of enzymes from active to resting state, estimated to be 1.88 hr-1. The second-order rate constant for histamine stimulation was estimated to be 0.064 hr-1 per histamine concentration unit and the maximum acid secretion was estimated to be 5.0 mmol H+/30 min. The second-order rate constant for the irreversible binding of omeprazole to H+, K(+)-ATPase, kome, was estimated to be 2.39 L/mumol.hr. By modeling the histamine-induced baseline response simultaneously with active treatment, predictions of the response are possible not only following different dosing regimens of omeprazole, but also following different degrees of histamine stimulation.

  • 3698.
    Åberg, Emma
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Saccoccia, Fulvio
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Grabherr, Manfred
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Ore, Wai Ying Josefin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Jemth, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Hultqvist, Greta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Evolution of the p53-MDM2 pathway2017Inngår i: BMC Evolutionary Biology, ISSN 1471-2148, E-ISSN 1471-2148, Vol. 17, artikkel-id 177Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: The p53 signalling pathway, which controls cell fate, has been extensively studied due to its prominent role in tumor development. The pathway includes the tumor supressor protein p53, its vertebrate paralogs p63 and p73, and their negative regulators MDM2 and MDM4. The p53/p63/p73-MDM system is ancient and can be traced in all extant animal phyla. Despite this, correct phylogenetic trees including both vertebrate and invertebrate species of the p53/p63/p73 and MDM families have not been published. Results: Here, we have examined the evolution of the p53/p63/p73 protein family with particular focus on the p53/ p63/p73 transactivation domain (TAD) and its co-evolution with the p53/p63/p73- binding domain (p53/p63/p73BD) of MDM2. We found that the TAD and p53/p63/p73BD share a strong evolutionary connection. If one of the domains of the protein is lost in a phylum, then it seems very likely to be followed by loss of function by the other domain as well, and due to the loss of function it is likely to eventually disappear. By focusing our phylogenetic analysis to p53/p63/ p73 and MDM proteins from phyla that retain the interaction domains TAD and p53/p63/p73BD, we built phylogenetic trees of p53/p63/p73 and MDM based on both vertebrate and invertebrate species. The trees follow species evolution and contain a total number of 183 and 98 species for p53/p63/p73 and MDM, respectively. We also demonstrate that the p53/p63/p73 and MDM families result from whole genome duplications. Conclusions: The signaling pathway of the TAD and p53/p63/p73BD in p53/p63/p73 and MDM, respectively, dates back to early metazoan time and has since then tightly co-evolved, or disappeared in distinct lineages.

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  • 3699.
    Åhlin, Andrea
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Evaluation of interventions to reduce infusion errors at The Alfred Hospital2014Independent thesis Advanced level (degree of Master (Two Years)), 20 poäng / 30 hpOppgave
    Abstract [en]

    Introduction: Medical errors are estimated to be the 8th largest cause of death in the USA and medication-related errors the largest single cause of errors in hospital. Intravenous administration is strongly associated with higher risk and more severe errors than other medication routes and the rates of intravenous drug errors are high. Multiple interventions have been made at the Alfred Hospital during the last five years in order to reduce infusion errors and improve safety intravenous therapies.

    Aim: Evaluation of the impact of infusion related medication safety initiatives on infusion errors at The Alfred Hospital 2009-2014.

    Materials and Methods: Prospective observational studies at a tertiary referral teaching hospital. The study included data collection in 2014 and analysis of data collected in 2009, 2011, 2012 and 2014 in order to make comparison. Discrepancies and errors found were evaluated for risk severity by an expert panel.

    Results: The number of significant errors identified were 63 of 469 infusions assessed (13.4%) 2009, 54 of 744 (7.3%) 2011, 23 of 685 (3.4%) 2012 and 37 of 701 (5.3%) 2014. The number of potentially serious errors were estimated to 1 (0.2%) 2009, 2 (0.3%) 2011 and none 2012 and 2014. Compliance to the drug library was 90.4% in 2014 when looking at all infusion and 39.1% when looking at the infusions with significant errors. A pharmacist had annotated the drug chart 67.2% of all infusions 2014 and 45.9% when looking at the infusions with significant errors.

    Conclusions: Intravenous infusion errors have significantly decreased since infusion interventions have been made at the Alfred. Smart pumps intercept serious errors and pharmacy annotation, as well as drug library compliance, lower risks of significant errors. Education on the use of smart pumps and non-compliance should be prioritized in order to further decrease infusion related errors.

  • 3700.
    Åhlén, Victor
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Population PK Modeling of Plasma Derived Coagulation Factor IX2011Independent thesis Basic level (professional degree), 20 poäng / 30 hpOppgave
    Abstract [en]

    The aims of this project were to first develop a population pharmacokinetic

    model of plasma derived coagulation factor IX and secondly to investigate if

    coagulation factor IX has 3-compartment pharmacokinetics rather than

    2-compartment pharmacokinetics. A total of 999 plasma samples along with

    the patient characteristics bodyweight, age and factor IX preparation from 26

    patients served as data for the project. Population pharmacokinetic curve

    fitting was performed by means of NONMEM 6. Clotting factor IX had

    3-compartment pharmacokinetics rather than 2-compartment pharmacokinetics.

    This allowed for the computation of the three half-lives. The typical value

    terminal half-life for coagulation factor IX was shorter than published mean

    values of 29-43 hours, while the terminal half-lives for individual patients were

    well within the interval of reported terminal half-lives. The new model shows

    that inter-occasion variance is lower than inter-individual variance, which is a

    requirement for pharmacokinetic based dosing. Model performance was evaluated

    using tools for model diagnostics. Goodness of fit plots along with calculations

    of epsilon and eta shrinkage showed good fit with low shrinkage. Visual

    predictive check indicated excellent performance of the 3-compartment model

    of clotting factor IX. The development of the first population pharmacokinetic

    model of plasma derived coagulation factor IX and the estimations of variance

    and pharmacokinetic parameters allows for treatment optimization through

    multiple-dose simulations, optimization of sampling for determination of

    individual pharmacokinetics and statistical support for pharmacokinetic based

    dosing.

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