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  • 101. Ahmed, Aisha S.
    et al.
    Li, Jian
    Ahmed, Mahmood
    Hua, Long
    Yakovleva, Tatiana
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Ossipov, Michael H.
    Bakalkin, Georgy
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Stark, André
    Attenuation of Pain and Inflammation in Adjuvant-Induced Arthritis by the Proteasome Inhibitor MG1322010Ingår i: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 62, nr 7, s. 2160-2169Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Objective. In rheumatoid arthritis (RA), pain and joint destruction are initiated and propagated by the production of proinflammatory mediators. Synthesis of these mediators is regulated by the transcription factor NF-kappa B, which is controlled by the ubiquitin proteasome system (UPS). The present study explored the effects of the proteasome inhibitor MG132 on inflammation, pain, joint destruction, and expression of sensory neuropeptides as markers of neuronal response in a rat model of arthritis. Methods. Arthritis was induced in rats by injection of heat-killed Mycobacterium butyricum. Arthritis severity was scored, and nociception was evaluated by mechanical pressure applied to the hind paw. Joint destruction was assessed by radiologic and histologic analyses. NF-kappa B DNA-binding activity was analyzed by electromobility shift assay, and changes in the expression of the p50 NF-kappa B subunit and the proinflammatory neuropeptides substance P (SP) and calcitonin generelated peptide (CGRP) were detected by immunohistochemistry. Results. Arthritic rats treated with MG132 demonstrated a marked reduction in inflammation, pain, and joint destruction. The elevated DNA-binding activity of the NF-kappa B/p50 homodimer and p50, as well as the neuronal expression of SP and CGRP, observed in the ankle joints of arthritic rats were normalized after treatment with MG132. Conclusion. In arthritic rats, inhibition of proteasome reduced the severity of arthritis and reversed the pain behavior associated with joint inflammation. These effects may be mediated through the inhibition of NF-kappa B activation and may possibly involve the peripheral nervous system. New generations of nontoxic proteasome inhibitors may represent a novel pharmacotherapy for RA.

  • 102. Ahmed, Aisha S
    et al.
    Li, Jian
    Erlandsson-Harris, Helena
    Stark, André
    Bakalkin, Georgy
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Mahmood, Ahmed
    Suppression of pain and joint destruction by inhibition of the proteasome system in experimental osteoarthritis2012Ingår i: Pain, ISSN 0304-3959, E-ISSN 1872-6623, Vol. 153, nr 1, s. 18-26Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Osteoarthritis is a degenerative joint disease with pain and loss of joint function as major pathological features. Recent studies show that proteasome inhibitors reduce pain in various pathological conditions. We evaluated the effects of MG132, a reversible proteasome inhibitor on pain and joint destruction in a rat model of osteoarthritis. Osteoarthritis was induced by intraarticular injection of monosodium iodoacetate into the rat knee. Knee joint stiffness was scored and nociception was evaluated by mechanical pressure applied to the respective hind paw. Knee joint destruction was assessed by radiological and histological analyses. Expression of matrix metalloproteinase-3 (MMP-3) was analyzed by quantitative reverse transcription polymerase chain reaction in the knee articular cartilage. Expression of substance P (SP) and calcitonin gene-related peptide (CGRP) was studied in the dorsal root ganglia (L4–L6) by quantitative reverse transcription polymerase chain reaction and in the knee joints by immunohistochemistry. Our results indicate that daily treatment of osteoarthritic rats with MG132 significantly increases their mobility while the swelling, pain thresholds, and pathological features of the affected joints were reduced. Furthermore, the upregulated expression of MMP-3, SP, and CGRP in the arthritic rats was normalized by MG132 administration. We conclude that the proteasome inhibitor MG132 reduces pain and joint destruction, probably by involving the peripheral nervous system, and that changes in SP and CGRP expression correlate with alterations in behavioural responses. Our findings suggest that nontoxic proteasome inhibitors may represent a novel pharmacotherapy for osteoarthritis.

  • 103.
    Ahmed, Aisha Siddiqah
    et al.
    Karolinska Inst, Dept Clin Neurosci, S-17177 Stockholm, Sweden.
    Ahmed, Mahmood
    Karolinska Inst, Dept Neurobiol Care Sci & Soc, Ctr Family & Community Med, Huddinge, Sweden.
    Li, Jian
    Karolinska Inst, Karolinska Univ Hosp, Dept Mol Med & Surg, Stockholm, Sweden.
    Gu, Harvest F
    Karolinska Inst, Karolinska Univ Hosp, Dept Mol Med & Surg, Stockholm, Sweden.
    Bakalkin, Georgy
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Stark, André
    Karolinska Inst, Danderyd Hosp, Dept Clin Sci, Stockholm, Sweden.
    Harris, Helena Erlandsson
    Karolinska Inst, Karolinska Univ Hosp, Dept Med, Ctr Mol Med, Stockholm, Sweden.
    Proteasome inhibitor MG132 modulates inflammatory pain by central mechanisms in adjuvant arthritis.2017Ingår i: International journal of rheumatic diseases, ISSN 1756-185X, Vol. 20, nr 1, s. 25-32Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    AIMS: In rheumatoid arthritis (RA), pain and inflammation are initial symptoms followed by various degrees of bone and cartilage destruction. Previously, we have shown that reversible proteasome inhibitor MG132 attenuates pain and joint inflammation in a rat model of adjuvant-arthritis. Our present study aims to study the effects of MG132 on molecular changes in the dorsal root ganglia (DRG) and in the spinal cord (SC) using the same animal model.

    METHODS: Arthritis was induced by heat-killed Mycobacterium butyricum in rats. The expression of substance P (SP) was analyzed by quantitative reverse transcription polymerase chain reaction and immunohistochemistry in DRG and in the SC. The nuclear factor-κB (NF-κB) DNA-binding activity in the SC was analyzed by electromobility shift assay.

    RESULTS: Arthritic rats treated daily with MG132 demonstrated a marked reduction of SP gene expression in the DRG and number of SP-positive cells was reduced. In the spinal cord of arthritic rats elevated SP messenger RNA levels were normalized and NF-κB-DNA-binding activity was down-regulated in arthritic rats treated with MG132.

    CONCLUSION: Our results indicate that proteasome inhibitor MG132 attenuates pain in adjuvant arthritis by targeting the sensory neuropeptide substance P in the peripheral and central nervous systems. These effects may be mediated through the inhibition of NF-κB activation.

  • 104. Ahmed, Laeeq
    et al.
    Georgiev, Valentin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Capuccini, Marco
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Matematisk-datavetenskapliga sektionen, Institutionen för informationsteknologi, Tillämpad beräkningsvetenskap.
    Toor, Salman
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Matematisk-datavetenskapliga sektionen, Institutionen för informationsteknologi, Tillämpad beräkningsvetenskap.
    Schaal, Wesley
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Laure, Erwin
    Spjuth, Ola
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Efficient iterative virtual screening with Apache Spark and conformal prediction2018Ingår i: Journal of Cheminformatics, ISSN 1758-2946, E-ISSN 1758-2946, Vol. 10, artikel-id 8Artikel i tidskrift (Refereegranskat)
  • 105. Ahmed, Sara
    et al.
    Schwartz, Carolyn
    Ring, Lena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Sprangers, Mirjam A. G.
    Applications of health-related quality of life for guiding health care: advances in response shift research2009Ingår i: Journal of Clinical Epidemiology, ISSN 0895-4356, E-ISSN 1878-5921, Vol. 62, nr 11, s. 1115-1117Artikel i tidskrift (Refereegranskat)
  • 106. Ahn, Jae Eun
    et al.
    Karlsson, Mats O.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Dunne, Adrian
    Ludden, Thomas M.
    Likelihood based approaches to handling data below the quantification limit using NONMEM VI2008Ingår i: Journal of Pharmacokinetics and Pharmacodynamics, ISSN 1567-567X, E-ISSN 1573-8744, Vol. 35, nr 4, s. 401-421Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    PURPOSE: To evaluate the likelihood-based methods for handling data below the quantification limit (BQL) using new features in NONMEM VI. METHODS: A two-compartment pharmacokinetic model with first-order absorption was chosen for investigation. Methods evaluated were: discarding BQL observations (M1), discarding BQL observations but adjusting the likelihood for the remaining data (M2), maximizing the likelihood for the data above the limit of quantification (LOQ) and treating BQL data as censored (M3), and like M3 but conditioning on the observation being greater than zero (M4). These four methods were compared using data simulated with a proportional error model. M2, M3, and M4 were also compared using data simulated from a positively truncated normal distribution. Successful terminations and bias and precision of parameter estimates were assessed. RESULTS: For the data simulated with a proportional error model, the overall performance was best for M3 followed by M2 and M1. M3 and M4 resulted in similar estimates in analyses without log transformation. For data simulated with the truncated normal distribution, M4 performed better than M3. CONCLUSIONS: Analyses that maximized the likelihood of the data above the LOQ and treated BQL data as censored provided the most accurate and precise parameter estimates.

  • 107. Ahn, Jae Eun
    et al.
    Plan, Elodie L
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Karlsson, Mats O
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Miller, Raymond
    Modeling longitudinal daily seizure frequency data from pregabalin add-on treatment2012Ingår i: Journal of clinical pharmacology, ISSN 0091-2700, E-ISSN 1552-4604, Vol. 52, nr 6, s. 880-892Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The purpose of this study was to describe longitudinal daily seizure count data with respect to the effects of time and pregabalin add-on therapy. Models were developed in step-wise manner: base model, time effect model, and time and drug effect (final) model, using a negative binomial distribution with Markovian features. Mean daily seizure count (λ) was estimated to be 0.385 (RSE 3.09%) and was further increased depending on the seizure count on the previous day. An overdispersion parameter (OVDP), representing extra-Poisson variation, was estimated to be 0.330 (RSE 11.7%). Inter-individual variances on λ and OVDP were 84.7% and 210%, respectively. Over time, λ tended to increase exponentially with a rate constant of 0.272 year-1 (RSE 26.8%). A mixture model was applied to classify responders/non-responders to pregabalin treatment. Within the responders, λ decreased exponentially with respect to dose with a constant of 0.00108 mg-1 (RSE 11.9%). The estimated responder rate was 66% (RSE 27.6%). Simulation-based diagnostics showed the model reasonably reproduced the characteristics of observed data. Highly variable daily seizure frequency was successfully characterized incorporating baseline characteristics, time effect, and the effect of pregabalin with classification of responders/non-responders, all of which are necessary to adequately assess the efficacy of antiepileptic drugs.

     

  • 108.
    Ahnfelt, Emelie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    In vitro evaluation of formulations used in the treatment of hepatocellular carcinoma2018Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Hepatocellular carcinoma (HCC) causes ~ 600,000 deaths annually, making it the second most deadly cancer form. HCC is classified into five stages and for the intermediate HCC treatment, the two most commonly used drug delivery systems (DDSs) are lipiodol-based emulsions and drug-eluting beads. The aims of this thesis were to develop in vitro methods suitable for studying these DDSs. It is important to investigate the release mechanisms and release rates with relevant in vitro methods, as this can improve the understanding of the in vivo performance. Miniaturized in vitro methods with sample reservoirs separated from the release medium by a diffusion barrier were developed and shown to be suitable for studying drug release from particle DDSs (Paper I). In Paper II these methods were further developed and used to study the release of doxorubicin (DOX) from the clinically used drug-eluting beads. DOX release rates were affected by the method set-up and the characteristics of the release medium. The choice of method and volume of release medium could improve the in vivo-likeness of the in vitro release profiles. Applied theoretical models suggested a film-controlled type of DOX release mechanism from the beads when self-aggregation, DOX-bead interaction, and DOX deprotonation were taken into account.

    A micropipette-assisted microscopy method was used to further improve the understanding of the release mechanism of amphiphilic molecules from the beads (Paper III). A detailed analysis suggested an internal depletion-layer model dependent on molecular self-aggregation for the release. It was further suggested that a simple ion-exchange mechanism is unrealistic in physiological conditions.

    The important pharmaceutical factors for the emulsion-based formulations were investigated in Paper IV. DOX solubility, lipid phase distribution, and emulsion stability increased when the contrast agent iohexol was added. Also, an increase in release half-life (h) was observed from emulsions with iohexol.

    The in vitro methods and theoretical models presented in this thesis can be used during development and optimization of future DDSs.

    Delarbeten
    1. A miniaturized in vitro release method for investigating drug-release mechanisms
    Öppna denna publikation i ny flik eller fönster >>A miniaturized in vitro release method for investigating drug-release mechanisms
    2015 (Engelska)Ingår i: International Journal of Pharmaceutics, ISSN 0378-5173, E-ISSN 1873-3476, Vol. 486, nr 1-2, s. 339-349Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    We have evaluated a miniaturized in vitro method, based on the mDISS Profiler (TM) technique that enables on-line monitoring of drug release from a 21 mu l sample with 10 ml of release medium. Four model drugs in eight clinically used formulations, including both solid and non-solid drug delivery systems, were investigated. The acquired data were compared with historical in vitro release data from the same formulations. Use of the Weibull function to describe the in vitro drug-release profiles allowed discrimination between the selected formulations with respect to the drug-release mechanisms. Comparison of the release data from the same formulation in different in vitro set-ups showed that the methodology used can affect the mechanism of in vitro release. We also evaluated the ability of the in vitro methods to predict in vivo activity by comparing simulated plasma concentration-time profiles acquired from the application of the biopharmaceutical software GI-Sim to the in vitro observations. In summary, the simulations based on the miniaturized-method release data predicted the plasma profiles as well as or more accurately than simulations based on the historical release data in 71% of the cases and this miniaturized in vitro method appears to be applicable for both solid and non-solid formulations.

    Nyckelord
    In vitro release methods, Release mechanisms, Weibull function, GI-Sim, In vivo prediction
    Nationell ämneskategori
    Farmaceutiska vetenskaper
    Identifikatorer
    urn:nbn:se:uu:diva-255064 (URN)10.1016/j.ijpharm.2015.03.076 (DOI)000353999100037 ()25843760 (PubMedID)
    Tillgänglig från: 2015-06-22 Skapad: 2015-06-12 Senast uppdaterad: 2018-10-30Bibliografiskt granskad
    2. In Vitro Release Mechanisms of Doxorubicin From a Clinical Bead Drug-Delivery System
    Öppna denna publikation i ny flik eller fönster >>In Vitro Release Mechanisms of Doxorubicin From a Clinical Bead Drug-Delivery System
    2016 (Engelska)Ingår i: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017, Vol. 105, nr 11, s. 3387-3398Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    The release rate of doxorubicin (DOX) from the drug-delivery system (DDS), DC Bead, was studied by 2 miniaturized in vitro methods: free-flowing and sample reservoir. The dependencies of the release mechanisms on in vitro system conditions were investigated experimentally and by theoretical modeling. An inverse relationship was found between release rates and bead size, most likely due to the greater total surface area. The release rates correlated positively with temperature, release medium volume, and buffer strength, although the release medium volume had larger effect than the buffer strength. The sample reservoir method generated slower release rates, which described the in vivo release profile more accurately than the free-flowing method. There was no difference between a pH of 6.3 or 7.4 on the release rate, implying that the slightly acidic tumor microenvironment is less importance for drug release. A positive correlation between stirring rate and release rate for all DDS sizes was observed, which suggests film controlled release. Theoretical modeling highlighted the influence of local equilibrium of protonation, self-aggregation, and bead material interactions of DOX. The theoretical release model might describe the observed larger sensitivity of the release rate to the volume of the release medium compared to buffer strength. A combination of miniaturized in vitro methods and theoretical modeling are useful to identify the important parameters and processes for DOX release from a micro gel-based DDS.

    Nyckelord
    controlled release, diffusion, dissolution, dissolution rate, drug-delivery systems, in vitro models, mathematical model, microspheres
    Nationell ämneskategori
    Farmaceutiska vetenskaper
    Identifikatorer
    urn:nbn:se:uu:diva-311211 (URN)10.1016/j.xphs.2016.08.011 (DOI)000388268200018 ()27663384 (PubMedID)
    Forskningsfinansiär
    Vetenskapsrådet, 521-2011-373
    Tillgänglig från: 2016-12-22 Skapad: 2016-12-22 Senast uppdaterad: 2018-10-30Bibliografiskt granskad
    3. Single bead investigation of a clinical drug delivery system – a novel release mechanism
    Öppna denna publikation i ny flik eller fönster >>Single bead investigation of a clinical drug delivery system – a novel release mechanism
    Visa övriga...
    2018 (Engelska)Ingår i: Journal of Controlled Release, ISSN 0168-3659, E-ISSN 1873-4995, Vol. 292, s. 235-247Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Microgels, such as polymeric hydrogels, are currently used as drug delivery devices (DDSs) for chemotherapeutics and/or unstable drugs. The clinical DDS DC bead® was studied with respect to loading and release, measured as relative bead-volume, of six amphiphilic molecules in a micropipette-assisted microscopy method. Theoretical models for loading and release was used to increase the mechanistic understanding of the DDS.

    It was shown that equilibrium loading was independent of amphiphile concentration. The loading model showed that the rate-determining step was diffusion of the molecule from the bulk to the bead surface (‘film control’). Calculations with the developed and applied release model on the release kinetics were consistent with the observations, as the amphiphiles distribute unevenly in the bead. The rate determining step of the release was the diffusion of the amphiphile molecule through the developed amphiphile-free depletion layer. The release rate is determined by the diffusivity and the tendency for aggregation of the amphiphile where a weak tendency for aggregation (i.e. a large cacb) lead to faster release. Salt was necessary for the release to happen, but at physiological concentrations the entry of salt was not rate-determining. This study provides valuable insights into the loading to and release from the DDS. Also, a novel release mechanism of the clinically used DDS is suggested.

    Nyckelord
    Microgel, Drug delivery, Release mechanism
    Nationell ämneskategori
    Farmaceutiska vetenskaper
    Identifikatorer
    urn:nbn:se:uu:diva-360988 (URN)10.1016/j.jconrel.2018.11.011 (DOI)000452348100019 ()30419268 (PubMedID)
    Forskningsfinansiär
    Vetenskapsrådet, 521-2011-373
    Tillgänglig från: 2018-09-20 Skapad: 2018-09-20 Senast uppdaterad: 2019-01-21Bibliografiskt granskad
    4. In vitro evaluation of lipiodol-based emulsions in clinical use
    Öppna denna publikation i ny flik eller fönster >>In vitro evaluation of lipiodol-based emulsions in clinical use
    Visa övriga...
    (Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
    Nationell ämneskategori
    Farmaceutiska vetenskaper
    Identifikatorer
    urn:nbn:se:uu:diva-360987 (URN)
    Tillgänglig från: 2018-09-20 Skapad: 2018-09-20 Senast uppdaterad: 2018-10-30
  • 109.
    Ahnfelt, Emelie
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Al-Tikriti, Yassir
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Sjögren, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Lennernäs, Hans
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Hansson, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Single bead investigation of a clinical drug delivery system – a novel release mechanism2018Ingår i: Journal of Controlled Release, ISSN 0168-3659, E-ISSN 1873-4995, Vol. 292, s. 235-247Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Microgels, such as polymeric hydrogels, are currently used as drug delivery devices (DDSs) for chemotherapeutics and/or unstable drugs. The clinical DDS DC bead® was studied with respect to loading and release, measured as relative bead-volume, of six amphiphilic molecules in a micropipette-assisted microscopy method. Theoretical models for loading and release was used to increase the mechanistic understanding of the DDS.

    It was shown that equilibrium loading was independent of amphiphile concentration. The loading model showed that the rate-determining step was diffusion of the molecule from the bulk to the bead surface (‘film control’). Calculations with the developed and applied release model on the release kinetics were consistent with the observations, as the amphiphiles distribute unevenly in the bead. The rate determining step of the release was the diffusion of the amphiphile molecule through the developed amphiphile-free depletion layer. The release rate is determined by the diffusivity and the tendency for aggregation of the amphiphile where a weak tendency for aggregation (i.e. a large cacb) lead to faster release. Salt was necessary for the release to happen, but at physiological concentrations the entry of salt was not rate-determining. This study provides valuable insights into the loading to and release from the DDS. Also, a novel release mechanism of the clinically used DDS is suggested.

  • 110.
    Ahnfelt, Emelie
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Degerstedt, Oliver
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Lilienberg, Elsa
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Sjögren, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Hansson, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Lennernäs, Hans
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    In vitro evaluation of lipiodol-based emulsions in clinical useManuskript (preprint) (Övrigt vetenskapligt)
  • 111.
    Ahnfelt, Emelie
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Degerstedt, Oliver
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Lilienberg, Elsa
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Sjögren, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Hansson, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Lennernäs, Hans
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Lipiodol-based emulsions used for transarterial chemoembolization and drug delivery: Effects of composition on stability and product quality2019Ingår i: Journal of Drug Delivery Science and Technology, ISSN 1773-2247, Vol. 53, artikel-id UNSP 101143Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Transarterial chemoembolization with emulsion-based formulations using doxorubicin hydrochloride (DOX) and Lipiodol (R) is the golden standard for the loco-regional treatment of unresectable hepatocellular carcinoma (HCC). However, from a pharmaceutical quality perspective these emulsions are poorly characterized. In this study, clinically relevant Lipiodol (R)-based emulsions were characterized in terms of emulsion stability, continuous phase classification and droplet-size distribution. Also, the solubility of DOX in the different emulsion components and the distribution of DOX to the lipid phase were investigated. These are key features to investigate due to the claimed tumor-seeking properties of Lipiodol (R). The in vitro release of DOX was studied in a miniaturized dialysis method and an empirical release model was applied to adjust for the passage of DOX across the dialysis membrane. The most stable emulsion ( > 72 h) was classified as water-in-oil (w/o), had the highest distribution of DOX to the lipid phase (20%) and an aqueous-to-lipid phase ratio of 1:4. The composition of the aqueous phase was a mixture (v/v) of iohexol (85%) and water (15%). Emulsions containing iohexol and a high aqueousto-lipid phase ratio (1:2-1:4) displayed prolonged in vitro release profiles of DOX. This study further emphasizes the medical need to standardize these emulsion-based drug delivery systems.

  • 112.
    Ahnfelt, Emelie
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Sjögren, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Axén, N.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Lennernäs, Hans
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    A miniaturized in vitro release method for investigating drug-release mechanisms2015Ingår i: International Journal of Pharmaceutics, ISSN 0378-5173, E-ISSN 1873-3476, Vol. 486, nr 1-2, s. 339-349Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    We have evaluated a miniaturized in vitro method, based on the mDISS Profiler (TM) technique that enables on-line monitoring of drug release from a 21 mu l sample with 10 ml of release medium. Four model drugs in eight clinically used formulations, including both solid and non-solid drug delivery systems, were investigated. The acquired data were compared with historical in vitro release data from the same formulations. Use of the Weibull function to describe the in vitro drug-release profiles allowed discrimination between the selected formulations with respect to the drug-release mechanisms. Comparison of the release data from the same formulation in different in vitro set-ups showed that the methodology used can affect the mechanism of in vitro release. We also evaluated the ability of the in vitro methods to predict in vivo activity by comparing simulated plasma concentration-time profiles acquired from the application of the biopharmaceutical software GI-Sim to the in vitro observations. In summary, the simulations based on the miniaturized-method release data predicted the plasma profiles as well as or more accurately than simulations based on the historical release data in 71% of the cases and this miniaturized in vitro method appears to be applicable for both solid and non-solid formulations.

  • 113.
    Ahnfelt, Emelie
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Sjögren, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Hansson, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Lennernäs, Hans
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    In Vitro Release Mechanisms of Doxorubicin From a Clinical Bead Drug-Delivery System2016Ingår i: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017, Vol. 105, nr 11, s. 3387-3398Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The release rate of doxorubicin (DOX) from the drug-delivery system (DDS), DC Bead, was studied by 2 miniaturized in vitro methods: free-flowing and sample reservoir. The dependencies of the release mechanisms on in vitro system conditions were investigated experimentally and by theoretical modeling. An inverse relationship was found between release rates and bead size, most likely due to the greater total surface area. The release rates correlated positively with temperature, release medium volume, and buffer strength, although the release medium volume had larger effect than the buffer strength. The sample reservoir method generated slower release rates, which described the in vivo release profile more accurately than the free-flowing method. There was no difference between a pH of 6.3 or 7.4 on the release rate, implying that the slightly acidic tumor microenvironment is less importance for drug release. A positive correlation between stirring rate and release rate for all DDS sizes was observed, which suggests film controlled release. Theoretical modeling highlighted the influence of local equilibrium of protonation, self-aggregation, and bead material interactions of DOX. The theoretical release model might describe the observed larger sensitivity of the release rate to the volume of the release medium compared to buffer strength. A combination of miniaturized in vitro methods and theoretical modeling are useful to identify the important parameters and processes for DOX release from a micro gel-based DDS.

  • 114.
    Ahnfelt, Nils-Otto
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten.
    Gas chromatographic analysis of amines, aminophenols and aminobutyric acids: studies on the derivatization with chloroformate esters1982Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
  • 115.
    Ahnfelt, Nils-Otto
    et al.
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Historisk-filosofiska fakulteten, Institutionen för idé- och lärdomshistoria, Avdelningen för vetenskapshistoria. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för farmakognosi.
    Fors, Hjalmar
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Historisk-filosofiska fakulteten, Institutionen för idé- och lärdomshistoria, Avdelningen för vetenskapshistoria. Hagströmer Library, Karolinska Institutet, Stockholm.
    Making Early Modern Medicine: Reproducing Swedish Bitters2016Ingår i: Ambix, ISSN 0002-6980, E-ISSN 1745-8234, Vol. 63, nr 2, s. 162-183Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Historians of science and medicine have rarely applied themselves to reproducing the experiments and practices of medicine and pharmacy. This paper delineates our efforts to reproduce "Swedish Bitters," an early modern composite medicine in wide European use from the 1730s to the present. In its original formulation, it was made from seven medicinal simples: aloe, rhubarb, saffron, myrrh, gentian, zedoary and agarikon. These were mixed in alcohol together with some theriac, a composite medicine of classical origin. The paper delineates the compositional history of Swedish Bitters and the medical rationale underlying its composition. It also describes how we go about to reproduce the medicine in a laboratory using early modern pharmaceutical methods, and analyse it using contemporary methods of pharmaceutical chemistry. Our aim is twofold: first, to show how reproducing medicines may provide a path towards a deeper understanding of the role of sensual and practical knowledge in the wider context of early modern medical culture; and second, how it may yield interesting results from the point of view of contemporary pharmaceutical science.

  • 116.
    Ahnfelt, Nils-Otto
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Farmakognosi. Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Historisk-filosofiska fakulteten, Institutionen för idé- och lärdomshistoria.
    Fors, Hjalmar
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Historisk-filosofiska fakulteten, Institutionen för idé- och lärdomshistoria. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Farmakognosi. Hagströmer Library, Stockholm, Sweden..
    Reconstructing early modern pharmacy through "Elixir amarum Hiaernei" and its Theriac ancestor2016Ingår i: Planta Medica, ISSN 0032-0943, E-ISSN 1439-0221, Vol. 82Artikel i tidskrift (Övrigt vetenskapligt)
  • 117. Ahnström, J
    et al.
    Berntorp, E
    Lindvall, K
    Björkman, S
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    A six-year follow-up of dosing,coagulation factor levels and bleedings in relation to joint status in the prophylactic treatment of haemophilia.2004Ingår i: Haemophilia, Vol. 10, s. 689-697Artikel i tidskrift (Refereegranskat)
  • 118.
    Akay, Mervan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    En kartläggning av läkemedelsanvändning och köpbeteende vid köp av receptfria NSAID på apotek2015Självständigt arbete på avancerad nivå (masterexamen), 20 poäng / 30 hpStudentuppsats (Examensarbete)
    Abstract [sv]

    En kartläggning av läkemedelsanvändning och köpbeteende vid köp av receptfria NSAID på apotek

    Mervan Akay

    Handledare: Pia Frisk, Hälso- och sjukvårdsförvaltningen SLL Institutionen för farmaceutisk biovetenskap, avdelningen för farmakokinetik och läkemedelsterapi Examinator: Margareta Hammarlund-UdenaesFördjupningsprojekt i farmakoterapi D, 30 hp

    Introduktion: NSAID är en av de mest förskrivna läkemedelsgrupperna över hela världen. Efter omregleringen av apoteksmarknaden har tillgängligheten av NSAID-preparat ökat. Syfte: Att kartlägga läkemedelsanvändningen och köpbeteendet avseende receptfria läkemedel med diklofenak, ibuprofen, naproxen och acetylsalicylsyra, hos kunder som köper dessa läkemedel på öppenvårdsapotek. Detta med anledning av att det finns begränsad information om användningen av dessa receptfria substanser. Material och metoder: En prospektiv tvärsnittsstudie som omfattade fyra apotek i Stockholm-Uppsala regionen under tidsperioden 2014-09-15 till 2014-10-21. Data samlades in med hjälp av en enkät som delades ut av en observatör till individer som köpt ett preparat med diklofenak, ibuprofen, naproxen eller acetylsalicylsyra. Resultat: Det var fler kvinnor (148 stycken, 64,1 %) än män som köpte ett receptfritt NSAID-preparat. Den vanligaste åldersgruppen som köpte receptfritt NSAID var 40-49 år (20,8 %) medan det var 11,7 % som tillhörde åldersgruppen 70+. Den mest använda substansen bland NSAID var ibuprofen (46,3 %). De två vanligaste användningsområden för bägge könen var huvudvärk (43,1 %) och muskelvärk (30,4 %). Av samtliga deltagare var det 14 stycken (6,7 %) som kombinerade det köpta läkemedlet med ett annat receptfritt NSAID. Konklusion: Det var fler kvinnor än män som köpte receptfritt NSAID på apotek. Drygt 12 % av deltagarna, som var 70 år och äldre använde sig utav NSAID vilket är en olämplig läkemedelsklass för äldre personer.    

  • 119.
    Akbari Kenari, Sepideh
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    The role of serotonin and dopamine signalling within the prefrontal cortex and striatum in cognitive function in rats2012Självständigt arbete på grundnivå (kandidatexamen), 20 poäng / 30 hpStudentuppsats (Examensarbete)
  • 120.
    Akcan, Martina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmakokinetik och läkemedelsterapi.
    Smärtstillande läkemedelsbehandling hosäldre i Uppsala län - en retrospektiv studie2014Självständigt arbete på grundnivå (yrkesexamen), 10 poäng / 15 hpStudentuppsats (Examensarbete)
    Abstract [sv]

    Introduktion: Hos äldre är smärta relativt vanligt då det med ökad ålder uppkommerproblem i muskler, leder, senor och skelett, t.ex. artros, osteoporos och sarkopeni.Socialstyrelsen utformade 2004 en mall för god läkemedelsterapi hos äldre, s.k.kvalitetsindikatorer. T.ex. får paracetamol inte överstiga en dygnsdos på 4 g/dygn ochNSAID bör endast användas vid inflammatorisk smärta. När lätta analgetika inte hjälperrekommenderas behandling med starka opioider direkt utan att först använda lättaopioider lätta opioider då dessa anses olämpliga för äldre. Vid perifer neuropatisksmärta rekommenderas i första hand TCA (amitriptylin, nortriptylin) eller gabapentin.Syfte: Det övergripande syftet är att värdera kvaliteten i äldres smärtstillandeläkemedelsbehandling genom att relatera den till rekommenderad behandling för att ökakunskapen om hur behandling med smärtstillande läkemedel ser ut inom äldrevårdenidag. Material och metoder: Läkemedelslistor från 434 patienter från olikaäldreboenden i Uppsala län inkluderas i studien. Insamlade, avidentifierade data fördesin i Excel med information som student-ID, patient-ID, ålder, kön, substansnamn,stående dos, vidbehovsdos och stående + vidbehovsdos. Resultat: Gruppen bestod av299 kvinnor och 135 män med medelåldern 85,4 år. Totalt förskrevs 485 smärtstillandeläkemedel till de 434 patienterna. 75.8 % patienter förskrevs paracetamol, 27,2 %opioider, 3,45 % NSAID, 0,92 % amitriptylin respektive 1,61 % gabapentin.Rekommenderad dygnsdos av paracetamol överskreds hos 13 patienter, av diklofenakhos en patient medan 33 patienter inte hade maximal dygnsdos angiven. Förskrivning avett analgetikum var vanligast och förekom hos 179 patienter. Två analgetika förskrevstill 119 patienter medan två, en man och en kvinna, förskrevs 5 analgetika vardera.Totalt 94 personer, 21,4 %, använde inga smärtstillande läkemedel alls. Konklusion:Studien visar att smärtstillande läkemedelsbehandling hos äldre i Uppsala län inteskiljer sig markant från studier gjorda i övriga Sverige och Europa. Dock var det någrasom, enligt Socialstyrelsen kvalitetsindikatorer, överskred dygnsdosen och stod påläkemedel som anses vara olämpliga för äldre, vilket visar att det fortfarande finnsproblem med äldres läkemedelsterapi.

  • 121.
    Akerblom, EB
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi.
    Six new photolabile linkers for solid phase synthesis. 2. Coupling ofvarious building blocks and photolytic cleavage.1998Ingår i: Mol Divers, Vol. 4, s. 53-Artikel i tidskrift (Refereegranskat)
  • 122. Akhtar, Malik N.
    et al.
    Southey, Bruce R.
    Andrén, Per E.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Sweedler, Jonathan V.
    Rodriguez-Zas, Sandra L.
    Accurate Assignment of Significance to Neuropeptide Identifications Using Monte Carlo K-Permuted Decoy Databases2014Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, nr 10, s. e111112-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    In support of accurate neuropeptide identification in mass spectrometry experiments, novel Monte Carlo permutation testing was used to compute significance values. Testing was based on k-permuted decoy databases, where k denotes the number of permutations. These databases were integrated with a range of peptide identification indicators from three popular open-source database search software (OMSSA, Crux, and X! Tandem) to assess the statistical significance of neuropeptide spectra matches. Significance p-values were computed as the fraction of the sequences in the database with match indicator value better than or equal to the true target spectra. When applied to a test-bed of all known manually annotated mouse neuropeptides, permutation tests with k-permuted decoy databases identified up to 100% of the neuropeptides at p-value < 10(-5). The permutation test p-values using hyperscore (X! Tandem), E-value (OMSSA) and Sp score (Crux) match indicators outperformed all other match indicators. The robust performance to detect peptides of the intuitive indicator "number of matched ions between the experimental and theoretical spectra" highlights the importance of considering this indicator when the p-value was borderline significant. Our findings suggest permutation decoy databases of size 1x10(5) are adequate to accurately detect neuropeptides and this can be exploited to increase the speed of the search. The straightforward Monte Carlo permutation testing (comparable to a zero order Markov model) can be easily combined with existing peptide identification software to enable accurate and effective neuropeptide detection. The source code is available at http://stagbeetle.animal.uiuc.edu/pepshop/MSMSpermutationtesting.

  • 123. Akhtar, Malik N.
    et al.
    Southey, Bruce R.
    Andrén, Per E.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Sweedler, Jonathan V.
    Rodriguez-Zas, Sandra L.
    Evaluation of Database Search Programs for Accurate Detection of Neuropeptides in Tandem Mass Spectrometry Experiments2012Ingår i: Journal of Proteome Research, ISSN 1535-3893, E-ISSN 1535-3907, Vol. 11, nr 12, s. 6044-6055Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Neuropeptide identification in mass spectrometry experiments using database search programs developed for proteins is challenging. Unlike proteins, the detection of the complete sequence using a single spectrum is required to identify neuropeptides or prohormone peptides. This study compared the performance of three open-source programs used to identify proteins, OMSSA, X!Tandem and Crux, to identify prohormone peptides. From a target database of 7850 prohormone peptides, 23550 query spectra were simulated across different scenarios. Crux was the only program that correctly matched all peptides regardless of p-value and at p-value < 1 X 10(-2), 33%, 64%, and >75%, of the 5, 6, and >= 7 amino acid-peptides were detected. Crux also had the best performance in the identification of peptides from chimera spectra and in a variety of missing ion scenarios. OMSSA, X!Tandem and Crux correctly detected 98.9% (99.9%), 93.9% (97.4%) and 88.7% (98.3%) of the peptides at E- or p-value < 1 X 10(-6) (< 1 X 10(-2)), respectively. OMSSA and X! Tandem outperformed the other programs in significance level and computational speed, respectively. A consensus approach is not recommended because some prohormone peptides were only identified by one program.

  • 124. Akhtar, Malik N.
    et al.
    Southey, Bruce R.
    Andrén, Per E.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Sweedler, Jonathan V.
    Rodriguez-Zas, Sandra L.
    Identification of best indicators of peptide-spectrum match using a permutation resampling approach2014Ingår i: Journal of Bioinformatics and Computational Biology, ISSN 0219-7200, E-ISSN 1757-6334, Vol. 12, nr 5, s. 1440001-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Various indicators of observed-theoretical spectrum matches were compared and the resulting statistical significance was characterized using permutation resampling. Novel decoy databases built by resampling the terminal positions of peptide sequences were evaluated to identify the conditions for accurate computation of peptide match significance levels. The methodology was tested on real and manually curated tandem mass spectra from peptides across a wide range of sizes. Spectra match indicators from complementary database search programs were pro filed and optimal indicators were identified. The combination of the optimal indicator and permuted decoy databases improved the calculation of the peptide match significance compared to the approaches currently implemented in the database search programs that rely on distributional assumptions. Permutation tests using p-values obtained from software-dependent matching scores and E-values outperformed permutation tests using all other indicators. The higher overlap in matches between the database search programs when using end permutation compared to existing approaches con firmed the superiority of the end permutation method to identify peptides. The combination of effective match indicators and the end permutation method is recommended for accurate detection of peptides.

  • 125.
    Akin, Berivan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmakokinetik och läkemedelsterapi.
    En undersökning gällande val av antibiotika för behandling av nedre UVI hos kvinnor2016Självständigt arbete på grundnivå (kandidatexamen), 10 poäng / 15 hpStudentuppsats (Examensarbete)
    Abstract [sv]

    En undersökning gällande val av antibiotika för behandling av nedre UVI hos kvinnor Berivan Akin Handledare: Margareta Hammarlund-Udenaes – Institution för farmaceutisk biovetenskap Examinator: Agneta Freijs – Institution för farmaceutisk biovetenskap

    Introduktion: Nedre UVI är en infektion som lokaliseras till urinröret och orsakas till mestadels av de primära patogenerna E. coli eller S. saprophyticus. Infektionen kan diagnostiseras endast baserad på symtomen eller med tillägg av tester som leukocytesterastest, nitrittest samt urinodling. Användning av de testerna ger en säkrare diagnos och förskrivaren kan därmed ge patienten en lämpligare behandling. Detta kan skilja sig om det är sporadisk eller recidiverande nedre UVI. Antibiotika som förskrivs för nedre UVI är huvudsakligen nitrofurantoin, pivmecillinam, trimetoprim och ciprofloxacin. Syfte: Huvudsyftet med arbetet var att klargöra hur förskrivaren resonerar kring valet av tester och antibiotika för att behandla en patient med misstänkt nedre UVI. Metod: Förskrivare med olika bakgrund och erfarenhet intervjuades för att undersöka bakomliggande motiv tillbehandlingsvalet. En litteraturstudie genomfördes för att erhålla information om resistensproblematiken samt miljövänligheten av preparaten. Förskrivningsstatistik togs fram via Socialstyrelsens databas för läkemedel. Resultat: Det konstaterades att labprov och teststickor inte nödvändigtvis behövs för att förskriva läkemedel mot nedre UVI. Förskrivningsstatistiken visade att antalet recept med nitrofurantoin och pivmecillinam har ökat markant från år 2006 och framåt, medan trimetoprim och ciprofloxacin har minskat. Slutsats: Pivmecillinam förskrivs mest och därefter nitrofurantoin. Förskrivarna resonerar olika vid valet av antibiotika beroende på erfarenheten. Resistensproblematiken tas hänsyn till, men miljöproblematiken prioriteras lågt.

  • 126.
    Akkawi, Ranaa
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Eksborg, Staffan
    Andersson, Asa
    Lundeberg, Stefan
    Bartocci, Marco
    Effect of oral naloxone hydrochloride on gastrointestinal transit in premature infants treated with morphine2009Ingår i: Acta Paediatrica, ISSN 0803-5253, E-ISSN 1651-2227, Vol. 98, nr 3, s. 442-447Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Opioids are common drugs for pain treatment in preterm newborn infants, in spite of several adverse effects. Constipation is a frequent problem when opioids are used in both adults and neonates. Although several studies indicate that the oral administration of naloxone hydrochloride (NH) improves intestinal motility during opioid therapy, there is still a lack of evidence in newborns. Aim: The aim of this study was to assess the efficacy of NH against reduced intestinal motility during opioid treatment. Methods: A retrospective cohort study was performed. We analysed the medical records of fifteen infants (Group 1) treated with continuous morphine (MO) infusion and fourteen infants (Group 2) treated with both oral NH (3 mu g/kg 4 times daily) and MO. Results: There was no statistically significant difference in the total MO dose. Infants treated both with NH and MO had a tendency to improve their mean stool frequency/day. A statistically significant improvement was observed in the mean total food intake (mL/kg/day) of the infants treated with NH (p = 0.014). No difference in the mean food retention between the two groups was observed. Conclusion: Orally administrated NH seems to improve intestinal motility resulting in increased food intake/day and improved stool frequency/day in premature newborn infants treated with MO. Further studies are needed to corroborate these findings.

  • 127.
    Al Haj, Mahmoud
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Effects of Dehydration and Blockade of the Renin-Angiotensin System in the One-humped Camel (Camelus dromedarius)2013Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    The one-humped or the dromedarian camel is a pseudo-ruminant mammal, well adapted to the hot and dry climates of the desert. Its ability to withstand torrid heat and extreme desiccation is of paramount importance to its survival. The studies presented in this thesis were designed to investigate and document the effect of dehydration in the presence or absence of angiotensin II (Ang II) AT1 receptor blocker (losartan) on blood constituents, electrolytes, hormones, neurotransmitters as well as liver and kidney enzymes in a subset of dehydrated camels and to compare them with hydrated camels. Additionally, we studied the response of atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) and revealed for the first time the cardiac storage form of BNP in the camel heart. Dehydration induced significant increments in packed cell volume (PCV), white blood cells (WBC), gamma glutamyl-transferase (GGT), serum sodium, creatinine and urea levels, and a doubling in plasma cortisol and arginine vasopressin (AVP) levels. At the same time dehydration caused significant decrease in body weights, plasma insulin like growth factor-1 (IGF-1) and its binding protein-3 (IGFBP-3), and a 50% decrement in ANP and BNP levels. Moreover, dehydration with and without losartan resulted in significant changes in stress hormones and anti-oxidants in plasma, liver and kidney homogenates. Losartan on one hand enhanced the effect of dehydration resulting in significant increases in sodium, creatinine and urea levels. In addition losartan raised the  binding affinity of Ang II AT2 receptors in the small intestine with 8-fold and with 16-fold for liver AT1 receptors, indicating that Ang II AT1 and AT2 receptor binding sites were present in camel's small intestine while only AT1 receptor binding sites were found in the camel liver. One the other hand losartan resulted in significant decrease in body weights impaired the rise in anti-diuretic hormone and reduced aldosterone level. Finally, we showed that the proBNP is the storage form of BNP in the camel heart.

    Delarbeten
    1. Effect of Dehydration in the Presence and Absence of the Angiotensin Receptor Blocker Losartan on Blood Constituents in the Camel
    Öppna denna publikation i ny flik eller fönster >>Effect of Dehydration in the Presence and Absence of the Angiotensin Receptor Blocker Losartan on Blood Constituents in the Camel
    Visa övriga...
    2011 (Engelska)Ingår i: Journal of Medical Sciences, ISSN 1996-3262, E-ISSN 1996-3270, Vol. 4, nr 2, s. 73-78Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Aim: Dromedary camels are extremely well adapted to periods of water deprivation. The physiological mechanisms underlying this adaptation, however, are imperfectly understood. It is likely that the renin-angiotensin system plays an important role although few studies have addressed this possibility in the camel. Accordingly, the effects of long term dehydration alone and with angiotensin II type 1 receptor blocker, losartan, on whole blood and serum constituents were studied in camels.

    Methods:Twenty eight male camels 3-4 years old were studied while under shade during summer in the Gulf-region, where the ambient temperature was above 40 degree Celsius. The camels were divided into three groups: a control group(n=6) was allowed free access to feed and water, a dehydration group (n=16) was given food ad-lib during 20days of total water deprivation, and a dehydration plus losartan (losartan) group (n=6) which received losartan 5mg/Kg daily by intravenous injection during 20 days of dehydration.  

    Results: The body weight of the losartan group decreased by nearly 39.1% across dehydration whereas the reduction in body weight for the dehydration group was nearly 34.5% compared to controls. There was a significant increase in the packed cell volume (p<0.05) and leucocytes count (p<0.01) in the losartan group compared to controls. However, the mean corpuscular volume was significantly higher (p<0.05) in the dehydration group compared to controls. We observed major, statistically significant increases in serum urea (p<0.01) and creatinine (p<0.05) levels in the dehydration and losartan groups compared to controls. By the end of the period ofwater restriction, serum levels of gamma glutamyl transferase were significantly (p<0.01) lower in the losartan group compared to controls.

    Conclusion: The results of our experiment show that dehydration alone or in combination with Angiotensin II receptor blocker has major effects on the biochemical and hematological parameters of the camel blood.

    Nyckelord
    Blood, camel, dehydration, losartan, and serum
    Nationell ämneskategori
    Farmaceutiska vetenskaper
    Forskningsämne
    Farmaceutisk vetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-207413 (URN)10.2174/1996327001104020073 (DOI)
    Tillgänglig från: 2013-09-13 Skapad: 2013-09-13 Senast uppdaterad: 2018-01-11Bibliografiskt granskad
    2. Responses to Dehydration in the One-Humped Camel and Effects of Blocking the Renin-Angiotensin System
    Öppna denna publikation i ny flik eller fönster >>Responses to Dehydration in the One-Humped Camel and Effects of Blocking the Renin-Angiotensin System
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    2012 (Engelska)Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, nr 5, s. e37299-Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Our objectives were to compare the levels of circulating electrolytes, hormones, and renal function during 20 days of dehydration in camels versus the level in non-dehydrated camels and to record the effect of blocking angiotensin II AT1 receptors with losartan during dehydration. Dehydration induced significant increments in serum sodium, creatinine, urea, a substantial fall in body weight, and a doubling in plasma arginine vasopressin (AVP) levels. Plasma aldosterone, however, was unaltered compared with time-matched controls. Losartan significantly enhanced the effect of dehydration to reduce body weight and increase serum levels of creatinine and urea, whilst also impairing the rise in plasma AVP and reducing aldosterone levels. We conclude that dehydration in the camel induces substantial increments in serum sodium, creatinine, urea and AVP levels; that aldosterone levels are altered little by dehydration; that blockade of angiotensin II type 1 receptors enhances the dehydration-induced fall in body weight and increase in serum creatinine and urea levels whilst reducing aldosterone and attenuating the rise in plasma AVP.

    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-177622 (URN)10.1371/journal.pone.0037299 (DOI)000305343500092 ()
    Tillgänglig från: 2012-07-18 Skapad: 2012-07-17 Senast uppdaterad: 2017-12-07Bibliografiskt granskad
    3. Changes in insulin-like growth factor-1 and IGF-binding protein-3 in camel plasma during dehydration in the presence and absence of losartan
    Öppna denna publikation i ny flik eller fönster >>Changes in insulin-like growth factor-1 and IGF-binding protein-3 in camel plasma during dehydration in the presence and absence of losartan
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    2012 (Engelska)Ingår i: Comparative Clinical Pathology, ISSN 1618-5641, E-ISSN 1618-565X, Vol. 21, nr 6, s. 1745-1749Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    In the present study, the effect of 20 days of dehydration in the presence or absence of losartan (angiotensin II AT1 receptor antagonist) on insulin-like growth factor-1(IGF-1) and insulin-like growth factor-binding protein-3(IGFBP-3) in plasma of the one-humped camel was studied. Eighteen male camels, 3-4 years of age, were divided into three equal groups: control, dehydrated, and dehydrated-losartan-treated groups. The control camels were given food and water ad libitum. The two dehydrated groups underwent 20 days of water deprivation but were given food ad libitum. The dehydrated-losartan-treated camels were given losartan injection (Merck, USA), intravenously at a dose of 5 mg/kg body weight daily for 20 days. Our results demonstrated a progressive decrease in the circulating levels of IGF-1 and IGFBP-3 in the dehydrated and dehydrated-losartan-treated animals across dehydration compared to their basal levels and time-matched control. On day 5 of dehydration, the IGF-1 level in the losartan-treated group showed a decrease of 60 % and the dehydrated group showed 45 % decrease from their baseline levels and time-matched control. On day 10 the decrease in the losartan-treated animals reached 74 % and for the dehydrated was 62 %. On day 20 the decrease in the losartan-treated was 89 % and for the dehydrated reached 80 % from their baseline levels and time-matched control. Dehydration in the presence or absence of losartan caused a decrease in the circulating level of IGFBP-3. The decrement reached 26 % on day 10 and 20 for the treated camels, while the decrease for the dehydrated was 22 % on day 10 of dehydration and reached 29 % on day 20 compared to their baseline levels and time-matched control. In conclusion, dehydration alone, or in presence of Angiotensin II AT1 receptor blocker caused significant decrease in the circulating levels of IGF-1 and IGFBP-3 compared to their basal values and to time-matched controls. Losartan enhanced the effect of dehydration mainly in the early phase of dehydration for both parameters; albeit, no significant differences between the two dehydrated groups was observed. Finally, these findings suggest an essential role of IGF-1and IGFBP-3 in the dehydration state of these dromedarian camels.

    Nyckelord
    Camel, Dehydration, IGF-1, IGFBP-3, Losartan
    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-193751 (URN)10.1007/s00580-012-1562-y (DOI)
    Tillgänglig från: 2013-02-06 Skapad: 2013-02-06 Senast uppdaterad: 2017-12-06Bibliografiskt granskad
    4. ANP and BNP Responses to Dehydration in the One-Humped Camel and Effects of Blocking the Renin-Angiotensin System
    Öppna denna publikation i ny flik eller fönster >>ANP and BNP Responses to Dehydration in the One-Humped Camel and Effects of Blocking the Renin-Angiotensin System
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    2013 (Engelska)Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, nr 3, s. e57806-Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    The objectives of this study were to investigate and compare the responses of atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) in the circulation of hydrated, dehydrated, and dehydrated losartan - treated camels; and to document the cardiac storage form of B-type natriuretic peptide in the camel heart. Eighteen male camels were used in the study: control or hydrated camels (n = 6), dehydrated camels (n = 6) and dehydrated losartan-treated camels (n = 6) which were dehydrated and received the angiotensin II (Ang II) AT-1 receptor blocker, losartan, at a dose of 5 mg/kg body weight intravenously for 20 days. Control animals were supplied with feed and water ad-libitum while both dehydrated and dehydrated-losartan treated groups were supplied with feed ad-libitum but no water for 20 days. Compared with time-matched controls, dehydrated camels exhibited a significant decrease in plasma levels of both ANP and BNP. Losartan-treated camels also exhibited a significant decline in ANP and BNP levels across 20 days of dehydration but the changes were not different from those seen with dehydration alone. Size exclusion high performance liquid chromatography of extracts of camel heart indicated that proB-type natriuretic peptide is the storage form of the peptide. We conclude first, that dehydration in the camel induces vigorous decrements in circulating levels of ANP and BNP; second, blockade of the renin-angiotensin system has little or no modulatory effect on the ANP and BNP responses to dehydration; third, proB-type natriuretic peptide is the storage form of this hormone in the heart of the one-humped camel.

    Nationell ämneskategori
    Naturvetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-200116 (URN)10.1371/journal.pone.0057806 (DOI)000316849200019 ()
    Tillgänglig från: 2013-05-21 Skapad: 2013-05-20 Senast uppdaterad: 2017-12-06Bibliografiskt granskad
    5. Effects of Dehydration and Blockade of Angiotensin II AT1 Receptor on Stress Hormones and Anti-Oxidants in the one-humped camel
    Öppna denna publikation i ny flik eller fönster >>Effects of Dehydration and Blockade of Angiotensin II AT1 Receptor on Stress Hormones and Anti-Oxidants in the one-humped camel
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    2013 (Engelska)Ingår i: BMC Veterinary Research, ISSN 1746-6148, E-ISSN 1746-6148, Vol. 9, s. 232-Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Our objectives were to document and compare plasma levels of Catecholamines, Cortisol,Glutathione and Malondialdehyde in camels after long term dehydration (20 days) in the presenceor absence of angiotensin II AT1 receptor blocker (Losartan) versus levels in non-dehydratedcamels; and to record the effects on glutathione and malondialdehyde activity in liver and kidneyhomogenate in the one-humped camel. Eighteen male camels were used in this study, sixcontrols, six dehydrated and treated with losartan (5mg/kg daily) and six were dehydrated withouttreatment. Our results revealed significant decrease (P<0.05) in plasma epinephrine level in bothtreated and dehydrated camels; while, Plasma norepinephrine showed significant increase in bothdehydrated groups (P< 0.01). Levels of plasma dopamine were also significantly increased (P<0.01) in both dehydrated groups compared to control camels.Plasma levels of cortisol increased significantly across dehydration with or without losartanadministration (P<0.01) compared with time-matched levels in control camels. Losartan had nosignificant modulating effect on the cortisol response to dehydration.Plasma, liver and kidney homogenates revealed significant increase (P<0.05) in glutathione levelsin both dehydrated groups compared to control.Plasma, liver and kidney homogenates for malondialdehyde levels in both treated and dehydratedcamels also showed significant increase (P<0.05 & P<0.01) compared to controls.In conclusion, our study demonstrates that the effect of dehydration with or without losartaninduced oxidative stress in these camels, leading to significant changes in plasma catecholaminesand cortisol levels, together with significant increments in glutathione and malondialdehydeactivities in plasma, liver and kidney homogenate to counter act the damaging effect of the freeradicals in the dehydrated camels.

    Nyckelord
    Camel, Catecholamine, Cortisol, dehydration, Glutathione and Malondialdehyde
    Nationell ämneskategori
    Farmaceutiska vetenskaper
    Forskningsämne
    Farmaceutisk vetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-207417 (URN)10.1186/1746-6148-9-232 (DOI)000329620900001 ()
    Tillgänglig från: 2013-09-13 Skapad: 2013-09-13 Senast uppdaterad: 2018-01-11Bibliografiskt granskad
  • 128.
    Al Haj, Mahmoud
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Kazzam, E.
    Amir, N.
    Nyberg, Fred
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Adem, A.
    Changes in insulin-like growth factor-1 and IGF-binding protein-3 in camel plasma during dehydration in the presence and absence of losartan2012Ingår i: Comparative Clinical Pathology, ISSN 1618-5641, E-ISSN 1618-565X, Vol. 21, nr 6, s. 1745-1749Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    In the present study, the effect of 20 days of dehydration in the presence or absence of losartan (angiotensin II AT1 receptor antagonist) on insulin-like growth factor-1(IGF-1) and insulin-like growth factor-binding protein-3(IGFBP-3) in plasma of the one-humped camel was studied. Eighteen male camels, 3-4 years of age, were divided into three equal groups: control, dehydrated, and dehydrated-losartan-treated groups. The control camels were given food and water ad libitum. The two dehydrated groups underwent 20 days of water deprivation but were given food ad libitum. The dehydrated-losartan-treated camels were given losartan injection (Merck, USA), intravenously at a dose of 5 mg/kg body weight daily for 20 days. Our results demonstrated a progressive decrease in the circulating levels of IGF-1 and IGFBP-3 in the dehydrated and dehydrated-losartan-treated animals across dehydration compared to their basal levels and time-matched control. On day 5 of dehydration, the IGF-1 level in the losartan-treated group showed a decrease of 60 % and the dehydrated group showed 45 % decrease from their baseline levels and time-matched control. On day 10 the decrease in the losartan-treated animals reached 74 % and for the dehydrated was 62 %. On day 20 the decrease in the losartan-treated was 89 % and for the dehydrated reached 80 % from their baseline levels and time-matched control. Dehydration in the presence or absence of losartan caused a decrease in the circulating level of IGFBP-3. The decrement reached 26 % on day 10 and 20 for the treated camels, while the decrease for the dehydrated was 22 % on day 10 of dehydration and reached 29 % on day 20 compared to their baseline levels and time-matched control. In conclusion, dehydration alone, or in presence of Angiotensin II AT1 receptor blocker caused significant decrease in the circulating levels of IGF-1 and IGFBP-3 compared to their basal values and to time-matched controls. Losartan enhanced the effect of dehydration mainly in the early phase of dehydration for both parameters; albeit, no significant differences between the two dehydrated groups was observed. Finally, these findings suggest an essential role of IGF-1and IGFBP-3 in the dehydration state of these dromedarian camels.

  • 129.
    Al Haj, Mahmoud
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap. United Arab Emirates University.
    Kazzam, Elsadig
    United Arab Emirates University.
    Nagelkerke, Nicolas
    United Arab Emirates University.
    Nyberg, Fred
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Nicholls, Gary M.
    Otago University, Christchurch.
    Adem, Abdu
    United Arab Emirates University.
    Effect of Dehydration in the Presence and Absence of the Angiotensin Receptor Blocker Losartan on Blood Constituents in the Camel2011Ingår i: Journal of Medical Sciences, ISSN 1996-3262, E-ISSN 1996-3270, Vol. 4, nr 2, s. 73-78Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Aim: Dromedary camels are extremely well adapted to periods of water deprivation. The physiological mechanisms underlying this adaptation, however, are imperfectly understood. It is likely that the renin-angiotensin system plays an important role although few studies have addressed this possibility in the camel. Accordingly, the effects of long term dehydration alone and with angiotensin II type 1 receptor blocker, losartan, on whole blood and serum constituents were studied in camels.

    Methods:Twenty eight male camels 3-4 years old were studied while under shade during summer in the Gulf-region, where the ambient temperature was above 40 degree Celsius. The camels were divided into three groups: a control group(n=6) was allowed free access to feed and water, a dehydration group (n=16) was given food ad-lib during 20days of total water deprivation, and a dehydration plus losartan (losartan) group (n=6) which received losartan 5mg/Kg daily by intravenous injection during 20 days of dehydration.  

    Results: The body weight of the losartan group decreased by nearly 39.1% across dehydration whereas the reduction in body weight for the dehydration group was nearly 34.5% compared to controls. There was a significant increase in the packed cell volume (p<0.05) and leucocytes count (p<0.01) in the losartan group compared to controls. However, the mean corpuscular volume was significantly higher (p<0.05) in the dehydration group compared to controls. We observed major, statistically significant increases in serum urea (p<0.01) and creatinine (p<0.05) levels in the dehydration and losartan groups compared to controls. By the end of the period ofwater restriction, serum levels of gamma glutamyl transferase were significantly (p<0.01) lower in the losartan group compared to controls.

    Conclusion: The results of our experiment show that dehydration alone or in combination with Angiotensin II receptor blocker has major effects on the biochemical and hematological parameters of the camel blood.

  • 130.
    Al Jabri, Nagham
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Utvärdering av deltagarnas upplevelse och uppfattning om projektet Hälsoaktiv2018Självständigt arbete på avancerad nivå (masterexamen), 20 poäng / 30 hpStudentuppsats (Examensarbete)
  • 131.
    Al Shemaili, Jasem
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Mensah-Brown, E.
    Parekh, K.
    Thomas, S. A.
    Attoub, S.
    Hellman, Björn
    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.
    Adem, A.
    Collin, P.
    Adrian, T. E.
    Frondoside A enhances the antiproliferative effects of gemcitabine in pancreatic cancer2014Ingår i: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 50, nr 7, s. 1391-1398Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Pancreatic cancer has a very poor prognosis. While gemcitabine is the mainstay of therapy and improves quality of life, it has little impact on survival. More effective treatments are desperately needed for this disease. Frondoside A is a triterpenoid glycoside isolated from the Atlantic sea cucumber, Cucumaria frondosa. Frondoside A potently inhibits pancreatic cancer cell growth and induces apoptosis in vitro and in vivo. The aim of the present study was to investigate whether frondoside A could enhance the anti-cancer effects of gemcitabine. Effects of frondoside A and gemcitabine alone and in combination on proliferation were investigated in two human pancreatic cancer cell lines, AsPC-1 and S2013. To investigate possible synergistic effects, combinations of low concentrations of the two drugs were used for a 72 h treatment period in vitro. Growth inhibition was significantly greater with the drug combinations than their additive effects. Combinations of frondoside A and gemcitabine were tested in vivo using the athymic mouse model. Xenografts of AsPC-1 and S2013 cells were allowed to form tumours prior to treatment with the drugs alone or in combination for 30 days. Tumours grew rapidly in placebo-treated animals. Tumour growth was significantly reduced in all treatment groups. At the lowest dose tested, gemcitabine (4 mg/kg/dose), combined with frondoside A (100 mu g/kg/day) was significantly more effective than with either drug alone. To conclude: The present data suggest that combinations of frondoside A and gemcitabine may provide clinical benefit for patients with pancreatic cancer.

  • 132.
    Al Shemaili, Jasem
    et al.
    United Arab Emirates Univ, Fac Med, Dept Physiol, POB 17666, Al Ain, U Arab Emirates..
    Parekh, Khatija A.
    United Arab Emirates Univ, Fac Med, Dept Physiol, POB 17666, Al Ain, U Arab Emirates..
    Newman, Robert A.
    Phoenix Biotechnol Inc, San Antonio, TX 78217 USA..
    Hellman, Björn
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Woodward, Carl
    Coastside Bio Resources, Deer Isle, ME 04627 USA..
    Adem, Abdu
    United Arab Emirates Univ, Dept Pharmacol, Fac Med, POB 17666, Al Ain, U Arab Emirates..
    Collin, Peter
    Coastside Bio Resources, Deer Isle, ME 04627 USA..
    Adrian, Thomas E.
    United Arab Emirates Univ, Fac Med, Dept Physiol, POB 17666, Al Ain, U Arab Emirates..
    Pharmacokinetics in Mouse and Comparative Effects of Frondosides in Pancreatic Cancer2016Ingår i: Marine Drugs, ISSN 1660-3397, E-ISSN 1660-3397, Vol. 14, nr 6, artikel-id 115Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The frondosides are triterpenoid glycosides from the Atlantic sea cucumber Cucumaria frondosa. Frondoside A inhibits growth, invasion, metastases and angiogenesis and induces apoptosis in diverse cancer types, including pancreatic cancer. We compared the growth inhibitory effects of three frondosides and their aglycone and related this to the pharmocokinetics and route of administration. Frondoside A potently inhibited growth of pancreatic cancer cells with an EC50 of similar to 1 mu M. Frondoside B was less potent (EC50 similar to 2.5 mu M). Frondoside C and the aglycone had no effect. At 100 mu g/kg, frondoside A administered to CD2F1 mice as an i.v. bolus, the Cp-max was 129 nM, Cl-tb was 6.35 mL/min/m(2), and half-life was 510 min. With i.p. administration the Cp-max was 18.3 nM, Cl-tb was 127 mL/min/m(2) and half-life was 840 min. Oral dosing was ineffective. Frondoside A (100 mu g/kg/day i.p.) markedly inhibited growth cancer xenografts in nude mice. The same dose delivered by oral gavage had no effect. No evidence of acute toxicity was seen with frondoside A. Frondoside A is more potent inhibitor of cancer growth than other frondosides. The glycoside component is essential for bioactivity. Frondoside A is only effective when administered systemically. Based on the current and previous studies, frondoside A appears safe and may be valuable in the treatment of cancer.

  • 133.
    Alajlani, M.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Farmakognosi. Karl Franzens Univ Graz, Inst Pharmaceut Sci, Dept Pharmacognosy, Univ Pl 4, A-8010 Graz, Austria..
    Backlund, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Farmakognosi.
    Predicting the mechanism of action of antituberculosis agents using chemical global positioning system - natural product2016Ingår i: Planta Medica, ISSN 0032-0943, E-ISSN 1439-0221, Vol. 82Artikel i tidskrift (Övrigt vetenskapligt)
  • 134.
    Alamgir, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Uppföljning av PRISS-riktlinjer för antibiotikaprofylax vid elektiv knäprotesoperation på Södersjukhuset2018Självständigt arbete på avancerad nivå (magisterexamen), 20 poäng / 30 hpStudentuppsats (Examensarbete)
    Abstract [sv]

    Bakgrund och syfte: Södersjukhusets avdelning för vård och omsorg (vo) Ortopedi har inte tidigare i någon större utsträckning undersökt följsamheten till PRISS-riktlinjer som används för att förhindra protesrelaterade infektioner (PJI). Syftet med arbetet var att undersöka följsamheten av PRISS-riktlinjer för antibiotikaprofylax (ABP) vid elektiv knäprotesoperation (KPO) på Södersjukhuset vo Ortopedi. Resultatet från arbetet kommer användas som grund för kvalitetshöjande åtgärder.

    Metod: Journalgranskning utfördes av 273 elektiva KPO som opererats år 2016. Information kring ABP, operationstid, riskfaktorer och så vidare, extraherades ur journalerna och jämfördes sedan mot PRISS-riktlinjer. En annan metod användes för att jämföra icke-infekterade patienter från 2016 med infekterade patienter från år 2016 och år 2017 med hänseende på riskfaktorer. Två patienter som opererats under år 2016 och infekterats exkluderades från den icke infekterade populationen. Med en revisionsriskmodell jämfördes riskfaktorerna för 271 icke-infekterade patienter och fyra infekt