51.
Felth, Jenny, et al.
(författare)
Cytotoxic effects of cardiac glycosides in colon cancer cells, alone and in combination with standard chemotherapeutic drugs
2009
Ingår i: Journal of natural products (Print). - : American Chemical Society (ACS). - 0163-3864 .- 1520-6025. ; 72:11, s. 1969-1974
Tidskriftsartikel (refereegranskat) abstract
Cardiac glycosides have been reported to exhibit cytotoxic activity against several different cancer types, but studies against colorectal cancer are lacking. In a screening procedure aimed at identifying natural products with activity against colon cancer, several cardiac glycosides were shown to be of interest, and five of these were further evaluated in different colorectal cancer cell lines and primary cells from patients. Convallatoxin (1), oleandrin (4), and proscillaridin A (5) were identified as the most potent compounds (submicromolar IC50 values), and digitoxin (2) and digoxin (3), which are used in cardiac disease, exhibited somewhat lower activity (IC50 values 0.27−4.1 μM). Selected cardiac glycosides were tested in combination with four clinically relevant cytotoxic drugs (5-fluorouracil, oxaliplatin, cisplatin, irinotecan). The combination of 2 and oxaliplatin exhibited synergism including the otherwise highly drug-resistant HT29 cell line. A ChemGPS-NP application comparing modes of action of anticancer drugs identified cardiac glycosides as a separate cluster. These findings demonstrate that such substances may exhibit significant activity against colorectal cancer cell lines, by mechanisms disparate from currently used anticancer drugs, but at concentrations generally considered not achievable in patient plasma.
52.
Fransén, Nelly, et al.
(författare)
Clinical study shows improved absorption of desmopressin with novel formulation
2009
Ingår i: Pharmaceutical research. - : Springer Science and Business Media LLC. - 0724-8741 .- 1573-904X. ; 26:7, s. 1618-1625
Tidskriftsartikel (refereegranskat) abstract
To create improved pharmaceutical formulations for nasal and sublingual administration of desmopressin and investigate their pharmacokinetic profiles in comparison with a commercial nasal liquid spray and finally to evaluate the volunteers' opinions on the different dosage forms. Both formulations were based on the characteristics of interactive mixtures. The nasal powder spray was produced by a rotary evaporator technique with sodium starch glycolate as carrier material and the sublingual tablet by direct compression after dry mixing with mannitol as carrier. The clinical study was an open-label, randomised cross-over pharmacokinetic study in healthy volunteers. The nasal powder formulation gave a threefold increase in the absorption, unaltered time to maximum plasma concentration and a tendency to lower variability in the amount absorbed compared with the liquid spray. The powder was reported to be more irritating than the liquid but was still well accepted by the volunteers. The tablet did not improve the uptake of desmopressin, likely because of a poor disintegration sublingually. The nasal powder formulation is a promising new dosage form for the delivery of desmopressin and other compounds. The sublingual tablet has a beneficial means of production and may be further developed by decreasing its disintegration time.
53.
Frenning, Göran, et al.
(författare)
An effective-medium analysis of confined compression of granular materials
2009
Ingår i: Powder Technology. - : Elsevier BV. - 0032-5910 .- 1873-328X. ; 194:3, s. 228-232
Tidskriftsartikel (refereegranskat) abstract
A simplified model for confined compression of granular materials is considered, which idealizes the collection of particles as a (central) force network. Applying an effective-medium procedure, an equation with micromechanically well-defined parameters is derived, which relates the applied pressure to the engineering strain of the powder during uniaxial compression. Despite the simplicity of the model, comparison with experimental data for mm-sized spherical granules indicates that this equation is able to satisfactorily predict the overall compression profile from single-particle data.
54.
Frenning, Göran, et al.
(författare)
Aspects of pharmaceutical physics
2009. - 5
Ingår i: Modern Pharmaceutics, Volume 2. - New York : Informa Healthcare USA. - 9781420065688
Bokkapitel (övrigt vetenskapligt/konstnärligt)
55.
Frenning, Göran, et al.
(författare)
Effective Kawakita parameters for binary mixtures
2009
Ingår i: Powder Technology. - : Elsevier BV. - 0032-5910 .- 1873-328X. ; 189:2, s. 270-275
Tidskriftsartikel (refereegranskat) abstract
Despite the fact that many industrial processes use mixtures of powders with different physical and mechanical properties, most fundamental studies of powder compression have focused on single-component systems. There is thus an obvious need for an improved understanding of the compression behaviour of mixtures of particulate and granular solids. In this contribution, we show that the Kawakita equation may be particularly useful in this regard. The reason for this is that the degree of compression (i.e., the ratio between the volume reduction and the initial powder volume) for sufficiently high compression pressures P is a linear function of I I P. For ideal mixtures, for which the volume of each component may be determined independently of the others, this linearity implies that effective Kawakita parameters for the mixture may be readily expressed in terms of the parameters of its components. In order to validate the proposed approach, binary mixtures of mm-sized spherical agglomerates prepared by wet granulation followed by extrusion and spheronization were investigated experimentally. Predicted and measured Kawakita parameters were generally in good agreement, indicating that the assumption of ideal mixing behaviour is valid for this type of systems.
56.
Friberg, L. E., et al.
(författare)
An agonist-antagonist interaction model for prolactin release following risperidone and paliperidone treatment
2009
Ingår i: Clinical Pharmacology and Therapeutics. - : Springer Science and Business Media LLC. - 0009-9236 .- 1532-6535. ; 85:4, s. 409-417
Tidskriftsartikel (refereegranskat) abstract
A mechanistic pharmacokinetic/pharmacodynamic model is presented, characterizing the time course of prolactin in healthy as well as schizophrenic subjects following the administration of various doses and formulations of the antipsychotic drugs risperidone and paliperidone. Prolactin concentrations from nine studies (1,462 subjects) were analyzed in NONMEM. A competitive agonist-antagonist interaction model described the competition between these drugs and dopamine for the D(2) receptors that regulate prolactin release. Tolerance development was explained by a feedback loop with prolactin stimulating dopamine release, whereas models wherein tolerance is described in terms of depletion of a prolactin pool did not explain the data well. The diurnal prolactin rhythm was described by a two-period cosine function. Baseline prolactin was health-status dependent and higher in women than in men, although the drug-induced release was less than proportional to baseline. This quantitative mechanism-based model is the first to describe prolactin release in patients, and it confirms that paliperidone and risperidone have similar potencies for prolactin release.
57.
Friberg, Lena, et al.
(författare)
Modeling and Simulation of the Time Course of Asenapine Exposure Response and Dropout Patterns in Acute Schizophrenia
2009
Ingår i: Clinical Pharmacology and Therapeutics. - : Springer Science and Business Media LLC. - 0009-9236 .- 1532-6535. ; 86:1, s. 84-91
Tidskriftsartikel (refereegranskat) abstract
Modeling and simulation were utilized to characterize the efficacy dose response of sublingual asenapine in patients with schizophrenia and to understand the outcomes of six placebo-controlled trials in which placebo responses and dropout rates varied. The time course of total Positive and Negative Syndrome Scale (PANSS) scores was characterized for placebo and asenapine treatments in a pharmacokinetic-pharmacodynamic model in which the asenapine effect was described by an E-max model, increasing linearly over the 6-week study period. A logistic regression model described the time course of dropouts, with previous PANSS value being the most important predictor. The last observation carried forward (LOCF) time courses were well described in simulations from the combined PANSS + dropout model. The observed trial outcomes were successfully predicted for all the placebo arms and the majority of the treatment arms. Although simulations indicated that the post hoc probability of success of the performed trials was low to moderate, these analyses demonstrated that 5 and 10 mg twice-daily (b.i.d.) doses of asenapine have similar efficacy.
58.
Fridén, Markus, et al.
(författare)
Development of a High-Throughput Brain Slice Method for Studying Drug Distribution in the Central Nervous System
2009
Ingår i: Drug Metabolism And Disposition. - : American Society for Pharmacology & Experimental Therapeutics (ASPET). - 0090-9556 .- 1521-009X. ; 37:6, s. 1226-1233
Tidskriftsartikel (refereegranskat) abstract
New, more efficient methods of estimating unbound drug concentrations in the CNS combine the amount of drug in whole brain tissue samples measured by conventional methods with in vitro estimates of the unbound brain volume of distribution (Vu,brain). While the brain slice method is the most reliable in vitro method for measuring Vu,brain, it has not previously been adapted for the needs of drug discovery research. The aim of this study was to increase the throughput and optimize the experimental conditions of this method. Equilibrium of drug between the buffer and the brain slice within the 4-5 hours of incubation is a fundamental requirement. However, it is difficult to meet this requirement for many of the extensively binding, lipophilic compounds in drug discovery programmes. In this study, the dimensions of the incubation vessel and mode of stirring influenced the equilibration time, as did the amount of brain tissue per unit buffer volume. The use of casette experiments for investigating Vu,brain in a linear drug concentration range increased the throughput of the method. The Vu,brain for the model compounds ranged from mL*g brain(-1); the sources of variability are discussed. The optimized set-up of the brain slice method allows precise, robust estimation of Vu,brain for drugs with diverse properties, including highly lipophilic compounds. This is a critical step forward for the implementation of relevant measurements of CNS exposure in the drug discovery setting.
59.
Fridén, Markus, et al.
(författare)
Structure-brain exposure relationships in rat and human using a novel data set of unbound drug concentrations in brain interstitial and cerebrospinal fluids
2009
Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 52:20, s. 6233-6243
Tidskriftsartikel (refereegranskat) abstract
New experimental methodologies were applied to measure the unbound brain-to-plasma concentration ratio (K(p,uu,brain)) and the unbound CSF-to-plasma concentration ratio (K(p,uu,CSF)) in rats for 43 structurally diverse drugs. The relationship between chemical structure and K(p,uu,brain) was dominated by hydrogen bonding. Contrary to popular understanding based on the total brain-to-plasma concentration ratio (logBB), lipophilicity was not a determinant of unbound brain exposure. Although changing the number of hydrogen bond acceptors is a useful design strategy for optimizing K(p,uu,brain), future improvement of in silico prediction models is dependent on the accommodation of active drug transport. The structure-brain exposure relationships found in the rat also hold for humans, since the rank order of the drugs was similar for human and rat K(p,uu,CSF). This cross-species comparison was supported by K(p,uu,CSF) being within 3-fold of K(p,uu,brain) in the rat for 33 of 39 drugs. It was, however, also observed that K(p,uu,CSF) overpredicts K(p,uu,brain) for highly effluxed drugs, indicating lower efflux capacity of the blood-cerebrospinal fluid barrier compared to the blood-brain barrier.
60.
Funning, Sandra, et al.
(författare)
Quality assurance within the scope of Good Clinical Practice (GCP) - What is the cost of GCP- related activities? : A survey within the Swedish Association of the Pharmaceutical Industry (LIF)´s members
2009
Ingår i: Quality Assurance Journal. - : Wiley. - 1087-8378 .- 1099-1786. ; 12:1, s. 3-7
Tidskriftsartikel (refereegranskat) abstract
The bureaucracy that the Good Clinical Practice (GCP) system generates, due to industryover-interpretation of documentation requirements, clinical monitoring, dataverifications etc. is substantial. The aim of this study was to estimate the percentagecost of all such GCP-related activities within phase III clinical trials performed inSweden in 2005.Method: An electronic questionnaire on ICH GCP-activities and their related costs wassent to 47 of the 60 member companies of the Swedish Association of the PharmaceuticalIndustry (LIF).Results: The number of respondents was 29, giving a response rate of 62% andcovering 97% (n5250) of phase III trials performed in Sweden in 2005. Approximately50% of the total budget for a phase III study was reported to be GCP-related.50% of the GCP-related cost was related to Source Data Verification (SDV). A vastmajority (71%) of respondents did not support the notion that these GCP-relatedactivities increase the scientific reliability of clinical trials.
