| 1. |
- Berggren, S, et al.
(author)
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Regional transport and metabolism of roivacaine and its CYP3A4 metabolite PPX in human intestine
- 2003
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In: Journal of Pharmacy and Pharmacology. - : Oxford University Press (OUP). - 0022-3573 .- 2042-7158. ; 55:7, s. 963-972
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Journal article (peer-reviewed)abstract
- The major aim of this study was to investigate the CYP3A4 metabolism and polarized transport of ropivacaine and its metabolite 2',6'-pipecoloxylidide (PPX) in tissue specimens from the human small and large intestine. Ropivacaine has been shown to be effective in the treatment of ulcerative colitis in human colon. This study was conducted using a modified Ussing-chamber technique with specimens from jejunum, ileum and colon collected from 11 patients. The local kinetics of ropivacaine and PPX were assessed from their concentration-time profiles in mucosal and serosal compartments. The permeability (P-app) in the absorptive direction for both ropivacaine and PPX increased regionally in the order jejunum
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| 2. |
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| 3. |
- Ekelund, Mats
(author)
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Competition and innovation in the Swedish pharmaceutical market
- 2001
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Doctoral thesis (other academic/artistic)abstract
- This thesis consists of four essays in economics related to the pharmaceutical market. The first essay, Pharmaceutical Pricing in a Regulated Market, compares the pricing of new pharmaceuticals in the Swedish market where prices are regulated, with the results of Lu and Comanor who studied the pricing of new pharmaceuticals in the US market. The results indicate that price regulation discourages the use of penetration strategies and decreases price competition between brand name drugs. The second essay, Innovativeness and Market Shares in the Pharmaceutical Industry, analyzes the pharmaceutical market in a model of horizontal and vertical product differentiation. The implications from the model are tested on data from the Swedish pharmaceutical market. Vertically differentiated drugs are found to gain larger market shares, command higher prices, and be less sensitive to substitutes than drugs that are only horizontally differentiated. The third essay, Generic entry before and after reference prices, examines the effect of the reference pricing system on generic entry in markets where brand name pharmaceuticals lose patent protection. The main result is that savings due to increased competition in markets affected by the reference pricing system may have been outbalanced by higher prices due to less competition in markets where the reference pricing system led to deterred entry. The fourth essay, Innovative Drugs and the Increase in Pharmaceutical Expenditures, seeks to establish the most important factors behind the growth in pharmaceutical expenditures. One important conjecture is that the change in the drug price index has little impact on the rate at which pharmaceutical expenditures grow. Instead, the introduction of new innovative drugs seems to be the most important driving force of the growth in pharmaceutical expenditures.
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| 4. |
- Ekelund, Mats
(author)
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Generic entry before and after reference prices
- 2001
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Other publication (other academic/artistic)abstract
- This paper studies the effect of the reference pricing system on generic entry in markets where brand name pharmaceuticals lose patent protection. I find the likelihood of generic entry after patent expiration to decrease, after the introduction of the reference pricing system. According to my estimates savings due to increased competition in markets affected by the reference pricing system may have been outbalanced by higher prices, due to less competition in markets where the reference pricing system led to deterred entry.
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| 5. |
- Ekelund, Mats
(author)
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Innovative Drugs and the Increase in Pharmaceutical Expenditures
- 2001
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Other publication (other academic/artistic)abstract
- This paper investigates how the growth in pharmaceutical expenditures is determined. A theoretical model of the growth in pharmaceutical expenditures is analyzed and the impact of new innovative drugs on the growth of Swedish pharmaceutical expenditures is studied empirically. The result from the theoretical model is that the potential driving forces of the steady state growth in expenditures are inflation in introductory drug prices, the inflow of new innovative drugs and the increase in the underlying demand. The result from the empirical study is that introductory drug prices have,been stable durin'g this period but that new innovative drugs have opened up new markets and increased the drug consumption. An important conclusion is that the change in the drug price index is of little importance for the growth in pharmaceutical expenditures in steady state. At present, it might be necessary to reduce the access to new innovative drugs if the steady state growth rate is to be reduced.
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| 6. |
- Ekelund, Mats, et al.
(author)
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Pharmaceutical pricing in a regulated market
- 2003
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In: Review of Economics and Statistics. - : Massachusetts Institute of Technology Press (MIT Press): Economics Titles. - 1530-9142 .- 0034-6535. ; 85:2, s. 298-306
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Journal article (peer-reviewed)abstract
- We compare how new pharmaceuticals are priced in the price-regulated Swedish market with how they are priced in the U.S. market, as studied by Lu and Comanor (1998). We collect a data set consisting of all new chemical entities (NCEs) launched in Sweden between 1987 and 1997, and test the same models as Lu and Comanor. In line with their results, we find that introductory prices depend on the degree of therapeutic innovation. Contrary to the results from the U.S. market, Swedish real prices for NCEs fall substantially over time for all classes of therapeutic innovation. Also contrary to the findings of Lu and Comanor, we find no effect of the presence of branded substitutes on either introduction prices or price dynamics. Our results indicate that the price regulation discourages price competition between brandname drugs.
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| 7. |
- Liu, Q, et al.
(author)
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Administration of Lactobacillus plantarum 299v reduces side-effects of external radiation on colon anastomotic healing in an experimental model
- 2001
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In: Colorectal Disease. - : Wiley. - 1462-8910 .- 1463-1318. ; 3:4, s. 245-252
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Journal article (peer-reviewed)abstract
- OBJECTIVE: Preoperative radiotherapy of patients with rectal carcinoma is frequently used to reduce the incidence of local recurrence. However, the radiation therapy is associated with several complications, including diarrhea, retarded anastomotic healing and mucosal atrophy. Exogenous administration of lactobacilli has been demonstrated to be effective in stimulating intestinal mucosal growth and reduce mucosal inflammation. The objective of this study was to examine the effects of Lactobacillus plantarum 299v administration on external radiation injury in colon anastomotic healing at different time points. MATERIAL AND METHODS: Sprague-Dawley rats were treated with Lb. plantarum 299v or saline as control and received external radiation of the lower abdomen (10 Gy/day) on day 3 and 7 of the experiment. After 4 days, a colonic resection with anastomosis was performed. Animals were sacrificed on 4th, 7th and 11th day postoperatively. Body weight, white blood cell (WBC) count, mucosal myeloperoxidase (MPO) activity, hydroxyproline, nucleotide, DNA and RNA content, colonic bacterial microflora, bacterial translocation and histology were evaluated. RESULTS: On the 4th postoperative day body weight, WBC and MPO decreased significantly after radiation. On the 7th postoperative day MPO decreased after radiation. In the two irradiated groups it decreased significantly in the Lb. plantarum group compared to the radiated group without treatment. Collagen concentration on the 7th postoperative day was significantly higher in Lb. plantarum group without radiation compared to the group with radiation without Lb. plantarum. On the 11th postoperative day MPO was significantly higher in irradiated rats without treatment compared to Lb. plantarum treatment. The collagen concentration increased significantly in the irradiated Lb. plantarum group compared to the other two groups. CONCLUSION: The collagen content decreased and MPO activity increased significantly of the colonic anastomosis in irradiated rats without treatment compared to those treated with Lb. plantarum. It therefore seems that administration of Lactobacillus plantarum 299v reduces the intestinal injury and inflammation following external radiation and improves the colonic anastomotic healing.
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| 8. |
- Nejdfors, P, et al.
(author)
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Intestinal permeability in humans is increased after radiation therapy
- 2000
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In: Diseases of the Colon & Rectum. - 0012-3706. ; 43:11, s. 1582-1587
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Journal article (peer-reviewed)abstract
- PURPOSE: Irradiation inflicts acute injuries to the intestinal mucosa with rapid apoptosis induction and subsequent reduction in epithelial surface area. It may therefore be assumed that the intestinal barrier function is affected. The aim of this study was to compare the mucosal permeability in irradiated rectum and nonirradiated sigmoid colon from patients subjected to radiation therapy before surgical treatment for rectal cancer. METHODS: Segments from sigmoid colon and rectum obtained from irradiated and nonirradiated patients were stripped from the serosa-muscle layer and mounted in Ussing diffusion chambers. The mucosa-to-serosa passage of the marker molecules 14C-mannitol, fluorescein isothiocyanate-dextran 4,400, and ovalbumin was followed for 120 minutes. RESULTS: The permeability to the markers was size-dependent and increased linearly across time in all specimens. The passage of all markers was increased in irradiated rectum compared with nonirradiated sigmoid colon, whereas in specimens from nonirradiated patients there were no differences between rectum and sigmoid colon. Histologic signs of crypt and mucosal atrophy were found in the irradiated rectal specimens. CONCLUSIONS: Early gastrointestinal complications after radiation therapy may be the result of mucosal atrophy in addition to mucosal damage, with a loss of barrier integrity.
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| 9. |
- Nejdfors, P, et al.
(author)
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Mucosal in vitro permeability in the intestinal tract of the pig, the rat, and man: species- and region-related differences
- 2000
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In: Scandinavian Journal of Gastroenterology. - : Informa UK Limited. - 1502-7708 .- 0036-5521. ; 35:5, s. 501-507
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Journal article (peer-reviewed)abstract
- BACKGROUND: The barrier properties of the gastrointestinal mucosa may be studied by measuring its permeability to different-sized marker molecules. Owing to difficulties in obtaining human tissue it is, however, often necessary to extrapolate findings from experimental animals to man. The aim of the present study was to compare regional intestinal mucosal permeability in man, the rat, and the pig, using the same marker molecules and in vitro technique. METHODS: Segments from jejunum, ileum, colon, and rectum were mounted in Ussing diffusion chambers, and the mucosa-to-serosa passage of 14C-mannitol, fluorescein isothiocyanate (FITC)-dextran 4,400, alpha-lactalbumin, ovalbumin, and FITC-dextran 70,000 was studied. RESULTS: Irrespective of species or intestinal region an inverse relationship between the molecular weight of the markers and the permeability was seen. The mannitol permeability was higher in the small intestine than in the colon in man, whereas the rat showed a higher permeability in the ileum than in the jejunum and colon. The FITC-dextran 4,400 permeability was higher in all intestinal regions in the rat than in man and the pig. The macromolecules showed low permeability with no regional differences. CONCLUSIONS: The results showed differences between intestinal regions and between species. Permeability data from the pig correlated fairly well with those of man, whereas the rat differed, making it difficult to extrapolate from the rat to man.
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| 10. |
- Planck, Maria, et al.
(author)
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Cytogenetic aberrations and heterogeneity of mutations in repeat-containing genes in a colon carcinoma from a patient with hereditary nonpolyposis colorectal cancer.
- 2002
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In: Cancer Genetics and Cytogenetics. - 0165-4608. ; 134:1, s. 46-54
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Journal article (peer-reviewed)abstract
- The majority of tumors from patients affected by hereditary nonpolyposis colorectal cancer (HNPCC) exhibit a mutator phenotype characterized by widespread microsatellite instability (MSI) and somatic mutations in repeated sequences in several cancer-associated genes. An inverse relationship between MSI and chromosomal instability (CIN) has been demonstrated and HNPCC-associated tumors are generally characterized by diploid or near-diploid cells with few or no chromosomal rearrangements. We have studied MSI, somatic mutations in repeat-containing genes, DNA-ploidy, and cytogenetic aberrations in a colon carcinoma from a patient with a germline MLH1 mutation. Mutations in coding repeats were assessed in 10 macroscopically separate areas of the primary tumor and in two lymph nodes. Some of the genes studied (E2F4, MSH3, MSH6, TCF4, and TGFBRII) showed a consistent lack of mutations, whereas others (BAX, Caspase-5 and IGFIIR) displayed alterations in some tumor regions but not in others. The tumor had DNA-index 1.1-1.2 and a stable, aberrant karyotype with extra copies of chromosomes 7 and 12 and the structural aberrations i(1q), der(20)t(8;20), and der(22)t(1;22). The finding of CIN, MSI, and somatic mutations in coding repeats in this tumor suggests that these phenomena may act together in HNPCC tumorigenesis. Furthermore, the observed intratumoral heterogeneity of mutations in coding repeats implies these changes occur late in tumorigenesis and, thus, probably play a role in tumor progression rather than initiation.
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| 11. |
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| 12. |
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| 13. |
- Salehi, S Albert, et al.
(author)
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Total parenteral nutrition modulates hormone release by stimulating expression and activity of inducible nitric oxide synthase in rat pancreatic islets
- 2001
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In: Endocrine. - 1355-008X. ; 16:2, s. 97-104
-
Journal article (peer-reviewed)abstract
- The expression and activities of constitutive nitric oxide synthase (cNOS) and inducible nitric oxide synthase (iNOS) in relation to insulin and glucagon secretory mechanisms were investigated in islets isolated from rats subjected to total parenteral nutrition (TPN) for 10 d. TPN is known to result in significantly increased levels of plasma lipids during the infusion time. In comparison with islets from freely fed control rats, islets taken from TPN rats at d 10 displayed a marked decrease in glucose-stimulated insulin release (4.65 +/- 0.45 ng/[islet x h] vs 10.25 +/- 0.65 for controls) (p < 0.001) accompanied by a strong iNOS activity (18.3 +/- 1.1 pmol of NO/[min x mg of protein]) and a modestly reduced cNOS activity (11.3 +/- 3.2 pmol of NO/[min x mg of protein] vs 17.7 +/- 1.7 for controls) (p < 0.01). Similarly, Western blots showed the expression of iNOS protein as well as a significant reduction in cNOS protein in islets from TPN-treated rats. The enhanced NO production, which is known to inhibit glucose-stimulated insulin release, was manifested as a strong increase in the cyclic guanosine 5'-monophosphate content in the islets of TPN-treated rats (1586 +/- 40 amol/islet vs 695 +/- 64 [p < 0.001] for controls). Moreover, the content of cyclic adenosine monophosphate (cAMP) was greatly increased in the TPN islets (80.4 +/- 2.1 fmol/islet vs 42.6 +/- 2.6 [p < 0.001] for controls). The decrease in glucose-stimulated insulin release was associated with an increase in the activity of the secretory pathway regulated by the cAMP system in the islets of TPN-treated rats, since the release of insulin stimulated by the phosphodiesterase inhibitor isobutylmethylxanthine was greatly increased both in vivo after iv injection and after in vitro incubation of isolated islets. By contrast, the release of glucagon was clearly reduced in islets taken from TPN-treated rats (33.5 +/- 1.5 pg/[islet x h] vs 45.5 +/- 2.2 for controls) (p < 0.01) when islets were incubated at low glucose (1.0 mmol/L). The data show that long-term TPN treatment in rats brings about impairment of glucose-stimulated insulin release, that might be explained by iNOS expression and a marked iNOS-derived NO production in the beta-cells. The release of glucagon, on the other hand, is probably decreased by a direct "nutrient effect" of the enhanced plasma lipids. The results also suggest that the islets of TPN-treated rats have developed compensatory insulin secretory mechanisms by increasing the activity of their beta-cell cAMP system.
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| 14. |
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| 15. |
- Salehi, S Albert, et al.
(author)
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TPN-evoked dysfunction of islet lysosomal activity mediates impairment of glucose-stimulated insulin release
- 2001
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In: American Journal of Physiology: Endocrinology and Metabolism. - 1522-1555. ; 281:1, s. 171-179
-
Journal article (peer-reviewed)abstract
- We examined the relation between nutrient-stimulated insulin secretion and the islet lysosome acid glucan-1,4-alpha-glucosidase system in rats undergoing total parenteral nutrition (TPN). During TPN treatment, serum glucose was normal, but free fatty acids, triglycerides, and cholesterol were elevated. Islets from TPN-infused rats showed increased basal insulin release, a normal insulin response to cholinergic stimulation but a greatly impaired response when stimulated by glucose or alpha-ketoisocaproic acid. This impairment of glucose-stimulated insulin release was only slightly ameliorated by the carnitine palmitoyltransferase 1 inhibitor etomoxir. However, in parallel with the impaired insulin response to glucose, islets from TPN-infused animals displayed reduced activities of islet lysosomal enzymes including the acid glucan-1,4-alpha-glucosidase, a putative key enzyme in nutrient-stimulated insulin release. By comparison, the same lysosomal enzymes were increased in liver tissue. Furthermore, in intact control islets, the pseudotetrasaccharide acarbose, a selective inhibitor of acid alpha-glucosidehydrolases, dose dependently suppressed islet acid glucan-1,4-alpha-glucosidase and acid alpha-glucosidase activities in parallel with an inhibitory action on glucose-stimulated insulin secretion. By contrast, when incubated with intact TPN islets, acarbose had no effect on either enzyme activity or glucose-induced insulin release. Moreover, when acarbose was added directly to TPN islet homogenates, the dose-response effect on the catalytic activity of the acid alpha-glucosidehydrolases was shifted to the right compared with control homogenates. We suggest that a general dysfunction of the islet lysosomal/vacuolar system and reduced catalytic activities of acid glucan-1,4-alpha-glucosidase and acid alpha-glucosidase may be important defects behind the impairment of the transduction mechanisms for nutrient-stimulated insulin release in islets from TPN-infused rats.
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| 16. |
- Tingstedt, Bobby, et al.
(author)
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Management of appendiceal masses.
- 2002
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In: European Journal of Surgery. - : Oxford University Press (OUP). - 1102-4151. ; 168:11, s. 579-582
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Journal article (peer-reviewed)
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