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Biomedical subjects

A Lindahl

Publications and source records attributed to A Lindahl.

At least 37 records · Page 2Linked to original sources
PubMed1999

A comparison between direct determination of in vivo dissolution and the deconvolution technique in humans.

AIM: The primary objective of this study was to investigate the in vivo dissolution of carbamazepine in humans and to compare it with the dissolution estimated by deconvolution of plasma concentrations as well as the in vitro dissolution. METHODS: The in vivo study included six healthy volunteers, and consisted of two sequential parts. In part 1 the dissolution was measured by perfusing a semi-open segment in the proximal jejunum in humans. In part 2 the volunteers were given a solution of carbamazepine orally. In both parts of the study, plasma samples were collected up to 48 h after administration of the dose. The in vitro dissolution was measured in a flow-through cell using dissolution medium with and without the addition of bile acids (3 mM). RESULTS: The direct measured in vivo dissolution profile of carbamazepine and the deconvoluted profile were found to be similar. The two dissolution profiles of carbamazepine obtained in vitro were statistically lower than the two in vivo dissolution profiles. The higher in vivo dissolution rate is probably due to efficient sink conditions as a consequence of the high permeability of carbamazepine and more pronounced intestinal motility. CONCLUSION: The jejunal perfusion system was successfully used for in vivo dissolution measurements of carbamazepine and agreed with the deconvoluted plasma profile regarding rate and extent of dissolution. Single-pass perfusion is therefore a meaningful tool for further studies of in vivo dissolution.

Algorithms↗
PubMed1999

Surface activity and concentration dependent intestinal permeability in the rat.

PURPOSE: To investigate the relation between intestinal effective permeability (P(eff)) and surface activity of fluvastatin and verapamil. METHODS: P(eff)-values were determined for fluvastatin, antipyrine and D-glucose following colon perfusions in the rat in situ. The perfusion solitions differed regarding concentrations of fluvastatin (0-2500 microM) and surface tension (58.9-43.7 mN/m). A cellulose derivative, ethyl-(hydroxyethyl) cellulose (EHEC), was added to lower the surface tension of one of the perfusion solutions. The surface tension of perfusion solutions containing R/S-verapamil (8-814 microM) and R/S-verapamil + chlorpromazine (814 microM + 10 mM) were related to the corresponding P(eff)-values from the literature. RESULTS: The P(eff)of fluvastatin correlated inversely (r2 = 0.985, p < 0.05) with the surface tension of the perfusion solutions below the critical micelle concentration (CMC, 1 mM). Decreasing the surface tension with EHEC increased the P(eff) of fluvastatin by 36% (p < 0.001), but not to the extent anticipated from the correlation between the P(eff) and the surface tension. EHEC also increased the P(eff) of antipyrine by 49% (p < 0.01 ) but not for D-glucose. The P(eff) of R/S-verapamil correlated inversely with the surface tension (r2 = 0.980, p < 0.001). CONCLUSIONS: The ability of fluvastatin to decrease the surface tension at the membrane surface can partly explain the concentration dependent colonic P(eff) of fluvastatin. This study shows that the surface activity of the drug molecule itself is an important physicochemical factor that should be taken into consideration when evaluating drug absorption studies performed in vitro or in situ.

Animals↗
PubMed1998

The helix-loop-helix transcription factors Id1 and Id3 have a functional role in control of cell division in human normal and neoplastic chondrocytes.

The expression and localization of the helix-loop-helix transcription factors Id1 and Id3, as well as localization of the E12-protein, were studied in cells isolated from human articular cartilage and chondrosarcoma. Serum withdrawal down-regulated Id1 and Id3 expression in chondrocytes but not the Id1 expression in chondrosarcoma cells. Antisense oligonucleotides directed against Id1 and Id3 decreased BrdU labeling in both cell types. E12 was localized to the nucleus in chondrocytes and non-confluent tumor cells and in confluent tumor cells, E12 had a cytoplasmic localization. This study suggests a functional role for Id1 and Id3 in the control of proliferation and differentiation of cartilage.

Blotting, Western↗
PubMed1998

Cultured, autologous nucleus pulposus cells induce functional changes in spinal nerve roots.

STUDY DESIGN: Nerve conduction velocity in pig nerve roots was assessed after application of various preparations of nucleus pulposus and control. OBJECTIVE: To study whether cultured nucleus pulposus cells could reduce nerve conduction velocity after epidural application. SUMMARY OF BACKGROUND DATA: It is known that nucleus pulposus applied epidurally may reduce the nerve conduction velocity of the adjacent nerve roots and that this reduction seems to be related to the cells of the nucleus pulposus. METHODS: Nucleus pulposus cells and fibroblasts were cultured for 3 weeks, and various preparations were applied to the cauda equina in 29 pigs. The cells were always from the same animals from which they had been harvested. After 1 week, nerve conduction velocity was determined by local electrical stimulation. RESULTS: Application of live fibroblasts and conditioned culture medium from the nucleus pulposus cell culture dishes did not induce significant reduction of conduction velocity, compared with application of dead fibroblasts, which served as control. However, application of live and dead nucleus pulposus cells induced significant reductions. CONCLUSIONS: Application of nucleus pulposus cells reproduced the previously seen reduction in nerve conduction velocity induced by nonmodified nucleus pulposus. Because membranes of the nucleus pulposus cells had similar effects, it can be assumed that the effects are related to membrane-bound substances or structures.

Animals↗
PubMed1998

GFR measurement with iohexol and 51Cr-EDTA. A comparison of the two favoured GFR markers in Europe.

BACKGROUND: The aim of the present study was to compare the most commonly used GFR markers for clearance measurements, 51Cr-EDTA and iohexol, using two different methods for iohexol analysis, HPLC and X-ray fluorescence, referring both to the multiple-sample and single-sample calculations, using 51Cr-EDTA as the reference method. METHODS: Forty-nine patients with an estimated GFR >40 ml/min were included. 51Cr-EDTA and iohexol were injected simultaneously and blood samples were taken 150, 195 and 240 min after injection of the respective marker. RESULTS: The multiple-point clearances, determined from HPLC and X-ray fluorescence, compared to 51Cr-EDTA correlated highly (r=0.92 and 0.95 respectively). The results from single-point clearance comparison, iohexol measured by HPLC vs 51Cr-EDTA, yielded a correlation of r=0.91, while single-point clearance from iohexol, analysed by X-ray fluorescence, obtained a correlation of 0.93 and an intercept statistically different from origo. CONCLUSIONS: Iohexol and 51Cr-EDTA are comparable as GFR markers for multiple-point clearance measurements. The single-sample method for GFR >40 ml/min can be used with a high accuracy. The precision and accuracy of X-ray fluorescence analysis of low concentrations of iohexol were less than those of HPLC. Care should therefore be taken when using X-ray fluorescence that the injected dose of iohexol should result in a plasma concentration level of iodine of at least 0.06 mg/ml at the time of blood sampling.

Adult↗
PubMed1998

Concentration- and region-dependent intestinal permeability of fluvastatin in the rat.

The purpose of this study was to investigate the mechanisms of transport of fluvastatin across the intestinal mucosa in various regions of the intestine in the rat. In-situ single-pass perfusions of the jejunum, ileum and colon were performed and the effective permeability (Peff) of fluvastatin, antipyrine and D-glucose were assessed in each region, at three different perfusate fluvastatin concentrations (1.6, 16 and 160 microM). The effect of lovastatin acid on the bi-directional transport of fluvastatin across the ileal mucosa was also studied. The Peff of fluvastatin was found to be dependent both on the intestinal region and on the concentration in the intestinal lumen (P < 0.001). Fluvastatin had the lowest Peff (0.55 +/- 0.10 x 10(-4) cm s(-1)) in the jejunum at 1.6 microM, and the highest Peff (1.0 +/- 0.16 x 10(-4) cm s(-1)) in the colon at 160 microM. The highest concentration of fluvastatin increased the average absorption of water from the intestine by 209% (P < 0.05), and the average Peff of D-glucose by 29% (P < 0.05). The presence of excess lovastatin acid (100 microM, compared with fluvastatin 1.6 microM) at the luminal side increased the average absorption of water by 218% (P < 0.001), and the Peff of fluvastatin in the ileum and the colon by 44 and 50%, respectively (P < 0.05). The presence of lovastatin acid on the luminal side in the ileum also increased the blood-to-lumen transport (exsorption) of fluvastatin by 43% (P < 0.001). The increased intestinal absorption of fluvastatin at higher concentrations does not suggest that substantial absorption occurs by any carrier-mediated process in the absorptive direction. The increased bi-directional transport when lovastatin acid was added to the lumen suggests that fluvastatin is not a P-glycoprotein substrate. Instead, the concentration-dependent increase in the absorption of fluvastatin, water and D-glucose suggests a direct effect of fluvastatin on the transcellular passive transport.

Animals↗
PubMed1997

Influence of fibrin sealant (Tisseel) on osteochondral defect repair in the rabbit knee.

Fibrin adhesives have been shown to improve the natural repair of musculoskeletal tissues. Growth hormone (GH) has a chondrogenic effect on immature cartilage. To test if a fibrin adhesive with and without GH could improve the natural repair of a joint surface lesion, we made a 9 x 4 mm2 osteochondral defect in the femoral groove of adult New Zealand rabbits. The defect in one of the knees was filled with the fibrin adhesive Tisseel, while the defect in the other knee was left untreated as a control. Another group of rabbits was treated in both knees with fibrin adhesive with local addition of GH during 1 week on one side. The experiments showed that the fibrin treatment impaired the natural repair of the osteochondral defect and that GH addition had no effect on the healing process. In a second in vitro experiment, chondrocyte migration into the fibrin adhesive Tisseel was compared to migration into rabbit and human blood clots. No cell migration was seen into the fibrin adhesive, while there was migration into the blood clots. We conclude that a fibrin adhesive like Tisseel is not suitable as a scaffold to promote repair of osteochondral defects in the rabbit knee.

Animals↗
PubMed1997

Characterization of fluids from the stomach and proximal jejunum in men and women.

PURPOSE: To chemically characterize the fluids available for drug dissolution in the upper gastrointestinal tract during the fasted state in humans, and to examine variations and potential gender differences regarding the physico-chemical properties of these fluids. METHODS: Twenty-four healthy volunteers, 12 females and 12 males, were intubated, and fluids from the stomach and upper jejunum were collected separately. Bulk pH, osmolality, electrolytes and total concentrations of bile acids and proteins were assessed. To study intraindividual variations, eleven of the individuals were studied on more than one occasion. RESULTS: The stomach and upper jejunal fluids varied significantly in all the measured entities, except the total concentration of proteins. The intraindividual variability was pronounced in some of the individuals, both in the stomach and the upper jejunum. We did not, however, observe any gender differences. CONCLUSIONS: This study demonstrates the complex nature of the fluids available for drug dissolution in the stomach and the upper small intestine in humans. The results can be used when designing a more physiological in vitro dissolution media representative for the fasted state. When designing such a medium, we suggest that gender differences not be taken into account.

Adult↗
PubMed1997

No evidence for involvement of the growth hormone/insulin-like growth factor-1 axis in psoriasis.

We have examined whether alterations in the growth hormone/insulin-like growth factor-1 axis play a role in the pathogenesis of psoriasis. Serum, urine, full skin biopsies, and suction blister roofs were obtained from patients with psoriasis and from healthy controls. Serum concentrations of insulin-like growth factor-1 and insulin-like growth factor binding protein-3 were measured by radioimmunoassay. Growth hormone-binding protein was measured by ligand-mediated immunofunctional assay. Growth hormone concentration in urine was measured by an immunometric assay, and growth hormone receptor-gene expression was measured by RNase protection assay or by quantitative reverse transcriptase polymerase chain reaction in total RNA isolated from epidermal suction blister roofs. Serum concentrations of insulin-like growth factor-1 (249 +/- 12 micrograms per liter, mean +/- SEM, n = 42, and 277 +/- 21 micrograms per liter, n = 9, for psoriatic patients and controls, respectively), insulin-like growth factor binding protein-3 (3.1 +/- 0.08 mg per liter, n = 42, and 3.3 +/- 0.22 mg per liter, n = 9), growth hormone-binding protein (344 +/- 65 pmol per liter, n = 10, and 311 +/- 83 pmol per liter, n = 9), urinary growth hormone excretion during 24 h (12.8 +/- 2.7 microIU per 24 h, n = 12, and 12.3 +/- 1.6 microIU per 24 h, n = 9), and epidermal growth hormone receptor gene expression [32 +/- 12 x 10(3) mRNA transcripts per microgram total RNA (involved skin), n = 11, and 47 +/- 14 x 10(3) mRNA transcripts per microgram total RNA, n = 9] were similar in patients and controls. For insulin-like growth factor-1 and insulin-like growth factor binding protein-3 the values in psoriatic patients were also similar to those in larger control groups, n = 195 and n = 400, respectively. In addition, we found no evidence of local expression of growth hormone or prolactin in full skin punch biopsies from psoriatic involved skin by reverse transcriptase polymerase chain reaction. In conclusion, our results suggest that alterations in the growth hormone/ insulin-like growth factor-1 axis do not play a major role in the pathogenesis of psoriasis.

Adult↗
PubMed1997

Regional intestinal permeability in rats of compounds with different physicochemical properties and transport mechanisms.

Because the absorption of orally administered drugs depends on intestinal permeability, we have investigated how absorptive capacity varies from the proximal to distal intestine in rats. The effective permeabilities of compounds with a range of physicochemical properties and different absorption mechanisms were estimated by use of a previously validated in-situ, single-pass perfusion model. The low colonic permeabilities of D-glucose and L-dopa indicate the absence or low capacity of the glucose- and amino-acid-transporters in this region. With the exception of the small and moderately lipophilic non-steroidal anti-inflammatory drug, naproxen, for which permeability was maintained throughout the intestine, the passive intestinal permeabilities for hydrophilic and lipophilic drugs were approximately twice as high in the jejunum and ileum as in the colon. These observations are in accord with those made in recent studies. However, the reasons for the high colonic permeability of non-steroidal anti-inflammatory drugs, and results obtained in previous animal experiments demonstrating that the colon is the region of the intestine with the highest absorptive capacity were not fully clarified. These data show that the permeability to hydrophilic and lipophilic drugs decreases along the intestine, whereas it is maintained throughout the intestine for the small and moderately lipophilic naproxen. Further investigations are required to clarify the interplay between membrane composition, fluidity and permeability under various conditions in different absorption models.

Administration, Oral↗
PubMed1997

Reduced serum levels of the growth hormone-dependent insulin-like growth factor binding protein and a negative bone balance at the level of individual remodeling units in idiopathic osteoporosis in men.

Idiopathic osteoporosis in younger individuals could be related to reduced bone formation rather than increased bone resorption, and disturbances in GH or insulin-like growth factor (IGF)-I production could be involved in its pathogenesis. In the present study, men with idiopathic osteoporosis were compared with healthy men, with respect to bone histomorphometry and to serum levels of IGF-I, IGF-II, IGF binding protein (IGFBP)-2 and IGFBP-3, and 24-h urinary excretion of GH. Mean wall thickness was reduced in the patients (48.3 +/- 7.2 vs. 61.7 +/- 5.4 microns, P < 0.001). Also, resorption depth was decreased, albeit to a lesser degree (54.4 +/- 3.8 vs. 60.7 +/- 5.3 microns, P < 0.01), thus creating a pronounced negative balance (-6.04 +/- 9.8 vs. 0.96 +/- 3.2 microns, P < 0.05). In the patients, serum concentrations of IGFBP-3 were reduced, compared with controls, with a 46% lower mean value; whereas levels of IGF-I, IGF-II, IGFBP-2, and GH were similar in the two groups. Thus, there was a significant negative balance caused by a pronounced decrease in wall thickness in men with idiopathic osteoporosis. The finding of low IGFBP-3 levels in these patients is interesting, in view of previous clinical and experimental findings, but its pathophysiological significance remains to be determined.

Adult↗
PubMed1997

The CCAAT/enhancer-binding protein-alpha is expressed in the germinal layer of the growth plate: colocalisation with the growth hormone receptor.

The transcription factor C/EBP alpha, a member of the CCAAT/enhancer-binding protein family, is highly expressed in the liver and in adipose tissue. The aim of this study was to determine if C/EBP alpha is expressed in rat growth cartilage. The expression pattern of C/EBP alpha in monolayer-cultured growth plate chondrocytes was similar to that of C/EBP alpha during hepatocyte and preadipocyte differentiation. Immunohistochemistry with a polyclonal antibody for C/EBP alpha revealed that the C/EBP alpha protein is present in the perichondrial ring, in the germinal layer of the growth plate and on the surface of the articular cartilage. The growth hormone (GH) receptor has a similar distribution in the rat tibial growth plate, and hypophysectomised rats were used to investigate a possible connection between C/EBP alpha and GH. C/EBP alpha mRNA levels were decreased in rib cartilage after hypophysectomy. However, GH treatment did not counteract this effect, indicating that other pituitary hormones regulate the C/EBP alpha mRNA levels in growth plate cartilage. We thus demonstrate, for the first time, that C/EBP alpha is expressed in cartilage. The finding that C/EBP alpha, like the GH receptor, is predominantly expressed in stem cell areas of the rat growth plate indicates a possible functional role for C/EBP alpha during early chondrogenic differentiation.

Animals↗
PubMed1997

Collagenase-3 (MMP-13) is expressed during human fetal ossification and re-expressed in postnatal bone remodeling and in rheumatoid arthritis.

To explore possible physiologic functions for the metalloproteinase collagenase-3, we have examined its temporal and spatial expression during human fetal development. Except for mesenchymal cells in the umbilical cord at 4 weeks of gestation, signal for collagenase-3 mRNA was confined to mineralizing skeletal tissue and detected in hypertrophic chondrocytes and osteoblastic cells involved in ossification beginning at 10 weeks and continuing through gestation. These cells were also immunoreactive with collagenase-3 antiserum, indicating their ability to produce collagenase-3 protein. In osteoblastic cells, the expression of membrane-type 1 metalloproteinase and 72-kd gelatinase mRNA, which have the capacity to activate collagenase-3 in vitro, colocalized with that of collagenase-3. In postnatal tissues, collagenase-3 was re-expressed in processes involving skeletal remodeling, such as bone cysts and ectopic bone and cartilage formation. Multinucleated osteoclasts were consistently negative for collagenase-3. Furthermore, in patients with seropositive rheumatoid arthritis, expression of collagenase-3 was prominent in articular cartilage, and collagenase-3 protein was detected by immunoblotting in synovial fluids. Consistent with its substrate specificities, a plausible function for collagenase-3 in these processes is to preferentially degrade type II collagen, thus serving a role during primary ossification, in skeletal remodeling, and in destructive joint disease.

Aged↗
PubMed1996

Jejunal permeability and hepatic extraction of fluvastatin in humans.

OBJECTIVES: The primary objective was to investigate the effective permeability and the hepatic extraction of fluvastatin, a new 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor, during a jejunal perfusion in humans. The secondary objective was to investigate the relationship between human jejunal effective permeability values and physicochemical properties for four different drugs. METHODS: Nine healthy male volunteers were included in the study, which consisted of two sequential study parts. In the first part, the jejunal effective permeability of fluvastatin, antipyrine, metoprolol, and atenolol was assessed with use of the regional jejunal perfusion approach (150 minutes, 2.0 ml/min). After a washout period of at least 5 days, the same subjects received an intravenous infusion of fluvastatin (20 minutes, 2.0 mg). Plasma samples were taken in both parts of the study and were analyzed for the content of fluvastatin. RESULTS: The mean hepatic extraction of fluvastatin was 67% after the jejunal perfusion and 73% after the intravenous infusion. The half-life of fluvastatin was approximately 60 minutes after both administration routes. The jejunal effective permeability and the fraction absorbed both correlated (r2 = 0.968, p < 0.05; and r2 = 0.994, p < 0.05) with the partition coefficient (log D, pH 6.5) but not with the molecular size or the hydrogen bond number. CONCLUSION: Fluvastatin is extracted by the liver to a large extent (about 70%) and has a short half-life after both oral and intravenous administration. In this study, the human jejunal effective permeability and the fraction absorbed for these four drugs were better predicted by log D (pH 6.5) than both the molecular size and the hydrogen bond number.

Adult↗