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  • 1.
    Agrup, Måns
    et al.
    Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences.
    Stål, Olle
    Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences.
    Olsen, Karen
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Department of Molecular and Clinical Medicine, Forensic Medicine. Linköping University, Faculty of Health Sciences.
    Wingren, Sten
    Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences.
    C-erbB-2 overexpression and survival in early onset breast cancer2000In: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 63, no 1, p. 23-29Article in journal (Refereed)
    Abstract [en]

    Young breast cancer patients have a decreased survival rate and it has been demonstrated that young age is an independent predictor of adverse prognosis. Overexpression of c-erbB-2 protein (also known as HER-2/neu) has been shown to be a prognostic indicator in breast cancer in general and especially among patients with axillary nodal metastases. The present study was initiated to determine the prognostic significance of c-erbB-2 protein overexpression in early onset breast cancer.

    A population consisting of 110 young breast cancer patients, ≤ 36-year-old at diagnosis, was analyzed with immunohistochemical staining for c-erbB-2 protein.

    Thirty patients (27%) were found to overexpress the c-erbB-2 protein. C-erbB-2 positivity was significantly associated with poor survival when all patients were included in the analysis (P = 0.002) and for patients with axillary nodal metastases (P = 0.0007). No such association was found for node-negative patients. Furthermore, the difference in prognosis in relation to c-erbB-2 among node-positive patients was maintained, when these were stratified in groups treated or not treated with adjuvant chemotherapy.

    The study indicates that overexpression of c-erbB-2 protein is a strong prognostic factor in young breast cancer patients with axillary nodal metastases. Moreover, the adverse prognosis associated with c-erbB-2 overexpression in node-positive patients was observed whether or not the patients had received adjuvant chemotherapy.

  • 2.
    Bendtsen, Preben
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Department of Health and Society, Division of Preventive and Social Medicine and Public Health Science. Östergötlands Läns Landsting, Centre for Public Health Sciences, Centre for Public Health Sciences.
    Jones, AW
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Forensic Medicine.
    Impact of water-induced diuresis on excretion profiles of ethanol, urin-creatinine, and urine-osmolality. 1999In: Journal of Analytical Toxicology, ISSN 0146-4760, E-ISSN 1945-2403, Vol. 23, p. 565-569Article in journal (Refereed)
  • 3.
    Druid, H
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Forensic Medicine.
    Dödstidpunktsbestämning i praktiken.  1999In: Nordisk Rettsmedisin, ISSN 0809-1498, Vol. 5Article in journal (Other (popular science, discussion, etc.))
  • 4.
    Druid, H
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Forensic Medicine.
    Holmgren, P
    Carlsson, B
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Clinical Chemistry. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Chemistry.
    Ahlner, Johan
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Clinical Pharmacology.
    Cytochrome P450 2D6 (CYPP2D6) genotyping on postmortem blood as a supplementary tool for interpretation of forensic toxicological results.  1999In: Forensic Science International, ISSN 0379-0738, E-ISSN 1872-6283, Vol. 99, p. 25-34Article in journal (Refereed)
  • 5.
    Druid, Henrik
    Linköping University, Department of Molecular and Clinical Medicine, Forensic Medicine. Linköping University, Faculty of Health Sciences.
    Experimental acute ischemic renal failure and anticoagulation1998Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    This thesis is based on experimental studies on acute renal failure (ARF) in rats. The model employed is that of renal artery clamping, which causes a standardized, ischemic trauma to the kidney. The proximate objective of the investigations was to study iflocal coagulation in the kidney may be induced by a pure ischemic trauma, and whether such a coagulation could be of importance for the development of ARF in this experimental model.

    The content of isotope-labeled fibrinogen and albumin was determined in postischemic kidneys and controls. After 60rnin of unilateral ischemia, the fibrin(ogen)/degradation products (FIB) and albumin content of the kidney increased rapidly and significantly, approximately averaging 200% of controls. The total kidney weight increased only to 130% of controls. Pretreatment with heparin in a dose of 2000 IU/kg BW, markedly attenuated the increase in kidney weight and content of FIB and albumin.

    Pretreatment with a lower dose of heparin, 400 IU!kg BW, and warfarin (given intraperitoneally 24 h before the experiment) produced a similar reduction of these parameters, whereas pretreatment with a heparin analog, devoid of anticoagulant effect, did not.

    In post-ischemic kidneys, scanning electron microscopy (SEM) of cautiously handled freezedried tissue revealed granular and fibrillary material in the tubules and in Bowman's space, at some locations displaying prominent network patterns. Immunofluorescence against FIB showed immunoreactive material in vasa recta, the peritubular capillaries, Bowman's space and in the tubules. By transmission electron microscopy (TEM), fibrin strands lacking periodicity were seen. As compared to controls, the postischemic kidneys generally showed a marked dilatation of Bowman's capsule. No fibrin deposition was seen in heparin pretreated animals.

    To determine if anticoagulation exerts the described effects by prevention of tubular obstructions or by attenuation of increased glomerular permeability, morphometry of glomeruli was performed by light microscopy and TEM Postischemic kidneys from rats pretreated with saline showed a marked widening of Bowman's space, most likely due to tubular obstruction, whereas Bowman's space width in anticoagulated rats did not differ from controls. Structural changes of the podocyte foot processes as a marker of increased macromolecular permeability were severe in both saline pretreated and anticoagulated kidneys.

    Glomerular filtration rate fell to 6% of controls after 40 min of ischemia. Warfarin-pretreatment attenuated this decrease significantly. Urinary protein excretion increased in both salinepretreated and anticoagulated rats. The excretion of FIB was significantly increased in warfarinpretreated rats, consistent with the previous observation of an attenuation of FIB content of postischemic kidneys by anticoagulation. This result thus suggests that warfarin did not prevent macromolecular sieving, but reduced the formation of protein-containing tubular casts.

    In summary, these studies show that a pure ischemic injury to the kidney results in a local coagulation in the kidney, most prominently within Bowman's space and in the tubules. It is suggested that the increased glomerular permeability to macromolecules causes sieving of fibrinogen, which may precipitate in Bowman's space and tubuli and promote the development of tubular obstructions.

  • 6.
    Druid, Henrik
    et al.
    Linköping University, Department of Molecular and Clinical Medicine, Forensic Medicine. Linköping University, Faculty of Health Sciences.
    Holmgren, Per
    Linköping University, Department of Medical and Health Sciences, Forensic Science and Toxicology . Linköping University, Faculty of Health Sciences.
    A compilation of fatal and control concentrations of drugs in postmortem femoral blood1997In: Journal of Forensic Sciences, ISSN 0022-1198, E-ISSN 1556-4029, Vol. 42, no 1, p. 79-87Article in journal (Refereed)
    Abstract [en]

    A compilation of postmortem femoral blood concentrations of drugs is presented. The samples are collected from cases in which the cause of death was: A) certified intoxication by one substance alone, B) certified intoxication by more than one substance and/or alcohol, and C) certified other cause of death without incapacitation due to drugs. The concentrations were compared with blood concentrations detected in suspected drugged drivers (D), and with previously published fatal and therapeutic concentrations. The special features of this compilation are: 1) exclusively femoral blood concentrations are quoted, 2) all analyses are based on samples handled according to a standardized, quality-controlled procedure, 3) two control groups are included, and 4) one-substance-only intoxications are separated from other intoxications. The material is based on a selection of 15,800 samples sent to the Department of Forensic Chemistry in Linkoping, Sweden, during 1992 to 1995 from the six forensic pathology units in Sweden, and the list includes 83 drugs. The compilation includes drugs, where previously published data are scarce. Furthermore, the data gathered from cases with other cause of death than intoxication (group C) constitute a new kind of reference information, which probably offers a better estimate of obviously non fatal levels in postmortem blood than any compilation of therapeutic concentrations in living subjects. The possible factors influencing postmortem drug concentrations are discussed.

  • 7.
    Druid, Henrik
    et al.
    Linköping University, Department of Molecular and Clinical Medicine, Forensic Medicine. Linköping University, Faculty of Health Sciences.
    Nilsson, I
    Rammer, Lennart
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Forensic Medicine.
    Skude, G
    Effect of anticoagulation on renal function and protein excretion in experimental acute ischemic renal failure.1999In: Renal failure, ISSN 0886-022X, E-ISSN 1525-6049, Vol. 21, p. 647-657Article in journal (Refereed)
  • 8.
    Edston, Erik
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Forensic Medicine.
    Spåren på kroppen kan avslöja tortyr. Fem års erfarenhet av tortyrskadedokumentation.  1999In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 96, p. 628-631Article in journal (Other (popular science, discussion, etc.))
  • 9.
    Edston, Erik
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Forensic Medicine.
    Druid, H
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Forensic Medicine.
    Holmgren, P
    Öström, M
    Postmortem measurements of thyroid hormones in blood and vitreous humor combined with histology2001In: American Journal of Forensic Medicine and Pathology, ISSN 0195-7910, E-ISSN 1533-404X, Vol. 22, no 1, p. 78-83Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to investigate whether clinical reference premortem values can be used to assess postmortem concentrations of thyroxine, triiodothyronine, and thyroid stimulating hormone (TSH), to compare the postmortem concentrations in blood and vitreous humor, and to study the possibility of diagnosing hyperthyroidism by comparing thyroid histologic appearance and postmortem hormone values. Biochemical analyses of free thyroxine (FT4), free triiodothyronine (FT3), and TSH in femoral blood and vitreous humor were made in 38 cases. In 40 cases, the hormones and thyroid histologic appearance were studied, 22 had no significant pathologic changes, and 18 showed focal hyperplasia of the follicular epithelium. A positive correlation was seen between the femoral blood and vitreous humor concentrations of FT4 (R = 0.66) but not between the corresponding concentrations of FT3 and TSH. A positive correlation was also seen between FT3 and FT4 in femoral blood (R = 0.74). In cases with normal thyroid histologic appearance, 58% were found to have FT4 values >24 pmol/L (clinical reference interval 9-24 pmol/L), mean value 27.5 ▒ 9.4 pmol/L), which did not differ from the FT4 values in the cases with hyperplasia, 31.6 ▒ 15 pmol/L. Only 5% of the T3 measurements in the group with normal histologic appearance were >9 pmol/L (clinical reference interval 3-9 pmol/L). The mean value of FT3 in cases with normal histologic appearance was 3.4 ▒ 1.3 pmol/L, and in the group with hyperplasia 8.6 ▒ 6.1 pmol/L. The difference was statistically significant P < .005). It is concluded that postmortem values of FT3 and FT4 in femoral blood are fairly comparable to premortem clinical reference values, but the upper normal limit, especially for T4. has to be adjusted upward. Analysis of vitreous humor cannot be used post mortem to assess thyroid function. Histologically, hyperplastic changes correlate well with elevated FT3 in femoral blood.

  • 10.
    Edston, Erik
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Forensic Medicine.
    Gidlund, E
    Wickman, M
    Ribbing, H
    van Hage-Hamsten, M
    Increased mast cell tryptase in sudden infant death - anaphylaxis, hypoxia or artefact? 1999In: Clinical and Experimental Allergy, ISSN 0954-7894, E-ISSN 1365-2222, Vol. 29, p. 1648-1654Article in journal (Refereed)
  • 11.
    Edston, Erik
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Forensic Medicine.
    Van Hage-Hamsten, M
    Death in anaphylaxis in a man with house dust mite allergy2003In: International journal of legal medicine (Print), ISSN 0937-9827, E-ISSN 1437-1596, Vol. 117, no 5, p. 299-301Article in journal (Refereed)
    Abstract [en]

    Up to recently the post-mortem diagnosis of anaphylaxis has been based solely on circumstantial evidence. With the development of assays for mast cell tryptase it is now possible to verify cases of suspected anaphylaxis. Here we present one such case, which initially appeared to be due to sudden death of unknown cause. A 47-year-old farmer was found dead in his bathroom around midnight. Hospital records revealed that he had previously been diagnosed with an allergy to house dust mites. He had also had infrequent episodes of airway symptoms, nausea, hypotension and diarrhoea usually after going to bed. The forensic autopsy did not give any clue to the cause of death. Serum tryptase in post-mortem blood was found to be substantially elevated in two samples (170 and >200 ╡g/L). Analysis of allergen-specific IgE showed high values for Dermatophagoides pteronyssinus and farinae. High mite allergen levels were found in dust obtained from the patient's mattress. The results of the immunological tests support the assumption that he died of anaphylactic shock. The circumstances and the patient's history of previous attacks after going to bed point to the fact that exposure to mite contaminated food and/or exposure to mite allergens in bed might have caused his death.

  • 12.
    Edston, Erik
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Forensic Medicine.
    van Hage-Hamsten, M
    Mast cell tryptase and hemolysis after trauma2003In: Forensic Science International, ISSN 0379-0738, E-ISSN 1872-6283, Vol. 131, no 1Article in journal (Refereed)
    Abstract [en]

    Background: We have previously found increased mast cell tryptase in accidental deaths due to trauma, indicating that mast cell degranulation had occurred. The present study was designed to confirm the previous observation and to determine if tryptase release after trauma is acute or delayed. Furthermore, the importance of hemolysis and direct trauma to the mast cells was investigated. Materials and methods: Mast cell tryptase was measured in post-mortem blood from the femoral vein in 27 cases of death from trauma and in 27 control cases by means of a commercially available immunoassay. The trauma cases were further classified into groups with single versus multiple trauma, and groups with short survival time (i.e. death at the scene of the accident) versus longer survival time (death in hospital). In five multi-trauma deaths, blood was sampled locally from the sites of crush injury. Results: The mean value of tryptase in femoral vein blood was 35.6▒34.6╡g/l in the entire trauma group and 14.7▒6.5╡g/l in the controls (P<0.005). In bloody liquid sampled from crush injuries, tryptase was substantially elevated in all cases, with a mean of 227▒146╡g/l. In cases with short survival time, tryptase was significantly higher than in those who died after several hours or days in hospital (P<0.001). No statistically significant difference was seen between multi- and single-trauma cases. A correlation between hemolysis in the samples and elevated tryptase was found only in the trauma cases (P<0.05), but experimentally induced hemolysis in vitro was not found to influence the measurements. Conclusion: Mast cell tryptase becomes elevated in trauma deaths and this seems to be ascribable either to direct mechanical injury to tissue mast cells and/or to cell lysis. In patients initially surviving severe injuries, the effects of massive release of histamine and other mast cell mediators might be of importance for treatment strategies and prognosis.

  • 13.
    Forsman, Lina
    et al.
    Department of Forensic Medicine, Umeå University, Umeå, Sweden.
    Edston, Erik
    Linköping University, Department of Molecular and Clinical Medicine, Forensic Medicine. Linköping University, Faculty of Health Sciences.
    Medicolegal certificates in investigations of asylum applications2000In: Journal of Medical Ethics, ISSN 0306-6800, E-ISSN 1473-4257, Vol. 26, no 4, p. 289-289Article in journal (Other academic)
    Abstract [en]

    No abstract available.

  • 14.
    Gentile, Massimiliano
    et al.
    Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences.
    Bergman Jungeström, Malin
    Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences.
    Olsen, K. E.
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Department of Molecular and Clinical Medicine, Forensic Medicine. Linköping University, Faculty of Health Sciences.
    Söderkvist, Peter
    Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
    Wingren, Sten
    Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences.
    p53 and survival in early onset breast cancer: analysis of gene mutations, loss of heterozygosity and protein accumulation1999In: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 35, no 8, p. 1202-1207Article in journal (Refereed)
    Abstract [en]

    The p53 protein has proven to be central in tumorigenesis by its cell cycle regulatory properties and both gene mutations and protein accumulation have been associated with poor prognosis in breast cancer. The present study was undertaken to investigate the prognostic significance of gene mutations, p53 protein accumulation and of loss of heterozygosity (LOH) at the TP53 locus in young (age <37 years) breast cancer patients. In total, gene mutations were found in 21 of the 123 patients (17%), LOH in 20 of the 47 informative cases (43%) and protein accumulation in 47 of the 102 available cases (46%). Log rank analysis revealed no significant association between survival and TP53 mutations (in general), p53 protein accumulation or LOH. However, missense mutations localised to the zinc binding domain were significantly (P=0.0007) associated with poorer prognosis. As indicated in this as well as other studies, p53 protein accumulation is frequently found in young breast cancer patients, but this protein overexpression appears to be of minor significance for survival. Nevertheless, the present report also suggests that specific mutations contribute substantially to tumour aggressiveness.

  • 15.
    Gentile, Massimiliano
    et al.
    Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences.
    Olsen, K.
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Department of Molecular and Clinical Medicine, Forensic Medicine. Linköping University, Faculty of Health Sciences.
    Dufmats, Monika
    Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences.
    Wingren, Sten
    Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences.
    Frequent allelic losses at 11q24.1–q25 in young women with breast cancer: association with poor survival1999In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 80, no 5/6, p. 843-849Article in journal (Refereed)
    Abstract [en]

    Previous studies have demonstrated that the pathological features of breast cancer are more aggressive in younger women than in their older counterparts, and that young age may be an independent marker for adverse prognosis. These findings have raised the question whether these differences are also present at the molecular level. In order to characterize the genetic alterations associated with early-onset breast cancer, 102 cases selected for age under 37 at diagnosis were examined for loss of heterozygosity (LOH) at nine different loci on chromosomes 11, 13 and 17. Ninety cases (88%), exhibited LOH for at least one marker. The D17S855 marker, intragenic in the BRCA1 gene, showed a high proportion of LOH (63%), whereas the intragenic marker for the TP53 gene, HP53, exhibited LOH in 43% of the cases. On chromosome 11, frequencies of LOH peaked at the D11S969 and D11S387 markers, which expressed LOH in 53% and 48% of the informative cases, whereas D11S1818, which is proximate to the ATM gene, exhibited an LOH frequency of 24%. A statistically significant correlation was found between LOH at the D11S387 marker and poor survival (P = 0.028). No such correlation was found for the adjacent D11S969 marker, located approximately 500 kb centromeric to D11S387. We conclude that one or more as yet unidentified genes, situated in chromosome bands 11q24.1–q25, could be involved in the initiation and/or progression of breast cancer in younger women.

  • 16. Hasselqvist, Diana
    et al.
    Rammer, Lennart
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Forensic Medicine.
    Criminal death detected at forensic autopsy.2003In: Nordisk Rettsmedisin, ISSN 0809-1498, Vol. 9Article in journal (Refereed)
  • 17. Isacsson, G
    et al.
    Holmgren, P
    Druid, H
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Forensic Medicine.
    Bergman, U
    Psychotropics and suicide prevention.  1999In: British Journal of Psychiatry, ISSN 0007-1250, E-ISSN 1472-1465, Vol. 174, p. 259-265Article in journal (Refereed)
  • 18.
    Naidu Sjöswärd, Kerstin
    et al.
    Linköping University, Department of Medicine and Care, Anaesthesiology. Linköping University, Faculty of Health Sciences.
    Josefsson, Martin
    Linköping University, Department of Molecular and Clinical Medicine, Forensic Medicine. Linköping University, Faculty of Health Sciences.
    Ahlner, Johan
    Linköping University, Department of Molecular and Clinical Medicine, Forensic Medicine. Linköping University, Faculty of Health Sciences.
    Andersson, Rolf
    Linköping University, Department of Medicine and Care, Pharmacology. Linköping University, Faculty of Health Sciences.
    Schmekel, Birgitta
    Linköping University, Department of Medicine and Care, Clinical Physiology. Linköping University, Faculty of Health Sciences.
    Metabolism of salbutamol differs between asthmatic patients and healthy volunteers2003In: Pharmacology and Toxicology, ISSN 0901-9928, E-ISSN 1600-0773, Vol. 92, no 1, p. 27-32Article in journal (Refereed)
    Abstract [en]

    Patients with asthma are a target group for medication with β2-agonists, often in combination with corticosteroids. Salbutamol is commonly marketed as racemate. R-Salbutamol carries β2-agonistic property whereas S-salbutamol does not. The racemate undergoes stereoselective sulphatisation by sulfotransferases mainly in the gut and liver, so that S-salbutamol rests for a longer time in the body and reaches higher plasma levels than R-salbutamol. Ten patients with mild stable asthma and at present without cortisone medication were given racemic salbutamol as ventoline 4 mg orally. Plasma and urine levels were estimated until 24 hr after ingestion. For comparison healthy volunteers were treated in the same way.The group of asthma patients was then treated with budesonide inhalations 800 μg daily for one week and the initial programme resumed. Non-cortisone-treated asthmatic patients displayed higher levels of both R- and S-salbutamol in plasma than did healthy volunteers after one single ingestion of racemic salbutamol (CMAX both comparisons P<0.05). Plasma levels of salbutamol isomers in cortisone-treated asthmatic patients resembled the levels in volunteers. The most plausible explanation for the discrepancy in values between asthmatic patients and volunteers is a defective metabolic function by asthmatic patients possibly enzymatic in origin.

  • 19.
    Naidu Sjöswärd, Kerstin
    et al.
    Linköping University, Department of Medicine and Care, Anaesthesiology. Linköping University, Faculty of Health Sciences.
    Josefsson, Martin
    Linköping University, Department of Molecular and Clinical Medicine, Forensic Medicine. Linköping University, Faculty of Health Sciences.
    Ahlner, Johan
    Linköping University, Department of Molecular and Clinical Medicine, Forensic Medicine. Linköping University, Faculty of Health Sciences.
    Schmekel, Birgitta
    Linköping University, Department of Medicine and Care, Clinical Physiology. Linköping University, Faculty of Health Sciences.
    Preserved bronchial dilatation after salbutamol does not guarantee protection against bronchial hyperresponsiveness2003In: Clinical Physiology and Functional Imaging, ISSN 1475-0961, E-ISSN 1475-097X, Vol. 23, no 1, p. 14-20Article in journal (Refereed)
    Abstract [en]

    Racemic salbutamol, a β2-adrenoceptor agonist used for dilatation of airways, has recently been shown to induce lessened relaxation of bronchial smooth muscle and partial loss of bronchoprotection, seen as increased hyperresponsiveness, after regular treatment. The racemate undergoes stereo-selective disposition, giving higher plasma levels of S-salbutamol than that of bronchodilating R-salbutamol, thus raising S : R ratios after repeated administration. Our aim was to evaluate whether increased bronchial hyperresponsiveness (BHR) could be found even after 1 day of repeated salbutamol inhalations, with β2-receptor-induced bronchial smooth muscle relaxation remaining and whether this would be associated with plasma levels of either enantiomer. Fifteen patients with stable asthma, aged 19–54 years, were included in a randomized, cross-over study. An indirect bronchial challenge method was used [voluntary isocapnic hyperventilation of cold air (IHCA)], and airway condition tested by means of impulse oscillometry. Racemic salbutamol was inhaled three times during a 6-h period. IHCA was performed and plasma concentrations of enantiomers were measured 4 h after the last dose. Tests were also performed without preceding drug treatment. β2-Agonist-produced bronchial dilatation and protection persisted in the majority of the 15 patients 4 h after repeated inhalations of salbutamol during 1 day. In only two of the 15 patients we could trace increased BHR after salbutamol. Neither dilatation nor protection could be linked to plasma levels of either R- or S-salbutamol. The underlying mechanisms of BHR remain unknown and are dissociated from β2-receptor-mediated dilatation.

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