| 1. |
- Magnusson, Marie, et al.
(författare)
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A placebo-controlled study of retinal blood flow changes by pentoxifylline and metabolites in humans
- 2006
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Ingår i: British Journal of Clinical Pharmacology. - : Wiley. - 0306-5251 .- 1365-2125. ; 61:2, s. 138-147
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Tidskriftsartikel (refereegranskat)abstract
- AIM: To investigate the possible effects of pentoxifylline metabolites on retinal blood flow in humans. METHODS: A randomized, placebo-controlled, four-period cross-over study that was observer blinded and partly blinded for the eight participants. On one occasion a placebo was given as an intravenous (i.v.) infusion over 100 min. On the other three occasions pentoxifylline was administered as i.v. infusions over 100 min at a rate of 3 mg min(-1). Before two of the pentoxifylline infusions the subjects were pretreated with either ciprofloxacin or rifampicin. Retinal blood flow was measured by scanning laser doppler flowmetry (SLDF) in a selected area of the central temporal retina before, during and until 5 h after the end of infusion. Blood samples for concentration analyses of pentoxifyllin, R-M1, S-M1, M4 and M5 were taken serially and areas under the curves (AUCs) were calculated. Linear mixed models were used for the statistical analyses. RESULTS: Mean AUCs (ng h ml(-1)) were significantly increased for pentoxifylline (1964 vs. 1453) and S-M1 (5804 vs. 4227), but not R-M1 when pentoxifylline was co-administered with ciprofloxacin. The mean AUC for M5 was significantly reduced when subjects were pretreated with rifampicin (2041 vs. 3080). Pentoxifylline with and without pretreatment with rifampicin significantly increased retinal blood flow assessed as mean flow, pulsation (i.e. 1-systole/diastole), and diastolic flow (but not during systole), compared with placebo. The increases over placebo were more pronounced on diastolic flow, 9.7% (95% confidence interval 4.2, 15.5) than on mean flow, 4.6% (1.1, 8.3) after pentoxifylline administration. With pentoxifylline after rifampicin pretreatment the corresponding differences were 11.7% (5.8, 17.9) and 5.1% (1.4, 7.8) over placebo, respectively. After co-administration of pentoxifylline and ciprofloxacin we saw only a nonsignificant trend towards increased flow during diastole, but a significant decrease in pulsation. When AUCs for pentoxifylline and its metabolites were used as regressor variables to retinal mean flow we found that pentoxifylline, R-M1 and M5 had coefficients with a positive sign indicating that they enhanced the retinal blood flow. In contrast, S-M1 and M4 had coefficients with negative sign and thus appeared to decrease the blood flow in subjects treated with pentoxifylline. CONCLUSION: The R-M1 and M5 metabolites of pentoxifylline contributed significantly to the effects of pentoxifylline on retinal blood flow.
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| 2. |
- Ederoth, Per, et al.
(författare)
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Blood-brain barrier transport of morphine in patients with severe brain trauma
- 2004
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Ingår i: British Journal of Clinical Pharmacology. - : Wiley. - 0306-5251 .- 1365-2125. ; 57:4, s. 427-435
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Tidskriftsartikel (refereegranskat)abstract
- AIMS: In experimental studies, morphine pharmacokinetics is different in the brain compared with other tissues due to the properties of the blood-brain barrier, including action of efflux pumps. It was hypothesized in this clinical study that active efflux of morphine occurs also in human brain, and that brain injury would alter cerebral morphine pharmacokinetics. METHODS: Patients with traumatic brain injury, equipped with one to three microdialysis catheters in the brain and one in abdominal subcutaneous fat for metabolic monitoring, were studied. The cerebral catheter locations were classified as 'better' and 'worse' brain tissue, referring to the degree of injury. Morphine (10 mg) was infused intravenously over a 10-min period in seven patients in the intensive care setting. Tissue and plasma morphine concentrations were obtained during the subsequent 3-h period with microdialysis and regular blood sampling. RESULTS: The area under the concentration-time curve (AUC) ratio of unbound morphine in brain tissue to plasma was 0.64 (95% confidence interval 0.40, 0.87) in 'better' brain tissue (P < 0.05 vs. the subcutaneous fat/plasma ratio), 0.78 (0.49, 1.07) in 'worse' brain tissue and 1.00 (0.86, 1.13) in subcutaneous fat. The terminal half-life and T(max) were longer in the brain vs. plasma and fat, respectively. The relative recovery for morphine was higher in 'better' than in 'worse' brain tissue. The T(max) value tended to be shorter in 'worse' brain tissue. CONCLUSIONS: The unbound AUC ratio below unity in the 'better' human brain tissue demonstrates an active efflux of morphine across the blood-brain barrier. The 'worse' brain tissue shows a decrease in relative recovery for morphine and in some cases also an increase in permeability for morphine over the blood-brain barrier.
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| 3. |
- Rekić, Dinko, 1984, et al.
(författare)
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In silico prediction of efavirenz and rifampicin drug-drug interaction considering weight and CYP2B6 phenotype
- 2011
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Ingår i: British Journal of Clinical Pharmacology. - : Wiley. - 0306-5251 .- 1365-2125. ; 71:4, s. 536-43
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Tidskriftsartikel (refereegranskat)abstract
- Aims: To test whether a pharmacokinetic simulation model could extrapolate non-clinical drug data to predict human efavirenz exposure after single and continuous dosing as well as the effects of concomitant rifampicin and further to evaluate the weight based dosage recommendations used to counteract the rifampicin-efavirenz interaction. Methods: Efavirenz pharmacokinetics were simulated using a physiologically-based pharmacokinetic model implemented in the Simcyp population-based simulator. Physicochemical and metabolism data obtained from the literature were used as input for prediction of pharmacokinetic parameters. The model was used to simulate the effects of rifampicin on efavirenz pharmacokinetics in 400 virtual patients, taking into account bodyweight and CYP2B6 phenotype. Results: Apart from the absorption phase, the simulation model predicted efavirenz concentration-time profiles reasonably well with close agreement with clinical data. The simulated effects of rifampicin co-administration on efavirenz treatment showed only a minor decrease of 16% (95%CI 13; 19) in efavirenz area under the concentration-time curve (AUC), in magnitude with what has been clinically observed (22%). Efavirenz exposure depended on CYP2B6 phenotype and bodyweight. Increasing the efavirenz dose during concomitant rifampicin was predicted to be most successful in patients over 50 kg regardless of CYP2B6 status. Conclusion: Our findings, although based on a simulation approach using limited in vitro data, support the current recommendations for using a 50 kg bodyweight cut-off for efavirenz dose increment when co-treating with rifampicin.
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| 4. |
- Pettersson, Jonas, et al.
(författare)
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Muscular exercise can cause highly pathological liver function tests in healthy men.
- 2008
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Ingår i: British Journal of Clinical Pharmacology. - : Wiley. - 1365-2125 .- 0306-5251. ; 65:2, s. 253-259
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Tidskriftsartikel (refereegranskat)abstract
- What is already known about this subject • The occurrence of idiosyncratic drug hepatotoxicity is a major problem in all phases of clinical drug development and the leading cause of postmarketing warnings and withdrawals. • Physical exercise can result in transient elevations of liver function tests. • There is no consensus in the literature on which forms of exercise may cause changes in liver function tests and to what extent. What this study adds • Weightlifting results in profound increases in liver function tests in healthy men used to moderate physical activity, not including weightlifting. • Liver function tests are significantly increased for at least 7 days after weightlifting. • It is important to impose relevant restrictions on heavy muscular exercise prior to and during clinical studies. Aim To investigate the effect of intensive muscular exercise (weightlifting) on clinical chemistry parameters reflecting liver function in healthy men. Methods Fifteen healthy men, used to moderate physical activity not including weightlifting, performed an 1 h long weightlifting programme. Blood was sampled for clinical chemistry parameters [aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LD), gamma-glutamyl transferase (γGT), alkaline phosphatase (ALP), bilirubin, creatine kinase (CK) and myoglobin] at repeated intervals during 7 days postexercise and at a follow-up examination 10–12 days postexercise. Results Five out of eight studied clinical chemistry parameters (AST, ALT, LD, CK and myoglobin) increased significantly after exercise (P < 0.01) and remained increased for at least 7 days postexercise. Bilirubin, γGT and ALP remained within the normal range. Conclusion The liver function parameters, AST and ALT, were significantly increased for at least 7 days after the exercise. In addition, LD and, in particular, CK and myoglobin showed highly elevated levels. These findings highlight the importance of imposing restrictions on weightlifting prior to and during clinical studies. Intensive muscular exercise, e.g. weightlifting, should also be considered as a cause of asymptomatic elevations of liver function tests in daily clinical practice.
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| 5. |
- Mukonzo, Jackson K, et al.
(författare)
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A novel polymorphism in ABCB1 gene, CYP2B6*6 and sex predict single-dose efavirenz population pharmacokinetics in Ugandans.
- 2009
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Ingår i: British journal of clinical pharmacology. - : Wiley. - 1365-2125 .- 0306-5251. ; 68:5, s. 690-9
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Tidskriftsartikel (refereegranskat)abstract
- AIMS: Efavirenz exhibits pharmacokinetic variability causing varied clinical response. The aim was to develop an integrated population pharmacokinetic/pharmacogenetic model and investigate the impact of genetic variations, sex, demographic and biochemical variables on single-dose efavirenz pharmacokinetics among Ugandan subjects, using NONMEM. METHODS: Efavirenz plasma concentrations (n = 402) from 121 healthy subjects were quantified by high-performance liquid chromatography. Subjects were genotyped for 30 single nucleotide polymorphisms (SNPs), of which six were novel SNPs in CYP2B6, CYP3A5 and ABCB1. The efavirenz pharmacokinetics was described by a two-compartment model with zero- followed by first-order absorption. RESULTS: Apparent oral clearance (95% confidence interval) was 4 l h l(-1) (3.5, 4.5) in extensive metabolizers. In the final model, incorporating multiple covariates, statistical significance was found only for CYP2B6*6 and CYP2B6*11 on apparent oral clearance as well as ABCB1 (rs3842) on the relative bioavailability. Subjects homozygous for CYP2B6*6 (G516T, A785G) and *11 displayed 21 and 20% lower apparent oral clearance, respectively. Efavirenz relative bioavailability was 26% higher in subjects homozygous for ABCB1 (rs3842). The apparent peripheral volume of distribution was twofold higher in women compared with men. CONCLUSIONS: The model identified the four factors CYP2B6*6, CYP2B6*11, a novel variant allele in ABCB1 (rs3842) and sex as major predictors of efavirenz plasma exposure in a healthy Ugandan population after single-dose administration. Use of mixed-effects modelling allowed the analysis and integration of multiple pharmacogenetic and demographic covariates in a pharmacokinetic population model.
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| 6. |
- Hakkarainen, K M, et al.
(författare)
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Prevalence, nature and potential preventability of adverse drug events - A population-based medical record study of 4970 adults
- 2014
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Ingår i: British Journal of Clinical Pharmacology. - : Wiley-Blackwell. - 0306-5251 .- 1365-2125. ; 78:1, s. 170-183
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Tidskriftsartikel (refereegranskat)abstract
- AIMS: To estimate the 3-month prevalence of adverse drug events (ADEs), categories of ADEs, and preventable ADEs, and the preventability of ADEs among adults in Sweden. Further, to identify drug classes and organ systems associated with ADEs and estimate their seriousness.METHODS: A random sample of 5025 adults in Swedish county council in 2008 was drawn from the Total Population Register. All their medical records in 29 inpatient care departments in three hospitals, 110 specialised outpatient clinics, and 51 primary care units were reviewed retrospectively in a stepwise manner, and complemented with register data on dispensed drugs. ADEs, including adverse drug reactions (ADRs), sub-therapeutic effects of drug therapy (STEs), drug dependence and abuse, drug intoxications from overdose, and morbidities due to drug-related untreated indication, were detected during a 3-month study period, and assessed for preventability.RESULTS: Among included 4970 individuals, the prevalence of ADEs was 12.0% (95% confidence interval 11.1-12.9%), and preventable ADEs 5.6% (5.0-6.2%). ADRs (6.9%; 6.2-7.6%) and STEs (6.4%; 5.8-7.1%) were more prevalent than the other ADEs. Of the ADEs, 38.8% (35.8-41.9%) was preventable, varying by ADE category and seriousness. ADEs were frequently associated with nervous system and cardiovascular drugs, but the associated drugs and affected organs varied by ADE category.CONCLUSIONS: The considerable burden of ADEs and preventable ADEs from commonly used drugs across care settings warrants large-scale efforts to redesign safer, higher quality healthcare systems. The heterogeneous nature of the ADE categories should be considered in research and clinical practice for preventing, detecting and mitigating ADEs.
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| 7. |
- Petersen, AH, et al.
(författare)
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The effect of exercise on the absorption of inhaled human insulin in healthy volunteers
- 2008
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Ingår i: British Journal of Clinical Pharmacology. - : Wiley. - 1365-2125 .- 0306-5251. ; 65:2, s. 165-171
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Tidskriftsartikel (refereegranskat)abstract
- What is already known about this subject * Exercise is known to affect absorption of other inhaled substances, but so far there are no reports on the effect of exercise on the absorption of inhaled insulin in humans. What this paper adds * This report is the first to investigate the effect of exercise on the absorption of inhaled insulin. * In this study in healthy volunteers we found that exercise early after dosing increased absorption (15-20%) of inhaled insulin over the first 2 h after start of exercise, with an approximately 30% increase in maximal insulin concentration, and unchanged overall absorption. Aims To investigate the effect of moderate exercise on the absorption of inhaled insulin. Methods A single-centre, randomized, open-label, three-period cross-over trial was carried out in 12 nonsmoking healthy subjects. A dose of 3.5 mg inhaled human insulin was administered via a nebulizer and followed in random order by either 1) no exercise (NOEX), 2) 30 min exercise starting immediately after dosing (EX0), or 3) 30 min exercise starting 30 min after dosing (EX30). The study was carried out as a 10 h euglycaemic glucose clamp (90 mg dl(-1) (5.0 mmol l(-1))). Results The absorption of insulin over the first 2 h after start of exercise was 16% increased for EX0 (ratio (95%CI) 1.16 (1.04, 1.30), P = 0.01) and 20% increased for EX30 (1.20 (1.05, 1.36), P < 0.01), both compared with NOEX; the overall insulin absorption during 6 h and 10 h after dosing was not influenced by exercise. The maximum insulin concentration (C(max)) increased by 32% for EX0 and 35% for EX30 (both P < 0.01) compared with NOEX, while the time to C(max) was 31 min faster for EX0 (P < 0.01), but not significantly different after EX30, compared with NOEX. Conclusions A significant and clinically relevant increase of insulin absorption over the first 2 h after the beginning of exercise was observed. Until data from studies using the specific insulin inhalers exists, patients using inhaled insulin should be made aware of a potential increased absorption and higher concentration of insulin in connection with exercise.
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| 8. |
- Bondesson, Eva, et al.
(författare)
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Site of deposition and absorption of an inhaled hydrophilic solute
- 2007
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Ingår i: British Journal of Clinical Pharmacology. - : Wiley. - 1365-2125 .- 0306-5251. ; 63:6, s. 722-731
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Tidskriftsartikel (refereegranskat)abstract
- Aims To characterize the absorption kinetics and bioavailability of an inhaled hydrophilic solute deposited at various sites within the airways. Methods Nine healthy nonsmokers received one intravenous, one oropharyngeal and two pulmonary doses of technetium-99 m-labelled diethylene triamine pentaacetic acid (Tc-99m-DTPA) in an open and crossover fashion. Pulmonary doses were administered as nebulized large and fine droplet-sized aerosols by Pari and UltraVent nebulizers at fairly rapid and slow inhalation flows, respectively. Plasma concentration-time profiles and 24 h urinary excretion of radioactivity were determined. One dose of Tc-99m-labelled Nanocoll, as a marker of mucociliary clearance (MCC), was also administered by Pari for similar lung deposition as the Tc-99m-DTPA and followed by repeated chest gamma-imaging. Results Intrapulmonary deposition patterns of Tc-99m-DTPA differed significantly (the mean ratio of penetration index (Pari : UltraVent) was 76% with 95% CI 63%, 91%). However, no differences in rate or extent of Tc-99m-DTPA absorption were detected. Mean absorption time was 1.8 h (mean difference (Pari-UltraVent): -0.1 h with 95% CI -0.6 h, 0.3 h) and the bioavailability was 70% (mean ratio (Pari : UltraVent): 101% with 95% CI 90%, 115%). The pulmonary elimination half-life of Tc-99m-Nanocoll (8 h and 45 min) was significantly longer than that of Tc-99m-DTPA (less than 2 h). The oral bioavailability of Tc-99m-DTPA was estimated to be 3.1%. Conclusions The main elimination pathway of the inhaled hydrophilic solute Tc-99m-DTPA from the lungs is trans-epithelial absorption. Despite different intrapulmonary radioaerosol deposition patterns, as verified by gamma scintigraphy, no differences in Tc-99m-DTPA absorption kinetics or bioavailability were detected.
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| 9. |
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| 10. |
- Petersen, Astrid H., et al.
(författare)
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The effect of terbutaline on the absorption of pulmonary administered insulin in subjects with asthma
- 2010
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Ingår i: British Journal of Clinical Pharmacology. - : Wiley. - 1365-2125 .- 0306-5251. ; 69:3, s. 271-278
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Tidskriftsartikel (refereegranskat)abstract
- center dot People with mild and moderate asthma have been shown to absorb less inhaled insulin than healthy subjects. center dot In people with moderate asthma, the administration of a bronchodilator before inhalation of insulin has been shown to lead to increased uptake of inhaled insulin compared with no prior administration of bronchodilator. WHAT THIS STUDY ADDS center dot This study is the first to show that in people with asthma, reduction of bronchoconstriction leads to increased absorption of inhaled insulin. center dot This study illustrates that due to the effect of terbutaline on glucose metabolism, the effect of insulin on plasma glucose is complex when terbutaline is administered concomitantly. AIM To investigate the effect of prior administration of a bronchodilator on the absorption of inhaled insulin in people with asthma treated with inhaled corticosteroids. METHODS A single-centre, randomized, open-label, two-period cross-over trial was carried out in 41 nondiabetic subjects with asthma treated with inhaled steroids, with reversible bronchoconstriction (Rev+; n = 25) or without reversible bronchoconstriction (Rev-; n = 16). A dose of 0.10 U kg-1 inhaled human insulin was administered on each dosing day with or without prior administration of the bronchodilator terbutaline (in random order). RESULTS Prior administration of terbutaline led to a 44% increase in absorption of insulin over 6 h for the Rev+ group compared with no prior administration of bronchodilator [ratio (95% confidence interval) 1.44 (1.13, 1.82), P = 0.004], whereas no effect was seen for the Rev- or the whole group. The maximum insulin concentration (C-max) increased by 34% for the Rev+ group (P = 0.018) and 17% for the whole group (P = 0.046), whereas no significant effect of prior terbutaline administration was seen for Rev-. The time to C-max was not significantly different for the Rev+ group, whereas it was approximately 30% longer after bronchodilator administration for the Rev- group (P = 0.044) and the whole group (P = 0.032). CONCLUSIONS In people with asthma and reversible bronchoconstriction, the administration of a bronchodilator prior to administration of inhaled insulin led to increased absorption of insulin, whereas no effect on insulin absorption in subjects without significant reversibility could be detected.
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