Linda Björkhem-Bergman

Vitamin D and Respiratory Tract Infections: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Background Low levels of 25-OH vitamin D are associated with respiratory tract infection (RTI). However, results from randomized controlled trials are inconclusive. Therefore, we performed a systematic review and meta-analysis to assess the preventive effect of vitamin D supplementation on RTI. Methods Randomized, controlled trials of vitamin D for prevention of RTI were used for the analysis. The risks of within-trial and publication bias were assessed. Odds ratios of RTI were pooled using a random-effects model. Heterogeneity was assessed using Cochrans Q and I2. Meta-regressions and subgroup analyses were used to assess the influence of various factors on trial outcome. The pre-defined review protocol was registered at the PROSPERO international prospective register of systematic reviews, registration number CRD42013003530. Findings Of 1137 citations retrieved, 11 placebo-controlled studies of 5660 patients were included in the meta-analysis. Overall, vitamin D showed a protective effect against RTI (OR, 0.64; 95% CI, 0.49 to 0.84). There was significant heterogeneity among studies (Cohrans Q p<0.0001, I2 = 72%). The protective effect was larger in studies using once-daily dosing compared to bolus doses (OR = 0.51 vs OR = 0.86, p = 0.01). There was some evidence that results may have been influenced by publication bias. Interpretation Results indicate that vitamin D has a protective effect against RTI, and dosing once-daily seems most effective. Due to heterogeneity of included studies and possible publication bias in the field, these results should be interpreted with caution.

Vitamin D3 supplementation in patients with frequent respiratory tract infections: a randomised and double-blind intervention study

Background Low serum levels of 25-hydroxyvitamin D3 are associated with an increased risk of respiratory tract infections (RTIs). Clinical trials with vitamin D3 against various infections have been carried out but data are so far not conclusive. Thus, there is a need for additional randomised controlled trials of effects of vitamin D3 on infections. Objective To investigate if supplementation with vitamin D3 could reduce infectious symptoms and antibiotic consumption among patients with antibody deficiency or frequent RTIs. Design A double-blind randomised controlled trial. Setting Karolinska University Hospital, Huddinge. Participants 140 patients with antibody deficiency (selective IgA subclass deficiency, IgG subclass deficiency, common variable immune disorder) and patients with increased susceptibility to RTIs (>4 bacterial RTIs/year) but without immunological diagnosis. Intervention Vitamin D3 (4000 IU) or placebo was given daily for 1 year. Primary and secondary outcome measures The primary endpoint was an infectious score based on five parameters: symptoms from respiratory tract, ears and sinuses, malaise and antibiotic consumption. Secondary endpoints were serum levels of 25-hydroxyvitamin D3, microbiological findings and levels of antimicrobial peptides (LL-37, HNP1–3) in nasal fluid. Results The overall infectious score was significantly reduced for patients allocated to the vitamin D group (202 points) compared with the placebo group (249 points; adjusted relative score 0.771, 95% CI 0.604 to 0.985, p=0.04). Limitations A single study centre, small sample size and a selected group of patients. The sample size calculation was performed using p=0.02 as the significance level whereas the primary and secondary endpoints were analysed using the conventional p=0.05 as the significance level. Conclusions Supplementation with vitamin D3 may reduce disease burden in patients with frequent RTIs.

What is a relevant statin concentration in cell experiments claiming pleiotropic effects

Apart from their lipid-lowering effects statins have been ascribed a number of other functions including anti-inflammatory and immunomodulatory properties [1]. Notably, most available evidence for the proposed pleiotropic effects of statins is based on in vitro studies. We claim that the results from these in vitro studies are potentially misleading, because of the high statin concentrations used.

Drug-resistant human lung cancer cells are more sensitive to selenium cytotoxicity. Effects on thioredoxin reductase and glutathione reductase.

The human U-1285 and GLC(4) cell lines, both derived from small cell carcinoma of the lung, are present in doxorubicin-sensitive (U-1285 and GLC(4)) and doxorubicin-resistant MRP-expressing (U-1285dox and GLC(4)/ADR) variants. These sublines were examined here with respect to their susceptibilities to the toxic effects of selenite and compared to the toxic effects of selenite on the promyelocytic leukemia cell line HL-60 and its doxorubicin-resistant P-glycoprotein expressing variant. The drug-resistant U-1285dox and GLC(4)/ADR sublines proved to be 3- and 4-fold, respectively, more sensitive to the cytotoxicity of selenite than the drug-sensitive U-1285 and GLC(4) sublines, whereas no difference was observed between the HL-60 sublines. The presence of doxorubicin at a concentration equal to the IC(10) did not significantly potentiate the toxic effects of selenite. The presence of selenite did not significantly affect the expression of the multi-drug resistant proteins (MRP1, LRP and topoisomerase IIalpha) in the drug-resistant cells. The activities of thioredoxin reductase (TrxR) were higher (50 and 25%, respectively) in the drug resistant cell sublines U-1285dox and GLC(4)/ADR compared to the drug-sensitive parental lines. The activity of glutathione reductase (GR) was essentially the same in the drug-sensitive and -resistant cell lines. Exposure to selenite resulted in a 4-fold increase in both TrxR and GR activities in U-1285 cells, an effect, which was less pronounced in the presence of doxorubicin. Under similar conditions the increase in the TrxR activity in the resistant U-1285dox cell line, was only 30% and the activity of GR was unaltered. Different responses in the activity of the key enzymes in selenium metabolism are one possible mechanism explaining the differential cytotoxicity of selenium in these cells.

Interface management of pharmacotherapy. Joint hospital and primary care drug recommendations

PurposeIn September 2012 an interactive course on the “Interface Management of Pharmacotherapy” was organized by the Stockholm Drug and Therapeutics Committee in cooperation with Department of Clinical Pharmacology at Karolinska Institutet and at Karolinska University Hospital in Stockholm, Sweden, in collaboration with the WHO. The basis for the course was the “Stockholm model” for the rational use of medicines but also contained presentations about successful models in interface management of pharmacotherapy in other European countries.MethodsThe “Stockholm model” consists of 8 components: 1) Independent Drug and Therapeutics Committee with key role for respected drug experts with policy for “interest of conflicts”, 2) The “Wise List”, recommendations of medicines jointly for primary and hospital care, 3) Communication strategy with continuous medical education, 4) Systematic introduction of new expensive medicines, 5) E-pharmacological support at “point of care”, 6) Methods and tools for follow-up of medicines use, 7) Medicines policy strategy and 8) Operative resources.ResultsThe course highlighted the importance of efficient and targeted communication of drug recommendations building on trust among prescribers and patients for the guidelines to achieve high adherence. Trust is achieved by independent Drug and Therapeutics Committees with a key role for respected experts and a strict policy for “conflicts of interest”. Representations of GPs are also crucial for successful implementation, being the link between evidence based medicine and practice.ConclusionThe successful models in Scotland and in Stockholm as well as the ongoing work in Catalonia were considered as examples of multifaceted approaches to improve the quality of medicine use across primary and hospital care.

Studies on the Antibacterial Effects of Statins - In Vitro and In Vivo

Background Statin treatment has been associated with a beneficial outcome on respiratory tract infections. In addition, previous in vitro and in vivo experiments have indicated favorable effects of statins in bacterial infections. Aim The aim of the present study was to elucidate possible antibacterial effects of statins against primary pathogens of the respiratory tract. Methods MIC-values for simvastatin, fluvastatin and pravastatin against S. pneumoniae, M. catarrhalis and H. influenzae were determined by traditional antibacterial assays. A BioScreen instrument was used to monitor effects of statins on bacterial growth and to assess possible synergistic effects with penicillin. Bacterial growth in whole blood and serum from healthy volunteers before and after a single dose of simvastatin, fluvastatin and penicillin (positive control) was determined using a blood culture system (BactAlert). Findings The MIC-value for simvastatin against S pneumoniae and M catarrhalis was 15 µg/mL (36 mmol/L). Fluvastatin and Pravastatin showed no antibacterial effect in concentrations up to 100 µg/mL (230 µmol/L). Statins did not affect growth or viability of H influenzae. Single doses of statins given to healthy volunteers did not affect growth of pneumococci, whereas penicillin efficiently killed all bacteria. Conclusions Simvastatin at high concentrations 15 µg/mL (36 µmol/L) rapidly kills S pneumoniae and M catarrhalis. However, these concentrations by far exceed the concentrations detected in human blood during simvastatin therapy (1–15 nmol/L) and single doses of statins given to healthy volunteers did not improve antibacterial effects of whole blood. Thus, a direct bactericidal effect of statins in vivo is probably not the mechanism behind the observed beneficial effect of statins against various infections.

Metformin for weight reduction in non-diabetic patients on antipsychotic drugs: a systematic review and meta-analysis

Weight gain is a clinically important side effect of antipsychotic drug therapy. The aim of this study was to determine the effect of the antidiabetic drug metformin on antipsychotic-induced weight gain in non-diabetic patients. In a systematic literature review we identified 195 citations from which seven randomized, placebo-controlled studies (398 patients) were included in the final analysis. Studies in adults (n = 5) and in children (n = 2) were analysed separately. Compared with placebo, metformin treatment caused a significant body weight reduction in adult non-diabetic patients treated with atypical antipsychotics (4.8%, 95% CI 1.6 to 8.0) and in children (4.1%, 95% CI 2.2 to 6.0). There was evidence of substantial heterogeneity among studies, and when the analysis was restricted to patients with a manifest (>10%) body weight increase prior to randomisation metformin reduced weight by 7.5% (95% CI 2.9 to 12.0). The effect was larger in Asians (7.8%, 95% CI 4.4 to 11.2) than in Hispanics (2.0%, 95% CI 0.7 to 3.3). In conclusion, metformin has a pronounced weight-reducing effect in antipsychotic-treated patients, especially in those with a manifest weight gain. Although direct comparisons are lacking, the observed effect on body weight compares favourably with the effect of sibutramine and orlistat, approved for weight reduction. However, metformin is not approved for use in non-diabetic patients and it is still not generally advisable to recommend metformin to counteract antipsychotic-induced weight gain.

Statin treatment and mortality in bacterial infections--a systematic review and meta-analysis.

Background Several studies have reported improved survival in severe bacterial infections among statin treated patients. In addition, statins have been ascribed beneficial anti-inflammatory effects. The aim of this study was to evaluate the effect of statin-treatment on mortality in patients with bacterial infections, by means of a systematic review and a meta-analysis. Methodology and Principal Findings Studies investigating the association between statin use and mortality in patients with bacterial disease were identified in a systematic literature review and a meta-analysis was performed to calculate the overall odds ratio of mortality in statin users. The literature search identified 947 citations from which 40 relevant studies were extracted. In all, 15 studies comprising 113 910 patients were included in the final analysis. Statin use was associated with a significantly (p<0.0001) reduced mortality in patients suffering from bacterial infections (OR 0.52, 95% CI 0.42–0.66). However, all studies included were of observational design and funnel plot analyses indicated influence by a possible publication bias (Eggers bias test p<0.05). When a precision estimate test was used to adjust for publication bias the effect of statin treatment was no longer significant, with an OR of 0.79 (95% CI 0.58–1.07). Conclusion/Significance According to the meta-analysis of observational studies presented here, patients on statin therapy seem to have a better outcome in bacterial infections. However, the association did not reach statistical significance after adjustment for apparent publication bias. Thus, there is a great need for randomised controlled trials investigating the possible beneficial effect of statins in bacterial infections.

Comparison of Endogenous 4β-Hydroxycholesterol with Midazolam as Markers for CYP3A4 Induction by Rifampicin

CYP3A4, considered the most important enzyme in drug metabolism, is often involved in drug-drug interactions. When developing new drugs, appropriate markers for detecting CYP3A4 induction are needed. Our study compared endogenously formed 4β-hydroxycholesterol with the midazolam clearance in plasma and the 6β-hydroxycortisol/cortisol ratio in urine as markers for CYP3A4 induction. To this end, we performed a clinical trial in which 24 healthy subjects were randomized to 10, 20, or 100 mg daily doses of rifampicin for 14 days (n = 8 in each group) to achieve a low and moderate CYP3A4 induction. The CYP3A4 induction could be detected even at the lowest dose of rifampicin (10 mg) via the estimated midazolam clearance, the 4β-hydroxycholesterol ratio (both P < 0.01), and the 6β-hydroxycortisol ratio (P < 0.05). For the three dosing groups (10, 20, and 100 mg), the median fold induction from baseline was 2.0, 2.6, and 4.0 for the estimated midazolam clearance; 1.3, 1.6, and 2.5 for the 4β-hydroxycholesterol/cholesterol ratio; and 1.7, 2.9, and 3.1 for the 6β-hydroxycortisol/cortisol ratio. In conclusion, the 4β-hydroxycholesterol ratio is comparable to midazolam clearance as a marker of CYP3A4 induction, and each may be used to evaluate CYP3A4 induction in clinical trials evaluating drug-drug interactions for new drugs.

The antifungal drug voriconazole is an efficient inhibitor of brain cholesterol 24S-hydroxylase in vitro and in vivo

Cholesterol 24S-hydroxylase (CYP46A1) is of key importance for cholesterol homeostasis in the brain. This enzyme seems to be resistant toward most regulatory factors and at present no drug effects on its activity have been described. The crystal structures of the substrate-free and substrate-bound CYP46A1 were recently determined (Mast et al., Crystal structures of substrate-bound and substrate-free cytochrome P450 46A1, the principal cholesterol hydroxylase in the brain. Proc. Natl. Acad. Sci. USA. 2008. 105: 9546–9551). These structural studies suggested that ligands other than sterols can bind to CYP46A1. We show here that the antifungal drug voriconazole binds to the enzyme in vitro and inhibits CYP46A1-mediated cholesterol 24-hydroxylation with a Ki of 11 nM. Mice treated with daily intraperitoneal injections of voriconazole for 5 days had high levels of voriconazole in the brain and significantly reduced brain levels of 24S-hydroxycholesterol. The levels of squalene, lathosterol, and HMG-CoA reductase mRNA were reduced in the brain of the voriconazole-treated animals as well, indicating a reduced cholesterol synthesis. Most of this effect may be due to a reduced utilization of cholesterol by CYP46A1. One of the side-effects of voriconazole is visual disturbances. Because CYP46A1 is also expressed in the neural retina, we discuss the possibility that the inhibition of CYP46A1 by voriconazole contributes to these visual disturbances.