Lauri I. Kajosaari

Polymorphic Organic Anion Transporting Polypeptide 1B1 is a Major Determinant of Repaglinide Pharmacokinetics

A large interindividual variability exists in the plasma concentrations of repaglinide. Our aim was to investigate possible associations between the pharmacokinetics of repaglinide and single nucleotide polymorphisms (SNPs) in the genes encoding for the drug transporters organic anion transporting polypeptide 1B1 (OATP1B1) (SLCO1B1) and P‐glycoprotein (MDR1, ABCB1) and the drug‐metabolizing enzymes cytochrome P450 (CYP) 2C8 and CYP3A5.

Cyclosporine markedly raises the plasma concentrations of repaglinide

Repaglinide is an antidiabetic drug metabolized by cytochrome P450 (CYP) 2C8 and 3A4, and it appears to be a substrate of the hepatic uptake transporter organic anion transporting polypeptide 1B1 (OATP1B1). We studied the effects of cyclosporine (INN, ciclosporin), an inhibitor of CYP3A4 and OATP1B1, on the pharmacokinetics and pharmacodynamics of repaglinide.

Telithromycin, but not montelukast, increases the plasma concentrations and effects of the cytochrome P450 3A4 and 2C8 substrate repaglinide.

The antidiabetic repaglinide is metabolized by cytochrome P450 (CYP) 2C8 and CYP3A4. Telithromycin, an antimicrobial agent, inhibits CYP3A4 in vitro and in vivo. Montelukast, an antiasthmatic drug, is a potent inhibitor of CYP2C8 in vitro. We studied the effects of telithromycin, montelukast, and the combination of telithromycin and montelukast on the pharmacokinetics and pharmacodynamics of repaglinide.

Characterization of novel CYP2C8 haplotypes and their contribution to paclitaxel and repaglinide metabolism

Cytochrome P450 2C8 (CYP2C8) plays a major role in the metabolism of therapeutically important drugs which exhibit large interindividual differences in their pharmacokinetics. In order to evaluate any genetic influence on this variation, a CYP2C8 phenotype–genotype evaluation was carried out in Caucasians. Two novel CYP2C8 haplotypes, named B and C with frequencies of 24 and 22% in Caucasians, respectively, were identified and caused a significantly increased and reduced paclitaxel 6α-hydroxylation, respectively, as evident from analyses of 49 human liver samples. In healthy white subjects, CYP2C8*3 and the two novel haplotypes significantly influenced repaglinide pharmacokinetics in SLCO1B1c.521T/C heterozygous individuals: haplotype B was associated with reduced and haplotype C with increased repaglinide AUC (0–∞). Functional studies suggested −271C>A (CYP2C8*1B) as a causative SNP in haplotype B. In conclusion, two novel common CYP2C8 haplotypes were identified and significantly associated with altered rate of CYP2C8-dependent drug metabolism in vitro and in vivo.

Cyclosporine A Increases Plasma Concentrations and Effects of Repaglinide

We read with interest the article by Türk et al. titled ‘Repaglinide in the Management of New-Onset Diabetes Mellitus After Renal Transplantation’ (1). While we agree with the conclusions of this observational study that repaglinide can be effective in the treatment of new-onset diabetes mellitus (NODM) after renal transplantation, we are concerned about the risk of interaction between cyclosporine A and repaglinide.

Second branchial cleft fistulae: Patient characteristics and surgical outcome

BACKGROUNDS Second branchial cleft anomalies predispose to recurrent infections, and surgical resection is recommended as the treatment of choice. There is no clear consensus regarding the timing or surgical technique in the operative treatment of these anomalies. Our aim was to compare the effect of age and operative techniques to patient characteristics and treatment outcome. METHODS A retrospective study of pediatric patients treated for second branchial sinuses or fistulae during 1998-2012 at two departments in our academic tertiary care referral center. Comparison of patient characteristics, preoperative investigations, surgical techniques and postoperative sequelae. RESULTS Our data is based on 68 patients, the largest series in the literature. One-fourth (24%) of patients had any infectious symptoms prior to operative treatment. Patient demographics, preoperative investigations, use of methylene blue, or tonsillectomy had no effect on the surgical outcome. There were no re-operations due to residual disease. Three complications were observed postoperatively. CONCLUSIONS Our patient series of second branchial cleft sinuses/fistulae is the largest so far and enables analyses of patient characteristics and surgical outcomes more reliably than previously. Preoperative symptoms are infrequent and mild. There was no difference in clinical outcome between the observed departments. Performing ipsilateral tonsillectomy gave no outcome benefits. The operation may be delayed to an age of approximately three years when anesthesiological risks are and possible harms are best avoided. Considering postoperative pain and risk of postoperative hemorrhage a routine tonsillectomy should not be included to the operative treatment of second branchial cleft fistulae.

Retropharyngeal involvement in Kawasaki disease--a report of four patients with retropharyngeal edema verified by magnetic resonance imaging.

Kawasaki disease is an acute systemic vasculitis of childhood. The diagnosis is based on clinical criteria. Prognosis with adequate treatment is favorable. Untreated patients, however, may develop coronary manifestations predisposing to acute myocardial infarction. Retropharyngeal edema is a rare but known manifestation of Kawasaki disease. We present a case series of four Kawasaki patients presenting with clinical findings for retropharyngeal abscess and the magnetic resonance imaging findings of these patients, diagnosed during a six week period. To our knowledge, this is the first systematic report of cervical MRI findings of Kawasaki patients.

Cervical Chondrocutaneous Branchial Remnants.

Objective Cervical chondrocutaneous branchial remnants are rare malformations usually found in the lower neck. As high as 76% of patients have been reported to have associated anomalies. We review the literature and report a case series of seven patients with cervical cartilaginous remnants. Design A retrospective case series of seven patients identified from the electronic hospital records. Results Seven patients with cervical chondrocutaneous branchial remnants were identified (six boys and one girl). Only one of the patients had associated anomalies. Conclusions A review of the literature revealed no evidence for sinuses or cysts related to cervical chondrocutaneous branchial remnants. Operative treatment can be postponed to a suitable and safe age. There is marked variation in the reported prevalence of associated anomalies, ranging from 11% to 76%.