Otoplasty for prominent ears - demographics and surgical timing in different populations.

INTRODUCTION: Prominent ears are seen in approximately 5% of the population. This benign condition can be treated surgically to reduce or prevent psychological and social problems, most commonly in children before the start of school. Our aim was to examine the demographic characteristics of patients undergoing prominent ear surgery in Finland, and compare findings with international data. METHODS: A retrospective study of all the patients treated for prominent ears in our academic tertiary care referral center during 2007-2011 was performed to gather demographic details of operated patients. A systematic review of published series of prominent ear surgery after the year 2000 was performed to gather demographic details for international comparison. RESULTS: A total of 180 patients were operated in our institution for prominent ears, most of the cases (78.9%) were bilateral. Age at operation ranged between 3 and 36 years, with mean of 9.2 y and median of 7 y. The most common reason for seeking operative treatment was aesthetic complaint, followed by bullying. Review process gathered 20 publications, describing a total of 4433 patients who had been operated for prominent ears. There was wide variation the mean age at operation, ranging 7-38 y while the mean overall was 15.0y. Gender distribution of patient samples was also very variable, with percentage of females ranging from 38 to 71% (overall 52%). There was also considerable variation in the tendency to perform unilateral operations: from 0% up to 21% of the reported population. There were no statistically significant correlations linking these demographic variables, though there was a trend that females are more likely to have this operation performed at an older age. CONCLUSIONS: The treatment culture of prominent ear surgery varies substantially in international comparison. The age at which this operation is performed showed most variation. Omitting some of the basic demographic variables while reporting the results of surgery was common in the reviewed publications.

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%.

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.

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.

[Acute mastoiditis in children]. / Lasten akuutti mastoidiitti.

Acute mastoiditis in children develops when acute otitis media (AOM) spreads into the mastoid air cells inside the temporal bone. The diagnosis is based on clinical findings of AOM with simultaneous signs of infection in the mastoid area. The most common pathogen causing acute mastoiditis in children is Streptococcus pneumoniae. Intravenous antimicrobial medication, tympanostomy and microbial sample are the cornerstones of the treatment. If a complication of mastoiditis is suspected, imaging studies are needed, preferably with magnetic resonance imaging. The most common complication of acute mastoiditis is a subperiosteal abscess.

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

BACKGROUND AND OBJECTIVE: 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. METHODS: In a randomized 4-phase crossover study, 12 healthy volunteers received 800 mg telithromycin, 10 mg montelukast, both telithromycin and montelukast, or placebo once daily for 3 days. On day 3, they ingested a single 0.25-mg dose of repaglinide. Plasma and urine concentrations of repaglinide and its metabolites M1, M2, and M4, as well as blood glucose concentrations, were measured for 12 hours. RESULTS: Telithromycin alone raised the mean peak plasma repaglinide concentration to 138% (range, 91%-209%; P = .006) and the total area under the plasma concentration-time curve from 0 hours to infinity [AUC0-infinity] of repaglinide to 177% (range, 125%-257%; P < .001) of control (placebo). Telithromycin reduced the AUC0-infinity ratio of the metabolite M1 to repaglinide by 68% (P < .001) and the urinary excretion ratio of M1 to repaglinide by 77% (P = .001). In contrast to previous estimates based on in vitro CYP2C8 inhibition data, montelukast had no significant effect on the pharmacokinetics of repaglinide or its metabolites and did not significantly alter the effect of telithromycin on repaglinide pharmacokinetics. Telithromycin, unlike montelukast, lowered the maximum blood glucose concentration (P = .002) and mean blood glucose concentration from 0 to 3 hours (P = .008) after repaglinide intake, as compared with placebo. CONCLUSIONS: Telithromycin increases the plasma concentrations and blood glucose-lowering effect of repaglinide by inhibiting its CYP3A4-catalyzed biotransformation and may increase the risk of hypoglycemia. Unexpectedly, montelukast has no significant effect on repaglinide pharmacokinetics, suggesting that it does not significantly inhibit CYP2C8 in vivo. The low free fraction of montelukast in plasma may explain the lack of effect on CYP2C8 in vivo, despite the low in vitro inhibition constant, highlighting the importance of incorporating plasma protein binding to interaction predictions.

Pioglitazone, an in vitro inhibitor of CYP2C8 and CYP3A4, does not increase the plasma concentrations of the CYP2C8 and CYP3A4 substrate repaglinide.

OBJECTIVE: Pioglitazone, a thiazolidinedione antidiabetic, inhibits cytochrome P450 (CYP) 2C8 and CYP3A4 enzymes in vitro. Repaglinide, a meglitinide analogue antidiabetic, is metabolised by CYP2C8 and CYP3A4. In patients with type 2 diabetes, the pioglitazone-repaglinide combination has acted synergistically on glycaemic parameters. Our aim was to determine whether pioglitazone increases the plasma concentrations of repaglinide. METHODS: In a randomized, 2-phase cross-over study, 12 healthy volunteers received 30 mg pioglitazone or placebo once daily for 5 days. On day 5, they ingested a single 0.25 mg dose of repaglinide 1 h after the last pretreatment dose. Plasma repaglinide and pioglitazone, and blood glucose concentrations were measured for 12 h. RESULTS: During the pioglitazone phase, the mean peak plasma repaglinide concentration (C(max)) and the total area under the concentration-time curve [AUC(0-infinity)] of repaglinide were 100% (range 53-157%, P=0.99) and 90% (range 63-120%, P=0.22), respectively, of those during the placebo phase. Also the half-life of repaglinide was unaffected, but the median peak time of repaglinide was shortened from 40 min to 20 min by pioglitazone (P=0.014). The short-term pioglitazone administration did not modify the blood glucose-lowering effect of a single dose of repaglinide. CONCLUSIONS: Pioglitazone does not increase the plasma concentrations of repaglinide, indicating that the inhibitory effect of pioglitazone on CYP2C8 and CYP3A4 is very weak in vivo, probably due to its extensive plasma protein binding. The synergistic effect of repaglinide and pioglitazone on the glycaemic parameters, seen in patients with type 2 diabetes during their long-term use, is unlikely to be caused by inhibition of repaglinide metabolism by pioglitazone.

Differential inhibition of cytochrome P450 3A4, 3A5 and 3A7 by five human immunodeficiency virus (HIV) protease inhibitors in vitro.

The effects of five HIV protease inhibitors (amprenavir, indinavir, nelfinavir, ritonavir and saquinavir) on cytochrome P450 (CYP) 3A4, 3A5 and 3A7 activities were studied in vitro using testosterone 6beta-hydroxylation in recombinant CYP3A4, CYP3A5 and CYP3A7 enzymes. The protease inhibitors showed differential inhibitory effects on the three CYP3A forms. Ritonavir and saquinavir were non-selective and preferential inhibitors of CYP3A4 and CYP3A5 (K(i) 0.03 microM and 0.6-0.8 microM for ritonavir and saquinavir, respectively), and weaker inhibitors of CYP3A7 (K(i) 0.6 microM and 1.8 microM, respectively). Nelfinavir was a potent and non-selective inhibitor of all three CYP3A forms (K(i) 0.3-0.4 microM). Amprenavir and indinavir preferentially inhibited CYP3A4 (K(i) 0.1 microM and 0.2 microM, respectively), with weaker inhibitory effects on CYP3A5 (K(i) 0.5 microM and 2.2 microM, respectively) and CYP3A7 (K(i) 2.1 microM and 10.6 microM, respectively). In conclusion, significant differences exist in the inhibitory potency of protease inhibitors for different CYP3A forms. Ritonavir, nelfinavir, saquinavir and amprenavir seem to be prone to drug-drug interactions by inhibiting both CYP3A4 and CYP3A5. Especially nelfinavir and ritonavir also have a potential to inhibit foetal CYP3A7-mediated drug metabolism and some endogenous pathways that may be crucial to normal foetal development, while indinavir has the lowest potential to inhibit CYP3A5 and CYP3A7.

Cyclosporine markedly raises the plasma concentrations of repaglinide.

BACKGROUND AND OBJECTIVE: Repaglinide is an antidiabetic drug metabolized by cytochrome P450 (CYP) 2 C 8 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. METHODS: In a randomized crossover study, 12 healthy volunteers took 100 mg cyclosporine or placebo orally at 8 pm on day 1 and at 8 am on day 2. At 9 am on day 2, they ingested a single 0.25-mg dose of repaglinide. Concentrations of plasma and urine repaglinide and its metabolites (M), blood cyclosporine, and blood glucose were measured for 12 hours. The subjects were genotyped for single-nucleotide polymorphisms in CYP2C8, CYP3A5, SLCO1B1 (encoding OATP1B1), and ABCB1 (P-glycoprotein). The effect of cyclosporine on repaglinide metabolism was studied in human liver microsomes in vitro. RESULTS: During the cyclosporine phase, the mean peak repaglinide plasma concentration was 175% (range, 56%--365%; P=.013) and the total area under the plasma concentration-time curve [AUC0--infinity] was 244% (range, 119%--533%; P<.001) of that in the placebo phase. The amount of unchanged repaglinide and its metabolites M2 and M4 excreted in urine were raised 2.7--fold, 7.5--fold, and 5.0--fold, respectively, by cyclosporine (P<.001). The amount of M1 excreted in urine remained unchanged, but cyclosporine reduced the ratio of M1 to repaglinide by 62% (P<.001). Cyclosporine had no significant effect on the elimination half-life or renal clearance of repaglinide. Although the mean blood glucose-lowering effect of repaglinide was unaffected in this low-dose study with frequent carbohydrate intake, the subject with the greatest pharmacokinetic interaction had the greatest increase in blood glucose-lowering effect. The effect of cyclosporine on repaglinide AUC0-infinity was 42% lower in subjects with the SLCO1B1 521TC genotype than in subjects with the 521TT (reference) genotype (P=.047). In vitro, cyclosporine inhibited the formation of M1 (IC50 [concentration of inhibitor to cause 50% inhibition of original enzyme activity], 0.2 micromol/L) and M2 (IC50, 4.3 micromol/L) but had no effect on M4. CONCLUSIONS: Cyclosporine raised the plasma concentrations of repaglinide, probably by inhibiting its CYP3A4-catalyzed biotransformation and OATP1B1-mediated hepatic uptake. Coadministration of cyclosporine may enhance the blood glucose-lowering effect of repaglinide and increase the risk of hypoglycemia.

Metabolism of repaglinide by CYP2C8 and CYP3A4 in vitro: effect of fibrates and rifampicin.

Repaglinide is an antidiabetic drug metabolised by cytochrome P450 (CYP) 2C8 and CYP3A4 enzymes. To clarify the mechanisms of observed repaglinide drug interactions, we determined the contribution of the two enzymes to repaglinide metabolism at different substrate concentrations, and examined the effect of fibrates and rifampicin on CYP2C8, CYP3A4 and repaglinide metabolism in vitro. We studied repaglinide metabolism using pooled human liver microsomes, recombinant CYP2C8 and recombinant CYP3A4 enzymes. The effect of quercetin and itraconazole on repaglinide metabolism, and of gemfibrozil, bezafibrate, fenofibrate and rifampicin on CYP2C8 (paclitaxel 6alpha-hydroxylation) and CYP3A4 (midazolam 1-hydroxylation) activities and repaglinide metabolism were studied using human liver microsomes. At therapeutic repaglinide concentrations (<0.4 microM), CYP2C8 and CYP3A4 metabolised repaglinide at similar rates. Quercetin (25 microM) and itraconazole (3 microM) inhibited the metabolism of 0.2 microM repaglinide by 58% and 71%, and that of 2 microM repaglinide by 56% and 59%, respectively. The three fibrates inhibited CYP2C8 (Ki: bezafibrate 9.7 microM, gemfibrozil 30.4 microM and fenofibrate 92.6 microM) and repaglinide metabolism (IC50: bezafibrate 37.7 microM, gemfibrozil 111 microM and fenofibrate 164 microM), but had no effect on CYP3A4. Rifampicin inhibited CYP2C8 (Ki 30.2 microM), CYP3A4 (Ki 18.5 microM) and repaglinide metabolism (IC50 13.7 microM). In conclusion, both CYP2C8 and CYP3A4 are important in the metabolism of therapeutic concentrations of repaglinide in vitro, but their predicted contributions in vivo are highly dependent on the scaling factor used. Gemfibrozil is only a moderate inhibitor of CYP2C8 and does not inhibit CYP3A4; inhibition of CYP-enzymes by parent gemfibrozil alone does not explain its interaction with repaglinide in vivo. Rifampicin competitively inhibits both CYP2C8 and CYP3A4, which can counteract its inducing effect in humans.

Polymorphic organic anion transporting polypeptide 1B1 is a major determinant of repaglinide pharmacokinetics.

BACKGROUND AND OBJECTIVE: 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. METHODS: A total of 56 healthy volunteers ingested a single 0.25-mg dose of repaglinide. Plasma repaglinide and blood glucose concentrations were measured for up to 7 hours. All subjects were genotyped for the -11187G>A and 521T>C SNPs in SLCO1B1 and the 3435C>T and 2677G>T/A SNPs in ABCB1 , as well as for the CYP2C8*3 (416G>A, 1196A>G), CYP2C8*4 (792C>G), and CYP3A5*3 (6986A>G) alleles. RESULTS: The area under the plasma concentration-time curve from time 0 to infinity [AUC(0-infinity)] and peak concentration in plasma (Cmax) of repaglinide varied 16.9-fold and 10.7-fold, respectively, between individual subjects. Multiple regression analyses indicated that the SLCO1B1 521T>C SNP and the CYP2C8*3 allele were independent predictors of the AUC(0-infinity) and Cmax of repaglinide (adjusted multiple R2 = 45% and 36%, respectively). In subjects with the SLCO1B1 521CC genotype, the AUC(0-infinity) of repaglinide was 107% and 188% higher, respectively, than in subjects with the SLCO1B1 521TC or 521TT (reference) genotype (P < .0001). In subjects with the CYP2C8*1/*3 genotype, the AUC(0-infinity) and Cmax of repaglinide were 48% and 44% lower, respectively, than in those with the CYP2C8*1/*1 genotype (P < .05). The pharmacokinetics of repaglinide was not associated with the studied ABCB1 SNPs or the CYP3A5*3 allele. The elimination half-life of repaglinide was not associated with any SNP. Only the SLCO1B1 -11187GA genotype was significantly associated with an enhanced effect of repaglinide on blood glucose. CONCLUSIONS: Genetic polymorphism in SLCO1B1 is a major determinant of interindividual variability in the pharmacokinetics of repaglinide. The effect of SLCO1B1 polymorphism on the pharmacokinetics of repaglinide may be clinically important.

Lack of effect of bezafibrate and fenofibrate on the pharmacokinetics and pharmacodynamics of repaglinide.

AIMS: Gemfibrozil markedly increases the plasma concentrations and blood glucose-lowering effects of repaglinide, but the effects of other fibrates on repaglinide pharmacokinetics are not known. Our aim was to investigate the effects of bezafibrate and fenofibrate on the pharmacokinetics and pharmacodynamics of repaglinide. METHODS: In a randomized, three-phase cross-over study, 12 healthy subjects received 400 mg bezafibrate, 200 mg fenofibrate or placebo once daily for 5 days. On day 5, a single 0.25 mg dose of repaglinide was ingested 1 h after the last pretreatment dose. The concentrations of plasma repaglinide, bezafibrate and fenofibrate and blood glucose were measured up to 7 h postdose. RESULTS: During the bezafibrate and fenofibrate phases, the total area under the concentration-time curve [AUC(0, infinity )] of repaglinide was 99% (95% confidence interval of the ratio to the control phase 73, 143%) and 99% (85, 127%) of the corresponding value during the placebo (control) phase, respectively. Bezafibrate and fenofibrate had no significant effect on the peak concentration (Cmax) of repaglinide. The mean half-life of repaglinide was 1.3 h in all phases. The blood glucose-lowering effect of repaglinide was not affected by bezafibrate or fenofibrate. The AUC(0,8 h) values for bezafibrate and fenofibrate varied 3.0-fold and 4.4-fold between individual subjects, respectively. Neither bezafibrate nor fenofibrate affected the pharmacokinetic variables of repaglinide. CONCLUSIONS: Bezafibrate and fenofibrate do not affect the pharmacokinetics or pharmacodynamics of repaglinide.

The CYP2C8 inhibitor trimethoprim increases the plasma concentrations of repaglinide in healthy subjects.

AIMS: Our aim was to investigate the effect of the CYP2C8 inhibitor trimethoprim on the pharmacokinetics and pharmacodynamics of the antidiabetic drug repaglinide, and to examine the influence of the former on the metabolism of the latter in vitro. METHODS: In a randomized, double-blind, crossover study with two phases, nine healthy volunteers took 160 mg trimethoprim or placebo orally twice daily for 3 days. On day 3, 1 h after the last dose of trimethoprim or placebo, they ingested a single 0.25 mg dose of repaglinide. Plasma repaglinide and blood glucose concentrations were measured for up to 7 h post-dose. In addition, the effect of trimethoprim on the metabolism of repaglinide by human liver microsomes was investigated. RESULTS: Trimethoprim raised the AUC(0, infinity ) and C(max) of repaglinide by 61% (range, 30-117%; P= 0.0008) and 41% (P = 0.005), respectively, and prolonged the t((1/2)) of repaglinide from 0.9 to 1.1 h (P = 0.001). Trimethoprim had no significant effect on the pharmacokinetics of its aromatic amine metabolite (M1), but decreased the M1 : repaglinide AUC(0, infinity ) ratio by 38% (P = 0.0005). No effect of trimethoprim on the blood glucose-lowering effect of repaglinide was detectable. In vitro, trimethoprim inhibited the metabolism of (220 nm) repaglinide in a concentration-dependent manner. CONCLUSIONS: Trimethoprim raised the plasma concentrations of repaglinide probably by inhibiting its CYP2C8-mediated biotransformation. Although the interaction did not significantly enhance the effect of repaglinide on blood glucose concentration at the drug doses used, the possibility of an increased risk of hypoglycaemia should be considered during concomitant use of trimethoprim and repaglinide in patients with diabetes.