Paul Mulder

Effect of CYP2C19*2 and *17 mutations on pharmacodynamics and kinetics of proton pump inhibitors in Caucasians

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECTnThe influence of CYP2C19 on the kinetics and dynamics of omeprazole, lansoprazole and rabeprazole has been studied in Japanese subjects. * It has been suggested that subjects with *1/*1 genotype might need stronger acid suppression than *1/*2 and *2/*2 subjects. This suggestion comes from data in Japanese subjects and has not been confirmed in Caucasians. * Furthermore, a novel CYP2C19 mutation, *17, which mainly occurs in Caucasians has been discovered. This mutation has been associated with clinical failure, but its relevance for therapy with PPIs has not been studied yet.nnnWHAT THIS STUDY ADDSnIn this study, the influence of CYP2C19 on both the pharmacokinetics and dynamics in Caucasian subjects after single and repeated dosing has been investigated. * This is the first study showing that Caucasian subjects with *1/*1 and *1/*17 mutations need stronger acid-inhibition. In this study three proton pump inhibitors (omeprazole, lansoprazole and pantoprazole, in different doses) were studied of which pantoprazole had not been studied before in this setting, not even in Japanese.nnnAIMSnTo investigate the impact of CYP2C19 mutations *2-*6 and *17 on acid-inhibition and pharmacokinetics of lansoprazole (L15), omeprazole (O10, O20) and pantoprazole (P40) in Caucasians.nnnMETHODSnCYP2C19 genotyping for *2-*6 and *17 mutations was assessed in subjects who were H. pylori negative in two randomized crossover trials. The influence of CYP2C19 mutations on single and repeated administration of L15 and O10 (study A) and O20 and P40 (study B) was investigated. Pharmacokinetics and the cumulative percentage of time with intragastric pH above 4 (% > pH 4) were assessed on day 1 and 6.nnnRESULTSnFor study A CYP2C19 genotyping found five *1/*1, four *1/*2, one *1/*17 and one *2/*17. For study B the results were six *1/*1, two *1/*2, six *1/*17, one *2/*2 and one *2/*17. For all PPIs AUC was highest in *2/*2 and lowest in *1/*17. On day 1, all PPIs significantly increased percentage >pH 4 compared with baseline. *1/*1 genotype showed no significant acid-inhibition after L15, O10 and O20. *1/*17 genotype showed no significant acid-inhibition after O20 and P40. *1/*2 genotype showed significant acid-inhibition after L15 and O10. On day 6, all four PPIs showed significantly increased acid-inhibition. *1/*1 and *1/*17 showed a significantly increased percentage > pH 4 after treatment with O20 and P40. However, in *1/*1 subjects percentage > pH 4 was not significantly increased after L15 and O10. *1/*2 genotype showed a significant acid-inhibitory effect after repeated dosing with L15 and O10.nnnCONCLUSIONSnCaucasian subjects with *1/*1 and *1/*17 genotype need stronger acid-suppression therapy, especially during the first days of treatment or with on-demand therapy.

The effect of nasal steroid aqueous spray on nasal complaint scores and cellular infiltrates in the nasal mucosa of patients with nonallergic, noninfectious perennial rhinitis ☆ ☆☆ ★

Topical corticosteroids are the therapy of choice for nonallergic, noninfectious perennial rhinitis (NANIPER). However, the efficacy of steroid therapy in NANIPER is controversial, as is its mode of action. To our surprise, of 300 patients initially diagnosed as having NANIPER, only 65 reached threshold nasal symptom scores. Patients were randomized into four different treatment regimens: placebo administered twice daily (BD) for 8 weeks, fluticasone propionate aqueous nasal spray (FPANS) (200 microg) once daily (OD) and placebo OD for 8 weeks, FPANS (200 microg) OD and placebo OD for 4 weeks followed by FPANS (200 microg) BD for 4 weeks, and FPANS (200 microg) BD for 8 weeks. A small decrease in nasal symptoms was found, which only reached significance for sneezing in the FPANS 200 microg BD group. A significant dose-dependent decrease in immunocompetent cells was found in nasal biopsy specimens obtained before, after 4 weeks, and after 8 weeks of treatment. We conclude that FPANS did not significantly reduce nasal symptoms in this group of selected NANIPER patients, even though a significant effect on cells in the nasal mucosa was seen.

Intravitreal dexamethasone as adjuvant in the treatment of postoperative endophthalmitis: a prospective randomized trial.

PurposeTo study whether intravitreal dexamethasone as adjuvant to intravitreal antibiotics improves the outcome in patients with suspected postoperative bacterial endophthalmitis.DesignProspective randomized clinical trial.SettingTertiary referral center.Patient populationTwenty-nine consecutive patients with suspected postoperative bacterial endophthalmitis within 6 weeks of cataract surgery.InterventionPatients underwent a vitreous biopsy followed by intravitreal injection of antibiotics (0.2xa0mg vancomycin and 0.05xa0mg gentamicin) and 400xa0μg dexamethasone or placebo. After 3–4 days the intravitreal injection of antibiotics and dexamethasone or placebo was repeatedPrimary outcome measureSnellen visual acuity at 3 and 12 months after treatment.ResultsIn 20/29 patients (69%) the vitreous cultures were positive. 13/29 patients received dexamethasone. Seven patients had a functionally lost eye (final vision of hand movements or less), in four due to retinal detachment. Visual acuity tended to be better in the dexamethasone treated patients than in those given placebo, at both 3 months (P=0.055) and 12 months (P=0.080).ConclusionThis small prospective, placebo-controlled series showed a trend towards a better visual outcome in patients with suspected bacterial endophthalmitis when treatment with intravitreal antibiotics was combined with intravitreal dexamethasone. Our findings justify a larger multicenter randomized study.

A comparison of the acid-inhibitory effects of esomeprazole and rabeprazole in relation to pharmacokinetics and CYP2C19 polymorphism

Esomeprazole and rabeprazole are metabolised in the liver by means of the CYP2C19 enzyme, which has several functional genetic polymorphisms. Among Caucasians, 70% of the population has a fast metaboliser phenotype, 25–30% an intermediate and 2–5% a slow metaboliser phenotype. It is unknown whether different PPIs are affected to the same extent by these phenotypic differences.

Long‐term outcome of bipolar depressed patients receiving lamotrigine as add‐on to lithium with the possibility of the addition of paroxetine in nonresponders: a randomized, placebo‐controlled trial with a novel design

OBJECTIVEnIn two previous manuscripts, we described the efficacy of lamotrigine versus placebo as add-on to lithium (followed by the addition of paroxetine in nonresponders) in the short-term treatment of bipolar depression. In this paper we describe the long-term (68 weeks) outcome of that study.nnnMETHODSnA total of 124 bipolar depressed patients receiving lithium were randomized to addition of lamotrigine or placebo. After eight weeks, paroxetine was added to nonresponders for another eight weeks. Responders continued medication and were followed for up to 68 weeks or until a relapse or recurrence of a depressive or manic episode.nnnRESULTSnAfter eight weeks, the addition of lamotrigine to lithium was significantly more efficacious than addition of placebo, while after addition of paroxetine in nonresponders both groups further improved with no significant difference between groups at week 16. During follow-up the efficacy of lamotrigine was maintained: time to relapse or recurrence was longer for the lamotrigine group [median time 10.0 months (confidence interval: 1.1-18.8)] versus the placebo group [3.5 months (confidence interval: 0.7-7.0)].nnnCONCLUSIONnIn patients with bipolar depression, despite continued use of lithium, addition of lamotrigine revealed a continued benefit compared to placebo throughout the entire study.

Efficacy and safety of two treatment algorithms in bipolar depression consisting of a combination of lithium, lamotrigine or placebo and paroxetine

van der Loos MLM, Mulder P, Hartong EGThM, Blom MBJ, Vergouwen AC, van Noorden MS, Timmermans MA, Vieta E, Nolen WA, for the LamLit Study Group. Efficacy and safety of two treatment algorithms in bipolar depression consisting of a combination of lithium, lamotrigine or placebo and paroxetine.

Computer-generated versus nurse-determined strategy for incubator humidity and time to regain birthweight

OBJECTIVEnTo compare effects on premature infants weight gain of a computer-generated and a nurse-determined incubator humidity strategy. An optimal humidity protocol is thought to reduce time to regain birthweight.nnnDESIGNnProspective randomized controlled design.nnnSETTINGnLevel IIIC neonatal intensive care unit in the Netherlands.nnnPARTICIPANTSnInfants of 24 to 30 weeks gestational age with a birthweight less than 1,500 g.nnnINTERVENTIONnTwo incubator humidity strategies were studied: computer-generated and nurse-determined humidity.nnnMAIN OUTCOME MEASUREnTime needed to regain birthweight.nnnRESULTSnOne hundred thirty six infants were enrolled: 65 were exposed to the computer-generated strategy and 71 to the nurse-determined strategy. Demographic characteristics were well balanced between groups, with birthweight 981 +/- 245 versus 991 +/- 213 g, mean gestational age 27.7 +/- 1.7 versus 27.7 +/- 1.6 weeks. Main outcome did not significantly differ between strategies: survival analysis showed an equal number of days needed to regain birthweight (median 9 days, with 95% CIs 8-10 and 7-11 for infants exposed to the computer-generated and nurse-determined humidity strategy, respectively).nnnCONCLUSIONnComputer-generated strategy does not reduce the time needed to regain birthweight.

Body proportions before and during growth hormone therapy in children with chronic renal failure

Growth retardation is a common problem in children with chronic renal failure (CRF). Few published data are available on whether the normalization of height in these children during growth hormone (GH) treatment is accompanied by proportional growth of the other parts of the body. In this study, body proportions before and during GH therapy were assessed in children with severe growth retardation due to CRF. Various body segments, such as sitting height, arm span, tibia, hand and foot length, biacromial and biiliacal diameter were measured in 15 children participating in a double-blind placebo-controlled cross-over trial and in 22 children participating in a double-blind dose-response trial. Twelve children continued GH therapy after having participated in one of the two former trials and received GH therapy for 4xa0years. All results were adjusted for age and sex, and expressed as SD scores using reference values for healthy Dutch children. To assess body proportions, the various body segments were related to height and expressed as shape values (SV). At baseline all body segments SD scores were significantly lower than zero, indicating that the stunted growth of children with CRF included all body segments. Since height was not significantly more or less affected than the other body segments, all children had normal SV, indicating normal body proportions. The placebo-controlled study showed a significant increase of the SD scores of height and several body segments during 6xa0months of GH [28xa0IU/m2 per week (or 1.3xa0mg/m2 per day)] versus placebo. The dose-response study demonstrated that height SDS as well as all other body segments SD scores increased significantly during 2xa0years of GH therapy with 28xa0IU/m2 per week, compared with treatment with 14xa0IU/m2 per week. Also during 4xa0years of GH therapy with 28xa0IU/m2 per week, body segment SD scores increased to the same extent as height SDS, showing that GH did not significantly change SV i.e., body proportions. Both before and during GH therapy, children on dialysis had normal body proportions, comparable with children on conservative renal treatment. In conclusion, children with severe growth retardation due to CRF maintain normal body proportions in spite of their chronic disease. GH therapy with 28xa0IU/m2 per week induces and maintains catch-up growth of height and all body segments without signs of disproportionate growth. Thus GH therapy does not negatively influence body proportions in children with severe growth retardation secondary to CRF.

A double-blind randomized study comparing plasma level-targeted dose imipramine and high-dose venlafaxine in depressed inpatients

OBJECTIVEnTo compare the efficacy of plasma level-targeted dose imipramine and high-dose venlafaxine in depressed inpatients in a randomized double-blind study.nnnMETHODSnThe study included 85 patients with a diagnosis of major depressive episode according to the DSM IV criteria and a 17-item Hamilton Rating Scale for Depression (HAM-D) score ≥ 17. Patients were randomized to imipramine or venlafaxine. The dose of imipramine was adjusted for each patient to a predefined blood level of 200-300 ng/ml. The dose of venlafaxine was increased gradually to 300-375 mg/day. Efficacy was evaluated after 7 weeks of treatment.nnnRESULTSnThe mean age of the study group was 54.5 (range 29-82) years. There was no significant difference according to the primary outcome criterion of a ≥50% reduction on the HAM-D score: 17 of 43 (39.5%) patients on imipramine were responders compared to 21 of 42 (50%) patients on venlafaxine. When considering remission as outcome criterion (HAM-D score ≤ 7), 10 of 43 (23.3%) patients on imipramine were remitters compared to 15 of 42 (35.7%) patients on venlafaxine; again, no significant difference. When analysing a subpopulation of patients without psychotic features, with remission as outcome criterion, a significant difference was found: 5 of 34 (14.7%) patients on imipramine were remitters compared to 12 of 31 (38.7%) patients on venlafaxine.nnnCONCLUSIONSnThe present study used optimal doses in depressed inpatients and showed that venlafaxine is at least equal in efficacy to imipramine. The results in the subgroup without psychotic features indicate a possible superiority of venlafaxine.

Quality of Life in Perspective to Treatment of Postoperative Edema After Peripheral Bypass Surgery

BACKGROUNDnTo examine the effects of peripheral bypass surgery on patients quality of life (QoL) as well as to compare two treatment modalities to reduce postoperative edema with regard to patients QoL.nnnMETHODSnThis was a randomized controlled trial set in the department of vascular surgery in a nonacademic teaching hospital. Ninety-three patients (mean age, 70 years; 33% Rutherford 5-6), enrolled between August 2006 and September 2009, who underwent peripheral bypass surgery (autologous 57, polytetrafluoroethylene 36). Patients were assigned to intermittent pneumatic compression (n = 46) or to compression stockings (n = 47). The main outcome measure was QoL, measured with the World Health Organization Quality of Life assessment instrument (short form: WHOQOL-BREF).nnnRESULTSnQoL improved on the domain of Physical Health by 7.18 points (P < 0.001 [range, 0-100]) after 2 weeks and by 10.03 points (P < 0.001) after 3 months. Patients who received a polytetrafluoroethylene bypass scored 0.45 points (P = 0.0008 [range, 1-5]) lower at baseline on Global QoL than patients who received an autologous bypass. Type of bypass or edema treatment method did not affect the improvements. Edema did not correlate with QoL.nnnCONCLUSIONnImprovement in QoL on the domain Physical Health following femoropopliteal bypass surgery was found as soon as 2 weeks after surgery. Improvement in QoL domains was not influenced by the type of bypass reconstruction. No specific effects of edema on QoL were detected.