The relevance of CYP2D6 genetic polymorphism on chronic metoprolol therapy in cardiovascular patients

BACKGROUND AND OBJECTIVE: CYP2D6 polymorphisms are well described in normal populations but there are few data on its clinical significance. We therefore investigated the influence of CYP2D6 polymorphism on steady-state plasma concentrations and apparent oral clearance of metoprolol in patients with cardiovascular diseases. METHODS: Ninety-one patients on metoprolol were recruited. Plasma concentrations of metoprolol and alpha-hydroxy metoprolol were measured at 4-h post-dose. CYP2D6 genotyping (*1, *3, *4, *5, *9, *8, *10, *17 and duplication) were performed on the DNA extracted. Ratio of plasma concentrations of metoprolol and alpha-hydroxy metoprolol and the apparent oral clearance of metoprolol were calculated. The influences of CYP2D6 genotypes were investigated. RESULTS: A 100-fold variation was noted for both plasma concentrations of metoprolol and alpha-hydroxy metoprolol. There was a weak correlation between the total daily doses and plasma concentrations of both. Plasma concentrations were found to be higher in patients with genotypes that predicted lower enzyme activity. One patient homozygous for CYP2D6*4 had the highest metoprolol concentration per unit dose. With an antimode of 10. Two patients were identified as poor metabolizers (PMs) (2.1%; 95% CI: 2.9). The PMs who had a plasma metabolic ratio (pMR) of 37.8 was homozygous CYP2D6*4 whereas the other with pMR 14.5 was genotyped CYP2D6 *4/*10. There was a 36-fold difference between the highest and lowest clearance values. Large overlaps in the clearance values were noted between most of the genotypes. CONCLUSIONS: Our data suggest that pharmacogenetic measures could be used to design a more individualized metoprolol dosage regimen for patients.     

A report of a national mutation testing service for the MEN1 gene: clinical presentations and implications for mutation testing

Introduction: Mutation testing for the MEN1 gene is a useful method to diagnose and predict individuals who either have or will develop multiple endocrine neoplasia type 1 (MEN 1). Clinical selection criteria to identify patients who should be tested are needed, as mutation analysis is costly and time consuming. This study is a report of an Australian national mutation testing service for the MEN1 gene from referred patients with classical MEN 1 and various MEN 1-like conditions. Results: All 55 MEN1 mutation positive patients had a family history of hyperparathyroidism, had hyperparathyroidism with one other MEN1 related tumour, or had hyperparathyroidism with multiglandular hyperplasia at a young age. We found 42 separate mutations and six recurring mutations from unrelated families, and evidence for a founder effect in five families with the same mutation. Discussion: Our results indicate that mutations in genes other than MEN1 may cause familial isolated hyperparathyroidism and familial isolated pituitary tumours. Conclusions: We therefore suggest that routine germline MEN1 mutation testing of all cases of "classical" MEN1, familial hyperparathyroidism, and sporadic hyperparathyroidism with one other MEN1 related condition is justified by national testing services. We do not recommend routine sequencing of the promoter region between nucleotides 1234 and 1758 (Genbank accession no. {"type":"entrez-nucleotide","attrs":{"text":"U93237","term_id":"1945388","term_text":"U93237"}}U93237) as we could not detect any sequence variations within this region in any familial or sporadic cases of MEN1 related conditions lacking a MEN1 mutation. We also suggest that testing be considered for patients <30 years old with sporadic hyperparathyroidism and multigland hyperplasia.     

Doxycycline vs. macrolides in combination therapy for treatment of community-acquired pneumonia

We assessed the comparative efficacy of empirical therapy with beta-lactam plus macrolide vs. beta-lactam plus doxycycline for the treatment of community-acquired pneumonia (CAP) among patients in the Australian Community-Acquired Pneumonia Study. Both regimens demonstrated similar outcomes against CAP due to either 'atypical' (Chlamydophila, Legionella or Mycoplasma spp.) or typical bacterial pathogens.     

Modified positioning of a smartphone based single-lead electrocardiogram device improves detection of atrial flutter

Introduction

The AliveCor Kardia Mobile (AKM) is a handheld, smartphone based cardiac rhythm monitor that records a lead-I electrocardiogram (ECG). Despite being efficacious for detection of atrial fibrillation (AF), it is unclear whether atrial flutter (AFL) may be misdiagnosed as sinus rhythm due to regular R-R intervals. We hypothesised that generating lead-II tracings through repositioning of the AKM may improve visualisation of flutter waves and clinician diagnosis of AFL compared to traditional lead-I tracings.

Systemic lupus erythematosus pregnancies: the Sarawak experience and review of lupus pregnancies in Asia

We performed a cross-sessional study of all systemic lupus erythematosus (SLE) pregnancies during a 4-year period (2006–2009) to describe the clinical features, maternal and foetal outcomes in our centre. There were 48 pregnancies in 44 women with SLE. Our patients have a mean age of 30.0 years (SD 6.36) and a mean disease duration of 40.67 months (SD 48.23). Our patients have complicated pregnancies: 32.7% have SLE flares, 17.3% have preeclampsia and 48.9% needed caesarean sections. There were 20.0% foetal losses and 17.8% preterm deliveries in our patients. SLE flares contributed to 60.0% of foetal losses in our patients. Lupus pregnancies in our centre generally have a good maternal and foetal outcome comparable to developed countries in Asia. The low incidence of APS, the high usage of hydroxychloroquine and the high SLE remission rate in our patients prior to conceptions contributed to the good outcome.