Angioedema associated with angiotensin II receptor antagonists: challenging our knowledge of angioedema and its etiology.

INTRODUCTION: Use of angiotensin converting enzyme inhibitors has long been associated with angioedema. Increased levels of bradykinin caused by the inhibition of angiotensin converting enzyme have been thought to be responsible for this side effect. Angiotensin II receptor antagonists (AT2 blockers), such as losartan potassium (Cozaar; Merck & Co., West Point, PA), are a new class of antihypertensives developed in part to eliminate cough and angioedema associated with ACE inhibitors. These agents act by selectively binding to angiotensin II receptor sites, thereby eliminating the hypertensive effects of angiotensin without affecting local and systemic bradykinin levels. We present three cases of AT2 receptor antagonist-induced angioedema, and examine its significance in the treatment of angioedema and its proposed etiology. METHODS: A retrospective chart review and review of the literature. RESULTS: Three patients taking the AT2 blocker losartan presented with mucosal swelling in the head and neck clinically consistent with angioedema. All three patients had prior episodes of angioedema while on losartan. Two patients presented with involvement of the anterior tongue and face that resolved within 12 hours of discontinuation of the losartan and a course of intravenous steroids. The third patient experienced recurring episodes of angioedema that eventually required a tracheotomy for airway compromise. After discontinuing the losartan and receiving a course of intravenous steroids, the angioedema resolved in 5 days. The patient was decannulated 10 days after onset of symptoms. CONCLUSION: Angioedema is a potentially life-threatening condition commonly associated with ACE inhibitor use. AT2 blockers bind to angiotensin II receptor sites and have no demonstrable effect on local or systemic bradykinin levels. We present three cases that demonstrate AT2 blocker-induced angioedema. They were all complicated by the fact that the inciting agent, losartan, was not discontinued after the initial episode and resulted in recurrent episodes of angioedema, one of which required surgical airway intervention. The incidence of AT2 blocker-induced angioedema brings into question prior theories on the etiology of angioedema and bradykinin's role in its pathogenesis.     

High-dose Cisplatin with amifostine: ototoxicity and pharmacokinetics

OBJECTIVES/HYPOTHESIS: Ototoxicity is a common side effect of high-dose cisplatin treatment. Thiol-containing chemoprotectors ameliorate cisplatin ototoxicity under experimental conditions. The trial was initiated to test the efficacy of amifostine protection in high-dose cisplatin treatment (125-150 mg/m) for metastatic malignant melanoma, to correlate the ototoxic outcome with cisplatin pharmacokinetics, and to evaluate the importance of using a selective analytical method for the quantification of cisplatin. STUDY DESIGN: Prospective study of 15 patients with stage IV malignant melanoma. METHODS: Clinical follow-up of therapeutic response, pure-tone audiometry, and analysis of cisplatin and its monohydrated complex in blood ultrafiltrate by liquid chromatography with postcolumn derivatization were performed. Ultrafiltered blood platinum was analyzed by inductively coupled plasma mass spectrometry. RESULTS: Ototoxicity and gastrointestinal toxicity were the most prominent side effects. Three patients ultimately required hearing aids. All patients had audiometric changes at one or more frequencies after the second treatment course, and all but one patient reported auditory symptoms. No correlation was found between hearing loss and blood cisplatin pharmacokinetics. Platinum levels determined by inductively coupled plasma mass spectrometry were higher than total platinum levels calculated from cisplatin and monohydrated complex concentrations obtained by liquid chromatography analysis. CONCLUSION: Ototoxicity was unacceptable despite amifostine treatment. Cisplatin pharmacokinetics during the first treatment course were not predictive of hearing loss. Amifostine caused a lowering of dose-normalized area under the concentration-time curve for cisplatin and monohydrated complex. Use of the unselective inductively coupled plasma mass spectrometry analysis leads to an overestimation of active drug. Selective analysis of cisplatin is especially important when evaluating cisplatin pharmacokinetics during chemoprotector treatment.     

Successful Treatment of Postpeak Stage Patients with Class Ⅱ Division 1 Malocclusion Using Non-extraction and Multiloop Edgewise Archwire Therapy： A Report on 16 Cases

Aim To determine cephalometrically the mechanism of the treatment effects of non-extraction and multiloop edgewise archwire （MEAW） technique on postpeak Class Ⅱ Division 1 patients.
Methodology In this retrospective study, 16 postpeak Class Ⅱ Division 1 patients successfully corrected using a non-extraction and MEAW technique were cephalometrically evaluated and compared with 16 matched control subjects treated using an extraction technique. Using CorelDRAW software, standardized digital cephalograms preand post-active treatments were traced and a reference grid was set up. The superimpositions were based on the cranial base, the mandibular and the maxilla regions,and skeletal and dental changes were measured. Changes following treatment were evaluated using the paired-sample t-test. Student＇s t-test for unpaired samples was used to assess the differences in changes between the MEAW and the extraction control groups.
Results The correction of the molar relationships comprised 54% skeletal change （mainly the advancement of the mandible） and 46% dental change. Correction of the anterior teeth relationships comprised 30% skeletal change and 70% dental change.
Conclusion The MEAW technique can produce the desired vertical and sagittal movement of the tooth segment and then effectively stimulate mandibular advancement by utilizing the residual growth potential of the condyle.     

Common mutation analysis of GJB2 and GJB6 genes in affected families with autosomal recessive non-syndromic hearing loss from Iran: simultaneous detection of two common mutations (35delG/del(GJB6-D13S1830)) in the DFNB1-related deafness

OBJECTIVE: DFNB1 locus has been reported as a major cause of autosomal recessive non-syndromic hearing loss (ARNSHL) worldwide. 35delG and del(GJB6-D13S1830) are thought to be two common mutations in this locus among Caucasians. The aim of this study is to determine the significance of these two mutations in aetiology of ARNSHL in Iran. METHODS: One hundred and thirty-three unrelated patients with ARNSHL were tested by using multiplex allele-specific PCR assay after validation by positive control samples. RESULTS: The frequency of 35delG was about 18.5%, however, del(GJB6-D13S1830) was not found in the studied patients. Parental consanguinity was observed in 50% of 35delG-mutated families. CONCLUSIONS: Our results support founder effect regarding these mutations.