Robust anti-arrhythmic efficacy of verapamil and flunarizine against dofetilide-induced TdP arrhythmias is based upon a shared and a different mode of action

BACKGROUND AND PURPOSE

The high predisposition to Torsade de Pointes (TdP) in dogs with chronic AV-block (CAVB) is well documented. The anti-arrhythmic efficacy and mode of action of Ca²⁺ channel antagonists, flunarizine and verapamil against TdP were investigated.

EXPERIMENTAL APPROACH

Mongrel dogs with CAVB were selected based on the inducibility of TdP with dofetilide. The effects of flunarizine and verapamil were assessed after TdP and in different experiments to prevent dofetilide-induced TdP. Electrocardiogram and ventricular monophasic action potentials were recorded. Electrophysiological parameters and short-term variability of repolarization (STV) were determined. In vitro, flunarizine and verapamil were added to determine their effect on (i) dofetilide-induced early after depolarizations (EADs) in canine ventricular myocytes (VM); (ii) diastolic Ca²⁺ sparks in RyR2^R4496+/+ mouse myocytes; and (iii) peak and late I_Na in SCN5A-HEK 293 cells.

KEY RESULTS

Dofetilide increased STV prior to TdP and in VM prior to EADs. Both flunarizine and verapamil completely suppressed TdP and reversed STV to baseline values. Complete prevention of TdP was achieved with both drugs, accompanied by the prevention of an increase in STV. Suppression of EADs was confirmed after flunarizine. Only flunarizine blocked late I_Na. Ca²⁺ sparks were reduced with verapamil.

CONCLUSIONS AND IMPLICATIONS

Robust anti-arrhythmic efficacy was seen with both Ca²⁺ channel antagonists. Their divergent electrophysiological actions may be related to different additional effects of the two drugs.     

Surviving the 'heartsink' experience

The authors describe a pilot workshop designed to help doctorsachieve a greater understanding of and ability to cope withtheir ‘heartsink’ patients. Participants were askedto list their personal objectives in attending and a numberof cases were discussed in the group. A ‘heartsink survivalkit’ was provided which consisted of skills and strategieswhich are useful in difficult consultations and an approachto reassessing the goals of the relationship which might promotea more realistic understanding. The workshop was videotapedand two scenarios are presented. The implications for furthertraining are discussed.     

Primitive neuroectodermal tumours of the cerebrum

Summary Eighteen cases of cerebral tumour composed partly or totally of primitive embryonal cells are reported. These lesions comprise 2.8% of all primary cerebral hemisphere tumours in the histopathology files of The Royal Marsden Hospital between 1971 and 1980 inclusive. Most exhibited some degree of differentiation towards neuronal or glial elements and, as more than one type of differentiation was often present in the same lesion, we agree with others that the term primitive neuroectodermal tumour (PNET) is more appropriate to describe these lesions than terms based on histogenesis. The extent of the primitive component varied, but usually accounted for more than 80% of the tumour. Although the tumours bear some similarities to posterior fossa medulloblastomas, they exhibit important differences in histology, immunohistology, natural history and response to treatment. Nearly all PNETs examined expressed some glial fibrillary acidic (GFAP) both in primitive areas and zones of astrocytic differentiation. GFAP staining may thus be of value in distinguishing PNETs from undifferentiated non-neurogenic tumours. Of 14 patients referred for radiotherapy, the survival rate at 3 years was 29% (\414) and 5 years 25% (\312). Patients with tumours in which at least 90% of the tissue was undifferentiated exhibited an extremely poor prognosis with none of 9 patients still alive at 3 years in contrast to 3 of 5 patients (60%) with tumours showing less than 90% undifferentiation. Radical tumour removal, where feasible, followed by irradiation of the whole cerebrospinal axis is recommended. Adjuvant chemotherapy with such agents as CCNU and Vincristine may be of value: the 3 long term survivors in the present series (7–11 years), including one who presented disseminated intracranial disease, received such adjuvant treatment.     

Reference values for radial bone width and mineral content using single photon absorptiometry in healthy children aged 4 to 10 years

Bone width and mineral content were measured in 420 healthy Cambridge children aged 4 to 10 years using single photon absorptiometry. The results are expressed first in the form of standard centile charts, with additional prediction charts which provide body-size-adjusted estimates for the measurements, and interpretation centiles for comparing these estimates with the actual measurements. The values obtained are similar to those reported for American children aged five to six years after adjusting for body-size differences. We suggest that appropriate application of these prediction charts will facilitate the use of single photon absorptiometry in monitoring and treating children who have disorders of bone growth and mineralization.     

Resurgence of Acanthamoeba keratitis in Auckland,New Zealand: a 7‐year review of presentation and outcomes

Purpose: To investigate the presentation, clinical characteristics and outcomes of Acanthamoeba keratitis (AK) in Auckland, New Zealand over a 7‐year period. Methods: Retrospective analysis of all cases of AK treated by the tertiary corneal service at Auckland City Hospital/ University of Auckland Department of Ophthalmology (August 2001 to May 2008). Data were collected regarding age, gender, contact lens history, presenting signs and symptoms, diagnosis at first presentation, time to final diagnosis, identifiable risk factors, presenting and final visual acuity, results of microbiological testing, medical treatment, surgical interventions, recurrence of disease and length of follow up. All photographs and in vivo confocal microscopy images were reviewed. Results: Twenty‐five eyes of 25 patients were identified with a diagnosis of AK (mean age 40 ± 13 years). Ninety‐six per cent were contact lens wearers. Mean time to diagnosis was 41 ± 49 days (range 0–181 days, median 21 days). Fourteen patients (56%) had been treated with topical corticosteroids prior to the diagnosis. Early diagnosis of AK (<21 days) was associated with significantly better final visual acuity and did not require any surgical intervention compared with those diagnosed at a later stage. Six patients, all in the late diagnosis group, required surgical intervention. Conclusions: AK has become significantly more common in New Zealand in the current decade. This study highlights the fundamental importance of early diagnosis and appropriate management in ensuring favourable outcomes. Practitioners should maintain a clinical suspicion of AK, especially as 96% of the subjects in this study were contact lens wearers.     

Atrial septal defects: Magnetic resonance and computed tomography appearances

Atrial septal defects are associated with significant morbidity and mortality. Echocardiography is the first‐line imaging modality, but MR and CT imaging can provide complimentary information, especially for the detection of associated anomalies and for assessing changes in the pulmonary vasculature. The aim of this pictorial essay is to review the spectrum of atrial septal defects, with particular reference to their cross‐sectional imaging appearances and issues pertaining to management.     

Introductory comment

Objectives Injectable poly‐l ‐lactic acid (PLLA; Sculptra^®) is widely used throughout Europe and the USA to restore volume in depressed areas of the face by stimulating neocollagenesis. Injectable PLLA was previously marketed as New‐Fill™, which was often injected incorrectly and at too high a concentration, resulting in some physicians losing confidence in this product. Today, Sculptra^® is still regarded with a degree of scepticism by some physicians, due to direct or indirect experience with New‐Fill. Sculptra^®, both in formulation and use, is vastly superior to New‐Fill and clinical experience with this product dispels the myths associated with the earlier types of injectable PLLA. Results PLLA is a very safe, biodegradable compound that has been used in a wide range of medical devices for the last 30 years. In injectable form a good safety profile has been proven; however, when the device is overconcentrated, localized overstimulation of the fibroblasts can result in the formation of small lumps (subcutaneous papules), which are non‐pathological but nevertheless palpable by the patient. Physicians must also be trained in the injection of this device, as incorrect injection technique can cause device‐related adverse events. Conclusion New product guidelines have ensured that problems with PLLA concentration have been countered, and tried and tested injection techniques have been shown to ameliorate device‐related adverse events, both of which are dispelling the myths associated with modern injectable PLLA.