Determination of sertaconazole nitrate, a new imidazole antifungal, by high-performance liquid chromatography.

A high-performance liquid chromatographic method is developed for the determination of bulk sertaconazole nitrate and related compounds (potential impurities and degradation products) as well as a sertaconazole nitrate cream formulation. A 10-microns Spherisorb CN column is used along with a mobile phase consisting of acetonitrile and aqueous 0.01 M sodium phosphate (37:63, v/v). The sertaconazole nitrate peak is monitored at a wavelength of 260 nm; the retention time being 19.3 min. The detector response for sertaconazole nitrate is linear over the concentration range from 64 to 96 micrograms ml-1. The method is found to be sufficiently selective for the reliable determination of related compounds, FI-7001, FI-7009 and FI-7011, as indicated by same-day and between-day relative standard deviations (RSD) for replicate assays of 1.72% (n = 9) and 2.17% (n = 24), respectively. The application of this method to a cream formulation of sertaconazole nitrate is found to give a mean percentage recovery of 99.4% with RSD of 1.14% (n = 9); none of the cream vehicle peaks are found to interfere with the determination of sertaconazole nitrate.     

Intraoperative radiotherapy in the multidisciplinary treatment of bone sarcomas in children and adolescents

From September 1984 to December 1989, 38 patients of pediatric age with localized bone sarcomas received intraoperative radiotherapy (IORT) as part of a multidisci plinary treatment program. The age ranged from 6 to 21 years. The tumor histologies were 22 osteosarcomas and 16 Ewing's sarcomas. Thirty-four had initial primary disease (90%) and 4 were treated for local recurrence (10%). IORT was used on 32 untreated patients and in 6 previously treated with external beam radiotherapy (EBR). The IORT field included the surgically exposed tumor bed area. Single radiation doses ranging from 10 to 20 Gy were delivered, using 6–20 MeV electron beams. The median follow-up time for the entire group is 25 months (2–65+ months). The projected 5-year disease-free and overall survival rates are 65% and 69%, respectively. One patient developed a local recurrence in each histological group: one chondroblastic osteosarcoma and one cervical Ewing's sarcoma. Six patients died from metastatic progression: 3 initially recurrent tumors and three primary disease cases. Severe neuropathy and soft tissue necrosis were seen in some patients as IORT related complications. IORT is a feasible technique to be integrated in multidisciplinary programs that may promote local control in pediatric and adolescent patients with bone sarcomas. Peripheral nerves are dose-limiting tissue structures for IORT.     

Diagnostic utility of S100A1 expression in renal cell neoplasms: an immunohistochemical and quantitative RT-PCR study.

S100A1 is a calcium-binding protein, which has been recently found in renal cell neoplasms. We evaluated the diagnostic utility of immunohistochemical detection of S100A1 in 164 renal cell neoplasms. Forty-one clear cell, 32 papillary, and 51 chromophobe renal cell carcinomas, and 40 oncocytomas, 164 samples of normal renal parenchyma adjacent to the tumors and 13 fetal kidneys were analyzed. The levels of S100A1 mRNA detected by quantitative RT-PCR analysis of frozen tissues from seven clear cell, five papillary, and six chromophobe renal cell carcinomas, four oncocytomas, and nine samples of normal renal tissues adjacent to neoplasms were compared with the immunohistochemical detection of protein expression. Clear cell and papillary renal cell carcinomas showed positive reactions for S100A1 in 30 out of 41 tumors (73%) and in 30 out of 32 (94%) tumors, respectively. Thirty-seven renal oncocytomas out of 40 (93%) were positive for S100A1, whereas 48 of 51 (94%) chromophobe renal cell carcinomas were negative. S100A1 protein was detected in all samples of unaffected and fetal kidneys. S100A1 mRNA was detected by RT-PCR in all normal kidneys and renal cell neoplasms, although at very different levels. Statistical analyses comparing the different expression of S100A1 in clear cell and chromophobe renal cell carcinomas observed by immunohistochemical and RT-PCR methods showed significant values (P<0.001), such as when comparing by both techniques the different levels of S100A1 expression in chromophobe renal cell carcinomas and oncocytomas (P<0.001). Our study shows that S100A1 protein is expressed in oncocytomas, clear cell and papillary renal cell carcinomas but not in chromophobe renal cell carcinomas. Its immunodetection is potentially useful for the differential diagnosis between chromophobe renal cell carcinoma and oncocytoma. Further, S100A1 protein expression is constantly detected in the normal parenchyma of the adult and fetal kidney.     

An evaluation of the cardiovascular safety profile of duloxetine: findings from 42 placebo-controlled studies.

BACKGROUND AND OBJECTIVE: In recent years, new classes of medication, such as the serotonin-noradrenaline reuptake inhibitors (SNRIs), have been developed for use in the treatment of major depressive disorder (MDD). For many years, treatment options were largely limited to the use of monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs). However, there have been published reports of orthostatic hypotension, arrhythmias and corrected QT (QTc) interval changes in patients treated with TCAs. As new medications become available, it is important to understand how their cardiovascular safety profile compares with that of more established agents to aid clinicians and patients in choosing the best treatment options. This study was designed to evaluate the cardiovascular safety profile of the SNRI duloxetine through evaluation of cardiovascular-related parameters and adverse events (AEs). METHODS: The cardiovascular safety of duloxetine was assessed using all placebo-controlled duloxetine clinical trial data as of December 2005. This consisted of data from 42 placebo-controlled clinical trials of 8504 patients who were treated with duloxetine. Additional information from a high-dose clinical pharmacology study and postmarketing safety surveillance are also presented. Of the placebo-controlled trials included in this analysis, clinical indications under investigation included MDD (15 studies), diabetic peripheral neuropathic pain (3 studies), fibromyalgia (2 studies), generalised anxiety disorder (3 studies) and lower urinary tract disorders (19 studies, all related to incontinence). Cardiovascular safety was evaluated based on vital signs, ECGs and the incidence of treatment-emergent AEs potentially related to cardiovascular safety. These safety parameters were analysed across all indications. To identify both serious and non-serious cardiovascular-related AEs, as well as AEs reported as the reason for discontinuation, a comprehensive list of terms derived from the Medical Dictionary for Regulatory Activities (version 8.0) was generated and used to search the duloxetine databases for cardiovascular-related events. RESULTS: Calculation of change from baseline to maximum in ECG parameters showed significant differences between treatment groups for all parameters, with decreases from baseline in RR, QRS and QT intervals for patients receiving duloxetine and increases from baseline for patients treated with placebo. These shifts were related to small heart rate changes, but the mean differences were not considered clinically relevant. Categorical analyses of shifts from normal to abnormal (or abnormal to normal) for heart rate and QT corrected for heart rate using Fridericia's formula (QTcF) values showed that most patients did not shift from their baseline category. Patients with MDD who were treated for up to 1 year with duloxetine had blood pressure changes early in treatment that then stabilised. Even in patients with elevated blood pressure at baseline in these clinical trials, no increased risk of sustained blood pressure elevation with duloxetine treatment was found. CONCLUSION: Overall, the findings presented here support our conclusions that use of duloxetine does not appear to be associated with significant cardiovascular risks in patients with conditions for which the drug has been approved or studied.     

Two-dimensional echocardiography in the diagnosis of intracardiac masses: A prospective study with anatomic validation

The accuracy of two-dimensional echocardiography in the detection of intracardiac masses was verified in 334 patients who underwent cardiac catheterization in our laboratory over 21 consecutive months. A complete two-dimensional echocardiographic (2DE) examination was performed a day before catheterization. The presence or absence of a mass was verified at surgery in 77 patients who successively underwent mitral or aortic valve replacement (51), left ventricular aneurysmectomy with or without myocardial revascularization (25), and resection of atrial myxoma (2). In 32 patients 2DE revealed the presence of a mass-left or right atrial thrombi in 12, left atrial myxoma in 2, left ventricular thrombi in 16, and endocardial vegetations in 2. The other 45 patients were free of intracardiac masses on 2DE. Anatomic verification at surgery revealed the presence of an intracardiac mass in 34 patients. In 30 (true positives) of these, 2DE revealed the mass as well, and in 4 (false negatives) the presence of a mass had not been identified by 2DE. In 2 patients (false positives) the predicted mass was not found at surgery. Absence of a mass was correctly predicted by 2DE in 41 patients (true negatives). Thus 2DE detected intracardiac masses with sensitivity of 88.2% and a specificity of 95.3%. We recommend that 2DE be performed in all patients prior to hemodynamic study and/or cardiac surgery to enable safer management of patients with intracardiac masses during cardiac catheterization and/or cardiac surgery.     

Detection of moderate and severe coronary artery stenosis with technetium-99m tetrofosmin myocardial single-photon emission tomography

The aim of this study was to determine the diagnostic accuracy of technetium-99m tetrofosmin myocardial imaging for the localization of coronary artery stenoses of different degrees of severity. Stress-rest single-photon emission tomography (SPET) was performed on separate days in 80 patients (64 males, 16 females; mean age 61 years; 43 patients with previous myocardial infarction; 18 patients with pharmacological stress), within 6 months of coronary angiography. Scintigraphic images were blindly and independently evaluated by three observers. Coronary stenosis was defined as a >50% narrowing in luminal diameter; severe stenosis was defined as a proximal stenosis of >75% or a peripheral stenosis of >90%. Coronary angiography revealed normal coronary arteries or insignificant coronary stenosis in 13 patients and significant coronary stenoses in 67 patients. The sensitivity and specificity of ^99mTc-tetrofosmin SPET in respect of severely stenosed vessels were, respectively, 80% and 65% for the left anterior descending artery (LAD), 100% and 46% for the right coronary artery (RCA) and 58 and 78% for the left circumflex artery (LCx) territories. Considering all the significantly stenosed vessels, a significant decrease in sensitivity was observed for LAD territories (to 59%, P=0.05), and a nonsignificant decrease for RCA (88%) and LCx (47%) territories while specificity values remained essentially unchanged. No significant changes in sensitivity or specificity were observed when regions with previous myocardial infarction were excluded. In conclusion, the sensitivity of ^99mTc-tetrofosmin SPET for the localization of individual stenosed vessels is only moderate when all significant stenoses are considered, but the ability of this technique to predict the location of severe coronary artery stenoses seems satisfactory, with the exception of the low specificity in respect of RCA territories. Received 26 April and in revised form 7 June 1997     

Prospective study of phobic anxiety and risk of Parkinson's disease.

Anxiety disorders are common in Parkinson's disease (PD). However, the risk of PD among people with anxiety has not been examined in a prospective cohort study. We examined this relation prospectively within the Health Professionals Follow-Up Study, a cohort of US male health professionals. In 1988, anxiety was assessed using the Crown-Crisp phobic anxiety index in 35,815 men without PD, stroke, or cancer at baseline. There were 189 incident cases of PD during 12 years of follow-up. After adjusting for age, smoking, and caffeine intake, the relative risk of PD among men with the highest level of anxiety (Crown-Crisp index scores of 4 and above) was 1.5 (95% CI = 1.0-2.1; P-trend = 0.01) compared to men with the lowest level of anxiety. This positive association persisted after excluding cases of PD with onset in the first 2 years of follow-up. Use of anxiolytic medication was also associated with an elevated risk of PD (RR= 1.6; 95% CI = 0.9-3.1), but adjusting for this potential confounder did not materially affect the association between anxiety and risk of PD. Our results suggest that anxiety is a risk factor for PD. Whether this association is causal or the result of shared underlying biology remains a question.     

Revisiting the prognostic role of gallium scintigraphy in low-grade Non-Hodgkin’s lymphoma

The purpose of this study was threefold: to evaluate the role of gallium-67 scintigraphy in the staging of low-grade non-Hodgkin’s lymphomas (LGNHL), to assess the relationship between the expression of CD71 on the surface of the neoplastic cells and the ⁶⁷Ga uptake by the tumour, and to establish the contribution of ⁶⁷Ga scan in defining the prognosis of LGNHL. Forty-eight patients with untreated LGNHL diagnosed in a single institution over a decade were reviewed. The end point of the study was survival of the patients according to the scintigraphic ⁶⁷Ga score at diagnosis. In addition to ⁶⁷Ga scan, other prognostic variables were studied, relating to the neoplastic burden, the biology of the tumour and the host. Univariate and multivariate analyses were used. ⁶⁷Ga scan identified only 116/286 (41%) nodes involved by lymphoma that were detected by clinical examination or computed tomography scan. A scintigraphic scoring system with an arbitrary cut-off value of 3 (high scan score) was able to predict patients with a dismal prognosis: with a mean follow-up of 47 months (range: 1–146 months) the median survival time was 28 months in patients with a high scan score and 74 months in patients with a low scan score (P=0.002). CD71 values were 27.4%±14.9% (mean ±SD) in the former and 8.9%±7.2% in the latter (P=0.0001). Only performance status and extranodal sites were significant variables for prognosis in multivariate analysis. It is concluded that ⁶⁷Ga scan is inaccurate in staging but might be very important in defining the prognosis in LGNHL, in association with other prognostic variables. Received 1 May and in revised form 6 August 1997