Syntheses of Novel Pyridazinomorphinans by Inverse Electron Demand Cycloaddition and their Binding to μ and κ Receptors

A number of novel pyridazinomorphinans have been synthesized by the inverse electron demand Diels-Alder reaction of various 3,6-disubstituted 1,2,4,5-tetrazines with enamines derived from dihydrocodeinone and with codeinone. Reduction of some of the pyridazinomorphinans did not furnish the expected pyrroloepoxymorphinans; in all cases investigated reductive cleavage of the epoxybridge was observed to yield dihydropyridazino- or pyrrolomorphinans. The structures of all new compounds were assigned by the spectral data, that of the cycloadduct of codeinone was additionally verified by X-ray crystallography. Compounds 5a, 8, 11a , and 16 have been evaluated for their affinity at μ and κ opioid receptors in radioligand binding assays. Their ability to inhibit [³H]DAMGO binding at μ and [³H]U 69.593 binding at κ receptors, respectively as compared to codeine has been found to be lower.     

Intravitreal bevacizumab in aggressive posterior retinopathy of prematurity.

The anatomic response to intravitreal bevacizumab injection in three patients with aggressive, posterior retinopathy of prematurity is described. In all cases, the worse eye was treated with a single intravitreal injection of 0.75 mg of bevacizumab as monotherapy or complementary to laser therapy. In 24 hours, all injected eyes showed regression of the tunica vasculosa lentis and iris vessel engorgement and disappearance of iris rigidity. In addition, plus disease and retinal proliferation began to regress. None of the eyes required additional treatment. Follow-up of up to 10 months     

Strategies for Reducing Risks in Smoking: Opportunity or Threat?

The smoking control policies recommended by the World Health Organisation have achieved a slight decrease in smoking prevalence in developed countries, although associated mortality is still very high. The use of tobacco products other than cigarettes and even medicinal nicotine (known as nicotine replacement therapy [NRT]) has been proposed as a risk reduction strategy. Among the tobacco products with less individual risk than cigarettes would be any type of tobacco without smoke (smokeless) with a low content in nitrosamines and modified cigarettes; both forms included under the PREP (Potentially Reduced Exposure Products) concept. The idea would be to promote these products among patients who cannot quit smoking or wish to reduce their risk without giving up nicotine intake. The possible effects of risk reduction strategies, including PREP, on the decreased prevalence and morbidity and mortality are reviewed, and the possible implications that this measure could have in Spain are analysed. Tobacco control measures in Spain have only been made recently and are still insufficient. Therefore, the current priority in Spain is to develop control policies that have proven to be more than effective. The marketing and advertising of new tobacco products, even with reduced potential risk, seems more a serious threat than an opportunity for developing smoking control policies.     

Features of the metabolic syndrome of "hypertriglyceridemic waist" and transplant coronary artery disease.

BACKGROUND: This study evaluated the prevalence of the atherogenic metabolic triad and the hypothesis that waist circumference and fasting triglyceride concentrations could be used as screening tools for identification of the atherogenic metabolic triad in a population of heart transplant men. It also evaluated the relationship between the atherogenic metabolic triad and coronary artery disease (CAD). METHODS: In the study group of 83 consecutive male heart transplant patients having their routine annual coronarography, 23 patients (28%) were characterized by the atherogenic metabolic triad defined by the presence of elevated fasting insulin and apolipoprotein B concentrations and by small low-density lipoprotein (LDL) particles. RESULTS: Seventy-seven per cent of patients with waist circumference values >/= 90 cm and with elevated triglyceride levels (>/=2.0 mmol/liter) were characterized by this atherogenic metabolic triad. Patients with the atherogenic metabolic triad were at markedly increased risk of CAD (odds ratio of 25.3, 95% CI: 1.11-577.3, p < 0.04) compared to heart transplant patients without the atherogenic metabolic triad. CONCLUSIONS: About 30% of heart transplant patients showed the features of the atherogenic metabolic triad. Measurement and interpretation of waist circumference and fasting triglycerides could be used among heart transplant patients to early identify men characterized by the presence of elevated fasting insulin and apolipoprotein B concentrations and small LDL particles. The presence of the atherogenic metabolic triad identified patients at high risk of CAD even in the heart transplant population.     

Stress cardiomyopathy in thromboembolic arterial disease.

Apical ballooning is a novel clinical entity reported in different contexts of physical and psychological stress, which is more common in middle-aged women. Of unknown etiology, the syndrome is characterized by a sudden and transient dilatation of the left ventricular apex in the absence of obstructive atherosclerotic coronary disease or evidence of myocardial necrosis, with total late recovery of ventricular function. The authors report the case of a 53-year-old woman who was admitted to the emergency room with left arm ischemia and low cardiac output, requiring ventilatory support. Left catheterization showed typical medial and apical myocardial dysfunction, with normal coronary arteries. Transesophageal echocardiography revealed a thrombus attached to the lower face of the aortic arch, which probably explained the thromboembolism of the arm but was unlikely to be the cause of the left ventricular dysfunction since there were no enzymatic or electrocardiographic signs of myocardial necrosis and normal wall motion was fully recovered.     

Familial stenosis of the pulmonary artery branches with a JAG1 mutation.

Although most congenital heart defects are isolated abnormalities of embryonic development, with little genetic contribution, a small number are components of syndromes. In such cases, an accurate diagnosis has important implications for individual prognosis and familial genetic counseling. Alagille syndrome (AGS) is a dominantly inherited multisystem developmental disorder, which primarily affects the liver, heart, eyes, skeleton, and face. In recent years, the identification of the AGS gene has drawn attention to the existence of subclinical carriers, and broadened the spectrum of phenotypical variation associated with this syndrome. The authors present a case of mother and son with benign stenosis of the pulmonary artery branches. Subtle facial aspects suggested the diagnosis of AGS, which was confirmed by molecular analysis. Relevant clinical investigations and diagnostic implications are discussed.     

Bioimpedance analysis highlights changes in body composition at the early stages of impairment of kidney transplant function.

OBJECTIVE: Kidney transplantation restores renal filtration, although it does not achieve the function of 2 native kidneys, and with time it may involute back to chronic renal failure. We hypothesized that bioelectrical impedance analysis (BIA) might highlight differences for body compartments among kidney transplants (Tx) with different filtration rates. METHODS: Thirty transplantation patients (19 male, 11 female) were studied at 62.4+/-26.6 months postsurgery and were divided into 3 groups: good creatinine clearance (crCl, mL/min/1.73 m2; >65.0), borderline (35.0相似文献   

REM sleep behavior disorder and vocal cord paralysis in Machado-Joseph disease.

We evaluated the occurrence of REM sleep behaviour disorder (RBD) and vocal cord abductor paralysis (VCAP) in a group of 9 Machado-Joseph disease (MJD) patients. RBD was diagnosed by clinical history plus audiovisual polysomnography in 4 men and 1 woman (55%). While dreaming, 4 fell out of the bed and the other injured his arms. Laryngoscopy detected bilateral VCAP in 1 patient with stridor who required emergency tracheotomy, and partial vocal cord abductor restriction in 2. RBD and VCAP are two potentially injurious conditions that should be considered part of the clinical spectrum of MJD.     

Transesophageal echocardiography-guided cardioversion of atrial fibrillation. Selection of a low-risk group for immediate cardioversion.

INTRODUCTION: In patients (pts) with atrial fibrillation (AF) of more than 48 hours' duration, electrical cardioversion (ECV) should only be performed after 3 weeks of effective anticoagulation. Transesophageal echocardiography (TEE) allows earlier ECV; however, despite exclusion of thrombi in the atrium and left atrial appendage (LAA), cases of thromboembolism related to ECV have been documented in AF. To define a low-risk group for cardioversion without previous anticoagulation, pts were selected for immediate ECV if no thrombi or dynamic spontaneous echo contrast (auto-contrast) were found after TEE and if LAA velocity was more than 0.25 m/sec. METHODS AND RESULTS: We performed TEE in 31 consecutive pts referred for ECV for AF of more than 48 hours' duration and without previous anticoagulation. After TEE the pts eligible for immediate ECV began anticoagulation with low molecular weight heparin (enoxaparin), subcutaneously in therapeutic doses, together with warfarin immediately before cardioversion. Enoxaparin was continued until an INR of over 2 was reached. Based on the TEE findings, the pts were divided in 2 groups: immediate ECV, group A, 20 pts with a mean age of 62 +/- 13 years, 6 female; and conventional therapy with warfarin before ECV, group B, 11 pts, mean age of 67 +/- 10 years (p < 0.05), 2 female. None of the pts in either group had mitral stenosis or previous episodes of thromboembolism. The mean transverse diameter of the left atrium in the 31 pts was 47 +/- 4.5 mm, without statistically significant differences between the 2 groups. Of the 11 pts in group B, 3 had a thrombus in the LAA, 6 dynamic spontaneous echo contrast and the remainder LAA velocities of less than 0.25 m/sec. ECV was achieved in all the pts, with no complications. Oral anticoagulation was maintained for at least a month. At one month, sinus rhythm was maintained in 75% of group A and 45% of group B (p < 0.01). CONCLUSION: In pts with AF of more than 48 hours' duration and no previous history of thromboembolism, the use of our exclusion criteria during TEE enabled stratification of a low-risk population for immediate ECV, which was accomplished effectively and safely in 2/3 of the pts. This strategy is associated with early symptomatic improvement, and may contribute to maintenance of sinus rhythm after one month, which was significantly better than in the pts who had prolonged therapy with warfarin before ECV, despite the differences found in age and left ventricular function.