N-ω-Carbethoxypentyl-4-quinolones: A New Class of Leukotriene Biosynthesis Inhibitors

6-[(4-Quinolinyl)oxy]hexanoic acids and the corresponding esters were designed and synthesized as inhibitors of the production of arachidonic acid metabolites. The inhibitory activities were assayed in vitro by evaluation of serum leukotriene B₄ and thromboxane B₂ production. While all 6-[(4-quinolinyl)oxy]hexanoic acids and their esters proved to be inactive, the N-alkyl-4-quinolones, obtained as by-products in their synthesis, were found to be a new class of leukotriene biosynthesis inhibitors.     

Positive and negative interactions in the behavioural expression of D1 and D2 receptor stimulation in a model of Parkinsonism: role of priming.

Previous exposure to a dopaminergic agonist (priming) strongly potentiates contralateral turning behaviour in response to D1 and D2 agonists in unilaterally 6-hydroxydopamine-lesioned rats. In order to study the influence of priming on the behavioural interaction of D1 and D2 receptors, we examined the effect of selective D1 and D2 receptor blockade on the contralateral turning induced by the mixed D2/D2 agonist apomorphine in drug-naive and primed 6-hydroxydopamine-lesioned rats. In drug-naive rats, apomorphine induced a dose-related, apparently monophasic rotation curve. Administration of selective D1 (SCH 23390) or D2 (raclopride) antagonists abolished the contralateral turning induced by 0.1 mg/kg of apomorphine and partially inhibited that induced by 0.5 mg/kg. In primed rats low doses of apomorphine (0.05 mg/kg) induced an apparently monophasic contralateral turning which was reduced by D1 receptor blockade and completely abolished by D2 receptor blockade; a higher dose of apomorphine (0.1 mg/kg) instead elicited a biphasic (two-peak) pattern of rotation. After this dose of the agonist, blockade of D1 or D2 receptors abolished the second peak of rotation but, while D1 blockade reduced the total number of turns, D2 blockade failed to do so. Quantitative analysis of the interaction between D1 and D2 receptors in the overall turning effect, as well as in the time-course of turning behaviour, indicates that D1 and D2 receptors interact not only positively but also negatively. After higher doses of apomorphine, both negative and positive interactions take place sequentially during the time-course of apomorphine action and provide a clue for explaining the two-peak pattern of rotation observed after apomorphine in rats previously exposed to the drug.     

Frequency and determinants of direct stenting in routine percutaneous coronary interventions: data on 835 consecutive procedures in a single center.

BACKGROUND: Recent studies evaluated the technique of direct coronary stenting as compared to stenting-after-predilation in selected anatomic and clinical settings. However, the impact of direct stenting in routine interventional practice remains poorly elucidated. METHODS: From April 1999 to March 2001, all percutaneous coronary interventions performed at our Center were prospectively analyzed to determine the frequency of direct stenting, the success rate and the variables associated with its utilization. RESULTS: 1151 lesions were treated in 835 procedures. Stenting was attempted in 835/1151 lesions (72.5%), 309 (37%) with direct stenting and 526 (63%) with stenting-after-predilation. Direct stenting was successful in 300/309 (97%) and stenting-after-predilation in 515/526 (98%). The success rate of direct stenting was significantly lower in small vessels (< or = 2.75 mm) (89.2 vs 98.5%, p = 0.005). Patients treated with direct stenting were younger (63 +/- 11 vs 65 +/- 11 years, p = 0.024). Direct stenting was preferentially used in saphenous vein grafts and at the ostium of the left anterior descending coronary artery, while it was avoided in bifurcation lesions and with increasing calcium burden. Operators with a caseload > 140 interventions per year were significantly more likely to perform direct stenting than less experienced operators (p = 0.017). In direct stenting, the total contrast medium and the fluoroscopy and procedural times were all significantly (p < 0.0001) lower than those observed in case of stenting-after-predilation. CONCLUSIONS: Direct coronary stenting is currently performed in about one third of the overall caseload. Variables pertaining to the operator's experience, lesion morphology and length, vessel size, and the clinical presentation are all important factors determining the selection of candidates suitable for direct stenting.     

Endovascular repair for concomitant multilevel aortic disease.

OBJECTIVE: Patients with multilevel aortic disease represent a small subgroup with the need for extensive surgical treatment at considerable risk. We present our experience of endovascular exclusion for simultaneous thoracic and abdominal aortic disease in four patients. METHODS: Between January 2002 and January 2005, four patients underwent endovascular repair for simultaneous thoracic and abdominal aortic disease. Mean age was 69+/-10 years (range, 60-81). Thoracic lesions included penetrating aortic ulcer (n=2, ruptured=1), atherosclerotic aneurysm (n=1), and chronic type B dissection (n=1). Abdominal aortic disease included atherosclerotic infrarenal (n=3) and juxtarenal (n=1) aortic aneurysms. Thoracic aortic stent-grafts had been the following: Excluder/TAG (n=3) or Talent (n=1) straight tube devices. Abdominal aortic stent-grafts used were as following: Excluder (n=3) or Zenith (n=1). All patients were followed-up with CT-angiography and chest X-rays 1, 4, 12 months after the procedure, and once per year thereafter. RESULTS: Stent-graft deployment was technically successful in all cases. Intraoperative mortality was not observed. Mean procedure time was 94+/-34 min (range, 70-145). Early postoperative complications occurred in one patient that developed acute renal failure but dialysis was not required. Mean hospitalisation was 8+/-5 days (range, 4-15). Late death occurred in one patient for an undetected ruptured thoracic type 1 endoleak. All three survivors are currently well 16.5 months (range, 3-36) after surgery. No neurological complications developed. CONCLUSION: Simultaneous abdominal and thoracic endovascular repair for multilevel aortic disease is feasible and could be a viable alternative in high-risk patients, who otherwise may not be suitable candidates for conventional repair.     

Adrenal function under long-term raloxifene administration.

The aim of the present study was to evaluate the effect of long-term (12 months) administration of raloxifene hydrochloride (60 mg/day) on the steroid production of the adrenal cortex and on the hypothalamic-pituitary-adrenal axis in postmenopausal women. We performed a basal evaluation, a corticotropin releasing factor (CRF) (100 microg i.v. bolus) test and a dexamethasone (DXM) (0.25 mg) suppression-adrenocorticotropic hormone (ACTH) (10 microg i.v. bolus) stimulation test in 11 postmenopausal women, before and after 3, 6 and 12 months of raloxifene treatment. Raloxifene administration significantly modified circulating levels of adrenal steroids, decreasing cortisol (-24%), dehydroepiandrosterone (DHEA) (-36%), and its sulfate (DHEAS) (-41%), and androstenedione (-29%), and increasing circulating allopregnanolone (+39%) levels. Progesterone and 17OH-progesterone levels remained unmodified, while estradiol and estrone levels showed a significant decrease (-51% for estradiol and -61% for estrone). We also observed an increase in circulating ACTH (+58%) and beta-endorphin (+120%). No modifications in the hormonal responses to CRF were observed during the treatment. DXM significantly suppressed circulating steroids at any time with a lower suppression of cortisol from the third month and a higher suppression of DHEA at 12 months. ACTH administration was associated with a significantly blunted cortisol response from the sixth month and a significantly increased response of allopregnanolone from the third month. The present data exclude a raloxifene effect on pituitary sensitivity to CRF and demonstrate a reduced adrenal sensitivity to ACTH, sustained by the opposite changes in basal cortisol and Delta5 androgens, which were reduced, and in ACTH and beta-endorphin, which were increased, as well by the reduced response of cortisol to the direct ACTH stimulus. The reduction of circulating cortisol levels and cortisol response to the ACTH challenge suggests that raloxifene protects against the neurotoxic effects of endogenous glucocorticoids. Furthermore, the progressive increase in basal allopregnanolone and its increased response to ACTH indicate that chronic raloxifene administration exerts direct effects on the pattern of adrenal enzymes, leading to specific changes in the circulating levels of this anxiolytic progesterone metabolite. The important reduction in the circulating levels of estradiol and estrone under long-term raloxifene administration may represent a further mechanism by which this molecule may exert a protective effect against breast and endometrial malignancies.     

Capillary blood flow as an index of the therapeutic effect of folinic acid in ischemia-reperfusion syndrome]

OBJECTIVE: An intestinal reperfusion study with two aims: a) to assess the usefulness of intestinal capillary blood flow measurement by laser-Doppler for intestinal reperfusion studies; and b) to compare the effects of racemic and levo forms of folinic acid in treating the syndrome. EXPERIMENTAL DESIGN: A murine model of intestinal ischemia by completely clamping the superior mesenteric artery for 90 minutes. A comparison was made of three treatment groups: saline, folinic acid, and levo-folinic acid. The following factors were analyzed: changes in biochemical parameters (levels of creatine kinase, lactic dehydrogenase, and alkaline phosphatase at 60 minutes, and at two and seven days after restoring blood flow), capillary flow in the jejunum and ileum by laser-Doppler (during ischemia and after the first hour of reperfusion), intestinal mucosa injury, and survival curve. RESULTS: Laser-Doppler provided reliable data on how the different treatments affected capillary flow during intestinal reperfusion. Levo-folinic acid improved capillary flow in the ileum after 25 minutes of reperfusion, and also reduced mucosal injury in the same stretch of intestine by the seventh day post-reperfusion (p<0.05). On the other hand, it produced an initial increase in serum enzymes during reperfusion, and did not modify survival. CONCLUSIONS: The changes observed in intestinal capillary blood flow measurement by laser-Doppler have similarities with the effects of drugs on pathological mucosal changes. We could not prove that the levo form of folinic acid has a stronger protective effect versus racemic folinic acid in intestinal ischemia-reperfusion syndrome.     

Management of Constipation in Patients with Cancer

In patients with cancer, constipation is a common complication. However, unlike in the general population, the impact of the symptoms of constipation on the quality of life in cancer patients is often greater. More importantly, in patients who are in the more advanced stages of the disease, constipation may also be suggestive of disease progression. Constipation as a symptom in this population is of significant importance as it may lead to life-threatening complications, i.e. bowel perforation due to fecal impaction. Therefore, in this regard, this problem deserves particular attention, as early recognition and management of complications may prevent further physical deterioration. This review aims to provide an overview of the management of constipation in patients with cancer. A symptom-based criteria definition for chronic constipation and prevalence of the problem in cancer patients provides a brief introduction. For the initial assessment and evaluation of constipation in cancer patients, an algorithm is described. The different possible etiologies of constipation in cancer patients are also discussed. Regarding therapeutic management, guidelines and recommendations for the use of different types of laxatives, stool softeners, suppositories and rectal enemas, prokinetic agents, antidepressant medications, and miscellaneous agents are succinctly discussed. Management of fecal impaction and opioid-induced bowel dysfunction are also described. Lastly, a brief overview of the management of acute colonic pseudo-obstruction and surgical or endoscopic options for large bowel obstruction are described.     

Carotid endarterectomy with internal carotid artery segmental resection, temporary shunt and vein patch angioplasty: early and mid-term results.

AIM: The authors report an alternative procedure to carotid endarterectomy with internal carotid artery (ICA) segmental resection and end-to-end anastomosis associated with temporary shunt and venous patch angioplasty. Design: prospective cohort study. METHODS: Between May 1995 and December 2004, 192 patients underwent 200 primary CEAs for significant ICA stenosis. There were 131 men and 61 women with a mean age of 72.4+/-8.4 years. The indications for CEA were asymptomatic lesions in 51.5%, transient ischemic attack in 27.5% and stroke in 21%. RESULTS: The combined early morbidity and mortality rate was 2%. Two patients died, one due to fatal intracerebral hemorrhage and the second patient died of acute mesenteric ischemia. Neurological complications occurred in 2 patients, including 1 TIA and 1 nondisabling cerebrovascular accident. Non-neurological complications occurred in 26 patients (13.5%). Seventeen patients (8.8%) developed hypertension, 3 neck hematomas (1.5%) required surgical evacuation, 1 patient had reversible supraventricular arrhythmia (0.5%) and 1 patient had pneumonia (0.5%). Furthermore, 1 asymptomatic carotid occlusion was identified (0.5%) and 3 patients suffered permanent cranial nerve injury (1.5%). Mean follow-up was 45.7 months and there were 41 late deaths (21.8%). Survival rates at 1 and 5 years were 96.7+/-1.2% and 73.58+/-4.2%, respectively. CONCLUSIONS: CEA with ICA shortening and reanastomosis is a safe and reliable procedure without any increase in morbidity or mortality.