When and where are N-acylethanolamine phospholipids and anandamide formed?
Explore the source record for details and available documents.
Animals↗
Biomedical subjects
H H Hansen
Publications and source records attributed to H H Hansen.
Non-small-cell lung cancer--stalemate or progress?
Explore the source record for details and available documents.
Antineoplastic Combined Chemotherapy Protocols↗
N-Acylethanolamines and precursor phospholipids - relation to cell injury.
The present review focuses on the relationship between formation of N-acylethanolamine phospholipids (NAPEs) and N-acyletransferase (NAEs) catalyzed by N-acyltranferase and NAPE-hydrolyzing phospholipase D, respectively, and cell injury in tissues like brain, heart, and testis. A number of mechanisms are proposed by which these two groups of lipids may have cytoprotective properties. The mechanisms may involve activation of cannabinoid receptors, as well as non-receptor-mediated effects such as stabilization of membrane bilayers, antioxidant mechanisms, inhibition of calcium leakage from mitochondria, and direct inhibition of ceramidase. Anandamide (20:4-NAE) is formed as a minor component along with other NAEs during cell injury. Whether 20:4-NAE has a separate physiological role is at present not known, but some data suggest that 20:4-NAE may be formed, e.g. in the uterus, by a more selective mechanism without being accompanied by a vast majority of saturated and monounsaturated NAEs.
Animals↗
A dose escalating study of topotecan preceding cisplatin in previously untreated patients with small-cell lung cancer.
BACKGROUND: The aim was to define the MTD of topotecan (TPT) given before cisplatin in patients with previously untreated SCLC. PATIENTS AND METHODS: Alternating cycles A and B to a total of 6 cycles were given. Cycle A: TPT days 1-5 and cisplatin (50 mg/m2) day 5. Cycle B consisted of teniposide, carboplatin, vincristine, and cisplatin. TPT was escalated at doses 0.75, 1.0, 1.25, and 1.5 mg/m2. DLT was defined for the first cycle as grade 4 neutropenia with fever or when lasting > 7 days, or grade 4 thrombocytopenia. RESULTS: Fifteen patients with limited disease and six patients with extensive disease were included. No episodes of DLT were recorded in the first cycles A and consequently 1.5 mg/m2 was defined as MTD. At 1.5 mg/m2 (11 patients, 30 cycles), four and three episodes of grade 4 thrombocytopenia and neutropenia lasting more than seven days occurred in subsequent cycles A. Thrombocytopenia and anaemia were cumulative as more cycles were administrated. Non-hematological toxicity was mild. The response rate was 86% (95% confidence interval (95% CI): 64%-97%) with 33% (95% CI: 15%-57%) achieving CR. CONCLUSIONS: 1.5 mg/m2 TPT can be delivered safely with 50 mg/m2 cisplatin on day 5 in patients with previously untreated SCLC.
Adolescent↗
A clinical model for quality of life assessment in cancer patients receiving chemotherapy.
BACKGROUND: The pattern of symptoms experienced by cancer patients during chemotherapy is very complex. Consequently, quality of life (QOL) assessment has to be carefully planned to capture clinically relevant changes. PATIENTS AND METHODS: A clinical model of changes in symptoms experienced by symptomatic metastatic patients during several courses of chemotherapy has been developed. The model differentiates cancer-related symptoms, acute side-effects, chronic side-effects and symptoms not related to cancer. The model was used to predict changes in each of these four symptom groups. Three time points were selected (post-cycle 2, pre-cycle 3, post-cycle 5) and an appropriate window around each time point was set. The model predictions were tested empirically with 56 patients with advanced ovarian cancer who completed the EORTC QLQ-C30 plus disease specific items during a six-cycle course of chemotherapy. RESULTS: The changes observed in the sample were in accordance with the changes predicted by the clinical model. Results from patients who did not complete the questionnaire within the specified time windows tended to dilute the findings from the group who did. CONCLUSIONS: A clinical model is useful in the planning of QOL assessments in order to capture clinically relevant effects. Such models also facilitate the interpretation of QOL studies, particularly when cyclic short-term effects and chronic side-effects are overlaid on disease symptoms, as is the case with chemotherapy for cancer.
Antineoplastic Agents↗
Determination of the phospholipid precursor of anandamide and other N-acylethanolamine phospholipids before and after sodium azide-induced toxicity in cultured neocortical neurons.
Phospholipase D-mediated hydrolysis of N-acylethanolamine phospholipids (NAPEs) releases anandamide and other N-acylethanolamines, resulting in different actions at cellular targets in the CNS. Recently, we have demonstrated that these N-acyl lipids accumulate in cultured neocortical neurons subjected to sodium azide-induced cell injury. We here extend the information on the NAPE response, reporting on the composition of N-acylspecies of NAPE, employing a new methodological approach of HPLC-coupled electrospray ionization mass spectrometry. Exposure to sodium azide (5 mM) increased the total amount of NAPE threefold over control levels; however, no alteration of the relative composition of NAPE species was detected. The anandamide precursor (20 : 4-NAPE) constituted only 0.1% of all NAPEs detected in the neurons. Total NAPE species in control cells amounted to 956-1,060 pmol/10(7) cells. Moreover, we detected the presence of an unknown NAPE species with molecular weight identical to 20 : 4-NAPE. This may suggest the presence of a putative stereoisomer of the anandamide precursor with at least one trans-configured double bond in the N-arachidonoyl moiety. These results show that with the present method, neuronal NAPE species can be identified and quantified with respect to N-acyl composition, including a trans-isomer of the anandamide precursor. The anandamide precursor is up-regulated to the same extent as other NAPEs upon neuronal injury.
Animals↗
Percutaneous transluminal coronary angioplasty versus thrombolysis in acute myocardial infarction.
The aim of this study was to evaluate the outcome of primary percutaneous transluminal coronary angiography (PTCA) in the treatment of acute myocardial infarction (AMI) The study included patients with electrocardiographic signs of transmural AMI, symptom duration of less than 12 h, and with no contraindications to thrombolytic therapy. Patients who had undergone primary PTCA were matched consecutively, for age, gender, infarct localization and duration of symptoms, to patients who had received thrombolytic therapy (82 patients to each group). Patients who were admitted to hospital during daytime had a primary PTCA, whereas those admitted outside daytime were given thrombolytic therapy. In the primary PTCA group, 9 patients had a combined endpoint compared with 22 patients in the thrombolysis group (p < 0.02 ). In-hospital mortality was 3.7% in the PTCA group and 4.9% in the thrombolysis group (ns). At six months, a combined endpoint occurred in 23 patients in the primary PTCA group and in 50 patients in the thrombolysis group (p < 0.00005). Six months' mortality was 4.9% in the PTCA group and 7.3% in the thrombolysis group (ns). Among patients in the PTCA group, left ventricular ejection fraction was significantly higher, stay in hospital was shorter and there were significantly fewer incidences of heart failure and severe arrhythmias than among patients in the thrombolysis group. The results of primary PTCA implemented in our departments are comparable with those reported in randomized trials from experienced centres. Our study indicates that patients treated with primary PTCA have fewer complications, a better left ventricular systolic function and a shorter hospital stay compared with patients treated with thrombolysis.
Adult↗
Phase I study of single, escalating doses of a superantigen-antibody fusion protein (PNU-214565) in patients with advanced colorectal or pancreatic carcinoma.
To develop a T-cell-based therapy for carcinomas, the superantigen staphylococcal enterotoxin A (SEA) was supplied with tumor specificity by means of a recombinant fusion of the Fab fragment of the monoclonal antibody C242 recognizing human colorectal (CRC) and pancreatic carcinomas (PC). Using this Fab-SEA fusion protein (PNU-214565), potent cytotoxicity by activation of T cells can be obtained in the targeted area. Twenty-one patients with CRC and 3 with PC were treated with single, escalating doses of PNU-214565 to establish the maximum tolerated dose (MTD) and to define toxicities. The doses ranged from 0.01 ng/kg to 4.0 ng/kg with three patients at each dose level, except for the dose of 1.5 ng/kg with which six patients were treated because of dose-limiting toxicity. Adverse events (AE) were transient: 13 patients experienced mild to moderate fever. In one patient, a grade 3 fever was followed by a grade 2 hypotension. Other mild or moderate AEs were fatigue, nausea, vomiting, diarrhea, and abdominal pain. No significant hematological toxicity occurred. Immune activation was highly variable with strong activity in peripheral blood seen only in two patients at the dosage level 1.5 ng/kg. They showed pronounced elevations of interleukin-2 (IL-2), IL-6, tumor necrosis factor-alpha, and interferon-gamma, 3-5 hours after the start of infusion. In one patient, IL-2 and IL-6 increased substantially (2,925 U/mL and 32,000 U/mL) concomitantly with grade 3 fever and transient grade 2 neutropenia, grade 2 lymphopenia, and grade 2 monocytopenia. In conclusion, a single 3-hour infusion of PNU-214565 could be safely administered up to 4 ng/kg. MTD was not determined. Instead, a repeat-dose trial was initiated starting at 0.5 ng/kg, considered safe in this trial, with the objective of defining the MTD.
Adult↗
[Smoking cessation in patients with stable or unstable ischemic heart disease].
The purpose of this study was to investigate the relation between severity of disease and smoking cessation in patients with ischaemic heart disease (IHD). Patients admitted to hospital with IHD, who were current smokers, entered the study. Patients were grouped as either stable or unstable IHD (unstable angina or acute myocardial infarction). All patients received identical information on smoking and IHD. After three months patients were interviewed about present smoking habits. In 42 patients a carbonmonoxide-haemoglobin (CO-hgb) test was done to evaluate the reliability of the answers. One hundred and five patients entered the study; 67 patients in the unstable group and 38 in the stable group. At follow-up 39% of patients in the unstable group had stopped smoking compared to only 13% in the stable group (p < 0.05). Two patients who claimed to be ex-smokers had CO-hgb-values indicating current smoking. We conclude that smoking cessation in patients with IHD seems to be dependent on the severity of IHD.
Adult↗
Electrospray ionization mass spectrometric method for the determination of cannabinoid precursors: N-acylethanolamine phospholipids (NAPEs).
N-Acylethanolamine phospholipids (NAPEs) serve as endogenous precursors of N-acylethanolamines (NAEs), e.g. N-arachidonoylethanolamine (anandamide) and N-palmitoylethanolamine that are endogenous ligands of cannabinoid receptors. Under physiological conditions, NAPE is found in very low concentrations in mammalian tissue (3-12 nmol g(-1)). However, pathophysiological conditions may increase the endogenous NAPE levels, which again may cause an increase in endocannabinoid concentrations. This paper presents a simple and selective method for the determination of NAPE standards using negative electrospray ionization mass spectrometry (ESI-MS). The procedure provides complete positioning of all acyl and alkenyl groups contained in each NAPE species. The calibration curve for standard NAPE was linear over the range 100 fmol-50 pmol (0.1-50 ng) per injection. The lower limit of detection (signal-to-noise ratio of 3) was 100 fmol, implying that this method is superior to previous methods for the determination of NAPE. These results suggest that this ESI-MS method can be used to identify and quantify NAPE species in mammalian tissues and provide information on the corresponding NAEs to be released from the endogenous NAPE pool.
Animals↗
Coenzyme Q10 treatment in serious heart failure.
Several noninvasive studies have shown the effect on heart failure of treatment with coenzyme Q10. In order to confirm this by invasive methods we studied 22 patients with mean left ventricular (LV) ejection fraction 26%, mean LV internal diameter 71 mm and in NYHA class 2-3. The patients received coenzyme Q10 100 mg twice daily or placebo for 12 weeks in a randomized double-blinded placebo controlled investigation. Before and after the treatment period, a right heart catheterisation was done including a 3 minute exercise test. The stroke index at rest and work improved significantly, the pulmonary artery pressure at rest and work decreased (significantly at rest), and the pulmonary capillary wedge pressure at rest and work decreased (significantly at 1 min work). These results suggest improvement in LV performance. Patients with congestive heart failure may thus benefit from adjunctive treatment with coenzyme Q10.
Adult↗
Formation of N-acyl-phosphatidylethanolamine and N-acylethanolamine (including anandamide) during glutamate-induced neurotoxicity.
N-Acyl-phosphatidylethanolamine (NAPE) is present in very small amounts in mammalian tissues (less than 0.1% of total phospholipids). However, NAPE as well as its degradation product, N-acylethanolamine (NAE), can be formed in certain neuronal tissues in response to increased [Ca2+]i. A high [Ca2+]i will activate the NAPE-forming N-acyltransferase using the sn-1 acyl group of a donor phospholipid as substrate in the transfer reaction. This membrane-bound enzyme seems to have no substrate specificity with respect to transfer of acyl groups; thus the fatty acids in the N-acyl group of NAPE are mainly 16:0 and 18:1, corresponding to the fatty acids in the sn-1 acyl group of the donor phospholipids. The NAPE-hydrolyzing phospholipase D also seems not to be acyl-group specific. In mouse neocortical neurons in primary culture, formation of NAPE and NAE is stimulated by glutamate via activation of the N-methyl-D-aspartate-receptor. Both NAPE and, to a lesser extent, NAE accumulate in a linear fashion for many hours while at the same time the neurons are dying. Likewise, in neurons prelabeled with 14C-arachidonic acid, 14C-arachidonic acid-labeled NAPE, and anandamide (= N-arachidonoylethanolamine) are accumulating. The formation of NAPE and NAE may represent a cytoprotective response in relation to various forms of neurotoxicity.
Acyltransferases↗
Paclitaxel, gemcitabine, and cisplatin in non-resectable non-small-cell lung cancer.
BACKGROUND: Paclitaxel, gemcitabine, and cisplatin are each active in non-small-cell lung cancer (NSCLC), and with different modes of action. Hence, a phase II study combining these drugs were conducted. PATIENTS AND METHODS: Treatment was paclitaxel 110 mg/m2 and cisplatin 60 mg/m2 day 1 and 15, with gemcitabine 800 mg/m2 day 1, 8, and 15, every four weeks. Patients had previously untreated NSCLC, measurable disease, age 18-70 years, performance status < or = 2, and no brain metastases. RESULTS: Among 49 patients, 6 (group 1) received chemotherapy as described above, while 43 patients (group 2) did not receive gemcitabine day 8. In group 1, all experienced grade 4 neutropenia and four achieved a partial response (67%). In group 2, neutropenia grade 4 occurred in 58%, with one episode of febrile neutropenia and no toxic death. No other grade 4 toxicities occurred, while grade 3 toxicity occurred with respect to thrombocytopenia (9%), nausea/vomiting (12%), neurotoxicity (12%), and nephrotoxicity (7%). There were 3 complete and 20 partial responses (response rate 54%, 95% confidence limits 38%-69%), median response duration 29 weeks (range 10-66+), median time to progression 28 weeks (range 4-66+), median survival 46 weeks (4-89+) and one-year survival rate 42%. CONCLUSION: This regimen of paclitaxel, gemcitabine, and cisplatin has neutropenia as dose limiting toxicity, but septicemic episodes were rare and toxic death did not occur. Other grade 4 toxicities than neutropenia did not occur. The regimen appears safe and with a noteworthy activity both in terms of response rate, time to progression, and survival.
Adult↗
Early death during chemotherapy in patients with small-cell lung cancer: derivation of a prognostic index for toxic death and progression.
Based on an increased frequency of early death (death within the first treatment cycle) in our two latest randomized trials of combination chemotherapy in small-cell lung cancer (SCLC), we wanted to identify patients at risk of early non-toxic death (ENTD) and early toxic death (ETD). Data were stored in a database and logistic regression analyses were performed to identify predictive factors for early death. During the first cycle, 118 out of 937 patients (12.6%) died. In 38 patients (4%), the cause of death was sepsis. Significant risk factors were age, performance status (PS), lactate dehydrogenase (LDH) and treatment with epipodophyllotoxins and platinum in the first cycle (EP). Risk factors for ENTD were age, PS and LDH. Extensive stage had a hazard ratio of 1.9 (P = 0.07). Risk factors for ETD were EP, PS and LDH, whereas age and stage were not. For EP, the hazard ratio was as high as 6.7 (P = 0.0001). We introduced a simple prognostic algorithm including performance status, LDH and age. Using a prognostic algorithm to exclude poor-risk patients from trials, we could minimize early death, improve long-term survival and increase the survival differences between different regimens. We suggest that other groups evaluate our algorithm and exclude poor prognosis patients from trials of dose intensification.
Age Factors↗
Phase II study of gemcitabine and vindesine in patients with previously untreated non-resectable non-small-cell lung cancer.
Because both vindesine and gemcitabine are active drugs in advanced non-small-cell lung cancer (NSCLC), with different modes of action and only partly overlapping toxicity, a phase II study was performed. Gemcitabine 1000 mg m(-2) was given on days 1, 8 and 15 every 4 weeks, while vindesine 3 mg m(-2) was administered weekly for 7 weeks, then every 2 weeks. A total of 42 patients with nonresectable NSCLC were included. The median age of patients was 56 years; 57% were men, 52% had adenocarcinoma, 31% squamous cell carcinoma and 17% had large-cell carcinoma. The performance status ranged from 0 to 2 with 83% in performance status 1. The majority (55%) had stage IV disease, while 40% had stage III B and 5% stage III A disease. WHO grade 3-4 leucopenia occurred in five patients (12%) and 9% had grade 4 neutropenia. Thrombocytopenia grade 3-4 was observed in six patients (15%). There were no septic death or bleeding episodes. One patient had a transient WHO grade 4 increase in bilirubin, and four patients had a decrease in glomerular filtration rate below the normal limit; one of these patients developed a non-reversible renal insufficiency. Ten patients (24%) complained of dyspnoea of uncertain mechanism, possibly involving bronchoconstriction. There were one complete and seven partial responses among 40 assessable patients (20%, 95% confidence limits 9-36%). Median response duration was 31 weeks (range 11-83 weeks) and median survival time 31 weeks (range 2-171 weeks). The current combination of gemcitabine and vindesine does not appear to be promising for further examination because of the toxicity and somewhat disappointing activity.
Adult↗
Surgery in limited stage small cell lung cancer.
The role of surgery in small cell lung cancer (SCLC) is controversial. Surgery has several potential advantages because it may reduce the frequency of local relapses, it does not impede the intensity of chemotherapy, it does not affect the bone marrow, and surgical staging may be of prognostic significance. Several smaller retrospective studies which focus on surgery alone, surgery with adjuvant chemotherapy or radiotherapy, or chemotherapy followed by adjuvant surgery have been reported. Five-year survival data have ranged from 10-50% according to stage, both T-status and nodal status appearing to be significant prognostic factors. Only one prospective randomized trial has been reported concerning the addition of surgery to chemotherapy alone. This trial does not favour surgery. The reason for this could be a selection bias in the smaller non-randomized studies or a result of stage migration. Nevertheless, surgery may yet play an important role in SCLC, especially in diagnosis and staging, and with new improved non-invasive staging procedures, such as positron emission tomography, resection may lead to cure in selected patients. Prospective randomized studies are needed to settle this issue.
Carcinoma, Small Cell↗
Twenty-five years of chemotherapy in small cell lung cancer sends us back to the laboratory.
Explore the source record for details and available documents.
Antineoplastic Agents↗
In-hospital outcome for diabetic patients with acute myocardial infarction in the thrombolytic era.
A 3-year retrospective study was carried out at the Department of Cardiology, Aalborg Hospital, Denmark. The aim of the study was to investigate the in-hospital mortality and complications resulting from acute myocardial infarction in diabetic patients compared with non-diabetic patients in the thrombolytic era and to investigate the correlation between mortality and blood glucose levels in diabetic patients. All patients admitted to the study suffered acute myocardial infarctions. One hundred and twenty-three patients with diabetes and 856 patients without diabetes were included. Mortality was 13% (110 patients) in non-diabetic patients compared with 28% (34 patients) in diabetic patients (p = 0.00002). Eighty-nine patients with diabetes (72%) experienced heart failure or a worsening of heart failure compared with 424 patients without diabetes (50%), p = 0.00001. Twenty-eight diabetic patients (23%) had high-degree atrioventricular block, compared with only 99 non-diabetic patients (12%), p = 0.001. Atrial fibrillation developed in 35 patients with diabetes (28%) and in only 141 patients without diabetes (16%), p = 0.002. No difference was seen in occurrence of ventricular tachyarrhythmias. Diabetic patients with a fatal outcome had significantly higher blood glucose values at admission compared with diabetic patients who survived (17.1 +/- 8.3 vs 13.5 +/- 6.3 mmol/l; p = 0.034), and during hospitalization (85.7 +/- 26.0% of blood glucose values exceeding 10 mmol/l vs 64.5 +/- 33.1; p = 0.00065). In the thrombolytic era diabetic patients with acute myocardial infarction had a higher mortality and experienced more complications during hospitalization compared with non-diabetic patients, and diabetic patients with a fatal outcome had higher blood glucose levels compared with surviving diabetic patients.
Aged↗