Evaluation of the pharmacological activity of the pure cysteinyl-leukotriene receptor antagonists CGP 45715A (iralukast) and CGP 57698 in human airways.
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Benzopyrans↗
Biomedical subjects
M Bolla
Publications and source records attributed to M Bolla.
Pathological prognostic factors in a series of 137 stage I TNM/UICC endometrial carcinomas.
PURPOSE: We report on the long-term results of combination surgery-radiotherapy in cT1 carcinoma of the endometrium according to prognostic factors. PATIENTS AND METHODS: From 1974 to 1993, 130 women suffering from cT1Nx-O Mo endometrial carcinoma, underwent surgical resection. The median age was 62 years. Thirteen received pre-operative irradiation, two pre-operative brachytherapy followed by post-operative external irradiation and 115 patients (88.35%) underwent post-operative irradiation therapy by brachytherapy or external beam irradiation. RESULTS: The median follow-up is 67 months. Overall and specific survival rates for patients with cT1pT1 tumours were 71.1 and 85% at 10 years. For overall survival, lymph node invasion was the most powerful prognostic factor in the multivariate analysis (P = 0.02). If lymph node invasion is not taken into account, the WHO histological grade exerts a significant prognostic impact (P = 0.001). CONCLUSION: For stage cT1 endometrial carcinoma, primary surgery allows radiotherapy to be adjusted according to the WHO histological grade, myometrial invasion and the pelvic lymph node status.
Adult↗
The use of a semi-customized phantom for verification of conformal plans.
We have developed a technique for inverse treatment planning of prostate therapy designed to improve the degree of conformation between the dose distribution and the target volume. We compared the inverse plan with a "standard" four-field box technique as well as a four-field technique using oblique fields ("cross technique"). We validated the dosimetry of the inverse plan using Fricke gel solution in phantom specifically designed for this purpose. The phantom is a Plexiglas tank with a cross section, which approximates the dimensions of the pelvis. Anatomical data from computed tomography (CT) images of a patient were used to simulate organs in our phantom. This allows us to calculate dose distributions with the external geometry of the phantom and internal anatomy of the patient. Dose-volume histograms (DVHs) for the three different plans were calculated. The phantom containing the Fricke gel was irradiated according to the inverse plan. Magnetic resonance (MR) images was used to determine the dose distribution delivered to the phantom. We observe, on DVHs, that the inverse plan significantly reduces the dose to the rectum and the bladder but slightly increases the inhomogeneity inside the target volume. Correlation is good between isodoses on MR images and calculated isodoses. We conclude that inverse planning software can greatly improve the conformal degree of treatment to the prostate. This technique could be applied to other complex anatomic sites at which dose to organs at risk is a limiting factor and increased dose to the target volume is indicated. Our phantom and the Fricke gel solution are convenient to carry out validation of conformal treatments.
Humans↗
Is postoperative irradiation after radical prostatectomy necessary?
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Clinical Trials as Topic↗
Analysis and classification of interval cancers in a French breast cancer screening programme (département of Isère).
The objective of this study is to analyse detection rates and stage of diagnosis of interval cancers in the mass screening mammography programme of Isère (France), launched in 1990. Interval cancers are defined as breast cancers diagnosed within 30 months after a negative screening assessment, for women attending the programme between November 1990 and December 1994. Stages of diagnosis of these cancers are compared with those of screened cancers and to those of cancers diagnosed outside the programme. The rates of invasive interval cancers are 17.7% of the expected incidence rate during the first year, 60.0% during the second year and 58.8% after the second year. Sensitivity of the programme (one test every 30 months) is 74%; sensitivity at one year is 82%. Results are better for women aged 60-69 years than for younger women (50-59 years). Diagnosis is made at an early stage with 8% of in situ cases, and with 40% of very small tumours (sizes < or = 10 mm). Those stages are very close to the ones for screened cases. Interval cancer rates are low during the first year. Higher rates for the second year and early stages of diagnosis could be explained by self-referred screening practice in our area.
Age Distribution↗
Accelerated radiotherapy, carbogen, and nicotinamide in glioblastoma multiforme: report of European Organization for Research and Treatment of Cancer trial 22933.
PURPOSE: A three-step phase I/II trial associating accelerated radiotherapy with carbogen (step 1, ARCO), with nicotinamide (step 2, ARN), or with both (step 3, ARCON) was conducted, the aim of which was to overcome the effects of proliferation and hypoxia as potential causes of tumor radioresistance in glioblastoma multiforme. PATIENTS AND METHODS: Radiotherapy consisted of 60 Gy delivered over 4 weeks in 1.5-Gy fractions twice daily, 5 days a week. Carbogen breathing was started 5 minutes before each fraction and continued until the end of each treatment session. Nicotinamide was given daily as a single oral dose of 85 mg/kg. RESULTS: A total of 115 patients with a median age of 55 years were registered. Of 107 eligible patients, 23 were registered in step 1, 28 in step 2, and 56 in step 3. The planned treatment was administered without any interruption in 72% of patients (86% in ARCO but 68% in ARN and ARCON). The incidence and severity of acute skin and mucous membrane toxicity were higher in patients who received nicotinamide (ie, the ARN and ARCON groups). Grade 1 to 2 gastrointestinal toxicity was observed in 44% of patients in the ARN group and 32% of patients in the ARCON group, but only in 8% of patients in the ARCO group. Eight percent of evaluated patients presented with abnormal liver test results at treatment completion. The dose of corticosteroids had to be increased in 44% of patients. Late neurologic side effects were similar in all treatment steps and were observed mostly in patients with disease progression. Median survival times for patients treated with ARCO, ARN, and ARCON were 10.1, 9.7, and 11.1 months, respectively. CONCLUSION: Feasibility of ARCO treatment was good but that of ARN and ARCON was only fair. This probably reflected the higher acute toxicity rate, particularly gastrointestinal, for patients receiving nicotinamide. The dose of corticosteroids had to be increased frequently during treatment, suggesting a higher than expected acute neurologic toxicity. Overall survival was similar in the three treatment steps and not different when compared with results of other series that used radiotherapy alone.
Administration, Inhalation↗
Adjuvant hormonal treatment with radiotherapy for locally advanced prostate cancer.
OBJECTIVES: Long-term results of radiotherapy in locally advanced prostate cancer are poor due to local and distant failures. Since prostate cancer is hormone dependent, tumor androgen deprivation may enhance tumor eradication. METHODS: Three randomized phase III trials, RTOG and EORTC are reported: they assess androgen suppression by using a luteinizing hormone-releasing hormone analogue (LH-RHa) with or without androgen blockade before and during, or during and after external irradiation. RESULTS: A gain in disease-free, local relapse-free and metastasis-free survival has been obtained (p < 0.001). Only the EORTC 22863 trial has reported a significant improvement in overall survival (p = 0.001) with an LH-RHa started the first day of radiotherapy and administered every 4 weeks over 3 years. In the RTOG 85-10 trial, and LH-RHa, initiated in the last week of radiation therapy and continued until relapse, increased overall survival only in patients with poorly differentiated tumor with a Gleason score of 8-10 (p = 0.03). CONCLUSION: Androgen suppression prior to and during radiation improves disease-free survival; adjuvant hormonal therapy with an LH-RHa during and after radiation improves overall survival.
Androgen Antagonists↗
Alternating radiotherapy and chemotherapy for inoperable Stage III non-small-cell lung cancer: long-term results of two Phase II GOTHA trials. Groupe d'Oncologie Thoracique Alpine.
PURPOSE/OBJECTIVE: To report on two consecutive Phase II cooperative trials in which we evaluated the combination of alternating hyperfractionated accelerated radiotherapy and cisplatin-based chemotherapy in inoperable Stage III non-small cell lung cancer (NSCLC). PATIENTS & METHODS: Between February 1986 and September 1989, 65 patients were entered in the first trial (GOTHA I), and between December 1989 and October 1992 67 were enrolled in the second trial (GOTHA II). In both protocols, radiotherapy (RT) was administered twice daily, at 6 h intervals, 5 days a week, to a total dose of 63 Gy in 42 fractions of 1.5 Gy. RT was given during weeks 2, 3, 6, and 7, over an elapsed time of 6 weeks. In GOTHA I, three cycles of cisplatin, 60 mg/m2 day 1, mitomycin, 8 mg/m2 day 1, and vindesin 3 mg/m2 day 1 and the first day of the following week, were given during weeks 1, 5, and 9; in GOTHA II, cisplatin 70 mg/m2 day 1 and vinblastin 5 mg/m2 day 1 and the first day of the following week were given during weeks 1, 5, 9, 13, 17, and 21. RESULTS: With a minimum follow-up of 3 years, the 1-, 2-, 5-, and 8-year overall survival probability was 56% (95% CI 47-64%), 27% (20-35%), 12% (7-18%) and 9% (3-16%), respectively, with a median survival of 13.6 months (11.4-16.8). Median follow-up for survivors was 6 years (3.3-9.9). There were no survival differences between Stages IIIA and IIIB (p = 0.84), performance status 0, 1, 2 (p = 0.87), sex (p = 0.45) or between the two treatment protocols. At this time, 14 patients are alive, and 118 have died: 102 from NSCLC, 4 from acute toxicity, 2 from secondary surgery, 4 from other medical causes, and 6 from unknown causes. Correlation between response and long-term survival was poor, since of the 24 patients who survived 3 years or more, only 6 (25%) were classified as having a complete response; the remainder having either a partial response (11, 46%), no change (6, 25 %), or "progressive disease" (1, 4 %). First site of relapse was local in 31% of these cases, distant in 43%, local and distant in 15 %, and unknown in 11%. Main grade 3-4 acute toxicities were nausea-vomiting (17%), mucositis (15%), leukopenia (41%), and thrombocytopenia (11%). Eight patients presented with grade 3-4 symptomatic lung radiation pneumopathy. CONCLUSION: Based on this experience with 132 patients, this combination of alternated RT and chemotherapy (CT) for inoperable Stage III NSCLC is feasible with acceptable toxicity, and long-term results suggest a gain in survival when compared to those obtained with conventional RT alone. However, the still high local and distant failure rates indicate that both local and systemic therapies need to be improved.
Adult↗
Delapril slows the progression of atherosclerosis and maintains endothelial function in cholesterol-fed rabbits.
The renin-angiotensin system is an important modulator of arterial blood pressure and inhibitors of the angiotensin-converting enzyme (ACE-Is) and are currently used in the treatment of hypertension. The pleiotropic actions exerted by angiotensin II (AngII) on the functionality of the vessel wall may have pro-atherosclerotic outcomes; evidence for an anti-atherosclerotic effect of ACE-Is has been presented and an antioxidant effect has been attributed to thiol-containing ACE-Is, like Captopril. The present study has been undertaken to investigate the effect of Delapril, a lipophilic ACE-I, on the development of atherosclerosis in cholesterol-fed rabbits. While it did not correct hyperlipidemia, Delapril dose dependently inhibited the development of atherosclerosis, expressed as aortic area covered by lesions (23.3+/-4.1, 21.3+/-2.4 and 18.5+/-3.3% with Delapril at the daily dose of 5, 10 and 20 mg/kg, respectively, versus 38.2%+/-6.4 for control animals) and its effect was similar to that of Captopril (14.5+/-5.1% at the daily dose of 25 mg/kg). Furthermore, Delapril partially and dose dependently restored endothelium-dependent relaxation, which is impaired in vessels from hypercholesterolemic animals (51.80+/-12.18, 59.74+/-5.16, 69.13+/-8.70 maximal percent relaxation versus 48.26+/-3.05% for the untreated control and 67.67+/-6.72% for Captopril-treated animals). An antioxidant mechanism is unlikely to explain this data, since Delapril does not contain thiol groups. These observations suggest that Delapril may represent an effective pharmacological approach for the treatment of atherosclerosis during its early phases.
Angiotensin-Converting Enzyme Inhibitors↗
Pharmacokinetics of nicotinamide in cancer patients treated with accelerated radiotherapy: the experience of the Co-operative Group of Radiotherapy of the European Organization for Research and Treatment of Cancer.
BACKGROUND: The EORTC has initiated studies to combine nicotinamide with carbogen in accelerated fractionation schedules (ARCON), since for some tumour types, acute and chronic hypoxia as well as treatment protraction may prejudice the outcome of radiotherapy. The tolerable dose of nicotinamide and the optimal interval for administration need to be ascertained. AIM: Full pharmacokinetic profiles of nicotinamide concentrations in plasma were analyzed repeatedly in 15 patients to determine the inter- and intra-patient variability in peak plasma concentrations and the optimum times for administering nicotinamide as a radiosensitizer. METHODS: Nicotinamide (Nicobion) was administered in tablet form to patients with advanced head and neck and non-small cell lung carcinomas. A standard 6 g dose was given regardless of body weight after an overnight fast and at least 30 min before breakfast. In 15 patients, blood samples were taken prior to and 1, 2, 4, 6, 8, 12 and 24 h after administration of the drug. This full profile was determined on two to four occasions for the head and neck cancer patients and on two occasions for the lung cancer patients. For each profile, the maximum concentration of nicotinamide (Cmax), time to peak plasma concentration (Tmax), elimination half-lives (t1/2) and area under the curve (AUC) were determined. Compliance was recorded and nausea and vomiting were graded on a 0-3 scale. Complete profiles of the five major metabolites were also obtained. RESULTS: In the 48 complete sets of blood samples, peak plasma concentrations ranged from 787 to 2312 nmol/ml with a median value of 1166 nmol/ml. The peak plasma concentration was achieved at 1 h in only 54% of the pharmacokinetic profiles, but at this time 92% of the profiles had already exceeded the target concentration of 700 nmol/ml, the level required in the mouse for tumour radiosensitization. The median t1/2 for all 15 cases was 9.3 h, with minimum and maximum values of 4.2 and 26.8 h. The highest concentrations of nicotinamide metabolites were found to be the N-oxide, 2-pyridone and 1-methylnicotinamide. The toxicity (nausea and vomiting) was scored and found not to be correlated with any of the pharmacokinetic parameters. CONCLUSIONS: The plasma concentrations considered necessary to radiosensitize can easily be exceeded with a dose of 6 g taken as 12 x 500 mg in tablet form; 700 nmol/ml was achieved in all patients and apparently would have been achieved in most even with a considerable reduction in dose. An adequate time between administration and radiotherapy appeared to be 1 h with this drug formulation for 92% of the profiles.
Administration, Oral↗
Quality of life after radiation therapy of cerebral low-grade gliomas of the adult: results of a randomised phase III trial on dose response (EORTC trial 22844). EORTC Radiotherapy Co-operative Group.
In 1985, the EORTC Radiotherapy Co-operative Group launched a randomised phase III study comparing high-dose (59.4 Gy in 6.5 weeks) versus low-dose (45 Gy in 5 weeks) radiotherapy with conventional techniques in patients diagnosed with low-grade cerebral glioma. The primary endpoint of the study was survival. No difference in survival was observed between the two treatment strategies. A quality of life (QoL) questionnaire consisting of 47 items assessing a range of physical, psychological, social, and symptom domains was included in the trial to measure the impact of treatment over time. Patients who received high-dose radiotherapy tended to report lower levels of functioning and more symptom burden following completion of radiotherapy. These group differences were statistically significant for fatigue/malaise and insomnia immediately after radiotherapy and in leisure time and emotional functioning at 7-15 months after randomisation. These findings suggest that for conventional radiotherapy for low-grade cerebral glioma, a schedule of 45 Gy in 5 weeks not only saves valuable resources, but also spares patients a prolonged treatment at no loss of clinical efficacy.
Adult↗
[Current studies of combined radiotherapy-hormone therapy in localized and locally advanced prostatic cancers].
In locally advanced prostate cancer three clinical randomized trials have shown that external irradiation combined with LHRH analogue with or without antiandrogen improved survival: disease-free survival, local recurrence-free survival, metastasis-free survival (P < 0.001). EORTC trial 22863 alone has shown a significant improvement of overall survival (P = 0.001), with an LHRH analogue (goserilin acetate, zoladex) started the first day of irradiation and followed every 4 weeks for 3 years; for RTOG trial 85-31 the same LHRH analogue started during the last week of irradiation and given until relapse increases survival of patients with poor differentiated tumours with gleason score ranging from 8 to 10 (P = 0.03). In locally confined prostate carcinoma randomized trials are ongoing to assess the impact of conventional irradiation or three dimensional conformal radiotherapy with or without adjuvant hormonotherapy.
Antineoplastic Agents, Hormonal↗
Pharmacological characterization of the cysteinyl-leukotriene antagonists CGP 45715A (iralukast) and CGP 57698 in human airways in vitro.
1. Cysteinyl-leukotrienes (cysteinyl-LTs) are important mediators in the pathogenesis of asthma. They cause bronchoconstriction, mucus hypersecretion, increase in microvascular permeability, plasma extravasation and eosinophil recruitment. 2. We investigated the pharmacological profile of the cysteinyl-LT antagonists CGP 45715A (iralukast), a structural analogue of LTD4 and CGP 57698, a quinoline type antagonist, in human airways in vitro, by performing binding studies on human lung parenchyma membranes and functional studies on human isolated bronchial strips. 3. Competition curves vs [3H]-LTD4 on human lung parenchyma membranes demonstrated that: (a) both antagonists were able to compete for the two sites labelled by [3H]-LTD4; (b) as in all the G-protein coupled receptors, iralukast and CGP 57698 did not discriminate between the high and the low affinity states of the CysLT receptor labelled by LTD4 (Ki1=Ki2= 16.6 nM+/-36% CV and Ki1= Ki2 = 5.7 nM+/-19% CV, respectively); (c) iralukast, but not CGP 57698, displayed a slow binding kinetic, because preincubation (15 min) increased its antagonist potency. 4. In functional studies: (a) iralukast and CGP 57698 antagonized LTD4-induced contraction of human bronchi, with pA2 values of 7.77+/-4.3% CV and 8.51+/-1.6% CV, respectively, and slopes not significantly different from unity; (b) the maximal LTD4 response in the presence of CGP 57698 was actually increased, thus clearly deviating from apparent simple competition. 5. Both antagonists significantly inhibited antigen-induced contraction of human isolated bronchial strips in a concentration-dependent manner, lowering the upper plateau of the anti-IgE curves. 6. In conclusion, the results of the present in vitro investigation indicate that iralukast and CGP 57698 are potent antagonists of LTD4 in human airways, with affinities in the nanomolar range, similar to those obtained for ICI 204,219 and ONO 1078, two of the most clinically advanced CysLT receptor antagonists. Thus, these compounds might be useful drugs for the therapy of asthma and other allergic diseases.
Antigens↗
Influence of the 'directions for use' on positivity rates of the Hemoccult II test.
OBJECTIVE: A concise, detailed, and complete instruction sheet is indispensable for adequate completion by the users of a product. This sheet should be enclosed in the envelope which contains Hemoccult II slides. The authors found that the instructions provided by the French manufacturer were unsatisfactory. They designed a short and simple notice, adequately detailed to be understandable by all volunteers and to obtain satisfactory stool smears. Positivity rates of Hemoccult II performed with the manufacturer's notice were compared to those obtained with Hemoccult II performed with the authors' instructions. METHODS: This study was made during the third screening campaign carried out by the Office Departemental de Lutte contre le Cancer (ODLC). This screening programme only concerned women 59 to 69 years of age. Six thousand three hundred and ninety-two Hemoccult II containing the manufacturer's instructions were received at the laboratory during March, April, May, June and July 1996, and 2633 Hemoccult II containing the ODLC instructions during March, April, May, June and July 1997. All Hemoccult II were developed and read by one trained technician in the Biochemistry Laboratory (Grenoble University Hospital). RESULTS: The two populations, studied in 1996 and 1997, were strictly comparable in terms of age and number of previous screenings. Out of 6392 Hemoccult II containing the manufacturer's instructions, 157 (2.5%) were found positive, as compared to 36 (1.4%) Hemoccult II out of 2633 which contained the authors' instructions. This difference is highly significant (P = 0.001). CONCLUSION: The directions for use provided with Hemoccult II had a crucial influence on positivity rates, and therefore on the cost of screening. The instruction sheet provided by the French manufacturer is not satisfactory as it contains too much needless information, while several important pieces of advice are missing.
Aged↗
Leukotrienes: lipid bioeffectors of inflammatory reactions.
The leukotrienes arise from oxidative metabolism of arachidonic acid through the action of the 5-lipoxygenase enzyme, leading to the unstable allylic epoxide leukotriene A4. This intermediate represents the substrate for two different specific enzymes, namely leukotriene A4-hydrolase and leukotriene C4-synthase, generating LTB4 and cysteinyl leukotrienes, respectively. The name "leukotriene" is referring to the cellular source (leukocytes are one of the major sources) as well as the conjugated triene that characterizes their structure. LTC4 and LTD4 are potent contracting agents of smooth muscle in airways and blood vessels; in addition, they induce mucus secretion and promote plasmatic exudation with direct action on endothelial cells. On the other side, LTB4 is known as a potent chemokinetic and chemotactic agent. A number of evidences reported in the literature underline the potential role of leukotrienes in the inflammatory responses that characterize asthma and other pathological conditions. These potent lipid bioeffectors are synthesized during the course of inflammatory reactions and their pharmacological modulation is able to significantly attenuate the clinical manifestations associated with different inflammatory pathologies.
Animals↗
Experimental single controlled study of burned bones: contribution of scanning electron microscopy.
Burned bones were studied using Scanning Electron Microscopy. The samples were cut from a maxillary-mandibular block taken during an autopsy. These fragments were heated in a furnace under controlled temperature conditions for 60 minutes. The temperatures ranged from 150 to 1150 degrees Celsius. The results are as following: (i) there are significant alterations of the bone, more and more obvious as the temperature increases, (ii) it appears to be difficult to establish a precise correlation between the temperature and the scanning electron microscopy patterns.
Aged↗
Adjuvant Hormonal Treatment with Radiotherapy for Locally Advanced Prostate Cancer.
Objectives: Long-term results of radiotherapy in locally advanced prostate cancer are poor due to local and distant failures. Since prostate cancer is hormone dependent, tumor androgen deprivation may enhance tumor eradication. Methods: Three randomized phase III trials, RTOG and EORTC are reported: they assess androgen suppression by using a luteinizing hormone-releasing hormone analogue (LH-RHa) with or without androgen blockade before and during, or during and after external irradiation. Results: A gain in disease-free, local relapse-free and metastasis-free survival has been obtained (p < 0.001). Only the EORTC 22863 trial has reported a significant improvement in overall survival (p = 0.001) with an LH-RHa started the first day of radiotherapy and administered every 4 weeks over 3 years. In the RTOG 85-10 trial, and LH-RHa, initiated in the last week of radiation therapy and continued until relapse, increased overall survival only in patients with poorly differentiated tumor with a Gleason score of 8-10 (p = 0.03). Conclusion: Androgen suppression prior to and during radiation improves disease-free survival; adjuvant hormonal therapy with an LH-RHa during and after radiation improves overall survival.
Journal Article↗
Macroscopic and microscopic aspects of incinerated teeth.
Fifty-eight premolars, extracted for orthodontic reasons, were incinerated for one hour in a furnace at temperatures varying from 150 degrees C to 1150 degrees C, increasing at 100 degrees C intervals. Between 150 degrees C and 700 degrees C the teeth changed from light yellow to bluish-white passing through brown. The scanning electron microscope showed that at 150 degrees C cracks appeared in the enamel, increasing in number as the temperature rose. At 450 degrees C the internal surface detached from the dentine and showed the same cracked surface as the exterior. Above 1100 degrees C the enamel fragments had a prismatic structure difficult to identify due to their melted structure. Dentine retained its tubular structure up to 1150 degrees C even when the tubules' diameter decreased at 700 degrees C. The cementum cracked as the temperature increased. Certain cracked areas actually detached at 600 degrees C giving a corroded aspect to the cementum and the residual zones became irregular when the temperature rose and eventually at 1150 degrees C the cementum was no longer identifiable.
Adolescent↗