Structure-property relationships of trimetazidine derivatives and model compounds as potential antioxidants.

Twenty-five compounds (trimetazidine derivatives and other compounds, mostly having a free phenolic group) were examined for their radical scavenging and antioxidant properties. Their reaction with DPPH (2,2-diphenyl-1-picrylhydrazyl) as a measure of radical scavenging capacity was assessed by two parameters, namely EC50 (the concentration of antioxidant decreasing DPPH by 50%), and log Z, a kinetic parameter proposed here and derived from initial second-order rate constants and antioxidant/DPPH ratios. Antioxidant activities were determined by the inhibition of lipid peroxidation and albumin oxidation. The most active compounds were derivatives having a trolox or hydroquinone moiety. Physicochemical and structural properties were determined by molecular modeling as lipophilicity (virtual log P calculations) and H-Surf (solvent-accessible surface of hydroxyl hydrogen) and by quantum mechanical calculations (deltaH(ox) = oxidation enthalpy; deltaH(abs) = enthalpy of hydrogen abstraction). QSAR models were derived to identify molecular mechanisms responsible for the reactivity toward the DPPH radical and for the inhibition of lipid peroxidation. A useful prediction of antioxidant capacity could be achieved from calculated molecular properties and the kinetic parameter developed here.

Radiation therapy for head and neck cancers in the elderly.

Three hundred and thirty-one patients, aged more than 70 years, were treated for an upper aerodigestive tract carcinoma from 1978 to 1983. Larynx accounted for 28% of the primary sites, oropharynx for 27%, and the oral cavity for 16%. One-third of these patients had a contraindication to anesthesia. The treatment was consistent with our protocols in only half of the cases. Fifty-nine patients underwent a radiosurgical combination; 249 underwent an exclusive irradiation with a curative intent. Fifty-four patients underwent a palliative irradiation, which lead up to a "curative dose" in half of the cases. The immediate and long-term tolerance of the irradiation was good. The local control was 71% for patients treated with a curative intent and 19% for the palliatively irradiated patients. Five-year survival of the population was 33%. No significant relationship between age, general status, and the carcinologic outcome could be observed.

[(3)H]-trimetazidine mitochondrial binding sites: regulation by cations, effect of trimetazidine derivatives and other agents and interaction with an endogenous substance.

Trimetazidine, an antiischaemic drug, has been shown to restore impaired mitochondrial functions. Specific binding sites for [(3)H]-trimetazidine have been previously detected in liver mitochondria. In the present study we confirm this observation and provide additional evidence for the involvement of these sites in the pharmacological effects of the drug. Inhibition experiments using a series of trimetazidine derivatives revealed the presence of three classes of binding sites. An N-benzyl substituted analogue of trimetazidine exhibited a very high affinity (K(i)=7 nM) for one of these classes of sites. Compounds from different pharmacological classes were evaluated for their ability to inhibit [(3)H]-trimetazidine binding. Among the drugs tested pentazocine, ifenprodil, opipramol, perphenazine, haloperidol, and to a lower extent prenylamine, carbetapentane and dextromethorphan competed with high affinity, suggesting a similarity of high affinity [(3)H]-trimetazidine sites with sigma receptors. [(3)H]-Trimetazidine binding was modulated by pH. Neutral trimetazidine had about 10 fold higher affinity than protonated trimetazidine for its mitochondrial binding sites. Various cations also affected [(3)H]-trimetazidine binding. Ca(2+) was the most potent inhibitor and totally suppressed the binding of [(3)H]-trimetazidine to the sites of medium affinity. An endogenous cytosolic ligand was able to displace [(3)H]-trimetazidine from its binding sites. Its activity was not affected by boiling for 15 min, suggesting a non-protein compound. These data suggest that mitochondrial [(3)H]-trimetazidine binding sites could have a physiological relevance and be involved in the antiischaemic effects of the drug.

Changes in the oxygenation of head and neck tumors during carbogen breathing.

The oxygenation of head and neck tumors and changes during carbogen breathing were assessed in 20 patients. The median oxygen tension (pO2) for each patient was lower in tumors before breathing carbogen than in normal tissues. The median pooled pO2 of all the tumors was 20 mmHg; for normal tissue it was 60 mmHg. Low values (below 10 mmHg) were found in 4 patients for the normal tissue and in 18 patients for tumors. During carbogen breathing, the median (61 mmHg) pO2 readings for all tumors was higher than that recorded before carbogen breathing. The frequency of low (< 10 mmHg) pO2 values decreased with carbogen breathing in 11 patients; only 4 patients still exhibited very low values (< 2 mmHg). Maximal effect was obtained within 1-6 min of gas exposure. The pO2 stayed high under carbogen breathing in 15 out of 16 patients. Return to pre-carbogen levels of oxygenation occurred in 1 min after the end of gas exposure. These data suggest that carbogen breathing increases tumor oxygenation as assessed by polarography. The breathing time appears to be important for therapeutical use and should to be taken into consideration.

The neuroprotective activity of 8-alkylamino-1,4-benzoxazine antioxidants.

Antioxidant 8-alkylamino-1,4-benzoxazines, (R,S)-(3-tert-butyl-8-phenylethylamino-3,4-dihydro-2H-1,4-benzoxazin-5-yl) (phenyl) methanone (S 24429) and (R,S)-(3-cyclopentyl-8-benzylamino-3,4-dihydro-2H-1,4-benzoxazin-5-yl) (phenyl) methanone (S 24718), were prepared according to a two-step one-pot electrochemical procedure. These compounds had been selected from a previous study of structure/activity. Both compounds (1-100 microM) prevented the fall in ATP levels caused by 24 h of hypoxia in astrocytes. Both compounds (1 and 10 mg/kg i.p.) were powerful neuroprotective agents in protecting against the lesions induced by 15 microg S-bromo-willardiine injected into the cortex or white matter of 5-day old mice pups. In contrast, exifone, an antioxidant compound, was inactive at these doses. S 24429 and S 24718 appear to be novel neuroprotective agents, which are effective in a model of brain damage mimicking the lesions underlying cerebral palsy.

Squamous cell carcinoma of the pyriform sinus: retrospective study of 351 cases treated at the Institut Gustave-Roussy.

The first part of the study was devoted to 199 tumors treated by surgery, either conservative for the smallest tumors (18 cases) or radical (181 cases), with systematic postoperative radiotherapy. The 3-year survival rate was 48% and the 5-year, 33%, with a 12% local recurrence rate, a 7.5% neck recurrence rate, and 27.6% rate distant metastases. Histologic correlations were developed. The second part of the study reported 152 cases treated by external radiotherapy alone either as a variant of our treatment protocol for the small-sized tumors (31 cases) or, for the major part (121 cases), as a result of surgical inoperability or patient refusal. The former subgroup had a variable survival rate (65% at 3 years and 40% at 5 years) equivalent to similarly staged patients treated with conservation laryngeal surgery, whereas the prognosis of the latter subgroup was poor. The two main causes of failure were the inability to apply the curative treatment protocol in 35% of patients ineligible for a surgery and the high risk of distant metastases in the 65% of patients able to undergo the usual management.

Aesthesioneuroblastoma.

Forty patients were treated or followed up for aesthesioneuroblastoma between 1980 and 1995 at Institut Gustave Roussy, France. There were three T1, seven T2, 15 T3 and 15 T4 lesions. The cervical metastatic rate at presentation was 18 per cent. Distant metastases were detected by bone marrow biopsy and bone scan in three patients at presentation. Treatment modalities included surgery alone in eight patients, radiotherapy alone in three patients, combined modality surgery plus radiotherapy in 11 patients, chemotherapy alone in two patients, chemotherapy plus radiotherapy in 10 patients, and multimodality therapy chemotherapy plus surgery plus radiotherapy in six patients. The five-year survival rate was 51 per cent. Multimodality treatment offered better survival (63 per cent at five years) and disease-free interval (54 months). Overall local, regional, and distant failure rates were 58 per cent, 15 per cent and 40 per cent respectively. Distant metastases commonly occurred in bone (82 per cent). Cervical metastasis was an unfavourable prognostic indicator (0 per cent survival at two years). In conclusion, aesthesioneuroblastoma is sensitive to chemotherapy and radiotherapy. Multimodality therapy should be used initially.

[Medicines interacting with mitochondria: anti-ischemic effects of trimetazidine]. / Médicaments interagissant avec les mitochondries: effets anti-ischémiques de la trimétazidine.

While mitochondria are key factors in energy production in cells they are also key factors in their life cycle because under certain circumstances they can provoke cellular apoptosis. Some 45 per cent of myocardial volume is taken up by mitochondria. Furthermore, mitochondria are key to many aspects of neuronal activity and can trigger neurodegenerative processes. Lipid oxidation is responsible for the production of much ATP resynthesis in the heart but this process is less oxygen efficient than glucose oxidation. During ischaemia, lipid oxidation is suddenly blocked, but markedly increased during reperfusion, causing accumulation of potentially toxic metabolites (acylcarnitines, acyl-CoA, lysophospholipids). These metabolites can change calcium handling, inducing arrhythmias. Trimetazidine, and another product in development, ranolazine, by inhibiting lipid oxidation favours glucose oxidation and inhibits the production of deleterious lipid metabolites. Thus this class of drugs can have beneficial effects on myocardial metabolism without direct haemodynamic effects.

[Percutaneous gastrostomy in interventional radiology in cervico-facial oncology. Apropos of 174 cases]. / Gastrostomie percutanée en radiologie interventionnelle en carcinologie cervico-faciale. A propos de 174 cas.

We report a series of 174 percutaneous gastrostomies implanted in our interventional radiology unit in patients with cancer of the upper airway and upper digestive tract: two localizations, hypopharynx and oropharynx comprised 68% of the cases (106/174). Tumor stage had reached palliative treatment in 80 cases, was in the initial phase of treatment in 57 cases and was in a sequelae phase after treatment in 37 cases. Despite problems related to anatomic modifications and tumor volume or sequelae of prior or ongoing treatment, we did not record any failures. The rate of minor complications was 15%. The one severe complication (peritonitis) required laparotomy. The duration of enteral nutrition via the gastrostomy varied from 3 weeks to more than 3 years. There were no long-term complications. We thus suggest that interventional percutaneous gastrostomy is a useful alternative to endoscopic percutaneous gastrostomy or the nasoesophageal tube, particularly in patients with voluminous tumors restricting the hypopharynx and oropharynx.

[Reconstruction with free jejunal graft after total circular pharyngolaryngectomy. 73 cases]. / Reconstruction par transplant libre de jéjunum après pharyngolaryngectomie totale circulaire. Soixante-treize cas.

Among the various procedures of pharyngeal reconstruction after circumferential pharyngolaryngectomy, the free jejunal autograft (FJA) has become a common one. We retrospectively reviewed 73 cases of reconstruction with FJA after resection for advanced hypopharyngeal carcinomas (70 primary reconstructions, 3 secondary reconstructions). Postoperative outcome, functional and carcinologic results were studied. There were 1 postoperative death, medical complications in 19 patients, 4 graft failures (5.5%), 11 salivary fistulas. The nasogastric tube was removed before the 15th day in more than a half of the patients. One year postoperatively all the evaluable patients were able to take an oral diet (solid or soft diet for 97% of them). The postoperative radiotherapy was well tolerated. Cancer developed further in 33 patients (13 local and/or nodal recurrences, 13 isolated metastasis, 7 second primaries). The overall survival rate was 44.8% at three years. It seems clear that FJA allows good functional results and increases the quality of life in such patients with poor prognosis.

[Pharmacological modulation of mitochondrial oxidative phosphorylation: inhibition by cyclosporine A, restoration by trimetazidine]. / Modulation pharmacologique de la phosphorylation oxydative mitochondriale: la cyclosporine A l'inhibe, la trimétazidine la restaure.

When applied to a suspension of isolated mitochondria extracted from rat hepatocytes, cyclosporine A decreases ATP synthesis and induces Ca2+ accumulation. Both effects are considered as possible determinants, even partly, of renal toxicity observed with this drug. Trimetazidine antagonizes both effects at concentrations easily reached in man with therapeutic dosages. It is concluded that the association of both drugs may improve the renal tolerance of Cyclosporine A.

[Lacrimal duct tumors: diagnostic and therapeutic dilemmas]. / Tumeurs primitives des voies lacrymales: pièges diagnostiques et thérapeutiques.

INTRODUCTION: Fewer than 250 primary tumors of the lacrimal duct have been reported in the international literature. Because their signs and symptoms are nonspecific and usually subclinical, delayed diagnosis is common. Treatment for malignant epithelial tumors is surgical, with or without radiation. PATIENTS AND METHODS: The present study is a retrospective analysis of five patients with malignant lacrimal duct tumors. RESULTS: Three patients were diagnosed with carcinoma requiring wide en bloc surgical resection with surgical reconstruction. One underwent adjuvant radiation therapy. Another experienced simultaneous local and lymph node recurrence after 3 years and underwent curative surgery. Two additional patients were diagnosed with diffuse malignant large B-cell non-Hodgkins lymphoma. DISCUSSION: Early symptoms of lacrimal duct tumors are nonspecific and mimic acute dacryocystitis. Lacrimal system CT, MRI and rhinoscopy may allow for earlier diagnosis. Surgical treatment requires resection with wide margins and reconstruction of the medial canthal region. CONCLUSION: Only an early diagnosis can reduce the impairment related to surgery and the extent of the required reconstruction, as well as improve survival.

Studies on NK cell purification by negative selection in human peripheral blood.

We have attempted to improve negative selection procedures for the large scale purification of human CD-3 CD56+ NK cells. In a series of experiments, purifications of NK cells from 10(8) PBMC were performed by T cell depletion using either direct or indirect anti-CD3 labeling and the Magnetic Activated Cell Separation (MACS) procedure. Contaminating CD3+ cells were still present using either one of these two different T cell depletion protocols as shown by phenotyping IL-2 supplemented cell cultures on day 12. A second cycle of purification was therefore added. When MACS and Dynabeads were compared as complementary procedures to the first MACS cycle starting with 10(8) cells, the Dynabeads method was found to be superior to the MACS with regard to the elimination of residual T cells. Starting from 10(9) PBMC, we showed that this MACS+Dynabeads procedure gave similar satisfactory results when compared to the scaling-up of a previously established two steps procedure using Dynabeads. These two approaches (MACS+Dynabeads and 2 cycles of Dynabeads) have been also tested in a clinical setting to purify NK cells from cancer patients prior to in vitro expansion. The results indicate that the two methods are equivalent with respect to purity and recovery rate; a slight advantage in terms of feasibility was found in favor of 2 cycles of Dynabeads.

Surgical management of posterior pharyngeal wall carcinomas: functional and oncologic results.

BACKGROUND: The optimal primary treatment for posterior pharyngeal wall tumors remains controversial. METHODS: To assess the relevance of surgical treatment from a functional and oncologic point of view, we reviewed the cases of 77 patients surgically treated between 1984 and 1995. Among them 23 had been previously irradiated. Fifty-five patients underwent a conservative surgery (CS) sparing the larynx; 19 direct closures, 6 reconstructions of the posterior wall with a thoracic myocutaneous flap, 15 with a platysma flap, and 15 with a free forearm flap were performed. Twenty-two patients underwent radical surgery (RS). All previously untreated patients had postoperative radiotherapy. The functional assessment concerned the CS group. Oncologic results, especially local control and survival were studied for the whole group. RESULTS: Of the 55 patients who underwent CS, 53 (96%) had their canula and 49 (89%) their feeding tube removed. At 1 year, in the platysma and free forearm groups, 21 of the 24 assessable patients were back to exclusive oral intake. For patients treated by primary surgery followed by radiotherapy, the rate of local failure was 11% (18% for tumors greater than 4 cm), and the 5-year survival rate was 35%. For patients who had previous radiotherapy, the rates were, respectively, 52% and 16%. CONCLUSION: The satisfactory functional results, caused by the improvement of reconstructive procedures, allow conservative surgery even in the case of large tumors. Oncologic results, especially local control, suggest that primary surgery followed by radiotherapy is effective for the treatment of posterior wall cancer. The oncologic results of surgery in a previously irradiated area are poor, and CS is not recommended in these cases.

Tumor oxygenation after 1) carbogen and/or perflubron emulsion administration in tumor xenografts 2) carbogen administration in patients.

This study examines the changes in tumor pO2 distribution assessed by polarography (KIMOC 6650, Eppendorf) in 1) two human tumor xenografts after carbogen inhalation with or without a perflubron (perfluorooctylbromide) emulsion (Oxygent, Alliance Pharmaceutical corp.) and in 2) human head and neck carcinomas after carbogen inhalation. Mice bearing HRT18 or NA11+ tumors were restrained and their body temperature was kept constant. Perflubron emulsion (4 ml/kg) was injected i.v. in the mice. In patients, oxygenation of the head and neck metastatic lymph nodes was assessed before and/or during carbogen exposure. The distribution of pO2 values shifted upwards during carbogen exposure in both animals and patients while the proportion of low pO2 values decreased. The maximal effect was obtained with patients after 1 to 6 minutes of carbogen exposure, but 4 patients still maintained very low pO2s. Carbogen plus 4 ml/kg perflubron emulsion was more efficient than carbogen alone for increasing hypoxic tumor pO2 in animals. If the animals data could be extrapolated to humans, then the effect of carbogen on tumor oxygenation should be increased by perflubron emulsion administration.

Subtotal laryngectomy with cricohyoidopexy as first treatment procedure for supraglottic carcinoma: Institut Gustave-Roussy experience (146 cases, 1974-1997).

PATIENTS AND METHODS: Between 1974 and 1997, 297 patients underwent a subtotal laryngectomy at the Institut Gustave-Roussy; 146 of these patients underwent cricohyoidopexy (CHP) for a supraglottic primary as their first treatment. The majority of patients were men (137) aged from 33 to 78 years (median 54 years). The tumour stage at presentation was T1 in 2, T2 in 87, T3 in 53 (preepiglottic space involvement), and T4 (minimal thyroid cartilage invasion) in 4 patients. One hundred and twenty-five patients were N0 (86%) and 21 patients were Np (palpable); 98% had homolateral and 55% had bilateral neck dissections. RESULTS: One patient died postoperatively of a myocardial infarction and 68% patients had an uneventful course. Aspiration was the commonest complication (23 patients, 19%). The median time to removal of the tracheotomy cannula was 10 days and for the nasogastric tube 21 days during the past 10 years. Completion of subtotal laryngectomy into total laryngectomy was done in 21 cases (15%): eight times because of oncological events [five local failures, two second primary (hypopharynx), one positive margin] and 13 times because of aspiration (9%). There were six local failures (4%) and eight nodal failures (5%). The rates of distant metastases and second primaries were 6% and 16% respectively. Half of the local and nodal failures were subsequently sterilized. Findings at death were two local recurrences, four nodal recurrences, eight distant metastases, and 11 second primaries. The 3- and 5-year overall survival rates were 92% and 88% respectively, with an overall laryngeal preservation rate of 86%. CONCLUSION: When supraglottic laryngectomy is not feasible for supraglottic cancer, subtotal laryngectomy with CHP is a safe and effective oncological procedure, with preservation of satisfactory laryngeal function.

Oxygenation of head and neck tumors.

BACKGROUND: Tumor hypoxia could play a role in the response to radiation therapy. Few data are available on oxygen tension (pO2) measurements in head and neck tumors. METHODS: The KIMOC-6650 Histograph (Eppendorf, Hamburg, Germany) was used to measure the oxygenation status of normal tissues and head and neck tumors in 20 patients. RESULTS: The median pO2 for normal tissues was 43 mmHg with very low pO2 values (2.0 mmHg or less) recorded in two patients. Low median pO2 levels (10 mmHg or less) were recorded in 2 of 5 primary tumors and in 11 of 15 metastatic lymphadenopathies, with very low values in 11 nodes. The median pO2 in tumors was lower than that of normal tissues in 12 of 15 patients with comparative measurements. Oxygen tension was recorded in three nodes after an evaluation of tissue density (by computed tomographic scanner); in two nodes, the mean and median pO2 values were lower in the hypodense areas than in isodense areas. The data for N2 and N3 nodes showed significantly more values below 2.0 mmHg as nodal size increased (P < 10(-4), by chi-square test). No systematic decrease in pO2 was recorded from the periphery to the center of the tumors. CONCLUSIONS: Very low pO2 values, corresponding to radiobiologic hypoxia, were found in most of these tumors. The prognostic value of these pO2 measurements in regard to treatment response remains to be demonstrated.