Biomedical subjects
Publications and source records attributed to J Y Petit.
A new method of bipedicled transverse rectus abdominis myocutaneous flap splitting to reconstruct the contralateral breast 1 year after the first breast reconstruction is presented. This technique can be useful in cases of large salvage mastectomy for asynchronous breast cancers allowing a bilateral thoracic closure.
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The fact that tumour necrosis factor-alpha (TNF-alpha) is clearly involved in the pathogenesis of intestinal bowel disease, especially Crohn's disease, suggests that TNF-alpha synthesis inhibitors could be beneficial for treatment. The present study assessed the effect of chronic oral gavage of two in vitro TNF-alpha synthesis inhibitors, JM 34 maleate or [N-(4,6-dimethylpyridin-2-yl)-furane-2-carboxamide)] maleate and XC 21 or (N-betapicolyl-tetrafluorophtalimide), on colonic inflammation in trinitrobenzene sulphonic acid-induced colitis in rats. Rats received JM 34 maleate (100 mg/kg) and XC 21 (50 mg/kg) 1 h before colitis induction and then daily for 8 days by oral gavage. The colon was removed on day 8 and processed for clinical score, myeloperoxidase activity, and soluble TNF-alpha release. Treatment with XC 21, as well as dexamethasone and sulphasalazine, reduced colonic damage and decreased (except with dexamethasone) the incidence of diarrhoea. JM 34 maleate failed to improve the clinical signs of chronic colitis. After trinitrobenzene sulphonic acid-induced colitis, myeloperoxidase activity and TNF-alpha colonic mucosal production were substantially increased compared to the control (saline instillation). Both of these inflammatory indicators were then significantly decreased (P< or =0.05) after the four chronic treatments (JM 34 maleate, XC 21, sulphasalazine, and dexamethasone). XC 21 appeared to be as efficient as sulphasalazine in improving colonic inflammation.
The effects of lepadiformine, a natural marine alkaloid isolated from the ascidians Clavelina lepadiformis (Müller) and C. moluccensis (Sluiter), were studied in vivo by arterial blood pressure (aBP) recordings and electrocardiograms (ECG) in anaesthetised rats and in situ by peripheral vascular pressure recordings on perfused rabbit ear. Transmembrane resting (RP) and action (AP) potentials were also recorded by intracellular microelectrodes on electrically stimulated left ventricular papillary muscle and spontaneously beating atrium isolated from rat and frog hearts, respectively. Intravenous injection of lepadiformine (6mg/kg) produced marked bradycardia and a lengthening of ECG intervals as well as a transient decrease of aBP, which rapidly returned to normal. The decrease of aBP may have been related to a vasoconstrictor effect observed in the perfused ear experiment. Lepadiformine did not alter RP, but significantly lengthened the repolarising phase of AP in rat papillary muscle and frog atrium. Lepadiformine also mimicked the effect of Ba(2+) (0.2mM) on the rat AP repolarising phase. Moreover, the lengthening of the AP in frog atrium induced by lepadiformine still developed after the delayed outward K(+) current (I(K)) was blocked by tetraethylammonium (10mM). These observations suggest that lepadiformine-induced lengthening of AP duration was not due to a decrease of I(K), but may reasonably be attributed to a reduction of the inward rectifying K(+) current (I(K1)). This blockade of I(K1) could account for the cardiovascular effects of lepadiformine in vivo and in vitro and suggests that lepadiformine has antiarrhythmic properties.
N-substituted-(indol-3-yl)carboxamides 10-15 and alkanamides 16-18 were prepared starting from the corresponding acids and submitted to screening for evaluation of their anti-inflammatory activity. None of the considered carboxamides exhibited significant inhibitory effect in the carrageenin-induced rat paw oedema after oral administration of 0.1 mM x kg(-1); nevertheless introduction of an alkyl chain, leading to alkanamides 16-18, induced moderate to high activity: 46-95% inhibition. The efficacy of these compounds in the inhibition of topical inflammation was confirmed by measuring reduction of ear thickness in the acute tetradecanoyl phorbol acetate (TPA)-induced mouse ear swelling assay. Preliminary pharmacomodulation brought to the fore that toxic effects induced, at 0.4 mM x kg(-1), by N-(pyridin-4-yl)(indol-3-yl)propanamide (17) could be attenuated or suppressed by 5-fluorination or introduction of a methoxycarbonylborane moiety, leading to 18 and 21.
The topical anti-inflammatory activity of a series of N-pyridinyl(methyl)1,2-dihydro-4-hydroxy-2-oxoquinoline-3-carboxamides, analogues of roquinimex, has been evaluated by measuring their inhibitory effect in the phorbol myristate acetate (PMA)-induced mouse ear swelling test, used as a screening test. All the eight carboxamides tested (9-16) exhibited significant inhibitory activity at 0.4 and 0.2 mM kg(-1). The most potent compound, the 6-bromo derivative 12, induced a 73% inhibition at 0.2 mM kg(-1). Pharmacomodulation was carried out by heterocycle opening and molecular simplification leading to pentafluorobenzoylacetamide 17, pentafluorocinnamamides 18 and 19, and pentafluorobenzaldimines 20 and 21. All the five compounds exerted a reduction in swelling (49-63% at 0.2 mM kg(-1)) comparable with ibuprofen (56%). Anti-inflammatory activity of the most efficient compounds was evaluated by carrageenan-induced rat paw oedema inhibition. The pentafluorobenzaldimine 20 showed the highest activity with an inhibition percentage of 85% at 0.2 mM kg(-1).
In the Ivory coast, Parkia biglobosa (Mimosaceae) is used in traditional medicine as an analgesic drug, especially against dental pain. Of the three extracts obtained from the plant bark, the hexane fraction was studied to determine its analgesic and/or antiinflammatory activities. The results show that this extract possesses a marked analgesic activity when evaluated with the abdominal writhing test in mice, but, like paracetamol, was ineffective with the hot-plate method, a feature suggesting a peripheral mechanism of action. This activity was accompanied by an antiinflammatory effect, somewhat weaker than the analgesic one.
Basal cell carcinoma is the most frequent cutaneous carcinoma, and it is characterized by its local spreading and an exceptional tendency to metastasize. Radical excision or destruction ensures the highest chance of cure. The most frequent site of this tumor is the face, where radical excision is limited by the proximity of essential anatomic structures. The main difficulty is to avoid mutilation and to provide good cosmetic results despite the vicinity of the eyes, the nose, and the mouth. Surgery and radiotherapy are known to provide similar chances of cure, but results concerning cosmetic sequelae are controversial, depending sometimes on the specialty of the physician in charge of the treatment. A randomized trial was performed at the Gustave-Roussy Institute to compare basal cell carcinomas of the face treated either by surgery or by radiotherapy. In summary, a significant advantage was observed in favor of surgery, as has been published elsewhere. Looking at the details of the cosmetic results, we analyzed the specific methodology of the cosmetic evaluation set up to eradicate the usual bias owing to subjective judgments. We looked also to the evolution of the cosmetic results with time. A panel of five judges performed repeated evaluations during the follow-up, and standardized photographs were taken at each visit and rated later by three nonmedical judges. In total, 174 patients were treated by surgery and 173 by radiotherapy; the choice of the treatment was allocated by randomization. Postoperative complications were higher in the radiotherapy group. The final cosmetic results after 4 years of follow-up were rated significantly better with surgery than with radiotherapy (good in 87 percent versus 69 percent according to the patient, 79 percent versus 40 percent according to the dermatologist, and respectively for each of the observers). Evolution of the ratings during the follow-up demonstrated an improvement of the cosmesis after surgery and stable or deteriorated results after radiotherapy. The same trend was observed regardless of the site of the tumor on the face, except for the nose, where the difference--still in favor of the surgery--was not significant. Concordance of all assessments in our study was the main guarantee of reliability of our methodology for cosmetic evaluation.
Integration of plastic surgery is currently widely practiced in cases of mastectomy. Immediate breast reconstruction with an implant or autologous tissue procedures is frequently proposed to the patient before the mastectomy. However, breast conserving surgery (BCS) is recognized as the treatment of choice in most cancers: breast conservation is proposed in more than 70% of the patients with primary cancer treated at the European Institute of Oncology in Milan. This high percentage of preservation has been made possible by the integration of plastic surgery at the time of primary surgery. The size of the tumorectomy remains a matter of discussion. Based on the Milan II trial and Holland's pathological studies, Veronesi recommended so-called "local radical surgery." For a tumor 1 cm in size, a free margin of 2 cm produces a final specimen at least 5-6 cm in diameter. In small or medium-sized breasts, such a resection results in a wide glandular defect and poor esthetic results if direct closure is carried out. Plastic surgery derived from reduction mammaplasty procedures allows much better final cosmetic results, which is the goal of conservative treatment. In 25% of our patients treated with BCS, the plastic surgeon is called upon by the general surgeon to close the glandular defect. However, such glandular remodeling changes the size and position of the breast. Therefore, in 15% of these cases a symmetry procedure is performed on the opposite breast. The reduction procedure in the opposite breast should be taken as a good opportunity to check the glandular tissue. Special attention should therefore be given to the contralateral mammogram in order to focus the glandular resection on the most dubious areas. Occult carcinomas, half of them infiltrating, were found in 4% of a series of 350 symmetry procedures performed during breast reconstruction at the Gustave Roussy Cancer Institute. In conclusion, close collaboration between oncologists and plastic surgeons is required not only to obtain the best cosmetic results but also to allow improved radicality of the tumor resection and a histological check-up of the contralateral breast.
Compounds able to inhibit phospholipases A2 can be considered as potential anti-inflammatory drugs. In this respect, the inhibitory effect of the phospholipid analogue 1-decyl 2-octyl-rac-glycero-3-phosphocholine (decyloctyl-GPC) added to the culture medium of rat peritoneal macrophages stimulated with ionophore A23187 was determined. (a) The substrate of phospholipase A2 1-octadecanoyl 2-[14C]eicosatetraenoyl-sn-glycero-3-phosphocholine ([14C]20:4-GPC) was added to the culture medium. In macrophages + extracellular fluids, its hydrolysis at the 2-position, produced [14C]non-phosphorous lipids which reached 12% of the dose at 0.14 microM, 73% at 0.9 and > 90% at 1.6 microM; in experiments where macrophages and extracellular fluids were analyzed separately, decyloctyl-GPC initially added at 4 microM, significantly inhibited the release of [14C]fatty acids and the eicosanoid synthesis, demonstrating its ability to inhibit secreted and/or intracellular phospholipases A2. (b) Extracellular fluids were separated from the macrophages and incubated with [14C]20:4-GPC: 48% of the dose was hydrolyzed by extracellular fluid-associated secreted phospholipase A2 and decyloctyl-GPC at 3 microM, reduced this hydrolysis by 50%. (c) [3H]arachidonic acid ([3H]20:4) was added to the culture medium and was esterified in the macrophage membrane phospholipids. Activation of intracellular phospholipase A2 induced the release of [3H] fatty acids and eicosanoid synthesis. These releases were inhibited by 50% with decyloctyl-GPC added at 4 microM. (d) [3H]20:4 and [14C]20:4-GPC were added to the culture medium of the macrophages. [3H] and [14C] fatty acids and eicosanoids were released in macrophages or extracellular fluids. They were significantly reduced by the phospholipid analogue added at 4 microM. It is concluded that secreted and intracellular phospholipases A2 were both inhibited by decyloctyl-GPC which extensively reduced the 20:4 release from exogenous and membrane phospholipids and therefore eicosanoid synthesis.
Our on going work in the series of enamido-diketones issued from 2-azaarylindane-1,3-diones led us to synthesize and experiment N and C2-substituted derivatives of 2-(2 and 4-pyridinyl)indane-1,3-diones as well as of structurally related compounds resulting from the replacement of pyridine by quinoline and benzimidazole. Pharmacological evaluation of their anti-inflammatory activity (by inhibition of carrageenan foot edema) and their anticoagulant activity (by prothombin assay) led to the conclusion of the possibility of achieving a selective anti-inflammatory effect. It has been previously established that anticoagulants are liable to exert a protective effect in the development of cancer metastasis. Nevertheless none of the six experimented 2-(pyridin-2-yl)indane-1,3-diones extended survival time of mice treated by P388 lymphocytic leukemia.
At concentrations 1-20 microns in culture medium of rat peritoneal macrophages which were stimulated with ionophore A23187, the phospholipid analogues 1-decyl-2-octyl-glycerophosphocholine and 1-dodecyl-2-octanamido-2-deoxy glycerophosphocholine were found more potent inhibitors than 1-octyl-2-deoxy glycerophosphocholine to lower the phospholipase A2 activities. The inhibitory effect was measured by [3H] eicosatetraenoic acid ([3H]20:4) release in macrophages and extracellular fluids and synthesis of [3H] eicosanoids after incubation of macrophages with traces of the molecular species of lecithin 1-octadecanoyl-2-[3H] eicosatetraenoyl glycerophosphocholine. The three phospholipid analogues developed higher inhibitory effects than mepacrine, dexamethasone or bromophenacyl bromide, at corresponding concentrations in medium.
Several non-steroidal anti-inflammatory drugs of the N-pyridinyl-benzamide series that produce experimental peripheral and central anti-inflammatory effects possess a dopaminomimetic component and inhibit eicosanoid synthesis without acting directly on the enzymes classically involved in this process. We compared the anti-inflammatory and analgesic activities of one of the most active benzamide derivatives with those of clonidine. Rat paw and brain edemas were inhibited by these two agents, whereas different methods showed that yohimbine counteracted this effect and the analgesia it induced. The involvement of an alpha2-adrenergic and/or serotoninergic components in these activities is considered, without excluding the possibility that the mechanism of action is in part due to inhibition of prostaglandin synthesis.
BACKGROUND: Exploration of the contralateral breast in case of breast cancer has been advocated by many investigators, based on the incidence of contralateral cancer expected to be around 10-15%. METHOD: From 1978 to 1993, 813 contralateral mammaplasties were performed to obtain symmetry in the course of breast reconstruction, including 373 mastopexies and 440 reduction mammaplasties (RMs). All these operations were performed in patients treated for a cancer of the opposite breast. Clinical and radiologic examination before the reduction mammaplasty showed tissue to be free of evident tumor. RESULTS: Twenty clinically and radiologically occult contralateral cancers were found in the reduction specimen (4.6%). Most of them were located in the lower and central quadrants (70%). The macroscopic size of the tumors varied from 3 to 16 mm. Twelve carcinomas were in situ, and eight cases were infiltrating. CONCLUSION: The symmetry procedure allows a good check-up of the glandular tissue of the contralateral breast at the time of the breast reconstruction, especially when there is no evidence of tumor. The different techniques of breast reduction provide specific possibilities for such exploration and should be chosen according to the preferential area that should be explored.
Basal cell carcinomas (BCCs) are very frequent cutaneous cancers, often located on the face. Cure rates with surgery and radiotherapy are high, but these treatments have never been compared prospectively. A randomized trial was initiated in 1982 to compare surgery and radiotherapy in the treatment of primary BCC of the face measuring less than 4 cm. The primary end point was the failure rate (persistent or recurrent disease) after 4 years of follow-up. The secondary end point was the cosmetic results assessed by the patient, the dermatologist and three persons not involved in the trial. In the course of the trial, 347 patients were treated. Of the 174 patients in the surgery group, 71% had local anaesthesia and 91% frozen section examination. Of the 173 patients in the radiotherapy group, 55% were treated with interstitial brachytherapy, 33% with contactherapy and 12% with conventional radiotherapy. The 4-year actuarial failure rate (95% CI) was 0.7% (0.1-3.9%) in the surgery group compared with 7.5% (4.2-13.1%) in the radiotherapy group (log-rank P = 0.003). The cosmetic results assessed by four of the five judges were significantly better after surgery than after radiotherapy. Eighty-seven per cent of the surgery-treated patients and 69% of the radiation-treated patients considered the cosmetic result as good (P < 0.01). Thus, in the treatment of BCC of the face of less than 4 cm in diameter, surgery should be preferred to radiotherapy.
A considerable interest in autologous tissue breast reconstructions has developed recently, especially since Food and Drug Administration (FDA) experts have raised the polemic on silicone implants. Although such enthusiasm for the transverse rectus abdominis musculocutaneous (TRAM) flap is justified in what concerns the final cosmetic result of the reconstructed breast, the risk of abdominal sequelae should be explained to the patient. Abdominal scarring, parietal weakness, strength loss, and back pain have been recorded in a series of pedicled TRAM flap reconstructions performed at the Institut Gustave-Roussy before 1991. Cosmetic results of the abdomen were tested by three independent judges on the photographs taken of 132 patients. The global appearance of the abdomen was rated as "natural" in 70 percent of the patients. The umbilical scar was unacceptable in 25 percent and very good or not visible in 21 percent. The lower abdominal scar was rated as "not acceptable" in 35 percent. Abdominal strength was tested among the 38 patients who underwent both preoperative and postoperative muscular testing, of whom 18 had single-pedicled and 20 had bipedicled TRAM flap reconstructions. In the first group, the physiotherapist observed an impairment of function of the upper portion of the rectus abdominis and of the oblique muscle in almost 50 percent. In the second group, the same muscles were more severely impaired (in 60 percent), as well as the function of the lower portion of the rectus (in 15 percent). The percentage of patients complaining of "light back pain" in the 6-month postoperative period was 55 percent in the single-pedicle group and 30 percent in the double-pedicle group. However, 20 percent of the bipedicled patients complained of "severe" back pain, while there was none in the single-pedicled group. In conclusion, abdominal sequelae after TRAM flap breast reconstruction should not be underestimated and constitute one of the drawbacks of the technique when it is compared with reconstruction with a prosthesis.
The [14C] phospholipid analogue 1-dodecyl-2-[1-14C] octanamido-sn-2-deoxy glycero-3-phosphocholine was synthetized. With 2 short fatty chains linked by alkyl and amido bonds to positions 1 and 2 of the glycerophosphate backbone, it was an inhibitor of phospholipase A2 in ionophore A23187-stimulated macrophages. Its uptake by rat peritoneal macrophages and its resistance towards phospholipases A2 were determined at nanomolar or micromolar concentrations in the culture medium. A control substrate for phospholipases A2 activity was established with the lecithin 1-octadecanoyl 2-[3H] eicosatetraenoyl-sn-glycero-3-phosphocholine ([3H] 20:4-GPC), a source of [3H] arachidonic acid after cleavage at position 2. Non-stimulated- or ionophore A23187-stimulated macrophages incorporated extensively the [14C] phospholipid analogue added at 30-4000 nM. At 4000 nM which induced 50% inhibition of the phospholipase, 40% of the dose was found associated with the [14C] phospholipids of 2 x 10(6) stimulated macrophages after 120 min incubation, while only low amounts of [14C] non-phosphorous lipids were detected. It is concluded that the [14C] phospholipid analogue was readily taken up by the macrophages with limited hydrolysis.
Derivatives of N-(4,6-pyridin-2-yl)arylcarboxamides resulting from the integration of the amidic function into 4H-1,2,4-triazole, triazol-3(2H)-one and 1H-tetrazole rings were evaluated as potential anti-inflammatory compounds. The level of activity decreased as compared to carboxamides, nevertheless their precursors and notably the corresponding amidrazones exhibited potent activity; amidrazone 21, whose ID50 was 34.4 mg.kg-1 in the rat paw edema test, was selected for further investigation. These heteroarylcarboxamide derivatives could represent an interesting alternative to classical non-steroidal anti-inflammatories in so far as they partly act by inhibition of tumor necrosis factor-alpha production.