[Keratoacanthomas on recent tattoos: Two cases]. / Kératoacanthomes sur tatouages récents : deux cas.

BACKGROUND: Increasing numbers of reports of rapidly arising, isolated or eruptive keratoacanthomas (KA) and squamous cell carcinomas (CSC) on the red part of tattoos tend to suggest a non-fortuitous link with the procedure. We report herein two different presentations of KAs on tattoos: one patient with multiple eruptive KAs on sun-exposed areas of a recent red tattoo and another with a solitary lesion on a recent tattoo. We discuss the issues related to the distinction between KAs and CSCs in this particular context. PATIENTS AND METHODS: Case No. 1: A 55-year-old heavily tattooed man presented multiple round keratotic verrucous-like lesions restricted to a red tattoo. The tattoo had been performed by a professional tattooist in summer 2016, a week before the onset of the symptoms. The patient did not protect a part of his tattoo from sun-exposure during the healing phase and lesions developed only on the sun-exposed tattooed parts. In January 2017, he consulted with about ten lesions. The histologic study by shaving of a lesion militated in favor of a CSC, KA type. The physical examination was unremarkable. He had no previous history of skin cancer. Two weeks later, most of the lesions regressed spontaneously. Based on the clinical history and progression of the lesions, a diagnosis was made of eruptive KA on a red tattoo. Residual lesions were treated by cryotherapy or excision. Case No. 2: A 72-year-old woman developed a 1-cm painful dome-shaped nodule with a central crust three weeks after tattooing. Full excision confirmed the diagnosis of KA. DISCUSSION: To date, we have found 31 case reports and series (17 men, median age: 50.5 years) of KA and CSC on tattoos. Lesions usually develop rapidly after completion of the tattoo, after between one week and several months. Exceptional cases have been described in old tattoos. Red tattoo ink is most commonly the culprit. The main difficulty lies in distinguishing between KA and CSC. Nowadays pathologists agree that a KA should be considered as a variant of CSC. Eruptive forms of KA present a peculiar situation. They may sometimes be inherited, and KA on recent traumatized areas or drug-induced have been described. Like other authors, we believe that cases of CSC on red tattoos belong rather to the KA type. The physiopathogenesis of tattoo-associated eruptive KA and CSC is not clearly understood, but could be multifactorial, involving: the trauma induced by tattooing, local inflammatory reaction, a component of the red ink, external factors such UV exposure, and a possible genetic predisposition. Rapidly arising KA and eruptive KA on top of recent (red) tattoos are not fortuitous. The lesions should be excised and the patient monitored. Additional studies on tumor specimens are warranted to identify the possible causative agents in tattoo ink that may be responsible for such reactions.

[Granulomatous slack skin associated with metastatic testicular seminoma]. / Mycosis fongoïde chalazodermique associé à un séminome testiculaire métastatique.

BACKGROUND: Granulomatous slack skin (GSS) is an extremely rare subtype of T-cell lymphoma, a variant of mycosis fungoides (MF). Herein, we describe the first reported case of GSS associated with metastatic testicular seminoma. PATIENTS AND METHODS: A 28-year-old male patient presented with circumscribed erythematous loose skin masses, especially in the body folds and which had been relapsing for 4years. Skin biopsy showed a loss of elastic fibers and an atypical granulomatous T-cell infiltrate with epidermotropism, enabling a diagnosis of GSS to be made. A biopsy of a retroperitoneal lymphadenopathy showed testicular seminoma metastasis. DISCUSSION: Patients suffering from GSS have a statistically higher risk of developing a second primary cancer, especially Hodgkin's lymphoma. The association found between GSS and a lymphoproliferative malignancy requires long-term follow-up and determines the patient's prognosis. CONCLUSION: It is not possible to prove a formal link between GSS and testicular seminoma. However, this case illustrates the value of screening for a second cancer, particularly where extra-cutaneous lesions appear during GSS treatment. Lymph node biopsy should be performed routinely in the event of GSS with possible lymph node involvement.

Potential antidepressants displayed combined alpha(2)-adrenoceptor antagonist and monoamine uptake inhibitor properties.

Classical antidepressants are thought to act by raising monoamine (serotonin and noradrenaline) levels in the brain. This action is generally accomplished either by inhibition of monoamine metabolism (MAO inhibitors) or by blockade of monoamine uptake (tricyclic antidepressants and selective serotonin or noradrenaline reuptake inhibitors). However, all such agents suffer from a time lag (3--6 weeks) before robust clinical efficacy can be demonstrated. This delay may reflect inhibitory actions of noradrenaline at presynaptic alpha(2A)-adrenergic auto- or heteroreceptors which gradually down-regulate upon prolonged exposure. Blockade of presynaptic alpha(2A)-adrenoceptors by an antagonist endowed with monoamine uptake inhibition properties could lead to new antidepressants with greater efficacy and a shorter time lag. In the literature, only two molecules have been described with such a pharmacological profile. Of these, napamezole (2) was chosen as a point of departure for the design of 4(5)-[(3,4-dihydro-2-naphthalenyl)methyl]-4,5-dihydroimidazole (4a), which displayed the desired profile: alpha(2A)-adrenoceptor antagonist properties and serotonin/noradrenaline uptake inhibition. From this original molecule, a series of derivatives was designed and synthesized, encompassing substituted as well as rigid analogues. Structure-activity relationships permitted the selection of 14c (4(5)-[(5-fluoroindan-2-yl)methyl]-4,5-dihydroimidazole) as a development candidate.

S18616, a highly potent, spiroimidazoline agonist at alpha(2)-adrenoceptors: I. Receptor profile, antinociceptive and hypothermic actions in comparison with dexmedetomidine and clonidine.

S18616 ((S)-spiro[(1-oxa-2-amino-3-azacyclopent-2-ene)-4, 2'-(8'-chloro-1',2',3',4'-tetrahydronaphthalene)]) displayed high affinity at native rat alpha(2)-adrenoceptors (AR)s (pK(i), 9.8), native human (h)alpha(2A)-ARs (9.6), and cloned halpha(2A)- (9.5), halpha(2B)- (9.2), and halpha(2C)- (9.0) ARs. It showed 40-fold lower affinity for halpha(1A)-ARs (8.4) and >/=100-fold lower affinity for rat alpha(1)-ARs (7.1), halpha(1B)-ARs (7.7), halpha(1D)-ARs (7.6), imidazoline(1) (7.4), and imidazoline(2) (7.4) sites and >100-fold lower affinity for all other (>50) sites. At halpha(2A)-ARs, in guanosine-5'-O-(3-[(35)S]thio)triphosphate binding studies, S18616 was a potent (partial) agonist: log effective concentration (pEC(50)), 9.3/maximal effect, 51%. This observation was corroborated employing a halpha(2A)-Gi1alpha fusion protein/GTPase assay (9.0/40%) in which the actions of S18616 were blocked by pertussis toxin. Employing guanosine-5'-O-(3-[(35)S]thio)triphosphate binding assays, S18616 was also a partial agonist at halpha(2C)-ARs (8.2/63%) but a full agonist (8.4/124%) at halpha(2B)-ARs. At halpha(2A)-, halpha(2B)-, and halpha(2C)-ARs, the selective alpha(2)-AR antagonist, atipamezole, abolished the actions of S18616: pK(b) values of 9.1, 9. 1, and 9.4, respectively. As determined by depletion of membrane-bound [(3)H]phosphatidyl inositols, S18616 behaved as a (less potent) agonist (7.8/79%) at halpha(1A)-ARs, an action abolished by prazosin (pK(b), 8.9). Reflecting alpha(2)-AR agonist properties, S18616 potently (>/=1 microg/kg, s.c.) and dose dependently elicited hypothermia and antinociception (nine diverse models) in rodents. These actions were dose dependently inhibited by chemically diverse alpha(2)- versus alpha(1)-AR antagonists, atipamezole, idazoxan, RX821,002, and BRL44418 (a preferential alpha(2A)-AR ligand). In contrast, the actions of S18616 were unaffected by the alpha(1)-AR antagonists, ARC239 and prazosin (which preferentially block alpha(2B/2C)- versus alpha(2A)-ARs). Although the affinity of dexmedetomidine at alpha(2)-ARs was lower than S18616; it displayed a similar receptor and functional profile. Clonidine displayed lower efficacy than S18616, was substantially less potent, and had marked affinity for imidazoline(1) sites and alpha(1)-ARs. In conclusion, S18616 is a novel, selective, and highly potent agonist at alpha(2)-ARs.

S18616, a highly potent spiroimidazoline agonist at alpha(2)-adrenoceptors: II. Influence on monoaminergic transmission, motor function, and anxiety in comparison with dexmedetomidine and clonidine.

The alpha(2)-adrenoceptor (AR) agonist, S18616 ((S)-spiro[(1-oxa-2-amino-3-azacyclopent-2-ene)-4,2'-(8'-chloro-1' , 2',3',4'-tetrahydronaphthalene)] accompanying article), suppressed electrical activity of adrenergic neurons in the locus ceruleus, an action reversed by the alpha(2)-AR antagonist, idazoxan, which itself enhanced their firing rate. Electrical activity of serotonergic neurons in the dorsal raphe nucleus was similarly suppressed, an action likewise blocked by idazoxan, which did not, itself, influence firing. In freely moving rats, S18616 decreased extracellular levels of norepinephrine (NE), serotonin (5-HT), and dopamine (DA) in frontal cortex and hippocampus. The selective alpha(2)- versus alpha(1)-AR antagonists, atipamezole and BRL-44408 (a preferential alpha(2A)-AR antagonist), elevated levels of NE and DA but not 5-HT. In their presence, the influence of S18616 on frontocortical levels of NE, DA, and 5-HT was blocked. In contrast, prazosin, a selective alpha(1)- versus alpha(2)-AR antagonist (which also preferentially blocks alpha(2B/2C)-ARs) dose dependently decreased levels of 5-HT, but not NE and DA, and failed to modify the actions of S18616. Ultrasonic vocalizations elicited by rats in an aversive environment were inhibited by S18616, which also suppressed aggressive and marble-burying behaviors in mice. Furthermore, S18616 (biphasically) enhanced punished responses in the Vogel conflict test and active social interaction tests in rats. At higher doses, S18616 displayed sedative/hypnotic properties. Both anxiolytic and motor actions of S18616 were inhibited by atipamezole and BRL-44408 but not prazosin. Dexmedetomidine mimicked the actions of S18616 at higher doses except for more potent sedative/hypnotic properties. Clonidine also mimicked S18616, but only at markedly higher doses. In conclusion, via activation of alpha(2)-ARs, S18616 potently inhibits corticolimbic adrenergic, serotonergic, and (frontocortical) dopaminergic transmission in parallel with the expression of its anxiolytic and sedative properties.

Design, synthesis and structure-activity relationships of novel strychnine-insensitive glycine receptor ligands.

The in vitro activities of 3-hydroxy-imidazolidin-4-one derivatives demonstrated very restricted structure-activity relationships at the strychnine-insensitive glycine site of the NMDA receptor. The most active compound (3a) was completely unsubstituted and exhibited affinity and efficacy similar to that of D-cycloserine, the prototypical partial agonist at this site.

(S)-spiro[(1,3-diazacyclopent-1-ene)-5,2'-(7'-methyl-1',2',3',4'- tetrahydronaphthalene)]: resolution, stereospecific synthesis, and preliminary pharmacological characterization as a partial alpha-adrenergic agonist.

Recently, we reported on the design, synthesis, and structure-activity relationships of a series of spiroimidazolines endowed with alpha-adrenergic agonist activities. Among the compounds described, (R,S)-spiro(1,3-diazacyclopent-1-ene)-[5,2'](7'-methyl-1'2',3', 4',-tetrahydronaphthalene) fumarate (5RS) was chosen for further development as a venotonic agent. The resolution of this compound, as well as the pharmacological characterization of the enantiomers, stereospecific synthesis of eutomer (5S, S 18149), and determination of absolute configuration by single-crystal X-ray diffraction analysis, are described.

Recording of the saphenous vein compliance by an ultrasonic echo-tracking device in the dog: effects of S 18149.

1. Saphenous vein reactivity was recorded in the anaesthetized dog by use of an ultrasonic echo-tracking device to measure the internal diameter of the vein and to calculate the venous compliance. This method was used to investigate the effects of a new partial alpha1/alpha2-adrenoceptor agonist, S 18149, on the canine saphenous vein in vivo after intravenous (i.v.) or oral administration. 2. Venoconstrictions induced by i.v. or local administration of compounds were evaluated by continuous recording of the internal diameter of the saphenous vein with the echo-tracking method. Venous compliance was calculated in two ways: (1) as the slope of the diameter-pressure curve obtained by increasing the venous pressure with an inflatable cuff and (2) in veins in which pressure was higher than 12 mmHg, pulsatile variations in the venous diameter and venous pressure were detected and used to calculate the pulsatile compliance of the vein. 3. S 18149 administered i.v. at 0.5 microg kg(-1) min(-1) for 10 min induced a decrease in the saphenous vein diameter (-15+/-3%) and blood flow (-72+/-6%) associated with an increase in saphenous vein resistance; at the dose used, S 18149 did not modify venous pressure and caused only a weak increase in arterial pressure (+7+/-2 mmHg). 4. The pulsatile compliance of the saphenous vein averaged 8.65+/-1.37 mm2 x 100 mmHg(-1) in control dogs and was significantly decreased to 5.13+/-0.68 mm2 x 100 mmHg(-1) in the same animals after treatment with S 18149 at 100 microg kg(-1) per os (n=10). The saphenous vein compliance calculated with the increased external pressure method averaged 24.90+/-1.49 microm mmHg(-1) in control dogs and was significantly reduced in the same animals after treatment with S 18149 at 100 microg kg(-1) per os to 9.06+/-3.42 microm mmHg(-1) (n=5). When constrictions of the vein were induced with increasing doses of (-)-phenylephrine, injected locally at 1, 3 or 6 microg min(-1), only the responses obtained with the lower dose of (-)-phenylephrine were increased in dogs treated with S 18149 100 microg kg(-1) per os (-16+/-4% versus -4+/-3%, n=5). 5. These results show that the high resolution echo-tracking device previously used for arterial compliance measurements, allows the detection of pulsatile changes in the canine saphenous vein and thus permits calculation of both the pulsatile and the static compliance of superficial veins in vivo. Using this technique, we have demonstrated that the novel alpha-adrenoceptor agonist S 18149 constricts the canine saphenous vein in vivo and decreases the saphenous vein compliance after oral administration.

Synthesis of 1,2-diacyl-3-nicotinoyl glycerol derivatives and evaluation of their acute effects on plasma lipids in the rat.

Nicotinic acid (CAS 59-67-6) is the only hypolipidemic agent whose activity has been shown both on atherosclerotic lesions and on long term mortality. Unfortunately, its use is hindered by the frequent occurrence ( > 70%) of adverse reactions (i.e. cutaneous rash, pruritus and, most significantly, flush). New prodrugs of nicotinic acid have been prepared by the use of diacylglycerol esters. In the rat, after acute oral administration of these products, a significant decrease of the free fatty acid plasma levels was obtained without the dramatic increase in nicotinic acid plasma levels observed after the oral administration of an equimolecular dose of nicotinic acid. The most interesting ester, S 16961 ((d,l)-1,2-dipalmitoyl-3-nicotinoyl glycerol, CAS 160555-46-4) is undergoing clinical trials.

Design, synthesis, and structure-activity relationships of a new series of alpha-adrenergic agonists: spiro[(1,3-diazacyclopent-1-ene)-5,2'-(1',2',3',4'- tetrahydronaphthalene)].

The contractions induced by a partial alpha 1-adrenoceptor agonist in cutaneous veins, such as the saphenous vein, show a particular sensitivity to changes in local temperature: the contractility to a partial alpha 1-adrenoceptor agonist increases when the temperature is raised, a response that contrasts to that noted with full alpha 1- and alpha 2-adrenoceptor agonists. This observation may be of importance for the treatment of the symptoms of venous insuffiency, favored during warm summer days. A new series of full and partial alpha-adrenergic agonists was designed and synthesized, the spiro[(1,3-diazacyclopent-1-ene)-5,2'-(1',2',3',4'- tetrahydronaphthalene)] 7a-kk or spiro-imidazolines. Using in vitro (femoral artery and saphenous vein) and in vivo (pithed rat) biological evaluations, structure-activity relationships could be defined which allowed the discovery of a full alpha 2-agonist (34b), a full alpha 1-agonist (7s), and a nonselective partial alpha 1/alpha 2-agonist (7aa) endowed with an outstanding veinotonic selectivity as compared to its effect on mean arterial pressure. The latter compound is presently undergoing extensive pharmacological and toxicological evaluations, as a clinical candidate.

The antagonist properties of S 11978 on 5HT3 receptors in N1E-115 neuroblastoma cells.

The effects of the novel antagonist S 11978 (Endo-7-[(8-methyl-8-azabicyclo[3,2,1]-3-octyl)oxycarbonyl] benzo[b] thiophene) on 5HT3 receptors were examined in N1E-115 mouse neuroblastoma x rat glioma hybrid cells, with radioligand binding and whole cell patch clamp techniques. The 5HT3 receptor ligand [3H] quipazine was displaced by ICS 205-930, GR 38032F and S 11978 with KI values of 2.25 nM, 36.5 nM and 1.75 nM respectively. Electrophysiological studies showed that S 11978 is a potent 5HT3 antagonist: IC50 values for inhibition of 5HT-induced inward current by ICS 205-930, GR 38032F and S 11978 were 0.22 nM, 0.63 nM and 0.43 nM respectively at a holding potential of -65 mV. It is concluded that S 11978 is a potent, high affinity 5HT3 receptor antagonist.

Enzyme-activated irreversible inhibitors of monoamine oxidase: phenylallylamine structure-activity relationships.

Seventeen 2-aryl-3-haloallylamine derivatives were prepared and evaluated as inhibitors of monoamine oxidase (MAO, EC 1.4.3.4). The synthesis of these compounds was achieved from either alpha-methylstyrene or ring-substituted phenylacetic acid derivatives. With one exception, these 2-arylallylamines were found to be enzyme-activated, irreversible inhibitors of MAO. The most potent inhibitors were ring-substituted derivatives of (E)-2-phenyl-3-fluoroallylamine with IC50 values ranging from 10(-6) to 10(-8) M. Selectivity for the A and B form of MAO was found to depend on the nature of aromatic ring substitution. In general, hydroxyl substitution favored the inactivation of the A form of MAO, while very selective B inhibitors were obtained when the aromatic ring was substituted with a 4-methoxy group. (E)-2-(4-Methoxyphenyl)-3-fluoroallylamine and (E)-2-(3,4-dimethoxyphenyl)-3-fluoroallylamine proved to be in vitro as selective for the B form of MAO as deprenyl.

[Multicystic peritoneal mesothelioma. Ultrastructural and immunohistochemical study apropos of a case]. / Le mésothéliome multikystique péritonéal. Etude ultrastructurale et immunohistochimique à propos d'une observation.

Authors present the case of a 59 years old man in whom an intra abdominal mass was discovered fortuitly. A surgical intervention permitted to remove a retroperitoneal mass. The macroscopic features were similar to those of multicystic mesothelioma. A review of literature of the 31 cases published permits to present the characteristics of cystic mesothelioma. This entity was confound during a long time with cystic lymphangioma, from which it was distinguished in 1979 with the use of electron microscopy. Interest of studies in immunochemistry, already unpublished, is demonstrated here for Factor VIII and cytokeratin.