The use of Nexobridtm in debriding chronic ulcers: a preliminary observational study.

Nexobrid is a highly selective enzymatic debriding agent used in the acute management of burns to perform escharectomy. From October 2016 to April 2017, we treated 6 patients affected with lower limb chronic ulcers of different etiologies with Nexobrid in order to perform eschar removal by enzymatic debridement. For all patients, a dosage of Nexobrid, calculated as 2gr per 1% TBSA, was applied in a 2-3 mm thick uniform layer on the ulcer eschar and fibrin tissue and left for 4 hours, covered with an occlusive dressing. Patients were assessed in terms of ulcer cleansing 24 hours and 7 days post Nexobrid debridement, by wound bed score (WBS) and % of remaining necrotic tissue. A patient pain VAS was also recorded at 24 hours and 7 days post debridement. Adverse events at these time points were also noted. The results documented a complete removal of necrotic tissue in a time frame of 4 hours. At 24 hours, all lesions were completely debrided. At 7 days, there was a partial recurrence of necrotic tissue, as also documented by decreased WBS. All patients reported none to mild pain, and no adverse events were noted, except for mild erythema along the edges of the lesion on healthy skin in one case. This is a preliminary observation. Optimal dosage and application of Nexobrid in this indication needs to be validated by further controlled data.

Nexobrid est un agent de débridement hautement sélectif utilisé dans la prise en charge des brûlés pour réaliser une excision enzymatique. Entre octobre 2016 et avril 2017, nous l'avons utilisé pour réaliser ce même type d'excision chez 6 patients souffrant d'ulcères chroniques de jambe, d'étiologies variées. Nous avons appliqué 2g de Nexobrid par % de surface coporelle atteinte, en une couche uniforme de 2-3 mm d'épaisseur laissée en place 4h sous pansement occlusif. À 24 h et 7 jours, nous avons évalué le score de fond de plaie (Wound Bed Score-WBS), le pourcentage restant de tissu nécrotique, la douleur (EVA) et les effets secondaires. À 4h, les tissus nécrosés avaient entièrement disparu, ne réapparaissant pas à 24 h. À J7, on notait une réapparition, sur une surface moindre, de tissus nécroiques et une altération du WBS. Les patients étaient non ou peu douloureux. Le seul effet secondaire observé, chez un patient, a été un érythème modéré de la peau saine circonscrivant la lésion. À la suite de cette étude préliminaire, des études plus larges permettront de préciser les modalités d'utilisation de Nexobrid dans cette indication.

Spontaneous healing and scar control following enzymatic debridement of deep second-degree burns.

Scarring after a burn injury remains the greatest unmet challenge in the treatment of functional and psychosocial sequelae of burns. The hypertrophic scar represents the most common type of cicatrix after burns, and it has a prevalence of up to 70%. We present a case of upper and lower extremity partial-thickness burns in a female patient treated in two different modalities. Superficial seconddegree burns on the upper extremities were treated with conservative dressing with fairly early wound closure but they developed hypertrophic scars. Deeper, lower extremity burns were debrided with a new bromelain-based debriding agent, resulting in scar-free healing. The pathophysiology of hypertrophic scar formation is based on the perturbation of collagen production or degradation or both. The duration and magnitude of the inflammatory phase of wound healing also appears to play a role in hypertrophic scarring. Bromelain has demonstrated an anti-angiogenic effect in various cancer cell lines and it has been shown to regulate a variety of pro-angiogenic growth factors. This case raises the classical question of the relationship between time to healing and formation of hypertrophic scars after burn injury, pointing to other potential factors that may play an important role in burn healing.

La cicatrisation après une brûlure reste le plus grand défi du traitement des séquelles à la fois sur le plan fonctionnel et sur le plan psychologique. La cicatrisation hypertrophique représente l'évolution la plus fréquente après brûlure et sa prévalence est supérieure à 70 %. Nous présentons une observation de brûlures du 2e degré au niveau du membre supérieur et du membre inférieur chez une patiente traitée suivant deux modalités différentes. Les brûlures du second degré superficiel du membre supérieur furent traitées par un pansement classique avec une cicatrisation précoce, mais suivie de cicatrices hypertrophiques. Les brûlures plus profondes du membre inférieur furent détergées avec le nouvel agent à base de bromelaïne, et permirent une guérison sans cicatrice. La physiopathologie de la cicatrisation hypertrophique est basée sur les troubles de production des fibres de collagène, ou de leur dégradation, ou des deux. La durée et l'amplitude de la phase inflammatoire de la cicatrisation paraît aussi jouer un rôle dans l'hypertrophie cicatricielle. La bromelaïne a démontré son effet anti-angiogénique dans plusieurs lignées cellulaires cancéreuses ; elle a montré aussi son aptitude à réguler les divers facteurs de croissance pro-angiogéniques. Cette observation soulève la question classique de la relation entre le temps de cicatrisation et l'apparition de cicatrices hypertrophiques après brûlure, en soulignant les autres facteurs potentiels jouant un rôle important dans la cicatrisation des brûlures.

Synthesis and immunosuppressive activity of novel prodigiosin derivatives.

Prodigiosins (Ps) represent a family of naturally occurring red pigments characterized by a common pyrrolylpyrromethene skeleton. Some members of this family have been shown to possess interesting immunosuppressive properties exerted with a novel mechanism of action, different from that of currently used drugs. In fact, Ps inhibit phosphorylation and activation of JAK-3, a cytoplasmic tyrosine kinase associated with a cell surface receptor component called common gamma-chain, which is exclusive of all IL-2 cytokine family receptors. Blocking common gamma-chain transduction activity results in a potent and specific immunosuppressive activity. With respect to the interesting and unexploited immunomodulating properties of this family of compounds we initiated a medicinal chemistry program aimed at finding novel prodigiosin derivatives with improved immunosuppressive activity and lower toxicity. Utilizing an unprecedented and flexible way of assembling the prodigiosin frame, a number of new derivatives have been prepared and tested leading to the choice of 4-benzyloxy-5-[(5-undecyl-2H-pyrrol-2-ylidene)methyl]-2, 2'-bi-1H-pyrrole (PNU-156804, 16) as a lead immunosuppressant.

New immunosuppressive drug PNU156804 blocks IL-2-dependent proliferation and NF-kappa B and AP-1 activation.

We had previously shown that the drug undecylprodigiosin (UP) blocks human lymphocyte proliferation in vitro. We have now investigated the mechanism of action of a new analogue of UP, PNU156804, which shows a more favorable activity profile than UP in mice. We demonstrate here that the biological effect of PNU156804 in vitro is indistinguishable from UP: PNU156804 blocks human T cell proliferation in mid-late G1, as determined by cell cycle analysis, expression of cyclins, and cyclin-dependent kinases and retinoblastoma phosphorylation. In addition, we show that PNU156804 does not block significantly the induction of either IL-2 or IL-2R alpha- and gamma-chains but inhibits IL-2-dependent T cell proliferation. We have investigated several molecular pathways that are known to be activated by IL-2 in T cells. We show that PNU156804 does not inhibit c-myc and bcl-2 mRNA induction. On the other hand, PNU156804 efficiently inhibits the activation of the NF-kappa B and AP-1 transcription factors. PNU156804 inhibition of NF-kappa B activation is due to the inhibition of the degradation of I kappa B-alpha and I kappa B-beta. PNU156804 action is restricted to some signaling pathways; it does not affect NF-kappa B activation by PMA in T cells but blocks that induced by CD40 cross-linking in B lymphocytes. We conclude that the prodigiosin family of immunosuppressants is a new family of molecules that show a novel target specificity clearly distinct from that of other immunosuppressive drugs such as cyclosporin A, FK506, and rapamycin.

Equilibrium and kinetics of rotamer interconversion in immunosuppressant prodigiosin derivatives in solution.

The equilibrium and relative rate of rotamer interconversion around the bond joining the 2,2'-bipyrrolyl and pyrromethene moieties in a synthetic analogue of immunosuppressant prodigiosin are investigated as a function of pHapp in a water/acetonitrile mixture (1/1 by volume). Two chromatographically separable isomeric forms are obtained in acid solutions (pHapp < 4), whereas rapid interconversion occurs above neutrality. Furthermore, pH modulates the conformational preference of the molecule according to nitrogen protonation on the three pyrrole rings system (pKa = 7.2). At high pHapp (neutral form), the same conformer that is observed in pure acetonitrile prevails, whereas the other one is preferred by the protonated form. The nuclear magnetic resonance data indicate that the structures of the two conformers mainly differ in the value of the torsion angle around the aforementioned C-C bond. Kinetic and equilibrium data are quantitatively interpreted with a cyclic mechanism including two protonation (pKa1 = 8.23 +/- 0.03, pKa2 = 5. 4 +/- 0.2) and two conformational rearrangement steps. A molecular interpretation of the observed behavior includes, for the preferred conformer at low pH, formation of a new hydrogen bond between the exocyclic oxygen and the neighboring pyrrole NH upon protonation of the three pyrrole rings system.

4-Aminoandrostenedione derivatives: a novel class of irreversible aromatase inhibitors. Comparison with FCE 24304 and 4-hydroxyandrostenedione.

FCE 24928 (4-aminoandrosta-1,4,6-triene-3,17-dione) was selected among a series of 4-aminoandrostenedione derivatives as a novel irreversible aromatase inhibitor. Its in vitro and in vivo properties have been studied and compared to FCE 24304 (6-methylenandrosta-1,4-diene-3,17-dione) and 4-OHA (4-hydroxyandrostenedione). FCE 24928 caused time-dependent inhibition of human placental aromatase with a t1/2 of 4 min and Ki of 59 nM. Enzyme inactivation by FCE 24928 was faster than by FCE 24304 (t1/2 13.9 min). In PMSG-treated rats, microsomal ovarian aromatase activity was reduced 24 h after FCE 24928 dosing by both the s.c. (ED50 1.2 mg/kg) and the oral (ED50 14.1 mg/kg) routes. The compound was more potent than FCE 24304 and 4-OHA (ED50 1.8 and 3.1 mg/kg s.c.). FCE 24928 did not show any interference with 5 alpha-reductase and desmolase activity nor any significant binding affinity for androgen and estrogen receptors. Slight binding affinity for androgen receptor was observed with FCE 24304 and 4-OHA (0.21 and 0.25% of DHT). In immature, castrated rats, FCE 24928 did not show any intrinsic androgenic activity, up to 100 mg/kg/day s.c., in contrast to a slight androgenic activity observed with FCE 24304 at 10 mg/kg s.c.

Synthesis, DNA-binding properties, and antitumor activity of novel distamycin derivatives.

A group of potential alkylating agents have been synthesized that are structurally related to the oligopeptide antiviral antibiotic distamycin. All derivatives form complexes with native calf-thymus DNA but compounds 2, 3, and 6 give rise to covalent adducts. Cytostatic activity against both human and murine tumor cell lines in vitro is displayed by the new compounds. Compounds 3 and 4 are active on melphalan-resistant L1210 leukemia in mice.

[Renal tubular acidosis during a course of liver cirrhosis]. / Acidosi renale tubulare in corso di cirrosi epatica.

In a group of 23 patients suffering from liver cirrhosis, metabolic acidosis was always observed, in most cases corrected by respiratory alkalosis. In 8,6% of cases a tubular renal acidosis (type I), in 8,6% (type II) and 8,6% a loss of urinary bicarbonate without acidosis were observed.