Role of nitric oxide in skin flap delay.

Surgical delay of skin flaps before transfer is known to improve flap viability. This study attempts to elucidate the mechanism of vasodilation by exploring the effects of nitric oxide on the microcirculation of delayed skin flaps. Using a skin flap model in 22 CD-1 white mice, the diameter of two nonterminal choke arteries was measured using in vivo videomicroscopy. Vessel flow was also measured using an optical Doppler velocimeter. Similar measurements were recorded in several animals on the same vessels in which subcutaneous dissection without elevation was performed. Average vessel diameter ranged from 21.77 to 25.55 microm before skin flap delay. Average flow ranged from 1.72 to 2.44 nl/sec before delay. Next, each animal received an intraperitoneal dose of nitro-aminomethyl-1-arginine (L-NAME), a nitric oxide synthase inhibitor delivered by means of osmotic pump at a level of 0 (n = 13 arteries), 20 (n = 10), 50 (n = 8), or 100 mg/kg/day (n = 7). Flaps were re-elevated 72 hours later and the aforementioned measurements were repeated. Vessel diameter increased to 44.92 microm in the control (0 mg/kg L-NAME) animals. Flow increased to 7.66 nl/sec in the control animals. Vessel dilation and flow did not change significantly in the nonoperative vessels. As the dose of L-NAME increased in the treated animals, there was a significant decrease in vasodilation and flow (p = 0.015 and p = 0.03, respectively). The authors' results demonstrate that nitric oxide is an important element of vasodilation and contributor to the phenomenon of skin flap delay.

Application of the bicyclo[1.1.1]pentane motif as a nonclassical phenyl ring bioisostere in the design of a potent and orally active γ-secretase inhibitor.

Replacement of the central, para-substituted fluorophenyl ring in the γ-secretase inhibitor 1 (BMS-708,163) with the bicyclo[1.1.1]pentane motif led to the discovery of compound 3, an equipotent enzyme inhibitor with significant improvements in passive permeability and aqueous solubility. The modified biopharmaceutical properties of 3 translated into excellent oral absorption characteristics (~4-fold ↑ C(max) and AUC values relative to 1) in a mouse model of γ-secretase inhibition. In addition, SAR studies into other fluorophenyl replacements indicate the intrinsic advantages of the bicyclo[1.1.1]pentane moiety over conventional phenyl ring replacements with respect to achieving an optimal balance of properties (e.g., γ-secretase inhibition, aqueous solubility/permeability, in vitro metabolic stability). Overall, this work enhances the scope of the [1.1.1]-bicycle beyond that of a mere "spacer" unit and presents a compelling case for its broader application as a phenyl group replacement in scenarios where the aromatic ring count impacts physicochemical parameters and overall drug-likeness.

Metabolism-directed design of oxetane-containing arylsulfonamide derivatives as γ-secretase inhibitors.

A metabolism-based approach toward the optimization of a series of N-arylsulfonamide-based γ-secretase inhibitors is reported. The lead cyclohexyl analogue 6 suffered from extensive oxidation on the cycloalkyl motif by cytochrome P450 3A4, translating into poor human liver microsomal stability. Knowledge of the metabolic pathways of 6 triggered a structure-activity relationship study aimed at lowering lipophilicity through the introduction of polarity. This effort led to several tetrahydropyran and tetrahydrofuran analogues, wherein the 3- and 4-substituted variants exhibited greater microsomal stability relative to their 2-substituted counterparts. Further reduction in lipophilicity led to the potent γ-secretase inhibitor and 3-substituted oxetane 1 with a reduced propensity toward oxidative metabolism, relative to its 2-substituted isomer. The slower rates of metabolism with 3-substituted cyclic ethers most likely originate from reductions in lipophilicity and/or unfavorable CYP active site interactions with the heteroatom. Preliminary animal pharmacology studies with a representative oxetane indicate that the series is generally capable of lowering Aß in vivo. As such, the study also illustrates the improvement in druglikeness of molecules through the use of the oxetane motif.

Formation of functional neovagina with vertical rectus abdominis musculocutaneous (VRAM) flap after total pelvic exenteration.

BACKGROUND: Pelvic exenteration may be the only curative option for women with recurrent pelvic malignancies. After total pelvic exenteration, the resultant perineal defect heals slowly if left to do so by secondary intention. Reconstruction with the vertical rectus abdominis musculocutaneous (VRAM) flap brings a generous bulk of healthy tissue into the defect, speeding recovery by facilitating primary healing. METHODS: Six women underwent reconstruction of a neovagina using a vertical rectus abdominis musculocutaneous flap. All 6 had total pelvic exenteration for advanced gynecologic malignancy. Primary diagnosis was cervical carcinoma (n = 3), vulvar carcinoma (n = 1), nonsmall cell vaginal cancer (n = 1), and vaginal melanoma (n = 1). Four patients had received adjuvant radiotherapy preoperatively. RESULTS: All flaps remained 100% viable postoperatively. There were no cases of fistula, infection, or bowel obstruction. Two patients died of cardiovascular arrest postoperatively. The 4 other patients report satisfaction with reconstruction. Three had vaginal intercourse with orgasm. CONCLUSION: The inferiorly based vertical rectus abdominis musculocutaneous flap is a dependable source of tissue for pelvic reconstruction and is the flap of choice in the Division of Plastic Surgery. In addition to facilitating healing, the VRAM flap (neovagina) improves a woman's psychosocial well-being.

Perioperative considerations in the autologous breast reconstruction patient with systemic lupus erythematosus.

Following mastectomy, women with breast cancer are faced with choices for reconstruction. In women with systemic lupus erythematosus (SLE), with or without antiphospholipid syndrome (APS), concurrent morbidities are important considerations when deciding the method of reconstruction. The 2 cases we present represent the variable spectrum of SLE and/or APS and their potential complications. When deciding the best course of action, it is most important to consider each case on an individual basis, with important emphasis on preoperative disease status.

Reconstruction after extirpation of sacral malignancies.

Defects after extirpation of either sacral or rectal tumors often present a reconstructive challenge to plastics surgeons. Because of their relative infrequency, management guidelines, in the authors' opinion, have been overlooked. They think that successful, comprehensive treatment lends itself to an integrated team approach. They review their experience with immediate reconstruction after total sacrectomy for sacral malignancies performed between 1996 and 2001. Medical records were reviewed retrospectively for the surgical procedure, postoperative complications, and eventual outcome. A total of 9 patients underwent sacrectomy with a gluteus maximus flap for reconstruction. Six patients had a simultaneous omental flap for complete obliteration of the surgical defect. The authors' experience suggests that this combination of techniques is a reliable approach for reconstruction of these extensive surgical defects.