Enhancing Philtrum Morphology Using Fat Grafting Combined with Percutaneous Rigottomy in Repaired Unilateral Cleft Lip.

BACKGROUND: Improving the philtrum morphology of patients with a secondary cleft lip deformity has been a challenge in cleft care. Combining fat grafting with percutaneous rigottomy has been advocated for treatment of volumetric deficiency associated with a scarred recipient site. This study assessed the outcome of synchronous fat grafting and rigottomy for improvement of cleft philtrum morphology. METHODS: Consecutive young adult patients ( n = 13) with a repaired unilateral cleft lip who underwent fat grafting combined with rigottomy expansion technique for enhancement of philtrum morphology were included. Preoperative and postoperative three-dimensional facial models were used for three-dimensional morphometric analyses including philtrum height, projection, and volume parameters. Lip scar was qualitatively judged by a panel composed by two blinded external plastic surgeons using a 10-point visual analogue scale. RESULTS: Three-dimensional morphometric analysis revealed a significant (all P < 0.05) postoperative increase of the lip height-related measurements for cleft philtrum height, noncleft philtrum height, and central lip length parameters, with no difference ( P > 0.05) between cleft and noncleft sides. The postoperative three-dimensional projection of the philtral ridges was significantly ( P < 0.001) larger in cleft (1.01 ± 0.43 mm) than in noncleft sides (0.51 ± 0.42 mm). The average philtrum volume change was 1.01 ± 0.68 cm 3 , with an average percentage fat graft retention of 43.36% ± 11.35%. The panel assessment revealed significant ( P < 0.001) postoperative scar enhancement for the qualitative rating scale, with mean preoperative and postoperative scores of 6.69 ± 0.93 and 7.88 ± 1.14, respectively. CONCLUSION: Synchronous fat grafting and rigottomy improved philtrum length, projection, and volume and lip scar in patients with repaired unilateral cleft lip. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

Dual angiotensin II and endothelin A receptor antagonists: synthesis of 2'-substituted N-3-isoxazolyl biphenylsulfonamides with improved potency and pharmacokinetics.

In a previous report we demonstrated that merging together key structural elements present in an AT(1) receptor antagonist (1, irbesartan) with key structural elements in a biphenylsulfonamide ET(A) receptor antagonist (2) followed by additional optimization provided compound 3 as a dual-action receptor antagonist (DARA), which potently blocked both AT(1) and ET(A) receptors. Described herein are our efforts directed toward improving both the pharmacokinetic profile as well as the AT(1) and ET(A) receptor potency of 3. Our efforts centered on modifying the 2'-side chain of 3 and examining the isoxazolylsulfonamide moiety in 3. This effort resulted in the discovery of 7 as a highly potent second-generation DARA. Compound 7 also showed substantially improved pharmacokinetic properties compared to 3. In rats, DARA 7 reduced blood pressure elevations caused by intravenous infusion of Ang II or big ET-1 to a greater extent and with longer duration than DARA 3 or AT(1) or ET(A) receptor antagonists alone. Compound 7 clearly demonstrated superiority over irbesartan (an AT(1) receptor antagonist) in the normal SHR model of hypertension in a dose-dependent manner, demonstrating the synergy of AT(1) and ET(A) receptor blockade in a single molecule.

Discovery of 4'-[(imidazol-1-yl)methyl]biphenyl-2-sulfonamides as dual endothelin/angiotensin II receptor antagonists.

A series of 4'-[(imidazol-1-yl)methyl]biphenylsulfonamides has potent antagonist activity against both angiotensin II AT(1) and endothelin ET(A) receptors. Such dual-acting antagonists could have utility in the treatment of hypertension, heart failure, and other cardiovascular diseases in a broad patient population. Certain compounds in the present series are orally active in a rat model of angiotensin II-mediated hypertension.

Discovery of N-isoxazolyl biphenylsulfonamides as potent dual angiotensin II and endothelin A receptor antagonists.

The ET(A) receptor antagonist (2) (N-(3,4-dimethyl-5-isoxazolyl)-4'-(2-oxazolyl)-[1,1'-biphenyl]-2-sulfonamide, BMS-193884) shares the same biphenyl core as a large number of AT(1) receptor antagonists, including irbesartan (3). Thus, it was hypothesized that merging the structural elements of 2 with those of the biphenyl AT(1) antagonists (e.g., irbesartan) would yield a compound with dual activity for both receptors. This strategy led to the design, synthesis, and discovery of (15) (4'-[(2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl]-N-(3,4-dimethyl-5-isoxazolyl)-2'-[(3,3-dimethyl-2-oxo-1-pyrrolidinyl)methyl]-[1,1'-biphenyl]-2-sulfonamide, BMS-248360) as a potent and orally active dual antagonist of both AT(1) and ET(A) receptors. Compound 15 represents a new approach to treating hypertension.