Novel AP2238-clorgiline hybrids as multi-target agents for the treatment of Alzheimer's disease: Design, synthesis, and biological evaluation.

Cholinesterase and monoamine oxidase are potential targets for the therapy of Alzheimer's disease. A series of novel AP2238-clorgiline hybrids as multi-target agents were designed, synthesized and investigated in vitro for their inhibition of cholinesterases and monoamine oxidases. Many compounds displayed balanced and good inhibitory activity against AChE, BuChE and MAO-B with an obvious selective inhibitory effect on MAO-B. Among them, Compound 5l showed the most balanced potency to inhibit ChEs (eeAChE: IC50 = 4.03 ± 0.03 µM, eqBuChE: IC50 = 5.64 ± 0.53 µM; hAChE: IC50 = 8.30 ± 0.04 µM, hBuChE: IC50 = 1.91 ± 0.06 µM) and hMAO-B (IC50 = 3.29 ± 0.09 µM). Molecular modeling and kinetic studies showed that 5l was a mixed inhibitor for both AChE and BuChE, and a competitive MAO-B inhibitor. Compound 5l exhibited no toxicity to PC12 and BV-2 cells at 12.5 µM and no acute toxicity at a dosage of 2500 mg/kg. Moreover, 5l can improve the memory function of mice with scopolamine-induced memory impairment and have an excellent ability to cross the blood-brain barrier. Overall, these findings suggested that compound 5l could be deemed as a promising, balanced multi-target drug candidate against Alzheimer's disease.

[The application of forward and reversal flow axial island flap based on the superficial temporal artery in the orbital skin defects].

OBJECTIVE: To investigate the application of forward and reversal flow axial island flap in the orbital skin defects. METHODS: According to the distribution of superficial temporal artery as well as the anastomoses with the branches of supraorbital artery and supratrochlear artery, etc, the frontal, scalp, preauricular and postauricular island flaps were designed. The flaps were displaced through subcutaneous tunnel to cover all kinds of orbital skin defects. RESULTS: 13 cases of forward flow flap and 9 of reversal flow flap out of 22 cases in all were observed. One postauricular reversal flow axial island flap showed the obstruction of venous refluence in early postoperative stage, however, after active treatment, mere the distal epidermal necrosis was revealed. There were six re-operations on the postoperative flap hypertrophy. The others were in good shape and functional state. CONCLUSIONS: The superficial temporal artery is one of most vital blood supply in the upper face. It has wide anastomoses with the supraorbital artery and supratrochlear artery. As the colors and the nature of the frontal, preauricular and post auricular skin are close to orbital skin, the application of forward and reversal flow axial island flap based on the superficial temporal artery can be used in the reconstruction of all kinds of orbital skin defects.

[Longitudinal gracilis musculocutaneous flaps with a crossing boundary blood supply from the obturator artery].

OBJECTIVE: The traditional gracilis musculocutaneous flap is supplied by a branch of deep femoral artery, which enters the muscle in between the upper and middle third of it. So the flap barely reaches the pelvis and perineum region for reconstruction. By exploring the blood supply pattern we tried to rotate the flap Upon at the higher point starting at the obturator foramen in order to let it cover a bigger area. METHODS: anatomical reviewing of the blood supply of the gracilis branches of obturator, medial femoral circumflex and deep femoral arteries. Based on this a new type of longitudinal gracilis musculocutaneous flap supported only by the obturator artery was designed to reach the pelvis, female genitalia, pubic symphysis, inguinal area easily. RESULTS: The new kind of flap has been applied to 9 patients for deformity repairing and tissue replacement in the pelvic and perineal area. All the flaps survived and achieved satisfactory result with 3 months to 3 years' follow up. CONCLUSIONS: Longitudinal gracilis musculocutaneous flaps supplied by the obturator artery can be used as regular musculocutaneous flap clinically.

[A study on the survival mechanism of the reverse-flow axial skin flap].

OBJECTIVE: To investigate the survival mechanisms of the reverse-flow flap. METHODS: A skin flap measuring 8.0 cm x 2.5 cm based on the left deep circumflex iliac vessel (DCIV) was designed and elevated on the rat's dorsum with 4.0 cm of it's length crossing the midline. The flap was served as the reverse-flow flap model. The survival area, the dynamic microcirculation including flow direction, microvessel number, caliber, pressure and vasculature were assessed respectively at 6 hour, 24 hour, 48 hour, 72 hour, 7 day and 14 day after operation. RESULTS: The average gradient of perfusion pressure was 0 kPa before operation and was 4.9 KPa postoperatively between the proximal and the distal site of the flap. By anastomosis of bilateral DCIV, the blood flow run in a reversed pattern in the region distal to the midline. No venous valves were observed. Distal congestion developed in 20% of the flaps within 72 h. After that, the number and caliber of venous anastomosis increased with pressure dropping in the midline region. The axial vessels extended its branches progressively along the dilated anastomotic rami. As a result, the vasculature of the flap became similar to that of the conventional axial flap by the 14th day. With these changes, flap congestion was alleviated gradually and subsided within 7 days. All the flaps survived completely. CONCLUSIONS: Anastomosis connecting the two axial vessels is the circulation route of the reverse-flow flap. By the gradient pressure between the proximal and distal region, blood is driven reversely. Within 72 h, the distal part is susceptible to congestion. In this period, increasing number and caliber and decreasing pressure of anastomosis is important mechanism to support the circulation. After that, the new vasculature similar to the conventional axial flap provides the flap with reliable and permanent blood supply.

[Correction of hemifacial atrophy by use of a chest dermal-fat flap with the platysma pedicle].

OBJECTIVE: To present a new dermal-fat flap for the correction of hemifacial atrophy. METHODS: An upper chest dermal-fat flap was created with its upper margin 1 cm cranial to the clavicle. The platysma pedicle of the dermal-fat flap, 5 cm in width, was dissected subcutaneously through a skin incision caudal to the mandibular margin. The platysma pedicle was turned over at the mandibular margin so that the dermal-fat-flap could be transposed fitly to the atrophic face. RESULTS: Eight cases were treated by this technique. Good results were achieved. CONCLUSION: This flap is suitable for the correction of hemifacial atrophy for its good blood circulation and a large amount of tissue.

[Repairing large alar defects by using a retro-grade auricular flap].

OBJECTIVE: To evaluate a retro-grade auricular flap for repairing large alar defects. METHODS: Twenty-nine adult cadavers were anatomically used for vascular investigation of the frontal, nasal and temporal regions by injecting a dye into the main vessels. Based on the anatomical study in these regions, a retro-grade auricular flap was designed for repairing alar defects in 16 patients. RESULTS: The blood supply of the auricle could be nourished by the inner carotid artery system from the supratrachlear artery and supraorbital artery through the frontal arterial anastomotical network into the frontal branch of the superficial temporal artery. It is then passing the main trunk of the superficial temporal artery into the ear area through the auricular branches of the superficial temporal artery. The retro-grade auricular island flap could be formed by basing the supratrachlear artery and the supraorbital artery through the vascular network between the superficial temporal artery and the supratrachlear artery or the supraorbital artery. Sixteen patients with large alar defects and half-sized nasal defects were successfully repaired by this technique. CONCLUSIONS: The retro-grade auricular island flap, based on the inner carotid artery system, could be a good and safe flap for repairing a large alar defect or half-sized nasal reconstruction.