Femoral Skin Research Articles

Surgical Venous Thrombectomy for Japanese Patients with Acute Deep Vein Thrombosis: A Review of 5 Years' Experience

Deep vein thrombosis (DVT) is a major risk factor for pulmonary thromboembolism (PTE). We carefully selected patients for surgical thrombectomy to treat acute-phase thrombosis and obtained favorable results. Over the past 5 years, we have performed surgical thrombectomy via a minimum femoral skin incision in 11 patients. Surgery was considered for patients with persistent phlegmasia cerulea dolens, despite thrombolytic therapy. All of our patients underwent surgery within 14 days of the onset of symptoms. During the operation, the patients were kept in the supine anti-Trendelenburg position to prevent PTE, and general anesthesia was maintained with positive-pressure mechanical ventilation. Blood flow to the inferior vena cava was occluded with a blocking catheter, and thrombectomy was performed with a thrombectomy catheter inserted parallel to the blocking catheter. A cell separator device was used effectively for autologous blood transfusion. To prevent reocclusion and promote collateral perfusion, we constructed an arteriovenous fistula for an iliac venous spur. There were no major postoperative complications, such as PTE or peritoneal bleeding, and no cases of postthrombotic syndrome after an average 38.4 months of follow-up. This surgical technique for venous thrombectomy is minimally invasive and safe for Japanese patients; surgical thrombectomy should be considered a treatment option for DVT in Japan.

Free anterolateral femoral skin flap addied radiotherapy and chems repair primarily the raw surface of malignant tumor cut on lower limbs

Objective To study the effect of free anterolateral femoral skin flap addied radiotherapy and chems primary repair the raw surface of malignant tumor cut on lower limbs.Methods Superficial malignant tumor were given radiotherapy 10～30 times with 3000～7000Gy,and large dose comprehensiveness chems must be given if osseous metastasis occurred.The raw surface of malignant tumor cut on lower limbs were repaired with free anterolateral femoral skin flap,after the operation,radiotherapy were given with 5000～6000Gy,and chems routly.Results All the raw surface of malignant were repaired successfully,most of the patients were retained with labour ability and full self-care.Survival rate of five years was reached to 92.2%.According to the survival quality evaluation criterion,68.6% of patients were gained good effect.Conclusion Free anterolateral femoral skin flap addied radiotherapy and chems could repair primary the raw surface of malignant tumor cut on lower limbs,the effect were good. Key words: Anterolateral femoral skin flap; Malignant tumor; Raw surface; Repair

Clinical application of modified anterolateral femoral skin flaps

股前外侧皮瓣因其血管蒂长、解剖恒定、操作方便,被广泛运用于四肢皮肤软组织缺损伴有骨、肌腱外露创面的修复,但因手背、足背等非功能区运用皮瓣修复后外观臃肿,一定程度上影响了手术效果.因此,2000年以来,我们将股前外侧组织瓣改良设计成一半为筋膜瓣,另一半为皮瓣游离移植的新方法分别修复手、足软组织缺损创面的非功能区与功能区,术后受区在外形、功能上与游离股前外侧皮瓣移植、游离股前外侧筋膜瓣移植联合植皮修复手、足软组织缺损的方法比较,报告如下。

The clinical study of direct cutaneous artery flap of the upper thigh

Objective To study the anatomic basis of direct cutaneous artery flap of the upper thigh and review the clinical outcome of its application. Methods The direct cutaneous arteries of the upper thigh were dissected in 20 sides of the adult embalmed cadaverie specimens perfused with red relax. The arteries were perfused with Chinese ink in 2 fresh cadaver specimens to observe the distribution area. During surgical harvesting of anterolateral femoral skin flap in 50 cases, the occurrence rate, source artery, diameter and course of the direct cutaneous arteries of the upper thigh were noted. Forty-two cases of soft tissue defects were repaired with direct cutaneous artery skin flap of the upper thigh. Results Direct cutaneous arteries of the upper thigh oecurred in 15 of 20 sides of the adult embalmed cadaveric specimens perfused with red relax. The occurrence rate thereof was 75.0%. The size of the flaps dyed with Chinese ink was 11.0 cm × 18.0 cm. The occurrence rate of direct cutaneous arteries during dissection of the 50 cases of anterolateral femoral skin flap was 72.0% (36 arteries in 36 cases). Direct cutaneous artery of the upper thigh came from the lateral femoral circumflex artery ( 56.9%, 29 sides), the deep femoral artery( 15.7%, 8 sides) or the femoral artery ( 27.4%, 14 sides ). The mean diameter of origin site. of these direct cutaneous arteries was (2.7 ±0.2) mm. Among the 42 cases of direct cutaneous artery skin flap of the upper thigh, 3 flaps survived with partical necrosis and healed after changing dressing or skin graft. The others survived completely, the size of flaps ranged from 6.0 cm × 8.0 cm to 11.1cm×18.0cm(11 free skim flaps andm 31 pedicle flaPS), Conclusion The direct eutaneous artery skin flap of the upper thigh has good blood supply and is easy to harvest. It can be made into not only pedicled flap but also free transplantable flaps. It is possible to harvest the flap without any muscle. The lateral femoral cutaneous nerve can be harvested and anastomosed with a cutaneous nerve of the recopient site. Key words: Surgical flaps; Hand injuries; Mierosurgery; Direct eutaneousarteries of superior thigh

2-{4-[(5,6-Diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}-N-(methylsulfonyl)acetamide (NS-304), an Orally Available and Long-Acting Prostacyclin Receptor Agonist Prodrug

Prostacyclin (PGI(2)) and its analogs are useful for the treatment of various vascular disorders, but their half-lives are too short for widespread clinical application. To overcome this drawback, we have synthesized a novel diphenylpyrazine derivative, 2-[4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy]-N-(methylsulfonyl)acetamide (NS-304), a prodrug of the active form [4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy]acetic acid (MRE-269). NS-304 is an orally available and potent agonist for the PGI(2) receptor (IP receptor). The inhibition constant (K(i)) of MRE-269 for the human IP receptor was 20 nM; in contrast, the K(i) values for other prostanoid receptors were >2.6 microM. MRE-269 was therefore a highly selective agonist for the IP receptor. The plasma concentrations of MRE-269 remained near peak levels for more than 8 h after oral administration of NS-304 to rats and dogs, and NS-304 increased femoral skin blood flow in rats in a long-lasting manner without affecting the hemodynamics. These findings indicate that NS-304 acts as a long-acting IP receptor agonist in vivo. The continuous vasodilation evoked by NS-304 was not attenuated by repeated treatment, indicating that NS-304 is unlikely to cause severe desensitization of the IP receptor in rats. Moreover, a microdose pharmacokinetic study in which NS-304 was orally administered to healthy male volunteers showed conversion of NS-304 to MRE-269 and a long plasma elimination half-life for MRE-269 (7.9 h). In conclusion, NS-304 is an orally available and long-acting IP receptor agonist prodrug, and its active form, MRE-269, is highly selective for the IP receptor. Therefore, NS-304 is a promising drug candidate for various vascular diseases, especially pulmonary arterial hypertension and arteriosclerosis obliterans.

Clinical application of anterolateral femoral skin flap pedicled with high site cutaneous branches of the transverse branch of lateral circumflex femoral artery

目的 报道应用以旋股外侧动脉横支高位皮支为血管蒂的股前外侧皮瓣游离移植修复软组织缺损的临床效果. 方法 对7例术中发现旋股外侧动脉降支皮支细小或缺如时,改用以旋股外侧动脉横支发出的高位皮支为血管蒂游离移植股前外侧皮瓣修复前臂、手部、小腿及足部软组织缺损,切取皮瓣的范围为15 cm×6 cm～28 cm×13 cm,并带部分肌瓣、骼胫束以及股外侧皮神经,骨折分别行内固定或外固定. 结果 本组7例术后股前外侧皮瓣全部成活,一期修复后外观、感觉、功能均达到优良,患肢功能恢复良好. 结论 以旋股外侧动脉横支高位皮支为血管蒂的股前外侧皮瓣是一种血供可靠、切取范围大、部位隐蔽、可带肌肉及股外侧皮神经的皮瓣;当旋股外侧动脉降支皮支细小或缺如时,以此高位皮支为血管蒂游离移植股前外侧皮瓣,是一种确实可靠的手术方法。

Application of vascularized free tissue transplantation in emergency repair of traumatized limbs: report of 86 cases

目的 报道应用吻合血管的游离组织移植急诊修复四肢创伤的效果.方法 1988年4月至2004年8月,进行急诊游离组织移植86例,修复肢体54例,再造拇指32例.移植的组织包括背阔肌肌皮瓣、股前外侧皮瓣、小腿内侧皮瓣、足背皮瓣、足底内侧皮瓣、废弃肢体的复合组织块及(足母)趾皮甲瓣.手术在伤后1～5 d内进行.结果 术后发生血管危象8例,均行血管探查手术,5例危象解除,3例失败.移植组织的成功率为96.5%(83/86).随访1～16年,平均7.5年.修复的肢体均保留或恢复了有用的功能,再造拇指功能优良率为87.5%.结论 急诊游离组织移植是实现创伤肢体急诊修复及拇指再造的有效方法。

FGF10 is a mesenchymally derived stimulator for epidermal development in the chick embryonic skin

The development of avian cutaneous appendages, feathers and scales, is known to arise from the epithelial–mesenchymal interaction. Here we show that FGF10 is associated with this developmental process as an early signal from mesenchymal cells underlying nascent cutaneous placodes. Expression of Fgf10 was detected in the mesenchymal cells underneath the developing placodes. Forced expression of Fgf10 in the femoral skin suppressed expression of Shh and a zinc finger gene snail-related ( cSnR), while induced expression of Bmp2 in the interbud region, resulting in thickening of the epidermal layer. Furthermore, forced expression of Fgf10 in the foot skin caused marked ingrowings of the epidermis. The cells in the epidermal ingrowings expressed β-catenin, proliferating cell nuclear antigen, and an epidermal stem cell marker p63. These results support the idea that FGF10 is a mesenchymally derived stimulator of epidermal development through crosstalk with bone morphogenetic protein (BMP), β-catenin, and other signaling pathways.

A new species of Mantidactylus (subgenus Guibemantis) from Madagascar, with a comparative survey of internal femoral gland structure in the genus (Amphibia: Ranidae: Mantellinae)

A new species of Mantidactylus (subgenus Guibemantis) from the rainforests of eastern Madagascar is described. The new species is sympatric with the closely related M. depressiceps (Boulenger, 1882) and M. tornieri (Ahl, 1929) but differs by larger size, a more strongly developed prepollex, and by advertisement calls. Mantidactylus acuticeps Ahl, 1929 and Rhacophorus mocquardii Boulenger, 1896 are confirmed to be junior synonyms of M. depressiceps. The presence of distinct femoral glands in the new species was noted; a feature so far not reliably recognized in other members of the subgenus Guibemantis. Femoral gland structure was investigated in representatives of each of the subgenera included in Mantidactylus by dissecting and reflecting the femoral skin. Four femoral gland types were identified. Type 1: many small, single granules in an ill-delimited patch, grouped in rosettes at the patch edges; type 2: a group of moderately sized granules in a well-delimited patch; type 3: comprising two different structures: distal granules enclosing externally a distinct central depression, and smaller proximal granules or groups of granules; type 4: as type 3, but lacking the proximal granules. Mantidactylus rivicola Vences, Glaw and Andreone, 1997, M. cf. malagasius (Methuen and Hewitt, 1913) and M. ventrimaculatus (Angel, 1935) differed from all other species examined; their femoral glands comprise a reduced number of large granules with an indistinct central depression in external view. The presence of a distal granule group with external central depression (types 3 and 4 above) provides a probable synapomorphy for the subgenera Brygoomantis, Ochthomantis, Hylobatrachus, Chonomantis and Mantidactylus. In females of these subgenera rudimentary femoral glands are present, but they lack completely in females of the other groups.

Anterolateral thigh flap: A review of 168 cases.

The anterolateral thigh flap based on the descending branch of the lateral circumflex femoral vessel is one of the musculocutaneous or septocutaneous flaps in the thigh. The descending branch of the lateral circumflex femoral vessel has either perforating branches or direct cutaneous branches from the intermuscular space to the anterolateral femoral skin. Since 1983, we have transferred 168 anterolateral thigh flaps for reconstruction of old burn scars, infected wounds, carcinoma excisions, for coverage of open bone fracture of the lower leg, and for congenital diseases. One hundred fifty-two cases were free flaps. The other 16 cases were pedicled flaps. The skin branches were divided into four types in our clinical series: musculocutaneous perforators (135/168 [80.4%]); intermuscular cutaneous perforators (16/168 [9.5%]); direct cutaneous branches (14/168 [8.3%]); and tiny cutaneous perforators (3/168 [1.8%]). The results were satisfactory. Only one case resulted in a failure due to tiny cutaneous branches.

Effects of beraprost sodium and prostaglandin E 1 on skin blood flow in diabetic rats and normal dogs

1. 1. The present study was undertaken to compare the effects of beraprost sodium (BPS), a stable prostaglandin I 2 analog, with prostaglandin E 1 (PGE 1) on the skin blood flow in anesthesized diabetic rats and anesthetized dogs. 2. 2. In anesthetized diabetic rats, BPS, but not PGE 1, caused a dose-dependent and significant increase in femoral skin blood flow. 3. 3. In anesthetized dogs, PGE 1 significantly increased femoral arterial blood flow than BPS. However, BPS significantly increased in-step skin blood flow than PGE 1. 4. 4. The above data suggest that BPS may be clinically useful for the treatment of circulatory insufficiency of lower extremities in diabetic patients.

Post-prandial effects in reactivity of forehead and mid-femoral skin blood flow and heart rate in neonates

The effect of post-prandial period on the cutaneous vascular reactivity was studied in twelve full-term infants on their 3rd postnatal day. The differences in vasomotor reactions between the forehead and femoral skin were also investigated. Two 10-min control registrations about 30 and 90 min after feeding were followed by a registration of equal duration during thermal stimulation of the skin. The lower extremity of each infant was stimulated by warm and cool air currents (5 cycles/min) to induce periodic vasomotor changes. The fast Fourier transform was used to compute variability spectra for the recorded skin blood flow, heart rate and respiratory wave form signals. The skin blood flow became synchronised to the thermal stimulation in both skin regions. Neither the spontaneous nor synchronised oscillations of the skin blood flow differed significantly between femoral skin and forehead. The post-prandial time did not have any influence on this synchronisation. Heart rate variability was synchronised to the periodicity of thermal stimulation more 1.5 h after feeding than 0.5 h after feeding. Respiration was not affected. The results show that increasing post-prandial time has no influence on the synchronised oscillations of skin blood flow. However, it potentiates reactivity of heart rate to perturbations in the peripheral vasculature.

Intrathecal phentolamine increases blood flow and skin temperature in the hind limbs of dogs.

Spinal anesthesia with local anesthetics increases blood flow and skin temperature in the lower extremities. Although the effect of α2 adrenoceptor agonists on the spinal cord has been confirmed, there has been no such report of the effects of α-adrenoceptor antagonists. We studied the effects of intrathecal administration of phentolamine on the blood flow in the femoral artery and skin temperature in the hind limbs of seven dogs. One ml of 3% lidocaine (L group) or 1 ml of 0.1% phentolamine (P group) was injected into the intrathecal space. Blood flow significantly increased at 3 min in both groups, and no significant difference was observed between the groups at any phase. Pad skin temperature in the hind limbs increased significantly at 5 min in the L group and at 3 min in the P group (P<0.05). The only significant difference was observed at 30 min. High pad skin temperature continued for 60 min in the L group and for 90 min in the P group. With phentolamine i.v. (1 mg), there were no changes in blood flow in the femoral artery or pad skin temperature; there was only a decrease in blood pressure. In conclusion, the intrathecal α-adrenoceptor antagonist, phentolamine, increases blood flow in the femoral artery and pad skin temperature in hind limbs in dogs similar to lidocaine.

A Double Isotope Technique to Determine Regional Albumin Permeability: Effects of Anesthesia

The transvascular leakage of albumin in various organs and tissues was studied with a double isotope technique in rats anesthetized with sodium pentobarbital, given intraperitoneally or intravenously, and in unanesthetized (conscious) rats. 125I-labeled albumin and 131I-labeled albumin were injected into the tail vein 1 hr apart. The albumin permeability index in tissues and organs is indicated by the local ratio (Xa/Ya)/(Xb/Yb), where (Xa/Ya) is the ratio of 125I/131I-albumin activities per g of tissue and (Xb/Yb) is the ratio of 125I/131I-albumin activities per g of blood. If there is no passage of albumin across the capillary membrane over the 1-hr period of study, the permeability index will be equal to one. In unanesthetized rats, the liver, lung, kidney, femoral muscle, and femoral skin were regions with a high albumin permeability index (above 2). In these organs, intraperitoneal and intravenous anesthesia caused a decrease or no significant change of the albumin permeability index. There was no significant albumin leakage over 1-hr period (index not significantly different from 1) in the mesentery, abdominal muscle, abdominal skin, cremaster, heart, and brain of unanesthetized rats. Intraperitoneal anesthesia caused the albumin permeability index to increase to approximately 4 in the mesentery, abdominal muscle, and the abdominal skin, but not in the cremaster, heart, or brain. These results demonstrate that pentobarbital anesthesia when given into the peritoneal cavity causes a significant increase in albumin leakage in the abdominal region.

Post-occlusive reactive hyperaemia in the heart, skeletal muscle and skin of control and capsaicin-pre-treated pigs.

In the present study we have tried to characterize and quantify the post-occlusive hyperaemia in the pig heart, skeletal muscle and skin circulation. In addition, the possible involvement of caspaicin-sensitive sensory nerves in the reactive hyperaemia was investigated. Reperfusion after total stop-flow ischaemia for 1, 5 or 15 min elicited a marked hyperaemia in all vascular beds studied. The post-occlusive hyperaemia after 5 min ischaemia was 512 +/- 74%, 328 +/- 94% and 444 +/- 87% in the heart, femoral artery and saphenous artery respectively. Also, in the skin the blood flow following 5 min ischaemia was increased fivefold. Furthermore, the duration of the hyperaemia after 5 min ischaemia was significantly (P less than 0.01) longer in the heart (382 +/- 32 s) than that in the femoral artery (192 +/- 27 s), saphenous artery (182 +/- 48 s) and skin (95 +/- 14 s). Increasing the ischaemic time period prolonged the duration as well as elevated the peak increase of the hyperaemia. Capsaicin pre-treatment significantly reduced (by about 70%) the tissue levels of calcitonin gene-related peptide (CGRP)-like immunoreactivity (-LI), which is present in sensory nerves, but not neuropeptide Y-LI, which is of sympathetic origin, in the left ventricle of the heart, quadriceps muscle and skin in the pig. However, there were no differences in the post-occlusive hyperaemia in control and capsaicin-pre-treated pigs. Capsaicin administered intracutaneously caused a long-lasting (about 20 min) increase in skin blood flow in the pig. This enhanced blood flow was completely abolished after systemic capsaicin pre-treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Applied Anatomy of the Anterolateral Femoral Flap

A study of the source of the blood supply to the anterolateral femoral flap was carried out on 42 lower limbs of adult cadavers (among them 35 cadavers with injection of red latex and 1 with india ink into the arteries and 6 vascular cast specimens), and the surface locations of the vascular pedicle were detected on 50 healthy adults. It was found that the descending branch of the lateral circumflex femoral vessel was an ideal axial vessel. There are constant perforating branches of the myocutaneous artery or cutaneous branches from the intermuscular space to the anterolateral femoral skin. The area extends about 12 x 30 cm. Within the flap, the anterior branch of the anterolateral cutaneous nerve of the high is located. This flap has been widely used for free transplantation in China since 1983 with satisfactory results.

Inguinal Bodies of Some Bufo Species

Previously undescribed large elongated bodies over the muscles of the groin region (inguinal bodies) have been found in some representatives of the genus Bufo but not in specimens of the genera Rana, Bombina, and Hyla. Anurans were captured in the field in several localities in southern Poland. On the same day they were killed and examined. Three species of the genus Bufo live in Poland: the common toad, Bufo bufo, the green toad, Bufo viridis, and the relatively rare natterjack, Bufo calamita. In May, the following specimens of the genus Bufo were examined: 7 adults (3 females and 4 males) of B. viridis; 1 adult female and 1 adult male of B. calamita; 8 adults (5 females and 3 males) of B. bufo. In July-August the following specimens of this genus were investigated: 13 adults (7 females and 6 males) and 7 juveniles of B. viridis; 2 adult males of B. calamita; 10 adults (6 females and 4 males) and 3 juveniles of B. bufo. In August, the representatives of both sexes of other anurans living in Poland were also examined, namely the European common frogsRana temporaria (7 adults and 10 juveniles); the frogsRana lessonae (4 adults and 6 juveniles); the yellowbellied toads-Bombina variegata (15 adults and 20 juveniles); the fire-bellied toads-Bombina bombina (5 adults and 7 juveniles); the European tree frogs-Hyla arborea (4 adults and 7 juveniles). In each individual investigated the pelvic part of the abdominal skin and the proximal part of the femoral skin were removed and the groin regions were macroscopically observed. A pair of large elongated bodies (inguinal bodies) supplied by pelvic arteries and veins were visible macroscopically in the groins of each investigated individual of B. viridis (Fig. 1A) and B. calamita. In B. bufo such distinctive structures were never observed (Fig. 1B), however, in a few individuals small accumulations of fat were present in either one or both groins along the pelvic vessels. Similar structures were absent in all investigated representatives of the genera Rana, Bombina, and Hyla. Inguinal bodies of B. viridis and B. calamita, as well as fat accumulations of specimens of B. bufo were easily excised, fixed in Bouin's fluid, routinely embedded in paraffin, serially sectioned, and stained with haematoxylin-eosin or May-Griinwald-Giemsa stain. In B. viridis captured in May, the inguinal bodies were macroscopically brownish and histologically classified as lymphomyeloid bodies (Fig. 2A) since they possesed abundant populations of lymphocytes and granulocytes. In B. viridis captured in July-August, the similar structures of both adults and juveniles were macroscopically yellow and fatty, but serial sections revealed within the fat tissue a few lymphoid foci (Fig. 2B). This suggests that the inguinal bodies of B. viridis undergo conspicuous seasonal changes. In FIG. 1. Inguinal regions of Bufo viridis (Fig. 1A) and Bufo bufo (Fig. 1B). Contours of the inguinal body in the left groin of B. viridis have been outlined (Fig. 1A).

口腔悪性腫よう切除創に対する植皮例の検討

Seven split and 3 full thickness skin grafts for malignant tumors after radiotherapy were performed for the following purposes: Biological dressing and promotion of healing for resection wounds and retention of the reduction after marsupialization wounds of the maxillary sinus. The skin grafts were used for reconstruction of defects following surgery of the smaller superficial tumors. All grafts were taken from femoral skin. Recipient sites were as follows; 1 maxilla, 5 maxillae and buccal mucosae, 3 mandibles and 1 tongue. In 10 patients preoperative chemotherapy was carried out and also in 8 of them irradiation of 10-88 Gy.All grafts were alive and a necrotic bone piece each was found in the wounds of a maxilla and a mandible 1 or 2 months later. The skin grafts were very useful for insertion of denture except 1 patient with teeth and satisfactory results were obtained.

Agenesis of the corpus callosum with associated facial anomalies.

Prostacyclin (PGI₂) and its analogs are useful for the treatment of various vascular disorders, but their half-lives are too short for widespread clinical application. To overcome this drawback, we have synthesized a novel diphenylpyrazine derivative, 2-{4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}-<i>N</i>-(methylsulfonyl)acetamide (NS-304), a prodrug of the active form {4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}acetic acid (MRE-269). NS-304 is an orally available and potent agonist for the PGI₂ receptor (IP receptor). The inhibition constant (<i>K</i>_i) of MRE-269 for the human IP receptor was 20 nM; in contrast, the <i>K</i>_i values for other prostanoid receptors were &gt;2.6 μM. MRE-269 was therefore a highly selective agonist for the IP receptor. The plasma concentrations of MRE-269 remained near peak levels for more than 8 h after oral administration of NS-304 to rats and dogs, and NS-304 increased femoral skin blood flow in rats in a long-lasting manner without affecting the hemodynamics. These findings indicate that NS-304 acts as a long-acting IP receptor agonist in vivo. The continuous vasodilation evoked by NS-304 was not attenuated by repeated treatment, indicating that NS-304 is unlikely to cause severe desensitization of the IP receptor in rats. Moreover, a microdose pharmacokinetic study in which NS-304 was orally administered to healthy male volunteers showed conversion of NS-304 to MRE-269 and a long plasma elimination half-life for MRE-269 (7.9 h). In conclusion, NS-304 is an orally available and long-acting IP receptor agonist prodrug, and its active form, MRE-269, is highly selective for the IP receptor. Therefore, NS-304 is a promising drug candidate for various vascular diseases, especially pulmonary arterial hypertension and arteriosclerosis obliterans.