Pleiotropic effects of the rho-kinase inhibitor fasudil after subarachnoid hemorrhage: a review of preclinical and clinical studies.

There is growing evidence that Rho-kinase contributes to cardiovascular disease, which has made Rho-kinase a target for the treatment of human diseases. To date, the only Rho-kinase inhibitor employed clinically in humans is fasudil, which has been used for the prevention of cerebral vasospasm and subsequent ischemic injury after surgery for subarachnoid hemorrhage (SAH). A number of pathological processes, in particular hemodynamic dysfunctions and inflammatory reactions, are thought to be related in the pathogenesis of delayed cerebral vasospasm and subsequent ischemic injury after SAH. This review focuses on fasudil's pleiotropic therapeutic effects: amelioration of hemodynamic dysfunction and inflammation, and discusses in detail the clinical studies on fasudil administered after the occurrence of SAH.

Mechanical evaluation of long titanium alloy clip--comparison of cobalt alloy clip.

Long titanium aneurysm clips have recently been released. In the present study, comparative study of long titanium and cobalt alloy clips was performed. Two kinds of Sugita long clips (straight clips of 25- and 35-mm blade length) made of titanium and cobalt alloys were tested by measuring the closing force, the anti-scissoring torque, and the maximum opening width. There were some differences between the two materials. In the 25-mm blade length clip, closing force and maximum opening width of titanium alloy clip were greater than those of cobalt alloy clip. By contrast, the anti-scissoring torque of 35-mm blade length titanium clip was stronger than that of the cobalt. The long titanium clips would have equivalent endurance to long cobalt clip and are safe for clinical use.

Calculation method for a quadrature phase-shifting interferometer and its applications.

A calculation method for a quadrature phase-shifting interferometer is presented, and its applications to specular and speckle interferometers and digital holography are described. Two sets of quadrature phase-shifted interferograms are acquired, and the calculation method proposed gives the phase distribution of the interferograms. The principle of the calculation method with error analysis and experimental results for specular and speckle interferometers and digital holography are also given.

Scissoring of cerebral aneurysm clips: mechanical endurance of clip twisting.

Although the cerebral aneurysm clip "scissoring" phenomenon is known to occur due to twisting of the aneurysm clip blades during surgery, there have been few previous studies of scissoring. In the present study, we examined the in vitro endurance of clip twisting to assess clip scissoring. To evaluate the clip-scissoring effect, we measured torque at the rotating aneurysm clip head (Sugita and Yasargil clips) using our own manufactured product. A silicon sheet 1 mm thick was clipped at several depths (3, 6, and 9 mm), and the clip head was mechanically rotated. Straight and fenestrated clips of titanium alloy were used in the present study. Cobalt alloy straight clips were also examined. Preliminary experiments indicated that torque values during clip head rotation dropped when the blades crossed. In addition, torque values before blade crossing showed resistance to slippage of the blades. Torque values of both Sugita and Yasargil clips were directly proportional to the blade depth. There were no differences between straight and fenestrated Sugita clips. Although the torque was greater in cobalt alloy than titanium alloy Sugita clips, the torque values of Yasargil cobalt and titanium clips were identical. We found some differences in torque values during clip head rotation between Sugita and Yasargil clips. Based on the results of twisting experiments, scissoring is likely to occur when occluding the neck of the aneurysm only with the tips of long clip blades.

Antivasospastic effects of hydroxyfasudil, a Rho-kinase inhibitor, after subarachnoid hemorrhage.

We investigated the anti-vasospastic potential of fasudil's active metabolite, hydroxyfasudil, a Rho-kinase inhibitor, after subarachnoid hemorrhage (SAH) and also its effect on hemorheological abnormalities following cerebral ischemia. Chronic cerebral vasospasm was produced using a two-hemorrhage canine model. On day 7, angiographic vasospasm was observed in all animals, and intravenous administration of hydroxyfasudil (3 mg·kg(-1)·30 min(-1)) significantly reversed the vasospasm (predose diameter of the basilar artery, 57.9% ± 2.0% of the baseline before the injection of blood; postdose diameter, 64.5% ± 1.9%). The viscosity of whole blood was significantly increased 24 h after 1 h middle cerebral artery occlusion in rats. Hydroxyfasudil (3 and 10 mg/kg, i.p.) significantly decreased blood viscosity. The specificity of hydroxyfasudil was examined against a panel of 17 protein kinases using ELISA analysis. Hydroxyfasudil inhibited Rho-kinase α and ß at a concentration of 10 µM by 97.6% and 97.7%, respectively. No other protein kinase was inhibited with 10 µM hydroxyfasudil by over 40%. The present results indicate hydroxyfasudil is a selective inhibitor of Rho-kinase. The results also suggest that hydroxyfasudil contributes to the potency of fasudil to prevent cerebral vasospasm and hyperviscosity and suggest the potential utility of hydroxyfasudil as a therapeutic agent for patients with SAH.

Antivasospastic Effects of Hydroxyfasudil, a Rho-Kinase Inhibitor, After Subarachnoid Hemorrhage.

We investigated the anti-vasospastic potential of fasudil's active metabolite, hydroxyfasudil, a Rho-kinase inhibitor, after subarachnoid hemorrhage (SAH) and also its effect on hemorheological abnormalities following cerebral ischemia. Chronic cerebral vasospasm was produced using a two-hemorrhage canine model. On day 7, angiographic vasospasm was observed in all animals, and intravenous administration of hydroxyfasudil (3 mg·kg-1·30 min-1) significantly reversed the vasospasm (predose diameter of the basilar artery, 57.9% ± 2.0% of the baseline before the injection of blood; postdose diameter, 64.5% ± 1.9%). The viscosity of whole blood was significantly increased 24 h after 1 h middle cerebral artery occlusion in rats. Hydroxyfasudil (3 and 10 mg/kg, i.p.) significantly decreased blood viscosity. The specificity of hydroxyfasudil was examined against a panel of 17 protein kinases using ELISA analysis. Hydroxyfasudil inhibited Rho-kinase α and ß at a concentration of 10 µM by 97.6% and 97.7%, respectively. No other protein kinase was inhibited with 10 µM hydroxyfasudil by over 40%. The present results indicate hydroxyfasudil is a selective inhibitor of Rho-kinase. The results also suggest that hydroxyfasudil contributes to the potency of fasudil to prevent cerebral vasospasm and hyperviscosity and suggest the potential utility of hydroxyfasudil as a therapeutic agent for patients with SAH.

Three-dimensional displacement measurement for diffuse object using phase-shifting digital holography with polarization imaging camera.

The amount of displacement of a diffused object can be measured using phase-shifting digital holography with a polarization imaging camera. Four digital holograms in quadrature are extracted from the polarization imaging camera and used to calculate the phase hologram. Two Fourier transforms of the phase holograms are calculated before and after the displacement of the object. A phase slope is subsequently obtained from the phase distribution of division between the two Fourier transforms. The slope of the phase distribution is proportional to the lateral displacement of the object. The sensitivity is less than one pixel size in the lateral direction of the movement. The longitudinal component of the displacement can be also measured separately from the intercept on the phase axis along the phase distribution of the division between two Fourier transforms of the phase holograms.

A simplified model for explaining negative feedback to beginners in life sciences.

It may not be easy to present to beginners CO(2) and O(2) having the opposite effect on respiration, using the conventional diagram explaining negative feedback. In the new diagram we developed, the "cause", its facilitating effect on the "result", the facilitating and inhibiting noises on the "result", the current magnitude of the "result", the set-point, their comparison, and feedback effect on the "cause" are all clearly illustrated. For example, the engine RPM is the "cause", increase in speed is the "result", a downhill slope is the facilitating noise, and an uphill slope is the inhibiting noise. By having direction in the "result", such as INCREASE in speed, INCREASE in O(2), and DECREASE in CO(2), the same diagram could be used to present CO(2) and O(2) having the opposite effect on respiration.

Comparison of fat tissues used in intracordal autologous fat injection.

CONCLUSIONS: The buccal fat pad appears to be more useful as a source of fat tissues in intracordal fat injection than the abdominal fat tissues used previously. However, further studies are required to confirm this point. OBJECTIVES: Fat tissues used in vocal fold augmentation surgery have primarily been harvested from the subcutaneous region of the lower abdomen. It is often difficult to obtain sufficient fat tissue for injection due to the physical features of the individual patient. We have thus adopted a method using fat tissue from the buccal fat pad, which is already used in other plastic surgeries. METHODS: This was a retrospective study. We evaluated and compared the histological characteristics of fat cells and the condition of vocal folds after injection of fat tissue extracted from the subcutaneous region of the lower abdomen and from the buccal fat pad. RESULTS: Buccal fat cells were relatively smaller than abdominal fat cells and were not influenced by body mass index (BMI), showing less individual differences according to the physical features of the patient. Numbers of vascular endothelial cells tended to be higher in buccal fat tissues. The percentage of cases showing continuous effects for more than 6 months was slightly higher in cases using buccal fat.

Digital holography with a quadrature phase-shifting interferometer.

An alternative method for digital holography using a quadrature phase-shifting interferometer for high-speed measurement is presented. We show that it has image quality equal to the four-bucket method. In addition, it requires fewer imaging devices. Two quadrature phase-shifting fringe patterns are acquired in each state of an object changed temporally. The phase calculation method with these four fringe patterns gives the phase distribution of the hologram. This digital phase hologram is reconstructed to yield an object image by the Fresnel transform using digital convolutions with the fast Fourier transform algorithm. Verification results of simulations and experiments are given.

Simultaneous formation of four fringes by using a polarization quadrature phase-shifting interferometer with wave plates and a diffraction grating.

We present a new type of quadrature phase-shifting interferometer, which utilizes wave plates, a diffraction grating, and two lasers with different wavelengths, in order to acquire two sets of two quadrature fringe patterns in each wavelength formed on a single image sensor. This method for calculating with four phase-shifted fringe patterns gives us the phase sum and difference distributions between the phases in two wavelengths. This is also substantiated by results of our experiments.

Phase-shifting interferometer based on changing the direction of linear polarization orthogonally.

We present a new type of phase-shifting interferometer, which utilizes a polarizing prism to form quadrature phase-shifted fringe patterns onto a single imaging sensor. By changing the direction of linear polarization of the incident light orthogonally, four phase-shifted fringe patterns in quadrature are obtained by taking images twice; thus it is possible to reduce phase errors caused by mechanical vibrations and air turbulence that occur in temporal phase-shifting interferometers. We present the principle of this interferometer with its theoretical analysis, using the Jones matrix, along with experimental results.

Safety and efficacy of fasudil monotherapy and fasudil-ozagrel combination therapy in patients with subarachnoid hemorrhage: sub-analysis of the post-marketing surveillance study.

Sub-analysis of the fasudil post-marketing surveillance study compared the safety and efficacy of fasudil plus ozagrel to fasudil only. A total of 3690 patients received fasudil and 1138 received fasudil plus ozagrel between 1995 and 2000. The occurrence of adverse events, occurrence of low density areas associated with vasospasm on computed tomography, absence of symptomatic vasospasm, and poor clinical outcomes associated with vasospasm were compared between the fasudil and fasudil plus ozagrel groups. The pharmacokinetics of fasudil were assessed in 5 patients with subarachnoid hemorrhage. The drug interaction between fasudil and ozagrel was pharmacologically investigated in vitro and in vivo. The occurrence of adverse events and clinical outcomes were similar between the two groups. The occurrences of symptomatic vasospasm and low density areas were lower in the fasudil group than in the fasudil plus ozagrel group. The average trough value (8-hour value) of the fasudil active metabolite, hydroxyfasudil, was 50 nM. Fasudil showed no pharmacological interaction with ozagrel. The combination of fasudil plus ozagrel was well tolerated, but did not result in better efficacy than fasudil only.

A postmarketing surveillance study of fasudil treatment after aneurysmal subarachnoid hemorrhage.

BACKGROUND: The aim of the present study was, first, to assess safety of fasudil (Eril; Asahi Kasei Pharma Corp, Tokyo, Japan) and, second, to investigate whether the effects of fasudil in the phase 3 trial could be reproduced in a PMS study. METHODS: Between 1995 and 2000, a total of 1462 patients met the eligibility criteria of the phase 3 trial and were treated with fasudil in a PMS study. Adverse events, low-density areas on CT scans, symptomatic vasospasm, and clinical outcome were all recorded. The results were compared with those in the phase 3 trial. Patients with Fisher grade 3 on admission were selected (subgroup), and the results were also compared with those in the phase 3 trial. RESULTS: The occurrence of adverse events, including intracranial bleeding and hypotension, low-density areas, and clinical outcomes were similar between the fasudil-treated patients in the phase 3 trial and the patients in the PMS study. The absence of symptomatic vasospasm was more common in the PMS study than in the phase 3 trial. Of the 1462 patients, 842 met the criteria for the subgroup. In the subgroup, the occurrence of low-density areas, the absence of symptomatic vasospasm, and clinical outcomes were similar between the fasudil-treated patients in the phase 3 trial and the patients in the PMS study. CONCLUSIONS: The present PMS study described the tolerability, safety, and efficacy of fasudil in a large number of patients undergoing surgery for SAH, as demonstrated previously in the phase 3 trial.

[Case of spontaneous bilateral VA dissecting aneurysm presenting with SAH].

We report a case of bilateral vertebral artery (VA) dissecting aneurysm presenting subarachnoid hemorrhage (SAH). It was difficult to decide which side was responsible for SAH because the patient's symptom and head CT suggested that the left VA aneurysm had ruptured, but angiography and MRA showed an irregular pearl and string sign on the right side. He was successfully treated by trapping of the right VA dissecting aneurysm and we confirmed by intraoperative evaluation that the right VA dissecting aneurysm had ruptured. The left unruptured aneurysm decreased its size spontaneously. In the treatment of the bilateral VA dissecting aneurysms, angiography needs to be performed over and over again because contralateral unruptured aneurysm may grow or rupture due to increased hemodynamic stress. Various combinations of direct sugery with or without arterial reconstruction and endovascular treatment should be considered when treating bilateral VA dissecting aneurysms.

Effects of fasudil in acute ischemic stroke: results of a prospective placebo-controlled double-blind trial.

BACKGROUND: A multicenter, double-blind, placebo-controlled study was conducted to assess the efficacy and safety of fasudil, a Rho-kinase inhibitor (RKI), in the treatment of acute ischemic stroke. METHODS: A total of 160 patients, who were able to receive drug treatment within 48 h of acute ischemic stroke onset were enrolled. Patients received either 60 mg fasudil or a placebo (saline) by intravenous injection over 60 min, twice daily for 14 days. The primary end points were neurological status at 2 weeks after the start of treatment, and clinical outcome at 1 month after the onset of symptoms. RESULTS: Fasudil treatment resulted in significantly greater improvements in both neurological functions (p=0.0013), and clinical outcome (p=0.0015). There were no serious adverse events reported in the fasudil group. The average trough value (12 h values) of active metabolite hydroxyfasudil, another RKI, in healthy elderly volunteers receiving 60 mg of fasudil was 0.077 microM-a concentration well above that needed to inhibit Rho-kinase (0.025-0.05 microM). CONCLUSION: Treatment with fasudil within 48 h of acute ischemic stroke onset significantly improved the patient's clinical outcome. This study found fasudil to be a useful and safe drug for patients with acute ischemic stroke. Further evaluations, for example, 3-month functional outcomes in a larger clinical trial, may help to define the efficacy of fasudil in acute ischemic stroke.

Multiple neurenteric cysts in the posterior fossa and cervical spinal canal--case report.

A 46-year-old woman presented with multiple neurenteric cysts in the posterior fossa and spinal canal. Neuroimaging demonstrated neurenteric cysts in the interspace between the left cerebellar hemisphere and vermis, the lateral side of the right cerebellar hemisphere, and the ventral side of the spinal cord at the C-2 and C-4 levels. Total resection of the paravermian cyst and partial removal of the spinal cyst at the C-4 level were performed. Histological examination showed the cyst wall consisted of single or multiple layers of columnar epithelial cells with secretory granules, with mucin secretion verified by periodic acid-Schiff staining. Immunohistochemical staining showed the walls were positive for the cytokeratin, epithelial membrane antigen, and carcinoembryonic antigen, and negative for glial fibrillary acidic protein and S-100 protein. These findings confirmed the endodermal origin. The diagnosis was neurenteric cyst. The paravermian cyst disappeared, but the spinal cyst at the C-4 level recurred 8 months later. Reoperation became necessary 16 months later. The other two cysts also showed enlargement at 6 or 15 months. Total removal of neurenteric cyst is recommended if possible.

Cross-over comparison between respiratory muscle stretch gymnastics and inspiratory muscle training.

OBJECTIVES: To compare the effect of respiratory muscle stretch gymnastics (RMSG), proposed as a possible additional form of rehabilitation for patients with chronic obstructive pulmonary disease (COPD), with that of inspiratory muscle training (IMT). PATIENTS: Twelve naive outpatients with COPD at a university hospital. METHOD: The patients performed IMT (2 sessions of 10 minutes of training at 30% of PImax, daily) for 4 weeks and RMSG (3 sessions of 5 RMSG patterns 4 times each, daily) for 4 weeks, in randomized order, with a 4-week washout period between the two interventions. MEASUREMENTS AND RESULTS: PImax increased with IMT (mean 66.1 to 79.1 cmH2O), but not with RMSG (mean 66.0 to 69.4 cmH2O). RMSG and IMT similarly increased maximum chest wall expansion. FRC was significantly decreased by 158 ml with RMSG, but not with IMT. There were no significant changes in VC, FEV1, or PEF nor in arterial blood gases with either form of rehabilitation. Six-minute walking distance was more significantly increased with RMSG (mean 383 to 430 m), than with IMT (mean 386 to 412 m). CONCLUSIONS: RMSG may have clinically significant benefits, which may be somewhat different from the benefits of IMT, in patients with COPD.

Local injection of botulinum toxin type A for hemifacial spasm.

The preliminary experience of botulinum toxin treatment for hemifacial spasm is reported in this study. Five patients were treated with 10 injections of botulinum toxin in total. Botulinum toxin had a good to excellent effect in all cases. Improvement was observed 2 weeks to 1 month after the injection. The duration of improvement was 0-9 months (mean 4.2 months). The peak rank tended to decrease and the duration of improvement increased after several treatments. Hemifacial spasm caused by the anterior inferior cerebellar artery tended to subside easily. In contrast, compression by the vertebral artery was more refractory. Continuous facial spasm caused by operative trauma subsided after the injection, but paroxysmal spasm still occurred when eating or laughing. Spasm caused by trauma disappeared 4.5 months after the injection. The complications, which were facial nerve paresis in two cases (3 injections, 30%) and diplopia in one case (1 injection, 10%), were transient and subsided in 2 weeks.