Biomedical subjects

C Fukaya

Publications and source records attributed to C Fukaya.

At least 19 recordsLinked to original sources

PubMed2002

Deep brain stimulation therapy for a persistent vegetative state.

Twenty cases of a persistent vegetative state (PVS) caused by various kinds of brain damage were neurologically and electrophysiologically evaluated at 3 months after persistence of the PVS, and were treated by deep brain stimulation (DBS) therapy. The stimulation sites were the mesencephalic reticular formation (2 cases) and CM-pf complex (18 cases). Seven of the patients emerged from the PVS, and became able to obey verbal commands. However, they remained in a bedridden state. These 7 cases revealed a desynchronization or slight desynchronization pattern on continuous EEG frequency analysis. The Vth wave of ABR and N20 of SEP could be recorded even with a prolonged latency, and the pain-related P250 was recorded with an amplitude of over 7 microV. We conclude that chronic DBS therapy may be useful for allowing the patient to emerge from a PVS, if the candidates are selected according to the neurophysiological criteria. In view of the severely disabled state of the patients who emerged from the PVS, a special rehabilitation program which includes neurostimulation therapy may be necessary for treatment of the PVS.

Adult↗

PubMed2002

Control of post-stroke movement disorders using chronic motor cortex stimulation.

The effects of motor cortex (MC) stimulation on post-stroke movement disorders were analyzed in 50 patients. These individuals either underwent MC stimulation primarily for the purpose of controlling their post-stroke involuntary movements (n = 8) or underwent MC stimulation for the purpose of controlling their post-stroke central pain (n = 42). In the latter patients, the effects of MC stimulation on co-existent involuntary or voluntary movement disorders were analyzed retrospectively. Good control of involuntary movements was observed in 2 of 3 patients with hemichoreo-athetosis, 2 of 2 patients with distal resting or action tremor, and 1 of 3 patients with proximal postural tremor. Subjective improvements in motor performance were reported by 8 patients who had mild motor weakness, and the effects appeared to be attributable to attenuation of rigidity. We consider that these findings justify further clinical studies on MC stimulation for the control of post-stroke movement disorders.

Electric Stimulation Therapy↗

PubMed2002

Increase in focal concentration of deoxyhaemoglobin during neuronal activity in cerebral ischaemic patients.

BACKGROUND AND PURPOSE: Blood oxygenation level dependent contrast functional magnetic resonance imaging (BOLD-fMRI) has been applied to functional mapping in brain disorders, based on the assumption that normal adults and patients with brain disorders exhibit similar evoked cerebral blood oxygenation (CBO) changes. This study compared evoked CBO changes measured by near infrared spectroscopy (NIRS) with the activation mapping obtained by BOLD-fMRI in patients with cerebral ischaemia. METHODS: The study involved six normal adults and six patients with cerebral ischaemia. Hand grasping was performed as a motor task. All patients could perform the task similarly to the controls at the time of examination, but single photon emission computed tomography demonstrated low baseline cerebral blood flow and a decreased haemodynamic reserve in the primary sensorimotor cortex on the lesion side. Using NIRS, concentration changes of deoxyhaemoglobin (Deoxy-Hb), oxyhaemoglobin (Oxy-Hb), and total haemoglobin (Total-Hb) were measured in the primary sensorimotor cortex contralateral to the task. BOLD-fMRI signals were measured by 1.5 T magnetic resonance imaging using an echo-planar technique. Activation maps were calculated by statistical parametric mapping. RESULTS: In the controls, Deoxy-Hb decreased in association with increases of Oxy-Hb and Total-Hb in the primary sensorimotor cortex during the task. However, in the patients, Deoxy-Hb increased significantly from baseline, while Oxy-Hb and Total-Hb also increased, indicating the presence of rCBF increases in response to neuronal activation. BOLD-fMRI demonstrated only limited activation areas in the primary sensorimotor cortex on the lesion side. CONCLUSION: The CBO changes in patients with cerebral ischaemia differed from those of normal adults; Deoxy-Hb was increased in activation areas of the patients. This implies that BOLD-fMRI may overlook activation areas in the patients unless both increases and decreases of signal are taken into consideration.

Adult↗

PubMed2001

Synthesis, structure-activity relationships, and pharmacokinetic profiles of nonpeptidic alpha-keto heterocycles as novel inhibitors of human chymase.

We designed nonpeptidic chymase inhibitors based on the structure of a peptidic compound (1) and demonstrated that the combination of a pyrimidinone skeleton as a P3-P2 scaffold and heterocycles as P1 carbonyl-activating groups can function as a nonpeptidic chymase inhibitor. In particular, introduction of heterobicycles such as benzoxazole resulted in more potent chymase-inhibitory activity. Detailed structure-activity relationship studies on the benzoxazole moiety and substituents at the 2-position of the pyrimidinone ring revealed that 2r (Y-40079) had the most potent chymase-inhibitory activity (K(i) = 4.85 nM). This compound was also effective toward chymases of nonhuman origin and showed good selectivity for chymases over other proteases. Pharmacokinetic studies in rats indicated that 2r was absorbed slowly after oral administration and showed satisfactory bioavailability (BA) (T(max) = 6.0 +/- 2.3 h, BA = 19.3 +/- 6.6%, t(1/2) = 35.7 +/- 13.3 h). In conclusion, 2r is a novel, potent, and orally active chymase inhibitor which would be a useful tool in elucidating the pathophysiological roles of chymase.

Animals↗

PubMed2001

Synthesis, structure-activity relationships, and pharmacokinetic profiles of nonpeptidic difluoromethylene ketones as novel inhibitors of human chymase.

Potent human chymase inhibitors with high enzymatic selectivity and satisfactory metabolic stability were obtained by replacing the Val-Pro (P3-P2) dipeptide portion of the previously described inhibitor 1 with a nonpeptidic pyrimidinone skeleton. The potency of the novel compounds was further enhanced by the introduction of carbamoyl-substituted difluoromethylene ketone moieties. The most potent chymase inhibitor of the newly created series was 2u (Y-40018), which had a K(i) of 2.62 nM. Compound 2u possessed high selectivity for human chymase since it lacked significant activity toward other representative human proteolytic enzymes. Moreover its strict specificity for human chymase suggested that 2u strongly inhibited human and canine chymases but not rat and mouse ones. Pharmacokinetic studies in rats and dogs indicated that 2u was absorbed rapidly after oral administration and had satisfactory bioavailability in these experimental animal species (rat, 17%; dog, 32%). In conclusion, 2u is a novel, potent, and orally active chymase inhibitor which would prove very useful in revealing the precise roles of the latter in various pathophysiological processes.

Animals↗

PubMed2001

Non-peptidic inhibitors of human chymase. Synthesis, structure-activity relationships, and pharmacokinetic profiles of a series of 5-amino-6-oxo-1,6-dihydropyrimidine-containing trifluoromethyl ketones.

Chymase possesses a wide variety of actions, including promotion of angiotensin II production and histamine release from mast cells. However, due to a lack of effective inhibitors featuring both high inhibitory activity and high metabolic stability, the pathophysiological role of chymase has not been fully elucidated. We designed non-peptidic inhibitors based on the predicted binding mode of the peptidic chymase inhibitor Val-Pro-Phe-CF3 and demonstrated that the Val-Pro unit is replaceable with a (5-amino-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl)acetyl moiety. Structure-activity relationship studies revealed that phenyl substitution at the 2-position of the pyrimidinone ring is indispensable for high activity. The most potent compound 1h (Ki = 0.0506 microM) is superior in potency to the parent peptidic inhibitor Val-Pro-Phe-CF3 and has good selectivity for chymase over other proteases. The related analogue 1e was orally absorbed and maintained high plasma levels for at least 2h. These results suggest that the derivatives reported here could be developed as agents for treatment of chymase-induced disease.

Animals↗

PubMed2001

Intraoperative wake-up procedure with propofol and laryngeal mask for optimal excision of brain tumour in eloquent areas.

This is the first thesis describing a new technique for awake craniotomy using a laryngeal mask. Awake craniotomy with propofol infusion has become increasingly popular for the optimal excision of brain tumours located in eloquent areas. During awake craniotomy, tracheal intubation is not performed and propofol infusion is limited to within doses which render the patient just sedated. This asleep-awake procedure is occasionally associated with difficulty in controlling brain volume, especially in patients with a significant mass effect of their brain tumours, since sufficient sedation with propofol tends to cause hypercapnea. We report an intraoperative wake-up procedure employing a laryngeal mask, which enables general anaesthesia to be performed at a sufficient dose of propofol and with control of the brain volume under mechanically assisted ventilation. Before the beginning of cortical mapping, propofol infusion is completely terminated, so allowing the patient to wake up within 5-15 min. Following completion of the tumour excision, general anaesthesia is re-induced at a sufficient dose of propofol. The laryngeal mask can be temporarily removed and repositioned with ease, if necessary. In our experience, this technique is applicable for the optimal excision of brain tumours, especially in patients who are very obese or those who have very large lesions.

Anesthetics, Intravenous↗

PubMed2001

Motor cortex stimulation for phantom limb pain: comprehensive therapy with spinal cord and thalamic stimulation.

The effects of spinal cord stimulation (SCS), deep brain stimulation (DBS) of the thalamic nucleus ventralis caudalis (VC) and motor cortex stimulation (MCS) were analyzed in 19 patients with phantom limb pain. All of the patients underwent SCS and, if the SCS failed to reduce the pain, the patients were considered for DBS and/or MCS. Satisfactory pain control for the long-term was achieved in 6 of 19 (32%) by SCS, 6 of 10 (60%) by DBS and 1 (20%) of 5 by MCS. SCS and DBS of the VC sometimes produced a dramatic effect on the pain, leading to a long pain-free interval and infrequent use of stimulation. The effects of both DBS of the VC and MCS were tested in four. One patient of them reported better pain control by MCS than by DBS, whereas two reported the opposite results. There is no evidence at present for an advantage of MCS over SCS and DBS of the VC in controlling phantom limb pain.

Adult↗

PubMed2001

Motor cortex stimulation for post-stroke pain: comparison of spinal cord and thalamic stimulation.

We analyzed the effects of spinal cord stimulation (SCS), deep brain stimulation (DBS) of the thalamic nucleus ventralis caudalis (VC) and motor cortex stimulation (MCS) in 45 patients with post-stroke pain. Satisfactory pain control was obtained more frequently as the stimulation site was moved to higher levels (7% by SCS, 25% by DBS and 48% by MCS). A painful sensation was sometimes produced by stimulation of the VC as well as the post-central, pre-central and pre-frontal cortices. Such a sensation occurred less frequently as the stimulation site was moved to higher levels (50% at the VC, 39% at the post-central cortex, 6% at the pre-central cortex and 3% at the pre-frontal cortex). These findings imply that abnormal processing of nociceptive information develops at the level of deafferentation and spreads to higher levels to a varying extent. This may be one of the reasons why satisfactory pain control was obtained more frequently as the stimulation site was moved to higher levels.

Analgesia↗

PubMed2001

Subthalamic nucleus stimulation for Parkinson disease: benefits observed in levodopa-intolerant patients.

OBJECT: A blinded evaluation of the effects of subthalamic nucleus (STN) stimulation was performed in levodopa-intolerant patients with Parkinson disease (PD). These patients (Group I, seven patients) were moderately or severely disabled (Hoehn and Yahr Stages III-V during the off period), but were receiving only a small dose of medication (levodopa-equivalent dose [LED] 0-400 mg/day) because they suffered unbearable side effects. The results were analyzed in comparison with those obtained in patients with advanced PD (Group II, seven patients) who were severely disabled (Hoehn and Yahr Stages IV and V during the off period), but were treated with a large dose of medication (500-990 mg/day). METHODS: The patients were evaluated twice at 6 to 8 months after surgery. To determine the actual benefits afforded by STN stimulation to their overall daily activities, the patients were maintained on their medication regimen with optimal doses and schedules. Stimulation was turned off overnight for at least 12 hours. It was turned on in the morning (or remained turned off), and each patient's best and worst scores on the Unified Parkinson's Disease Rating Scale during waking daytime activity were recorded as on- and off-period scores, respectively. The order of assessment with respect to whether stimulation was occurring was determined randomly. The STN stimulation markedly improved daily activity and total motor scores in Group I patients. The percentage time of immobility (Hoehn and Yahr Stages IV and V) became 0% in patients who were intermittently immobile while not receiving stimulation. Improvements were demonstrated in tremor, rigidity. akinesia, and gait subscores. The STN stimulation produced less marked but still noticeable improvements in the daily activity and total motor scores in Group II patients. The percentage time of immobility as well as the LED was reduced in patients who displayed intermittent immobility with pronounced motor fluctuations while not receiving stimulation. Improvements were demonstrated in tremor, rigidity, and dyskinesia subscores in these patients. In contrast, STN stimulation did not improve the overall daily activities at all in patients who had become unresponsive to a tolerable dose of levodopa and were continuously immobile, even though these patients' tremor and rigidity subscores were still improved by stimulation. CONCLUSIONS: Consistent with earlier findings, the great benefit of STN stimulation in levodopa-intolerant patients is that STN stimulation can reduce the level of required levodopa medication. This suggests that STN stimulation could be a therapeutic option for patients with less-advanced PD by allowing levodopa medication to be maintained at as low a dose as possible, and to prevent adverse reactions to the continued use of large-dose levodopa.

Adult↗

PubMed2001

New method of deep brain stimulation therapy with two electrodes implanted in parallel and side by side.

Reversibility and adaptability are preferred features of long-term therapeutic deep brain stimulation (DBS). In such therapy, a permanent stimulating electrode with four contact points is placed at the stimulation site and, generally speaking, bipolar stimulation is induced by various pairs of adjacent contact points on one electrode. The stimulation sites are thus all located along the trajectory of the implanted electrode. In a patient with unilateral severe essential tremor, the authors implanted two electrodes side by side and parallel to each other in the unilateral thalamic ventralis intermedius nucleus. Using these electrodes, the authors were able to deliver current flow not only along the electrode trajectory, but also between the two electrodes in a direction parallel to the anterior commissure-posterior commissure line. Although individual stimulations, delivered by each of the two electrodes using all parameters and all stimulation points, were unable to stop the patient's tremor completely without adverse effects, the new stimulation method, in which electrical currents passed between the two electrodes, effected complete abolition of the tremor without adverse effects. With the aid of this method, one can use two electrodes, implanted in parallel and side by side, to achieve maximum efficacy and to reduce adverse effects in some instances of DBS therapy.

Aged↗

PubMed2000

Double blinded evaluation of the effects of pallidal and subthalamic nucleus stimulation on daytime activity in advanced Parkinson's disease.

The results of a double blinded evaluation of the effects of globus pallidus (GPi; n=7) and subthalamic nucleus (STN; n=11) stimulation in patients with advanced Parkinson's disease are summarized. The patients were evaluated at 6-8months after surgery. In order to determine the benefits afforded by the stimulation to the actual daily activities, the patients were maintained on-medication with optimal doses and schedules. The stimulation was turned off overnight for at least 12h. It was turned on in the morning (or maintained turned off), and the best and worst scores during daytime activity were recorded, as on-period and off-period scores, respectively. A reduction in total motor score on the Unified Parkinson's Disease Rating Scale was clearly elicited by GPi and STN stimulation at both the off-period (-57 and -29%, respectively) and the on-period (-36 and -25%, respectively). The difference in effects between GPi and STN stimulation appeared to be due largely to an unintended difference in the patients' preoperative symptoms. The benefits provided by stimulation to the actual daily activities appears to be limited in patients who have become unresponsive to a large dose of levodopa. Two advantages of GPi and STN stimulation were identified. Firstly, the stimulation can supplement a reduced action of levodopa during the off-period. It thus improves the patient's daily activities through attenuation of the motor fluctuations. Secondly, the stimulation can replace part of the action of levodopa during the on-period. It thus attenuates dopa-induced dyskinesia through a reduced dose of medication. More importantly, the stimulation improves the daily activities in dopa-intolerant patients who are being administered a small dose of levodopa because of unbearable side effects. In addition, GPi stimulation has its own inhibitory effect on dopa-induced dyskinesia. Clinically important improvement was observed in severe gait freezing in 2 patients following unilateral anterodorsal GPi stimulation on the right side alone.

Journal Article↗

PubMed2000

Molecular modelling and conformational analysis of novel glycoprotein (Gp) IIb/IIIa antagonists. Molecular orbital calculation and the condensed heterocyclic derivatives.

A naphthalene compound was chosen as lead compound to develop a new series of fibrinogen receptor antagonists. Eight new compounds with different condensed heterocyclic parts were prepared and their in vitro activities were evaluated. 5-Amidinobenzofuran compound 2, 6-amidinobenzothiophene 7, and 5-amidinofuro[2,3-b]pyridine 8 were more active than lead compound 1. Molecular orbital calculation studies suggested the presence of a preferred spatial orientation between the amidine and the carboxylic acid.

Acetates↗

PubMed2000

Thalamotomy caused by cardioversion in a patient treated with deep brain stimulation.

Deep brain stimulation (DBS) has been applied mainly for the treatment of intractable pain and involuntary movement disorders. Based on the rising numbers of patients undergoing DBS therapy, the possibility of emergent application of cardioversion for the treatment of occasional severe arrhythmia in DBS patients has also increased. However, there has been insufficient discussion about cardioversion in DBS patients. We employed a radiofrequency receiver that transmits to the brain impulses provided by an external generator through an antenna applied to the skin in front of the receiver. We experienced a patient who displayed almost complete cessation of his action tremor with thalamic stimulation. He also developed central dysesthetic pain and showed complete disappearance of his action tremor, even without stimulation, following successful application of cardioversion. It is considered that slight changes in the high-voltage electrical current or high-voltage electrical current spread induced central dysesthetic pain and almost identical effects to thalamotomy. We report for the first time a case of thalamotomy induced by cardioversion in a DBS patient. Clearly, we need to bear in mind that cardioversion has the capability to cause brain lesions in DBS patients with a radiofrequency receiver implanted subcutaneously at the anterior chest wall.

Atrial Fibrillation↗

PubMed2000

Effects of anterodorsal pallidal stimulation on gait freezing (Kinesia paradoxa) in Parkinson's disease.

The results of a double-blind evaluation of the effects of internal globus pallidus (GPi) stimulation in 7 patients with advanced Parkinson's disease are summarized. The evaluation was performed 6-8 months after surgery while the patients were on medication with an optimal dose and schedule. The stimulation was turned off for at least 12 h. It was turned on in the morning (or maintained turned off), and the best and worst scores during their daytime activity were recorded as the on-period and off-period scores, respectively. A significant reduction in the total score on part III of the Unified Parkinson's Disease Rating Scale was induced by GPi stimulation at the off-period (-57%) as well as the on-period (-36%). Clinically important improvement was also achieved in severe gait freezing (kinesia paradoxa) in 2 patients when stimulation was applied to the anterodorsal portion of the GPi. Such an effect was observed during unilateral stimulation of the right side alone.

Aged↗

PubMed1999

Preparation and pharmacological evaluation of novel glycoprotein (Gp) IIb/IIIa antagonists. 1. The selection of naphthalene derivatives.

The synthesis and design using molecular modeling techniques for non-peptide, low molecular weight novel fibrinogen receptor (glycoprotein IIb/IIIa: Gp IIb/IIIa) antagonists, is reported. We used a highly potent serine protease inhibitor, Nafamostat, having an amidinonaphthyl unit as the starting compound. The compounds 4-(6-amidino-2-naphthylaminocarbonyl)phenoxyacetic acid (5a) and 4-(6-amidino-2-naphthalenecarboxamido)phenoxyacetic acid (5b) inhibited adenosin-5'-diphospate (ADP)-induced aggregation of human platelet-rich plasma (PRP) with IC50 values of 0.05 and 0.07 microM, respectively, and had lost their ability to inhibit a variety of serine proteases, including thrombin, factor Xa, plasmin and trypsin.

Adenosine Diphosphate↗

PubMed1999

Preparation and pharmacological evaluation of novel glycoprotein (Gp) IIb/IIIa antagonists. 2. Condensed heterocyclic derivatives.

A novel series of platelet receptor glycoprotein (Gp) IIb/IIIa antagonists with condensed heterocycles as their basic core was synthesized. In an in vitro assay, trans-4-(5-amidinobenzofuran-2-carboxamido)cyclohexyloxyacetic+ ++ acid 17e and trans-3-[4-(5-amidinobenzofuran-2- carboxamido)cyclohexyl]propionic acid 17f produced marked inhibitions with IC50 values of 0.018 and 0.006 microM, respectively in a human platelet adenosin-5'-diphospate (ADP)-induced aggregation assay; they also exhibited a wide spectrum of inhibition toward major aggregation agonists (ADP, collagen, thrombin, PMA (tumor promoter) and arachidonic acid). These compounds were > 2-3 orders of magnitude more effective in inhibiting platelet aggregation than human umbilical vein endothelial cell (HUVEC) binding. The oral administration of 10 mg/kg of either 17e and 17f to guinea pig, resulted in a 60% inhibition of ex vivo platelet aggregation after 5 h. Oral administration of ethyl trans-4-(5-amidinoben-zofuran-2- carboxamido)cyclohexyloxyacetate 18e (10 mg/kg) resulted in 80% inhibition of platelet aggregation in dogs for 6 h after oral administration with a return to baseline by 24 h. Ethyl trans-3-[4-(5-amidinobenzofuran-2-carboxamido)cyclohexyl]propionat e 18f (AR0598) produced 80% inhibition for 5 h after oral administration. Prodrug 18e showed a good profile in dogs with a long duration of action. 18e (AR0510) was selected as suitable clinical candidate for development as an orally active antithrombotic agent.

Adenosine Diphosphate↗

PubMed1999

Intraoperative electrooculographic monitoring of oculomotor nerve function during skull base surgery. Technical note.

Intraoperative monitoring techniques for protecting the integrity of the oculomotor nerves during skull base surgery have been reported by several investigators, all of which involved the use of electromyographic responses to extraocular muscles. However, these techniques have not yet become popular because of the complexity of the procedures. The authors report an extremely simple and far more reliable technique in which electrooculographic (EOG) monitoring is used. The oculomotor nerves were stimulated with a monopolar electrode during skull base exposure. The polarity of the EOG responses recorded with surface electrodes placed on the skin around the eyeball yielded precise information concerning the location and function of the oculomotor and abducent nerves. In addition, with the aid of continuous EOG monitoring that detected transient changes in the background waves, surgical procedures that might impinge on oculomotor nerve function could be avoided. The present technique has been used in eight patients with skull base tumors and with it, the authors have achieved excellent results.

Electrooculography↗