Genetic and environmental factors in the pathogenesis of Parkinson's disease.
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Environment↗
Biomedical subjects
N Morikawa
Publications and source records attributed to N Morikawa.
Entrapment of islets into reversible disulfide hydrogels.
Currently, there are three types of devices for a bioartificial pancreas; microencapsulation, an extravascular diffusion chamber, and an intravascular diffusion chamber. The purpose of the present study was to provide a new extracellular matrix hydrogel for the devices of extra- and intravascular diffusion chamber types. As the sol-gel transition of this hydrogel is reversible, refilling of islets in vivo will be possible without a severe traumatic procedure. The hydrogel was produced from a polyacrylamide derivative carrying thiol groups synthesized by radical copolymerization of acrylamide and N,N'-bis-acrylcystamine, followed by reduction of the disulfide bonds in the copolymer. This water-soluble copolymer was used to entrap hamster islets by re-formation of disulfide bonds on the copolymer to produce a hydrogel. The formed hydrogel was easily reliquefied by reduction of the disulfide crosslinks to thiols. Insulin release from the islet-entrapped hydrogel continued for more than 1 month when examined in vitro. A static glucose stimulation test for the entrapped islets exhibited an increased insulin release.
Animals↗
Discontinuous total parenteral nutrition prevents postischemic mitochondrial dysfunction in rat liver.
Although discontinuous total parenteral nutrition (d-TPN) has recently been favored for clinical use over continuous total parenteral nutrition (c-TPN) to ameliorate liver dysfunction, mechanisms for the protection against postoperative liver dysfunction remain unknown. This study aimed to examine differences in mitochondrial function in d-TPN- and c-TPN-pretreated livers during ischemia-reperfusion. Rat livers pretreated with d-TPN or c-TPN were perfused with Krebs-Ringer buffer and were exposed to 25% low-flow hypoxia followed by reperfusion. Intrahepatic mitochondrial membrane potential (triangle up) and cell viability were assessed by dual-color digital microfluorography using rhodamine 123 (Rh123) and propidium iodide (PI), respectively. In response to hypoxia, livers pretreated with c-TPN, d-TPN, and an ordinary chow diet exhibited a significant triangle up reduction among the entire lobules. Upon reperfusion, the regional triangle up values further decreased in the c-TPN liver, whereas those in the d-TPN-treated or chow-treated livers displayed a rapid recovery toward the control levels. The severity of cell injury did not differ among the groups, showing that the reperfusion-induced triangle up drop in the c-TPN-pretreated liver is not a consequence of cell injury. Differences in the triangle up drop among the groups appear to occur irrespective of those in the glycogen storage, because the livers undergoing d-TPN display a marked triangle up recovery even when reperfused at the end of a fasted state. These results indicate that c-TPN, but not d-TPN, jeopardizes mitochondrial re-energization and suggest that a circadian pattern of the TPN serves as a potentially beneficial strategy to reduce the risk of postischemic mitochondrial dysfunction in the liver.
Animals↗
Pharmacokinetics of nimustine, methotrexate, and cytosine arabinoside during cerebrospinal fluid perfusion chemotherapy in patients with disseminated brain tumors.
OBJECTIVE: This study was conducted to evaluate the pharmacokinetics of anticancer drugs in cerebrospinal fluid (CSF) perfusion chemotherapy. METHODS: We administered CSF perfusion chemotherapy with nimustine (ACNU), methotrexate (MTX), and cytosine arabinoside (Ara-C) to three patients with disseminated malignant brain disease. The drugs were infused via Ommaya's reservoirs to the lateral ventricle and removed by drainage from the temporal lobe or lumbar spine. CSF and plasma concentrations of the anticancer drugs were determined by high-performance liquid chromatography and fluorescence polarization immunoassay. RESULTS: The concentrations of anticancer drugs in the discharged CSF peaked about 40 min after the start of a 1-h CSF perfusion. After the perfusion, the drug level in CSF decreased exponentially in a monophasic manner. ACNU and Ara-C were not detectable in the discharged CSF in the temporal lobe at 6 h and 48 h after perfusion, respectively, but MTX was detectable at 48 h. The maximum concentration ratio of anticancer drugs and the duration of perfusion were inversely correlated. The plasma concentrations of anticancer drugs were much lower than those in CSF. The half-life of ACNU was very short (0.2-1.1 h), whereas the half-lives of MTX and Ara-C were relatively long (2.81-13.5 h and 1.84 6.25 h, respectively). The half-lives of the anticancer drugs in CSF tended to decrease with repeated CSF perfusion chemotherapy. CONCLUSION: Results suggest that CSF perfusion chemotherapy enables a high concentration of anticancer drug to be administered for dissemination in the spinal cord within a short period of time, with minimal adverse effects.
Adult↗
Effects of various tetrahydroisoquinoline derivatives on mitochondrial respiration and the electron transfer complexes.
We report effect of various tetrahydroisoquinoline derivatives on mitochondrial respiration and the electron transfer complexes. Generally these compounds were potent inhibitors of NADH-linked mitochondrial state 3 respiration and complex I. Presence of a phenyl group at the C1 position or oxidation of N-methylated isoquinones into N-methylisoquinolinium ion augmented the potency to inhibit mitochondrial respiration and complex I. Many of these compounds have been identified in human brains. In view of the mitochondrial and oxidative stress hypothesis, our results suggest involvement of these neurotoxins as potential causes of mitochondrial failure in Parkinson's disease.
Animals↗
The potential of anticomplement synthetic sulfonic polymers for xenotransplantation.
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Animals↗
Different pharmacokinetics of (4R)-hexahydro-7,7-dimethyl-6-oxo-1,2,5-(3-14C)dithiazocine-4-carboxyli c acid between the fasting and non-fasting rat: role of intestinal microorganisms.
1. We report differences in the pharmacokinetics of (4R)-hexahydro-7,7-dimethyl-6-oxo-1,2,5-(3-14C)dithiazocine-4-carb oxylic acid (14C-SA3443) between the normal fasting and non-fasting rat, especially in the blood concentration-time curves and respiratory excretion. Exhalation of 14CO2 was an important route of elimination and accounted for 21.2% of the dose in the non-fasting rat but only 3.7% in fasting animals. 2. In the intestinal microorganism-compromised rat, we found little differences in the pharmacokinetics of 14C-SA3443 between fasting and non-fasting states. No respiratory excretion was observed in the intestinal microorganism-compromised animal. 3. In the reaction mixture of 14C-SA3443 with the cecal contents of rat, 14C-acetic acid and 14C-butyric acid were detected and 14CO2 barely detected. 4. The amounts of 14C-acetic acid and 14C-butyric acid in the reaction mixture of 14C-SA3443 with non-fasting rat cecal contents were more than those with fasting rat cecal contents. 5. We concluded that the reason for the different pharmacokinetics of 14C-SA3443 between the fasting and non-fasting rat was the differences in participation of the metabolism of 14C-SA3443 by intestinal microorganisms.
Adjuvants, Immunologic↗
Pharmacokinetics of intra-arterially administered pirarubicin in plasma and cerebrospinal fluid of patients with glioma.
The present paper investigates the pharmacokinetics of pirarubicin (THP) in the plasma and cerebrospinal fluid (CSF) of two patients with glioma during hyperosmotic disruption of the blood-brain barrier (HODBBB) and intra-arterial combination chemotherapy. A 42-year-old Japanese man (patient A) with glioblastoma and a 21-year-old Japanese woman (patient B) with astrocytoma received a course of HODBBB and intra-arterial combination chemotherapy with THP, methotrexate, peplomycin, and vindesine. Patient A was initially administered mannitol, followed by the infusion of anticancer drugs into the right internal carotid artery. Patient B was initially administered mannitol, followed by the infusion of anticancer drugs into the right internal carotid artery and, immediately thereafter, into the right vertebral artery. Samples of blood and of CSF in the brain ventricle were obtained. THP concentration was measured by HPLC, and the pharmacokinetic parameters of this drug were estimated in plasma and CSF. In both patients, the plasma concentration of THP peaked at the end of infusion, then decreased in a bi-exponential decay pattern during the remainder of the treatment period. THP was detectable in CSF beginning 1.0 h after the initiation of infusion, then was slowly eliminated from the ventricle. The maximum CSF concentration of THP was 0.97% of plasma in patient A and 0.89% in patient B. The CSF AUC of THP was 28.4% of plasma in patient A and 13.1% in patient B.
Adult↗
Pharmacokinetics of pirarubicin in plasma and cerebrospinal fluid.
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Adult↗
Pharmacokinetics of anticancer drugs in cerebrospinal fluid.
OBJECTIVE: To examine the pharmacokinetics of anticancer drugs in the cerebrospinal fluid (CSF) during chemotherapy by the lumbar-ventricular (LV) and ventricular-lumbar (VL) routes. CASE SUMMARY: A 69-year-old Japanese woman with disseminated glioblastoma received two LV and four VL courses of CSF perfusion chemotherapy with methotrexate, nimustine, and cytarabine hydrochloride. Samples of CSF from the ventricles and lumbar spinal canal were obtained via Ommaya reservoirs during one LV and one VL course. Drug concentrations in the CSF were measured by fluorescence polarization immunoassay or HPLC. RESULTS: During LV CSF perfusion, the highest CSF drug concentrations in both the ventricles and the lumbar spinal canal were observed at the end of perfusion. During treatment, the concentrations of all three drugs in the lumbar spinal canal were higher than those in the ventricles. The CSF AUC of methotrexate in the ventricles was 16.1% of that in the lumbar spinal canal. During VL CSF perfusion, the highest drug concentrations were also observed at the end of perfusion. The drug concentrations in the lumbar spinal canal were initially lower than those in the ventricles. However, the concentrations of methotrexate and cytarabine in the lumbar spinal canal exceeded those in the ventricles 3 hours after perfusion. The AUC of methotrexate in the lumbar spinal canal was 174.9% of that in the ventricles. CONCLUSIONS: The pharmacokinetics of anticancer drugs in ventricular CSF differ from those in lumbar CSF during LV and VL perfusion chemotherapy.
Aged↗
Nontoxic embolic liquids for treatment of arteriovenous malformations.
Interventional radiology is becoming one of the standard treatments of arteriovenous malformation (AVM). Cyanoacrylate derivatives and polymer solutions are widely used to occlude the AVM nidus by their injection through a catheter, but they are far from satisfactory embolic liquids. For instance, cyanoacrylate derivatives sometimes glue the catheter to the artery, resulting in serious complications; in addition, the organic solvents used to dissolve polymers cause damage to the surrounding brain tissue of the AVM. Therefore, we attempted to develop embolic liquids by dissolving poly(2-hydroxyethyl methacrylate-co-methyl methacrylate) in Iopamiron with an addition of a small amount of ethyl alcohol. This new embolic liquid is not cytotoxic and is easily injected into the AVM through a thin, long catheter to effectively occlude the AVM.
Animals↗
Novel subtype-selective nonpeptide bradykinin receptor antagonists FR167344 and FR173657.
We describe the receptor binding and antagonistic properties of two novel nonpeptide antagonists, FR167344 (3-bromo-8-[2,6-dichloro-3-[N-[(E)-4-(N,N-dimethylcarbamoyl)cinnamido acetyl]-N-methylamino]benzyloxy]-2-methylimidazo[1,2-a]pyridine hydrochloride) and FR173657 (8-[3-[N-[(E)-3-(6-acetamidopyridin-3-yl)acryloylglycyl]-N-m ethylamino]-2,6-dichlorobenzyloxy]-2-methylquinoline), for the human bradykinin receptor subtypes (B1 and B2). In competitive experiments using membranes prepared from Chinese hamster ovary cells expressing the bradykinin receptor subtypes, FR167344 and FR173657 showed a high affinity binding to the B2 receptor with IC50 values of 65 and 8.9 nM, respectively, and no binding affinity for the B1 receptor. FR167344 and FR173657 inhibited the B2 receptor-mediated phosphatidylinositol (PI) hydrolysis and produced a concentration-dependent rightward shift in the dose-response curve to bradykinin. This shift was accompanied by a progressive reduction of maximal response. Estimated pA2 values for the antagonism of bradykinin-induced PI hydrolysis by FR167344 and FR173657 were 8.0 and 9.0, respectively. FR167344 and FR173657 showed no stimulatory effects on PI hydrolysis. Therefore, FR167344 and FR173657 are potent, highly selective, and insurmountable antagonists for the human bradykinin B2 receptor.
Animals↗
Nonpeptide mimic of bradykinin with long-acting properties at the bradykinin B2 receptor.
Kinins, members of a family of peptides released from kininogens by the action of kallikreins, exhibit a variety of biological activities including vasodilation, increased vascular permeability, contraction of smooth muscle cells, and activation of sensory neurons. However, investigation of the physiological actions of kinins has been greatly hampered because its effects are curtailed by rapid proteolysis in blood, lung, and liver. We describe the pharmacological characteristics of a novel nonpeptide bradykinin receptor agonist FR190997 (8-[2,6-dichloro-3-[N-[(E)-4-(N-methylcarbamoyl)cinnamidoacetyl ]-N-methylamino]benzyloxy]-2-methyl-4-(2-pyridylmethoxy)quinoli ne). FR190997 markedly stimulated phosphatidylinositol hydrolysis in Chinese hamster ovary cells permanently expressing the human bradykinin B2 receptor. The response of phosphatidylinositol hydrolysis was antagonized by the B2 receptor selective antagonist Hoe 140 (D-Arg-[hydroxyproline3,beta-thienylalanine4,D-Tic7,++ +Oic8]bradykinin). In competitive experiments using membranes prepared from Chinese hamster ovary cells expressing the human bradykinin receptor subtypes, FR190997 showed a high affinity binding to the B2 receptor with IC50 value of 5.3 nM and no binding affinity for the B1 receptor. In vivo, FR190997 mimics the biological action of bradykinin and induces hypotensive responses in rats with prolonged duration. Therefore, FR190997 is a highly potent and subtype-selective nonpeptide agonist which displays high intrinsic activity. This compound should represent a powerful tool for further investigation of the physiology and pathophysiology of bradykinin receptors.
Animals↗
Encapsulation of mammalian cells into synthetic polymer membranes using least toxic solvents.
Immunoisolation, that is, enclosure of cells within a semipermeable membrane to protect them from immunological rejection, may enable the transplantation of cells without use of immunosuppressive drugs. Therefore, in addition to naturally-occurring ionic polymers, several synthetic nonionic polymers which can form dense and strong membranes in water have been studied as materials for immunoisolation. However, such nonionic polymers are required to be soluble in organic solvents which are mostly cytotoxic. In this report we describe enclosure of insulin-releasing cells into water-insoluble poly(2-hydroxyethyl methacrylate) and poly(2-hydroxyethyl methacrylate-co-methyl methacrylate) membranes using X-ray contrast medium as a solvent without use of any special apparatus. The contrast medium employed in our study is iopamidol aqueous solution. Insulin release was observed for 1 months when insulin-releasing cells were encapsulated into these membranes. The permeability of five solutes through the membranes prepared from the iopamidol aqueous solution was also studied to determine their potential immunoisolative efficacy.
Animals↗
Pharmacokinetics of methotrexate in plasma and cerebrospinal fluid.
OBJECTIVE: To investigate the pharmacokinetics of methotrexate (MTX) in plasma and cerebrospinal fluid (CSF) during osmotic disruption of the blood-brain barrier and the intraarterial administration of combination chemotherapy postoperatively in a patient with glioblastoma. CASE SUMMARY: A 60-year-old Japanese woman with a glioblastoma received two courses of combination intraarterial chemotherapy. In the first course of treatment, 20 mL of mannitol 20%, peplomycin 10 mg, vindesine 2 mg, and MTX 500 mg were administered via the right internal carotid artery, and then via the right vertebral artery. In the second course of treatment, 20 mL of mannitol 20%, peplomycin 15 mg, vindesine 2.5 mg, and MTX 1000 mg were similarly administered. Blood samples and CSF samples from the ventricle and the space left by tumor removal were obtained; the MTX concentrations were measured from these sites by fluorescence polarization immunoassay. The pharmacokinetic parameters of MTX in plasma and CSF were estimated. DISCUSSION: The plasma concentration of MTX decreased in a biexponential decay pattern during each course of treatment. CSF concentrations of MTX in the ventricle and in the space left by tumor removal peaked at 2 and 6 hours, respectively, after drug administration and decreased monoexponentially. When the dose of MTX was doubled, the AUC for the plasma MTX concentration increased 2.4-fold and the AUCs for MTX in the ventricle and the space left by tumor removal increased 3.4- and 9.1-fold, respectively. The half-life of MTX in the CSF in the space left by tumor removal exceeded the half-lives of MTX in the plasma and in the ventricular CSF. CONCLUSIONS: The CSF AUCs of MTX in the ventricle and the space left by tumor removal increased markedly and in parallel with the MTX dosage increase during osmotic disruption of the blood-brain barrier and intraarterial combination chemotherapy. Such treatment improves the delivery of chemotherapy agents to the brain.
Antineoplastic Combined Chemotherapy Protocols↗
[(Neurological CPC.55). A 60-year-old woman with progressive cerebellar ataxia, myoclonus, and dementia].
We report a 60-year-old woman with progressive ataxia, myoclonus, choreoathetosis, and dementia. She was well until 27 years of the age when she noted an onset of gait disturbance and speech disturbance. She noted abnormal involuntary movements in her four limbs at 42 years of the age. Her symptoms had progressively become worse and she fell down frequently by her 52 years of the age. In addition, her family members noted gradual decline in her intelligence. She was admitted to our hospital in February of 1993 when she was 57-year-old. On admission, she showed dementia, scanning speech, ataxic gait, limb ataxia, action myoclonus, and choreic movements which involved her four limbs. Deep tendon reflexes were slightly exaggerated in the lower limbs; no Babinski sign was noted. Sensation was intact. Laboratory findings were unremarkable. Cerebral MRI revealed atrophy of the cerebellar cortex, superior cerebellar peduncle, brain stem, and the cerebral cortex; the third ventricle and the lateral ventricles were dilated; furthermore, T2-high signal lesions were seen in the cerebral white matter and in the pontine base. Her clinical course was one of the progressive deterioration of her ataxia, involuntary movements, and dementia. She expired on April 24, 1996 when she was 60-year-old. She was discussed in a neurologic CPC and the chief discussant arrived at the conclusion that the patient had dentatorubral-pallidoluysian atrophy. A minor opinion was that she might have had myoclonus epilepsy with ragged-red fibers. Postmortem examination revealed atrophy, gliosis, and neuronal loss in the external segment of the globus pallidus, subthalamic nucleus, red nucleus, and in the dentate nucleus. In addition, the gracil and cuneiform nuclei showed neuronal loss and spheroid formation; the spinocerebellar tracts were retained. The substantia nigra and the locus coeruleus were intact. No ragged-red fibers were seen in the muscle biopsy specimen taken in February, 1993. The neuropathologic findings were consistent with the diagnosis of dentatorubral-pallidoluysian atrophy.
Atrophy↗
Effect of dopamine, dimethoxyphenylethylamine, papaverine, and related compounds on mitochondrial respiration and complex I activity.
We report the effect of papaverine, tetrahydro-papaverine, laudanosine, dimethoxyphenylethylamine, dopamine, and its metabolites on mitochondrial respiration and activities of the enzymes in the electron transfer complexes, as mitochondrial toxins may be implicated in the etiology and the pathogenesis of Parkinson's disease. Papaverine was the most potent inhibitor of complex I and NADH-linked mitochondrial respiration among the compounds tested next to rotenone. Tetrahydropapaverine, dimethoxyphenylethylamine, and laudanosine also inhibited NADH-linked mitochondrial respiration and complex I activity in this order. Dopamine and its metabolites showed either no inhibition or only very week inhibition. Compounds with dimethoxy residues in the phenyl ring were associated with more potent inhibition of complex I than those without. Our results warrant further studies on these and some related compounds as candidate neurotoxins causing Parkinson's disease.
Animals↗
An immuno-isolative membrane capable of consuming cytolytic complement proteins.
In an earlier article we demonstrated that xenogeneic islets of Langerhans in an agarose/poly(styrenesulfonic acid) (PSSa) microcapsule were protected from the host's immune rejection and that diabetic animals maintained a normal glucose level for a long period of time after their transplantation. In this study, we attempted to make clear the immuno-isolative mechanisms of the agarose-PSSa microcapsule from the standpoint of permeability of antibodies and complement proteins through this microcapsule membrane. It was found that the microcapsule was unable to prevent the permeation of IgG for longer than a few days, but protect the encapsulated cells from cytolytic complement attack. This strongly suggests that the cytolytic complement activity was lost during permeation through the microcapsule, probably because of the strong interaction of PSSa in the membrane with complement proteins. Based on these findings we proposed the minimum requirement for the immuno-isolative membrane to be applicable to xenotransplantation.
Animals↗