Biomedical subjects

T Kumazawa

Publications and source records attributed to T Kumazawa.

At least 19 recordsLinked to original sources

PubMed1996

Inhibitors of acyl-CoA: cholesterol acyltransferase. II. Preparation and hypocholesterolemic activity of optically active dibenz[b,e]oxepin-11-carboxanilides.

In a previous paper, we reported a novel inhibitor of acyl-CoA: cholesterol acyltransferase (ACAT), 2-bromo-N-(2,6-diisopropylphenyl)-6,11- dihydrodibenz[b,e]oxepin-11-carboxamide (1). In this work, we prepared both enantiomers and tested them for ability to inhibit ACAT (liver microsomes from cholesterol-fed rabbits) in vitro and to decrease serum total cholesterol in cholesterol-fed golden hamsters in vivo. The precursor carboxylic acid 4 was optically resolved with cinchonidine. The obtained (-)- and (+)-4 were converted to (-)- and (+)-1 without racemization, respectively. The enantiomer (-)-1 showed potent ACAT inhibitory activity in vitro with an IC50 value of 8 nM and was approximately 10-fold more active than (+)-1. Furthermore, (-)-1 showed strong hypocholesterolemic activity in vivo, whereas (+)-1 was inactive. A molecular modeling study showed that the difference of ACAT inhibitory activity between the enantiomers was derived from the spatial alignment of the bromine. Compound (-)-1 was selected for further evaluation as KW-3033.

Animals↗

PubMed1995

Gas chromatography with surface ionization detection: a highly sensitive method for determining underivatized codeine and dihydrocodeine in body fluids.

Underivatized codeine and dihydrocodeine in human plasma and urine have been determined with a high degree of accuracy by capillary gas chromatography (GC) with surface ionization detection (SID). The drugs were extracted with the aid of Sep-Pak C18 cartridges. Recovery of both drugs was > or = 90%. The calibration curves obtained with dimemorfan as an internal standard showed linearity in the range 4.5-72.3 and 3.0-75.5 ng/ml of plasma for codeine and dihydrocodeine, respectively. The detection limit was about 100 pg on column (2.5 ng/ml sample). Codeine was determined quantitatively in plasma and urine obtained from a volunteer who had received 10 mg codeine phosphate orally 3 h before the sampling: the levels were found to be 14.1 and 142 ng/ml, respectively. The present GC-SID method has been compared carefully with GC-NPD (nitrogen-phosphorus detection) using the same extracts; the sensitivity of GC-SID was more than ten times greater than that of GC-NPD, with background noise correspondingly lower.

Adult↗

PubMed1995

(E)-4-(2-[[3-(indol-5-yl)-1-oxo-2-butenyl]amino]phenoxy)butyric acid derivatives: a new class of steroid 5 alpha-reductase inhibitors in the rat prostate. 1.

A series of (E)-4-(2-[[3-(indol-5-yl)-1-oxo-2-butenyl]amino]phenoxy)butyric acid derivatives was prepared, and the derivatives were demonstrated to be potent inhibitors of steroid 5 alpha-reductase in the rat prostate. The structure-activity relationships were as follows. An alpha-branched alkyl or benzyl substituent of proper size at position 1 of the indole is crucial for optimal enzyme inhibitory activity. N-Methylation of the amide NH resulted in complete loss of activity. Thus, coplanarity of the benzene ring and amide moiety is essential for such activity. Among the compounds prepared, (E)-4-(2-[[3-[1-[bis(4-fluorophenyl)methyl]indol-5-yl]-1-oxo-2- butenyl]-amino]phenoxy)butyric acid (57, KF18678) was one of the most potent compounds (rat prostate 5 alpha-reductase IC50 = 3.3 nM).

5-alpha Reductase Inhibitors↗

PubMed1995

Rapid extraction and capillary gas chromatography for diazine herbicides in human body fluids.

A simple and rapid method for the extraction of four diazine herbicides (terbacil, bromacil, norflurazon and PAC) from human whole blood, plasma and urine with use of Bond Elut C18 cartridges is presented. Whole blood, plasma and urine samples containing the herbicides, after mixing with distilled water, were loaded on Bond Elut C18 cartridges and the herbicides were eluted with chloroform/methanol (9:1). They were detected by capillary gas chromatography with flame ionization detection (FID) with splitless injection. Separation of the four diazine herbicides from each other and from impurities was generally satisfactory with the use of an intermediately polar DB-17 capillary column. The recovery of all compounds, which had been added to whole blood, plasma and urine, was > 89%. The calibration curve for the herbicides, which has been added to whole blood, plasma and urine, showed linearity in the range 1.6-100 ng on column. Their detection limits were 1.2-1.4 ng on column for whole blood and plasma, and 1.1-1.2 ng on column for urine.

Bromouracil↗

PubMed1995

Levels of pyrroloquinoline quinone in various foods.

The levels of free pyrroloquinoline quinone (PQQ) in various foods were examined by the use of gas chromatography-mass spectrometry. PQQ was extracted from the samples, after addition of [U-13C]PQQ as internal standard, with n-butanol and Sep-Pak C18 cartridges. After derivatization of PQQ with phenyltrimethylammonium hydroxide, molecular peaks at m/z 448 and 462 were used for detection of PQQ and [U-13C]PQQ respectively, by selected ion monitoring. Free PQQ could be detected in every sample in the range 3.7-61 ng/g or ng/ml. Since its levels in human tissues and body fluids are 5-10 times lower than those found in foods, it is probable that PQQ existing in human tissues is derived, at least partly, from the diet.

Coenzymes↗

PubMed1995

A simple analysis of 5 thinner components in human body fluids by headspace solid-phase microextraction (SPME).

A simple method for the extraction of 5 thinner components from human whole blood and urine, using the headspace solid-phase microextraction (SPME) method is presented. After heating a vial containing the samples with 5 compounds (toluene, benzene, n-butyl acetate, n-butanol and n-isoamyl acetate) at 80 degrees C, a polydimethylsiloxane-coated SPME fiber was exposed to the headspace of the vial to allow adsorption of the compounds. The fiber needle was then injected into a capillary gas chromatography (GC) port. The headspace SPME-GC gave intense peaks for each compound and a low level of background noise was seen only for whole blood. Recovery rates of the 5 compounds by use of the headspace SPME-GC were 50-70%. Reproducibility for headspace SPME-GC data were excellent for both body fluids. The calibration curves showed linearity in the range 2-100 ng/0.5 ml whole blood or urine. The detection limits of each compound were 1.1-2.4 ng/0.5 ml sample. The present results on the analysis of 5 thinner components by headspace SPME-GC suggest its applicability to a number of other volatile compounds in forensic toxicology.

1-Butanol↗

PubMed1995

Comparative effects of halothane, enflurane, isoflurane and sevoflurane on function and metabolism in the ischaemic rat heart.

This study was designed to examined the effects of inhalation anaesthetics on function and metabolism in isolated ischaemic rat hearts. Four volatile anaesthetics in two different concentrations (1.0 to 1.5 MAC) were used before whole heart ischaemia was induced for 15 min followed by reperfusion for 30 min. The data were compared with a control group in which inhalation anaesthetics were not used. Before ischaemia, volatile anaesthetics depressed ventricular function. During reperfusion, ventricular function and coronary flow in both halothane groups were significantly lower than those in the control group. Myocardial ATP concentrations in the 1.0 MAC of enflurane and isoflurane groups were significantly higher than those in the control group. We conclude that halothane had more depressant effects than the other anaesthetics and that enflurane and isoflurane may enhance metabolic recovery in the ischaemic working rat heart.

Adenosine Triphosphate↗

PubMed1995

Isoflurane and sevoflurane produce a dose-dependent reduction in the shivering threshold in rabbits.

All general anesthetics markedly impair thermoregulatory responses; nonetheless, sufficient hyperthermia or hypothermia will trigger most protective reflexes. Shivering, however, remains an exception among thermo-regulatory responses: it is common during postanesthetic recovery, but is rare at typical anesthetic concentrations. This observation suggests that general anesthesia impairs shivering far more than other thermoregulatory defenses. Accordingly, we tested the hypothesis that low concentrations of isoflurane and sevoflurane would virtually obliterate shivering. Japanese white rabbits were anesthetized with isoflurane or sevoflurane at end-tidal concentrations of 0.2, 0.3, and 0.4 minimum alveolar anesthetic concentration (MAC) (n = 6 in each group); the normal core temperature for these rabbits is approximately 39 degrees C. Core temperatures were subsequently reduced by a water-perfused thermode positioned in the colon. The core temperature triggering shivering identified the threshold for this response. Five of the six rabbits given 0.2 MAC isoflurane shivered at a mean core temperature of 36.3 +/- 0.3 degrees C (mean +/- SD), and one rabbit failed to shiver at a minimum core temperature of 35.0 degrees C. Four of the six rabbits given 0.3 MAC isoflurane shivered at a mean core temperature of 36.2 +/- 0.6 degrees C, and two of these rabbits failed to shiver at a minimum core temperature of 35.0 degrees C. However, no rabbit given 0.4 MAC isoflurane shivered, even at minimum core temperatures of 35.0 degrees C. All of the rabbits given 0.2 MAC sevoflurane shivered at a mean core temperature of 36.6 +/- 0.7 degrees C.(ABSTRACT TRUNCATED AT 250 WORDS)

Anesthetics↗

PubMed1995

Effects of intravenous anesthetics on function and metabolism in the reperfused working rat heart.

We investigated the comparative effects of ketamine, flunitrazepam, diazepam and midazolam on function and metabolism in reperfused rat hearts. Seventy-two hearts were rapidly excised and perfused with buffer as a Neely's working model. Whole heart ischemia was induced for 15 min followed by reperfusion for 20 min. Four intravenous anesthetics in 2 different concentrations (10 and 50 times of therapeutic concentrations) were administered during reperfusion. The data were compared to a control group in which intravenous anesthetics were not used. At the end of reperfusion, myocardial metabolites were measured by liquid chromatography. Cardiac outputs in the both groups given lower and higher doses of ketamine and flunitrazepam and in the groups given the higher dose of diazepam and midazolam were significantly lower than that in the control group [at the end of reperfusion: control: 60.4; ketamine: 48.8 (lower) and 14.6 (higher); flunitrazepam: 50.2 (lower) and 50.6 (higher); diazepam: 62.6 (lower) and 42.5 (higher); midazolam: 59.5 (lower) and 51.2 (higher), ml/min]. The levels of ATP in all higher concentration anesthetic groups were significantly lower than those in the control group (control: 23.7, ketamine: 17.8, flunitrazepam: 17.8, diazepam: 17.7, midazolam: 17.7, mumol/g). These results suggest that ketamine and flunitrazepam moderately depress cardiac function more than diazepam and midazolam when they are given during reperfusion.

Anesthetics↗

PubMed1995

Effects of prostaglandin E1 on intra-operative central and peripheral temperatures during upper abdominal surgery.

Effects of prostaglandin E1 (PGE1) on temperatures during upper abdominal surgery under isoflurane anaesthesia were studied. Forty-five patients were randomly assigned to one of three groups (15 patients per group). One group received 0.05 micrograms kg-1 min-1 of PGE1, the second group received 0.1 microgram kg-1 min-1 of PGE1 just after the induction of anaesthesia, and the third group received no PGE1 during anaesthesia (control). Tympanic membrane (central) temperatures, forearm temperatures, and fingertip temperatures were recorded during surgery every 30 min. Tympanic membrane temperatures in the 0.05 micrograms kg-1 min-1 group during and at the end of surgery were significantly higher than those in the control group. In the 0.1 microgram kg-1 min-1 group, maximum decrease of tympanic membrane temperature was significantly larger than that in the control group. Fingertip temperatures in the 0.05 micrograms kg-1 min-1 group during surgery were significantly higher than those in the control group. This result suggests that 0.05 micrograms kg-1 min-1 of PGE1 may be superior to 0.1 microgram kg-1 min-1 of PGE1 for maintaining central and peripheral temperatures during surgery and general anaesthesia.

Abdomen↗

PubMed1995

[Effect of ritodrine hydrochloride on uterine and umbilical blood flow in patients with preeclampsia and IUGR].

Ritodrine hydrochloride is clinically used to prevent uterine contraction in preterm labor. Pregnancy toxemia is known to be a cause of intrauterine growth retardation (IUGR) due to disturbance of utero-placental circulation. In the present study, patients with preterm labor or pregnancy toxemia associated with IUGR were infused with ritodrine and the effects of ritodrine on uterine and umbilical blood flow were determined by using 2-D color Doppler. The effects of ritodrine infusion on fetal growth were also evaluated. Increases in fetal heart rate and maternal heart rate were observed following ritodrine infusion, but there was no other apparent side effect. The resistance index (RI) of the uterine and umbilical arteries of patients with preterm labor were significantly decreased by ritodrine infusion. The RI of both arteries of the patients associated with toxemia and IUGR was also decreased. A significant increase in FTA and EFBW was observed in IUGR fetuses following treatment with ritodrine for 2 weeks given to patients with toxemia when compared with the non-treated control. These results indicate that ritodrine administration may be effective not only in preventing preterm labor but also in treating IUGR by improving utero-placental blood flow.

Female↗

PubMed1995

[Anesthesia with transesophageal echocardiography for removal of pheochromocytoma].

A 45-year-old female was scheduled for left adrenalectomy because of a pheochromocytoma. Preoperative general condition was well controlled with alpha- and beta-blockers. Anesthesia was induced with thiamylal and vecuronium, and maintained with isoflurane (0.5-3%) and nitrous oxide in oxygen. Blood pressure was controlled with nicardipine and alpha-blocker during the manipulation of the tumor. After removal of the tumor, dopamine and norepinephrine were used. We used transesophageal echocardiography (TEE) to determine the fluid administration rate and doses of catecholamine. We could observe the wall motion and the mass of the heart, and see changes of the left ventricular enddiastolic volume, the cardiac output and the stroke volume. TEE monitoring seems to be very useful during the resection of pheochromocytoma.

Adrenal Gland Neoplasms↗

PubMed1995

[Alterations of cardiac function and metabolism in the rat heart-lung preparation by methyl methacrylate (MMA) and their protection by ulinastatin].

We have assessed the deleterious effects of methyl methacrylate (MMA) on cardiac function and metabolism in the isolated heart-lung preparation and their protection by ulinastatin. Twenty-four male Wistar rats were prepared for the heart-lung model. They were randomly divided into 3 groups. In the MMA (M) and ulinastatin (U) groups, MMA 1000 micrograms.ml-1 was administered 7 minutes after the start of perfusion. At the end of the experimental period, the hearts were freeze-clamped and then myocardial high energy phosphates, lactate and glycogen were measured. Cardiac output decreased significantly in the M and U groups. Po2 of the perfusion blood in the M and U groups was significantly lower than that in the control (C) group. Myocardial ATP in the M and U groups was significantly lower than that in the C group. ADP and AMP in the M and U groups were higher than those in the C group. Although there was no significant difference in lactate levels among the 3 groups, glycogen in the U and C groups was significantly higher than that in the M group. MMA 1000 micrograms.ml-1 is much higher than the blood level (0.05-31.89 micrograms.ml-1) reported clinically in patients who had femoral prosthesis. Ulinastatin increased myocardial glycogen content which had been reduced by MMA. This may suggest that ulinastatin has a protective effect on heart damaged by MMA.

Adenosine Diphosphate↗

PubMed1995

[Anesthetic management of a neonate with primary cardiac rhabdomyoma].

We have experienced anesthetic management for cardiac rhabdomyoma in a 21-day-old male, whose pulmonary trunk was obstructed by the tumor. He was anesthetized with fentanyl 70 micrograms.kg-1 and oxygen. The operative and post-operative courses were uneventful. Cardiac tumor, especially cardiac rhabdomyoma, in infant is rare. Anesthesia for the resection of the cardiac tumor must be carried out carefully, because sudden death due to arrhythmias as well as cardiac or respiratory failure is the most dangerous complication.

Anesthesia↗

PubMed1995

[Anesthetic management of a patient with cardiac sarcoidosis].

We report the anesthetic management of a patient with cardiac sarcoidosis. Cardiac sarcoidosis is characterized by a high incidence of complete atrioventricular block, right bundle branch block, and ventricular arrhythmias. Cases of sudden death during stable cardiac function have been reported. Therefore, careful anesthetic management is necessary. The patient was premedicated with scopolamine, intramuscularly. Before the induction, he received lidocaine, propranolol, and pentazocine, intravenously. Anesthesia was induced with midazolam and vecuronium, and the trachea was intubated. Anesthesia was maintained with nitrous oxide, sevoflurane in oxygen. Anesthetic method adapted to prevent severe complications including sudden death resulted in good condition of the patient during the perioperative period.

Adult↗

PubMed1994

Effects of kainic acid in the parabrachial region for ongoing respiratory activity and reflexive respiratory suppression.

We previously reported that the electrical stimulation of gastrocnemius muscle nerve afferents given at a suprathreshold intensity for C-fiber afferents induces naloxone-reversible reflexive respiratory suppression ('after suppression'). The effects of kainic acid (KA) microinjections into the parabrachial area (nucleus parabrachialis lateralis: NPBL and nucleus parabrachialis medialis: NPBM) on (1) ongoing respiratory activity and (2) the 'after suppression' were studied in chloralose-urethane anesthetized, bivagotomized, paralyzed, and artificially ventilated cats. A large dose of KA (1.91 nmol in 0.1 microliters) microinjected into the unilateral NPBL induced significant long-lasting respiratory facilitation, while a subsequent KA injection into the ipsilateral NPBM induced significant, long-lasting respiratory depression. A small dose of KA (0.48 nmol in 0.1 microliters) into the unilateral NPBL (right side) induced significant respiratory facilitation, and the 'after suppression' effect was eliminated. A small dose into the unilateral NPBM (right side) caused initial transient respiratory facilitation followed by respiratory depression before 'after suppression' was restored. Subsequent KA injections into the NPBL on the other side (left side) significantly augmented respiration. The 'after suppression' effect was again eliminated after an injection of KA into the bilateral NPBL. It was concluded that NPBL may exhibit tonic inhibitory activities on respiration and play a critical role in the 'after suppression' effect, since an injection of KA into the NPBM counteracted both of these effects in the NPBL.

Animals↗

PubMed1994

Norepinephrine excitation of cutaneous nociceptors in adjuvant-induced inflamed rats does not depend on sympathetic neurons.

To test the contribution of sympathetic postganglionic neurons (SPGNs) to adrenergic excitation of cutaneous nociceptor activities in adjuvant-inflamed rats (AI rats), we studied the effects of norepinephrine (NE) in a group of sympathectomized AI rats. Sympathectomy was complete in 4-6 weeks by guanethidine (30-50 mg/kg). NE excited polymodal receptor units in the saphenous nerve at an incidence (25-30%) similar to that in AI rats, while CH-38083 blocked such excitation. These results show that alpha 2-adrenoceptors in SPGNs are not involved in the norepinephrine excitation of cutaneous nociceptors in AI rats.

Adrenergic alpha-Antagonists↗

PubMed1994

Possible involvement of the EP2 receptor subtype in PGE2-induced enhancement of the heat response of nociceptors.

Prostaglandin E2 augments bradykinin- and heat-induced discharges of polymodal receptors as studied in vitro preparations. Our previous study revealed the involvement of the EP3 receptor subtype in the PGE2 induced enhancement of the BK response [Brain Res. 632 (1993) 321-324]. The agonist for EP2 (butaprost; 10(-8) M) significantly augmented heat responses, but did not augment the BK responses at concentrations from 10(-8) to 10(-5) M; however, the agonist for EP3 (M&B28767) or EP1 (17-phenyl-trinor-PGE2) at 10(-7) M did not affect the heat responses. These findings indicate the involvement of the EP2 receptor subtype in the augmenting effect of PGE2 on heat responses.

Alprostadil↗