PubMed Health⌕ Search

Biomedical subjects

Kaoru Yamaoka

Publications and source records attributed to Kaoru Yamaoka.

10 recordsLinked to original sources
PubMed2005

[Evaluation of a combination chemotherapy with docetaxel and nedaplatin for patients with oral squamous cell carcinomas].

The purpose of this study was to evaluate the effectiveness and safety of combination chemotherapy with docetaxel (TXT) and nedaplatin (CDGP) for patients with oral squamous cell carcinomas. Eight patients were enrolled in this study (4 men and 4 women, with a mean age of 61.7 years). TXT and CDGP were administered at a dose of 60 mg/m(2) and 70 mg/m(2) by drip infusion for 120 minutes, respectively. Three patients received one more administration 4 weeks after the first one. The locoregional response was evaluated 4 weeks after the final administration of TXT and CDGP. As a result, the locoregional response rate after 1 course was 62.5% including 25.0% of complete response (CR). The response rate after 2 courses was 100.0% with 66.7% of CR. According to Oboshi and Shimosato's classification, histological evaluation of surgical specimens revealed that four cases were Grade IIa, two cases Grade IIb, and two cases Grade IV. The severe adverse events were neutropenia and leukopenia, which were effectively managed with granulocyte colony-stimulating factor (G-CSF). No other severe side effects were recognized. The present study suggested that the combination chemotherapy with TXT and CDGP would be an effective and safe regimen in neo-adjuvant chemotherapy for oral squamous cell carcinomas.

Adult↗
PubMed2004

A quantitative and comparative study of the effects of a synthetic ciguatoxin CTX3C on the kinetic properties of voltage-dependent sodium channels.

Ciguatoxins (CTXs) are known to bind to receptor site 5 of the voltage-dependent Na channel, but the toxin's physiological effects are poorly understood. In this study, we investigated the effects of a ciguatoxin congener (CTX3C) on three different Na-channel isoforms, rNa(v)1.2, rNa(v)1.4, and rNa(v)1.5, which were transiently expressed in HEK293 cells. The toxin (1.0 micromol l(-1)) shifted the activation potential (V(1/2) of activation curve) in the negative direction by 4-9 mV and increased the slope factor (k) from 8 mV to between 9 and 12 mV (indicative of decreased steepness of the activation curve), thereby resulting in a hyperpolarizing shift of the threshold potential by 30 mV for all Na channel isoforms. The toxin (1.0 micromol l(-1)) significantly accelerated the time-to-peak current from 0.62 to 0.52 ms in isoform rNa(v)1.2. Higher doses of the toxin (3-10 micromol l(-1)) additionally decreased time-to-peak current in rNa(v)1.4 and rNa(v)1.5. A toxin effect on decay of I(Na) at -20 mV was either absent or marginal even at relatively high doses of CTX3C. The toxin (1 micromol l(-1)) shifted the inactivation potential (V(1/2) of inactivation curve) in the negative direction by 15-18 mV in all isoforms. I(Na) maxima of the I-V curve (at -20 mV) were suppressed by application of 1.0 micromol l(-1) CTX3C to a similar extent (80-85% of the control) in all the three isoforms. Higher doses of CTX3C up to 10 micromol l(-1) further suppressed I(Na) to 61-72% of the control. Recovery from slow inactivation induced by a depolarizing prepulse of intermediate duration (500 ms) was dramatically delayed in the presence of 1.0 micromol l(-1) CTX3C, as time constants describing the monoexponential recovery were increased from 38+/-8 to 588+/-151 ms (n=5), 53+/-6 to 338+/-85 ms (n=4), and 23+/-3 to 232+/-117 ms (n=3) in rNa(v)1.2, rNa(v)1.4, and rNa(v)1.5, respectively. CTX3C exerted multimodal effects on sodium channels, with simultaneous stimulatory and inhibitory aspects, probably due to the large molecular size (3 nm in length) and lipophilicity of this membrane-spanning toxin.

Animals↗
PubMed2003

Identification of a non-selective cation channel current in myometrial cells isolated from pregnant rats.

Non-selective cation channel (NSCC) currents were identified in myometrial smooth muscle cells isolated from pregnant rats (day 18-20) using the whole-cell patch clamp method. NSCC currents had a linear current/voltage relationship and were time independent. Reduction of extracellular Na(+) substantially decreased the amplitude of NSCC currents, indicating that the NSCC is permeable to Na(+). NSCC currents were blocked by La(3+) and Gd(3+) with K(d) values of 2.2 and 1.0 micro M, respectively. The relative permeability of various monovalent cations for NSCC was estimated by measurement of the reversal potential. The relative permeability for K(+):Cs(+):Na(+):Li(+) was 1.3:1:0.9:0.8. NSCC also had a small, but detectable, permeability for Ca(2+). Extracellular Mg(2+) inhibited myometrial NSCC currents concentration dependently with a K(d) of 0.28 mM. The observed Mg(2+) block may reasonably explain the inhibitory effect of magnesium on uterine contractions in the treatment of pre-term labor. Our results suggest that the NSCC plays a role in the regulation of myometrial contractility.

Animals↗
PubMed2003

Distinct sites regulating grayanotoxin binding and unbinding to D4S6 of Na(v)1.4 sodium channel as revealed by improved estimation of toxin sensitivity.

Grayanotoxin (GTX) exerts selective effects on voltage-dependent sodium channels by eliminating fast sodium inactivation and causing a hyperpolarizing shift in voltage dependence of channel activation. In this study, we adopted a newly developed protocol that provides independent estimates of the binding and unbinding rate constants of GTX (k(on) and k(off)) to GTX sites on the sodium channel protein, important in the molecular analysis of channel modification. Novel GTX sites were determined in D2S6 (Asn-784) and D3S6 (Ser-1276) by means of site-directed mutagenesis; the results suggested that the GTX receptor consists of the S6 transmembrane segments of four homologous domains facing the ion-conducting pore. We systematically introduced at two sites in D4S6 (Na(v)1.4-Phe-1579 and Na(v)1.4-Tyr-1586) amino acid substituents with residues containing hydrophobic, aromatic, charged, or polar groups. Generally, substitutions at Phe-1579 increased both k(on) and k(off), resulting in no prominent change in dissociation constant (K(d)). It seems that the smaller the molecular size of the residue at Na(v)1.4-Phe-1579, the larger the rates of k(on) and k(off), indicating that this site acts as a gate regulating access of toxin molecules to a receptor site. Substitutions at Tyr-1586 selectively increased k(off) but had virtually no effect on k(on), thus causing a drastic increase in K(d). At position Tyr-1586, a hydrophobic or aromatic amino acid side chain was required to maintain normal sensitivity to GTX. These results suggest that the residue at position Tyr-1586 has a more critical role in mediating GTX binding than the one at position Phe-1579. Here, we propose that the affinity of GTX to Na(v)1.4 sodium channels might be regulated by two residues (Phe and Tyr) at positions Phe-1579 and Tyr-1586, which, respectively, control access and binding of GTX to its receptor.

Amino Acid Sequence↗
PubMed2003

Regulation of L-type Ca2+ channels in the heart: overview of recent advances.

Regulation of L-type Ca2+ channels is complex, because many factors, such as phosphorylation, divalent cations, and proteins, specified or unspecified, have been shown to affect the channel activities. An additional complication is that these factors interact with one another to achieve final outcomes. Recent molecular technologies have helped to shed light on the mechanisms governing the activity of L-type Ca2+ channels. In this review article, three major topics concerning regulation of L-type Ca2+ channels in the heart are discussed, i.e. c-AMP dependent channel phosphorylation, role of magnesium (Mg2+), and the phenomenon of channel run-down.

Animals↗
PubMed2003

[Combination chemotherapy with nedaplatin and 5-fluorouracil for oral squamous cell carcinomas].

We used a new combination chemotherapy with nedaplatin (CDGP) and 5-fluorouracil (5-FU) in eleven fresh patients with oral squamous cell carcinomas. 5-FU was administered at a dose of 1,000 mg/body by continuous infusion for 24 hours on days 1 to 5. CDGP was administered at a dose of 80 or 100 mg/m2 by drip infusion for 120 minutes on day 5. The response rates of total (1- or 2-course) and 2-course group were 54. 5% and 83.3%, respectively. Adverse drug reactions were limited to two cases of grade 3 toxicity with anorexia. The combination chemotherapy with 5-FU and CDGP in place of cisplatin and 5-FU seemed to play an important role as neo-adjuvant chemotherapy for oral squamous cell carcinomas.

Aged↗
PubMed2002

Structural determinants for the action of grayanotoxin in D1 S4-S5 and D4 S4-S5 intracellular linkers of sodium channel alpha-subunits.

We located a novel binding site for grayanotoxin on the cytoplasmic linkers of voltage-dependent cardiac (rH1) or skeletal-muscle (mu 1) Na(+) channel isoforms (segments S4-S5 in domains D1 and D4), using the alanine scanning substitution method. GTX-modification of Na(+) channels, transiently expressed in HEK 293 cells, was evaluated under whole-cell voltage clamp, from the ratio of maximum chord conductance for modified and unmodified Na(+) channels. In mu 1, mutations K237A, L243A, S246A, K248A, K249A, L250A, S251A, or T1463A, caused a moderate, but statistically significant decrease in this ratio. On making corresponding mutations in rH1, only L244A dramatically reduced the ratio. Because in mu 1, the serine at position 251 is the only heterologous residue with respect to rH1 (Ala-252), we made a double mutant L243A&S251A to match the sequence of mu 1 and rH1 in S4-S5 linkers of both domains. This double mutation resulted in a significant decrease in the ratio, to the same extent as L244A substitution in rH1 did, indicating that the site at Leu-244 in rH1 or at Leu-243 in mu 1 is a novel one, exhibiting a synergistic effect of grayanotoxin.

Alanine↗
PubMed2002

Molecular basis for exaggerated sensitivity to mexiletine in the cardiac isoform of the fast Na channel.

Cardiac sodium channels have been shown to have a higher sensitivity to local anesthetic agents, such as lidocaine, than the sodium channels of other tissues. To examine if this is also true for mexiletine, we have systematically measured mexiletine sensitivity of the Na channel isoforms, rH1, (mu)1, and rBII, which were transiently expressed in human embryonic kidney (HEK) 293 cells. We confirmed that the cardiac isoform rH1 exhibited the highest sensitivity among the three tested channel isoforms. In rH1, (mu)1, and rBII, the respective IC(50) values were 62, 294, and 308 microM mexiletine, in regard to tonic block, and 18, 54, and 268 microM mexiletine, in relation to use (8 Hz)-dependent block. The relatively high drug sensitivity of rH1 was an invariant finding, irrespective of channel state or whether channels were subjected to infrequent or frequent depolarizing stimuli. Mutating specific amino acids in the skeletal muscle isoform (mu)1 (namely, (mu)1-I433V and (mu)1-S251A) to those of the cardiac isoform at putative binding sites for local anesthetic agents revealed that only one of the point mutations ((mu)1-S251A) has relevance to the high cardiac drug sensitivity, because mexiletine produced significantly more use-dependent and tonic block in (mu)1-S251A than wild-type (mu)1.

Anti-Arrhythmia Agents↗
PubMed2002

Temperature-sensitive intracellular Mg2+ block of L-type Ca2+ channels in cardiac myocytes.

We examined the concentration-dependent blocking effects of intracellular Mg2+ on L-type Ca2+ channels in cardiac myocytes using the whole cell patch-clamp technique. The increase of L-type Ca2+ channel current (I(Ca)) (due to relief of Mg2+ block) occurred in two temporal phases. The rapid phase (runup) transiently appeared early (<5 min) in dialysis of the low-Mg2+ solution; the slow phase began later in dialysis (>10 min). Runup was not blocked by intracellular GTP (GTP(i)). The late phase of the I(Ca) increase (late I(Ca)) was suppressed by GTP(i) (0.4 mM) and was observed in myocytes of the guinea pig or frog at higher (32 or 24 degrees C, respectively) rather than lower temperatures (24 or 17.5 degrees C, respectively). At pMg = 6.0, raising the temperature from 24 to 32 degrees C evoked late I(Ca) with a Q10 of 14.5. Restoring the temperature to 24 degrees C decreased I(Ca) with a Q10 of only 2.4. The marked difference in the Q10 values indicated that late I(Ca) (pMg = 5-6) is an irreversible phenomenon. Phosphorylation suppressed the intracellular [Mg2+] dependency of late I(Ca). This effect of phosphorylation together with the inhibitory action of GTP(i) on Mg2+-dependent blocking of I(Ca) are common properties of mammalian and amphibian cardiomyocytes.

Animals↗