Biomedical subjects

Y Kuraishi

Publications and source records attributed to Y Kuraishi.

At least 19 recordsLinked to original sources

PubMed2001

A pharmacokinetic study of idarubicin in Japanese patients with malignant lymphoma: relationship with leukocytopenia and neutropenia.

To clarify the pharmacokinetic properties of idarubicin (IDA) in Japanese patients and to clarify the relationship between the pharmacokinetic parameters of IDA or idarubicinol (IDAol), an active metabolite of IDA, and leukocytopenia or neutropenia, we examined the pharmacokinetics of IDA in patients with malignant lymphoma. Nine of 21 patients registered in an early phase II study of IDA were enrolled in the pharmacokinetic study. IDA (12 or 15 mg/m2) was administered by intravenous infusion for 5 minutes. The elimination half lives (t 1/2) of IDA were 11.0 hours and 12.5 hours after administration of 12 and 15 mg/m2 IDA, respectively. IDAol appeared rapidly both in plasma and in blood cells, and its concentrations exceeded those of IDA within 4 hours. IDAol had a very long t 1/2 (69.2 hours and 70.0 hours for 12 and 15 mg/m2, respectively). The areas under the concentration curves of IDAol in plasma were 3.4 and 5.8 times higher than those of IDA after administration of 12 and 15 mg/m2 IDA, respectively. The t 1/2 of IDAol in plasma correlated significantly with the nadir of neutrophils, and the steady-state volume of distribution of IDA in plasma and in blood cells correlated significantly with the nadirs of white blood cells and neutrophils. These results suggest that both IDA and IDAol play an important role in leukocytopenia or neutropenia. No substantial differences between Japanese and Caucasian people in the pharmacokinetics of IDA were apparent.

Aged↗

PubMed2001

Induction by carrageenan inflammation of prepronociceptin mRNA in VR1-immunoreactive neurons in rat dorsal root ganglia.

Nociceptin (orphanin FQ) may act on primary afferents and be involved in the regulation of nociceptive processing. We have shown, using reverse transcription-polymerase chain reaction (RT-PCR), that carrageenan-produced peripheral inflammation induces the expression of prepronociceptin (PPN) mRNA in the dorsal root ganglia (DRG). The present experiments were conducted to determine the localization of PPN mRNA in primary sensory neurons after peripheral inflammation, using in situ hybridization. An intraplantar injection of carrageenan induced the expression of PPN mRNA in small and medium sized neurons in the DRG; the effect peaked 0.5 h after carrageenan and subsided by 6 h. All neurons positive for PPN mRNA were positive for vanilloid receptor subtype 1 (VR1)-like immunoreactivity and some VR1-immunoreactive neurons were negative for PPN mRNA. The results suggest that peripheral inflammation induces the production of nociceptin in a sub-population of VR1-positive primary sensory neurons and support the idea that nociceptin produced there is involved in the regulation of nociceptive processing.

Animals↗

PubMed2001

Characterization of itch-associated responses of NC mice with mite-induced chronic dermatitis.

To clarify the behavioral and pathological features of spontaneous scratching of NC mice with mite-induced chronic dermatitis, we investigated the spontaneous and pruritogen-evoked scratching of NC mice. Although the frequency of scratching of NC mouse did not increase under specific pathogen-free environment, it gradually and markedly increased from 3 to 6 weeks after transfer to conventional environment. The onset of increase in spontaneous scratching was similar to that of dermatitis development and the elevation of plasma concentration of immunoglobulin E. At chronic stage (16 weeks after environment change), the frequency of spontaneous scratching was roughly parallel to the degree of dermatitis, but not to the plasma concentration of immunoglobulin E. The spontaneous scratching of NC mice with dermatitis was inhibited by distraction and the opioid antagonist naltrexone, suggesting that the scratching is itch-associated response. An intradermal injection of serotonin, but not histamine and substance P, elicited scratching of the injected site. Methysergide and cyproheptadine inhibited the serotonin-induced scratching but not spontaneous scratching. The results suggest that marked elevation of plasma immunoglobulin E is not always the cause of spontaneous itch-associated response of NC mice with dermatitis. Serotonin, histamine and substance P may not play an important role in spontaneous itch-scratch response at a chronic stage.

Animals↗

PubMed2001

Involvement of leukotriene B(4) in substance P-induced itch-associated response in mice.

Intradermal injection of substance P elicits an itch sensation in human subjects and an itch-associated response in mice. The substance P-induced itch-associated response in mice is not inhibited by antihistamine. Therefore, the mechanisms of substance P-induced itch-associated response are unclear. In this study, we demonstrated one of the mechanisms. Substance P induces an arachidonate cascade to produce prostaglandins and leukotriene. In this study we considered whether arachidonate metabolites are involved in the substance P-induced itch-associated response. A phospholipase A(2) inhibitor arachidoryltrifluoromethyl ketone inhibited the substance P-induced itch-associated response in mice. Pre treatment with the glucocorticoids betamethasone and dexamethasone also produced inhibition of the substance P-induced itch-associated response in mice as well as humans. The 5-lipoxygenase inhibitor zileuton, but not the cyclooxygenase inhibitors indomethacin and diclofenac, suppressed substance P-induced itch-associated response. The leukotriene B(4) receptor antagonist 5-[2-(2-carboxyethyl)-3-[6-(4-methoxyphenyl)-5E-hexenyl]oxyphenoxy]valeric acid produced inhibition, whereas pranlukast (leukotriene C(4)/D(4)/E(4) receptor antagonist) and 5(Z)-7-[1S,2S, 3S,5R-3-(trans-b-styren)sulfonamido-6,6-dimethylbi cyclo(3,1,1)hept-2-yl]-5-heptenoic acid (EP(1) receptor antagonist) were without effect. Furthermore, when the production of leukotriene B(4) and prostaglandin E(2) was measured in skin injected with substance P and in mouse keratinocytes applied with substance P, the level of both products increased. As leukotriene B(4), but not prostaglandin E(2), also induces the itch-associated response in mice, these results suggest that leukotriene B(4) and keratinocytes, cutaneous cells which produced leukotriene B(4), play an important role in substance P-induced itch-scratch response in mice. Leukotriene B(4) receptor antagonist and 5-lipoxygenase inhibitor may be novel antipruritic drugs.

Animals↗

PubMed2001

Axonal transport of VR1 capsaicin receptor mRNA in primary afferents and its participation in inflammation-induced increase in capsaicin sensitivity.

Capsaicin receptors are expressed in primary sensory neurons and excited by heat and protons. We examined the inflammation-induced changes of the level of VR1 capsaicin receptor mRNA in sensory neurons and the sensitivity of primary afferents to capsaicin. Carrageenan treatment induced axonal transport of VR1 mRNA, but not that of preprotachykinin mRNA, from the dorsal root ganglia to central and peripheral axon terminals. The sensitivity of central terminals to capsaicin, which was estimated by measuring the capsaicin-evoked release of glutamate from the dorsal horn, was increased by peripheral inflammation, and such an increase was suppressed by inhibiting the RNA translation in the dorsal horn with cycloheximide and an intrathecal injection of VR1 antisense oligonucleotides. Thus, peripheral inflammation induces the axonal transport of VR1 mRNA, which may be involved in the hypersensitivity of primary afferents to capsaicin and the production of inflammatory hyperalgesia.

Afferent Pathways↗

PubMed2001

Inhibition of itch-scratch response by fruits of Cnidium monnieri in mice.

We previously screened the anti-itching activities of 33 herbal medicines in substance P (SP)-induced itching model mice. One of the most potent antipruritogenic extracts, the methanol extract of fruits of Cnidium monnieri (Cnidii Fructus) was studied further. The chloroform-soluble fraction of the methanol extract markedly inhibited SP-induced scratching. Among 10 subfractions of the chloroform-soluble fraction, the CS-3 fraction had the most potent inhibitory effect on scratching. Each of 3 subfractions of CS-3 showed significant anti-scratching activities. However, inhibitory potencies were not different among the three and weaker than that of CS-3 itself at a same dose. These 3 subfractions of CS-3 mainly contained xanthotoxin, isopimpinellin, bergapten, imperatorin and osthol. Single administration of osthol did not inhibit SP-induced scratching, and imperatorin very weakly subsided scratching. These results suggest that the strong antipruritic action was focused on the CS-3 fraction of the C. monnieri methanol extract, and it might result from the combined effects of these coumarin derivatives, or by undetermined minor compounds.

Animals↗

PubMed2001

[Pain, fever and prostanoids].

Although it has been known that prostanoids are involved in pain regulation and fever, the precise roles of their receptors and receptor subtypes are unclear. All prostanoid receptors have been cloned and mice deficient in each receptor have been developed. Recent studies using prostanoid-receptor-knockout mice are shedding some light on these issues. Nociceptive responses to an intraperitoneal injection of acetic acid and hyperalgesia induced by carrageenan were abolished by IP-receptor deficiency. In addition, the use of mice lacking prostanoid receptor is revealing an interesting role of prostanoid in neuropathic as well as inflammatory pain. With regard to pyrexia, PGE2 injected intracerebroventricularly induced the febrile response in wild-type mice, but it was without effect in mice lacking the EP3 receptor. Furthermore, febrile responses induced by IL-1 beta, an endogenous pyrogen, and LPS, an exogenous pyrogen, were specifically suppressed in mice lacking the EP3 receptor. These results indicate that PGE2 works as a common final mediator of the febrile response and that this action of PGE2 is mediated by the EP3 receptor. The determination of precise roles of prostanoids in pain and fever may provide novel targets for antipyretic analgesics with fewer side effects.

Animals↗

PubMed2001

Roles of mast cells and histamine in mosquito bite-induced allergic itch-associated responses in mice.

We investigated itch-associated responses (scratching) to mosquito bites and the role of histamine and mast cells in mosquito-induced itching in mice. Although the first bites of mosquito Aedes albopictus did not increase scratching, repeated bites increased scratching. The response was not diminished even after an interval of 2 months. Similarly, repeated intradermal (i.d.) injections of salivary gland extract (SGE) from Aedes albopictus increased scratching after SGE injection itself and mosquito bites. The scratching peaked within 10 min and almost subsided by 60 min. The opioid antagonist naloxone (1 mg/kg, s.c.) inhibited scratching following SGE injection. Although the non-sedative H1-histamine-receptor antagonist terfenadine (30 mg/kg, p.o.) significantly suppressed scratching induced by histamine (100 nmol/site, i.d.) in either naive or mosquito-sensitized mice, it did not affect mosquito-induced scratching in mosquito-sensitized mice. Repeated injections of SGE increased scratching in mast cell-deficient (WBB6F1-W/Wv) mice as well as in normal (WBB6F1-+/+) littermates. Repeated exposure to mosquito bites roughly doubled serum concentrations of total IgE and IgG1, but not IgG2a. Repeated injections of SGE markedly increased plasma extravasation induced by mosquito bites and such an increase was almost completely suppressed by terfenadine (30 mg/kg, p.o.). The results show the presence of histamine-mediated and histamine-independent mechanisms in cutaneous itching and suggest that histamine probably released from mast cells does not play an important role in itching in immediate allergic reaction. Our murine model of mosquito itching may be useful for studying the mechanisms of immediate allergic itching.

Aedes↗

PubMed2001

Gabapentin antinociception in mice with acute herpetic pain induced by herpes simplex virus infection.

The effects of systemic and local injections of gabapentin, a novel anticonvulsant agent, were tested on nociceptive behaviors in mice with acute herpetic pain. Transdermal infection with herpes simplex virus type-1 (HSV-1) produced nociceptive hypersensitivity of the infected hind paw to innocuous (allodynia) and noxious mechanical stimulation (hyperalgesia) with von Frey filaments. Systemic administration of gabapentin (10-100 mg/kg, peroral) produced a dose-dependent inhibition of both allodynia and hyperalgesia; gabapentin (30-300 mg/kg) did not affect locomotor activity. Intrathecal injection of gabapentin (10-100 microg/animal) also attenuated dose dependently both nociceptive hypersensitivities. In contrast, intraplantar, intracisternal, and intracerebroventricular administration of gabapentin (10-100 microg/animal) had no effect on the HSV-1-induced nociceptive hypersensitivities. Pretreatment with naltrexone (1 mg/kg) inhibited antinociceptive effect of morphine (5 mg/kg), but not gabapentin (100 mg/kg). Repeated administration of morphine (5 mg/kg, four times) led to tolerance of antinociceptive action, whereas gabapentin (100 mg/kg, four times) had antinociceptive effect even after the forth administration. The present results suggest that gabapentin is effective in the treatment of acute herpetic pain without apparent adverse effects, and analgesic action of gabapentin is mainly mediated by actions on the spinal cord.

Acetates↗

PubMed2001

[Effects of morphine on cancer pain and tumor growth and metastasis].

Management of pain is a great problem in patients with cancer. Morphine is a principal axis in drug therapy of pain, especially at the end stage of cancer. We developed an animal model of cancer pain and examined the effects of morphine on cancer pain and tumor growth and metastasis. Orthotopic inoculation of B16-BL6 melanoma cells into the hind paw of B16BL/6 mice produced hyperalgesia and spontaneous pain-like behavior; moderate hyperalgesia was apparent on day 7-10 post-inoculation(early phase), and the hyperalgesia became severe from day 14 post-inoculation(late phase). Morphine inhibited hyperalgesia on the both phases, but higher doses were needed on the late phase. When morphine at analgesic doses was administered daily from day 16 post-inoculation, tolerance was developed for analgesia after the sixth administration. Such morphine administration of morphine suppressed tumor growth and metastasis. Sciatic neurectomy, which was performed to block the pain signaling from the tumoral tissue, also suppressed tumor growth and metastasis. Management of cancer pain may be important not only to quality of life but also to cancer treatment itself.

Analgesics, Opioid↗

PubMed2001

[Breast cancer].

Neoadjuvant chemotherapy (NAC) represents a new approach based on sound theoretical, pharmacokinetic, and experimental principles. The purpose of NAC is to improve control of the primary site by downstaging and to improve control of micrometastatic disease. NAC has been standard therapy in the management of locally advanced breast cancer. Patients with earlier stage breast cancer may also benefit from treatment with NAC. Recently some investigators have mentioned that NAC can be used instead of adjuvant chemotherapy and would be most appropriate for patients who wish to preserve their breast but who have tumors too large for breast conserving surgery. In this article, we reviewed the present status of NAC (indication, clinical response, pathologic response, survival, possibility of breast conservation, prognostic/predictive factors, neoadjuvant endocrine therapy) and discussed several unanswered questions on NAC (survival benefit, optimal number of treatment cycles, optimal regimens) and future direction. Combined modality therapy including NAC appears to provide excellent local control, the possibility of breast conservation, and, probably, an increased survival rate, at least for some subsets of patients. Furthermore, through sequential sampling, NAC provides indeed the opportunity to identify molecular mechanisms associated with pathologic response and to study the possibility to guide the choice for induction treatment and patient populations submitted to neoadjuvant chemotherapy.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2001

[Early phase II clinical trial of amrubicin hydrochloride in patients with malignant lymphoma].

An early phase II multi-center collaborative study of amrubicin hydrochloride, a novel synthetic anthracycline derivative anticancer agent, was conducted for malignant lymphoma at 12 institutions nationwide. A total of 41 patients were enrolled in this study between January 1988 and October 1990. Of these, 36 patients, six patients with Hodgkin's disease (HD) and 30 patients with non-Hodgkin's lymphoma (NHL), were eligible for the study. The starting dose of amrubicin hydrochloride was 100 mg/m2 (body surface area) and it was administered once every three weeks, in principle. The efficacy was assessed for 34 patients, excluding two patients: one who has not been followed up adequately and the other violated the dosing schedule (once per week). The overall response rates (CR + PR) were 50.0% (3/6) for HD and 42.9% (12/28) for NHL. Furthermore, a relatively high response rate was noted in 8 (36.4%) of 22 NHL patients who had been treated with other anthracycline derivatives prior to the trial. The safety of amrubicin hydrochloride was assessed for 36 eligible patients. Leukopenia (grade 3 or higher) and thrombocytopenia were noted in 21 patients (58.3%) and 10 patients (27.8%), respectively. Anorexia, nausea/vomiting, fever, alopecia, decrease in hemoglobin and elevations of GOT and GPT levels were observed with a relatively high frequency. Other than myelosuppression, the following adverse reactions (grade 3 or higher) occurred during the course of the trial: diarrhea (two patients), alopecia (two patients), stomatitis (one patient), anorexia (one patient), nausea/vomiting (one patient) and fever (one patient). In conclusion, these results indicate that amrubicin hydrochloride is effective in the treatment of patients with malignant lymphoma.

Aged↗

PubMed2000

Involvement of blockade of leukotriene B(4) action in anti-pruritic effects of emedastine in mice.

The anti-pruritic activity of emedastine difumarate was studied in mice. Emedastine (0.03-0.3 mg/kg) inhibited scratching induced by intradermal injection of histamine (100 nmol/site). Scratching induced by substance P (100 nmol/site) and leukotriene B(4) (0.03 nmol/site), but not by serotonin (100 nmol/site), was also suppressed by emedastine (0.03-0.3 mg/kg). Intradermal injection of substance P increased the cutaneous concentration of leukotriene B(4), which was not affected by emedastine. These results suggest that the inhibition by emedastine of substance P-induced itch-associated response is mediated by the blockade of leukotriene B(4) action. Anti-leukotriene B(4) action, as well as the anti-histamine action, may contribute to the anti-pruritic effects of emedastine.

Animals↗

PubMed2000

Differential activation of brain-derived neurotrophic factor gene promoters I and III by Ca2+ signals evoked via L-type voltage-dependent and N-methyl-D-aspartate receptor Ca2+ channels.

Although the brain-derived neurotrophic factor (BDNF) gene is activated by the intracellular Ca(2+) signals evoked via Ca(2+) influx into neurons, little is known about how the activation of alternative BDNF gene promoters is controlled by the Ca(2+) signals evoked via N-methyl-d-aspartate receptors (NMDA-R) and L-type voltage-dependent Ca(2+) channels (L-VDCC). There is a critical range in the membrane depolarization caused by high K(+) concentrations (25-50 mm KCl) for effective BDNF mRNA expression and transcriptional activation of BDNF gene promoters I and III (BDNF-PI and -PIII, respectively) in rat cortical culture. The increase in BDNF mRNA expression induced at high K(+) was repressed not only by nicardipine, an antagonist for L-VDCC, but also by dl-amino-5-phosphonovalerate, an antagonist for NMDA-R, which was supported by the effects of antagonists on the Ca(2+) influx. Although the promoter activations at 25 and 50 mm KCl were different, BDNF-PIII was activated by either the Ca(2+) influx through NMDA-R or L-VDCC, whereas BDNF-PI was predominantly by the Ca(2+) influx through L-VDCC. Direct stimulation of NMDA-R supported the activation of BDNF-PIII but not that of BDNF-PI. Thus, the alternative BDNF gene promoters responded differently to the intracellular Ca(2+) signals evoked via NMDA-R and L-VDCC.

2-Amino-5-phosphonovalerate↗

PubMed2000

Inhibitory effect of Byakko-ka-ninjin-to on itch in a mouse model of atopic dermatitis.

Byakko-ka-ninjin-to (BN) is composed of gypsum, the root of anemarrhena, ginseng, licorice and rice. The effect of BN on the inhibition of itch was studied using an NC mouse model of atopic dermatitis. BN (200 mg/kg, p.o.) significantly inhibited the scratching frequency in NC mice, and decreased the skin temperature by 1.97 degrees C. The cooling action on the skin by BN may be involved in the inhibitory mechanism of itch, at least in part, since cooling the skin is known to inhibit the itch sensation in humans. Although the myocyte-specific enhancer binding factor 2C (MEF2C) mRNA is known to be increased in the cerebral cortex correlated with the itch sensation and skin lesions in NC mice, BN did not affect the expression level of the MEF2C mRNA. This result suggests that the inhibitory effect of BN on itch does not relate to inhibition of MEF2C expression in the cerebral cortex. The present study indicates that BN has an inhibitory effect on itch, and may be a useful antipruritic drug for atopic dermatitis.

Animals↗

PubMed2000

Allodynia and hyperalgesia induced by herpes simplex virus type-1 infection in mice.

Human subjects infected with herpes or varicella-zoster viruses complain of pain, such as allodynia, in or near the region with vesicles. However, the mechanisms of the pain are unclear. We show for the first time that infection with herpes simplex virus type-1 (HSV-1) induces allodynia and hyperalgesia in mice. When HSV-1 was inoculated on the hind paw of the mouse, eruption appeared on the back on day 5 post-inoculation, and zosteriform skin lesions were developed on the inoculated side. Allodynia and hyperalgesia became apparent in the hind paw on the inoculated side on day 5 and persisted until at least day 8. HSV-1 DNA was detected in the dorsal root ganglia from days 2 to 8 post-inoculation, with a peak effect on day 5. The application of heat-inactivated HSV-1 induced no allodynia, hyperalgesia and skin lesion. When started from days 0 or 2, repeated treatment with acyclovir, anti-HSV-1 agent, inhibited the appearance of allodynia, hyperalgesia, eruption and the viral proliferation in the dorsal root ganglia. In contrast, when started from days 5 or 6, acyclovir treatment slightly inhibited the development of skin lesions and the viral proliferation, but not allodynia and hyperalgesia. These results suggest that the propagation of HSV-1 in the dorsal root ganglia produces allodynia and hyperalgesia as a result of functional abnormality of the sensory neurons in mice. This may be a useful model for studying the mechanisms of herpetic pain.

Acyclovir↗

PubMed2000

Hypotensive action of Nangapiry, a Paraguayan natural medicine, in rodents.

Hypotensive action mechanism of a cation exchange resin adsorbate (IR-120A) separated from a Paraguayan Natural Medicine, Nangapiry, was investigated. Blood pressures of normal and pithed rats and contractions of isolated thoracic aorta and atria of mice were measured. The blood pressure on normal rats was reduced by an intravenous injection of IR-120A (5 mg/kg). The hypotensive effect on the pithed rat appeared more lasting than that on normal rats by IR-120A. The IR-120A (100 microg-3 mg/ml) concentration-dependently depressed prostaglandin (PG) F2alpha (10 microM)- or KCl (40 mM)-induced aortic contractions and electrically-evoked contraction of left atria, and at a lesser extent spontaneous beating rate of right atria. The 50% inhibitory concentrations (IC50) for the PGF2alpha- and KCl-induced aortic contractions were 713 and 828 microg/ml, respectively, and the IC50 values for the muscle contraction and the beating rate were 1.04 and >3 mg/ml, respectively. These results suggest that the hypotensive action of IR-120A are peripherally elicited by the dilatation of artery and the depression of heart contraction, but not the reduction of heart rate.

Animals↗

PubMed2000

CyclOBEAP (cyclophosphamide, vincristine, bleomycin, etoposide, doxorubicin, prednisolone) regimen with granulocyte colony-stimulating factor (G-CSF) for patients with aggressive non-Hodgkin's lymphoma: a pilot study. The Adult Lymphoma Treatment Study Group (ALTSG).

We conducted a multi-institutional collaborative study to examine the usefulness and safety of third-generation chemotherapy CyclOBEAP (cyclophosphamide, vincristine, bleomycin, etoposide, doxorubicin, prednisolone) combined with granulocyte colony-stimulating factor (G-CSF) in the treatment of aggressive non-Hodgkin's lymphoma (NHL). Subjects included patients with aggressive NHL who were 60 yr of age or younger and had been diagnosed as having a low-intermediate, high-intermediate, or high risk using the International Prognostic Index (IPI). A total of 24 patients were enrolled in the study between May 1997 and March 1998, including 9 low-intermediate-risk cases, 13 high-intermediate-risk cases and 2 high-risk cases. Although all 24 patients were originally enrolled in the study, one adult T-cell leukemia/lymphoma case was subsequently excluded. Thus, in the end, 23 cases were evaluated. Evaluation of the efficacy of therapy revealed complete remission in 20 patients (87%). Of these 20 patients, 8 were low-intermediate-risk cases (89%) and 12 were either high-intermediate- or high-risk cases (86%). Partial remission was achieved in 2 patients (8.7%). The 2-yr survival rate was 91.3%, and the 2-yr disease-free survival rate was 81.8%. Grade 3 or higher adverse reactions were granulocytopenia (87%), thrombocytopenia (17.4%) and liver dysfunction (4.3%). CyclOBEAP therapy has been associated with a high remission rate for aggressive NHL. When combined with G-CSF, a high relative dose intensity was maintained for each drug administered (0.94-0.97). Furthermore, although the observation period was short, both the survival rate and disease-free survival rate were good. Hence, we concluded that there were no problems associated with the procedure in terms of safety.

Adolescent↗