Acupuncture for reducing pruritus induced by intrathecal morphine at elective cesarean delivery: a placebo-controlled, randomized, double-blind trial.

BACKGROUND: Intrathecal morphine is a standard postoperative analgesic administered after cesarean delivery, but frequently causes pruritus. Acupuncture reportedly resolves refractory pruritus in certain patients. The aim of the study was to investigate the effectiveness of acupuncture in preventing pruritus induced by intrathecal morphine. METHODS: Thirty parturients received intrathecal hyperbaric bupivacaine (12 mg), fentanyl (10 µg), and morphine (150 µg) for spinal anesthesia at elective cesarean delivery at term. Patients were randomly divided into the acupuncture group (n=15) and the control group (n=15). In the acupuncture and control groups, certified acupuncturists inserted either indwelling press needles or sham needles, into Hegu (LI4), Neiguan (PC6), Quchi (LI11), and Zhigou (SJ6) on both arms the day before surgery. Needles were removed 48 hours postoperatively. The primary outcome was the incidence of postoperative pruritus. Adverse effects including nausea and vomiting were also investigated. RESULTS: There were no significant differences between the acupuncture group and the control group in the incidence of pruritus (67% vs. 67%, P=1.000, RR 1.0 [95% CI 0.60 to 1.66]) or the requirement for antipruritic therapy (6.7% vs. 20.0%, P=0.283, RR 0.33 [95% CI 0.04 to 2.85]). The incidence of postoperative nausea in the acupuncture group versus control group was 40.0% vs. 13.3%, P=0.099, RR 3.0 [95% CI 0.72 to 12.6]). The postoperative analgesic effect was comparable. CONCLUSION: Preoperatively administered acupuncture using press needles did not decrease intrathecal morphine-induced pruritus or the requirement for treatment.

Potential use of folate-polyethylene glycol (PEG)-appended dendrimer (G3) conjugate with α-cyclodextrin as DNA carriers to tumor cells.

We previously reported that polyamidoamine STARBURST dendrimer (generation 3, G3) (dendrimer) conjugate with α-cyclodextrin (α-CyD) having an average degree of substitution of 2.4 of α-CyD (α-CDE) provided remarkable aspects as novel carriers for DNA and small-interfering RNA. To develop novel α-CDE derivatives with tumor cell specificity, we prepared folate-appended α-CDEs (Fol-α-CDEs) and folate-polyethylene glycol (PEG)-appended α-CDEs (Fol-PαCs) with the various degrees of substitution of folate (DSF), and evaluated in vitro and in vivo gene transfer activity, cytotoxicity, cellular association and physicochemical properties. In vitro gene transfer activity of Fol-α-CDEs (G3, DSF 2, 5 or 7) was lower than that of α-CDE (G3) in KB cells, folate receptor (FR)-overexpressing cancer cells. Of the three Fol-PαCs (G3, DSF 2, 5 or 7), Fol-PαC (G3, DSF 5) had the highest gene transfer activity in KB cells. The activity of Fol-PαC (G3, DSF 5) was significantly higher than that of α-CDE (G3) in KB cells, but not in A549 cells, FR-negative cells. Negligible cytotoxicity of the plasmid DNA (pDNA) complex with Fol-PαC (G3, DSF 5) was observed in KB cells or A549 cells up to a charge ratio of 100/1 (carrier/pDNA). The cellular association of the pDNA complex with Fol-PαC (G3, DSF 5) could be mediated by FR on KB cells, resulting in its efficient cellular uptake. Fol-PαC (G3, DSF 5) had a higher binding affinity with folate-binding protein than α-CDE (G3), although the physicochemical properties of pDNA complex with Fol-PαC (G3, DSF 5) were almost comparable to that with α-CDE (G3), although the onset charge ratio and the compaction ability of Fol-PαC (G3, DSF 5) were slightly different. Fol-PαC (G3, DSF 5) tended to show a higher gene transfer activity than α-CDE (G3) 12 h after intratumoral administration in mice. These results suggest that Fol-PαC (G3, DSF 5), not Fol-α-CDEs, could be potentially used as a FR-overexpressing cancer cell-selective DNA carrier.

KF31327, a new potent and selective inhibitor of cyclic nucleotide phosphodiesterase 5.

The effects of KF31327 (3-ethyl-8-[2-(4-hydroxymethylpiperidino)benzylamino]-2,3-dihydro-1H-imidazo[4,5-g]quinazoline-2-thione dihydrochloride) on phosphodiesterase 5 (cyclic GMP-specific phosphodiesterase) activity and platelet aggregation were investigated and compared with those of sildenafil, a well-known phosphodiesterase 5 inhibitor. KF31327 inhibited phosphodiesterase 5 from canine trachea (K(i)=0.16 nM) more potently than sildenafil (K(i)=7.2 nM). The kinetic analysis revealed that KF31327 was a non-competitive inhibitor. In the presence of nitroglycerin (nitric oxide generator), both compounds inhibited the collagen-induced aggregation of rabbit platelets at less than 0.1 microM, augmenting intracellular cyclic GMP level without affecting cyclic AMP. In contrast, in the absence of nitroglycerin, a higher concentration (10 microM) of KF31327 was required to inhibit platelet aggregation and increased both cyclic nucleotide levels. However, 10 microM sildenafil did not affect aggregation despite elevation of cyclic GMP comparable to that in the presence of nitroglycerin. These results indicate that in the presence of nitroglycerin, the inhibition of platelet aggregation by KF31327 is due to the elevation of cyclic GMP, whereas the mechanism underlying the inhibition without nitroglycerin might be related to a rise in intracellular cyclic AMP.

Effects of adenosine A1- and A2A-receptor agonists on enhancement of dopamine release from the striatum in methamphetamine-sensitized rats.

We report here both adenosine A1- and A2A-receptor agonists inhibit the expression of methamphetamine (MAP)-induced behavioral sensitization in rats. Animals were treated with MAP (1.0 mg/kg, i.p.) every 3 days with a total of 5 administrations. The augmentation of dopamine release from the striatum was demonstrated by MAP re-administration (0.5 mg/kg, i.p.) after 7-day withdrawal by microdialysis. The augmentation of dopamine release was inhibited by pre-treatment not with N6-cyclohexyladenosine (0.01 mg/kg, i.p.) but by with 2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxy-amide adenosine (0.1 mg/kg, i.p.). These results suggested that adenosine A1 and A2A receptors play an inhibitory role in sensitization via different mechanisms.

Repeated adenosine pre-treatment potentiates the acute effect of methamphetamine in rats.

Adenosine was intraperitoneally (i.p.) injected to Wistar rats every 3 days with a total of 5 administrations. After a 7-day withdrawal, the animals were challenged with methamphetamine (0.5 mg/kg, i.p.). The effect of methamphetamine on locomotor activity was significantly potentiated by repeated adenosine pretreatment. Moreover, methamphetamine-induced dopamine release was also increased in the striatum. Methamphetamine-induced hyperactivity and dopamine release were significantly potentiated by repeated pretreatment of an adenosine A1 agonist, N6-cyclohexyladenosine (0.5 mg/kg, i.p.). These results suggest that the acute effect of methamphetamine is potentiated by repeated pre-treatment of adenosine via adenosine A1 receptors.

Relation between K-ras codon 12 mutation and p53 protein overexpression in gallbladder cancer and biliary ductal epithelia in patients with pancreaticobiliary maljunction.

It is well known that the incidence of biliary cancer is higher in patients with pancreaticobiliary maljunction (PBM) than in individuals without PBM. However, the relationship between PBM and the carcinogenesis remains unclear. The purpose of the present study was to examine histopathologic changes in the mucosa of the gallbladder and bile duct in patients with PBM, and to investigate K-ras oncogene mutation and overexpression of p53 protein in the mucosa. We examined 47 surgical specimens of gallbladder and 36 surgical specimens of bile duct obtained from 48 patients with PBM. The 48 patients were divided into three age groups: group A (0-3 years), group B (4-39 years), and group C (40 years or more). Investigation of K-ras mutation and overexpression of p53 protein was performed using an enriched polymerase chain reaction (PCR) and enzyme-linked mini-sequence assay (ELMA), and by the streptavidin-biotin (SAB) method, using DO-7 antibodies, respectively. Hyperplastic changes in the gallbladder mucosa were observed in patients in the three groups. However, metaplastic or dysplastic changes were observed in the mucosa of only groups B and C. K-ras gene mutation in the gallbladder mucosa was found in 18.8% of the hyperplastic mucosae in group B and in 20% in group C. The mutation was found in 33.3% of lesions with metaplastic change associated with hyperplastic changes and in 25% of lesions with dysplastic changes in group C. No mutation was observed in the non-cancerous mucosae of gallbladders and bile ducts without congenital dilatation of the bile duct. Overexpression of p53 protein was observed only in carcinoma of the gallbladder; in seven of nine advanced carcinomas and in two of three carcinomas in situ. We concluded that the mucosal epithelia of the biliary system in patients with PBM showed a high frequency of gene mutations and the carcinogenesis appeared in involve a multistage process of mutation in the K-ras gene and the p53 suppressor gene.

Roles of adenosine A(1) and A(2A) receptors in the expression and development of methamphetamine-induced sensitization.

We studied the effects of adenosine A(1) and A(2A) receptor agonists on the expression and development of methamphetamine-induced sensitization in rats. When animals were treated with the adenosine A(1) receptor agonist, N(6)-cyclohexyladenosine (CHA), along with methamphetamine every 3 days with a total of five administrations, the augmentation of hyperlocomotion by methamphetamine re-administration after 7-day withdrawal (methamphetamine challenge administration) was not inhibited. However, when the adenosine A(2A) receptor agonist, 2-p-(2-carboxyethyl) phenethyl-amino-5'-N-ethylcarboxy-amide adenosine (CGS21680), was administered according to the same schedule, the augmentation was significantly inhibited. On the other hand, when CHA or CGS21680 was administered 30 min before methamphetamine challenge, both drugs dose-dependently inhibited the augmentation of hyperlocomotion. These results suggested that both adenosine A(1) and A(2A) receptors play important roles in the expression of methamphetamine-induced sensitization, and that adenosine A(2A) receptors do so in the development of this sensitization.

Vulnerability of synaptic plasticity in the striatum of methamphetamine-sensitized rats.

We examined the influence of ischemia on methamphetamine (MAP)-induced behavioral sensitization and enhancement of dopamine (DA) release. After the recovery period of the ischemia operation, rats were treated with MAP (1 mg/kg, i.p.) once daily for 6 consecutive days. Re-administration of MAP (0.5 mg/kg, i.p.) potentiated the increase of locomotor activity after a 3-day withdrawal and the enhancement of DA release from striatal slices after a 6-day withdrawal. The MAP-induced sensitization was impaired by 5 min ischemia. On the other hand, the increase of locomotor activity induced by single MAP (1 mg/kg, i.p.) administration was impaired by 20 min of ischemia. Moreover, in saline-treated rats the increase of DA release from striatal slices induced by MAP (10 microM) application was also impaired by 20 min of ischemia. These results indicate that the neuronal plastic change may be very vulnerable to ischemia in MAP-induced sensitization.

Noradrenergic DSP-4 lesions aggravate impairment of working memory produced by hippocampal muscarinic blockade in rats.

To clarify the interactions between hippocampal cholinergic and adrenergic systems in working memory function of rats, the effects of hippocampal muscarinic receptor blockade combined with noradrenaline depletion on this behavior were examined with a three-panel runway task. Intrahippocampal administration of the muscarinic receptor antagonist scopolamine at a dose of 3.2 micrograms/side significantly increased the number of errors (attempts to pass through two incorrect panels of the three panel-gates at four choice points) in the working memory task, whereas the 0.32 microgram/side dose of scopolamine did not affect working memory errors. Administration of the noradrenergic neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) at 50 mg/kg IP caused a marked reduction in hippocampal noradrenaline concentration, but it had no effect on working memory errors. Intrahippocampal administration of 0.32 microgram/side scopolamine, the behaviorally ineffective dose in intact rats, significantly increased the number of working memory errors in the noradrenaline-depleted animals. These results suggest that hippocampal muscarinic/noradrenergic interactions are involved in neural processes mediating working memory function of rats.

Methamphetamine-induced sensitization of dopamine release via a metabotropic glutamate receptor mediated pathway in rat striatal slices.

We studied the roles of metabotropic glutamate receptors in methamphetamine (MAP)-induced sensitization of dopamine (DA) release from striatal slices. Rats were first treated with MAP (1 mg/kg, i.p.) once daily for 6 consecutive days. After a 6-day withdrawal, DA release from striatal slices evoked by +/- (-)1-aminocyclopentane-trans-1,3-dicarboxylic acid (trans-ACPD) was measured, trans-ACPD-induced DA release was significantly enhanced in MAP-sensitized rats, but the inactive form of trans-ACPD (1R,3S-ACPD) did not enhance DA release. The active form of trans-ACPD (1S,3R-ACPD) (0.1 mM)-evoked DA release was attenuated by treatment with 0.4 mM RS-alpha-methyl-4-carboxyphenylglycine, a metabotropic glutamate receptor antagonist. The present results suggest that metabotropic glutamate receptors play an important role in expression of MAP-induced sensitization.

Enhancement of dopamine release from the striatum through metabotropic glutamate receptor activation in methamphetamine sensitized rats.

An intracerebral microdialysis technique was applied to study the effect of metabotropic glutamate receptor (mGluR) agonist on dopamine release in the striatum of methamphetamine (MAP)-sensitized rats. Rats were treated with MAP (1 mg/kg, i.p.) once daily for 6 consecutive days, followed by a 6-day withdrawal. Perfusion of 0.1 mM (1S,3R)-1-aminocyclopentane-trans-1,3-dicarboxylic acid through a microdialysis probe placed in the striatum enhanced the extracellular dopamine level, and induced stereotyped behavior in MAP-sensitized rats. The enhancement of dopamine release and the stereotyped behavior were attenuated by co-perfusion of 0.4 mM RS-alpha-methyl-4-carboxyphenyl-glycine, a mGluR antagonist. The present results suggest that mGluRs may be involved in the expression of MAP-induced sensitization.

Beta-adrenergic dysfunction exacerbates impairment of working memory induced by hippocampal NMDA receptor blockade in rats.

To clarify the interactions between hippocampal glutamatergic and adrenergic systems in the working memory function of rats, the effects of hippocampal NMDA receptor blockade combined with noradrenaline depletion or alpha- and beta-adrenoceptor blockade on this behavior were examined with a three-panel runway task. Intrahippocampal administration of the potent and competitive NMDA receptor antagonist (+/-)-3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP) at a dose of 32 ng/side significantly increased the number of errors (attempts to pass through two incorrect panels of the three panels gates at four choice points) in the working memory task, whereas the 3.2 ng/side dose of CPP did not affect working memory errors. Administration of the noradrenergic neurotoxin N-(2-chloroethyl)-N-ethyl-2 -bromobenzylamine (DSP-4) at 50 mg/kg i.p. produced marked reductions in hippocampal and cortical noradrenaline contents, but it had no effect on working memory errors. Intrahippocampal administration of 3.2 ng/side CPP, the behaviorally ineffective dose in intact rats, significantly increased the number of working memory errors in the noradrenaline-depleted rats. The alpha-adrenoceptor antagonist phentolamine (3.2 mg/kg i.p.) did not affect working memory errors whether administered alone or in combination with intrahippocampal CPP (3.2 ng/side). The beta-adrenoceptor antagonist propranolol (10 mg/kg i.p.) also had no effect on working memory errors. However, propranolol (10 mg/kg) produced a significant increase in working memory errors when administered together with intrahippocampal CPP (3.2 ng/side). These results suggest that hippocampal NMDA/beta-adrenergic interactions are involved in neural processes mediating working memory function of rats.

Somatostatin alleviates impairment of working memory induced by hippocampal muscarinic M1 receptor blockade in rats.

The effects of somatostatin on the impairment of working memory induced in rats by blockade of hippocampal muscarinic M1 or NMDA receptors were examined, using a three-panel runway task. Both the muscarinic M1 receptor antagonist pirenzepine (1.0 microgram/side) and the competitive NMDA receptor antagonist CPP ((+/-)-3(2-carboxypiperazin-4-yl)-propyl-1-phosphonoic acid) (32 ng/side) significantly increased the number of working memory errors (attempts to pass through two incorrect panels of the three panel-gates at four choice points), when injected bilaterally into the dorsal hippocampus. This effect of intrahippocampal pirenzepine on working memory was alleviated by concurrent injection of 0.32 microgram/side somatostatin. However, concurrent somatostatin (0.1 or 0.32 microgram/side) had no significant effect on the intrahippocampal CPP-induced increase in working memory errors. These results suggest that somatostatin ameliorates the impairment of working memory resulting from hippocampal muscarinic M1 receptor blockade, possibly through activation of cholinergic functions.

[A case report of atypical Fabry's disease with colon cancer].

An atypical case of Fabry's disease, a rare congenital disorder of glyco-lipid metabolism, associated with sigmoid cancer was reported. A 50-year-old man who had been diagnosed as having atypical form of Fabry's disease complained of lower abdominal pain and difficult defection. A barium enema and an endoscopic examination disclosed sigmoid colon cancer. The cancer was curatively resected. Fabry's disease is often associated with intestinal disease, but the patient with Fabry's disease associated with intestinal malignancy has not been reported.

[Hepatic infusion-chemotherapy of liver metastases from stomach cancer--comparative study for intraarterial group and non-intraarterial group].

Metastasis to the liver was detected in 96 out of 1,825 patients with gastric cancer treated at our department from April 1980 to March 1990, and was respectively found to be synchronous and metachronous in 63 and 33 of the 96 patients. We compared survival durations among these 96 patients according to synchronous or metachronous metastasis by dividing them into the intermittent intra-arterial chemotherapy (FAM) group (18 patients) and non-intra-arterial chemotherapy group (78 patients). In the comparison between the intra-arterial and non-intra-arterial groups, the survival duration was determined to be significantly longer in the intra-arterial group by Wilcoxon generalized test and Cox-Mantel test (p less than 0.01). Among the patients with synchronous metastasis, a significantly longer survival duration was also observed in the intra-arterial group (p less than 0.01). The direct effect of intra-arterial chemotherapy through CT was seen in 56% of the patients in the intra-arterial group. These results indicated the usefulness of FAM hepatic infusion chemotherapy for the treatment of metastasis of gastric cancer to the liver. It is expected that therapeutic results will be much more improved by selecting more effective anticancer drugs in the future.

[Study of intermittent intra-arterial infusion chemotherapy in liver metastases from squamous cell carcinoma].

There are few reports about the methods, amounts, and kinds of dosage about intermittent intra-arterial chemotherapy of liver metastases from primal pathological type's squamous cell carcinoma. Because they are less than liver metastases from adenocarcinoma of colon or stomach. Although it is important of other factors about the operative method of primary focus and metastases of the other parts, it is possible that those cases obtained the good prognosis and protected liver failure, if those liver metastases could be controlled well. In our department from January 1987 to December 1989, 9 cases of inoperative liver metastases of squamous cell carcinoma (esophagus: 4 cases, larynx: 3 cases and cervix of uterus 2 cases) were treated of intra-arterial infusion chemotherapy of FAM (5Fu 500 mg/week, ADM 30 mg/4 weeks and MMC 4 mg/2 weeks) and CDDP methods (only CDDP 10 mg/week). Cases of esophagus carcinoma were treated with FAM method. On the CT-scan one of the cases showed the reduction rate of more than 50% and was a Progressive Response (PC), and the SCC tumor marker decreased in 2 cases. However, 2 other cases died of liver failure. Cases of larynx were treated with FAM and CDDP methods. However, on the CT-scan all of the cases showed No Change (NC) nor decrease in SCC. But thinking of prognosis FAM was better than CDDP. Cases of cervix of uterus were treated with the FAM and CDDP methods. FAM was not different than the CDDP in the prognosis and effect.

[A study of low-dose intermittent intra-arterial infusion chemotherapy for liver metastasis in colorectal cancer].

Since 1985 we have performed low-dose intermittent intra-arterial infusion chemotherapy using an implantable device for inoperable liver metastasis derived from colorectal cancer. We estimated the efficiency of this treatment in terms of effective rates and survival period. We classified subjects into intra-arterial infusion group and general administration group for comparison. The former group was comprised of 54 cases (37 synchronia, 17 heterochronia) treated with low-dose intermittent intra-arterial infusion (FAM ia) from July 1985 to June 1989. The latter comprised 32 cases (17 synchronia, 15 heterochronia) treated with general chemotherapy (general administration of 5-FU and MMC) for three years before December 1986. Of the 37 cases (23 synchronia, 14 heterochronia) evaluated in the intra-arterial infusion group, we recognized 9 PR cases (24.3%; including 5 synchronia, 4 heterochronia). On the other hand, we found only 1 PR case in the general administration group. The 50% survival period in the intra-arterial infusion group was 370 days (380 days synchronia, 340 days heterochronia), against 260 days (270 days synchronia, 250 days heterochronia) in the general administration group. There were no statistically significant differences between the two groups. Although it was not possible for us to obtain satisfactory results in terms of the efficiency of intermittent low-dose intra-arterial infusion treatment, we have been conducting a randomized study considering drug types, drug administration methods, and background of patients to further investigate the efficiency of arterial infusion treatment.

[Complete remission, obtained by multidisciplinary treatment of recurrent breast cancer with carcinomatous pleuritis, and cervical lymph node and diver metastasis].

A 46-year-old female, who had undergone a radical mastectomy for cancer of the breast 5 years previously at another institution presented a pleural effusion, in which malignant cells were detected, along with cervical lymph node metastasis. Although the patient initially responded to the H-CMcF regimen and intrathoracic injections of adriamycin (ADM), her condition subsequently was exacerbated, with metastasis occurring in the liver. A complete remission however, was achieved by local treatment, which included intrathoracic infusions of ADM and cis-platinum plus hepatic artery infusions of ADM and lipiodol, in addition to a systemic treatment consisting of a modification of the FEMP regimen employing UFT, CPA, MMC, and PDN, to which were added the immunopotentiators OK-432 and MPA. At present, 18 months after treatment, the patient is apparently disease free. The results obtained in this case suggest that even a distant metastasis can be controlled by aggressive local treatment for each metastatic lesion, in addition to a multidisciplinary treatment based mainly on intensive chemotherapy.

[First pass effect by infusing 99mTc-human serum albumin into the hepatic artery].

The fundamental principles of intra-arterial infusion chemotherapy are thought to be increased local drug concentration and the "first-pass" effect. The concentration in the rest of the body can only be decreased if there is local elimination of the infused drug before reaching the systemic circulation. This is referred to as the "first-pass" effect. In the evaluation of "first-pass" effect, the uptake of liver after infusing 99mTc-human serum albumin (99mTc-HSA) in the hepatic artery by injecting the subcutaneously implanted silicon reservoir was compared with that obtained after intravenous administration of 99mTc-HSA. In order to remove the factor of portal infusion, each count of liver up take had been continued for only 24 seconds after starting the liver uptake. The results are as follows: for 24 cases excepting 6 cases with catheter obstruction, the mean i.a./i.v. ratio was 7.92 +/- 3.34 (range 3.25 to 17.25). Although the elimination rate of drugs in the liver varies with each drug, the infusion of intraarterial chemotherapy should be about 8 times more concentrative than intravenous administration on the "first-pass" effect.

Mechanisms of transplantation tolerance induced by liver grafting in rats: involvement of serum factors in clonal deletion.

An adoptive transfer assay system was used to investigate the ability of serum from tolerant, liver-grafted rats to inactivate normal thoracic duct lymphocytes. PVG rats were rendered tolerant of DA alloantigens by liver grafting. Serum taken from such rats was used to treat normal PVG thoracic duct lymphocytes (TDL) in vitro and the transplant reactivity of the cells then tested in an adoptive transfer assay. Specific decreased responsiveness compared with TDL treated with normal sera was observed, indicating the functional elimination of alloreactive clones by agents in liver-graft serum.