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Several previous studies have shown that renal failure decreases not only renal elimination but also metabolic clearance of drugs, particularly those metabolized by CYP3A. However, whether recovery of renal function results in recovery of hepatic CYP3A activity remains unknown. In this study, we evaluated the effect of renal function on CYP3A activity after kidney transplantation in patients with end-stage renal disease (ESRD) by measuring the change in CYP3A activity using plasma concentration of 4β-hydroxycholesterol as a biomarker. The study enrolled 13 patients with ESRD who underwent the first kidney allograft transplantation. Morning blood samples were collected before and 3, 7, 10, 14, 21, 30, 60, 90, 120, 150 and 180 days after kidney transplantation. Plasma concentration of 4β-hydroxycholesterol was measured using GC-MS. Compared with before kidney transplantation, creatinine clearance increased significantly from day 3 after kidney transplantation and stabilized thereafter. Plasma concentration of 4β-hydroxycholesterol was elevated significantly on days 90 and 180 after kidney transplantation. In conclusion, this study suggests the recovery of CYP3A activity with improvement in renal function after kidney transplantation in patients with ESRD.

Therapeutic drug monitoring (TDM) of voriconazole is important to optimize efficacy and to minimize toxicity and intolerance. In this study, we evaluated the effect of sustained high plasma trough concentration of voriconazole on the incidence of hepatotoxicity in hospitalized Japanese patients.Thirty-nine patients were divided into 3 groups according to trough concentrations in two consecutive TDMs:4 μg/ml in the first TDM (group A, n=25),4 μg/ml in the first and4 μg/ml in the second TDM (group B, n=8), and4 μg/ml in both first and second TDMs (group C, n=6).Incidences of hepatotoxicity in groups A, B and C were 16.0, 25.0 and 83.3%, and significant differences were observed between groups A and C and groups B and C. Multiple logistic regression analysis identified the classification into groups A, B and C as an independent variable of hepatotoxicity.These results suggest that sustained high trough concentration of voriconazole may increase the risk of hepatotoxicity, and decreasing trough concentration to4 μg/ml by dose adjustment after the initial TDM may reduce the incidence of hepatotoxicity in patients treated with voriconazole.

Adrenomedullin (ADM) is a 52-amino acid peptide with a variety of physiologic functions such as immunomodulating activity, direct bactericidal activity, maintenance of renal homeostasis, and vasodilatory activity. Midregional proADM (MR-proADM) is derived from a larger 185-amino acid precursor peptide, prepro-adrenomedulin (preproADM), by posttranslational processing. It is suggested to be co-synthesized with ADM in equimolar amounts and has the advantages over ADM in having a longer half-life, no bioactivity, and no binding to protein. Therefore, MR-proADM serves as a surrogate for ADM secretion. In this study, we attempted to develop an enzyme immunoassay (EIA) for quantifying MR-proADM-like immunoreactive substance (IS), which is applicable for monitoring plasma MR-proADM levels. By using β-d-galactosidase-labeled preproADM(83-94) as a marker antigen, anti-rabbit IgG-coated immunoplate as a bound/free separator, and 4-methylumbelliferyl-β-d-galactopyranoside as a fluorogenic substrate, a sensitive and specific EIA was developed for the quantification of MR-proADM-IS in human plasma. The lower limit of quantification was 0.032 pmol/well, and the steep competitive inhibition EIA calibration curve obtained was linear between 0.16 and 10 nmol/L. By using human plasma samples containing 0.2 and 2.0 nmol/L of MR-proADM, the interassay coefficients of variation (reproducibility) were 10.78% and 8.83%, respectively, and intraassay coefficients were 3.91% and 7.81%. Plasma MR-proADM-IS level was significantly higher in patients with chronic renal failure (1.39 ± 0.50 nmol/L) compared with healthy subjects (0.19 ± 0.07 nmol/L). These results suggest that our EIA may be useful to evaluate plasma MR-proADM levels as a biomarker in various clinical settings. Copyright © 2012 European Peptide Society and John Wiley & Sons, Ltd.

SUMMARY What is known and Objective: Pilocarpine, a muscarinic receptor agonist, has been used for the treatment of dry mouth. Salivary glands are supplied with nerve fibres that contain neuropeptides, such as substance P, calcitonin gene-related peptide (CGRP) and vasoactive intestinal polypeptide (VIP), which are important modulators of salivation. It is known that measurement of salivary and plasma levels of neuropeptides is useful for assessing the dose‐pharmacological effect relationship of drugs. The relationship between the action of pilocarpine and neuropeptides in humans has not been studied. Moreover, studies evaluate the usefulness of drug salivary levels in the pharmacological evaluation of drugs are scarce. The aim of this study was to examine the effects of pilocarpine on the levels of substance P-, CGRP- and VIP-like immunoreactive substances (IS) in saliva and plasma taken in healthy humans. Methods: Five healthy male subjects participated in this study. Pilocarpine tablet (10 mg) or placebo tablet was orally administered with 100 mL of water. Each subject was administered placebo and drug with an interval of 4 weeks in between. Saliva was sampled before and at 20, 40, 60, 90, 120, 180 and 240 min after administration of the test substances. Venous blood samples (10 mL) were also taken from a forearm vein at each time interval. The samples were then enzyme immunoassayed using a highly sensitive system for substance P-, CGRPand VIP-IS. The amount of saliva was measured by the Saxon test. Results: A single oral administration of pilocarpine increased the release of salivary substance P-IS (the area under the concentration-time curve: AUC0 fi 240 min) compared with the placebo. Pilocarpine also significantly increased the release of salivary CGRP-IS (AUC0 fi 240 min). Pilocarpine significantly increased the release of plasma CGRP-IS. The salivary volume correlated with the salivary level of substance P and CGRPIS (r =0 AE84, P

Background:The duration of time for which the serum levels exceed the minimum inhibitory concentration (MIC) is an important pharmacokinetics (PK)/pharmacodynamics (PD) parameter correlating with efficacy for the antibiotic, ceftriaxone (CTRX). However, no reports exist regarding the PK or PD in patients undergoing continuous renal replacement therapy (CRRT). The purpose of this study was to examine the PK and safety of CTRX in patients undergoing CRRT in order to establish safer and more effective regimens.Methods:CTRX (1 g once a day) was intravenously administered four or more times to nine patients undergoing CRRT. Blood was collected after administration to measure CTRX concentrations in serum and the filtration fraction of CRRT by high-performance liquid chromatography. In addition to calculating PK parameters from serum CTRX, we (a) estimated by simulation CTRX concentrations when the dose interval was extended to once every 2 or 3 days, (b) calculated CTRX clearance via CRRT from CTRX concentrations in the filtration fraction, and (c) assessed the safety of CTRX use.Results:Total body clearance and the half-life of CTRX were 7.46 mL/min (mean) and 26.5 h, respectively, in patients undergoing CRRT. CTRX was found in the filtration fraction, and the estimated clearance by CRRT was about 70% of total body clearance. Simulations revealed that even when the dose interval is increased to 2 or 3 days, CTRX would retain its efficacy.Conclusions:Our findings suggest that, depending on the condition of patients undergoing CRRT, CTRX could be used safely against pathogens with a CTRX MIC ≤2 µg/mL, even when extending the dose interval.

Dai-kenchu-to (DKCT), a Japanese herbal (kampo) medicine, has been used for the treatment of abdominal obstructions including bowel obstructions and a feeling of coldness in the abdomen. The effect of DKCT on gastrointestinal motor activity has been reported to be closely related to changes in some neuropeptides in human plasma. In this study, we examined the effects of DKCT on salivary levels of substance P (SP), calcitonin gene-related peptide (CGRP), and vasoactive intestinal polypeptide (VIP)-like immunoreactive substances (IS) in humans. An open-labeled crossover study was conducted on five healthy volunteers. Saliva volume was measured and saliva samples were collected before and 20 to 240 min after a single oral dose of DKCT or placebo. Salivary levels of SP-, CGRP- and VIP-IS were measured using highly sensitive enzyme immunoassays. The salivary volume increased approximately 1.2- to 1.5-fold at 20 to 120 min after DKCT dosing compared with placebo, although the differences were not statistically significant. A single oral dose of DKCT resulted in a significant increase in salivary SP-IS level, and a significant correlation was observed between salivary SP-IS level and salivary volume. DKCT administration did not alter the salivary levels of CGRP- and VIP-IS compared with placebo. These findings suggest a close association of SP with the enhancement of salivary secretion by DKCT. DKCT may be especially useful in patients with xerostomia as an accompanying condition.

Some abnormalities of gastrointestinal function are presumed to result from changes in levels of stress-related hormones from the hypothalamic-pituitary-adrenal (HPA) axis and sympathetic nervous system (SNS), represented by adrenocorticotropic hormone (ACTH) and neuropeptide Y (NPY), respectively. We examined the effects of pantethine and fursultiamine on plasma levels of ACTH- and NPY-like immunoreactive substances (IS) in healthy subjects under continual stress from repetitive blood sampling. An open-labelled crossover study was conducted on five healthy volunteers. Each subject was administered a single oral dose each of pantethine, fursultiamine and placebo at intervals of one month. Venous blood samples were collected before and at 20, 40, 60, 90, 120, 180 and 240 minutes after each administration. Plasma levels of ACTH- and NPY-IS were measured using a highly sensitive enzyme immunoassay. Serial blood sampling increased plasma ACTH-IS and NPY-IS levels, presumably due to stress. Oral administration of pantethine resulted in a significant decrease in plasma ACTH-IS level compared to placebo. Fursultiamine administration resulted in a significant decrease in plasma NPY-IS level compared to placebo. These findings suggest that pantethine and fursultiamine may have modulatory effects on the HPA axis and SNS, respectively, and may be useful to treat postoperative ileus not only by improving gastrointestinal motility but also by ameliorating mental stress.

N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP) is a natural inhibitor of pluripotent hematopoietic stem cell proliferation and is normally found in human plasma. Because AcSDKP is hydrolyzed by the N-terminal active site of angiotensin converting enzyme and partially eliminated in urine, its plasma level is a result of a complex balance between its production, hydrolysis by ACE, and renal elimination. In this study, we attempted to establish an enzyme immunoassay (EIA) for quantifying AcSDKP-like immunoreactive substance (IS), which is applicable for monitoring plasma AcSDKP levels in healthy subjects and patients with chronic renal failure. Using β- d-galactosidase-labeled Gly-γAbu-SDKP as a marker antigen, an anti-rabbit IgG-coated immunoplate as a bound/free separator and 4-methylumbelliferyl-β- d-galactopyranoside as a fluorogenic substrate, a highly sensitive and specific EIA was developed for the quantification of AcSDKP-IS in human plasma. The lower limit of quantification was 0.32 fmol/well, and the sharp inhibition competitive EIA calibration curve obtained was linear between 8.0 and 513 fmol/ml. This EIA was so sensitive that only 10 µl plasma sample was required for a single assay. The coefficients of variation (reproducibility) for human plasma concentrations of 0.2 and 2.1 pmol/ml were 7.2 and 7.7%, respectively, for inter-assay and 13.3 and 7.8% for intra-assay comparisons. Plasma AcSDKP-IS level was significantly higher in patients with chronic renal failure (0.92 ± 0.39 pmol/ml) compared with healthy subjects (0.29 ± 0.07 pmol/ml). These results suggest that our EIA may be useful to evaluate plasma AcSDKP level as a biomarker in various patients. Copyright © 2012 European Peptide Society and John Wiley & Sons, Ltd.

Some depressions are presumed to result from changes in levels of stress-related hormones released from the hypothalamic-pituitary-adrenal (HPA) axis and sympathetic nervous system (SNS), represented by adrenocorticotropic hormone (ACTH) and neuropeptide Y (NPY), respectively. Venipuncture for blood sampling has been proposed to be a stress factor that increases circulating ACTH and NPY levels. We examined the effects of mirtazapine on plasma levels of ACTH- and NPY-like immunoreactive substances (IS) in healthy subjects under continual stress induced by repetitive venipunctures for blood sampling. An open-labeled crossover study was conducted on eight healthy volunteers. Each subject was administered a single oral dose of mirtazapine or placebo at an interval of 1 month. Venous blood samples were collected repetitively before and after each administration. Plasma levels of ACTH- and NPY-IS were measured using a highly sensitive enzyme immunoassay. In the placebo group, plasma ACTH-IS levels at 240 min and NPY-IS levels at 40 min increased significantly compared with the levels before administration, presumably due to stress. Oral administration of mirtazapine resulted in significant decreases in plasma ACTH-IS level at 60 and 240 min and NPY-IS level at 20 and 40 min compared with placebo administration. These findings suggest that the antidepressant activity of mirtazapine may involve the suppression of not only the HPA axis but also the SNS.

Background: We analyzed the pharmacokinetic-pharmacodynamic relationship of vancomycin to determine the drug exposure parameters that correlate with the efficacy and nephrotoxicity of vancomycin in patients with methicillin-resistant Staphylococcus aureus pneumonia and evaluated the need to use peak concentration in therapeutic drug monitoring (TDM). Methods: Serum drug concentrations of 31 hospitalized patients treated with vancomycin for methicillin-resistant S. aureus pneumonia were collected. Results: Significant differences in trough concentration (Cmin)/minimum inhibitory concentration (MIC) and area under the serum concentration-time curve (AUC0–24)/MIC were observed between the response and non-response groups. Significant differences in Cmin and AUC0–24 were observed between the nephrotoxicity and non-nephrotoxicity groups. Receiver operating characteristic curves revealed high predictive values of Cmin/MIC and AUC0–24/MIC for efficacy and of Cmin and AUC0–24 for safety of vancomycin. Conclusions: These results suggest little need to use peak concentration in vancomycin TDM because Cmin/MIC and Cmin are sufficient to predict the efficacy and safety of vancomycin.

Objectives The aim of this study was to establish the population protein binding parameters of valproic acid (VPA) in patients with epilepsy receiving VPA monotherapy and those receiving VPA combined with other antiepileptic drugs. Methods One hundred and thirty nine data sets from 63 Japanese patients with epilepsy were analysed. These patients were separated into two groups: VPA monotherapy and VPA combined with other binding-sensitive antiepileptic drugs, including phenytoin, clonazepam, clobazam, carbamazepine and phenobarbital (VPA polytherapy). The population protein-binding parameters of VPA were obtained by non-linear least-squares method in each group. Key findings The mean (95% confidence interval) dissociation constants were 38.9 µm (33.2–44.6 µm) and 36.9 µm (26.7–47.1 µm), and the numbers of binding sites were 1.36 (1.27–1.44) and 1.33 (1.19–1.47) in the monotherapy and polytherapy groups, respectively. No significant differences in the binding parameters of VPA to serum albumin were observed between the two groups. Conclusions The steady-state serum albumin binding of VPA in Japanese patients with epilepsy is not affected by co-administration of other antiepileptic drugs. These findings suggest that serum VPA concentration is stable at the steady state with regard to interaction by protein binding, even when other antiepileptic drugs with moderate-to-high binding properties are co-administered.

Faculty of Science, Department of Material and Biological Chemistry, Yamagata University, Kojirakawa, 1-4-12,Yamagata 990-8560, JapanReceived 23 December 2009, revised 21 May 2010, accepted 1 June 2010Published online 5 July 2010Keywords absorption spectra, excitons, oligomers, reflection spectra, surfaces, thiophene

Thermal cis–trans conversion has been examined in oligothiophene single molecules encapsulated in the molecular vessels of cyclodextrin and Na-mordenite. At high temperatures, optical absorption intensities are enhanced in bithiophene, terthiophene and quinquethiophene, while the intensity of quarterthiophene is temperature independent. Optical absorption comes from uncompensated transition dipole moment due to the thermal torsion between cis and trans forms.

Polarization dependence of the absorption spectra (ABS) and the luminescence spectra in α-quaterthiophene (4T) and α-quinquethiophene (5T) has been measured directly with near normal incident light on the ab, bc, and ca crystal planes of their thick single crystals (SCs). Vibronic excitons (Frenkel excitons) have been observed on each crystal plane of 4T and 5T. The polarizations of the ABS are consistent with the prediction obtained from the MOPAC calculations of the transition dipole moment directions of the molecules in the SCs. Excited electron relaxes to the lowest excited state which is composed of the LUMO states.

A 73-year-old female was operated with radical nephrectomy and cholecystectomy for renal cell carcinoma and suspected gallstones after 9 courses of sunitinib treatment. Gallbladder specimen showed gallbladder metastasis originating from the renal cell carcinoma. Gallbladder metastasis from renal cell carcinoma is rare. Here, we discuss a case of gallbladder metastasis from renal cell carcinoma.

From the viewpoint of hospital and risk management,it is very important to manage prescriptions brought by patients when they are hospitalized.However,with the multifarious tasks that pharmacists now have to perform it is difficult to check prescriptions soon after patients are hospitalized.In view of this,we devised a system that checks medicines brought in to hospital,outputs check sheets on which the names of drugs,their usage,dosage,remaining quantities and those with the same ingredients as drugs used in our hospital.The system also has a function for suggesting tests and items that need to be checked for drugs that require special caution (anticancer drugs,antidiabetics,antirheumatics,etc.) such as blood tests,adverse effects and therapeutic drug monitoring.It enabled us to check for interactions between drugs,or drugs and disease,and duplicated prescriptions quickly.The results of a questionnaire on our system that we gave to doctors and nurses showed that they appreciated it.We consider that the reinforced management of pharmaceuticals that it provides will contribute greatly to ensuring the proper use of drugs.Furthermore,if this system is linked with various order entry systems in the hospital (for blood tests,diseases,etc),pharmacists will be able to further improve the quality of their pharmaceutical counseling services.

The traditional Japanese Kampo medicine Bushirichu-to (Bushi-ninjin-to) has been empirically used for the treatment of chronic gastroenteritis, gastric atony, and chronic constipation accompanied by a feeling of coldness in the body. One of the mechanisms of the empirical effects is assumed to be due to local changes in gut-regulated peptide levels. We studied the effect of Bushi-richu-to on calcitonin gene-related peptide (CGRP)-, substance P-, vasoactive intestinal polypeptides (VIP)-, somatostatin-, and motilin-like immunoreactive substances (IS) in plasma taken from healthy subjects. Bushi-richu-to (4.5 g) or placebo was orally administered to five healthy males. Blood samples were taken before, and at 20, 40, 60, 90, 120, 180, and 240 min after administration, extracted, and then submitted to a highly sensitive enzyme immunoassay system for CGRP-, substance P-, VIP-, somatostatin-, and motilin-IS. A single oral administration of Bushi-richu-to caused significant increases in plasma CGRP-, substance P-, VIP-, and somatostatin-IS levels compared with placebo. It is concluded that Bushi-richu-to might improve a peripheral and uncomfortable feeling of cold and gastrointestinal dysmotility via gut-regulated peptide release.

A traditional Japanese Kampo medicine Keishininjinto has been empirically used for the treatment of headache, chronic gastroenteritis, gastric atony, and waterly diarrhea often accompanying abdominal pain, cold, fever, and headache. One of the mechanisms of the empirical effects is assumed to be due to local changes in gut-regulated peptide levels. We studied the effects of Keishininjinto on calcitonin gene-related peptide (CGRP)-, substance P-, vasoactive intestinal polypeptides (VIP)-, motilin-, and somatostatin-like immunoreactive substances (IS) in plasma taken from healthy subjects. Keishininjinto (6.0 g) or placebo was orally administered to five healthy males. Blood samples were taken before, and at 20, 40, 60, 90, 120, 180, and 240 min after administration, followed by the extracting procedure, and submitted to a highly sensitive enzyme immunoassay system for CGRP-, substance P-, VIP-, motilin-, and somatostatin-IS. A single oral administration of Keishininjinto caused significant increases in plasma CGRP-, and substance P-IS levels compared with placebo. On the other hand, a single oral administration of Keishininjinto transiently caused decreases in plasma VIP-IS levels compared with placebo. However, Keishininjinto had no effects on plasma motilin-, and somatostatin-IS levels. In this study, we hypothesized that Keishininjinto might stimulate capsaicin-sensitive afferent nerves and improve gastrointestinal mucosal blood flow, and that might affect intestinal secretion and motility in neuronal reflexes.

A new scanning method named “Overall scanning” will be applied for J-PARC E07’s emulsion plates to collect alpha decays which are calibration sources for range-energy relation in emulsion, rapidly. We carried out an operation of alpha search with current Overall scanning technology by E373’s emulsion. About 100 alpha rays were selected and measured in 17 days in 30mm*110mm*0.45mm volume of the plate with less man-power than before. Development of advanced image process and scanning software is on-going for speeding up. Besides, Overall scanning method will be applied to search for more events after regular analysis with hybrid method.

For analysis of double- hypernucleus in nuclear emulsion, it is necessary to know shrinkage factor and density of emulsion plate by measuring the track ranges of alpha particles. The kinetic energies of nuclear fragment from double- hypernucleus are measured by their ranges in the emulsion, which is dedicated photographic emulsion for nuclear physics. Then we have to reconstruct their original ranges since the emulsion plate shrinks about half in thickness after development. Besides, we have to calibrate range-energy relation because the density depends on the emulsion content of moisture. Therefore we use alpha-rays with monochromatic energy as calibration sources which were emitted from natural RI such as Thorium series in the emulsion. Technique which performs alpha-tracks measurement by image processing is being studied. In the E07 experiment at J-PARC [1], quick analysis is required for about 10 4 alpha tracks on about 100 double- hypernuclear events within a few years. At present, we are developing automated range measurement technique instead of traditional manual measurement. Alpha tracks are seen as black, bold lines in micrographs as shown in Fig.1 and 2. Image processing program detects such lines and the positions, angles, ranges of them in micrographs.

We carried out the E373 experiment at KEK and detected seven double- hypernuclear events. Only the NAGARA event was uniquely identified as a   He hypernucleus among them. For some events among the other six events, unique interpretation of the nuclide would be possible if one of daughter particles from production or decay vertex was identified uniquely. In order to obtain more information about the -interaction we planned to detect about one hundred double- hypernuclei in the J-PARC E07 experiment, and obtain new knowledge for the -interaction, which is independent of the information obtained from the NAGARA event. To study the -interaction with more nuclei which are uniquely assigned, we are developing a particle identification (PID) method which identified daughter isotopes by the measurement of energy losses in the emulsion. Track width which reflects energy-losses will be measured from stopping point up to ~100m with an image processing method. Under the assumption of tracks to be made of many cylinders with length of 1 μm, track volume values given by the width are summed up and expected to distinguish light nuclear species such as H, He, Li, Be or B.

Background Recently, increased plasma mid-regional pro-adrenomedullin (MR-proADM) concentrations have been demonstrated in patients with chronic renal failure. In this study, we attempted to identify significant clinical factors associated with MR-proADM concentration in stable kidney transplant recipients. Methods Forty-seven Japanese kidney transplant recipients who underwent transplantation > 180 days prior to the study were analyzed. To facilitate comparability of anti-hypertensive regimens across recipients taking different drugs, we calculated the treatment intensity score of anti-hypertensive drugs in each recipient. Morning blood samples were collected and plasma MR-proADM concentrations were measured using an enzyme immunoassay. Results Multiple regression analysis identified treatment intensity score for anti-hypertensive drugs, serum albumin, creatinine clearance and use of lipid-lowering agents as significant independent factors associated with plasma MR-proADM concentration. Adjusted coefficient of determination for this model was 0.46. Conclusion Apart from indicating lowered renal function, plasma MR-proADM concentration may be a useful biomarker for metabolic disorders, especially hypertension and hyperlipidemia, in stable kidney transplant patients.

Metoclopramide, a prokinetic drug, is widely used to treat vomiting and nausea. Delayed gastric emptying and continual stress are considered important factors, among others, that induce nausea and vomiting. One gastrointestinal motility regulatory factor has been assumed to be the induction of changes in the levels of peptides such as gastrin, somatostatin, motilin, and cholecystokinin (CCK) in plasma. In contrast, adrenocorticotropic hormone (ACTH) and cortisol are used as indicators of stress. Here, we studied the effects of metoclopramide on human plasma gastrin-, somatostatin-, motilin-, and CCK-like immunoreactive substances (ISs) and ACTH-IS and cortisol under stress conditions using repetitive blood sampling in healthy subjects. Metoclopramide hydrochloride at a dose of 30 mg or placebo was orally administered to five healthy male volunteers. Blood samples were taken before and 20, 40, 60, 90, 120, 180, and 240 min after administration, subject to extracting procedures, and submitted to a highly sensitive enzyme immunoassay system. A single administration of metoclopramide caused significant increases in plasma somatostatin-IS levels compared with the placebo. Metoclopramide significantly decreased plasma gastrin- and suppressed ACTH-IS and cortisol levels compared with the placebo. We hypothesize that metoclopramide might have an accelerating gastric-emptying effect and a modulatory effect on the hypothalamo-pituitary-adrenal (HPA) axis and the autonomic nervous function. These effects might be beneficial in stress-related diseases, which suggest that this medicine has clinicopharmacological activities. Copyright © 2005 European Peptide Society and John Wiley & Sons, Ltd.

Dai-kenchu-to has been used for the treatment of abdominal obstructions, including bowel obstructions and a feeling of coldness in the abdomen. We reported that Dai-kenchu-to increases plasma neuropeptide [motilin, vasoactive intestinal polypeptide (VIP), serotonin, calcitonin gene-related peptide (CGRP), and substance P]-like immunoreactive substances (IS) levels and that its pharmacologic effects on the gastrointestine are due to changes in gastrointestinal mucosa-regulatory peptide levels. We examined the effects of the selective M(1) muscarinic receptor antagonist pirenzepine on the elevation of Dai-kenchu-to-induced plasma neuropeptide (gastrin, motilin, somatostatin, VIP, CGRP, substance P)-IS levels in human volunteers and the area under the plasma neuropeptide concentration-time curve from 0 to 240 min (AUC(0-->240 min)), which were calculated from the plasma neuropeptide concentration-time curves from each volunteers. Oral pretreatment with pirenzepine reduced the Dai-kenchu-to-induced elevation of plasma motilin and VIP-IS levels and AUC(0-->240 min). Combined treatment with Dai-kenchu-to and pirenzepine increased plasma somatostatin-IS levels and decreased plasma gastrin-IS levels and had no effects on plasma CGRP- and substance P-IS levels and AUC(0-->240 min) compared with administration of Dai-kenchu-to alone. Dai-kenchu-to appeared to induce the release of motilin and VIP into plasma mainly through the activation of M(1) muscarinic receptors, and pirenzepine may affect the pharmacologic action of Dai-kenchu-to by elevation of plasma motilin and VIP levels.

Hange-koboku-to (Banxia-houpo-tang), a Traditional Chinese Medicine remedy, has been used to treat swallowing reflex disorder, and it has been recently suggested that one of the mechanisms for the empirical effect of Hange-koboku-to involves humoral changes in neuropeptide levels. We suggested to administer Hange-koboku-to to a 70-year-old man with swallowing reflex disorder due to multiple cerebral infarctions and investigated the relationship between changes in plasma-neuropeptide-like immunoactivity (LI) levels and swallowing for a period of 1 week. On the 4 th and 7 th day of administration, the patient' s plasma calcitonin gene-related peptide (CGRP) -LI levels were twice the concentration on day 0 and Hange-koboku-to had increased the patient' s plasma substance P-LI levels approximately 5-fold on these 2 days. The plasma substance P-LI levels on days 4 and 7 were close to the levels (mean±SD) of elderly subjects without swallowing reflex disorder. Following the administration of Hange-koboku-to, plasma somatostatin-LI and vasoactive intestinal polypeptide (VIP) -LI levels in this patient exceeded those of elderly subjects without swallowing reflex disorder (mean + SD). With regard to symptoms, the patient' s difficulty in swallowing had disappeared on the third day of administration.This study suggests that Hange-koboku-to relieves swallowing reflex disorder by stimulating neuropeptidergic nerves and that this effect is achieved within 1 week of administration. However, we need to study more cases of the use of Hange-koboku-to for swallowing reflex disorder and further investigate the relationship between changes in neuropeptide-LI levels and its pharmacological effects.

Cetraxate hydrochloride (cetraxate), an antiulcer drug, produces a dose related increase in mucosal blood flow. We have reported that cetraxate increases plasma calcitonin gene-related peptide (CGRP) and substance P in healthy human subjects (J. Pharm. Pharmacol., 56, p. 557, 2004). Cetraxate is rapidly metabolized to tranexamic acid in plasma. We investigated the effect of tranexamic acid on human plasma CGRP, substance P, gastrin and somatostatin. Tranexamic acid at a dose of 500 mg or placebo was orally administered in five healthy male volunteers. The blood samples were taken before and at 20, 40, 60, 90, 120, 180 and 240 min after administrations, followed by the extracting procedure, and submitted to the high sensitive enzyme immunoassay system for CGRP and substance P as previously developed. Single administration of tranexamic acid caused significant increases of plasma CGRP concentration at 60-90 min compared with placebo, but the level-time profile was a little different from that of cetraxate. Tranexamic acid had no significant effect on plasma gastrin, somatostatin and substance P levels compared with placebo. In this study, we thought that the gastroprotective effect of cetraxate might not be due to plasma metabolite, tranexamic acid, but direct stimulation of gastric mucosa.

Rabeprazole sodium (rabeprazole), a proton pump inhibitor (PPI), is widely used in the treatment of peptic ulcer and gastroesophageal reflux disease. Recently, some antiulcer medicines have been elucidated pharmacologically from the viewpoint of gut-regulated hormone levels. We examined the effects of rabeprazole on plasma levels of gastrointestinal peptides [gastrin, somatostatin, motilin, substance P, and calcitonin generelated peptide (CGRP)]. Rabeprazole at a dose of 20 mg or placebo was orally administered to 5 healthy male volunteers aged 25‐30 years. Venous blood samples were taken before and 30, 60, 90, 120, 180, 240, and 360 min after administration. Plasma peptide levels were measured using a sensitive enzyme immunoassay. Compared with the response of the placebo group, rabeprazole caused significant (p < 0.05) increases in gastrin-, somatostatin-, and CGRP-like immunoreactive substance (IS) at 360, 180, and 240 min, respectively. Rabeprazole significantly decreased motilin-IS levels at 180 min compared with the placebo group. However, rabeprazole had no effect on plasma substance P-IS levels. Although rabeprazole has potent antisecretry effects, the agent may have little effect on gastrointestinal peptides.

levels were measured using a sensitive enzyme immunoassay. Compared with the response of the placebo treated group, lansoprazole caused significant (p < 0.05) increases in somatostatin-, VIP-, substance P- and CGRP-like immunoreactive substance (IS) levels at 120, 120, 90‐240, and 120 min, respectively. Furthermore, lansoprazole significantly suppressed temporary elevation (30 min) of placebo gastrin-IS levels. But lansoprazole had no effect on plasma motilin-IS levels compared with the placebo. In this study, lansoprazole raised somatostatin-IS levels and inhibited the increase in gastrin-IS levels. On the other hand, lansoprazole raised substance P- and CGRP-IS levels. Recently, capsaicin-sensitive afferent nerves have been shown to play an important role in gastric mucosal defensive mechanisms. Capsaicin stimulates afferent nerves and enhances the release of CGRP and substance P in the stomach. We hypothesize that lansoprazole might not only potently inhibit gastric acid secretion but also exert gastroprotective actions via capsaicin-sensitive afferent nerves.

neuropeptides. In this study, we investigated the effects of Nichin-to on the plasma levels of gut-regulated peptides [gastrin, somatostatin, motilin, vasoactive intestinal peptide (VIP), calcitonin gene-related peptide (CGRP) and substance P] in healthy human subjects. A single oral administration of Nichin-to caused significant (p < 0.05) increases in plasma levels of gastrin-, somatostatin-, VIP-, motilin-, CGRP- and substance P-immunoreactive substance (IS), compared with placebo group. In conclusion, these results might indicate that the pharmacological action of Nichinto is closely related to changes in these peptide levels in human plasma, and we hypothesize that the pharmacological effect of Nichin-to might be due to improvement of digestion, and accelerating the rate of gastric emptying and intestinal propulsion.

The temperature dependence of the absorption spectra of 2,2'-bithiophene and 2,2':5',2''-terthiophene isolated molecules in cyclodextrin (CyD) were investigated between 15 K to room temperature (RT). The optical absorption spectra of BT molecules in β- and γ-CyD, (BT) β-CyD and (BT) γ-CyD are nearly the same between 15 K and RT. Those of TT are almost the same for (TT) β-CyD and (TT) γ-CyD . Anomalous temperature dependence of the absorption intensities was observed. The absorption intensities of the isolated molecules of BT and TT in CyD, (BT) CyD and (TT) CyD increase with increasing temperatures. The s-trans states of (BT) CyD and (TT) CyD convert to the s-cis states at high temperatures through the rotational vibration around the single bond between thiophene rings. The allowed transition of the s-cis conformation would mix to the forbidden transition of s-trans conformation, thus the absorption intensity increases at high temperatures.

In order to examine the effect of subsumption space of β- and γ-cyclodextrin (CyD) on the photophysics of oligothiophenes, 2, 2′-bithiophene (BT) and 2, 2′: 5′, 2″-terthiophene (TT), the fluorescence spectra were compared with those of the single crystals (SC) at 15, 77 K and room temperature (RT). Both the numbers of BT included in β- and γ-CyD are twin (BT2). The numbers of TT included in β- and γ-CyD are unit (TT1) and twin (TT2), respectively. Electronic excitation of BT encapsulated in β- and γ-CyD gives similar fluorescence spectra, showing bathochromic shift compared with that of BT single crystal, (BT)SC. The observation that the fluorescence spectra of encapsulated BT2 are similar to the spectra of its THF solution suggests the configuration of BT2 in β- and γ-CyD should be face-to-face configuration (BT2)∥. On the contrary, TT in β- and in γ-CyD afford quite different fluorescence spectra. Encapsulated TT in β-CyD exhibits the hypsochromic shift of fluorescence maxima compared to that of TT single crystal, (TT)SC. While the bathochromically shifted fluorescence spectra of TT2 in γ-CyD is also ascribed to the face-to-face configuration (TT2)∥ as in the case of BT2 in γ-CyD. Fluorescence spectra show the excited ground state complex of BT2 and TT2 in γ-CyD.

Cetraxate hydrochloride (cetraxate), an anti-ulcer drug, produces a dose-related increase in mucosal blood flow. Recently, it was found that capsaicin-sensitive afferent nerves play an important role in gastric mucosal defence. Capsaicin stimulates afferent nerves and enhances the release of calcitonin gene-related peptide (CGRP) and substance P in the stomach. We studied the effect of cetraxate on human plasma CGRP and substance P in healthy subjects. Cetraxate (800 mg) or placebo were orally administered to five healthy males. Blood samples were taken before, and at 20, 40, 60, 90, 120, 180 and 240 min after administration, followed by the extracting procedure, and submitted to a highly sensitive enzyme immunoassay system for CGRP and substance P. Single administration of cetraxate caused significant increases in plasma CGRP concentration at 60–120 min compared with placebo. Cetraxate significantly increased plasma substance P levels at 40–90 min compared with placebo. In this study, we hypothesized that cetraxate might indirectly stimulate capsaicin-sensitive afferent nerves and increase mucosal blood flow, and that this may be a key mechanism underlying its gastroprotective action.

The effect of histamine H2-receptor antagonists on plasma concentrations of acetaminophen was investigated with respect to hepatic metabolism.Acetaminophen (1000 mg) was administered orally together with ranitidine (300 mg), nizatidine (300 mg), nizatidine (150 mg) or placebo to five healthy male volunteers. Venous blood samples were taken before and after administration and plasma acetaminophen and acetaminophen conjugates (glucuronide and sulphate) were measured by high-performance liquid chromatography. The pharmacokinetic parameters were calculated from the plasma acetaminophen concentration-time curves for each volunteer.With ranitidine, compared with placebo, plasma acetaminophen concentrations were significantly increased from 15 to 120 min. and plasma acetaminophen glucuronide conjugate concentrations were significantly decreased from 15 to 45 min. With nizatidine, as compared with placebo, plasma acetaminophen concentrations were significantly increased from 45 to 120 min. and 45 to 60 min. for the high and low doses of the drug, respectively. Acetaminophen glucuronide concentrations were significantly decreased from 30 to 45 min. and at 30 min., respectively, for the high and low doses of nizatidine, respectively. However, with ranitidine and nizatidine, plasma acetaminophen sulphate concentrations were not significantly altered.Co-administration with ranitidine or nizatidine reduces plasma acetaminophen glucuronide concentrations and increases plasma acetaminophen concentrations dose-dependently. These effects of ranitidine and nizatidine could result from inhibi-tion of glucuronyltransferase. Therefore, care is necessary when administering acetaminophen together with ranitidine or nizatidine.

To investigate the role of the excited triplet state in the deactivation process of 5-hydroxyflavone (5HF), the photophysical process of 5HF was studied by transient absorption, phosphorescence spectroscopies, and semiempirical calculations. The triplet–triplet absorption (T–T) spectra of 5HF and 5-methoxyflavone (5MF) were observed upon direct and triplet-sensitized excitation. The T–T spectrum of 5HF ( λ max =350 nm, τ T =2.8 μs) was different from that of 5MF ( λ max =360 nm, τ T =6.8 μs). Estimations of the triplet energies of 5HF and 5MF by quenching experiments, phosphorescence, and semiempirical (PM3/CI4) calculation revealed that 5HF underwent an intramolecular hydrogen atom transfer and formed the tautomer in the excited triplet state. The triplet energy of the normal form of 5HF was 260 kJ mol −1 , while that of the tautomer form (5HF′) was 197 kJ mol −1 . The triplet energy of 5MF, the model compound of the normal form of 5HF, was 261 kJ mol −1 . The PM3/CI4 calculation supported the experimental observations and suggested that the most stable conformer in the triplet state of 5HF is the tautomer form.

Sho-hange-ka-bukuryou-to, a traditional Chinese herbal (Kampo) medicine, has been used to treat hyperemesis of pregnancy, nausea and vomiting. Most traditional herbal medicines are prepared from several herbs. For example, Sho-hange-ka-bukuryo-to is prepared from three herbs: Pinelliae Tuber, Zingiberis Rhizoma and Hoelen. Thus, to determine the precise mechanism of the pharmacological effects of Chinese herbal medicines is too difficult. So we have elucidated the effect of some Chinese herbal medicines by examining the change of the plasma levels of brain-gut peptides. In this study, we investigated the effects of Sho-hange-ka-bukuryo-to on the plasma levels of gut-regulated peptides (gastrin, somatostatin, motilin and vasoactive intestinal peptide (VIP)) and gastrointestinal mucosa regulatory neuropeptides (calcitonin gene-related peptide (CGRP) and substance P) in healthy human subjects. A single oral administration of Sho-hange-ka-bukuryo-to caused significant increases in plasma somatostatin-, CGRP- and substance P-immunoreactive substance (IS) levels, compared with a placebo group. Transient elevation of gastrin-IS levels in the placebo group was inhibited by the administration of Sho-hange-ka-bukuryo-to, but the medicine showed no effects on plasma motilin- or VIP-IS levels. In conclusion, these results might indicate that the pharmacological action of Sho-hange-ka-bukuryo-to is closely related to changes in gastrin-, somatostatin-, CGRP- and substance P-IS levels in human plasma.

A sensitive and specific double-antibody enzyme immunoassay (EIA) for nociceptin (orphanin FQ)-like immunoreactive substances (nociceptin-IS) was developed. In competitive reactions, the nociceptin-antibody was incubated with both a nociceptin standard (or plasma extract sample) and β-D-galactosidase (β-Gal)-labeled synthetic human nociceptin (delayed addition method). The free and antibody-bound enzyme haptens were separated using an anti-rabbit IgG-coated immunoplate. The enzyme activity on the immunoplate was determined fluorometrically. The present immunoassay allows the detection of 15‐700 pg/ml (sensitivity: 1.5 pg, 0.6 pg/well) of nociceptin. Using this EIA, the nociceptin-IS levels in human plasma were determined, and found to be in the range of 5.0 to 16.0 pg/ml. No circadian rhythms in the daytime (9:00‐19:00) or effects of eating meals on human plasma nociceptin levels were found. We have established an evaluation system for both nociceptin-IS and substance P-IS levels in 1 ml of human plasma. As for the evaluation of analgesic effects of drugs and pain, this sensitive and specific EIA system for endogenous nociceptin may be valuable for clinical use.

Regarding the gastroprotective function as a neural emergency system, sensory afferent neurons in the gastrointestinal mucosa regulate neuropeptide (calcitonin gene-related peptide (CGRP), substance P, etc.) levels, and those peptides play various physiological roles. To determine whether the pharmacological effects of Hange-shashin-to and Rikkunshi-to on the gastrointestine are due to changes in gastrointestinal mucosa regulatory peptides levels, we investigated the levels of CGRP-like immunoreactive substances (IS) and substance P-IS in plasma from healthy subjects. A single oral administration of Hange-shashin-to caused significant increases in CGRP-IS (40-60 min) and substance P-IS (60-180 min) levels in the plasma compared with the levels induced by a placebo. Rikkunshi-to and a 5.0 g Pinelliae tuber extract had no significant effect on CGRP-IS and substance P-IS levels. Extract of a 2.5 g Zingiberis rhizoma significantly caused increases in CGRP-IS at 40 min and in substance P-IS at 60 min. These results, in comparison with Kampo medicines, might indicate that the pharmacological actions of Hange-shashin-to closely are related to changes in CGRP-IS and substance P-IS levels, while Zingiberis rhizoma partially might participate in those effects of Hange-shashin-to.

Photocleavage of the N–O bond of N-(9-anthroyloxy)-9-fluorenylideneamine and its 1-and 2-anthroyloxy derivatives takes place efficiently in acetonitrile in the excited singlet state attributed to the fluorenylidene moiety. This made it possible for the first time to directly observe anthroyloxyl radicals by the transient absorption method. The quantum efficiency for photocleavage decreases remarkably in benzene, in which the lowest excited singlet state is attributed to the anthroate moiety. All the three kinds of anthroyloxyl radicals are much less reactive in decarboxylation, addition to olefins, and hydrogen-atom abstraction than benzoyloxyl and 1- and 2-naphthoyloxyl radicals; 9-anthroyloxyl radicals supposedly undergo intramolecular addition–elimination in the ipso-position in equilibrium with α-lactonic spirodihydroanthryl radicals, as indicated by one-color and two-color laser photolyses.

Nanocrystalline TiO2 (rutile and anatase) film electrodes usually show anodic photocurrents in aqueous electrolytes. Detailed photoelectrochemical studies have revealed that they also show cathodic photocurrents under particular conditions, e.g., in alkaline solutions containing dissolved oxygen under illumination from the TiO2-film side at short wavelengths such as 300 nm. The cathodic photocurrents appear in a potential region about 0.5∼0.9 V more positive than the flat-band potential (Ufb) of single-crystal n-TiO2 electrodes. It is shown that the appearance of the cathodic photocurrents can be attributed to efficient electron transfer from the conduction band of TiO2 particles to chemically adsorbed oxygen molecules, the density of which is largely increased in alkaline solutions through a charge-transfer interaction between surface anionic groups such as Ti−O- as an electron donor and oxygen molecules as an electron acceptor. The dependences of the cathodic and anodic photocurrents on the illumination...

Intramolecular hydrogen atom transfer and novel one-way photoisomerization of 2′-hydroxychalcone (2HC) were investigated by quantum yield measurements, transient absorption spectroscopy, and semiempirical calculations. The trans isomer of 2HC (trans-2HC) did not give the cis isomer, while cis-2HC underwent one-way isomerization to give the trans-2HC. The triplet-triplet absorption spectra of cis- and trans-2HC were similar and were assigned to the tautomer produced via the intramolecular hydrogen atom transfer in the excited triplet state. The triplet energies of the normal form and the tautomer form of trans-2HC were estimated by quenching experiments to be 229 and 177.5 kJ mol -1 , respectively. Heats of formation, the frontier molecular orbital coefficients, and optimized structures of trans-2HC and cis-2HC in the ground, the excited singlet, and the excited triplet states were calculated by semiempirical (MOPAC93 PM3/4CI) calculations. These calculations agree well with the experimental observations. Based on the experimental observations and theoretical considerations, a novel mechanism and the potential energy surface for the oneway photoisomerization of 2HC were proposed. The photoisomerization of 2HC was induced by hydrogen atom transfer in the excited triplet state. Thus, 2HC can be viewed as a molecule in which the mode of isomerization around the carbon-carbon double bond can be controlled by the remote intramolecular hydrogen bonding. Solvent affected the triplet lifetime without changing the mode of isomerization. On prolonged irradiation, trans-2HC gave flavanone by very low quantum yield (… ) 1.9 10 -3 in benzene). The cyclization reaction to form flavanone was studied and the quantum yields were determined.

Background We propose a simple, sensitive, and fast high-performance liquid chromatography ultraviolet detection (HPLC-UV) method for the quantitative determination of bosutinib in human plasma. Methods Plasma samples were processed using an Oasis hydrophilic-lipophilic balance extraction cartridge (1 mL, 30 mg). Bosutinib and the internal standard imatinib were separated using a mobile phase of 0.5% Na2PO4H2O (pH 3.5)-acetonitrile-methanol (55:25:20, v/v/v) on a CAPCELL PAK C18 MG II reversed-phase column 250 nm×4.6 nm i.d., at a flow rate of 1.0 mL/min, with ultraviolet detection at 250 nm. Results The calibration curve exhibited linearity over the bosutinib concentration range of 25-1500 ng/mL at 250 nm, with coefficient of variation for intraday precision of 2.42%, 6.04%, and 1.11% for 100, 250, and 1500 ng/mL, respectively, of bosutinib. The lower limit of detection was 20 ng/mL. The extraction recovery rates for bosutinib ranged from 84.36% to 85.82%. The intra- and interday precision was below 8.7%, and the accuracy ranged from −5.95% to 5.85% over the linear range. No notable matrix effects or astaticism were observed. Conclusion The proposed HPLC-UV method was successfully applied as an assay to detect bosutinib in human plasma.

Background The target trough concentration of vancomycin in patients with febrile neutropenia has not been reported. The aim of this study was to estimate the target trough concentration for febrile neutropenia in patients with hematological malignancy. Methods In this retrospective, single-center, observational cohort study, 63 hospitalized patients with hematological malignancy who were treated with vancomycin for febrile neutropenia due to bacteriologically documented or presumptive Gram-positive infections were analyzed. Results A significant difference in the first trough concentration of vancomycin was observed between the response and non-response groups, and between the nephrotoxicity and non-nephrotoxicity groups. Multiple logistic regression analyses identified the first trough concentration as the only independent variable associated with clinical efficacy and nephrotoxicity of vancomycin. The areas under the ROC curves were 0.72 and 0.83 for clinical efficacy and nephrotoxicity, respectively. The cut-off values of the first trough concentration were 11.1 μg/ml for clinical efficacy (sensitivity 60%, specificity 87%) and 11.9 μg/ml for nephrotoxicity (sensitivity 77%, specificity 82%). Conclusions These results suggest a relationship of trough vancomycin concentration with clinical efficacy and incidence of nephrotoxicity. We propose a target trough vancomycin concentration of around 11.5 μg/ml for febrile neutropenia in patients with hematological malignancy.

Teicoplanin (TEIC) is a glycopeptide currently used for the treatment of methicillin-resistant Staphylococcus aureus (MRSA). A plasma trough concentration (Cmin) of20 mg/l should be used for severe infections. The aim of this study was to assess the efficacy, safety and use of Cmin20 mg/l on day 4-6 in patients with complicated MRSA infections.Blood samples were drawn from the 41 included patients just before TEIC administration between day 4 and 6. The patients were divided into three groups (group A:20 mg/l, group B: 10-20 mg/l and group C:10 mg/l) based on their Cmin on day 4-6.Differences in efficacy between the groups were significant, but differences in safety were not. The patients in group A required lower cumulative doses than those in either groups B or C.The optimal clinical efficacy and safety might be associated with TEIC Cmin on the fourth to sixth day.

We report a case of elevated plasma N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP)-like immunoreactive substance (IS) level after multiple doses of a recombinant human erythropoietin (rHuEPO), darbepoetin alfa, in a 50 year-old Japanese female who underwent kidney transplantation. Plasma AcSDKP-IS levels showed a gradual decline after kidney transplantation. However, plasma AcSDKP-IS level showed a rapid rise on day 70, and remained at high levels for a period of time and then declined sharply on day 119. After maintaining relatively constant levels from day 119, plasma AcSDKP level showed a rapid rise again on day 168, and declined again on day 238. The two abrupt increases and subsequent sharp decreases of plasma AcSDKP-IS levels correlated temporally with the initiation and discontinuation of the two course of darbepoetin alfa. Although further detailed studies are necessary, administration of darbepoetin alfa may cause a marked increase in plasma AcSDKP level.

A competitive transannular reaction occurred to give 7-methyltricyclo[3.3.1.03,7]nonan-3-ol (5) and 1-adamantanol (6) in the non-mediated electroreduction of 7-methylenebicyclo[3.3.1]nonan-3-one (1) in N,N-dimethylformamide. The apparent temperature dependence of the regioselectivity of the reaction may be attributed to the competitive operation of both kinetic and thermodynamic controls in the cyclization of the ketyl radical anion. The differences in the parameter of activation between the 5-exo- and 6-endocyclizations of 1•-, ΔΔH‡(5-exo - 6-endo) and ΔΔS‡(5-exo - 6-endo), were evaluated to be -3.1 kcal mol-1 and -11 cal mol-1 K-1, respectively. Semiempirical PM3 (RHF and UHF) calculations were also carried out to elucidate the reaction mechanism.

The regio- and stereoselectivity in the solvomercuriation and intramolecular alkoxymercuriation of several cyclic olefinic alcohols were examined. The regioselectivity is controlled mainly by electronic factors, while the stereoselectivity is controlled by steric factors as well as electronic ones. The optimised structure of the mercurinium ion intermediate suggests that the attractive interaction between the hydroxy group in the molecule and the mercurinium ion moiety affects the selectivity.