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We present the autopsy procedure and findings of severe coronavirus disease 2019 (COVID-19) pneumonia in an 85-year-old man. The patient required intubation immediately after admission for severe COVID-19 pneumonia. He had severe hypoxia that did not improve despite treatment with remdesivir, corticosteroids, and appropriate mechanical ventilation. On day 13, the patient developed sudden hypercapnia. His renal dysfunction subsequently worsened and became associated with hyperkalemia, and he passed away on day 15. An autopsy was performed to clarify the cause of the hypercapnic hypoxia. None of the medical personnel involved in the autopsy developed symptoms of COVID-19. Histologic examination showed various stages of diffuse alveolar damage throughout the lungs, with intra-alveolar hemorrhage in the upper zones. Microscopic examination of the kidneys revealed acute tubular necrosis. There was no significant systemic thrombosis. The autopsy findings were consistent with those typical of COVID-19.

A solenoid magnet using high-temperature superconductor tape was designed, fabricated, and tested for its suitability as beam scanner. After successful cooling tests, the magnet performance was studied using DC and AC currents. With DC current the magnet was successfully operated as mirror coils for a 2.45 GHz ECR ion source. The coils could be operated at 100 A and frequencies above 1 Hz. The installation of iron pole pieces and return yokes, enabled us to generate fields in excess of 2 T at 197 A DC. In AC mode this magnet can be operated in the ranges of 0.14–1.73 and 1.22–1.67 T at frequencies of 0.05 and 0.25 Hz, respectively.

In addition to heavy ion collisions (RHIC Design Manual, Brookhaven National Laboratory), RHIC will also collide intense beams of polarized protons (I. Alekseev, et al., Design Manual Polarized Proton Collider at RHIC, Brookhaven National Laboratory, 1998 [2]), reaching transverse energies where the protons scatter as beams of polarized quarks and gluons. The study of high energy polarized protons beams has been a long term part of the program at BNL with the development of polarized beams in the Booster and AGS rings for fixed target experiments. We have extended this capability to the RHIC machine. In this paper we describe the design and methods for achieving collisions of both longitudinal and transverse polarized protons in RHIC at energies up to s =500 GeV .

A K2500 superconducting ring cyclotron with 6-sectors is being constructed at RIKEN as an energy booster of the existing K540 ring cyclotron. The bending magnet for beam injection should be superconducting. Required fields are about 4 T and curvature of the coils is about 1.2 m. We developed test cells for the bending magnet. The results are very promising for the real bending magnet. In the paper the results of the test cells and the design of the real bending magnets are described.

For the Relativistic Heavy Ion Collider (RHIC) Spin Project, super-conducting helical dipole magnets are being constructed. These magnets will be used in `Siberian Snakes’ and `Spin Rotators', which manipulate spin direction of proton beams in RHIC. The dipole field in these magnets rotates 360° and is required to reach a magnetic field strength of more than 4.0 T. The bore radius of the coils and the magnetic length of the magnets are 50 and 2400 mm, respectively. To ascertain the performance of these magnets, which are built using a new “coil in a slot” technique, a half-length model has been fabricated and tested. The quench performance, field uniformity and rotation angle have been investigated. The measured values in the model magnet agreed well with field calculations. These results demonstrate the adequacy of the fabrication method adopted in the model magnet.

A six-sector superconducting ring cyclotron (SRC) is being constructed as a primary post accelerator of the existing accelerator complex for the RIKEN RI beam factory. In the SRC some superconducting magnets with high performances will be used for beam injection and extraction. Design study and R&D of them are described along with brief description of the outline of the systems.

A six-sector superconducting ring cyclotron (SRC) is being constructed as a primary post accelerator of the existing accelerator complex for the RI beam factory. Mechanical design of the main coil vessel of the SRC is described.

A sixty-five-year old female, with a past history of variant angina and asthma, collapsed after complaining of chest pain and regained spontaneous circulation by resuscitation. An electrocardiograph showed a QS pattern on the precordial leads and sonography revealed a takotsubo cardiomyopathy-like movement. During induced hypothermic therapy for protection of her brain and heart using a drug which dilated the coronary artery, she collapsed again with ventricular flatter for 40 min; however, she re-obtained return of spontaneous circulation and eventually regained consciousness. After correction of eosinophilia by steroids, the variant angina with life-threatening arrhythmia and asthma attack subsided. She was discharged and ambulatory 14 days after admission with normal motion of the cardiac wall. This is the first case of Kounis syndrome associated with takotsubo cardiomyopathy. The mechanism of the concurrent condition of this case is herein discussed.

Design, especially about the structure and quench stability, of the superconducting sector magnets for the RIKEN superconducting ring cyclotron is described. Special features of the sector magnets are the triangular shape superconducting coil, cold pole arrangement for supporting of the huge magnetic forces and the cryogenic stable coils. A full-scale superconducting model is now under construction as a prototype sector magnet.

Superconducting sector magnets are to be the main components of the superconducting ring cyclotron for the RIKEN RI beam factory. A full-scale prototype sector magnet is being developed and constructed. One of the critical points of the design is how to support the huge magnetic force exerted on the superconducting main coil. A cold-pole arrangement is adopted as the solution to this problem. Unbalanced magnetic forces were measured using 1/6-scaled-Cu/Fe magnets. A cryogenic stabilizing method is applied to make the main and trim coils quench-free. The whole structure, magnetic force and its support structure, quench protection, eddy current loss in the cold-pole, and helium cooling system are described.

Superconducting sector magnets are to be the main components of the superconducting ring cyclotron for the RIKEN RI beam factory. The sector magnet has superconducting main and trim coils. A cryogenic stabilization method is applied to both coils in order to make them quench-free. Both superconducting coils and their wires, design of stabilization, quench simulation, and measurement of the stabilized currents using small test coils are described.

Starting from 2′,3′,5′-tri-O-acetyl-2-iodoadenosine, 9-(β-D-arabinofuranosyl)-2-(p-n-butylanilino)adenine and its 2′(S)-azido counterparts were synthesized in seven steps. These exhibited only moderate growth-inhibitory effects against mouse leukemic P388 cells (IC50 = 13–24 μM), although 5′-triphosphate derivatives showed strong and selective inhibitory action on calf thymus DNA polymerase α, but not on β- and ϵ-polymerases from eukaryotes. This paper is dedicated to the memory of Professor Tsujiaki Hata

Nasal transport of thymidine (Thd) was investigated using in vivo nasal absorption technique in rats. Radio active thymidine was administered and Thd concentrations in the cerebrospinal fluid (CSF) and plasma was determined by liquid scintillation counter. Thd concentrations in the fractionated CSF which located close to the nasal cavity following intranasal (i.n.) administration were higher than that following intravenous (i.v.) administration, thus these observation suggests Thd, like other compounds, transported from nasal cavity to CSF directly following i.n. administration. The fractionated CSF concentration and the area under plasma concentration-time curve (AUC) following i.n. administration of Thd at 1.338∼267.6 mM were determined. The relationships between both the fractionated CSF concentration and AUC, and dose of Thd seemed dose-independent, though saturation in the transport of Thd from nasal membrane to CSF and systemic circulation was observed. The CSF concentrations and AUC following i.n. administration of Thd at a dose of 13.38 mM with 2'-deoxyuridine (dUrd, 25, 50 and 100 mM) or 2'-deoxyinosine (dIno, 50 mM) were also determined. Decrease in the concentration of CSF and AUC was observed, and the inhibitory effect of dUrd was dose-dependent. In the case of coadministration of Thd and dIno, dIno also showed an inhibitory effect for Thd transport, while the effect was less significant than that of dUrd. These results suggests that the possibility of the presence of Thd sensitive transport systems on nasal membrane in rats, and the systems, if exist, may be useful for the delivery of nucleoside analogues for central nervous system and systemic circulation via nasal membrane.

The effects of four kinds of 2'-deoxy-L-nucleoside 5'-triphosphates and L-ATP, which are enantiomers of natural D-dNTPs and D-ATP, on deoxycytidine kinase (dCK) partially purified from mouse leukemic P388 cells were investigated. Only L-dCTP did not act as a phosphate donor while other L-dNTPs and L-ATP showed 15-30% of the activity of the corresponding D-dNTP or D-ATP. L-dCTP inhibited dCK non-competitively with 2'-deoxycytidine (D-dCyd) and competitively with phosphate donor D-ATP. These inhibitory effects of L-dCTP on dCK were similar to the results of earlier studies using D-dCTP. Thus, L-dCTP was shown to be capable of serving as a feedback inhibitor for dCK instead of D-dCTP. Mouse dCK was also able to phosphorylate L-dCyd, as demonstrated in the case of human dCK. The present results suggest that the chirality of not only dCyd as the substrate but also nucleotides as the substrate or effector is not strictly discriminated by dCK.

Antileukemic activity of several analogues containing 2′-deoxy-4′-methylcytidine and its araC counterpart were evaluated against murine leukemic P388 cells in vitro and in vivo. Both compounds showed significant cytostatic activity (both IC50=0.4 μM) in vitro and the former compound administered intraperitoneally at a dose of 3 mg/kg/day × 5 showed high activity (T/C=175%) in vivo. The mechanism of action of these 5′-triphosphates on DNA polymerases in detail will be also described.

Novel assay method for antisense effect of oligodeoxynucleotides was designed. Antisense oligodeoxynucleotides (21mer) complementary to the region of the translation start site of c-jun and c-fos protooncogene inhibit apoptotic FM3A cell death induced by 5-fluoro-2'-deoxyuridine. Since antisense effect can be detected as survival of the cells, non-specific cytotoxicity of oligodeoxynucleotides can de neglected in this system. Though this inhibition effect is not directly related to a certain clinical target, the system is useful for the evaluation of novel designs in oligodeoxynucleotide molecules and/or antisense carriers. Phosphorothioate and 3'-terminal modified oligodeoxynucleotides were evaluated for their antisense effect in this system.

A 180 degree superconducting bending magnet for a synchrotron radiation source has been designed and constructed based on 3-dimensional electromagnetic analysis. The magnet is covered by iron shield to prevent the leakage of magnetic fields. The liquid helium consumption of the equipment is very small in the persistent current mode. The measurement results are in good agreement with the analysed ones. This magnet is under operation as a synchrotron radiation source at a beam energy of 600MeV. The radiation can be used for several applications, such as, X-ray lithography in semiconductor industries.

The inhibitory effect of acyclothymidine[AcyT, 5-methyl-1-(2'-hydroxyethoxymethyl) uracil], a potent pyrimidine nucleoside phosphorylase (PyNPase) inhibitor, on 5'-deoxy-5-fluorouridine (5'-DFUR) phosphorolysis in human and mouse tumor cell homogenates was measured. Competitive inhibition was observed in MKN-74 and Lewis lung carcinoma (LLC), whereas non-competitive inhibition was observed in HeLa. The strength of the inhibitory effect by AcyT showed the following pattern: HeLa < human normal intestine < mouse normal intestine < Colon 26 < LLC < MKN-74 < DLD-1. From the kinetic parameter obtained, we simulated the inhibitory effect of AcyT on 5'-DFUR phosphorolysis in tumor cells and the intestine. These data indicated that AcyT was more sensitive in normal mouse intestine than in Colon 26 and LLC, and that orally administered AcyT can reduce the intestinal toxicity of 5'-DFUR without reducing the antitumor effect in the mouse. The present finding may have an important implication for attempts to introduce AcyT, a potent PyNPase inhibitor, into the clinic.

Nasal absorption of 2', 3'-didehydro-3'-deoxythymidine (D4T) and its esters (5'-acetyl D4T : C2-D4T and 5'-hemisuccinyl D4T : Suc-D4T) was investigated in rats. Bioavailability of D4T following intranasal (i.n.) administration was 98.0%, and the elimination from plasma was as rapid as that following intravenous administration of D4T. There seemed to be complete and rapid absorption of D4T from the nasal cavity. The plasma concentration-time profile of D4T following i.n. administration of C2-D4T was almost the same as that after administration of D4T itself. This suggests that C2-D4T was rapidly absorbed from the nasal cavity, and that some amount of dosing C2-D4T was hydrolyzed to D4T before entering the systemic circulation. In contrast, Suc-D4T showed slower absorption in the i.n. administration, and the plasma D4T level was maintained for a long period.

The metabolism of testosterone (TS) and its 17-O-acyl derivatives (acyl = acetyl, benzoyl and hemi-succinoyl) was studied using radioactive compounds in organotypic coculture of human dermal fibroblasts (living skin equivalent, LSE). When TS was applied to the epidermal-side of LSE in a small volume of acetone solution, both 5α-reduced and 17-dehydrogenated metabolites were observed in the dermal-side culture solution, though the formation of the 5α-reduced metabolites, dihydrotestosterone (DHT) and dihydroandrosterone (DHA), depended greatly on the culture conditions. The metabolic activity of LSE for testosterone was higher than that of excised hairless-rat skin. The metabolism of ester prodrugs of TS in LSE was dependent on their physicochemical properties and susceptibility to enzymatic hydrolysis. Application of acetyl-TS and benzoyl-TS resulted in a high formation of the 17-dehydrogenated metabolite, androstenedione (ADO), though a very small amount of the prodrug was observed in the dermal side. Succinoyl-TS, a hydrophilic ester with very low susceptibility to hydrolysis, was quite resistant to both 5α-reduction and 17-dehydrogenation, and more than 90% of the radioactivity appearing on the dermal side was from the prodrug itself and from TS. The hydrophilic and enzymatically stable TS derivative may be a good candidate compound with which to administer TS transdermally.

We have constructed 180 degree superconducting bending magnets for compact electron storage rings and tests of magnetic field qualities of the magnets have been performed. Measured field qualities are; (1) high field homogeneity (normalized field errors are less than 1/spl times/10/sup -3/ over the electron beam aperture), (2) high field stability (the decay of the field is less than 0.1%/year) at persistent current mode of 3.5 T, (3) small gradient of coil axis (the averaged value is 0.5 mrad), and (4) small difference of the fields between two magnets (the difference is less than /spl plusmn/1/spl times/10/sup -3/). From the tests of field qualities, we confirm that the magnets have good performance for electron beam storage. An electron beam of 600 MeV can be stored. >

The high performance of the superconducting joint of NbTi multifilament superconducting wires is achieved by using a sleeve that is reinforced and is tapered at the inner corner of the sleeve. The critical current of the joint is 1, 800A at 5T. This value is equal to the critical current of the superconducting wire. The superconducting joints are adopted as a superconducting magnet for synchrotron radiation. The critical currents of the joints between the wires for the coils are over 1, 100A at 5T for all joints, and those between the wires for the coil and persistent current switch exceed the quench current of the persistent current switch. By testing the superconducting joint using two filaments, it is suggested that the superconducting current passes at the joint when the interface of the NbTi filaments are slipped and deformed.

This study examined the inhibitory effect of acyclopyrimidinenucleosides on 5'-deoxy-5-fluorouridine (5'-DFUR) phosphorolysis in intestinal tissue derived from rabbit, rat, mouse, and human. 5-Bromoacyclouridine, 5-fluoroacyclouridine, acyclouridine, and 5-nitroacyclouridine showed little or only moderate effect, but acyclothymidine [5-methyl-1-(2'-hydroxyethoxymethyl)uracil] showed strong inhibitory effect on 5'-DFUR phosphorolysis in intestinal tissue homogenates derived from human. In the absence of inhibitor (acyclothymidine), the Vmax of 5'-DFUR phosphorolysis was 2.66 mumol/min and the Km was 0.57 mM in human intestinal homogenates. The Vmax was unaltered by increased inhibitor concentration. The maximal inhibitory effect of acyclothymidine on 5'-DFUR phosphorolysis in rat homogenates was over 90%. The Ki/Km was 0.63 in human, 2.14 in rabbit, 1.09 x 10(-2) in rat, and 1.71 x 10(-2) in mouse. These data show that acyclothymidine is a competitive inhibitor of 5'-DFUR phosphorolysis, and that it can inhibit not only uridine phosphorylase but also thymidine phosphorylase.

Novel stabilizing method for unmodified oligodeoxynucleotides (ODNs) has been investigated. Chemically modified ODNs, which carry complementary sequences of unmodified antisense ODN, can form a double-stranded complex with the ability to stabilize the unmodified oligomer. The modifications were made on phosphodiester back-bone (phosphorothioate, SO), thymine base (5-phenylethyl substitution), 5'-terminal(introduction of poly(ethylene glycol)). To determine the potential of this method, the in vitro stability in human plasma and in vivo retention in mouse after iv injection of the hemi-modified double-stranded ODNs were evaluated. Dissociation of unmodified antisensc ODN from the hemi modified double-strand and reconstitution of the double-strand with an unmodified sense ODN were also recognized.

Cisplatin is an anticancer drug with broad-spec-trum, that is especially effective against genitourinary tumors. But it shows serious toxicity in kidney and gastrointestinal tract in clinical use. In order to decrease nephrotoxicity of cisplatin, several approaches have been done, such as : (1) Change of administration route and combination therapy with other drugs ; (2) Development of new derivatives : (3) Novel dosage form (design of DDS forms) ; etc. In this paper, preparation of multiple-phase emulsion containing cisplatin and its combination therapy in mouse will be presented. The physicochemical properties and nephrotoxicity of the emulsion were also investigated.

To evaluate the response of patients with chronic atrial fibrillation (AF) to exercise, 79 male patients (mean age 64 +/- 1 years) with AF underwent resting two-dimensional and M-mode echocardiography and symptom-limited treadmill testing with ventilatory gas exchange analysis. Patients were classified by underlying disease into five subgroups: no underlying disease (LONE: n = 17), hypertension (HT: n = 11), ischemic heart disease (n = 13), cardiomyopathy or history of congestive heart failure (CHF: n = 26), and valvular disease (n = 12). A higher maximal heart rate than expected for age was observed (175 vs 157 beats/min), which was most notable in the LONE and HT subgroups. Maximal oxygen uptake (VO2 max) was lower than expected for age in all groups. Patients with CHF had a lower resting ejection fraction than all other patients (p < 0.001), a lower VO2 max, and a lower maximal heart rate than LONE and HT patients (p < 0.001). Stepwise regression analysis demonstrated that echocardiographic measurements at rest were poor predictors of VO2 max and VO2 at the ventilatory threshold. Among clinical, morphologic, and exercise variables, maximal systolic blood pressure accounted for the greatest variance in exercise capacity, but it explained only 35%. In patients with AF the higher than predicted maximal heart rates may be a compensatory mechanism for maintaining exercise capacity after the loss of normal atrial function. However, even in the absence of underlying disease, it does not appear to compensate fully for a compromised exercise capacity.(ABSTRACT TRUNCATED AT 250 WORDS)

A 180 degrees superconducting magnet has been constructed for a synchrotron radiation source. The authors describe the superconducting magnet design and some component test results for the compact synchrotron radiation source. The magnetic field at the electron orbit is 4.5 T. The bending radius is 0.593 m. The magnet has several features such as low liquid helium consumption ratio, persistent current operation, high homogeneous magnetic fields, and leakage flux shielding by the iron core surrounding the cryostat. Component tests of persistent current switches of 15 Omega and 3 Omega and a superconducting joint test have been performed. >

Acyclothymidine (AcyT, 5-methyl-1-(2'-hydroxyethoxymethyl)uracil), a potent inhibitor of pyrimidine nucleoside phosphorylase (PyNPase), was co-administered with 5'-deoxy-5-fluorouridine (5'-DFUR), a PyNPase activating prodrug of 5-fluorouracil (5-FU), to rabbits. The absorption and pharmacokinetic parameters of 5'-DFUR and its active metabolite 5-FU, after administration of 5'-DFUR in combination with AcyT, were evaluated in the animals. Animals were given an oral or intravenous administration of 5'-DFUR (50 mg/kg) in combination with an equimolar dose of AcyT (40 mg/kg). The half-lives (t1/2) of 5'-DFUR and 5-FU in plasma were 16.8 and 11.5 min, respectively. AUC (area under the plasma concentration-time curve) of 5'-DFUR and 5-FU following the oral administration of 5'-DFUR (50 mg/kg) was 1710 and 24.3 micrograms.min/ml, respectively. After the oral co-administration of 5'-DFUR and AcyT (at a molar ratio of 1:1), the AUC values for 5'-DFUR and 5-FU increased to 2680 and to 121.1 micrograms.min/ml, respectively. However, this combination had little effect on the t1/2 of 5'-DFUR.

Six ester prodrugs of 2’,3’-didehydro-3’-deoxythymidine (D4T) were synthesized, and their physicochemical properties were evaluated. Marked differences were observed. All of the prodrugs were chemically stable within the pH range 2-7. Hydrolysis of these esters was observed in all cases for four rat enzyme systems (plasma, liver, duodenum, and kidney), with D4T being regenerated. D4T or the prodrug was administered orally to rats, and the plasma concentrations of D4T and a corresponding prodrug were measured. The half-life of D4T after intravenous administration was 35.9 min. The half-life calculated from the terminal phase and the maximum concentration in plasma following oral administration of D4T were 35.9 min and 48.4 μM, respectively. After oral prodrug administration (with water or olive oil as a solvent), though none of the prodrugs was detected in plasma except for 5’-hemisuccinyl D4T and 5’-hemiglutaryl D4T with olive oil as a solvent, retention time of plasma D4T concentration was extended and the elevated D4T concentration in plasma decreased.

While there is still much debate in the literature regarding the specific MET levels at which there are differences in survival, the following points have become clear with the growing body of reports in the literature. Exercise capacity seems to be an independent predictor of mortality, and when it is combined with other clinical, exercise, or angiographic data, it becomes very powerful in this regard. This relates to both overall mortality and to that from cardiovascular disease. There is still a need for the establishment of mortality data related to MET levels adjusted for age and activity status. A low exercise capacity of less than 6 METs indicates a higher mortality group, probably regardless of the underlying extent of coronary disease or left ventricular function. Analysis of the CASS data has indicated that these patients benefit from coronary artery bypass surgery with respect to survival. An exercise capacity of greater than 10 METs designates an excellent survival group, again despite the extent of coronary artery disease or left ventricular function. If 10 METs truly exerts a “protective effect” that obviates any survival benefit from coronary artery bypass surgery, this has enormous implications for cost containment and medical care. It is nonetheless important to remember that this level of exercise capacity does not imply the absence of either coronary disease or triple-vessel coronary disease. Exercise capacity is related to more than just cardiovascular fitness and integrity. It is dependent upon a combination of other physiologic components as well, including pulmonary function, health status of other organ systems, nitrogen balance, nutritional status, medications, orthopedic limitations, and others. Nonetheless, exercise capacity has been established as a powerful predictor of survival and deserves equal emphasis with that of ST segment interpretation in the evaluation of exercise test responses.

Rectal absorption of Zidovudine (3′-azido-3′-deoxythymidine, AZT) was investigated in order to determine the feasibility of developing AZT suppositories. Although the small intestine shows a higher absorption rate than the stomach and large intestine in rats, considerable absorption of AZT was observed from the lower large intestine (8 cm above the anus). A sustained-release suppository was prepared by direct compression of hydroxypropyl cellulose (HPC) with AZT. During in vivo experiments in rats, this suppository (10 mg or 37.5 μmol AZT/kg) maintained constant plasma levels above 1 μM for more than 6 h. The results suggest that suppositories can prove useful as an alternative dosage form of AZT administration.

In vitro permeation of zidovudine (azidothymidine, AZT), a potent antiviral agent acting on acquired immunodeficiency syndrome, through a rat skin from isopropyi myristate (IPM) solution was significantly enhanced by the addition of N -methyl-2-pyrrolidone (MP) as a penetration enhancer. When 50 μl of the IPM solution containing 12 mg/ml of AZT and 20% of MP was applied on rat abdominal skin, about 1 μM of the plasma concentration of AZT was observed at 1–2 h after the application, though the concentration decreased rapidly and was undetectable at 6 h. Though 34% of the applied AZT remained in the IPM solution on the rat skin at 10 h, MP was not detected. In order to maintain a constant level of MP in the solution, ethylene-vinyl acetate copolymer membrane was used for its controlled release in the transdermal delivery system of AZT. A considerable plasma concentration of AZT could be maintained for 10 h after application of this MP release-controlled transdermal system.

The plasma concentration of atrial natriuretic peptide (pANP) was investigated at fixed times during 48 h following the onset of an initial attack of mild acute myocardial infarction (AMI) in 11 patients. Six hours after onset, the mean pANP was elevated, but 6 h later pANP had returned to the baseline level. Forty-eight hours after onset the mean pANP increased again. Thus, the curve of the time course of pANP consisted of 2 peaks separated by a dip. Six hours after onset, systemic hemodynamics and humoral factors were measured in 27 patients. At 48 h they were measured in 14 patients. The late elevation of pANP correlated with mean pulmonary arterial wedge pressure (r = 0.63, n = 14, p less than 0.05), while the early elevation of pANP did not (r = 0.31, n = 27, n.s.). The early elevation of pANP correlated with plasma concentrations of both noradrenaline (r = 0.55, n = 27, p less than 0.01) and creatine phosphokinase (r = 0.54, n = 27, p less than 0.01). In addition, noradrenaline levels positively correlated with mean pulmonary arterial wedge pressure (r = 0.38, n = 27, p less than 0.05). The cause of the early elevation of pANP in AMI is unclear, but it is suggested that injury to myocardium and activated sympathetic nerve activity may be responsible in part.

A cationic polymer, chitosan (CHI) is anticipated to be a potent component in several dosage forms involving transdermal drug delivery systems (TDDS). Solubility of CHI and its gelation in alcoholic aqueous solutions were investigated. Elastivity of the gel containing 3% CHI, 2% oxalic acid, as a crosslinking agent, and ethanol (EtOH) and/or 1, 3-butyleneglycol (BG) was also evaluated by a rheometer. The CHI solubility in the gel was dependent on the solubility parameters of the mixed solvent. High elasticity was observed in the CHI gel when an alcoholic solvent giving low solubility of CHI was used. A good correlation was found between the gel elasticity and the relative gel concentration (=concentraiton of CHI in gel/sulubility of CHI in gel). Since the polarity of mixed solvents also affected the thermodynamic activities of drugs and penetration enhancers, optimization of the vehicle composition for TDDS is important to assure suitable drug efficacy.

In an attempt to improve the skin delivery characteristics of Zidovudine (AZT, azidothymidine), five aliphatic esters (acetate, butyrate, hexanoate, octanoate, and decanoate) of AZT were synthesized and assessed as prodrugs of AZT. While the water solubility of the esters is lower than that of AZT, the solubilities in isopropylmyristate (IPM) and the partition coefficients (n-octanol: buffer) are higher. Susceptibility to enzymatic hydrolysis in the rat skin homogenate increases as the acyl chain of the ester is lengthened. Among the esters, acetate (C2-AZT) and hexanoate (C6-AZT) showed 2.4- and 4.8-fold enhanced permeation in human skin from an apolar vehicle (IPM) relative to application of AZT itself, respectively.

A primary cardiac malignant tumor is very rare; its prevalence is only 0.002-0.28%. Among most malignant tumors, angiosarcoma, leiomyosarcoma, and mesothelioma occupy the majority. A cardiac osteosarcoma is extremely rare: to our knowledge, only 36 cases have been reported worldwide. We present a 22-year-old case featuring severe congestive heart failure. Hemodynamically the tumor led to significant obstruction of the mitral valve. The patient underwent an emergency resection operation, but multiple metastases occurred. Though the characteristics still remain unclear because of the low prevalence, it is very important that these tumors be distinguished from benign tumors because of early resection operation.

Siberian snakes that consist of four helical dipole magnets will be installed in the Relativistic Heavy Ion Collider (RHIC) to preserve the polarization of the proton beam. To promote this project we are collaborating with Brookhaven National Laboratory (BNL) in studying helical magnet designs. At present, two types of helical magnets are being developed. One is being designed by the BNL magnet group, and the other by Advanced Magnet Technology (AML), Inc. These magnets use the same superconducting cable but have different shapes especially in the end regions. We are evaluating the performance of both magnet designs using the three dimensional (3D) magnetic field analysis code TOSCA. In particular, saturation effect, field strength, multipole component and magnet quenching features will be discussed.

An "RI beam factory" has started to be contracted as the next project of the RIKEN Accelerator Research Facility (RARF). The "RI beam factory" aims at production and acceleration of radioactive isotope beams covering the whole mass region. It requires the energy of ion beam to be higher than 100 MeV/nucleon. To accomplish this requirement, the following two ring cyclotrons have been adopted as post-accelerators of the existing RIKEN ring cyclotron (RRC): a 4-sector ring cyclotron for the first stage (IRC) and a 6-sector superconducting ring cyclotron for the second stage (SRC). The sector magnet of the SRC has to be flexible enough to generate isochronous fields in a wide range of energies and for various q/A values. In this report we describe the isochronous field generation and orbit analysis of the SRC.

A 6 T superconducting solenoid has been constructed to focus heavy ion beams on the production target of radio isotope beams. The design field on axis is 6.2 T with an average current density of 9,600 A/cm/sup 2/. The overall coil length is 1.1 meter, and the coil is divided into three equal-length sections to ease winding and to reduce IR drop through diode connection. A main feature of the system is that the solenoid is conductively cooled by a cryocooler directly attached onto the center coil without liquid helium involved. The solenoid was successfully trained to 6.2 T, and its optical properties were tested in the beamline at RIKEN. The design features and the test results are presented.

Cytarabine (cytosine arabinoside, Ara-C) is an effective chemotherapeutic agent for the treatment of acute myelogenous leukaemia and lymphocytic leukaemias. As cytarabine is an S-phase-specific drug, prolonged exposure of cells to cytotoxic concentrations is critical to achieve maximum cytotoxic activity. However, the activity of cytarabine is decreased by its rapid deamination to the biologically inactive metabolite uracil arabinoside. This rapid deamination is the reason for the ongoing search for effective formulations and derivatives of cytarabine that cannot be deaminated and exhibit better pharmacokinetic parameters. Protection of cytarabine from fast degradation and elimination has been investigated by encapsulating the drug into pharmaceutically acceptable carriers. Cytarabine derivatives have shown promise in vitro and in animal models. For example, ancitabine (cyclocytidine), enocitabine and cytarabine ocfosfate have been used clinically in Japan. Cytarabine encapsulated into multivesicular liposomes has been approved in several countries for the intrathecal treatment of lymphomatous meningitis. Although many compounds have been investigated, few cytarabine derivatives are currently available for clinical use. Further research is needed to improve the efficacy of cytarabine against haematological and solid tumours.

One of the most important causes of anticancer treatment failure is the development of multidrug resistance (MDR). The main characteristics of tumor cells displaying the MDR phenomena are cross-resistance to structurally unrelated cytotoxic drugs having different mechanisms of action and the overexpression of the MDR1 gene, which encodes a transmembrane glycoprotein named P-glycoprotein (P-gp). This study evaluated whether bromocriptine, a D2 dopaminergic receptor agonist, influenced anticancer drug cytotoxicity and P-gp activity in a P-gp-expressing cell line compared to a non-expressing subline. The K(i) values for P-gp of cyclosporine and verapamil were 1.09 and 540 microM, respectively, and that of bromocriptine was 6.52 microM in a calcein-AM efflux assay using porcine kidney epithelial LLC-PK1 and L-MDR1 cells, overexpressing human P-gp. Bromocriptine at 10 microM reduced the IC50 of doxorubicin (DXR) in K562-DXR from 9000 to 270 ng/ml and that of vincristine (VCR) in K562-VCR from 700 to 0.30 ng/ml, whereas the IC50 values of DXR and VCR in the K562 subline were only marginally affected by these drugs. Bromocriptine restored the anticancer effect of DXR, VCR, vinblastine, vinorelbine and etoposide on MDR-tumor cells overexpressing P-gp. These observations suggest that bromocriptine has the potential to reverse tumor MDR involving the efflux protein P-gp in the clinical situation.

Five ester prodrugs of 2'3'-dideoxyinosine (DDI) were synthesized for the purpose of improving oral bioavailability. The prodrugs, acetate (C2-DDI), octanoate (C8-DDI), stearate (C18-DDI), benzoate (Bz-DDI), and hemisuccinate (Suc-DDI) were proved to quantitatively regenerate their parent drug by enzymatic hydrolysis. Though the chemical stability of the prodrugs under acidic conditions was not improved, their solubility in water was significantly decreased by esterification, except for Suc-DDI. Bioavailability was evaluated by oral administration to rats. Two hydrophobic prodrugs (C8-DDI and Bz-DDI) showed higher absolute bioavailability (23.5% and 31.0%, respectively) than did DDI (15.2%), though that of C2-DDI (11.5%) and Suc-DDI (4.5%) was poor.