Optically active antifungal azoles. XII. Synthesis and antifungal activity of the water-soluble prodrugs of 1-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(1H-1-tetrazolyl)phenyl]-2-imidazolidinone.

1-[(1R,2R)-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(1H-1-tetrazolyl)phenyl]-2-imidazolidinone (1: TAK-456) was selected as a candidate for clinical trials, but since its water-solubility was insufficient for an injectable formulation, the quaternary triazolium salts 2 were designed as water-soluble prodrugs. Among the prodrugs prepared, 4-acetoxymethyl-1-[(2R,3R)-2-(2,4-difluorophenyl)-2-hydroxy-3-[2-oxo-3-[4-(1H-1-terazolyl)phenyl]-1-imidazolidinyl]butyl]-1H-1,2,4-triazolium chloride (2a: TAK-457) was selected as an injectable candidate for clinical trials based on the results of evaluations on solubility, stability, hemolytic effect and in vivo antifungal activities.

Oxythiamine hexafluorophosphate monohydrate, a thiamine antagonist with the same conformation as thiamine.

In the title compound, 3-[(3,4-dihydro-2-methyl-4-oxopyrimidin-5-yl) methyl]-5-(2-hydroxyethyl)-4-methylthiazolium hexafluorophosphate monohydrate,C(12)H(16)N(3)O(2)S(+).PF(6)(-).H(2)O, oxythiamine is a monovalent cation with a neutral oxopyrimidine ring. The molecule assumes the F conformation, which is a common form for thiamine but which is substantially different from the unusual V conformation found in the chloride and hydrochloride salts of oxythiamine. The anion-bridging interaction, C-H...anion...pyrimidine, is emphasized as being important for stabilization of the F conformation.

Disposition of the new antirheumatic agent ethyl 4-(3,4-dimethoxyphenyl)- 6,7-dimethoxy-2-(1,2,4-triazol-1-ylmethyl)quinoline-3-carboxylate (TAK-603) in rats and dogs.

The disposition of ethyl 4-(3,4-dimethoxyphenyl)-6,7-dimethoxy-2-(1,2,4- triazol-1-ylmethyl) quinoline-3-carboxylate (CAS 158146-85-1, TAK-603) after single oral dosing of 14C-labeled TAK-603 ([14C]TAK-603) at 10 mg/kg to rats and dogs was studied. In rats, the concentration of unchanged drug in plasma reached a peak (Cmax, 0.31 microgram/ml) 2 h (Tmax) after dosing of TAK-603 and declined biphasically with apparent half-lives (t 1/2 alpha, t 1/2 beta) of 1.5 and 3.6 h. In dogs, Tmax, Cmax, T 1/2 alpha, and t 1/2 beta were 1.7 h, 0.36 microgram/ml, 1.2, and 10.8 h, respectively. [14C]TAK-603 dosed orally was absorbed quantitatively in rats, while the extent of absorption in dogs was 54%. The bioavailability of TAK-603 was 53% and 42% in rats and dogs, respectively. In rats, 14C was distributed widely in various tissues, with relatively high concentrations in the liver, adrenal gland, and gut. The elimination of 14C from the thyroid was slower than that from other tissues. Unchanged TAK-603 and its pharmacologically active metabolite, M-I, which has the same potency as TAK-603, were distributed in articular soft tissues and synovial fluids, as target tissues, in rats and dogs, respectively. After oral administration of [14C]TAK-603, most of the 14C dosed was excreted within 48 h in rats and within 96 h in dogs. In both animals, a greater amount of the 14C dosed was excreted in feces than in urine. In biliary duct cannulated rats given [14C]TAK-603 intraduodenally, 69% of the dose was excreted in bile, and biliary 14C in part underwent enterohepatic circulation.

Potent NK1 receptor antagonists: synthesis and antagonistic activity of various heterocycles with an N-[3,5-bis(trifluoromethyl)benzyl]-N-methylcarbamoyl substituent.

Various N-[3,5-bis(trifluoromethyl)benzyl]-N-methylcarbamoyl heterocycles (1, 2 and 3) modified at rings A and B in the isoquinolone (1a) and pyrido[3,4-b]pyridine (2a) nuclei were prepared and evaluated for NK1 receptor antagonistic activities. The structure-activity relationship studies on this series, along with conformational analysis, showed that (i) for ring A, 6-membered heterocycles are preferable to 5-membered heterocycles (a ca. 300-fold difference in potency), (ii) the 6-membered ring seems to function as an anchor by fixing the pendant phenyl group in a desirable orientation for receptor binding, and (iii) since compounds with aromatic rings (2) and those with aliphatic rings (3) as ring B both show good potency, this ring does not seem to be essential for receptor recognition. Among the compounds synthesized, the tetrahydropyridine derivatives 3a, 3b and 3f exhibited excellent inhibitory effects both in vitro and in vivo, with potent activity upon oral administration (ED50 = 0.20-0.27 mg/kg) (capsaicin-induced plasma extravasation in guinea pig trachea).

Studies on the metabolism of the new antidiabetic agent pioglitazone. Identification of metabolites in rats and dogs.

Metabolic studies of pioglitazone (CAS 105355-27-9, AD-4833), a new agent, in rats and dogs using liquid chromatography/tandem mass spectrometry and 1H-nuclear magnetic resonance led to characterization of the following metabolites; the parent compound, (+/-)-5-(p-hydroxybenzyl)-2-4-thiazolidinedione (M-I), (+/-)-5-[p-[2-(5-ethyl-2-pyridyl)-2-hydroxyethoxy]benzyl] -2,4-thiazolidinedione (M-II), (+/-)- 5-[p-[2-(5-acetyl-2-pyridyl)ethoxy]benzyl]2,4-thiazolidinedione (M-III), (+/-)-5-[p-[2-[5-(1-hydroxyethyl)-2- pyridyl]ethoxy]benzyl]-2,4-thiazolidinedione (M-IV), (+/-)-5-[p-[2-(5- carboxymethyl-2-pyridyl)ethoxy]- benzyl]-2,4-thiazolidinedione (M-V), and (+/-)-5-[p-[2-(5-carboxy-2- pyridyl)ethoxy]benzyl]-2,4-thiazolidinedione (M-VI). Pioglitazone is considered to be metabolized by cleavage of aliphatic C-O bond to lead to M-I, hydroxylation of aliphatic methylene groups to form M-II and M-IV, oxidation of M-IV to give M-III, oxidation of the ethyl group to form M-V, and oxidative loss of the terminal carbon to lead to M-IV. Furthermore, part of metabolites exist as conjugated form. Among the conjugates, M-IV conjugated with sulfuric acid and M-V conjugated with taurine were identified.

Disposition of the new antidiabetic agent pioglitazone in rats, dogs, and monkeys.

The disposition of pioglitazone (CAS 105355-27-9, AD-4833) was studied after oral administration to rats, dogs, and monkeys using 14C-labeled drug. After oral dosing, pioglitazone was well absorbed from the gastrointestinal tract at an extent of 96, 95, and 90% in rats, dogs, and monkeys, respectively. In rats, the concentration of pioglitazone in plasma reached a peak (Cmax 0.71 micrograms/ml) at 4 h (tmax) after dosing and declined with a half-life (t1/2) of 2.6 h. In dogs, tmax, Cmax and t1/2 were 0.5 h 0.32 micrograms/ml and 2.1 h, and those for monkeys were 4.3 h, 0.43 micrograms/ml and 5.3 h, respectively. The drug was metabolized mainly to M-I to M-VI including the pharmacologically active metabolites (M-II, III and IV). The pharmacologically active compounds (total of the unchanged compound and the above three active metabolites) accounted for 87, 71, and 73% of the radioactivity in plasma of rats, dogs and monkeys, respectively. The radioactivity was widely distributed in tissues after oral administration to rats, and decreased to the very low concentration within 24 to 72 h after dosing. Radioactivity dose was almost completely excreted in urine and feces.

Pharmacological features of non-adrenergic non-cholinergic (NANC) relaxation induced by electrical vagal stimulation in isolated mouse stomach.

The non-adrenergic non-cholinergic (NANC) relaxatory response in mouse isolated whole stomach was investigated by electrical vagal stimulation (EVS) to clarify whether nitric oxide (NO) mediates vagal NANC transmission. The stomach was mounted in an organ bath, and the intragastric pressure was measured. Dual electrodes were placed on the esophagus. In the presence of atropine, propranolol and phentolamine, EVS induced a marked gastric relaxation. The response was frequency-dependent, and reproducible by repeated stimulation. The response was blocked by hexamethonium and NG-nitro-L-arginine (L-NNA), a NO synthase inhibitor, and significantly depressed by methylene blue, a soluble guanylate cyclase inhibitor, but not by hemoglobin, a radical trapping agent. The inhibitory effect of L-NNA was reversed by L-arginine, a substrate for NO synthase, but not by D-arginine. Exogenous NO caused a relaxation that was inhibited by hemoglobin and methylene blue, but not by L-NNA. The electrical field stimulation also elicited a gastric relaxation that was inhibited by L-NNA and methylene blue, but not by hexamethonium and hemoglobin. These results suggest that the inhibitory NANC response to EVS in the mouse stomach is largely mediated by release of NO, and it is exclusively due to stimulation of vagal preganglionic neurons.

Novel, potent, and orally active substance P antagonists: synthesis and antagonist activity of N-benzylcarboxamide derivatives of pyrido[3,4-b]pyridine.

A series of 4-phenylisoquinolone derivatives were synthesized and evaluated for NK1 (substance P) antagonist activity. Highly potent antagonists, 4-phenyl-3-isoquinolone-N-benzylcarboxamides (11), were discovered from the structure-activity relationship studies on the isoquinolone-urea lead 1a. Optimization of the activity in this series resulted in the development of 5-phenyl-6-pyrido[3,4-b]pyridine-N-benzylcarboxamides (30) which are highly potent orally active NK1 antagonists. Among the compounds synthesized, N-[3,5-bis(trifluoromethyl)benzyl]-7,8-dihydro-N,7-dimethyl-8-oxo-5- (substituted phenyl)-6-pyrido[3,4-b]pyridinecarboxamides (30a,f,g) showed excellent antagonist activities with IC50 values (in vitro inhibition of [125I]-BH-SP binding in human IM-9 cells) of 0.21-0.34 nM and ED50 values (in vivo inhibition of capsaicin-induced plasma extravasation in guinea-pig trachea, iv) of 0.017-0.030 mg/kg. These compounds exhibited significantly potent activity upon oral administration with ED50 values of 0.068-0.17 mg/kg. Conformational studies on 30g indicated that the two stable conformers of 30g are quite similar to those of CP-99,994.

Beneficial effect of CV-4151 (Isbogrel), a thromboxane A2 synthase inhibitor, in a rat middle cerebral artery thrombosis model.

Effects of thromboxane A2 (TXA2) synthase inhibitors (CV-4151 and ozagrel) on cerebral thrombosis and cerebral damage were examined in a rat middle cerebral artery (MCA) thrombosis model and their potencies were compared with the conventional antithrombotic agents, aspirin and ticlopidine. CV-4151 significantly inhibited photochemically induced MCA thrombosis by oral (1 and 10 mg/kg) and intravenous (1 mg/kg) administration. Ozagrel (10 mg/kg, p.o.) also inhibited it. The potency of CV-4151 was about 10 times stronger than that of ozagrel, being comparable with the inhibition of blood TXA2 generation. Aspirin (100 mg/kg, p.o.) and ticlopidine (300 mg/kg, p.o.) showed an inhibitory tendency on MCA thrombosis. Twenty-four h after photochemical stimulation, cerebral edema and cerebral infarction were observed, and the lactate content in the brain increased. CV-4151 and ozagrel prevented this edema, and the antiedema effects of the drugs were correlated with the antithrombotic effect on thrombotic MCA occlusion. CV-4151 (10 mg/kg, p.o.), furthermore, significantly reduced the infarct size and inhibited the increase in lactate content. These results indicate that TXA2 synthase inhibitors inhibit cerebral damage by inhibition of MCA occlusion with thrombosis, probably resulting from the inhibition of TXA2 generation, and their effects are superior to those of aspirin and ticlopidine. TXA2 might play an important role in cerebral damage in the MCA thrombosis model. CV-4151 might be a useful drug for the treatment of cerebral thrombosis and for the prevention of cerebral infarction.

Free radicals and brain damage due to transient middle cerebral artery occlusion: the effect of dimethylthiourea.

The objective of this study was to assess whether dimethylthiourea (DMTU), an established free radical scavenger, ameliorates ischaemic damage due to 2-3 h of transient middle cerebral artery (MCA) occlusion, induced by an intraluminal filament. A major point addressed was whether DMTU given before MCA occlusion only delayed the "maturation" of the damage, or if it had a lasting effect on infarct size. The end point was morphological, and either encompassed triphenyltetrazolium chloride (TTC) staining of tissue slices after 24 h or 48 h of recovery, or histopathological assessment of infarct size after 7 days of recovery. In a preliminary series of experiments, rats were subjected to 3 h of MCA occlusion, and infarct volume was assessed by TTC staining after 24 h of recovery. DMTU in a dose of 750 mg/kg reduced infarct volume by more than 50%. However, due to a high mortality rate, that protocol was not subsequently pursued. When the ischaemia duration was reduced to 2 h and the DMTU dose to 400 mg/kg, a similar amelioration of the tissue damage was observed. However, since DMTU reduced a spontaneous rise in body temperature to 39.0-39.5 degrees C, DMTU-treated animals in the main series of experiments with 24 and 48 h of recovery were treated so that they had the same temperature rise as the saline controls. Under such constant temperature conditions, the effect of DMTU at 24 h of recovery was borderline (P = 0.052) and at 48 h it was nil. The lack of a lasting effect of DMTU was supported by the findings on evaluation of infarct area after 7 days of recovery. The results raise the important question whether DMTU, and perhaps other free radical scavengers, delay rather than ameliorate the ischaemic lesion developing after transient MCA occlusion.

Upregulation of fibroblast growth factor-receptor messenger RNA expression in rat brain following transient forebrain ischemia.

Recently, we demonstrated that transient forebrain ischemia in rats leads to an early and strong induction of basic fibroblast growth factor (bFGF) synthesis in astrocytes in the injured brain regions. In this study, in order to clarify the targets of such raised endogenous bFGF levels, the messenger RNA (mRNA) expression of its receptors (flg and bek) in the hippocampus following transient forebrain ischemia induced by four-vessel occlusion for 20 min was investigated using an in situ hybridization technique. Transient forebrain ischemia induced an increase in the number of flg mRNA-positive cells from an early stage (24 h after ischemia) in the hippocampal CA1 subfield where delayed neuronal death occurred later (48-72 h after ischemia). This increase became more marked with the progression of neuronal death and was still evident in the same area 30 days later. The time course of the appearance and distribution pattern of flg mRNA-positive cells in the CA1 subfield were quite similar to those of bFGF mRNA-positive cells. On the other hand, in situ hybridization for bek mRNA showed only slight and transient (observed 72 h and 5 days after ischemia) increases in the number of mRNA-positive cells in the CA1 subfield following ischemia. The use of in situ hybridization and glial fibrillary acidic protein immunohistochemistry in combination demonstrated that the cells in the CA1 subfield that exhibited ischemia-induced flg or bek mRNA expression were astrocytes. These data indicate that transient forebrain ischemia induces upregulation of fibroblast growth factor-receptor expression, accompanied by increased bFGF expression in astrocytes, and suggest that the increased astrocytic bFGF levels in injured brain regions act on the astrocytes via autocrine systems and are involved in the development and maintenance of astrocytosis.

Does ischemia with reperfusion lead to oxidative damage to proteins in the brain?

Recent results suggest that even relatively brief periods of ischemia in gerbils (10 min) lead to oxidative damage to brain proteins, reflected in an increased carbonyl content in the soluble protein fraction and a decreased glutamine synthetase (GS) activity. Since we failed to reproduce these findings in rats subjected to 15 min of transient ischemia, we explored whether oxidative damage to proteins could be observed after longer ischemic periods. To that end, one middle cerebral artery was occluded in rats for either 1 or 3 h, with recirculation periods of 0 min, 15 min, 1 h, and 6 h. Protein carbonyl content and GS activity were determined in focal and perifocal tissues and compared with values obtained in the same areas on the contralateral side. Ischemia, particularly of 3-h duration, followed by various reperfusion periods was accompanied by a significant (16-35%) decrease in the concentration of proteins of the soluble protein fraction. However, in no group was there an increased carbonyl content of the remaining proteins in this fraction. When expressed per milligram of protein, GS activity remained unchanged or rose somewhat. An inconsistent (and moderate) decrease in GS activity was present only if GS activity was expressed per milligram of wet tissue. The present findings, which fail to document oxidative damage to proteins following focal ischemia of 1- or 3-h duration, are thus radically different from those obtained in gerbils. The results suggest that appreciable species differences exist and raise the question of whether free radical-mediated oxidation of proteins is an invariable component of ischemic brain damage.

In vitro closing behavior of the St. Jude Medical heart valve in the pulmonary position. Valve incompetence originating in the prosthesis itself.

We examined the in vitro closing behavior of the St. Jude Medical heart valve, simulating (1) a low-pressure system, (2) the anatomic peculiarity of the right ventricular outflow tract and the main pulmonary artery, and (3) disturbed diastolic compliance of the right ventricle. The variables in the experiment were the load impedance to the pump and the valve orientation. The results were as follows. The sequence of closure of the two semidiscs was based on the valve orientation; reduction in impedance caused the semidisc that closed last to remain open, while the other semidisc continued its open-close motion; further reduction in impedance prevented the semidisc, which continued its open-close motion, from closing completely. These results highlight the forces involved in semidisc closure and the existence of a threshold of force for completion of semidisc closure. Further, the results demonstrate that under certain circumstances the threshold cannot be exceeded via those forces. Therefore this incompetence must originate in the prosthesis itself. In this regard, we suggest an urgent need to reconsider the indications for St. Jude Medical heart valve pulmonic implantation. Finally, we advocate the necessity for an in vitro assessment of valve prostheses in a low-pressure system, to evaluate the safety of right-sided placement.

Senescence-accelerated mouse (SAM): age-related reduced anxiety-like behavior in the SAM-P/8 strain.

Age-related behavioral changes in the passive avoidance, food neophobia, elevated plus-maze, and water-lick conflict tests were studied using substrains of senescence-accelerated mouse (SAM-P/8 and SAM-R/1) at 2 to 20 months of age. SAM-P/8 mice exhibited a significant impairment of acquisition of passive avoidance compared with SAM-R/1 mice when they were trained repeatedly, and the acquired response in SAM-P/8 mice rapidly diminished in contrast to good retention in SAM-R/1 mice. SAM-P/8 mice showed an age-related decrease in the latency to eat novel food after a 24-h food deprivation as compared with SAM-R/1 mice at 2 to 12 months of age, despite no significant difference in latency to eat familiar food between the two strains. In the elevated plus-maze test, SAM-P/8 mice had apparent increases in the number of entries into open arms and time spent on open arms in comparison to SAM-R/1 mice at 4 through 12 months of age; this difference became obvious with aging, implying age-associated reduced anxiety in the SAM-P/8 strain. In addition, SAM-P/8 mice exhibited a significant increase in punished water drinking compared to SAM-R/1 mice in the water-lick conflict test, although unpunished water intake in SAM-P/8 mice did not differ from that in the SAM-R/1 control. Aged SAM-R/1 mice, 20 months old, exhibited low anxiety-like behavior in the food neophobia and elevated plus-maze tests such as was seen in SAM-P/8 mice, when compared with young (4-month-old) SAM-R/1 mice.(ABSTRACT TRUNCATED AT 250 WORDS)

Increase of basic fibroblast growth factor immunoreactivity and its mRNA level in rat brain following transient forebrain ischemia.

We examined the time course of basic fibroblast growth factor (bFGF) immunoreactivity and its mRNA level mainly in the hippocampus after transient forebrain ischemia using immunohistochemistry, enzyme immunoassay (EIA), Western blot analysis and in situ hybridization. Neuronal death in the hippocampal CA1 subfield was observed 72 h after 20 min of ischemia. The number of bFGF-immunoreactive(IR) cells increased 48 h-5 days after ischemia in all hippocampal regions. At 10 and 30 days, the bFGF-IR cells in the CA1 subfield had further increased in numbers and altered their morphology, enlarging and turning into typical reactive astrocytes with the advancing neuronal death in that area. In contrast, the number of bFGF-IR cells in other hippocampal regions had decreased 30 days after ischemia. The EIA study showed a drastic increase in bFGF levels in the hippocampus 48 h after ischemia (150% of that in normal rat) which was followed by further increases. In Western blot analysis, three immunoreactive bands whose molecular weights correspond to 18, 22 and 24 kDa were observed in normal rat and ischemia increased all their immunoreactivities. In the in situ hybridization study of the hippocampus, bFGF mRNA positive cells were observed in the CA1 subfield in which many bFGF-IR cells existed after ischemia. These data demonstrate that transient forebrain ischemia leads to an early and strong induction of bFGF synthesis in astrocytes, suggesting that the role of bFGF is related to the function of the reactive astrocytes which appear following brain injury.

Increase in basic fibroblast growth factor-like immunoreactivity in rat brain after forebrain ischemia.

Using immunohistochemical techniques, a study was conducted to determine whether basic fibroblast growth factor (bFGF) is generated as one of the 'self-repair' responses in rat brain following transient forebrain ischemia. In normal brain, slight bFGF-like immunoreactivity was observed. However, in rats exposed to 20 min of forebrain ischemia, intense bFGF-like immunoreactivity was observed in the CA1 subfield of the hippocampus and the caudate putamen, and marked activity was evident in the temporal cortex, corpus callosum and the CA4 subfield of the hippocampus. Marked neuronal degeneration was also observed in these brain regions following forebrain ischemia. These results suggest that induction of bFGF-like immunoreactivity may be related to the healing which follows brain ischemia.

Relationship between brain damage and memory impairment in rats exposed to transient forebrain ischemia.

The relationship between changes in learning behavior and neurological damage following transient forebrain ischemia was studied in rats. The transient forebrain ischemia was induced by 4-vessel occlusion, and behavioral experiments were started 4 weeks later when histological damage to the brain seemed to have stabilized. Histological evaluation of brain damage was conducted after completion of the behavioral studies. The rats showed marked learning impairment in a radial maze task done from 4 to 10 weeks after ischemia. In particular, there was an increase in the number of working memory errors according to the duration of forebrain ischemia. However, the same rats showed good avoidance responses in a passive avoidance task done 12 weeks after ischemia. The rats also showed good acquisition of escape response in a water maze task carried out 13 weeks after ischemia, but showed slight impairment of spatial navigation in the transfer test. Marked neuronal degeneration was observed in the hippocampal pyramidal cells of the rats exposed to ischemia. This neuronal damage was closely related to memory impairment in the radial maze task, as demonstrated by a significant negative correlation (r = -0.609 or -0.709) between the number of surviving neurons and the number of reference or working memory errors. These results suggest that rats exposed to transient forebrain ischemia show marked impairment of both reference and working memories as a result of postischemic hippocampal damage.

Synthesis of isoindolo[2,1-a]quinoline derivatives and their effects on N2-induced hypoxia.

A variety of isoindolo[2,1-a]quinoline derivatives as well as the following related heterocycles have been prepared: 11b,12-dihydro-5H-isoindolo[2,1-b][2]benzazepine-7,13-dione (8a), 7,8,14,14a-tetrahydroisoindolo[2,1-c][3]benzazocine-5, 13-dione (8b), 6a,7-dihydroisoquinolino[2,3-a]quinoline-5,12-dione (12), 2,3,3a-4-tetrahydropyrrolo[1,2-a]quinoline-1,5-dione (14), and pyrido[2',3':3,4]pyrrolo[1,2-a]quinoline-5,11(5H)-dione (17). The key synthetic step involves an intramolecular Friedel-Crafts reaction of acid chlorides such as isoindole-1-acetyl chlorides (4), the acids (3) of which were prepared starting with 2-arylisoindole-1,3(2H)-diones (2-arylphthalimides) (1). The protective effects of isoindolo[2,1-a]quinoline derivatives (19 and 20) against N2-induced hypoxia were examined. Among them, 6-(diethylaminomethyl)isoindolo[2,1-a]quinoline-5,11(5H)-dio ne (19b) showed the most potency.

Oral supplementation of vitamin K for pregnant women and effects on levels of plasma vitamin K and PIVKA-II in the neonate.

Levels of plasma vitamin K1 (VK1) and vitamin K2 (VK2) and protein-induced vitamin K absence-II (PIVKA-II) were measured in Japanese mothers and their newborn (N = 33). Twenty milligrams of VK1 (N = 11) or VK2 (N = 12) were given orally to randomly selected mothers 7 to 10 days prior to delivery. Means of plasma VK1 and VK2 concentrations were significantly higher in VK1 (p less than 0.01) and VK2 (p less than 0.01) treated mothers than in the controls at delivery, respectively. Similarly, these levels were significantly elevated in cord plasma in VK1 (p less than 0.05) and VK2 (p less than 0.05) treated groups, compared with findings in the control group, although there was a large concentration gradient between maternal and cord plasma (mostly less than one-tenth). A significant positive correlation was found in VK1 concentration between maternal and cord plasma (N = 33, p less than 0.01), and the proportion of PIVKA-II-positive infants was significantly lower in the VK treated groups than in the control group at birth (p less than 0.05). On the fifth postnatal day, mean levels of VK1 (p less than 0.01) and VK2 (p less than 0.01) in breast milk were significantly higher in the VK1 and VK2 treated mothers than in the control mothers, respectively. In the control group, 9 of 10 infants had a positive PIVKA-II, but no one in the treated groups was positive, thereby indicating significant differences between control and treated groups (p less than 0.01 and p less than 0.01, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

[Surgical treatment of aortic arch aneurysm associated with the aberrant right subclavian artery].

A 64-year-old man, who had an aneurysm of aortic arch associated with the aberrant right subclavian artery, was treated successfully. He was pointed out to have an aneurysm of aortic arch three years ago. Three years later angiograms and computed tomography revealed that it became larger compared with the initial finding. He underwent a replacement of the aortic arch using a woven Dacron graft under open distal method. Aberrant subclavian artery was not involved in the aneurysm. But because the left subclavian artery was involved in it, a woven Dacron graft was interposed between the ascending aorta and left subclavian artery. Postoperative course was uneventful and there were no complications.