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P2Y(2) and P2Y(4) receptors are G protein-coupled receptors, activated by UTP and dinucleoside tetraphosphates, which are difficult to distinguish pharmacologically for lack of potent and selective ligands. We structurally varied phosphate and uracil moieties in analogues of pyrimidine nucleoside 5'-triphosphates and 5'-tetraphosphate esters. P2Y(4) receptor potency in phospholipase C stimulation in transfected 1321N1 human astrocytoma cells was enhanced in N(4)-alkyloxycytidine derivatives. OH groups on a terminal δ-glucose phosphoester of uridine 5'-tetraphosphate were inverted or substituted with H or F to probe H-bonding effects. N(4)-(Phenylpropoxy)-CTP 16 (MRS4062), Up(4)-[1]3'-deoxy-3'-fluoroglucose 34 (MRS2927), and N(4)-(phenylethoxy)-CTP 15 exhibit ≥10-fold selectivity for human P2Y(4) over P2Y(2) and P2Y(6) receptors (EC(50) values 23, 62, and 73 nM, respectively). δ-3-Chlorophenyl phosphoester 21 of Up(4) activated P2Y(2) but not P2Y(4) receptor. Selected nucleotides tested for chemical and enzymatic stability were much more stable than UTP. Agonist docking at CXCR4-based P2Y(2) and P2Y(4) receptor models indicated greater steric tolerance of N(4)-phenylpropoxy group at P2Y(4). Thus, distal structural changes modulate potency, selectivity, and stability of extended uridine tetraphosphate derivatives, and we report the first P2Y(4) receptor-selective agonists.

Condensation of dihydrofuran- and -thiophenecarbonitriles (I) and (V) possessing an active methylene group with N,N-dimethylformamide dimethyl acetal (II) results in the formation of enamines (III) and (VI).

The enantiospecific synthesis of the oligomycin B degradation product 2 , corresponding to the C19–C34 spiroketal portion, has been achieved by sequential coupling of the C19–C21, C22–C27, and C28–C34 subunits, establishing the absolute stereochemistry of oligomycin B.

The procedure for the preparation of the title compounds, e.g. (IV), has the advantage of an easy work-up.

The ring opening of 2-acylamino-4,5-dihydro-3-furancarbonitriles with titanium (IV) chloride gave the corresponding N-acyl-4-chloro-2-cyanobutanamides (I). On treatment with potassium carbonate, compounds I were converted to the corresponding N-acyl-1-cyanocyclopropanecarboxamides . On the other hand, the reaction of 2-benzamido-4,5-dihydro-3-thiophenecarbonitriles with titanium (IV) chloride gave the corresponding 2-benzamido-4,5-dihydro-3-thiophenecarboxamides.

The reactions of 2-benzamido-4,5-dihydro-3-thiophene(-3-furan-)carbonitriles 1a–c (and 11a–c) with acetic (or propionic) anhydride in the presence of tin(IV) chloride give the corresponding 3-acetyl-5,6-dihydro-2-phenylthieno(-furo-)-[2,3-d]pyrimidin-4(3H)-ones 2a–c (and 12a–c) or 5,6-dihydro-2-phenyl-3-propionylthieno(-furo-)[2,3-d]pyrimidin-4(3H)-ones 3a–c (and 13a–c). Hydrolysis of compounds 2a–c (and 12a–c) or 3a–c (and 13a–c) leads to the corresponding N-acetyl-2-benzamido-4,5-dihydro-3-thiophene-(-3-furan-)carboxamides 4a–c (and 14a–c) or 2-benzamido-4,5-dihydro-N-propionyl-3-thiophene-(-3-furan-)carboxamides 5a–c (and 15a–c). The reaction of compounds 4a, b (or 14a, b) with acid anhydrides in the presence of potassium carbonate or triethylamine gives the corresponding 3-acyl-2-benzamido-4,5-dihydrothiophenes (or furans) 9, 10, 16, and 17.

The oligomycin B spiroketal portion, [2S,2(2R),3S,6R,8S,8(3R),9S,10R,11S]-2-[2-(t-butyldiphenylsilyloxy)propyl]-8-[3-(hydroxymethyl)pentyl]-3,9,11-trimethyl-1,7-dioxaspiro[5.5]undecane-5,10-diol (2), and polypropionate portion, ethyl (2E,4S,5R,6R,7S,8S,9R,10S,12R,13S,14R,16E)-5-(t-butyldimethylsilyloxy)7,9-(isopropylidenedioxy)-12,13-(4-methoxybenzylidenedioxy)-4,6,8,10,12,14-hexamethyl-11-oxo-18-phenylsulfonyloctadeca-2,16-dienoate (3), have been synthesized. The C19-C21 Wittig salt, [(2S,3R)-2-ethyl-3,4-(isopropylidenedioxy)butyl]triphenylphosphonium iodide (6), prepared from 2-butene-1,4-diol via Sharpless epoxidation, was coupled with the C22-C27 aldehyde, benzyl 2,4-dideoxy-3-O-(4-methoxybenzyl)-2,4-di-C-methyl-α,β-L-galacto-hexodialdopyranoside-(1,5) (7), prepared from (Z)-2-butene-1,4-diol via Sharpless epoxidation and the Brown’s crotylboration. The resulting coupling product was transformed to the C19-C27 lactone, [3S,4R,5R,6S,6(3R,4R)]-6-[3-ethyl-4,5-(isopropylidenedioxy)pentyl]-4-(4-methoxybenz...

The title carbonitriles (III) are readily converted into novel fused thiopyranthione (V) and thiophene derivatives (VI).

The P2Y(1) receptor is a prothrombotic G protein-coupled receptor (GPCR) activated by ADP. Preference for the North (N) ring conformation of the ribose moiety of adenine nucleotide 3',5'-bisphosphate antagonists of the P2Y(1) receptor was established by using a ring-constrained methanocarba (a bicyclo[3.1.0]hexane) ring as a ribose substitute. A series of covalently linkable N(6)-methyl-(N)-methanocarba-2'-deoxyadenosine-3',5'-bisphosphates containing extended 2-alkynyl chains was designed, and binding affinity at the human (h) P2Y(1) receptor determined. The chain of these functionalized congeners contained hydrophilic moieties, a reactive substituent, or biotin, linked via an amide. Variation of the chain length and position of an intermediate amide group revealed high affinity of carboxylic congener 8 (K(i) 23 nM) and extended amine congener 15 (K(i) 132 nM), both having a 2-(1-pentynoyl) group. A biotin conjugate 18 containing an extended epsilon-aminocaproyl spacer chain exhibited higher affinity than a shorter biotinylated analogue. Alternatively, click coupling of terminal alkynes of homologous 2-dialkynyl nucleotide derivatives to alkyl azido groups produced triazole derivatives that bound to the P2Y(1) receptor following deprotection of the bisphosphate groups. The preservation of receptor affinity of the functionalized congeners was consistent with new P2Y(1) receptor modeling and ligand docking. Attempted P2Y(1) antagonist conjugation to PAMAM dendrimer carriers by amide formation or palladium-catalyzed reaction between an alkyne on the dendrimer and a 2-iodopurine-derivatized nucleotide was unsuccessful. A dialkynyl intermediate containing the chain length favored in receptor binding was conjugated to an azide-derivatized dendrimer, and the conjugate inhibited ADP-promoted human platelet aggregation. This is the first example of attaching a strategically functionalized P2Y receptor antagonist to a PAMAM dendrimer to produce a multivalent conjugate exhibiting a desired biological effect, i.e., antithrombotic action.

A new and easy synthetic route to furo[2,3-b]furans 7a-d and furo[2,3-b]pyrroles 8a-d has been achieved by the C-phenacylation/cyclization reactions of 2-amino-4,5-dihydro-3-furancarbonitrile (5). Thermal treatment of the key intermediate 3-phenacylated tetrahydro-2-imino-3-furancarbonitriles 6a-d, which were prepared from compound 5 and phenacyl bromides, e.g. phenacyl bromide, 4-chlorophenacyl bromide, 4-methylphenacyl bromide and 4-methoxyphenacyl bromide, with acetic anhydride caused intramolecular cyclization to yield the corresponding furo[2,3-b]furans 7a-d. On the other hand, methanolic sodium methoxide-assisted cyclocondensation of compounds 6a-d gave the corresponding furo[2,3-b]pyrroles 8a-d.

The reactions of 2-benzamido-4,5-dihydro-3-thiophene(and -3-furan)carbonitriles (1a-c and 4a-c) with ethyl acetoacetate in the presence of tin(IV) chloride and triethylamine provided the corresponding ethyl 2-(5,6-dihydro-2-phenylthieno(and furo)[2,3-d]pyrimidin-4-yl)-3-oxobutanoates (2a-c and 9a-c). Similarly, compounds 1a-c and 4a-c reacted with dialkyl malonates to give the corresponding dialkyl(5,6-dihydro-2-phenylthieno(and furo)[2,3-d]pyrimidin-4-yl)propanedioates (5a-c, 6a-c, 10a-c and 11a-c).

Sulfonium ylides 1a-h reacted with sodium iodide to afford the corresponding thiopyrans 2a-h. On the other hand, compounds 1a-d were treated with thionyl chloride to give the ring opening products 3a-d. The reaction of compounds 3a-d with sodium iodide and triethylamine provided the corresponding thiopyrans 2a-d.

An approach to pyrano[2,3-c]pyrazoles starting from spirocyclopropanepyrazoles via a ring-opening/cyanomethylation and intramolecular cyclization is described. Reactions of spirocyclopropanepyrazoles with chloroacetonitrile in the presence of sodium hydride gave the corresponding cyanomethoxypyrazoles . Treatment of with sodium hydride at room temperature caused intramolecular Michael addition reaction to afford the corresponding pyrano[2,3-c]pyrazoles . J. Heterocyclic Chem., (2009).

An efficient Diels-Alder reaction is described in the furan series, leading to phthalimides in high yields. Thermal treatment of 2-(4-morpholinyl, 1-piperidinyl, and 1-pyrrolidinyl)-3-furancarbonitriles with maleimide derivatives, e.g. maleimide, N-methylmaleimide, N-benzylmaleimide, N-phenylmaleimide and N-(4-nitrophenyl)maleimide, in boiling acetic acid caused a [4 + 2] cycloaddition reaction to give the corresponding phthalimide derivatives.

Two methods for the preparation of N-methyl-4-(methylthio)thieno[2,3-d]pyrimidinium salts 6a,b and 13a,b are described. Treatment of 6a,b and/or 13a,b with active methylene compounds such as malononitrile and ethyl cyanoacetate in the presence of sodium methoxide caused nucleophilic addition followed by elimination of methanethiol, giving the corresponding N-methyl-4-ylidenethieno[2,3-d]-pyrimidines 7a,b, 8a,b, 14a,b and 15a,b.

麻酔導入時の誤嚥性肺炎の危険性とH2-ブロッカーの効果をコントロール群(C群)とファモチジン群(F群)で年齢別に比較検討した.C群では誤嚥性肺炎の危険性は若年者で高く,加齢とともに有意に低下した.F群でも同様の傾向がみられ,特に12～19歳では他の年齢層より危険性が有意に高かった.術前にH2-ブロッカーを投与していても,若年者(特に12～19歳)では誤嚥性肺炎に対する注意が必要と考えられる.

The novel preparation of 2‐cyanobutanamide derivatives starting from 2‐amino‐4,5‐dihydro‐3‐furancarbonitriles is described. Thermal treatment of 4,5‐dihydro‐2‐(4‐morpholinyl, 1‐piperidinyl, and 1‐pyrrolidinyl)‐3‐furancarbonitriles with various carboxylic acids in the absence of solvent caused a ring‐opening reaction to give the corresponding 2‐cyanobutanamide derivatives.

The one-pot synthesis of 4-alkoxy-5,6-dihydro-furo(and -thieno)[2,3-d]pyrimidines is described. The reactions of 2-benzamido-4,5-dihydro-3-furan(and -3-thiophene)carbonitriles 1a-d and 2a-c with ethanol and/or methanol in the presence of zinc chloride and triethylamine gave the corresponding 4-alkoxy-5,6-dihydro-furo(and -thieno)[2,3-d]pyrimidines 3a-d, 4a-d, 5a-c and 6a-c.

A novel and efficient approach to 2-pyrrolidinones and dihydropyrans via the ring transformation of 3-phenacylated tetrahydro-2-imino-3-furancarbonitriles in the presence of sodium iodide is described. The key feature in the ring transformation is that C-phenacylation of 2-amino-4,5-dihydro-3-furancarbonitriles using phenacyl bromides, e.g. phenacyl bromide, 4-chlorophenacyl bromide and 4-methoxyphenacyl bromide, proceeds smoothly and the ring-opening intermediate having leaving group such as iodide ion is produced.

Chymase is a chymotrypsin-like serine protease exclusively stored in secretory granules of mast cells and has been thought to participate in allergic diseases. It has already been shown that chymase inhibitor SUN13834 improves dermatitis in NC/Nga mice that spontaneously develop dermatitis resembling atopic dermatitis. In the present study, effect of chymase inhibitor SUN13834 on itch, the major feature of atopic dermatitis, was examined using a mouse dermatitis model induced by repeated topical application of 2,4-dinitrofluorobenzene (DNFB). Oral administration of SUN13834 once a day for 5 weeks inhibited not only skin swelling but accumulation of inflammatory cells including mast cells and eosinophils in the skin of the mice. In addition, SUN13834 also decreased significantly at 10 and 50 mg/kg the amount of scratching behavior induced by the DNFB challenge. This result indicates for the first time that mast cell chymase may be involved in itch induction. In conclusion, SUN13834 is thought to be useful as therapeutic agent for atopic dermatitis.

An approach to indole derivatives from N-arylhydroxamic acids and malononitrile via a [3,3]-sigmatropic rearrangement and intramolecular cyclization is described. Reactions of N-arylhydroxamic acids 1a-c, 2a-c and 3a-c with malononitrile in the presence of triethylamine at room temperature gave the corresponding α-cyanoacetamide derivatives 4a-c, 5a-c, 6a-c, 7a-c and 8a-c. Thermal treatment of 4a-c, 5a-c and 7a-c with a base, e.g. triethylamine and sodium methoxide, caused intramolecular cyclization and deacylation to afford the corresponding indole derivatives 9-11.

Although utility of 18F-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) has been rehearsed in large vessel vasculitides, it is not known if small vessel vasculitides are also associated with increased FDG uptake. Hereby described is a 64-year-old female patient with prolonged fever and splenomegaly, which was depicted as a hot area in FDG-PET. Splenectomy disclosed microaneurysms, giant cell granuloma, perivascular leukocytic infiltration with fibrinoid necrosis, consistent with granulomatous angitis. Serum myeloperoxidase-antineutrophil cytoplasmic antibody was positive. The present case illustrates that vasculitides affecting small vessels present increased FDG uptake as do those affecting large vessels.

S. Kido1, W. Yu2, Y. Nakajima3, T. Tanaka4, T. Miyasaka 5, S. Shirogane 6, Y. Yamanaka7, Y. Sunaga 1, H. Maruoka1, K. Takayanagi 1 1 Saitama Prefectural University, Department of Physical Therapy, School of Health and Social Services, Saitama, Japan; 2 Chiba University, Department of Medical System Engineering, Graduate School of Engineering, Chiba, Japan; 3 Hokkaido Research Organization, Industrial Research Institute, Hokkaido, Japan; 4 The University of Tokyo, Research Center for Advanced Science and Technology, Tokyo, Japan; 5 Hokkaido University of Science, Department of Physical Therapy, Faculty of Health Science, Hokkaido, Japan; 6 National Rehabilitation Center for Persons with Disabilities, Department of Assistive Technology, Saitama, Japan; 7 Himeji Dokkyo University, Hyogo, Japan

The unusual formation of 1-acyl-1,2-dihydro-3H-pyrazol-3-ones starting from 3-acyloxypyrazoles by Fries-type rearrangement is described. Under normal conditions, acylation of 2,4-dihydro-3H-pyrazol-3-ones 1 and 2 with acid chlorides or anhydrides in the presence of triethylamine gave the corresponding 3-acyloxypyrazoles 3a-f and 4a-f. Treatment of 3a-c and 4a-f with Lewis acid, e.g. titanium(IV) chloride and tin(IV) chloride, caused migration of acyl groups to afford the corresponding 1-acyl-1,2-dihydro-3H-pyrazol-3-ones 5a-c and 6a-f. Interestingly, the reactions of 3-acyloxypyrazoles 3e and 3f with tin(IV) chloride provided the corresponding tin(IV) complexes 8e and 8f.

We encountered a 39-year-old female patient with systemic lupus erythematosus (SLE) in whom thrombotic thrombocytopenic purpura (TTP) recurred. The patient was successfully treated with corticosteroid in combination with immunosuppressive agents. Because TTP complicating SLE is more resistant to treatment than idiopathic TTP, prompt diagnosis and efficacious initial treatment are critical.

A novel series of 6-benzyl substituted 4-aminocarbonyl-1,4-diazepane-2,5-diones was designed, synthesized, and evaluated as human chymase inhibitors. From this series, we identified several compounds which were effective, via oral administration, in a mouse model of chronic dermatitis.

A 23-year-old woman presented with recurrence of lupus cystitis, which had been in remission under daily administration of a single corticosteroid over a period of 8 years. She was treated with increased doses of corticosteroid and immunosuppressants, i.e., cyclosporin, cyclophosphamide, azathioprine, and salazosulfapyridine, but the cystitis remained active. Since her condition became critical by the complication of intestinal pseudo-obstruction, tacrolimus was administered. This agent induced a remission promptly without significant adverse events in this patient, suggesting an efficacy to lupus cystitis refractory to corticosteroid and other immunosuppressants.

The reaction of 2-acylamino-4,5-dihydro-3-furancarbonitriles 1 with sodium iodide in N,N-dimethyl-formamide gave the corresponding 1-acyl-2-oxo-3-pyrrolidinecarbonitriles 2 in good yields. Successive treatment of 1 with titanium(IV) chloride and potassium carbonate resulted in the formation of N-acyl-1-cyanocyclopropanecarboxamides 4. The same compounds 2 were also obtained by treatment of 4 with sodium iodide. The starting compounds 1 were synthesized by the reaction of 2-amino-4,5-dihydro-3-furan-carbonitrile with acyl chlorides in pyridine.

A series of cyclic sulfonium ylides 4a-h reacted with titanium(IV) chloride in the presence of triethyl-amine to give the corresponding fused 2,3-dihydro-1H-thieno[3,4-b]pyrroles 5a-h, via a ring opening and recyclization. In contrast, treatment of compounds 4a, 4b, 4e and 4f with titanium(IV) chloride, triethy-lamine and dimethylamine hydrochloride gave the corresponding thiophenes 6a, 6b, 6e and 6f. Furthermore, compounds 6a and 6b easily underwent cyclization with sodium hydride to afford the corresponding 5a and 5b.

Pneumomediastinum as a complication of interstitial pneumonia with leakage of air into the mediastinum or subcutaneous tissues is a rare complication of dermatomyositis (DM). Herein we report a case of pneumomediastinum complicating polymyositis (PM), which is usually associated with DM. A 61-year-old man was hospitalized in our department because of deterioration of interstitial pneumonia. Treatment with high-dose corticosteroid and cyclosporin A steadily improved his interstitial pneumonia. Two weeks later, he developed subcutaneous emphysema and chest X-ray showed pneumomediastinum. Both subcutaneous emphysema and pneumomediastinum improved gradually without any additional treatment.

We encountered a hilar bile duct cancer patient with intestinal Behcet's disease who manifested various symptoms during a short period in the acute stage after liver resection. Under a diagnosis of hilar bile duct cancer, a 52-year-old Japanese male was referred and admitted to our hospital. Hepatectomy and resection of the extrahepatic bile duct were performed. During the postoperative course, a large number of painful aphthous ulcers developed in the oral mucosa, along with a genital ulcer. A deep excavation-type ulcer was confirmed by colonoscopy in the ileum on the orifice side. We administered colchicine and mesalazine. Thereafter, the patient was treated at the outpatient clinic. Recurrent localized hilar bile duct cancer developed, and the patient died about 8 months after surgery. We present the clinical details of this rare case of hilar bile duct cancer with intestinal Behcet's disease.

2-Nitronaphthalene (1) and 6-nitroquinoline (2) underwent direct cyclocondensation with secondary and tertiary carbanions derived from a methylene and methine group bearing both a leaving group and electron-withdrawing group (e.g., methyl chloroacetate, ethyl chloroacetate, chloroacetonitrile, methyl 2-chloropropionate, ethyl 2-chloropropionate and 2-chloropropionitrile) in the sodium hydride/N,N-dimethylformamide system at low temperature, giving the corresponding dihydronaphth[2,1-c]isoxazole N-oxides 3 and dihy-droisoxazolo[4,3-f]quinoline N-oxides 4. On the other hand, nitroarenes 1 and 2 reacted with secondary carbanions in the sodium hydride/tetrahydrofuran system to yield the corresponding conventional vicarious nucleophilic substitution (VNS) products 5 and 6.

Arylnitroso compounds 1–3 easily reacted with dimethyl bromomalonate to give the corresponding N-aryl-C,C-dimethoxycarbonylnitrones (4–6). Treatment of C,C-dimethoxycarbonyl-N-( 1-naphthyl)nitrone (4) with acetylene compounds (dimethyl acetylenedicarboxylate, methyl 2-butynoate or ethyl phenylpropiolate) caused 1,3-dipolar cycloaddition to furnish the corresponding 1H-benz[g]indolines (7a-c). In a similar manner, the reactions of nitrones 5 and 6 with acetylene compounds afforded the corresponding indolines 9a-c and 11a-c together with 4-oxazolines 13a-c and 14a-c.

The ability to convert angiotensin (Ang) I to Ang II was compared between human alpha-chymase and two mouse beta-chymases, mouse mast cell protease (mMCP)-1 and mMCP-4. Human chymase hydrolyzed Ang I to produce Ang II without further degradation. mMCP-1 similarly generated Ang II from Ang I in a time-dependent manner and the formation of the fragment other than Ang II was marginal. In contrast, mMCP-4 hydrolyzed Ang I at two sites, Tyr(4)-Ile(5) and Phe(8)-His(9), with Ang II formation being tentative. Consistently, mMCP-4 but not human chymase hydrolyzed Ang II and mMCP-1 showed little hydrolytic activity against Ang II. These data suggest that not only human chymase but also mMCP-1 might possess a physiological role in Ang II formation. Our findings also imply that the Ang-converting activity of chymase may not be related to the categorization of chymase into alpha- or beta-type based on their primary structure.

The relationship between exercise capacity and left ventricular function has been evaluated in 35 patients with acute myocardial infarction (34 males and 1 female; mean age 55.5 ± 7.1 years). Single photon emission computed tomography (SPECT) was used to measure left ventricular function in the acute phase (4.9 ± 2.2 days after onset) and the chronic phase (188.5 ± 22.9 days after onset). More than 10% left ventricular dilatation from the acute phase to the chronic phase was defined as remodeling (RM) and the subjects were divided into 2 groups: RM and non-RM. Cardiopulmonary exercise testing was performed at 1 month (1M), 3 months (3M) and 6 months (6M) after onset. In the RM group, anaerobic threshold (AT) and peak oxygen uptake (Peak ) did not change significantly. In the non-RM group, AT was 15 ± 1 (ml/min/Kg) at 1M, 16 ± 2 at 3M and 18 ± 4 at 6M. Peak was 26 ± 3 (ml/min/Kg) at 1M, 30 ± 2 at 3M and 32 ± 3 at 6M. Both parameters in the chronic phase increased significantly compared with those at 1M (p

The reaction of 2-amino-4,5-dihydro-3-thiophenecarbonitriles 1a–c with ethyl acetoacetate in the presence of titanium(IV) chloride gave the corresponding ethyl 4-amino-2,3-dihydro-6-methylthieno[2,3-b]pyridine-5-carboxylates 3a–c. Similarly, compounds 1a–c reacted with diethyl malonate or ethyl cyanoacetate to give the corresponding ethyl 4-amino-2,3,6,7-tetrahydro-6-oxothieno[2,3-b]pyridine-5-carboxylates 4a–c or ethyl 4,6-diamino-2,3-dihydrothieno[2,3-b]pyridine-5-carboxylates 5a–c.

The reaction of ethyl N-2-(3-cyano-4,5-dihydro-2-furyl)carbamate (1), 1-cyano-N-(ethoxycarbonyl)cyclopropanecarboxamide (2), and ethyl 3-cyano-2-oxo-1-pyrrolidinecarboxylate (3) with sodium iodide gave 3-ethyl-2-oxo-3-pyrrolidinecarbonitrile (5). Similarly, the reaction of ethyl N-2-[3-cyano-4,5-dihydro-4-(or -5-)phenyl-2-furyl]carbamate (7 or 8) and trans-1-cyano-N-(ethoxycarbonyl)-2-phenylcyclopropane-carboxamide (9) afforded 3-ethyl-2-oxo-5-phenyl-3-pyrrolidinecarbonitrile (10).

Background and Purpose Little is known about bone changes in hemiplegic stroke patients. We evaluated the vitamin D status and bone changes on the hemiplegic and intact sides of stroke patients. Methods Sera were collected from 87 hemiplegic stroke patients (42 outpatients and 45 inpatients) and from 28 control subjects. The sera were assayed for 25-hydroxyvitamin D (25-OHD). Bone density was measured bilaterally from radiographs of the hands. Diet and sunlight exposure were assessed for all subjects. Results Serum 25-OHD concentrations were lower in patients (9.1±4.9 ng/mL for outpatients, 5.9±4.1 ng/mL for inpatients) than in control subjects (21.6±3.1 ng/mL). The difference in serum 25-OHD between the two patient groups also was statistically significant. The patients' microdensitometric scores for osteopenia were higher on the hemiplegic side than on the nonhemiplegic side. The microdensitometric scores and their side-to-side differences in patients correlated negatively with the serum 25-OHD concentration and positively with the degree of paralysis. Dietary intake of vitamin D was below the recommended level in 72% of the patients, and 89% of the patients were considered sunlight-deprived. Conclusions Bone mass was reduced significantly on the hemiplegic side in the stroke patients, which might increase the risk of hip fracture. Vitamin D deficiency and disuse are the probable causes of osteopenia in this population. The hypovitaminosis D might be corrected readily by routine use of vitamin D supplements.

Previous studies have demonstrated that hip fractures in stroke patients occurred almost exclusively on the hemiplegic side. We examined the bone changes in the second metacarpal of the hemiplegic side in terms of microdensitometric indices in 93 stroke patients with hemiplegia. All six indices indicated a significant decrease in bone mass on the hemiplegic side compared with the contralateral side. Differences in the indices between the hemiplegic and contralateral sides were correlated well with the duration of the illness and Brunstrom's stage for finger, arm, and leg. The same degree of osteopenia occurred in both small capsular and large hemispheric lesions. The same osteopenia was demonstrated in paralyzed and immobilized patients with myopathy. Thus a combination of weakness and immobilization is thought to be responsible for the osteopenia in the hemiplegic metacarpal bone. The osteopenia noted in the second metacarpal in the affected limb may account for the fact that hip fractures in stroke patients occur almost exclusively on the hemiplegic side.

The aim of the present study was to determine whether the level of plasma atrial natriuretic peptide (ANP), an indicator of atrial stretching, correlates with the formation of a thrombus in the left atrium during cardioembolic stroke with atrial fibrillation. Plasma concentrations of immunoreactive ANP and thrombin-antithrombin III complex (TAT) were measured in five age-matched groups including: 16 patients with acute cardioembolic stroke and atrial fibrillation (group 1), 26 patients with chronic cardioembolic stroke and atrial fibrillation (group 2), 27 patients with atrial fibrillation without previous stroke (group 3), 21 patients with acute lacunar stroke (group 4), and 27 healthy controls. The plasma ANP levels were higher in group 1, regardless of the stage, than those estimated at chronic stage in group 4 and in healthy controls. There were no stage-related differences between groups 1, 2 and 3. Plasma levels of ANP in group 2, a high risk group of cardioembolic stroke, were higher than in group 3, a low risk group. There was no correlation between plasma levels of ANP and mean blood pressure, pulse rate or plasma levels of TAT in any group. These results indicate that the determination of plasma ANP concentration is useful to distinguish a high risk patient from a low risk patient and also a cardioembolic stroke patient from a lacunar stroke patient. They also underscore the difficulties in recognizing left atrial thrombus formation by determining the plasma ANP concentration in cardioembolic stroke.

The phagocytic ability of polymorphonuclear cells and macrophages from aged, bed ridden patients was investigated. Phagocytosis of carbon in aged bed ridden patients did not differ from that of young controls, and extent of upregulation of granulocytes phagocytosis in response to elevation of incubation temperature was also similar between the two groups. Morphological changes of macrophages in response to ingestion of colloidal carbon was more prominent in young controls. These data suggest that a depressed phagocytosis is not an important factor in the increased susceptibility to infections of aged bed ridden patients, although the reactivity of macrophages may be more closely related to the infection defence.