Paramagnetic water-soluble metallofullerenes having the highest relaxivity for MRI contrast agents.

Water-soluble gadolinium (Gd) endohedral metallofullerenes have been synthesized as polyhydroxyl forms (Gd@C(82)(OH)(n)(), Gd-fullerenols) and their paramagnetic properties were evaluated by in vivo as well as in vitro for the novel magnetic resonance imaging (MRI) contrast agents for next generation. The in vitro water proton relaxivity, R(1) (the effect on 1/T(1)), of Gd-fullerenols is significantly higher (20-folds) than that of the commercial MRI contrast agent, Magnevist (gadolinium-diethylenetriaminepentaacetic acid, Gd-DTPA) at 1.0 T close to the common field of clinical MRI. This unusually high proton relaxivity of Gd-fullerenols leads to the highest signal enhancement at extremely lower Gd concentration in MRI studies. The strong signal was confirmed in vivo MRI at lung, liver, spleen, and kidney of CDF1 mice after i.v. administration of Gd-fullerenols at a dose of 5 micromol Gd/kg, which was 1/20 of the typical clinical dose (100 micromol Gd/kg) of Gd-DTPA.

Nucleosides and nucleotides. 208. Alternate-strand triple-helix formation by the 3'-3'-linked oligodeoxynucleotides with the anthraquinonyl group at the junction point.

The synthesis of 3'-3'-linked oligodeoxynucleotides (ODNs) with the anthraquinonyl group at the junction point is described. The ODNs were synthesized on a DNA synthesizer using a controlled pore glass (CPG) carrying pentaerythritol that has an intercalator at one of the four hydroxymethyl groups. Stability of the triplexes with the target duplexes was studied by thermal denaturation. The 3'-3'-linked ODNs with the anthraquinonyl group enhanced the thermal stability of the triplexes when compared with those without the intercalator and the unmodified nonamer 10. It was found that the ODNs 12 and 13 carrying the anthraquinonyl groups can form thermally stable triplexes by skipping two or three extra base pairs between two binding domains of the target duplexes. The ability of the 3'-3'-linked ODNs to inhibit cleavage of the target DNA 22 by the restriction enzyme Hind III was tested. It was found that the 3'-3'-linked ODN 16 with the anthraquinonyl group at the junction point inhibited the cleavage by the enzyme more effectively than the nonamer 14 and the 3'-3'-linked ODN 15 without the intercalator.

Potential of Gd-DTPA-mannan liposome particles as a pulmonary perfusion MRI contrast agent: an initial animal study.

UNLABELLED: Suga K, Mikawa M, Ogasawara N, et al. Potential of Gd-DTPA-mannan liposome particles as a pulmonary perfusion MRI contrast agent: An initial animal study. Invest Radiol 2001;36:136-145. RATIONALE AND OBJECTIVES: A paramagnetic, particle-type MR contrast agent, (Gd-diethylenetriamine pentaacetic acid [DTPA]-mannan-cholesterol)-coated liposomes, was designed to localize in the lung by the mechanism of capillary blockade, and the potential of this agent for pulmonary perfusion MRI was experimentally investigated. METHODS: Before and up to 60 minutes after slow injection of this contrast agent, MR images were sequentially acquired at 10-second intervals along the same transaxial plane of the lung by using a gradient-echo pulse sequence with a short echo time of 1.2 ms on a 1.5-T MR scanner. After the minimal dose for obtaining a sufficient lung enhancement effect was determined in five rabbits, the time course of the enhancement effect was evaluated in six dogs by arterial blood gas analysis. The efficacy of MRI for detecting perfusion defects was evaluated in seven other dogs with pulmonary embolism. RESULTS: Normal lungs were dose-dependently enhanced by this agent, and with a 2.0 mL/kg dose, dependent lungs were enhanced by more than 201%, with an average half-life of the enhancement effect of 35.7 +/- 5.3 minutes. With less than this dose (1.0-1.5 mL/kg), all of the embolized lung portions were clearly identified as perfusion defects. The prolonged enhancement effect allowed the acquisition of subsequent multisectional lung images, thus facilitating the assessment of anatomic location and extent of the perfusion defects. The reduction of PaO2 in room air after injection was within 5 mm Hg in both normal and embolized animals. CONCLUSIONS: These initial, experimental results show that paramagnetically labeled liposome particles may be a successful MR contrast agent for pulmonary perfusion imaging.

Alternate-strand triple-helix formation by the 3'-3'-linked oligodeoxynucleotides with the intercalators at the junction point.

3'-3'-Linked oligodeoxynucleotides (ODNs) with the anthraquinonyl group at the junction point were synthesized on a DNA synthesizer using a controlled pore glass (CPG), which has pentaerythritol carrying the intercalator at one of the four hydroxymethyl groups. Stability of the triplexes with the target duplexes was studied by thermal denaturation. The 3'-3'-linked ODNs with the anthraquinonyl group enhanced the thermal stability of the triplexes when compared with those without the intercalator and the unmodified nonamer. The inhibitory activity of the 3'-3'-linked ODNs against the cleavage of the target DNA by the restriction enzyme Hind III was tested. It was found that the 3'-3'-linked ODN with the anthraquinonyl group at the junction point inhibited the cleavage by the enzyme more effectively than the nonamer and the 3'-3'-linked ODN without the intercalator.

Gd(3+)-loaded polyion complex for pH depiction with magnetic resonance imaging.

In clinical diagnosis, gadolinium (Gd) ion/low molecular weight chelater complexes have been used as MRI contrast agents that disperse throughout a particular tissue and cause a brighter appearance in MRI. In order to provide a novel imaging concept for MRI, a contrast agent in which the T(1)-relaxation shortening activity (R(1) relaxivity) changes in response to the pH differences was studied. We prepared a polyion complex (PIC) consisting of a polyanionic Gd-chelater, poly(diethylenetriamine-N,N,N',N", N"-pentaaceto, DTPA) (1,3-propanediamide) (denoted as 1a) loaded with Gd ions at a [Gd]/[DTPA unit] ratio of 0.2 (denoted as 1b), and a polycation, poly[2-(diethylamino)ethyl methacrylate] (denoted as 2). The stoichiometric (based on ionic groups) mixture of 1b and 2 formed complex coacervates from pH 5 to pH 8. The R(1) relaxivity of Gd(3+) in the complex was considerably influenced by the pH, and the relative signal intensity changed from 4 at pH 7.2 to 11 at pH 5.0, as determined by an MRI phantom study. The pH responsivity of the complex solution varied with the composition of the PIC (i.e., the mixing ratio of 1b and 2), allowing us to modulate the pH sensibility. The ionic charge balance and swelling of PIC seemingly were related to the pH-dependent R(1) relaxivity change. It is expected that the PIC-based MRI contrast agent may provide a novel category of MRI methods and be useful in improving the detectability of an MRI-based diagnosis.

Nucleosides and nucleotides. 170. Synthesis and properties of oligodeoxynucleotides containing 5-[N-[2-[N,N-bis(2-aminoethyl)- amino]ethyl]carbamoyl]-2'-deoxyuridine and 5-[N-[3-[N,N-bis(3-aminopropyl) amino]propyl]carbamoyl]-2'-deoxyuridine.

The synthesis of oligodeoxynucleotides (ODNs) containing 5-[N-[2-[N,N-bis(2-aminoethyl)amino]ethyl]-carbamoyl]-2'-deoxyuridine (BAE) and 5-[N-[3-[N,N-bis(3-aminopropyl)amino]propyl]carbamoyl]-2'- deoxyuridine (BAP) is described. The thermal stabilities of duplexes containing these ODNs and either the complementary DNA or RNA strand and of triplexes consisting of these ODNs and the target duplex were studied by thermal denaturation. ODNs containing BAE or BAP stabilize duplex formation with either the complementary DNA or RNA strands but destabilize triplex formation with the target duplex. Furthermore, the resistance of these ODNs to nuclease hydrolysis was studied by using snake venom phosphodiesterase (a 3'-exonuclease) and nuclease S1 (an endonuclease). It was found that ODNs containing either BAE or BAP were more resistant to nucleolytic hydrolysis by either of the nucleases than the unmodified ODN.

Gas transfer and blood compatibility of fluorinated polyimide membranes.

Fluorinated polyimide derived from 2,2'-bis(3,4-dicarboxyphenyl) hexafluoropropane dianhydride (6FDA) and bis[4-(4-aminophenoxy) phenyl]sulfone (APPS) was synthesized to develop a novel membrane oxygenator combining excellent gas transfer and blood compatibility. The asymmetric gas exchange membranes of 6FDA-APPS made by a dry/wet process consisted of an ultrathin and defect-free skin layer supported by a porous substructure. O2 transfer through the 6FDA-APPS membrane was extremely augmented as compared with that of the presently available membrane, poly(dimethylsiloxane), and the previously reported 6FDA-DDS membrane. Since CO2 transfer through the 6FDA-APPS membrane increased with a decrease in CO2 pressure according to dual-mode transport theory, CO2 from the membrane was selectively removed at low CO2 pressure. For the evaluation of in vitro blood compatibility, the platelet adhesion and the plasma protein adsorption on the surface of the 6FDA-APPS membrane were observed by using scanning electron microscopy and the amounts of platelet and plasma protein were determined by an amino acid analyzer. The results indicated that the fluorinated polyimide membranes showed excellent blood compatibility.

A neonatal case of hydranencephaly caused by atheromatous plaque obstruction of aortic arch: possible association with a congenital cytomegalovirus infection?

A neonate was seen with hydranencephaly and aortic arch obstruction possibly caused by congenital cytomegalovirus infection. At autopsy the aortic arch was occluded by atheromatous plaque between the right brachiocephalic artery and left common carotid artery. Congenital cytomegalovirus infection may have caused cardiovascular disease and hydranencephaly in this case.

Hirschsprung disease, unusual face, mental retardation, epilepsy, and congenital heart disease: Goldberg-Shprintzen syndrome.

A 5-year-old girl with Hirschsprung disease, unusual facial appearance, psychomotor retardation, epilepsy, and congenital heart disease is reported. Patients with similar clinical features have been reported and they appear to exhibit the recently identified Goldberg-Shprintzen syndrome. It is believed that this girl also exhibits this new syndrome. Cranial computed tomography demonstrated abnormal findings that may suggest defective neuronal migration and/or dysgenesis of the brain. These findings were considered to cause psychomotor retardation and epilepsy in this patient.

Prolonged exposure to industrial noise causes hearing loss but not high blood pressure: a study of 2124 factory laborers in Japan.

To determine the role of noise exposure in the etiology of hypertension, a cross-sectional study was performed by measuring the blood pressure of 2124 male laborers working in a noisy factory. The prevalence of hypertension was 10.2% in group I (85-115 dB), 10.9% in group II (less than 85 dB) and 12.5% in group III (office workers). There was no difference in systolic or diastolic blood pressure among the three groups. There were 358, 439 and 71 laborers in groups I, II and III, respectively, all having worked in the same noise area for more than 10 years. Blood pressure was lower 10 years previously in each group, but the degree of increment did not significantly differ among the three groups. The prevalence of hearing loss was 16.5% in group I, which was significantly higher than that in group II (7.5%) and group III (2.8%). Blood pressure of laborers with hearing loss was equal to that of laborers with intact hearing acuity. There was no significant relationship between hearing loss and the prevalence of hypertension. Thus, prolonged exposure to industrial noise contributes to hearing loss. However, elevation of blood pressure was not found in laborers working in a noisy factory. This finding was not consistant with previously reported findings in the rat. An adaptability to prolonged noise in man may account for this discrepancy.

Reversal of left ventricular hypertrophy by terazosin in hypertensive patients.

To assess the reversibility of left ventricular hypertrophy (LVH) during terazosin therapy, we studied changes in LVH as determined by echocardiography and humoral parameters before and after three and 12 months of terazosin monotherapy in ten patients. Blood pressure decreased within four weeks of treatment and the antihypertensive effect was sustained throughout 12 months. Left ventricular mass index decreased significantly from 126 +/- 22 g/m2 to 109 +/- 24 g/m2 and 98 +/- 23 g/m2 after 3 and 12 months respectively. Interventricular septum (11.2 to 9.8 and 9.0 mm) and posterior wall thickness (10.4 to 9.6 and 8.8 mm) also decreased significantly, whereas left ventricular internal dimensions were unchanged. Total peripheral resistance decreased significantly after initiation of treatment, but cardiac output did not change. Plasma volume, plasma renin activity and plasma noradrenaltine levels were unchanged by terazosin. Thus, terazosin monotherapy reversed LVH associated with decreased peripheral resistance. It is suggested that the reversal of LVH by terazosin is mainly due to the reduction in ventricular afterload and that humoral factors are not involved in its mechanism.

Hemodynamic and endocrinological effects of a new selective alpha 1-blocking agent, terazosin, in patients with essential hypertension. Results of long-term treatment.

Thirteen patients with essential hypertension were treated with an alpha 1-adrenoceptor antagonist, terazosin (1 to 4 mg/day) for 12 months. To assess the mechanism of its antihypertensive effect, the hemodynamic and endocrinological responses to terazosin were determined before, 3, and 12 months after the administration of terazosin. Blood pressure significantly decreased within 2 weeks after the start of terazosin and its effect was sustained throughout the 12 month period. Pulse rate did not change except slight increase in the third month. The hemodynamic studies revealed that total peripheral resistance significantly decreased and cardiac output slightly increased, indicating that the antihypertensive effect of terazosin is mainly produced by its vasodilation. Blood volume and plasma volume did not change. Although plasma renin activity remained the same, plasma aldosterone significantly decreased in response to terazosin. Plasma noradrenaline increased in the third month, but returned to the baseline level in the twelfth month. Thus, terazosin monotherapy lowered blood pressure throughout one year without drug tolerance including volume expansion and/or accentuation of renin-angiotensin-aldosterone system or sympathetic function.

Does cytosolic free calcium concentration in platelets reflect tone and structural changes of resistance vessels?

To investigate tone and vascular changes of resistance vessels as related to cytosolic free calcium concentration [( Ca2+]i) in platelets, we measured forearm vascular resistance and free calcium concentration in platelets from 10 essential hypertensives and 15 normotensives. The [Ca2+]i in platelets was significantly higher in essential hypertensives than in normotensives (184 +/- 43 versus 146 +/- 23 nmol/l, P less than 0.01). The [Ca2+]i levels in platelets were significantly correlated with both systolic (r = 0.50, P less than 0.05) and diastolic blood pressures (r = 0.57, P less than 0.01). Resting vascular resistance and minimal vascular resistance were significantly higher in essential hypertensives than in normotensives (30.6 +/- 12.6 and 2.57 +/- 1.30 versus 16.3 +/- 8.0 and 1.47 +/- 0.63 mmHg/ml per min per 100 ml, P less than 0.05 and P less than 0.01, respectively). Both resting and minimal vascular resistance were significantly correlated with [Ca2+]i in platelets (r = 0.40 and P less than 0.05, r = 0.55 and P less than 0.01, respectively). These results suggest that [Ca2+]i in platelets reflects [Ca2+]i in vascular smooth muscle cells and may be a significant determinant of not only tone but also structural changes of resistance vessels.

Differences in vasodilating action between ketanserin, a 5-HT2-serotonergic receptor antagonist, and terazosin, an alpha 1-adrenoceptor antagonist, in anesthetized rabbits.

It has not yet been demonstrated clearly whether the antihypertensive action of ketanserin is due to 5-hydroxytryptamine type-2 (5-HT2)-serotonergic receptor blockade or to alpha 1-adrenergic receptor blockade. The present study was performed to evaluate in vivo the antihypertensive action of ketanserin in comparison with that of terazosin, a selective alpha 1-adrenoceptor antagonist. The changes of renal blood flow (RBF) after intrarenal injection of phenylephrine, 5-HT, or angiotensin II were measured in anesthetized rabbits. RBF responses induced by these vasoconstrictors with or without pretreatment with ketanserin (0.2, 1.0, and 5.0 mg/kg, i.v.) or terazosin (0.04, 0.2, and 1.0 mg/kg, i.v.) were examined. Following intrarenal injection, RBF decreased by 20.8%, 22.7%, and 23.0% respectively, without ketanserin and also decreased by 21.0%, 21.6%, and 24.4%, respectively, without terazosin. Following pretreatment with a small dose of ketanserin or terazosin, the vasoconstricting effects of phenylephrine were attenuated by 20% or 62% (delta% changes in RBF), respectively. The effects of 5-HT on RBF responsiveness were blocked by ketanserin in a dose-dependent manner. Ketanserin did not modify the RBF responses to angiotensin II. These findings indicate that the antihypertensive effect of ketanserin, to a certain extent, depends on the blockade of the 5-HT2-serotonergic receptor in addition to that of the alpha 1-adrenoceptor, whereas the renin-angiotensin system is not involved in the hypotensive effects of ketanserin.

Cardiovascular effects of ICI 118,587, a new beta-adrenoceptor partial agonist in man.

Effects of a new selective beta1 partial agonist, ICI 118,587, on cardiac function were assessed in clinical settings. In 7 patients, responses to multistage treadmill exercise were studied before and after an acute intravenous injection of the drug. The heart rate and blood pressure were not altered by ICI 118,587 at rest but increases in both parameters in response to exercise were significantly reduced. Neither oxygen consumption nor plasma norepinephrine level was modified by the drug both at rest and during exercise. The long term effects of ICI 118,587 were assessed in 6 patients with mild to moderate cardiac failure consequent upon ischemic heart disease. After chronic administration of the drug exercise duration was increased. The symptom-limited maximal oxygen consumption increased by 16%, associated with prolongation of the exercise tolerance. In those patients who also had symptoms of angina pectoris, exercise levels which caused angina during the control study were tolerated without symptoms after ICI 118,587. Twelve patients with nocturnal bradycardia resulting from atrial fibrillation of sick sinus syndrome were treated with ICI 118,587. Monitoring of heart rate by 24-hour Holter ECG showed that ICI 118,587 increased minimal heart rate during sleep. Being a beta1-adrenoceptor partial agonist, it has both agonist and antagonist properties. Thus, ICI 118,587 buffers the heart from an excessively low sympathetic tone which may occur during sleep and from an excessively high tone during exercise. It appears to be of benefit in the treatment of mild to moderate cardiac failure consequent upon ischemic heart disease. It also improves oxygen demand-supply imbalance without inducing further myocardial depression or inappropriate bradycardia at rest. ICI 118,587 may therefore be described as a cardiostabilizer.