Telmisartan has the strongest binding affinity to angiotensin II type 1 receptor: comparison with other angiotensin II type 1 receptor blockers.

There is a growing body of evidence that the renin-angiotensin system (RAS) plays a pivotal role in the pathogenesis of cardiovascular diseases. Indeed, large clinical trials have demonstrated a substantial benefit of the blockade of this system for cardiovascular-organ protection. Although several types of angiotensin II type 1 (AT1) receptor blockers (ARBs) are commercially available for the treatment of patients with hypertension, comparisons of the binding affinity to AT1 receptor among them remain to be elucidated. In this study, we examined the dissociation rate of several ARBs from AT1 receptor in vitro. Angiotensin II time-dependently dissociated telmisartan, olmesartan, candesartan, valsartan, losartan and an active metabolite of losartan, EXP3174, from membrane components containing human AT1 receptor The dissociation rate constant of each ARB was 0.003248, 0.004171, 0.005203, 0.009946, 0.01027 and 0.008561 min(-1), with corresponding half-lives of 213, 166, 133, 70, 67 and 81 min, respectively. These results demonstrate that telmisartan has the strongest binding affinity to AT1 receptor among various ARBs examined herein. The rank order of affinity was telmisartan > olmesartan > candesartan > EXP3174 > or = valsartan > or = losartan. The present findings suggest that telmisartan (Micardis) may have long-lasting blood pressure-lowering effects and superior cardioprotective properties in patients with hypertension due to its strongest AT1 receptor antagonistic ability.

Kinetics of faceting driven by attractive step-step interactions on vicinal Si(113).

We have studied the far-from-equilibrium kinetics of faceting caused by short-ranged attractive step-step interactions on vicinal Si(113), using scanning tunneling microscopy. We show that a network of step bunches coarsens via both zipping up of the neighboring step bunches and irreversible binding events which alter the local topological configuration. A step-network model which incorporates the irreversible step-bunch-binding events yields quantitative understanding of the experimental results.

Ethenesulfonamide and ethanesulfonamide derivatives, a novel class of orally active endothelin-A receptor antagonists.

In the previous paper, we described a series of 2-phenylethenesulfonamide derivatives, a novel class of ET(A)-selective endothelin (ET) receptor antagonists, including the 2-methoxyethoxy derivative 2a and the 2-fluoroethoxy derivative (2b). In this paper, we wish to report further details of structure-activity relationships (SARs) of the two regions of the molecule in compound 2b, which were the alkoxy region at the 6-position of the core pyrimidine ring and the 2-phenylethenesulfonamide region. In these modifications, replacement of the 2-fluoroethoxy group with a methoxy group (6e) and replacement of the 2-phenylethenesulfonamide group with a 2-(pyridin-3-yl)ethenesulfonamide group (6l) or 2-phenylethanesulfonamide group (6q) were well tolerated both in the ET(A) binding affinity and ET(A) selectivity. Among them, compound 6e showed further improvement in oral activity compared to 2b. After oral administration, compound 6e inhibited the big ET-1 induced pressor response in conscious rats at 0.3mg /kg with a duration of >6.5h. Compound 6e also exhibited a potent antagonistic activity in the pithed rats.

Ethenesulfonamide derivatives, a novel class of orally active endothelin-A receptor antagonists.

In the present article we wish to report the discovery of a novel class of ET(A)-selective endothelin (ET) receptor antagonists through the modification of the ET(A)/ET(B) non-selective antagonist, Ro47-0203 (Bosentan, 1). Replacement of the benzenesulfonamide group of 1 with a 2-phenylethenesulfonamide group gave compound 5a and resulted in improvement in ET(A)-selectivity. Optimization of the alkoxy side chain attached to the core pyrimidine ring yielded the 2-fluoroethoxy derivative (5n) with further improvement of ET(A)-selectivity. [IC50=2.1 nM for ET(A) receptor, ET(B)/ET(A) ratio=1200]. After oral administration, compound 5n inhibited the big ET-1 induced pressor response in pithed rats with a DR2 value of 2.6 mg/kg and also exhibited a potent antagonistic activity in conscious rats.

Synthesis and structure-activity relationships in a series of ethenesulfonamide derivatives, a novel class of endothelin receptor antagonists.

In the previous paper, we described a series of the 2-arylethenesulfonamide derivatives, a novel class of ETA-selective endothelin (ET) receptor antagonists, including the compounds 1a, b. Compound 1a showed excellent oral antagonistic activities and pharmacokinetic profiles, and the monopotassium salt of 1 (YM-598 monopotassium) is in clinical trials. In this paper, we wish to report the investigation of the further details of structure-activity relationships (SARs) of the 2-phenylethenesulfonamide region in 1a. It was found that methyl substitutions at the 2-, 4- and 6-positions of the phenyl group in 1a led to the discovery of the ET(A)/ET(B) mixed antagonist (6s) with an IC50 of 2.2 nM for the ET(A) receptor. We also found that introduction of an ethyl group to the 1-position of the ethenyl group in 1a gave the ET(A) selective antagonist (6u) with an oral endothelin antagonistic activity in rats.

Effect of YM435, a novel dopamine DA1 receptor agonist, in a canine model of acute congestive heart failure.

1. The effects of YM435, a dopamine DA1 receptor agonist, were evaluated in a canine model of acute congestive heart failure. 2. The model was induced in open-chest anesthetized dogs by left anterior descending coronary artery ligation, volume loading, and intravenous infusion of angiotensin II. This resulted in a moderate and stable congestive heart failure characterized by reduction in cardiac output and increases in left ventricular end-diastolic pressure and total peripheral vascular resistance. 3. Intravenous infusion of YM435 (1 microgram/kg/min) significantly decreased left ventricular end-diastolic pressure, total peripheral vascular resistance and mean blood pressure and significantly increased cardiac output and renal blood flow in this model. 4. These results indicate that intravenous infusion of YM435 can improve hemodynamics and cardiac function in a canine model of acute congestive heart failure. YM435 may be a useful therapeutic agent for the treatment of congestive heart failure.

Pharmacokinetics of CPT-11 in rhesus monkeys.

PURPOSE: To examine the pharmacokinetic relationships between humans and monkeys, we studied the disposition of 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin (CPT-11) and its active metabolite, 7-ethyl-10-hydroxycamptothecin (SN-38), in rhesus monkeys. METHODS: CPT-11 was administered to a total of six monkeys at doses of 3, 7, 15 and 25 mg/kg by intravenous infusion for 10 min and plasma concentrations and pharmacokinetic parameters of CPT-11 determined. RESULTS: Maximum plasma concentrations at 25 mg/kg reached around 10000 ng/ml, and dropped to 500 ng/ml in 8 h. Plasma concentrations of SN-38 remained between 2 and 10 ng/ml. Mean values of systemic clearance, mean residence time and distribution volume at steady state, the major pharmacokinetic parameters for CPT-11, were 13.3 (ml/min per kg), 192 (min) and 2553 (ml/kg), respectively. The initial plasma concentration ratio of lactone to total CPT-11, 76%, declined to about 20% within 75 min, and the final ratio was about 40% at 8 h; the initial ratio of SN-38 was 72%, dropped to 34% within 70 min and finally recovered to 55% at 8 h. CONCLUSION: Comparison with human data revealed that systemic clearances of CPT-11 and the maximum AUC of SN-38 were not as different between humans and monkeys as between humans and mice, but the metabolic conversion of CPT-11 into SN-38 in monkeys was significantly lower than in humans.

[Stenosis of Carpentier-Edwards pericardial bioprosthesis in the tricuspid position caused by adhesion of native valve cusps to the bioprosthesis].

We experienced a case of dysfunction of Carpentier-Edwards pericardial bioprosthesis in the tricuspid position. Explanted bioprosthesis showed overgrowth of neointima from ring to cusps and adhesion to remnants of native cusps. This restricted the motion of the pericardial leaflets resulting in orifice stenosis. Care must be taken in such valve replacement by this prosthesis leaving native valve tissue.

Different effect of anticholinergic agents and potassium channel openers on urinary bladder response to pelvic nerve stimulation in anaesthetized dogs.

1. Effects of the anticholinergic agents atropine, oxybutynin, and terodiline, and the potassium channel openers YM934 (2-(3,4-dihydro-2,2-dimethyl-6-nitro-2H-1,4-benzoxazin-4-yl) pyridine N-oxide) and cromakalim were examined on urinary bladder response to pelvic nerve stimulation in pentobarbital-anaesthetized dogs. 2. Pelvic nerve stimulation (PNS) produced a frequency-dependent increase in intravesical pressure in anaesthetized dogs. The response to PNS was abolished by topical tetrodotoxin, and markedly inhibited by intravenous hexamethonium, suggesting a neurogenic origin for the in vivo contractile response. 3. Atropine (0.3-3 mg kg-1 i.v.) and the anti-neurogenic bladder agents, oxybutynin (1-10 mg kg-1 i.v.) and terodiline (1-10 mg kg-1 i.v.) dose-dependently decreased the amplitude of the peak intravesical pressure response to PNS. At either frequency of PNS, these agents inhibited the response to a similar degree. 4. The potassium channel openers YM934 (1-10 micrograms kg-1 i.v.) and cromakalim (3-30 micrograms kg-1 i.v.) dose-dependently decreased the amplitude of the peak intravesical pressure response to PNS. The inhibitory effects of these drugs were more potent at lower than at higher frequencies of PNS. 5. These data suggest that the inhibitory effects of potassium channel openers on urinary bladder response to PNS are different from those of anticholinergic agents. The preferential inhibitory effect of potassium channel openers on detrusor smooth muscle contraction at lower frequencies of PNS may represent new potential for the treatment of neurogenic bladder.

Effect of alpha 1-adrenoceptor antagonists on urinary bladder function in urethane-anesthetized rats.

1. We investigated the effects of selective alpha 1-adrenoceptor antagonists on rhythmic bladder contraction and cystometrograms as representative of urinary bladder function in urethane-anesthetized rats. 2. The selective alpha 1-adrenoceptor antagonists tamsulosin (0.03-3 micrograms/kg IV), prazosin (0.03-3 micrograms/ kg IV) and bunazosin (0.03-3 micrograms/kg IV) exerted little effect on the amplitude and frequency of rhythmic bladder contraction in anesthetized rats. In contrast, the antipollakiuria agent flavoxate (5 and 10 mg/kg IV) induced a dose-dependent disappearance in frequency without affecting the amplitude of the contractions. 3. Tamsulosin (1 and 3 micrograms/kg IV), prazosin (1 and 3 micrograms/kg IV), and bunazosin (1 and 3 micrograms/kg IV) exerted no effect on the cystometrogram, either. However, flavoxate (5 and 10 mg/kg IV) raised the micturition threshold pressure and prolonged the time to micturition. 4. These results suggest that the alpha 1-adrenoceptor plays little role in urinary bladder contraction in anesthetized rats.

Responsiveness of smooth muscle in the lower urinary tract of rabbits to various agonists.

1. We compared the responsiveness of smooth muscle in the lower urinary tract and prostate from rabbits to the agonists noradrenaline, phenylephrine, clonidine, acetylcholine, prostaglandin F2 alpha, and histamine. 2. These agonists contracted smooth muscle in the lower urinary tract and prostate. In terms of maximal developed tension, contractile responses to the agonists were produced in the following order of potency: acetylcholine > prostaglandin F2 alpha > histamine > or = phenylephrine > or = noradrenaline > clonidine in the urinary bladder body; acetylcholine = noradrenaline = phenylephrine > prostaglandin F2 alpha > histamine > or = clonidine in the urinary bladder base; noradrenaline > or = phenylephrine > or = clonidine > acetyl-choline > prostaglandin F2 alpha > or = histamine in the urethra; and noradrenaline > or = phenylephrine > histamine = acetylcholine = clonidine = prostaglandin F2 alpha in the prostate. 3. These results suggest that considerable responsiveness variation occurs in the lower urinary tract and prostate and support the idea that the urinary bladder body is primarily governed by cholinergic mechanisms (parasympathetic nerves), whereas the urethra and prostate are regulated by alpha 1-adrenergic mechanisms (sympathetic nerves) and the bladder base by both.

Decreased contractile effect of endothelin-1 on hyperplastic prostate.

1. The contractile activity, binding activity and localization of endothelin (ET)-1 were evaluated in human nonhyperplastic (control) and hyperplastic prostates. 2. ET-1 caused contraction of both prostates in a dose-dependent manner. However, this contraction was markedly decreased in hyperplastic prostates. 3. Bmax and Kd values of hyperplastic prostates were greater than those of the control. 4. The muscle and proliferative epithelium of hyperplastic prostates showed strong staining for the anti-ET-1 antibody. However, the glandular epithelium of control prostates was weakly stained. 5. These findings indicate that responsiveness to ET-1 is decreased, though the ET-1 and ET-1 receptors increase in the hyperplastic prostate. Namely, the increase in ET-1 receptors is not effective in regulating the contractile response of the prostate, because its expression is rather dominant in proliferated gland. 6. These suggest that ET-1 may not have an important role in the release of the obstructive symptoms of benign prostatic hypertrophy.

Effect of tamsulosin, a novel alpha 1-adrenoceptor antagonist, on urethral pressure profile in anaesthetized dogs.

1. The effect of tamsulosin (YM617, (R) (-)-S-[2-[[2-(o-ethoxyphenoxy)ethyl]amino] propyl]-2-methoxybenzenesulfonamide HCl), a potent and selective alpha 1-adrenoceptor antagonist, was examined on urethral pressure profile (UPP) and mean arterial blood pressure (MBP) in pentobarbital anaesthetized male dogs. 2. Selective alpha 1-adrenoceptor antagonists tamsulosin (1-100 micrograms kg-1 i.v.), prazosin (1-100 micrograms kg-1 i.v.) and bunazosin (1-100 micrograms kg-1 i.v.) produced a dose dependent reduction in prostatic pressure in the UPP. Doses required to reduce prostatic pressure in UPP by 30% were 3.6 +/- 0.8 (n = 8), 6.9 +/- 1.5 (n = 8) and 4.6 +/- 0.9 (n = 8) micrograms kg-1 i.v., respectively. At the highest dose, tamsulosin exerted less hypotensive effect than prazosin and bunazosin. 3. The calcium antagonist nicardipine (0.1-10 micrograms kg-1 i.v.) and angiotensin converting enzyme inhibitor captopril (10-1,000 micrograms kg-1 i.v.) reduced MBP in a dose dependent manner, but exerted no effect on prostatic pressure in the UPP. The diuretic trichloromethiazide (1-100 micrograms kg-1 i.v.) exerted no effect on UPP or MBP. Treatment with nicardipine (3 micrograms kg-1 i.v.), captopril (100 micrograms kg-1 i.v.) or trichlormethiazide (100 micrograms kg-1 i.v.) did not affect relaxant effect of tamsulosin on prostatic pressure in UPP, or potentiate its hypotensive effect. 4. These results suggest that the alpha 1-adrenoceptor regulates urethral pressure as well as blood pressure in anaesthetized dogs, and that alpha 1-adrenoceptor antagonists may be useful in the treatment of micturition disorders associated with benign prostatic hyperplasia. In addition, as tamsulosin decreased urethral pressure with less hypotension, and as its effect was not influenced by treatment with hypotensive drugs, it may be a useful drug for the treatment of micturition disorders with few cardiovascular side effects.

[Operative removal of esophageal leiomyosarcoma: a case report].

This is a case report of 56-year-old man complaining of dysphasia. Upon admission, his chest X-ray film revealed medium amount of fluid accumulation in the right pleural space. Cytological examination of the aspirated fluid revealed nothing particular. Preoperative radiological examination including esophagogram, CT and MRI demonstrated cystic appearance of mass lesion, measuring approximately 5 cm in size located in posterior aspect of the lower portion of the mediastinum. Upon operation, it was found that a tumor with pedunculated connection to the esophageal muscle layer, suspecting diagnosis of leiomyoma of the esophagus. Then, tumor was removed together with the part of esophageal muscle. Postoperative pathology reported leiomyosarcoma of the esophagus with low grade malignancy. We added no esophagectomy. He made uneventful recovery without no sign of recurrence of the malignancy, 4 years after the surgery.

Pharmacological correlation between total drug concentration and lactones of CPT-11 and SN-38 in patients treated with CPT-11.

The pharmacokinetics of 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin (CPT-11) and its active metabolite, 7-ethyl-10-hydroxycamptothecin (SN-38), were examined to establish the pharmacokinetic variability of the active lactones of CPT-11 and SN-38 in comparison with that of the total (lactone and carboxylates) plasma CPT-11 and SN-38. Twelve patients with malignancies were entered in the study. All received 100 mg/m2 of CPT-11 by intravenous drip infusion over 90 min. Blood was sampled at 10 time points in heparin-containing syringes. Analysis by high-performance liquid chromatography showed that the ratio of CPT-11 lactone to total CPT-11 concentration was highest (66%) just after the end of infusion and gradually decreased to 30% at 24 h. Almost 70% of SN-38 lactone was detected after the end of infusion and this decreased to 50% within 24 h. The standard errors of percent lactone of CPT-11 of SN-38 to total drug concentration at each sampling point were less than 12%. The area under the concentration-time curve (AUC) of total CPT-11 and that of total SN-38 were significantly correlated with the AUCs of the lactone CPT-11 and those of lactone SN-38, respectively. We conclude that, for practical purposes, monitoring of total CPT-11 and SN-38 has essentially the same clinical significance as monitoring of lactone CPT-11 and SN-38.

Characterization of the adrenoceptor antagonistic and antihypertensive activity of oral amosulalol, a combined alpha- and beta-adrenoceptor antagonist, in hypertensive rats.

The adrenoceptor antagonistic and antihypertensive effects of amosulalol, 5-[1-hydroxy-2-[[2-(o- methoxy)ethyl]-2-ethylbenzenesulfonamide HCl, a combined alpha- and beta-adrenoceptor antagonist, were examined in hypertensive rats. Oral administration of amosulalol (1-30 mg/kg) produced a dose-dependent antihypertensive effect without reflex tachycardia in conscious spontaneously hypertensive rats (SHR) with a duration > 10 h after the higher doses (10 and 30 mg/kg). Amosulalol was approximately threefold more potent than labetalol and arotinolol in decreasing blood pressure (BP) in conscious SHR. Oral (p.o.) administration of amosulalol 10 mg/kg produced equally potent reductions in mean arterial BP (MBP) without reflex tachycardia in deoxycorticosterone acetate-salt rats (DHR) and renal hypertensive rats (RHR) as it did in SHR. Repeated oral administration (1, 4, 8, or 12 weeks) of amosulalol 10 mg/kg elicited an antihypertensive effect without evidence of tolerance in conscious SHR and produced a rightward shift in phenylephrine (PE)-induced vasopressor and isoproterenol (ISO)-induced positive chronotropic responses with dose ratios of 3.3-12.5 and 3.7-6.4, respectively, in pithed SHR. In addition, single p.o. administration of amosulalol 10 mg/kg produced a rightward shift in these responses with dose ratios of 12.1 and 3.5, respectively, in pithed SHR. Amosulalol exerted antihypertensive activity without tachycardia through blockade of vascular alpha- and cardiac beta-adrenoceptors, and its activities were constant even after repeated p.o. administration.

[An hourglass type intrathoracic lipoma--a case report of surgical treatment].

We report a rare case of hourglass type intrathoracic lipoma. Until now, there are 114 reported cases on intrathoracic lipoma in Japanese literature, among which 22 are hourglass type. The patient was a 43-year-old woman, who was found to have a pleural tumor on her chest X-ray examination for healthy check-up. Computed tomography showed that it had intra- and extrathoracic portion with almost the same density as the subcutaneous fat tissue. The tumor was excised along with pleura, periostia and intercostal muscle approximately 1 cm apart from it. It was dumbbell-shaped and weighed 30 grams. Microscopically it was found to be intramuscular lipoma. According to Fletcher, intramuscular lipoma was classified into two groups of infiltrative and non-infiltrative type. In their cases, infiltrative intramuscular lipomas recurred up to 19%, mainly secondary to incorrect resection. Our case corresponds to infiltrative type. We consider that intrathoracic lipoma, though benign, have to be resected radically with utmost care.

Characterization of [3H]YM617, R-(-)-5-[2-[[2[ethoxyring(n)-3H](o-ethoxyphenoxy)ethyl]amino]- propyl]-2-methoxybenzenesulfonamide HCl, a potent and selective alpha-1 adrenoceptor radioligand.

The binding properties of a new radioligand, R(-)-5-[2-[[2[ethoxyring(n)-3H](o- ethoxyphenoxy)ethyl]amino]propyl]-2-methoxybenzenesulfonamide++ + HCl ([3H]YM617), were studied in membranes of the rat hippocampus and spleen. [3H]YM617 rapidly associated with its binding sites in both membranes and reached steady state by 20 min at 25 degrees C. The specific binding of [3H]YM617 appeared to be saturable, and Scatchard analysis revealed a linear plot, suggesting a single population of binding sites with a dissociation constant of 0.170 +/- 0.016 nM (n = 6) in the hippocampus and 0.195 +/- 0.036 (n = 4) in the spleen. The maximal binding sites in the hippocampus and spleen were 203.0 +/- 43.2 (n = 6) and 72.4 +/- 17.0 (n = 4) fmol/mg protein, respectively. Chlorethylclonidine (10(-5) M for 10 min) treatment reduced the Bmax values of [3H]YM617 and [3H]prazosin to a similar degree in the rat hippocampus (10-15%) and spleen (40-50%). Alpha adrenoceptor agonists and antagonists competed with [3H]YM617 for binding sites in the following order: YM617 > prazosin > WB4101 > bunazosin > 5-methylurapidil > S(+)-isomer of YM617 > phentolamine > yohimbine > norepinephrine = phenylephrine > methoxamine in the hippocampus, and prazosin > YM617 > bunazosin > WB4101 > 5-methylurapidil > phentolamine > S(+)-isomer of YM617 > yohimbine > norepinephrine > phenylephrine > methoxamine in the spleen. In the hippocampus, prazosin and bunazosin produced biphasic displacement of [3H]YM617, but not [3H]prazosin binding. In contrast, only monophasic curves were obtained against either radioligand in the spleen.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of the optical isomers of YM-12617 on increased intra-urethral pressure induced by phenylephrine in anaesthetized dogs.

1. Effects of the individual optical isomers of YM-12617 (R, S 5-[2-[[2-(o-ethoxyphenoxy)ethyl]-amino]propyl]-2- methoxybenzenesulphonamide HCl, (+/-)-YM), a potent selective alpha 1-adrenoceptor antagonist, on the increase in intraurethral pressure (IUP) and diastolic blood pressure (DBP) induced by phenylephrine were evaluated in pentobarbital-anaesthetized female dogs. 2. Phenylephrine (0.1-30 micrograms kg-1 i.v.), an alpha 1-adrenoceptor agonist, dose-dependently increased IUP and DBP. 3. alpha-adrenoceptor antagonists (i.v.) dose-dependently antagonized the increase in IUP and DBP induced by phenylephrine, with a potency ranking of R(-)-YM greater than (+/-)-YM greater than prazosin greater than phentolamine greater than S(+)-YM greater than yohimbine. 4. These results suggest that the alpha 1-adrenoceptor mediates the increase in IUP as well as DBP in anaesthetized dogs, and that alpha 1-adrenoceptors in the urethra and arteries show a stereochemical preference for R(-)-YM.