Stereoselectivity of a potent calcium antagonist, 1-benzyl-3-pyrrolidinyl methyl 2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate

Four enantiomers (3a-d) of the title compound, YM-09730 (3), were synthesized by the reaction of (-)- or (+)-5-(methoxycarbonyl)-2, 6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid (1a or 1b) with (S)- or (R)-1-benzyl-3-pyrrolidinol (2a or 2b). [3H]Nitrendipine binding affinity and coronary vasodilating activity of these compounds were evaluated. The absolute configuration of the most potent enantiomer (3a) with the longest duration was unequivocally determined to be (S)-1,4-dihydropyridine-C4 and (S)-pyrrolidine-C3 (S,S) by X-ray crystallographic study on 3a X HBr as well as 3a X HCl. The configuration of 1a corresponds to R, and the other enantiomers of 3 were respectively determined by chemical correlation. The potency order of the four enantiomers was (S,S)-3a greater than (S,R)-3b greater than (R,R)-3d greater than (R,S)-3c. Latent chiral characters of nifedipine derivatives with the identical ester groups were assigned by comparison of their puckering modes of 1,4-dihydropyridine (DHP) rings with those found in 3a X HCl or 3a X HBr. On the basis of the assignment, it has been revealed that the (S)-DHP nifedipine derivatives possess the synperiplanar carbonyl group at C5. The conformational restriction may be a factor causing stereoselectivity of antagonism.     

Effects of dominant and nondominant eyes in binocular rivalry.

PURPOSE: To investigate the relation between sighting and sensory eye dominance and attempt to quantitatively examine eye dominance using a balance technique based on binocular rivalry. METHODS: The durations of exclusive visibility of the dominant and nondominant eye target in binocular rivalry were measured in 14 subjects. The dominant eye was determined by using the hole-in-card test (sighting dominance). In study 1, contrast of the target in one eye was fixed at 100% and contrast of the target in the other eye was varied from 100% to 80% to 60% to 40% to 20%, when using rectangular gratings of 1, 2, and 4 cycles per degree (cpd) at 2 degrees, 4 degrees , and 8 degrees in size. In study 2, contrast of the target in the nondominant eye was fixed at 100% and contrast of the target in the dominant eye was varied from 100% to 80% to 60% to 40% to 20%, when using a rectangular grating of 2 cpd at 4 degrees in size. RESULTS: In study 1, the total duration of exclusive visibilities of the dominant eye target; that is, the target seen by the eye that had sighting dominance was longer compared with that of the nondominant eye target. When using rectangular gratings of 4 cpd, mean total duration of exclusive visibility of the dominant eye target was statistically longer than that of the nondominant eye target (p < 0.05). In study 2, reversals (in which duration of exclusive visibility of the nondominant eye becomes longer than the dominant eye when the contrast of the dominant eye target is decreased) were observed for all contrasts except for 100%. CONCLUSIONS: The dominant sighting eye identified by the hole-in-card test coincided with the dominant eye as determined by binocular rivalry. The contrast at which reversal occurs indicates the balance point of dominance and seems to be a useful quantitative indicator of eye dominance to clinical applications.     

Treatment with hypotensive agents affects the impaired relaxation of the penile corpus cavernosum in hypertensive rats.

Treatment of erectile dysfunction (ED) in hypertensive subjects remains to be formally established. There is currently no standardized treatment for ED in hypertensive subjects. In this study, we tested our hypothesis that hypotensive drugs would improve impaired relaxation in the corpus cavernosum of spontaneously hypertensive rats (SHR). Ten-week-old SHR was treated with amlodipine, imidapril or hydralazine for 4 weeks. Although all three drugs achieved an equivalent decrease in systolic blood pressure (SBP), only amlodipine and imidapril induced an increase in relaxation in response to electrical field stimulation (EFS) of the corpus cavernosum. In the case of amlodipine, this effect was dose- and SBP-dependent. Nitric oxide (NO)-dependent relaxation was increased by amlodipine over a wide range of EFS frequencies, was increased by imidapril at low EFS frequencies, and was decreased by hydralazine. Carbon monoxide (CO)-dependent relaxation was only increased by hydralazine, and this increase occurred over a wide range of frequencies. The NOx and cGMP levels in the EFS-stimulated corpus cavernosum were increased by amlodipine. Amlodipine did not affect the thiobarbituric acid-reacting substance levels in the serum and the corpus cavernosum, but did decrease superoxide dismutase activity in the tissue. Imidapril and hydralazine inhibited the acetylcholine-induced relaxation in the corpus cavernosum. Sodium nitroprusside-induced relaxation in the tissue was increased by amlodipine. All three agents similarly inhibited the phenylephrine-induced contraction. These results suggest that impaired neurogenic relaxation in the corpus cavernosum of SHR is improved by amlodipine and imidapril through an increase in the synthesis and/or release of neuronal NO, but not CO, and presumably the inhibited detumescence of erection, which is induced by norepinephrine being released from sympathetic neuron. These findings indicate that amlodipine and imidapril may ameliorate the decreased relaxation of cavernous smooth muscle in the setting of hypertension.     

Atrial septal defect repair through limited lateral thoracotomy in children

Objective We have developed a surgical method for atrial septal defect repair through a limited right lateral thoracotomy in which the incision line begins 2 cm caudal from the lower angle of the scapula and ends at the midaxial line, thereby improving patient satisfaction with the cosmetic results of treatment. Methods We performed a retrospective review of 28 patients who underwent isolated atrial septal defect repair through a limited right lateral thoracotomy between January 2002 and August 2004. The mean age and mean body weight at the time of the operation were 85.8 months (range 9–236 months) and 23.0 kg (range 8.0–56.0 kg), respectively. All repaired defects were the ostium secundum type. Results There was no operative or late mortality and no late morbidity after a mean follow-up of 26 months (range 12–41 months). Echocardiography showed no residual shunt in any of the patients. The mean length of the skin incision was 7.8 cm (range 5.0–11.0 cm), and almost all the patients had satisfactory cosmetic results. Conclusion The atrial septal defect repair through a limited right lateral thoracotomy in pediatric patients showed satisfactory surgical results and excellent cosmetic results.     

Solitary right ventricle metastasis by renal cell carcinoma.

A 57-year-old man with a history of renal cell carcinoma presented with presyncope. He underwent nephrectomy years earlier followed by HLA-matched allogeneic peripheral-blood stem-cell transplantation. Echocardiographic investigation revealed a solitary right ventricle mass without contiguous vena caval or right atrial involvement. The mass was pathologically confirmed to be metastatic carcinoma in the right ventricular cavity. This case highlights the need to consider an underlying neoplastic syndrome in patients presenting isolated right ventricle mass by echocardiography.     

HTLV-I, HIV-I, and Hepatitis B and C Viruses in Western Province, Papua New Guinea: A Serological Survey

Seven hundred and twenty-three serum samples from individuals in 13 Gidra-speaking villages in Western Province, Papua New Guinea were tested for evidence of infection with human T- lymphotropic virus type I (HTLV-I), human immunodeficiency virus type I (HIV-I), hepatitis B virus (HBV) and hepatitis C virus (HCV). No samples were positive for antibodies to HIV-I. Antibodies to HTLV-I were found in 13 samples (1.8%), HBV surface antigens (HBsAg) were found in 86 samples (11.9%), and antibodies to HCV were found in 30 samples (4.1%). Six (46.2%) of 13 HTLV-I positive samples were positive for HCV or HBsAg. The seropositive rate varied in different villages and the incidence of HTLV-I and HCV was higher in coastal and riverine areas than inland.     

A CASE OF METASTATIC YOLK SAC TUMOR OF TESTIS IN A CHILD

We report a case of testicular yolk sac tumor in a child aged 3 years and 6 months with multiple bulky metastases to lung and retroperitoneum (stage 11182). After three courses of chemotherapy with a PV 8 regimen (cisplatin, vinblastine and bleomycin). complete and partial responses were obtained for lung and retroperitoneal lymph node metastases, respectively. The patient was followed-up closely. However, on the basis of a re-elevated alpha-letoprotein (AFP) after 4 months' follow-up, he was treated with three courses of salvage chemotherapy with a modified VAB-6 regimen (cyclophosphamide. etoposide. actinomycin D, bleomycin and cisplatin), lollowed by retroperitoneal lymph node dissection. Histologically, only necrotic tissue was found. There is no evidence of recurrence 24 months after lymphadenectomy. There is very little information in the literature on the appropriate management of postchemotherapy residual mass in pediatric testicular tumors.     

Surgical treatment for ischemic mitral regurgitation: strategy for a tethered valve.

Recently, ischemic mitral regurgitation (IMR) has been shown to be an individual risk factor for ischemic heart disease. The main mechanism of IMR is tethering of the leaflet secondary to left ventricular (LV) dilatation. In this situation, surgical treatment for IMR has been limited to ring annuloplasty with varying degrees of effectiveness. However, mid-term follow-up studies have shown that the results obtained with this approach are not satisfactory. Therefore, there has been a need to develop additional techniques to achieve more secure repair of IMR. The characteristics of the mitral leaflet configuration in IMR are apical displacement of the leaflets relative to the annulus, concavity of the leaflets, and a dilated annulus. Our basic strategy for a tethered mitral valve is rigid ring annuloplasty and inward correction of the outwardly displaced papillary muscle. For the latter correction, we employ the overlapping method or septal anterior ventricular exclusion (SAVE) procedure for LV volume reduction in cases of broad antero-septal infarction, or elevate the posterior papillary muscle by folding the LV wall at the root of the posterior papillary muscle via a small incision in the inferior wall in cases of infero-posterior infarction. An additional procedure is chordal cutting in combination with rigid ring annuloplasty and papillary muscle imbrication in combination with LV volume reduction. We have successfully combined these methods with the aid of detailed echocardiographic studies in individual patients. However, long-term follow-up will be necessary before this approach can be routinely adopted.