Effect of solvents on the thermal isomerization of 1 alpha-hydroxyprevitamin D3 diacetate to 1 alpha-hydroxyvitamin D3 diacetate

The thermal conversion of 1 alpha-hydroxyprevitamin D3 (1 alpha-OH-previtamin D3) diacetate to 1 alpha-hydroxyvitamin D3 (1 alpha-OH-vitamin D3) diacetate was investigated in five solvents. The fraction of 1 alpha-OH-vitamin D3 diacetate was calculated from the HPLC peak areas (UV detection) of 1 alpha-OH-previtamin D3 diacetate and 1 alpha-OH-vitamin D3 diacetate. When 1 alpha-OH-previtamin D3 diacetate was dissolved in ethanol, benzene, toluene, isopropyl ether, or n-hexane, and heated at 60 degrees C, the yield of 1 alpha-OH-vitamin D3 diacetate increased during the first 4 h, and reached an equilibrium level after 8.5 h. Differences in the ratio of 1 alpha-OH-previtamin D3 diacetate to 1 alpha-OH-vitamin D3 diacetate at thermal equilibrium, and in the rate of the thermal isomerization were observed among these five solvents. Molecular mechanics (MM) calculations were performed in order to estimate solvent effects on conformation for 1 alpha-OH-previtamin D3 diacetate and 1 alpha-OH-vitamin D3 diacetate. The solvent effect was treated by specifying a dielectric constant representative of each of the three solvents: ethanol (polar), n-hexane (nonpolar), and benzene (aromatic). The dielectric constants used were 24.3 for ethanol, 1.5 for n-hexane, and 2.3 for benzene. It is suggested that the conformation of 1 alpha-OH-vitamin D3 diacetate is stabilized in polar solvent. However, the order of conformational stability when solvent effects are included in the calculations is: ethanol greater than benzene greater than n-hexane. This order does not follow the experimental results. The proton NMR chemical shifts of 1 alpha-OH-vitamin D3 diacetate are different in deuterated n-hexane, ethanol, and benzene. The downfield shift of the C-6 vinyl proton of 1 alpha-OH-vitamin D3 diacetate, when compared to the chemical shift in benzene, is 0.15 and 0.11 ppm relative to the chemical shift in n-hexane and ethanol, respectively, and that of the C-7 proton was 0.30 and 0.33 ppm, respectively. No significant proton shift of 1 alpha-OH-previtamin D3 diacetate is recorded in these three solvents. To account for the increased ratio of 1 alpha-OH-vitamin D3 diacetate to 1 alpha-OH-previtamin D3 diacetate ratio in benzene, we suggest that 1 alpha-OH-vitamin D3 diacetate may be stabilized via specific solute-solvent interactions in benzene.     

Differentiation inducing effects of vesnarinone on human glioma cells

The effects of 3,4-dihydro-6-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]-2(1H)-quinolinone (vesnarinone) on the growth of glioma cells were examined in vitro. Vesnarinone at a dose of 100 mug/ml suppressed the growth of four different glioma cell lines, U-251MG, U-373MG, U-87MG and A-172, by approximately 50%, with an elongation of the cytoplasmic process on day 5 of culture. The long-term culture of U-87MG with 10 mug/ml of vesnarinone was continued up to day 34. Although growth suppression was approximately 25% on day 5, it reached over 95% on day 34. An increase in the cyclic adenosine monophosphate content of glioma cells cultured with vesnarinone was observed by enzyme-linked immunosorbent assay (ELISA). The accumulation of glial fibrillary acidic protein was observed to occur with vesnarinone by ELISA. These findings suggest that vesnarinone suppressed the growth and induced differentiation of glioma cells in vitro.     

Basic and clinical studies on imipenem/cilastatin sodium in the pediatric field

Basic and clinical studies have been performed on imipenem/cilastatin sodium (MK-0787/MK-0791) in the pediatric field. Antibacterial activities of MK-0787 against 14 clinical isolates of S. aureus and 67 isolates of E. coli were determined. The MIC of MK-0787 was 0.10 microgram/ml or less against all 14 strains of S. aureus. The MIC of MK-0787 was 0.39 microgram/ml or less against all 67 strains of E. coli. The pharmacokinetics of MK-0787/MK-0791 was studied at dose levels of 10 mg/10 mg/kg and 20 mg/20 mg/kg. The peak serum levels of MK-0787 achieved approximately 1 hour after the administration of 10 mg/10 mg/kg and 20 mg/20 mg/kg doses were 38.6 micrograms/ml and 36.2 micrograms/ml, respectively. The serum half-lives were 0.8 hour and 0.9 hour, respectively. The total 6-hour urinary excretions were 82.1% and 66.7%, respectively. The MK-0787/MK-0791 was administered to 13 children with bacterial infections. The clinical results were excellent or good in all cases. The overall efficacy rate was 100%. As a side effect, diarrhea was observed in 1 patient. Abnormalities in laboratory findings observed were elevation of direct bilirubin in 1 patient, thrombocytosis in 2, and a prolonged prothrombin time in 1 patient. Based on the above results, it can be concluded that MK-0787/MK-0791 is a safe and effective drug to use for the treatment of pediatric infections.     

Structure and solution conformation of the cytostatic cyclic tetrapeptide WF-3161, cyclo[L-leucyl-L-pipecolyl-L-(2-amino-8-oxo-9, 10-epoxydecanoyl)-D-phenylalanyl]

The sequence and configuration of amino acids in the cytostatic cyclic tetrapeptide WF-3161 are established as cyclo(L-Leu-L-Pip-L-Aoe-D-Phe) where Pip = pipecolic acid and Aoe = 2-amino-8-oxo-9,10-epoxydecanoic acid. In chloroform, WF-3161 adopts a conformation with a possible gamma-turn between Leu NH and Aoe C = O and a cis amide bond between Leu and Pip. The torsion angles for this conformation are L-Aoe, phi, -95 degrees, psi, +85 degrees, omega, -155 degrees; D-Phe, phi, +120 degrees, psi, -80 degrees, omega, -175 degrees; L-Leu, phi, -145 degrees, psi, +35 degrees, omega, -10 degrees; L-Pip, phi, +20 degrees, psi, -135 degrees, omega, -170 degrees. The cis,trans,trans,trans amide bond sequence is related to the dimethyl sulfoxide conformation of chlamydocin, another cytostatic cyclic tetrapeptide.     

The effects of chymase on matrix metalloproteinase-2 activation in neointimal hyperplasia after balloon injury in dogs.

Chymase is known to generate angiotensin II in the vascular wall. In this study we investigated a novel role for chymase other than angiotensin II production in vascular proliferation after balloon injury. Chymase promoted the migration of vascular smooth muscle cells in the matrix-coated invasion chambers and activated promatrix metalloproteinase-2 obtained from the culture medium of vascular smooth muscle cells. Two weeks after balloon injury, significant neointimal formation was found in dog carotid arteries. After injury, active matrix metalloproteinase-2 was increased in parallel with the augmentation of chymase activity that was seen in the proliferating region of the vascular wall. The oral administration of NK3201 (1 mg/kg per day), a chymase inhibitor, prevented neointimal formation and significantly suppressed both active matrix metalloproteinase-2 and chymase activities 2 weeks after injury. These results suggest that chymase inhibitors can prevent the development of intimal hyperplasia via the inhibition of matrix metalloproteinase-2 activation in balloon-injured arteries.     

Relation of inflammatory cytokines to atrial fibrillation after off-pump coronary artery bypass grafting.

OBJECTIVE: It has been observed that a systemic inflammatory response after on-pump coronary artery bypass grafting (CABG) participates in the pathogenesis of postoperative atrial fibrillation (AF). In patients undergoing off-pump CABG, it is plausible that inflammation is associated with the development of postoperative AF. The present study examined relation of proinflammatory cytokines, which play an important role in the upstream of inflammatory cascade, to the development of AF after off-pump CABG. METHODS: The present study included 39 patients undergoing off-pump CABG. Tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-6, and IL-8, were measured by enzyme-linked immunosorbent assay, on anesthetic induction, after sternotomy before anastomoses, at the completion of anastomoses, 3 and 6h thereafter, and on postoperative days (POD) 1-4. C-reactive protein (CRP) was also measured by turbidimetric immunoassay, preoperatively, and on POD 1, 2, 3, 6, 9, and 13. RESULTS: Eleven patients (28%) developed postoperative AF. Patients with postoperative AF were older (70+/-6.4 years vs 60+/-8.8 years, P=0.001); however, there was no difference in other pre- and perioperative variables. TNF-alpha level did not change during the study period. However, IL-8 and CRP levels significantly increased after the surgery, although there was no significant difference between the two groups. IL-6 level also increased after the surgery with its peak at 6h after the completion of anastomoses. IL-6 levels of 3 and 6h after anastomoses were significantly higher in patients with postoperative AF (360+/-143 pg/ml vs 230+/-94 pg/ml, P=0.0047, 435+/-175 pg/ml vs 247+/-102 pg/ml, P=0.0005, respectively). Logistic regression analysis indicated that the highest quartile of IL-6 level immediately after the surgery (odds ratio 7.63; 95% CI, 1.06-54.9; P=0.04) and age (odds ratio 1.18; 95% CI, 1.01-1.39; P=0.04) independently predict postoperative AF. Furthermore, the maximum level of IL-6 immediately after the surgery significantly correlated to age and intraoperative blood loss (r=0.04, P=0.01, and r=0.47, P=0.04, respectively). CONCLUSIONS: Advanced age was a major risk factor for postoperative AF. Furthermore, inflammatory response induced by surgical trauma was also associated with the development of AF after off-pump CABG.     

Repeat operations in the management of clival chordomas: palliative surgery.

Some chordomas have a very poor prognosis because of their aggressive growth nature, but the efficacy of repeat operations for these cases has not been well documented. This report concerns 3 patients with aggressive chordoma of the clivus, who underwent operations 6 to 12 times over a period of 8 to 17 years because of symptomatic regrowth. Overall mean interval between repeat operations was 18 months with a range from 5 to 57 months and survival times were 9 to19 years after the first surgery. Main symptoms before each operation were diplopia and visual disturbance. Repeat palliative operations by intentional extradural debulking of the tumour to decompress offending neural structures, as well as maximal removal of the tumour, using appropriate skull base approaches, can mitigate progressive symptoms, and may result in better quality and some prolongation of life, although our patients gradually deteriorated neurologically throughout the clinical course.