Benzofuran based PDE4 inhibitors.

Replacement of the 3,4-dialkoxyphenyl substructure common to a number of PDE4 inhibitors with a 2-alkyl-7-methoxybenzofuran unit is described. This substitution can result in either enhancement or substantial reductions in PDE4 inhibitory activity depending on the system to which it is applied. An in vitro SAR study of a potent series of 4-(2-heteroaryl-ethyl)-benzoiurans 26 is also presented.

Anterior thoracic corpectomy for spinal cord decompression performed endoscopically.

A prospective study was undertaken during the past 3 years to investigate the effectiveness of thoracoscopic corpectomy--endoscopic removal of the vertebral body in 15 cases (8 for pathologic fractures for tumors, 5 for traumatic fractures and 2 for infections). The average age of the patients was 53.2 years (range 28-85 years). The vertebral levels of corpectomy ranged from T3 to L1. The mean operating time was 211 min (range 83-450 min) and the mean estimated blood loss was 890 ml (range 150-2,800 ml). The postoperative morbidity appeared to be more favorable than with open thoracotomy [Alband OW, Corkill G. Thoracic disk herniation: treatment and prognosis. Spine 1979; 4:41-6; Landreneau RJ, Hazelrigg SR, Mack NJ. Postoperative pain-related morbidity: video-assisted thoracic surgery versus thoracotomy. Ann Thorac Surg (in press); McAfee PC. Complications of anterior approaches to the thoracolumbar spine: emphasis on Kaneda instrumentation. Clin Orthop 1994;306:110-9; McAfee PC, Bohlman HH, Yuan HA. Anterior decompression of traumatic thoracolumbar fractures with incomplete neurological deficit using a retroperitoneal approach. J Bone Joint Surg [Am] 1985;67: 89-104; Regan JJ, Mack MJ, Picetti GD, Guyer RD, Hochschuler SH, Rashbaum RF. A comparison of video-assisted thoracoscopic surgery (VATS) with open thoracotomy in thoracic spinal surgery. Today's Ther Trends 1994;11: 203-18.] because the mean chest tube duration was 1.22 days (range 1-3 days), the mean length of time in the intensive care unit was 2 days (range 1-4 days), and the mean length of total hospitalization was 6.5 days (range 2-12 days). Overall, the ability to visualize the anterior surface of the dura during corpectomy was better endoscopically than with open thoracotomy techniques--improved magnification, the ability of the operative assistant to see and therefore suction more efficiently, and the perspective of visualization was improved. It was possible to place the 30 degrees angled endoscope within the defect left by the resected vertebral body and look directly posteriorly at the dura, visualizing the epidural vessels and dural pulsations at close range. The limiting factor in wide application of the technique is the absence of a commercially available internal fixation system that can be applied endoscopically.

The incidence of complications in endoscopic anterior thoracolumbar spinal reconstructive surgery. A prospective multicenter study comprising the first 100 consecutive cases.

STUDY DESIGN: A prospective multicenter study on 100 consecutive surgical procedures. OBJECTIVES: A prospective multicenter study was performed to evaluate the early perioperative complications in 100 endoscopic spinal procedures--78 video-assisted thoracic surgical procedures and 22 laparoscopic lumbar instrumentation and fusion procedures. SUMMARY OF BACKGROUND DATA: Endoscopic procedures have been widely applied in general surgery for appendectomy, cholecystectomy, liver resection, Nissen fundoplication, colon resection, and hernia repairs. Video-assisted thoracic surgery is widely used for pleural biopsy, lung resection, and sympathectomy. This is the first large series to date investigating the safety and potential complications using endoscopic surgery for anterior decompression or fusion of the thoracolumbar spine. METHODS: Video-assisted thoracic surgical procedures included multilevel anterior thoracic releases for deformity, 27 patients; anterior thoracic discectomies with spinal canal decompression, 41 patients; pyogenic vertebral osteomyelitis decompression, 2 patients; and vertebral corpectomy for neurologic decompression, 8 patients. Mean operative time was 2 hours, 34 minutes (range, 45 minutes to 6 hours), and mean length of stay was 4.97 days (range, 2-21 days). Anterior laparoscopic interbody stabilization and fusion at L4-5 or L5-S1 was performed in 22 patients. The mean operative time was 4 hours, 17 minutes (range, 2 hours, 40 minutes to 9 hours), and the mean length of stay was 5.6 days (range, 1-23 days). RESULTS: The most common video-assisted thoracic surgical complications were transient intercostal neuralgia (six patients) and atelectasis (five patients). The most common laparoscopic complication was bone graft donor site infection (two patients). There were two endoscopic cases that were converted to open procedures, one for extensive pleural adhesions and one for a common iliac vein laceration. CONCLUSIONS: The endoscopic spinal approaches proved to be safe operative procedures in 100 consecutive cases. There were no permanent iatrogenic neurologic injuries and no deep spinal infections.

Reasons for admission among six profile subgroups of recidivists of inpatient services.

The incidence pattern of medication and program non compliance, violent acts, suicide attempts and chemical abuse defined as reasons for hospital admission was evaluated in a total sample (n = 416) of recidivists and their six constituent profile subgroups (n = 272). The total sample was drawn from two different state-operated hospitals and two different time periods. The incidence pattern observed for the total sample in order of descending priority was medication non compliance, program non compliance, chemical abuse, violent acts and suicide attempts. The incidence pattern ordering and the relevant percentages of occurrence were observed for both hospitals. There were time period differences in the ordering and percentages of the reasons for admission which revealed an increase in both medication and program non compliance as well as chemical abuse in the more recent sample. There were also specific subgroup differences in the incidence pattern concerning some reasons for admission. These subgroup differences are discussed in detail.

RG 12561 (dalvastatin): a novel synthetic inhibitor of HMG-CoA reductase and cholesterol-lowering agent.

RG 12561 (dalvastatin) is a prodrug which converts to its open hydroxyacid form in the body. The Na salt of RG 12561 (RG 12561-Na) is a potent inhibitor of 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme in the cholesterol biosynthetic pathway. It competitively inhibits rat liver HMG-CoA reductase with an IC50 value of 3.4 nmol/l. In the same assay, the IC50 values for other potent HMG-CoA reductase inhibitors, lovastatin-Na and pravastatin, were 2.3 and 8.9 nmol/l, respectively. In Hep G2 liver cells, RG 12561-Na, lovastatin-Na and pravastatin inhibited cholesterol biosynthesis from radiolabeled octanoate with IC50 values of 4 and 5 nmol/l and 1.1 mumol/l, respectively. In a rat ex vivo assay, orally administered RG 12561, lovastatin and pravastatin inhibited cholesterol biosynthesis in liver slices with ED50 values of 0.9, 0.5 and 12 mg/kg, respectively. In cholestyramine-fed hamsters, RG 12561 (0.1% in food for 18 days) reduced LDL cholesterol, whereas HDL was slightly increased. The reductions in the LDL/HDL ratio for RG 12561, RG 12561-Na, lovastatin and lovastatin-Na were 35, 76, 88 and 88%, respectively. At a higher dose, RG 12561 (0.4% in food) reduced serum cholesterol, LDL and LDL/HDL by 84, 97 and 91%, respectively. In WHHL rabbits, RG 12561 and lovastatin (5 mg/kg, b.i.d., 12 days) reduced serum cholesterol by 17 and 16%, respectively. These results demonstrate that RG 12561 is a potent cholesterol-lowering agent.

Spontaneous splenic rupture associated with thrombolytic therapy and/or concomitant heparin anticoagulation.

Two cases of spontaneous splenic rupture in connection with thrombolytic therapy and concomitant heparin anticoagulation are reported. One patient was being treated for peripheral arterial graft occlusion using intraarterial urokinase, the other received intravenous infusion of streptokinase for acute myocardial infarction. Neither patient had a condition predisposing to splenic rupture. Although rare, previous reports of spontaneous splenic rupture associated with thrombolytic therapy and/or anticoagulation have been reported. Splenic rupture as a complication of thrombolytic therapy and/or anticoagulation should be considered when unexplained abdominal symptoms, hypotension, or blood loss is encountered.

Angiotensin converting enzyme inhibitors. 10. Aryl sulfonamide substituted N-[1-carboxy-3-phenylpropyl]-L-alanyl-L-proline derivatives as novel antihypertensives.

Compounds 1a-g consisting of enalaprilat covalently bonded to aryl sulfonamides, including several known thiazide diuretics, were synthesized and tested for ACE inhibitory and diuretic and overall antihypertensive effects. All compounds were potent ACE inhibitors in vitro, with IC50 = 6.5-85 nM. At 10 mg/kg iv or ip in the rat, 1a-g inhibited the AI pressor response by 76-100%; inhibition declined significantly upon oral dosing. Compounds 1a and 1f at 100 mg/kg ip in the sodium-depleted, spontaneously hypertensive rats reduced blood pressure 28-35% and 41-42%, respectively. Compounds 1a and 1f elicited natriuresis and kaliuresis without accompanying volume increases in the rat; 1c at 25 mg/kg iv induced delayed diuresis. Compound 1f has been chosen for further development.

Angiotensin-converting enzyme inhibitors. 9. Novel [[N-(1-carboxy-3-phenylpropyl)amino]acyl]glycine derivatives with diuretic activity.

A series of molecules 1 having sulfonamide diuretic moieties covalently linked to non-sulfhydryl angiotensin-converting enzyme inhibitors (ACEI) were prepared and tested for both activities. IC50 values for ACEI as low as 7 nM were observed. Discernable diuretic activity was seen for several hydrochlorothiazide-based molecules. Effects of the ACEI and diuretic structures on the respective potencies are discussed.