3-Hydroxypyrrolidine and (3,4)-dihydroxypyrrolidine derivatives: inhibition of rat intestinal α-glucosidase.

Thirteen pyrrolidine-based iminosugar derivatives have been synthesized and evaluated for inhibition of α-glucosidase from rat intestine. The compounds studied were the non-hydroxy, mono-hydroxy and dihydroxypyrrolidines. All the compounds were N-benzylated apart from one. Four of the compounds had a carbonyl group in the 2,5-position of the pyrrolidine ring. The most promising iminosugar was the trans-3,4-dihydroxypyrrolidine 5 giving an IC50 of 2.97±0.046 and a KI of 1.18 mM. Kinetic studies showed that the inhibition was of the mixed type, but predominantly competitive for all the compounds tested. Toxicological assay results showed that the compounds have low toxicity. Docking studies showed that all the compounds occupy the same region as the DNJ inhibitor on the enzyme binding site with the most active compounds establishing similar interactions with key residues. Our studies suggest that a rotation of ∼90° of some compounds inside the binding pocket is responsible for the complete loss of inhibitory activity. Despite the fact that activity was found only in the mM range, these compounds have served as simple molecular tools for probing the structural features of the enzyme, so that inhibition can be improved in further studies.

Five-membered iminocyclitol α-glucosidase inhibitors: synthetic, biological screening and in silico studies.

The design and synthesis of a small library of pyrrolidine iminocyclitol inhibitors with a structural similarity to 1,4-dideoxy-1,4-imino-D-arabitol (DAB-1) is reported. This library was specifically designed to gain a better insight into the mechanism of inhibition of glycosidases by polyhydroxylated pyrrolidines or iminocyclitols. Pyrrolidine-3,4-diol 15a and pyrrolidine-3,4-diol diacetate 15b had emerged as the most potent α-glucosidase inhibitors in the series. Docking studies performed with an homology model of α-glucosidase disclosed binding poses for compounds 15a, 15b, 16a, and 16a' occupying the same region as the NH group of the terminal ring of acarbose and suggest a closer and stronger binding of compound 15a and 15b with the enzyme active site residues. Our studies indicate that 2 or 5-hydroxyl substituents appear to be vital for high inhibitory activity.

Incidence of pulmonary edema after tracheotomy for obstructive sleep apnea.

OBJECTIVE: The phenomenon of postobstructive pulmonary edema (POPE) has been associated with the relief of upper airway obstruction, which itself is fundamental to the pathophysiology of obstructive sleep apnea (OSA). A review of patients with OSA undergoing tracheotomy was performed to characterize this process. STUDY DESIGN: Retrospective chart review of study patients with OSA undergoing tracheotomy and of control patients without OSA undergoing tracheotomy for unrelated problems. Chest radiographs were reviewed in a double-blind fashion to score posttracheotomy changes in pulmonary status. SETTING: Academic tertiary referral center. RESULTS: Thirty (67%) of 45 OSA patients treated by tracheotomy had evidence of POPE, whereas only 5 (20%) of 25 control group patients had increased pulmonary edema. The remaining 15 (33%) of 45 OSA patients and 20 (80%) of 25 control patients had either no change or an improved pulmonary status. Those with OSA that developed POPE were mostly graded as having mild pulmonary edema (22/30, 73%). Far fewer were graded as having moderate pulmonary edema (6/30, 20%), and fewer still with severe pulmonary edema (2/30, 7%). Two (7%) of 45 patients with severe POPE died of complications related to cor pulmonale in the postoperative period. CONCLUSION: Results support maintaining a high index of suspicion for the development of postobstructive pulmonary edema in patients treated for OSA. Treatment options, such as positive pressure ventilation and diuresis, and an increased awareness of this condition may help reduce the morbidity and mortality associated with treatment of this disease.

Evaluation of airway obstruction using virtual endoscopy.

OBJECTIVES: This study examines the use of virtual endoscopy (VE) in the evaluation of patients with upper airway obstruction. The utility of VE compared with actual endoscopy was investigated with respect to accuracy of diagnosis and reproduction of endoscopic images. STUDY DESIGN: A random cohort of 30 patients with various causes of airway obstruction was examined. METHODS: The computed tomography (CT) data were reconstructed using a proprietary VE software program, FreeFlight, blind to the actual endoscopic findings. The cause of obstruction was identified and compared with actual endoscopic findings. This included 21 patients with airway stenoses, 8 patients with laryngotracheomalacia, 3 tracheal tumors, 2 glottic webs, 5 patients with innominate artery compression, 2 tracheal granulomas, and 7 patients with impaired true vocal cord mobility. RESULTS: Virtual endoscopic evaluation was accurate in assessing stenosis width and length of fixed airway lesions. Correlation of stenosis shape and contour between actual endoscopy and VE was excellent. The stenosis-to-lumen ratios were compared between VE and actual endoscopy and were found to be within 10% (SD = 8). However, virtual endoscopic evaluation could not illustrate one of the glottic webs, half of the cases of tracheomalacia, or any of the cases of impaired true vocal cord mobility. CONCLUSIONS: Virtual endoscopy was not as sensitive as actual endoscopy in detecting the cause of airway obstruction that was based on dynamic movement. However, VE was excellent for the measurement and definition of fixed airway lesions.

Benefits of routine maxillectomy and orbital reconstruction with the rectus abdominis free flap.

Maxillary defects lead to functional and cosmetic deficiencies, especially with tumor invasion of the orbit and cribriform plate. Additionally problematic is the near-total palatal resection in patients with poor dentition (ie, not useful for anchoring obturators) and the desire for return of deglutition and useful speech. A series of 12 patients is presented in whom a rectus abdominis free flap was used for reconstruction of the palate, maxilla, and/or orbit. Nine of 12 free flaps were used to reconstruct defects involving the maxilla and orbit; all were successful in restoring hard palate continuity and function without the use of an obturator. The remaining 3 patients underwent successful repair of defects involving the orbit and medial maxilla without complication. Four of those 9 patients with palatal reconstruction augmented their dental rehabilitation with either their existing upper denture plate or the use of a cosmetic appliance anchored to their remaining dentition. Objectively, the rectus abdominis myocutaneous free flap proved to be a reliable and expeditious method of restoring function and acceptable cosmesis. We believe this technique should be routinely considered in the reconstruction of these defects.

The etiology and pathogenesis of laryngeal carcinoma.

Epidemiologic data suggest that the etiology and pathogenesis of laryngeal carcinoma are influenced by environmental and lifestyle-related factors, such as tobacco use, ethanol consumption, and exposure to toxic substances. In addition, dietary factors, irradiation, papilloma virus infection, and laryngopharyngeal reflux seem to be significant carcinogenic cofactors. This article presents a multi-factorial model of laryngeal mucosal carcinogenesis.

The role of epidural cortisone injection in the treatment of diskogenic low back pain.

Primary treatment by epidural injection of cortisone in patients suffering from characteristic diskogenic disease was helpful in 82% of patients. However, when given after three months of back pain, after previous laminectomies, and in patients actually suffering from an unstable spine which required fusion, epidural injections were of little value. No complications resulted from the injection and there was no compelling evidence to indicate that the placement of the needle by radiologic means is necessary. Because of these benefits and the fact that all of the patients were candidates for laminectomy, the use of this injection prior to surgery should be considered. The number of injections that may reasonably be given, the degree to which the patient should become asymptomatic, and the period of time during which relief continues remain to be clarified by a larger and more sustained study.