2H-[1]benzothiepino [5,4-b]pyran derivatives with local anesthetic and antiarrhythmic activities

The synthesis of some N,N-disubstituted 4-amino-5,6-dihydro-3-phenyl-2H-[1]benzothiepino [5,4-b]pyran-2-ones by reaction of phenylchloroketene with a series of N,N-disubstituted (E)-4-aminomethylene-3,4-dihydro-1-benzothiepin-5(2H)-ones, followed by dehydrochlorination of the primary adducts with DBN, is described. The 4-methylphenylamino derivative showed a local anesthetic activity in mice superior to that of lidocaine and the 4-morpholino derivative showed an antiarrhythmic activity in rats comparable to that of quinidine.     

Oral tuberculosis associated with a treatment with anti-rheumatic drugs

BACKGROUND: The use of immunosuppressive medication is a dominant risk factor for infection in patients with rheumatoid arthritis (RA). Methotrexate (MTX) is one of the traditional disease-modifying antirheumatic drugs. Adalimumab [a human anti-tumor necrosis factor-alpha (anti-TNF-alpha) monoclonal antibody] represent an important advance in the treatment of RA and has been recently come in use. TNF-alpha plays a role in the host defense against Mycobacterium tuberculosis and notably in granuloma formation. Infections occur at a high rate among those who use one or the combination of the two medications. METHOD: We examined a female patient that was referred to our department for evaluation and treatment of a granular lesion on the soft palate and uvula, complaining of mild dysphagia. The patient was treated for 4 months with MTX and adalimumab for RA before the oral lesion appeared. RESULTS: The histopathological examination of a specimen of the oral lesion, taken by biopsy, showed a chronic inflammation characterized by tuberculous granulomas. Polymerase chain reaction test and culture of a new specimen was positive for M. tuberculosis. CONCLUSIONS: The therapeutic use of MTX or/and adalimumab for the treatment of RA or few others diseases, can cause oral tuberculosis.     

Mechanism of hydrolysis and structure-stability relationship of enaminones as potential prodrugs of model primary amines

The objective of this work was to investigate the chemistry and the structure-stability relationship of enaminones (a class of enamines formed between a primary amine and a 1,3-dicarbonyl compound) and to evaluate their potential usefulness as prodrugs of primary amines. The acid-catalyzed degradation of the enaminones was found to be very sensitive to minor differences in the structure of the 1,3-dicarbonyl compound used to form the enaminone, but relatively insensitive to changes in the amine portion of the enaminones. A correlation was found between the rate of enaminone hydrolysis and the pKa of the 1,3-dicarbonyl compound, suggesting that the rate-controlling step in the hydrolysis of the enaminones was the proton addition to the vinyl carbon of the enaminone. Enaminones formed with cyclic 1,3-dicarbonyl compounds were significantly more stable than those formed with structurally similar acyclic compounds. Based on chemical stability considerations alone, enaminones do not appear to be good candidates as prodrugs of primary amines. Evidence is presented, however, that enaminones formed between amines and 1,3-ketoesters or lactones may be subject to enzyme-catalyzed degradation. Further research on the design of enaminones destabilized by a triggering enzymatic event that results in the loss of conjugation (e.g., ester or lactone hydrolysis or an oxidation/reduction event) may prove worth pursuing.     

Success rate and duration of orthodontic treatment for adult patients with palatally impacted maxillary canines.

This study was undertaken to examine the success rate and the length of orthodontic treatment of impacted maxillary canines in adult patients. A sample of 19 adults (mean age, 28.8 +/- 8.6 years; range, 20-47 years), who had been treated for a total of 23 impacted maxillary canines, was compared with a younger control group (mean age, 13.7 +/- 1.3 years; range, 12-16 years). The control subjects were chosen for a similar degree of impaction difficulty by carefully matching the positions of the impacted canines in the 3 planes of space. The success rate among the adults was 69.5% compared with 100% among the younger controls. The lower success rate was due to 5 canines that had failed to erupt and 2 canines that had been partially extruded but could not be aligned in the arch. The duration of treating the overall malocclusion of the adults and young subjects did not materially differ. However, the adults showed significant increases in the duration and number of treatment visits required for resolving the canine impaction, in both the simpler and the more difficult cases. When further divided by age, all the failed canines were found in the older (over 30) adult subgroup. It was concluded that the prognosis for successful orthodontic resolution of an impacted canine in an adult is lower than that in a younger patient and that the prognosis worsens with age. Furthermore, when such treatment is undertaken, its successful completion should be expected to take considerably longer.     

Common carotid agenesis and internal carotid stenting.

Agenesis of common carotid artery is rare and no report of stenting procedures (carotid artery stenting) for associated stenosis of the internal carotid have been published. We report a case of internal carotid stenosis associated with this anomaly. A 73-year-old male with left internal carotid artery originating from the arch, with significant stenosis, was referred to us. Wallstent was deployed with success. Carotid artery stenting should be reserved to uncomplicated arch anatomy and plaques with low fragmentation risk.     

Degradation of Paclitaxel and Related Compounds in Aqueous Solutions III: Degradation Under Acidic pH Conditions and Overall Kinetics

Paclitaxel and related taxanes are complex molecules with numerous hydrolysable ester groups, possible epimerization at the 7‐position, and possessing a strained oxetane ring, a possible site for acid‐catalyzed cleavage. Presented here is the stability of paclitaxel, 10‐deacetylbaccatin III, baccatin III, and N‐benzoyl‐3‐phenylisoserine ethyl ester in aqueous solution over a pH range of 1–5 at various temperatures. Analysis of various samples was by HPLC–UV and LC–MS. Baccatin III, 10‐deacetylbaccatin III, and N‐benzoyl‐3‐phenylisoserine ethyl ester were found to undergo acid catalysis since pH‐rate profiles all followed a first‐order dependency in hydrogen ion concentration. No evidence of any epimerization was noted at acidic pH values. Baccatin III and 10‐deacetylbaccatin III showed similar degradation rates with possible products being possible dehydration around the 13‐hydroxy group and cleavage of the oxetane ring. Cleavage of the 10‐acetyl group of baccatin III was a minor initial pathway. N‐Benzoyl‐3‐phenylisoserine ethyl ester degraded significantly slower than both 10‐deacetylbaccatin III and baccatin III. At pH 2, paclitaxel degraded at a rate between that of N‐benzoyl‐3‐phenylisoserine ethyl ester and 10‐deacetylbaccatin III. The pH of maximum stability for all compounds appeared to be around pH 4. © 2009 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 99: 1288–1298, 2010