Analytical Chiral Separation of the Stereoisomers of a Novel Carbonic Anhydrase Inhibitor and Its Deethylated Metabolite,and the Assignment of Absolute Configuration of the Human Metabolite and Chiral Degradation Products

Several approaches to the separation of four stereoisomers, 1–4, of a novel, topically active, carbonic anhydrase inhibitor, 1, with two chiral centers in the molecule and four isomers, 5–8, of its chiral metabolite, 5, were evaluated. These methods include nonchiral derivatization followed by separation on chiral stationary phases (CSPs) and chiral derivatization and separation on nonchiral columns and on CSPs. Baseline separation of stereoisomers 1–4 was achieved in less than 15 min after chiral derivatization with (S)-(+)-l-(l-naphthyl)ethyl isocyanate (NEIC) and chiral chromatography on a (R)-N-(3,5-dinitrobenzoyl)phenyl glycine (DNBPG) column under normal phase (NP) conditions. Similarly, isomers 5-8 were baseline separated in less than 20 min after derivatization with NEIC and chromatography on nonchiral (nitrophenyl) and chiral [(S)-(3,5-dinitrobenzoyl)leucine; DNBL] columns in series under the same NP chromatographic conditions. Only partial separation of the diastereomeric derivatives was observed on a variety of nonchiral columns. In addition, all other direct and indirect chiral separation approaches gave only partial separation of at least two stereoisomers within the group of 1–4 or 5–8. The details of chiral separations using various methods and separation () and capacity factors (k) of the derivatized isomers 1–8 on a series of chiral and nonchiral columns are presented. Using these methods, the absolute configuration of the human metabolite of 1 was established as S ₁ S ₂ (5), and the heat (HD) and light (LD) degradation products of 1 as R ₁ S ₂ (3) and S₁ S ₂ (5), respectively.     

Efficacy of topical gentamicin treatment after 193-nm photorefractive keratectomy in an experimental Pseudomonas keratitis model

Background: The treatment of Pseudomonas keratitis has many limitations, and further investigation to identify more effective approaches is required. We therefore studied the possible contribution of the debridement effect of 193-nm excimer laser on Pseudomonas keratitis in rabbit eyes. Methods: Pseudomonas keratitis was induced in 30 rabbit eyes by inflicting controlled central corneal scratches and applying a drop of Pseudomonas aeruginosa suspension. After 24 h, one cornea of each animal was photo-ablated (excimer laser: fluency 90 mJ/cm², 10 Hz, 213 pulses), yielding 50 m of tissue ablation, while the follow cornea served as control. Five groups of six animals each were formed and received: a subconjunctival injection of gentamicin 20, mg (group 1), topical 14 mg/ml gentamicin hourly (group 2) or every 2.5 h (group 3), or NaCl 0.9% hourly (group 4) for 8 h. In group 5, animals were sacrificed without additional treatment. After 9 h corneas were excised, homogenized, serially diluted, and plated on agar blood plates. The numbers of colony-forming units (CFU) per cornea were statistically evaluated (Mann-Whitney test). Results: In control eyes, a greater decrease of CFU was observed in group 2 than in group 3 (P = 0.03). In laser-ablated eyes, there was no difference in CFU between groups 2 and 3. Comparison of the excimer-treated and control eyes revealed a greater number of bacteria (CFU) in controls only in group 3 (P=0.02). Conclusion: Our study suggests that controlled debridement of cornea with excimer laser may improve the effect of topical antibiotics.Presented at ECORA First Annual Meeting, 5 October 1993, Bonn, Germany     

The Trent Regional Day Case Commission. An initiative to investigate the constraints to the extension of the use of day surgery

In 1989, Trent Regional Health Authority set up a Commission to enquire into the organization of day case surgery and encourage its use. Improved methods for measuring and comparing day surgical activity were developed using routine data sources. These revealed even greater variation between hospitals and specialties in the amount of day surgery performed than did the usual analyses. Arrangements for day surgery differed considerably between specialties. Few theatres, beds, or surgeons' sessions were dedicated to day surgery, but general surgery and gynaecology used dedicated facilities more than other specialties such as ENT and ophthalmology. The Commission visited each hospital and found that day case facilities, organization and resources were poor in many of them. It was able to make specific recommendations for improvements. Day case surgery increased substantially over the period that the Commission operated, most hospitals reported that it had influenced changes in day surgery and that it had been useful, especially for local managers. Schemes to increase day surgery were funded. Highlights two elements for managing change: the need for good information about a problem, and the need to extend ownership of the issue throughout the organization.     

对99例髋臼骨折内固定治疗的分析

从1972年11月到1994年3月,401例髋臼骨折病人中的99例经手术治疗并获随访,包括30例双柱骨折,13例横骨折伴后壁骨折,9例后壁骨折,9例后柱骨折,9例前往骨折伴前壁骨折,13例T形骨折和16例横骨折.平均随访时间为7年(2～14).外科手术入路的选择,后入路53次,髂腹股沟入路23次,延长的髂股骨入路11次,放射状入路9次和结合性入路6次.复位情况用X线平片来评判,解剖复位的有59例(59.6%),接近解剖复位(<2mm的错位)的有19例(19.2%).总结果用Harris Hip Score来评判,优秀的有53例(53.5%),良好的有25例(25.3%),一般的有14例(14.1%),差的有7例(7%).并发症中,有10例(53%)为感染,7例(37%)为静脉栓塞.这些结果表明,对于错位严重的髋臼骨折,切开复位内固定是一种可以选择的治疗方法.     

The clinical pharmacology of the adenosine deaminase inhibitor 2′-deoxycoformycin

Summary 2-deoxycoformycin (2-dCF; Pentostatin), a stoichiometric inhibitor of mammalian adenosine deaminase (ado deaminase), exhibits immunosuppressive and antilymphocytic activity in animal test systems. A clinical pharmacology/phase I study of 2-dCF administered as a single agent has been completed (18 patients). Dose levels ranged from 0.1 mg/kgx1 to 0.25 mg/kg/dayx5; ado deaminase and 2-dCF were measured spectrophotometrically. Plasma decay curves were bi-exponential ( and t_1/2 values about 1 and 10 h respectively). Recovery of unchanged 2-dCF from urine (48 h) was 32%–48% of the administered drug. Major toxic manifestations were lymphocytopenia (all patients) and urate nephropathy (1 patient, with subsequent patients in the series receiving allopurinol, 300 mg/day). Three partial responses were seen in seven patients with acute lymphocytic leukaemia receiving 0.25 mg 2-dCF/kg/dayx5.     

Innovations in the design of clinical trials in breast cancer

Summary The execution of clinical trials is perhaps the most difficult way of carrying out a scientific experiment. This is especially true of chronic diseases, such as breast cancer, which require long-term follow-up and large numbers of patients. As a result, it is necessary to involve many physicians who can contribute patients to these studies. Unfortunately, many physicians are not comfortable participating in randomized studies because they feel the patient—physician relationship may be compromised. This paper discusses new ways of planning randomized clinical trials which do not interfere with the patient—physician relationship. The new designs are called randomized consent or prerandomized designs. The study designs are discussed from the point of view of statistical efficiency and the new ethical problems which may arise. Address for reprints: Marvin Zelen, Ph.D., Department of Biostatistics, Harvard School of Public Health, 677 Huntington Avenue, Boston, MA 02115, USA     

Jacques Lisfranc 1790–1847

Jacques Lisfranc was born in Saint-Paul-Jarrest (Loire), France, April 2nd, 1790, the son of a physician. Early in his youth he demonstrated a particular interest and aptitude for the field of medicine as he observed and commented upon his father's ministrations to his patients. He accomplished his preliminary studies at the Lyceum in Lyons and then went to Paris to continue his medical training at the Hôtel-Dieu. It was there that he came under the tutelage of Dupuytren. It was soon said that Lisfranc was at least as worthy as his superior. Later the two men developed a certain animosity toward each other which became manifest rather severely in the medical political arenas of the time. Lisfranc received his doctorate of medicine in 1812 at a time that France was involved in the Napoleonic wars. He was commissioned as a surgeon and distinguished himself in campaigns in Saxony and in France. Following the war he established his practice in Paris. Fortuitously, one day Lisfranc rescued a magistrate who fell from his horse. By this serendipitous meeting Lisfranc was invited to join the faculty of medicine at the Hospital of Pity. He rose rapidly to chief of surgery and developed the reputation of being extremely competent, truly a master surgeon. For over 20 years he was affiliated with that institution and wrote numerous articles on such diverse subjects as shoulder disarticulation, the application of the stethoscope in the diagnosis of fractures, and on diseases of the uterus. In addition, he wrote two books which were well received—one onSurgery at the Hospital of Pity and the other onOperative Medicine. ThisClassics presentation has been selected because it has been generally attributed that Lisfranc was the first person to remove a cancerous tumor from the rectum. The technique involves essentially a transanal approach. As was the custom of the day, the report appears as narrated presumably by one of his assistants. Among the many distinctions Lisfranc achieved, he was founding member and ultimately President of the French Academy of Medicine and Chevalier of the Legion of Honor. Lisfranc developed an enormous clinical practice, and in spite of many physical infirmities he persisted in his surgery until the day of his death, May 12, 1847, at the age of 57.