Transport,Uptake, and Metabolism of the Bis(pivaloyloxymethyl)-Ester Prodrug of 9-(2- Phosphonylmethoxyethyl)Adenine in an In Vitro Cell Culture System of the Intestinal Mucosa (Caco-2)

Purpose. To evaluate intestinal transport, uptake and metabolism characteristics of the bis(pivaloyloxymethyl)-ester [bis(POM)-ester] of the antiviral agent 9-(2-phosphonylmethoxyethyl)adenine [PMEA]. Methods. Intestinal transport, uptake and metabolism of bis(POM)-PMEA were studied using an in vitro cell culture system of the intestinal mucosa (Caco-2 monolayers). Concentrations of bis(POM)-PMEA and its metabolites mono(POM)-PMEA and PMEA were determined using a reversed-phase HPLC method. Enzymatic stability of bis(POM)-PMEA was evaluated by incubation with purified liver carboxylesterase, homogenates of Caco-2 cells and scraped pig small intestinal mucosa. Results. The use of bis(POM)-PMEA as a prodrug of PMEA resulted in a significant increase in transport of total PMEA [bis(POM)-PMEA, mono(POM)-PMEA and PMEA] across Caco-2 monolayers. While transepithelial transport of PMEA (500 M) was lower than 0.1% during a 3 hr incubation period, transport of total PMEA after addition of bis(POM)-PMEA (100 M) amounted to 8.8% over the same incubation period. Only 23% of the amount transported appeared as intact bis-ester at the basolateral side, while 33% of this amount was free PMEA and 44% was mono(POM)-PMEA, suggesting susceptibility of the prodrug to chemical and enzymatic degradation. Uptake studies revealed that only negligible amounts of bis(POM)-PMEA (< 0.2%) were present inside the cells. Very high intracellular concentrations of PMEA were found 1.2 mM, after a 3 hr incubation with 50 M bis(POM)-PMEA), which suggests that PMEA was trapped inside the cells probably due to its negative charge. This explains that efflux of PMEA was relatively slow (25% of the intracellular amount in 3 hr). Enzymatic degradation of the prodrug by carboxylesterase was confirmed by incubation of bis(POM)-PMEA with purified enzyme (K_m = 87 M and V_max = 9.5 M/min). Incubation of bis(POM)-PMEA (10 M) with cell homogenate of Caco-2 monolayers and pig small intestinal mucosa produced similar degradation profiles. Conclusions. The use of the bis(POM)-prodrug significantly enhances the intestinal permeability of PMEA. Intracellular trapping of PMEA in the intestinal mucosa may result in slow release of PMEA to the circulation after oral administration of bis(POM)-PMEA.     

'She thinks this is the Queen's Castle': women patients' perceptions of an Ontario psychiatric hospital

Drawing on the detailed information contained in patient case files, this study explores women patients' perceptions of the Ontario Hospital, Cobourg, a psychiatric facility for women which operated from 1920 to 1974. The paper concludes that, while twentieth-century psychiatry promoted an image of asylums as modern medical facilities, women patients continued to view these institutions as 'crazy houses', 'havens' and 'prisons'. It was not until the 1950s and 1960s, the eve of the decline of the authority of scientific psychiatry, that some women patients began to conceive of psychiatric hospitals as 'medical' facilities where therapeutic care could be sought.     

Nutrition education and oral health

At present, reduction of the consumption of fat is the main issue in nutritional education. However, this can lead to an increased consumption of mono- and disaccharides and, as a result, to increased dental caries. Individual variations in the susceptibility of caries make it necessary to differentiate the advice for the consumption of snacks between meals. Generally, consumption of complex carbohydrates, such as bread or bread products, can be advised as an alternative for fat and sugar containing snacks. Sugar-free products can also be advised, but not unlimited because of the laxative effect of sorbitol. To prevent tooth erosion the frequent consumption of fruits and fruit juices should be discouraged.     

HIV and dentistry. Part 10. Concluding remarks

In a summarizing report of the series 'HIV and dentistry' the most important aspects of the dental treatment of HIV-seropositive patients are dealt with, supplemented with some additional comments.     

Anxiety disorders in the dental practice. Part 2. Treatment of patients with anxiety

The purpose of the present paper is to provide the dentist with a number of treatment steps that may reduce anxiety and may enhance trust, feelings of control and application of coping skills. A distinction should be made between patients with specific fear for one or more aspects of dental treatment and patients with non-specific, general anxiety. Practical implications for dental treatment of both groups are given. Dentists should be familiar with the signs and symptoms of the various anxiety disorders, in order to be able to properly refer or treat the patient.     

HIV and dentistry. Part 7. The HIV positive dentist or student

What should a dentist or dental student do when he happens to be HIV-seropositive? Should he or she disclose the disease to the patients or, in case of a student, to the university? Does he has to give up his practice or perhaps not even open one? Apparently, the legal regulations differ in various parts of the world. In the Netherlands dentists are advised to take their own responsibility in this matter.     

Injuries of the distal radioulnar joint

Injuries of the distal radioulnar (DRU) joint are common. If the joint is unstable or discongruous, attempts should be made to restore anatomic alignment and stability. Although most acute injuries of the DRU joint are easily treated, they are often overlooked or misdiagnosed because they usually occur in association with other major injuries of the upper limb. Acute and chronic abnormalities are described briefly and the treatment for each is discussed. Appropriate diagnosis and management of the acute injury will yield a much higher success rate than reconstructive procedures to correct a chronic disorder. A differentiation should be made between DRU joint dysfunction and ulnar impingement against the carpus; ulnar shortening is the most commonly used technique to treat the latter condition. In an elderly patient, a Darrach procedure is the preferred treatment for a DRU joint dysfunction; in younger patients, the treatment of choice appears to be resection arthroplasty of the DRU joint with preservation of the ulnar length, the ulnar styloid, and the triangular fibrocartilage complex (TFCC). In cases of malunion of the distal radius with involvement of the DRU joint, the recommended treatment is corrective osteotomy and soft tissue reconstruction of the ligamentous support of the joint.     

Follow-up of patients with colorectal cancer. A meta-analysis.

OBJECTIVE: The authors sought to determine whether intensive follow-up improves 5-year survival rates in patients with colorectal cancer who were operated on for cure. SUMMARY BACKGROUND DATA: Intensive follow-up of patients with colorectal cancer is still controversial. The present uncertainty in regard to the value of intensive follow-up could be the result of the absence of prospective randomized studies comparing patients with and without follow-up. METHODS: Studies comparing two follow-up programs of different intensities were identified in the medical literature and were aggregated in a meta-analysis using the "random effects method." Seven nonrandomized studies describing 3283 patients were analyzed. RESULTS: Patients with intensive follow-up did have 9% better 5-year survival rates than did those with minimal or no follow-up, only when intensive follow-up included carcinoembryonic antigen (CEA) assays. In addition, more asymptomatic recurrences were detected and more recurrences were resected in patients with intensive follow-up. CONCLUSIONS: This meta-analysis indicated that intensive follow-up using CEA assays can identify treatable recurrences at a relatively early stage. Treatment of these recurrences appears to be associated with improved 5-year survival rates. However, not all intensive follow-up strategies will be equally effective. Follow-up may yield the best results if diagnostic tests are used only to detect those recurrences that can be operated on with curative intent and when follow-up is "individualized," according to patient characteristics.