Metabolism and pharmacokinetics of a dipeptidyl peptidase IV inhibitor in rats, dogs, and monkeys with selective carbamoyl glucuronidation of the primary amine in dogs.

The pharmacokinetics and metabolism of the l-threo isoleucine thiazolidide dipeptidyl peptidase IV inhibitor, di-[2S,3S]-2-amino-3-methyl-pentanoic-1,3-thiazolidine fumarate (ILT-threo) and its allo stereoisomer (ILT-allo) were evaluated in rats, dogs, and monkeys. Both compounds were well absorbed (>80%) in all species, and most of the dose (>60%) was recovered in urine. Metabolites identified in all species included a sulfoxide (M1), a sulfone (M2), and a carbamoyl glucuronide (M3). For both compounds, parent drug had moderate systemic clearance in rats and dogs ( approximately 20-35 ml/min/kg in both species) and lower clearance in monkeys ( approximately 6-9 ml/min/kg). In rats, M1 was present in systemic circulation in concentrations similar to that of parent drug, whereas in dogs and monkeys, exposures to M1 were higher than for parent drug. In dogs, exposures to the sulfoxide metabolite were approximately 2 to 3 times higher after administration of ILT-allo than after administration of ILT-threo. Carbamoyl glucuronidation was an important biotransformation pathway in dogs. Circulating levels of M3 were significant in the dog, and present only in trace levels in rats and monkeys. M3 could be produced in in vitro systems in a NaHCO3 buffer under a CO2-saturated atmosphere and in the presence of UDP-glucuronic acid and alamethicin.     

Phase II study of neoadjuvant carboplatin and paclitaxel followed by radiotherapy and concurrent cisplatin in patients with locoregionally advanced nasopharyngeal carcinoma: therapeutic monitoring with plasma Epstein-Barr virus DNA.

PURPOSE: To assess the efficacy of neoadjuvant paclitaxel and carboplatin (TC) followed by concurrent cisplatin and radiotherapy (RT) in patients with locoregionally advanced nasopharyngeal carcinoma (NPC) and to monitor treatment response with plasma Epstein-Barr virus (EBV) DNA. PATIENTS AND METHODS: Thirty-one patients with International Union Against Cancer stages III and IV undifferentiated NPC had two cycles of paclitaxel (70 mg/m2 on days 1, 8, and 15) and carboplatin (area under the curve 6 mg/mL/min on day 1) on a 3-weekly cycle, followed by 6 to 8 weeks of cisplatin (40 mg/m2 weekly) and RT at 66 Gy in 2-Gy fractions. Plasma EBV DNA was measured serially using the real-time quantitative polymerase chain reaction method. Results All patients completed planned treatment. Response to neoadjuvant TC was as follows: 12 patients (39%) achieved partial response (PR) and 18 achieved (58%) complete response (CR) in regional nodes; five patients (16%) achieved PR and no patients achieved CR in nasopharynx. At 6 weeks after RT, one patient (3%) achieved PR and 30 patients (97%) achieved CR in regional nodes, and 31 patients (100%) achieved CR in nasopharynx; 29 patients (93%) had EBV DNA level of less than 500 copies/mL. Neoadjuvant TC was well tolerated, and the most common acute toxicity of cisplatin plus RT was grade 3 mucositis (55%). At median follow-up of 33.7 months (range, 7 to 39.3 months), six distant and three locoregional failures occurred. Plasma EBV DNA level increased significantly in eight of nine patients who experienced treatment failure but did not increase in those who did not. The 2-year overall and progression-free survival rates were 91.8% and 78.5%, respectively. CONCLUSION This strategy was feasible and resulted in excellent local tumor control. Serial plasma EBV DNA provides a noninvasive method of monitoring response in NPC.     

Expression of nm23 protein in human osteosarcoma in relationship with early metastasis

Nm23 protein expression was analyzed by immunohistochemical staining using formalin-fixed, paraffin-embedded sections from 39 cases with osteosarcomas and compared with the histologic findings and early metastasis for the purpose of detecting nm23 expression in osteosarcoma and elucidating the clinical significance of its expression. Immunoreactivity of nm23 protein was detected in 48.7% of the total cases. There was no statistical difference between nm23 expression and early metastasis, but there was a trend for cases with nm23 expression to progress to early metastasis within 1 year after operation. The role of nm23 as a tumor metastasis suppressor in osteosarcomas appeared less prominent.     

Plasmapheresis-related hypotension

Hypotension is an uncommon complication of procedures involving extracorporeal circulation, including plasmapheresis. From November 1993 to March 1999, we treated 139 patients who underwent a total of 1,137 sessions of double filtration plasmapheresis (DFP). Hypotension was defined as a systolic blood pressure (BP) < 80 mm Hg or any decrease of systolic BP with systemic reactions. A total of 17 (1.5%) episodes of hypotension were documented in 15 patients during the study period. Hypotensive episodes occurred in 2.3% of patients with inflammatory neuropathy, 1.2% of patients with myasthenia gravis, and 1.2% of patients with all other medical diseases. Involvement of the autonomic nerve system (ANS) and a low baseline BP were associated with the occurrence of hypotension. Eight (47%) of 17 episodes were symptomatic and 2 were complicated with seizure. Patients with symptomatic hypotension had a higher level of systolic BP prior to DFP and a larger drop of systolic BP and pulse rate during hypotensive attacks compared to asymptomatic patients. Most hypotensive episodes were resolved briefly after intravenous infusion of saline within 30 min. Eight (47%) of the hypotensive episodes occurred during the first session of DFP treatment. Twelve (71%) of 17 episodes occurred during the last half period of treatment; 6 of them were noted during the terminating stage of DFP. In conclusion, in this series plasmapheresis-related hypotension occurred in 1.5% of DFP sessions and had a higher prevalence in patients with ANS instability and low BP. Extra caution in monitoring BP during DFP therapy is warranted in these vulnerable patients, especially during the termination phase of the first DFP session.     

Primary total hip arthroplasty in patients with ankylosing spondylitis

The results of total hip arthroplasty in a group of patients with ankylosing spondylitis are described. Ninety-five arthroplasties were performed in 56 men and 2 women whose average age at operation was 38.9 years (standard deviation [SD], 11.6; range, 19.2-78.8). They were followed for an average of 135.4 months (SD, 81.6; range, 24.4-331.2). We encountered 4 deep infections necessitating the removal of prostheses. Two of 3 dislocations were anterior dislocations. Nineteen arthroplasties were revised at an average of 162.0 months (SD, 49.6; range, 55.1-250.5) after the primary surgery; 9 of them had only the acetabular component revised because of aseptic loosening. Hyperextension of the hips is a common phenomenon that can lead to surgical error and predispose the prosthesis to anterior dislocation.     

Assessment of a three-dimensional operating system with skill tests in a pelvic trainer

OBJECTIVES: To compare the performance of laparoscopic skill assisted by a traditional two-dimensional (2D) and a three-dimensional (3D) endoscopic video system in a pelvic trainer. MATERIALS AND METHODS: The 3D imaging system (DeepVision((R)), Automated Medical Products Corp.) consists of a traditional single lens optic laparoscope, a light source, an endoscopic camera (Stryker), a DeepVision processor and a DeepVision monitor. The 2D images could be obtained with the same system without turning on the DeepVision processor. Thirty-four medical personnel with no laparoscopic surgical experience were enrolled to perform two skill tests, the object-pick-up and spatial orientation test in a trainer box. They were randomly divided into two groups, one group performed the test under 2D conditions first and 3D later, and another group performed the test under 3D conditions first and 2D later. The duration needed to complete the skill tests was recorded and the differences on performance time under 2D and 3D conditions were calculated for each participant. Two-way ANOVA was used to analyze the statistic difference on the performance time in two conditions. RESULTS: The duration needed to complete the initial skill tests was similar among 2D and 3D conditions. For both tests, the average performance time decreased significantly for the second attempt regardless of 2D or 3D conditions. Statistic analysis disclosed significant difference for learning factor (p < 0.001 for object-pick-up test and p < 0.01 for spatial orientation test), but no significant difference between 2D and 3D conditions (p = 0.276 for object-pick-up test and p = 0.327 for spatial orientation test). CONCLUSION: A significant decrease of the performance time at the second attempt reflected the importance of a learning process in laparoscopic surgery. It appears that no significant benefits were obtained by this 3D operating system for surgeons without laparoscopic surgical experience.     

Antagonism of arachidonic acid is linked to the antitumorigenic effect of dietary eicosapentaenoic acid in Apc(Min/+) mice

The multiple intestinal neoplasia (Apc(Min/+)) mouse possesses a germline mutation at codon 850 of the adenomatous polyposis coli (Apc) gene resulting in the formation of a nonfunctional truncated gene product. Following a somatic mutation of the remaining wild-type allele, mice spontaneously develop approximately 40-50 tumors throughout the intestinal tract. This mouse model has been used to study intestinal tumorigenesis because this mutation is analogous to the inherited APC mutation in humans with familial adenomatous polyposis (FAP). These individuals characteristically develop numerous adenomas throughout their intestinal tracts. Only a few studies have evaluated the effects of dietary fatty acids on tumorigenesis in this animal model with varying results, and none have linked these effects to alterations in arachidonic acid (AA) metabolism. This study was designed to evaluate the antitumorigenic effect of dietary (n-3) polyunsaturated fatty acids (PUFA) in the Apc(Min/+) mouse model and to determine whether these effects are related to inhibition of AA metabolism. Male Apc(Min/+)mice were fed diets supplemented with eicosapentaenoic acid (EPA), AA or a combination of AA + EPA. Mean tumor number in the EPA group was 68% lower (P<0.05) compared with the control group, whereas AA supplementation did not significantly alter tumor load. The reduction in tumor load coincided with significant reductions in intestinal AA content and levels of prostaglandins. However, supplementing AA to the EPA diet (AA + EPA) abolished the antitumorigenic effect of EPA, increased tissue AA content fourfold and prostaglandin production two- to fourfold. These results indicate that AA is involved in tumorigenesis and suggest that EPA's ability to reduce tumor load in Apc(Min/+) mice is related to reductions in tissue AA content or its metabolism.     

Mononucleosis syndrome and coincidental human herpesvirus-7 and Epstein-Barr virus infection

Two girls (a 5 year old and a 21 month old) experiencing mononucleosis syndrome with coincidental human herpesvirus (HHV)-7 and Epstein-Barr virus (EBV) infections are described. One patient had primary HHV-7 infection and reactivated EBV infection. The other had primary HHV-7 and EBV infections. These cases indicated that HHV-7 is capable of inducing infectious mononucleosis-like illness. Multiple herpesvirus infection in one of the patients also suggests that interaction among herpesviruses can occur in vivo. The consequence of this interaction may have clinical implications.