Ketamine and norketamine attenuate oxycodone tolerance markedly less than that of morphine: from behaviour to drug availability.

BACKGROUND: Ketamine attenuates morphine tolerance by antagonising N-methyl-d-aspartate receptors. However, a pharmacokinetic interaction between morphine and ketamine has also been suggested. The interaction between oxycodone and ketamine is unclear. We studied the effects of ketamine and norketamine on the attenuation of morphine and oxycodone tolerance focusing on both the pharmacodynamic and pharmacokinetic interactions. METHODS: Morphine 9.6 mg day-1 or oxycodone 3.6 mg day-1 was delivered to Sprague-Dawley rats by subcutaneous pumps. Once tolerance had developed, the rats received subcutaneous injections of ketamine or norketamine. Tail-flick, hot-plate, and rotarod tests were performed. Drug concentrations were measured with high-performance liquid chromatography-tandem mass spectrometry. RESULTS: Anti-nociceptive tolerance to morphine and oxycodone developed similarly by Day 6. Acute ketamine 10 mg kg-1 and norketamine 30 mg kg-1 attenuated morphine tolerance for 120 and 150 min, respectively, whereas in oxycodone-tolerant rats the effect lasted only 60 min. Both ketamine and norketamine increased the brain and serum concentrations of morphine, and inhibited its metabolism to morphine-3-glucuronide, whereas oxycodone concentrations were not changed. Morphine, but not oxycodone, pretreatment increased the brain and serum concentrations of ketamine and norketamine. Ketamine, but not norketamine, significantly impaired the motor coordination. CONCLUSIONS: Ketamine and norketamine attenuated morphine tolerance more effectively than oxycodone tolerance. Ketamine and norketamine increased morphine, but not oxycodone brain concentrations, which may partly explain this difference. Norketamine is effective in attenuating morphine tolerance with minor effects on motor coordination. These results warrant pharmacokinetic studies in patients who are co-treated with ketamine and opioids.

Population-based molecular detection of hereditary nonpolyposis colorectal cancer.

PURPOSE: Cancer morbidity and mortality can be dramatically reduced by colonoscopic screening of individuals with the hereditary nonpolyposis colorectal cancer (HNPCC) syndrome, creating a need to identify HNPCC. We studied how HNPCC identification should be carried out on a large scale in a sensitive and efficient manner. PATIENTS AND METHODS: Colorectal cancer specimens from consecutive newly diagnosed patients were studied for microsatellite instability (MSI). Germline mutations in the MLH1 and MSH2 genes were searched for in MSI(+) individuals. RESULTS: Among 535 colorectal cancer patients, 66 (12%) were MSI(+). Among these, 18 (3.4% of the total) had disease-causing germline mutations in MLH1 or MSH2. Among these 18 patients, five were less than 50 years old, seven had a previous or synchronous colorectal or endometrial cancer, and 15 had at least one first-degree relative with colorectal or endometrial cancer. Notably, 17 (94%) of 18 patients had at least one of these three features, which were present in 22% of all 535 patients. Combining these data with a previous study of 509 patients, mutation-positive HNPCC accounts for 28 (2.7%) of 1,044 cases of colorectal cancer, predicting a greater than one in 740 incidence of mutation-positive individuals in this population. CONCLUSION: Large-scale molecular screening for HNPCC can be done by the described two-stage procedure of MSI determination followed by mutation analysis. Efficiency can be greatly improved by using three high-risk features to select 22% of all patients for MSI analysis, whereby only 6% need to have mutation analysis. Sensitivity is only slightly impaired by this procedure.

Microsatellite instability in adenomas as a marker for hereditary nonpolyposis colorectal cancer.

Hereditary nonpolyposis colorectal cancer (HNPCC) is the most common of the well-defined colorectal cancer syndromes, accounting for at least 2% of the total colorectal cancer burden and carrying a greater than 80% lifetime risk of cancer. Significant reduction in cancer morbidity and mortality can be accomplished by appropriate clinical cancer screening of HNPCC patients with mutations in mismatch repair (MMR) genes. Thus, it is desirable to identify individuals who are mutation-positive. In individuals with cancer, mutation detection can be accomplished relatively efficiently by germline mutation analysis of individuals whose cancers show microsatellite instability (MSI). This study was designed to assess the feasibility of screening colorectal adenoma patients for HNPCC in the same manner. Among 378 adenoma patients, six (1.6%) had at least one MSI adenoma. Five out of the six patients (83%) had a germline MMR gene mutation. We conclude that MSI analysis is a useful method of prescreening colorectal adenoma patients for HNPCC.

Charge optimization leads to favorable electrostatic binding free energy.

Variational optimization of molecular electrostatic charge distributions is a tool for the study of association reactions of molecules in solution. In principle, this method can be used in drug design and protein folding to analyze and improve molecular interactions and to provide electrostatic templates for molecular design. This optimization problem reduces to an inverse source problem in classical electrostatics, where the sources are determined by a combination of external and self-polarization potentials. In this paper, we show that the electrostatic portion of the free energy of association for electrostatically optimized molecules has an upper bound of zero in many situations of physical interest. That is, variational optimization provides a ligand-charge distribution that contributes favorably to the energetics of binding, even in a strongly polar medium. This stabilizing effect on association reactions is contrary to the usual role of electrostatics in aqueous complexes, in which desolvation effects generally dominate. We also show the existence and nonuniqueness of the variational solution and make a connection to the electrostatic image charge problem.

Is there a relationship between the use of analgesics and non-steroidal anti-inflammatory drugs and acute upper gastrointestinal bleeding? A Finnish case-control prospective study.

BACKGROUND: Our object was to study the role of non-steroidal anti-inflammatory drugs (NSAIDs) as a risk factor in upper gastrointestinal bleeding. METHODS: Forty-eight patients with acute bleeding due to esophagitis, gastric or duodenal ulcer, or erosions and 156 age- and sex-matched control patients from the same emergency units were interviewed about the history of ulcer disease, smoking and alcohol habits, and use of analgesics or NSAIDs. RESULTS: Twenty-four patients (50%) and 90 controls (57.6%) had no previous upper abdominal symptoms (NS). There were more heavy smokers among patients (n = 9; 18.8%) than controls (n = 7; 4.5%) (p < 0.01). Five patients (10.4%) and one control (0.6%) had taken more than 20 drinks during the week before admission (p < 0.001). Twenty-nine patients (62.5%) and 81 controls (51.9%) had used some analgesics during the week before admission (NS). There was no difference in the duration of the use of analgesics in the patients and controls. CONCLUSION: The results do not support the concept that NSAIDs are a major factor associated with serious upper gastrointestinal bleeding.

Is "indeterminate colitis" Crohn's disease in the long-term follow-up?

The diagnosis of "indeterminate colitis" was found in 6 patients of 147 operated patients (4%) as compared to the indeterminate diagnosis in 59 of 465 non-operated colitis patients (13%) at the register of inflammatory bowel diseases of Tampere University Hospital. The long-term natural course of the six surgically treated "indeterminate colitis" patients was analysed. The term "indeterminate colitis" included macroscopically either Crohn's colitis or ulcerative colitis which histologically remained indeterminate both pre and peroperatively. Clinicopathological follow-up after the median 5 1/2 years indicated typical Crohn's disease in one case and probable in two cases. However, the final diagnosis remained indeterminate in three cases. The results of the present study showed that patients with indeterminate colitis may have a tendency for Crohn's colitis in the long-term follow-up and thus should be considered when planning an ileal pouch-anal anastomosis.

Treatment of hypothermic circulatory arrest with thoracotomy and pleural lavage.

We describe a successful case of severe hypothermia due to coldwater immersion. An eight-year-old boy was saved from cold water (4 degrees C) after forty minutes. Open rewarming and resuscitation was performed by thoracotomy and pleural lavage for cardiac arrest due to the low core temperature (25 degrees C). The patient recovered primarily well without any postoperative complications. The follow-up of two years shows good state of physical health but some neuropsychological defects disturbing normal progress in school work.

Anorectal function in Crohn's disease.

Anorectal function was assessed in 63 patients with Crohn's disease and in 10 controls. Eleven patients with Crohn's disease (17%) were partially and three (5%) totally incontinent. The results of anal sphincter function studies of continent patients with Crohn's disease were similar to those of partially incontinent patients and controls. Incontinent patients had significantly lower maximal basal pressure (P less than 0.01) and significantly lower maximal squeeze pressure (P less than 0.05) as compared to controls. There was no significant difference in rectal capacity between continent, partially incontinent and totally incontinent patients and controls. There were significantly more patients with symptoms of anal incontinence in the group of patients with anal Crohn's disease as compared to the Crohn's group with normal anorectum (P less than 0.001). Risk factors for total anal incontinence in Crohn's disease were severe anorectal stenosis and previous surgery for anal abscesses. The most important reason for partial incontinence was diarrhoea. In conclusion, Crohn's disease without macroscopic lesions in the anorectum and without diarrhoea does not affect anorectal function.

Anal lesions complicating Crohn's disease.

Anal lesions were registered in 19 of 72 patients (26%) operated on for Crohn's disease at the Tampere University Hospital during 1966-1988. During a median follow-up time of six years two patients with anal disease (10%) needed no therapy, while 11 (58%) required only minimal surgery: drainage of an anal abscess in six, anal fistulotomy in three and anal dilatation in two patients, four (21%) had proctectomy for anal disease and one had a resection of active proximal disease. One patient had fecal diversion to control anal disease with poor results. There was one anorectal carcinoma which developed into prolonged anorectal stenosis. One of 10 patients (10%) with proximal disease in the small bowel needed proctectomy for anal disease while three of seven (43%) with proximal disease in the large bowel had proctectomy. On re-examination of all 72 patients with Crohn's disease there were 11 new cases with anal symptoms after a median follow-up of 12 years (eight cases with skin tags and three with anal stenosis); these patients have not required surgery. The study shows that the natural course of anal lesions in Crohn's patients varies widely and only 21% have severe anorectal disease. One patient developed anorectal carcinoma which points to the need of regular follow-up of anorectal stenosis.

Gallstones in Crohn's disease.

The prevalence of gallstones in 52 patients operated on for Crohn's disease at the University Central Hospital of Tampere over a 17-year period (1972-1988) was 21%, as compared with 23% in an age- and sex-matched control population. The gallstone prevalence rate among patients with Crohn's ileitis was significantly higher than in patients with ileocolitis (p less than 0.05) or patients with Crohn's colitis (p less than 0.005). The prevalence of gallstones in 33 patients with ileal resection was 24%. In patients with an ileal resection of more than 50 cm in length the frequency of gallstones was 33% as against 17% in patients with a minor resection (p less than 0.001). Patients with gallstones had no significantly longer duration of Crohn's disease prior to the diagnosis of gallstones than patients with no gallstones during the median observation period of 12 years.

Resection for the treatment of Crohn's disease--a thirteen years experience in the Tampere region.

One hundred patients with Crohn's disease were treated at Tampere University Hospital during a thirteen year period 1972-84. 73 of these patients had undergone an operation during a 23 year observation period. Crohn's disease was suspected prior to the operation in 53% and was an incidental finding in 41% of cases. 71% had a resection as the first operation and 15% a later resection after non-resective operation, yielding a total resection rate of 86%. The main indications for resection were obstruction in 75%, bowel fistula in 8% and colitis in 10% of cases. The ileocaecal region was the most usual site (66%) for resection. Recurrence of the disease implicated a second-resection in 11 of the 63 cases (17%). There were no differences in respect of age, duration of symptoms or presentation of anal disease before the first resection in the patients with one or two resections. After second resections there were no third resections during the median follow-up of 17 months.

Clinical features of Crohn's disease: a clinical study of one hundred patients found in an unselected population.

One hundred patients (mean age 34 years, range from 12 to 70 years) were treated at Tampere University Hospital during the thirteen year period, 1972-1984. Our hospital takes responsibility for the treatment of patients with Crohn's disease found in an unselected population of 400,000 inhabitants. In 73% of cases Crohn's disease was diagnosed before the age of forty. The mean interval between the first clinical signs and the diagnosis was 3.3 years. In 57% of the patients the diagnosis was reached within one year. In nine patients the primary diagnosis was colitis ulcerosa. Most patient were anemic and were in the state of inflammation and/or catabolism suggested by low blood hemoglobin concentration and high ESR and CRP values on admission. Three percent of the patients had macroscopic Crohn's disease in all parts of the gastrointestinal tract, whereas 22% had it only in the small intestine and 18% only in the colon. Fifty of the hundred patients had lesions in the terminal ileum and 20% in the anus. The specific finding for the present series was a high frequency of rectal lesions, in 29% of the patients. Histologically the condition was more often (P less than 0.001) revealed by the laparatomy specimen than the endoscopic biopsy, which gave a positive histology more often (P less than 0.001) in the lower than in the upper gastrointestinal tract. No gastrointestinal malignancies were found.