Alpha-methyldopa induces a naltrexone-insensitive antinociception and hypomotility in rats.

1. This study served to investigate whether endogenous opioid peptides play a role in the putative antinociceptive and the sedative actions of alpha-methyldopa. 2. In conscious normotensive rats, alpha-methyldopa induced hypotension, starting around 1 h and reaching a maximum 3-4 h after administration. Pretreatment with naltrexone resulted in an inhibition of alpha-methyldopa-induced hypotension. 3. alpha-Methyldopa dose-dependently increased hot plate latency which became evident after a 4 h lag period and reaching a maximum effect at 6 h. The antinociceptive effect of alpha-methyldopa was not affected by naltrexone. 4. In a small open field, alpha-methyldopa dose-dependently suppressed locomotion and sniffing behaviour. These effects of alpha-methyldopa were apparent 1 h after administration and were naltrexone-insensitive. 5. No changes in the level of beta-endorphin-like immunoreactivity in plasma and cerebrospinal fluid were observed after administration of alpha-methyldopa. 6. The results indicate that endogenous opioid peptides are involved in the hypotensive action of alpha-methyldopa but not in alpha-methyldopa-induced hypomotility and antinociception.     

Astigmatism and visual recovery after phacoemulsification and conventional extracapsular cataract extraction

In this study we wanted to investigate the post-operative astigmatism and visual acuity after phacoemulsification and conventional extracapsular cataract surgery. Patients operated between April and June 1993 (n=150) were retrospectively analyzed. The patients were examined prior to surgery and at day 1, at day 10, and in week 6 post-operatively. The difference between the post-operative log mean visual acuity in the Phaco group and in the CECCE group was significant after 1 and 10 days, however it was not significant (p=0.191) after 6 weeks. The mean astigmatism was significantly less in the Phaco group than in the CECCE group during the whole post-operative check-up period. This study suggests that Phaco results in a lower post-operative astigmatism and an earlier visual rehabilitation compared to the CECCE technique.Abbreviations Phaco Phacoemulsification - CECCE Conventional extracapsular cataract extraction     

When poor solubility becomes an issue: From early stage to proof of concept

Drug absorption, sufficient and reproducible bioavailability and/or pharmacokinetic profile in humans are recognized today as one of the major challenges in oral delivery of new drug substances. The issue arose especially when drug discovery and medicinal chemistry moved from wet chemistry to combinatorial chemistry and high throughput screening in the mid-1990s. Taking into account the drug product development times of 8–12 years, the apparent R&D productivity gap as determined by the number of products in late stage clinical development today, is the result of the drug discovery and formulation development in the late 1990s, which were the early and enthusiastic times of the combinatorial chemistry and high throughput screening. In parallel to implementation of these new technologies, tremendous knowledge has been accumulated on biological factors like transporters, metabolizing enzymes and efflux systems as well as on the physicochemical characteristics of the drug substances like crystal structures and salt formation impacting oral bioavailability. Research tools and technologies have been, are and will be developed to assess the impact of these factors on drug absorption for the new chemical entities.

The conference focused specifically on the impact of compounds with poor solubility on analytical evaluation, prediction of oral absorption, substance selection, material and formulation strategies and development. The existing tools and technologies, their potential utilization throughout the drug development process and the directions for further research to overcome existing gaps and influence these drug characteristics were discussed in detail.     

Platelet aggregation,disc haemorrhage and progressive loss of visual fields in glaucoma

Platelet aggregationin vitro, deterioration of visual field defects (VFD) and the prevalence of disc haemorrhages (DH) were assessed in 49 patients with primary open angle glaucoma (POAG) and compared with the findings for 67 individuals with suspected glaucoma (GS) in a seven-year follow-up study (range 5.8 to 8.2 years). The percentage patients with spontaneous platelet aggregation (SPA) was higher for POAG patients with visual field deterioration (60%) than both POAG patients without progressive loss of visual fields (12.5%; P<0.005) and those with suspected glaucoma (22.4%; P<0.005). The occurrence of DH was higher among POAG patients with progressive loss of visual field (28%) compared to the GS group (8.4%; P<0.025) and the group of patients consisting of POAG patients without deterioration of VFD and GS (9.9%; P<0.05). DH also occurred more often in patients with low tension glaucoma (41.6%) than in the remaining POAG patients (13.5%; P<0.05). No relation between the patients with SPA and the patients with DH was observed.Abbreviations NPB normal platelet behavior - SPA spontaneous platelet aggregation - DH disc haemorrhage     

CARD15 in inflammatory bowel disease and Crohn''s disease phenotypes: An association study and pooled analysis

BACKGROUND: Three major polymorphisms of the Caspase-Activation Recruitment Domain containing protein 15 gene have been described to be associated with Crohn's disease. Genotype-phenotype studies reported in literature provide conflicting data on disease localisation and behaviour. We investigated the relation of Caspase-Activation Recruitment Domain containing protein 15 with inflammatory bowel disease and Crohn's disease phenotypic characteristics in a large Dutch cohort and performed a pooled analysis on inflammatory bowel disease patients and Crohn's disease phenotypic characteristics reported in association studies. METHODS: We genotyped 781 cases and 315 controls for the R702W, G908R and 1007fsinsC variants and for six microsatellite markers in and close to Caspase-Activation Recruitment Domain containing protein 15. In the pooled analysis data of 7201 inflammatory bowel disease patients and 3720 controls from 20 studies were included. RESULTS: Association was found for Crohn's disease with R702W and 1007fsinsC, including several disease characteristics, and not for ulcerative colitis. In the pooled analysis all three common Caspase-Activation Recruitment Domain containing protein 15 variants showed strong association with Crohn's disease (p<0.00001; odds ratio varying from 3.0 for single heterozygotes to 14.7 for compound heterozygotes) and not with ulcerative colitis. Phenotype analysis showed association with small bowel involvement, stricturing and penetrating disease. CONCLUSION: Caspase-Activation Recruitment Domain containing protein 15 is associated with Crohn's disease and not with ulcerative colitis. All three common Crohn's disease-associated variants are associated with small bowel involvement, the G908R and 1007fsinsC alleles also being associated with a complicated disease course.     

Bamboo joint-like appearance of stomach in Korean patients with Crohn's disease]

BACKGROUND/AIMS: Bamboo joint-like (BJL) appearance is an endoscopic finding characterized by swollen longitudinal folds transversed by erosive fissures or linear furrows on the lesser curvature side of gastric body and cardia. It has been reported to be associated with Crohn's disease (CD). This study was aimed to evaluate the incidence of BJL appearance in Korean patients with CD. METHODS: From January to December in 2005, we performed esophagogastroduodenoscopy (EGD) in patients diagnosed as CD and ulcerative colitis (UC) in our hospital. Non-inflammatory bowel disease (IBD) subjects with upper gastrointestinal symptoms who underwent EGD were consecutively enrolled during the same period. One endoscopist performed all the endoscopic examinations to avoid inter-observer variation. A dye-spraying technique with 0.4% indigocarmine was used to allow the detection of subtle changes during the endoscopic examination. RESULTS: A total of 21 patients with CD (mean age+/-SD, 40+/-15 yr; M/F, 13/8), 28 patients with UC (42+/-15 yr; 21/7), and 685 non-IBD subjects (49+/-14 yr; 354/331) were enrolled. EGD findings in CD patients were gastric erosions (11/21), chronic superficial gastritis (5/21), chronic atrophic gastritis (1/21), duodenal erosions or ulcers (2/21), and normal (2/21). Incidence of BJL appearance was significantly higher in patients with CD (47.6%, 10/21) than others (UC, 3.6%, 1/28; non-IBD, 0.1%, 1/685) (p< 0.0001). Among patients with CD, incidence of BJL appearance was not significantly different according to the sex, status of H. pylori infection, Vienna classification for phenotype, medications or EGD findings. CONCLUSIONS: BJL appearance on the gastric body and cardia can be a diagnostic clue to CD.     

The immunomodulatory effects of 3-monochloro-1,2-propanediol on murine splenocyte and peritoneal macrophage function in vitro.

3-Monochloro-1,2-propanediol (MCPD) is a well-known by-product of acid-hydrolyzed soy sauce during its manufacturing process. MCPD has been reported genotoxic in vitro, and reproductive toxicity and carcinogenicity in rats. To evaluate the immunomodulatory effect of MCPD on murine splenocyte and macrophage in vitro, we investigated splenocyte blastogenesis by concanavalin A (Con A), anti-CD3, and lipopolyssacharide (LPS), the production of cytokines from splenocyte, and the activity of mouse peritoneal macrophages. There was a significant decrease in lymphocyte blastogenesis to Con A or anti-CD3 at subtoxic dose of MCPD. A significant decrease in splenocyte blastogenesis to LPS was also observed. The production level of interferon (IFN)-gamma on splenocyte culture with Con A was significantly reduced at the higher concentration than 1.0mM of MCPD. The levels of interleukin (IL)-4 and IL-10 were also decreased at high concentrations of MCPD. There was a significant decrease in production of nitric oxide (NO) by peritoneal macrophages treated with MCPD. MCPD also inhibits tumor necrosis factor (TNF)-alpha production of stimulated macrophages. These results indicate that MCPD might be able to reduce the functionality of lymphocytes and peritoneal macrophages in vitro.     

Can a leukocyte depletion filter (LDF) reduce the risk of reintroduction of hepatocellular carcinoma cells?

During liver transplantation for hepatocellular carcinoma (HCC) patients, HCC could theoretically be introduced into the systemic circulation when salvaged blood is used with an autotransfusion device. Several reports have shown that some types of leukocyte depletion filters (LDFs) could completely reduce the risk for reintroducing some types of tumor cells. In this study, we tested the ability of the LDF (RCEZ1T, Pall Biomedical Co, NY, USA) to reduce the risk for reintroducing HCC cells in vitro by using a very sensitive detection method. We divided the test group into 6 groups: group I was 10 cells, group II was 20 cells, group III was 2 x 10(3) cells, group IV was 2 x 10(5) cells, group V was 2 x 10(6) cells, and group VI was 2 x 10(7) cells. The counted cells in 200 mL saline were passed through the RCEZ1T using the force of gravity. To identify the presence of cells, the pellet was resuspended, and polymerase chain reaction (PCR) was performed. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH), a housekeeping gene, was used as a primer. In groups I and II, the HCC cells were completely filtered in all experiments. However, in groups III, IV, and V, the HCC cells were not completely filtered in a few of the repeated experiments, with the unfiltered rate of tumor cells being between 8% and 20%. In group VI, the HCC cells were not completely filtered in all the repeated experiments. In conclusion, the RCEZ1T filter markedly reduced the risk for reintroduction of HCC cells. However, at high HCC cell load the filter cannot completely remove all the tumor cells. Further studies are required to assess the impact in clinical settings.     

Somatostatin receptor scintigraphy with indium-111-DTPA-D-Phe-1-octreotide in man: metabolism, dosimetry and comparison with iodine-123-Tyr-3-octreotide.

Scintigraphy with 123I-Tyr-3-octreotide has several major drawbacks as regards its metabolic behavior, its cumbersome preparation and the short physical half-life of the radionuclide. The use of another radiolabeled analog of somatostatin, 111In-DTPA-D-Phe-1-octreotide, has consequently been proposed. DTPA-D-Phe-1-octreotide can be radiolabeled with 111In in an easy single-step procedure. DTPA-D-Phe-1-octreotide is cleared predominantly via the kidneys. Fecal excretion of radioactivity amounts to only a few percent of the administered radioactivity. For the radiation dose to normal tissues, the most important organs are the kidneys, the spleen, the urinary bladder, the liver and the remainder of the body. The calculated effective dose equivalent is 0.08 mSv/MBq. Optimal 111In-DTPA-D-Phe-1-octreotide scintigraphic imaging of various somatostatin receptor-positive tumors was obtained 24 hr after injection. In the six patients studied, tumor localization with 123I-Tyr-3-octreotide and with 111In-DTPA-D-Phe-1-octreotide were found to be similar. However, the normal pituitary is more frequently visualized with the latter radiopharmaceutical. In conclusion, 111In-DTPA-D-Phe-1-octreotide appears to be a sensitive somatostatin receptor-positive tissue-seeking radiopharmaceutical with some remarkable advantages: easy preparation, general availability, appropriate half-life and absence of major interference in the upper abdominal region, because of its renal clearance. Therefore, 111In-DTPA-D-Phe-1-octreotide may be suitable for use in SPECT of the abdomen, which is important in the localization of small endocrine gastroenteropancreatic tumors.     

Anterior translocaton of pulmonary artery without aortic transection in repair of tetralogy of Fallot with absent pulmonary valve.

We developed a technique of translocation of the pulmonary artery anterior to the ascending aorta without transection of the aorta in the repair of tetralogy of Fallot with absent pulmonary valve. Our technique includes detachment of the main pulmonary artery (MPA) from the pulmonary annulus, vertical division of the MPA, anterior translocation of the pulmonary artery with patch augmentation between the vertically divided MPA.