Cationic analog of deoxycholate as an oral delivery carrier for ceftriaxone

A great number of currently available drugs and those being developed that fall under the class III of the BCS (biopharmaceutical classification system) possess high therapeutic potential but cannot be delivered by peroral absorption. In this study, we synthesized a cationic analog of deoxycholic acid and evaluated its efficacy as a potential oral drug carrier for anionic BCS class III drugs using ceftriaxone as a model drug. Cationic deoxycholylethylamine (DCEA), one of cationic analogs of deoxycholic acid, was synthesized and made into physical complexes at varied molar ratios with an anionic ceftriaxone. These drug complexes were formulated with propylene glycol and their oral bioavailabilities were evaluated. The results of the partition coefficient study revealed a highly water soluble ceftriaxone that became more hydrophobic as the molar ratio of the carrier in the complex increased. When the ceftriaxone/DCEA formulation was administered into a nonclosed segment of duodenum of rats, C(max) (the maximum drug concentration in plasma) and AUC (area under the curve) were significantly increased and its bioavailability was increased up to 70%. Therefore, the new cationic carriers proposed in this study could improve the absorption of BCS class III drugs in the intestine with maintaining their full biological activity.     

Targeting of<Emphasis Type="Italic"> lacZ</Emphasis> reporter gene expression with radioiodine-labelled phenylethyl-β-<Emphasis Type="SmallCaps">d</Emphasis>-thiogalactopyranoside

There has recently been increasing interest in the development of radioprobes that specifically target proteins transcribed from expression of reporter genes of interest. The purpose of this study was to develop a radioprobe that targets one of the most widely used reporter genes, the bacterial lacZ gene. We synthesised and purified radioiodine-labelled phenylethyl--d-thiogalactopyranoside (PETG), a competitive inhibitor specific against Escherichia coli -galactosidase. We showed that [¹²⁵I]iodo-PETG specifically binds to -galactosidase as verified by column chromatography and polyacrylamide gel electrophoresis after incubation of radiotracer with the protein. We also showed through enzyme kinetic studies that iodo-PETG retains inhibitory action against -galactosidase activity. COS-7 cells infected with a recombinant adenovirus expressing the lacZ gene had viral titre-dependent enhancements in [¹²⁵I]iodo-PETG uptake (r²=0.897; P=0.001), which reached up to 642.5%±16.7% of control levels (P<0.00001). Moreover, the level of uptake was highly correlated to luminescent measurements of -galactosidase activity (r²=0.878; P<0.0001). These results confirm that radioiodine-labelled PETG specifically targets -galactosidase and that its uptake rates faithfully reflect levels of expression of the lacZ reporter gene. Further investigations were performed in nude mice bearing human neuroblastoma tumours transferred with the lacZ gene. Compared with control tumours, lacZ-expressing tumours were slightly better visualised on [¹²³I]iodo-PETG images and had a modest increase in tumour to muscle count ratio (2.6±0.2 vs 1.9±0.1, P<0.05). The present results provide proof-of-principle for the potential of radiolabelled inhibitors as promising radiotracers to monitor lacZ gene expression levels. Future modifications to improve cell permeability should enhance in vivo contrast levels and may allow the use of radiolabelled -galactosidase inhibitors for non-invasive monitoring of lacZ gene expression.This work was presented in part at the 49th Annual Meeting of the Society of Nuclear Medicine, LA, USA, June 15–19, 2002.     

Discrimination of tuberculous spondylitis from pyogenic spondylitis on MRI

OBJECTIVE: The purpose of this study was to determine the accuracy of MRI for discrimination between tuberculous spondylitis and pyogenic spondylitis. MATERIALS AND METHODS: MR images of 52 patients who had MRI of the spine and confirmed spondylitis were retrospectively reviewed. After review of medical records, we compared MRI findings in 20 patients with tuberculous spondylitis and 20 patients with pyogenic spondylitis. Statistical analysis was performed with the chi-square test. RESULTS: The reviewer identified tuberculous spondylitis with sensitivity, specificity, and accuracy of 100% (20/20), 80% (16/20), and 90% (36/40), and pyogenic spondylitis with sensitivity, specificity, and accuracy of 80% (16/20), 100% (20/20), and 90% (36/40), respectively. The patients with tuberculous spondylitis had a significantly higher incidence of MRI findings as follows (p < 0.05): a well-defined paraspinal abnormal signal (95% [19/20] in tuberculous vs 25% [5/20] in pyogenic), a thin and smooth abscess wall (95% [19/20] vs 15% [3/20]), combination of both findings (90% [18/20] vs 0% [0/20]), presence of paraspinal or intraosseous abscess (95% [19/20] vs 50% [10/20]), subligamentous spread to three or more vertebral levels (85% [17/20] vs 40% [8/20]), involvement of multiple vertebral bodies (60% [12/20] vs 25% [5/20]), thoracic spine involvement (40% [8/20] vs 10% [2/20]), and hyperintense signal on T2-weighted images (95% [19/20] vs 65% [13/20]). CONCLUSION: MRI was accurate for differentiation of tuberculous spondylitis from pyogenic spondylitis.     

Primary peripheral T-cell lymphoma of the face other than mycosis fungoides. Computed tomography and magnetic resonance findings

OBJECTIVE: To describe the radiologic findings of primary peripheral T-cell lymphoma (PTCL) of the face other than mycosis fungoides. METHODS: Computed tomography (CT) and magnetic resonance imaging (MRI) findings of 5 consecutive patients with pathologically proven primary facial PTCL other than mycosis fungoides were retrospectively evaluated. Patients with PTCL involving the sinonasal cavity or lymph nodes were excluded. RESULTS: Diagnoses of patients included in this study consisted of natural killer/T-cell lymphoma (n = 2), subcutaneous panniculitis-like T-cell lymphoma (n = 1), anaplastic large cell lymphoma (n = 1), and PTCL not otherwise specified (n = 1). Infiltration or swelling of the superficial space of the face was noted on both CT and MRI, mimicking inflammation or infection. Also seen were well-enhancing small nodular (n = 2) or infiltrative mass-like lesions (n = 2) within the areas of infiltration, which showed intermediate signal intensity on T2-weighted images. One patient demonstrated infiltration and swelling alone. CONCLUSIONS: Primary facial PTCL is a rarely encountered tumor and demonstrates infiltration or swelling mimicking inflammation or infection. Nodular or infiltrative mass-like lesions may be helpful for its diagnosis.     

CT and MRI findings of cystadenofibromas of the ovary

The aim of this study was to assess imaging findings on CT or MR images of histologically proven ovarian cystadenofibromas. In the period 1995–2001, 32 histologically proven ovarian cystadenofibromas were identified in 28 women. Of the 32 ovarian cystadenofibromas, 16 tumors were purely cystic and the remaining 16 were complex cystic on CT or MR images. Solid components of 16 complex cystic tumors were seen as nodular (n=8) or trabecular (n=9) solid areas. One tumor had both nodular and trabecular solid components. Among 16 complex cystic tumors, 14 had thick or irregular septa; thus, half of ovarian cystadenofibromas had morphological imaging features of malignancy on CT or MR images. On histology, solid components in the cystic tumors were correlated with fibrous stromas that occasionally made a false-positive result for malignancy on imaging.     

Voiding diary for the evaluation of urinary incontinence and lower urinary tract symptoms: prospective assessment of patient compliance and burden

AIMS: Voiding diary duration may be related to patient compliance and burden. To test this hypothesis, we evaluated patient compliance and burden. METHODS: Between January and July 2002, we prospectively evaluated 162 patients (57 males and 105 females, mean age 53.0, range 20-81 years) with stress urinary incontinence or lower urinary tract symptoms. At the initial visit, all patients underwent a detailed clinical evaluation including an International Prostate Symptom Score (I-PSS) assessment and were randomly requested to complete 2-day, 3-day, or 7-day voiding diaries (the three study groups). At the second visit, a simple self-administered questionnaire was completed by all patients. The questionnaire included 11 items on subject demographics and voiding diary-keeping. RESULTS: No significant differences were found in either the accuracy of diary-keeping or the daily average number of omissions when the three groups were compared. However, as the diary duration increased, the mean burden scores increased (P = 0.005), and the mean preferred duration of the diary in the 7-day group was significantly higher than that of the 2-day or 3-day groups (P < 0.001). After categorizing patients into two groups according to the degree of patient burden, members of the group with a greater perceived burden were found to have a significantly higher I-PSS quality of life score (P = 0.045) and to have kept a diary for a longer time (P = 0.038). CONCLUSIONS: Our results suggest that keeping a diary for 7 days may increase patient burden and thus, we recommend that the 7-day diary should be reduced to cover fewer days.     

Immune reactions of lymphocytes and macrophages against PEG-grafted pancreatic islets

Graft rejection is the major limiting factor in islet transplantation and is closely related with the recruitment and activation of T cells and macrophages against the graft. To reduce the immunogenicity of islets, we have grafted biocompatible polyethylene glycol (PEG) onto the collagen capsule of islets without changing the morphology and function of islets. In this study, we evaluated whether the grafted PEG molecules on the collagen capsule of islet could prevent the activation of immune cells, and investigated factors that are mainly related to the immune reaction in vitro. During the co-culture with lymphocytes, the morphology and viability of PEG-grafted islets were not damaged, and the amounts of IL-2 and TNF-alpha secreted from lymphocytes co-cultured with PEG-grafted islets were significantly lower than that of free islets. However, when both kinds of islets were cultured with macrophages, there were no significant differences in morphology, viability and the secreted amounts of cytokines and nitric oxide. In conclusion, the grafted PEG could inhibit activation of lymphocytes, which are essential in initiating the graft rejection process. However, the grafted PEG molecules could not completely prevent the infiltration of cytotoxic molecules into the islets.     

Nocturia in patients with lower urinary tract symptoms: association with diurnal voiding patterns

OBJECTIVE: To determine whether diurnal voiding patterns predict nocturia in patients with lower urinary tract symptoms (LUTS), as few studies have evaluated the association between diurnal and nocturnal voiding patterns. PATIENTS AND METHODS: We prospectively analysed the frequency-volume charts (FVCs) of consecutive patients with LUTS. At the initial visit patients had a detailed clinical evaluation and subsequently were requested to complete a 72-h FVC. In all, 104 (41 men and 63 women, mean age 63 years, range 50-83) were included in the primary analyses. Associations between daytime variables and nocturia were described using maximum likelihood estimates of the relative risk and by 95% confidence intervals (CIs) based on logistic regression models. RESULTS: When at least one night-time void was used to define nocturia the multivariate logistic model showed a negative association of mean daytime voided volume with nocturia (P = 0.001). The odds ratio for nocturia decreased with this variable to 0.98 (95% CI 0.96-0.99). When 'voiding at least twice per night' was used to define nocturia only the number of daytime voids was positively related to nocturia (odds ratio 1.22; 95% CI 1.01-1.48; P= 0.040). CONCLUSION: Nocturia may be associated with diurnal voiding patterns; these results also suggest that the causes of nocturia of one or of two or more voids may differ. This highlights the role of bladder function in more severe forms of nocturia.     

Ipsilateral motor pathway confirmed by diffusion tensor tractography in a patient with schizencephaly

We evaluated the hand motor function of a right hemiparetic patient with schizencephaly using a combination of fMRI, transcranial magnetic stimulation, and diffusion tensor tractography (DTT). Only the unaffected (right) primary sensori-motor cortex was found to be activated during either affected (right) or unaffected hand movements. Evoked motor potentials with similar characteristics were obtained from both abductor pollicis brevis muscles simultaneously when stimulating the unaffected motor cortex. Moreover, a tract presumed to be a corticospinal tract was observed in the unaffected hemisphere by DTT, however, no tract was observed in the affected hemisphere. Our results indicate that the ipsilateral corticospinal tract extended from the unaffected (right) motor cortex to both hands. This finding may reflect functional reorganization of motor function in a patient with congenital brain disorder.     

Simple retrograde balloon dilation for treatment of ureteral strictures: etiology-based analysis

This study consists of an analysis of the results of simple retrograde balloon dilation in the treatment of ureteral strictures for the evaluation of the long-term efficacy of this procedure, and the factors affecting its success rate. A prospective study was performed on 43 ureteral strictures (22 malignant, 21 benign) from 37 patients treated with retrograde balloon dilation from October 1997 to May 1999. After the stricture segments were dilated, ureteral stents were indwelled uniformly for 3 weeks. Strictures were postoperatively followed up radiographically at 1, 3, 6 and 12 months, and annually thereafter. Success was defined by symptomatic and radiographic improvement. The follow-up periods ranged from 8 to 57 months (mean 41 months). The success rates of the benign strictures at 12 and 36 months were much higher than those of the malignant strictures (67 and 57% vs., 18 and 14%, p=0.0009). While 56% and 47% of the patients with strictures shorter than 2 cm were successful at 12 and 36 months, respectively, none with strictures longer than 2 cm were successful at the same follow-up periods (p=0.0002). Of the successful benign cases with a shorter segment at 12 months, 12 out of 14 (86%) showed persistent long-term successes at the 36 months follow-up. Other prognostic factors, such as sex, age, location, disappearance of a waist, dilation time and grade of hydronephrosis, were not found to influence the success rate. A multivariate analysis revealed the etiology and stricture length were the only significant prognostic factors affecting the final outcome (p=0.030 and p=0.0262, respectively, by Cox's proportional hazards model). In consideration of its minimal invasiveness and acceptable long-term outcome, simple retrograde balloon dilation is an effective treatment modality for benign ureteral stricture with a short segment (< or = 2 cm), and a shorter duration of stenting (3-weeks) is viable.