bluuebunny/crossref_metadata_2025 huggingface dataset:
The Rivermead Assessment of Somatosensory Performance (RASP): standardization and reliability data
Authors: Winward Charlotte E , Halligan Peter W , Wade Derick T
Published: October 2002

Objective: To develop a standardized, clinically relevant, quantitative assessment of somatosensory performance in patients with stroke. Design: Prospective observational study and test evaluation. Setting: Local Oxford hospitals and a regional neurological rehabilitation centre.

Subjects: Stroke patients with a ”rst, lateralized acute stroke in hospital, and age-matched control subjects.

Method: Each patient was assessed in a structured way using a new battery of formal tests of somatosensory performance.

Results: A total of 100 patients and 50 controls were fully investigated. Control subjects performed at or near ceiling on all tests, but patients showed impaired performance on all tests. The Rivermead Assessment of Somatosensory Performance (RASP) showed good intra-rater and inter-rater reliability for all subtests. There were however only weak relationships between scores of sensory impairment and scores of motor impairment or mobility and dependence.

Conclusions: The RASP provides a practical and reliable assessment of sensory loss, which provides the clinician with a comprehensive picture of the patient’s performance and can be used to inform and monitor rehabilitation and recovery.
A completed audit cycle and integrated care pathway for the management of depression following brain injury in a rehabilitation setting
Authors: Hassan Nibras , Turner-Stokes Lynne , Pierce Katherine , Clegg Frances
Published: October 2002

Objective: To develop an evidence-based multidisciplinary integrated care pathway (ICP) for the management of depression following brain injury in a rehabilitation setting, and to assess its impact on standards of care and documentation.

Setting: A regional rehabilitation unit providing inpatient rehabilitation for young patients (16–65) with complex disabilities mainly resulting from brain injury.

Methods and design: A completed cycle of audit including:

standards set for documentation, assessment, management and review; L an initial retrospective audit of documented patient management against those standards during a five-year period (26 patient records);

ICP development by a multidisciplinary team of doctors, psychologists and nurses based on clinical opinion and systematic review of the literature;

re-audit from the ICP documentation (48 patient records) over a period of 15 months.

Results: The initial audit demonstrated borderline acceptable documentation of baseline mood state and start of medication (54–61%), but poor documentation of review (29%) and subsequent treatment (27%). Introduction of the ICP improved all standards of documentation to 94–100%, except for assessment using a validated measure (84%) and follow-up assessment (76%).

Conclusions: This ICP raised staff awareness of depression, leading to improved documentation and possibly also standards of care.
Methylphenidate inhibits cytochrome P450 in the Swiss Webster mouse
Authors: Le Nedelec M J , Rosengren R J
Published: October 2002

Drug interactions have previously been reported following the co-administration of methylphenidate (MPH) and drugs metabolized by the cytochrome P450 (CYP450) system such as imipramine. Therefore, this study used the Swiss Webster mouse to determine the effect of MPH on CYP450 isozymes likely to be important in the interaction between MPH and imipramine. Single high doses of MPH (25, 50 and 100 mg/kg, i.p.) were administered to simulate the abuse of MPH. Under these conditions, MPH decreased total hepatic CYP450 to 50% of control. Additionally, MPH inhibited the catalytic activity of CYP1A and CYP2E1 by 50%, and decreased the polypeptide levels of CYP3A by 30%. In a second study designed to simulate more closely therapeutic use, MPH was administered orally for two weeks at 10-fold lower doses (2.5, 5 and 10 mg/kg/day). MPH decreased total hepatic CYP450 at both 5 and 10 mg/kg/day (0.96±0.01 and 0.96±0.06 nmol/mg versus 1.34±0.01 nmol/mg for saline control, P<0.05). The catalytic activity and protein levels of CYP1A were diminished by up to 50% of control, while catalytic activity and polypeptide levels for CYP2E1 and CYP3A remained unchanged. These results indicate that MPH inhibits the CYP450 system following both abuse and therapeutic scenarios. However, this effect was dependent on both the isoform of CYP450 and the duration of MPH administration.
Effect of mycophenolate mofetil on severity of nephritis and nitric oxide production in lupus-prone MRL/lpr mice
Authors: Lui S L , Tsang R , Wong D , Chan K W , Chan T M , Fung P C W , Lai K N
Published: October 2002

Mycophenolate mofetil (MMF), an immunosuppressive drug commonly used in organ transplantation, is increasingly being used to treat autoimmune diseases including systemic lupus erythematosus (SLE). Excessive production of nitric oxide (NO) by inducible nitric oxide synthase (iNOS) has been implicated in the pathogenesisof lupus nephritis. We evaluated the effect of MMF on the severity of nephritis and the production of NO in lupus-prone MRL/lpr mice.

Eight-week-old female MRL/lpr mice (n = 20) were treated with MMF (100 mg/kg/day) by oral gavage for 12 weeks. Control mice (n = 20) received vehicle on the same schedule. The mice were killed after 12 weeks of treatment. Treatment with MMF significantly decreased the amount of proteinuria, prolonged survival and reduced the histological severity of glomerulonephritis.Urinary nitrite/nitrate excretion in the MMF-treated mice was significantly reduced during the first 8 weeks of treatment. However, by the end of the 12 weeks' treatment period, there was no significant difference between vehicle and MMF-treated mice in terms of urinary nitrite/nitrate excretion, intra-renal production of NO, expression of iNOS protein and induction of iNOS mRNA.

We conclude that MMF is effective in attenuatingthe severity of nephritis in MRL/lpr mice. The beneficial effects of MMF on lupus nephritis during the early phase of the disease might be partly attributed to the inhibition of NO production. The inhibitory effect of MMF on NO production diminishes as the disease progresses. MMF probably has additional, as yet undefined mode of actions to fully account for its beneficial effects on lupus nephritis.
Thrombotic thrombocytopenic purpura in systemic lupus erythematosus: disease activity and the use of cytotoxic drugs
Authors: Vasoo S , Thumboo J , Fong K-Y
Published: October 2002

Thrombotic thrombocytopenicpurpura (TTP) is a rare and occasionally fatal haematologic disorder that can coexist with systemic lupus erythematosus (SLE) and other autoimmune diseases. We identified all cases of TTP seen in our institution over a 3 year period using a computerized database. We found that SLE activity (measured by the SLE Disease Activity Index) and TTP activity ran a parallel course in three patients with coexistent SLE and TTP. TTP in these three patients, although refractory to plasmapheresis, responded to cytotoxic therapy. These observations further support an autoimmune contribution to the pathogenesis of some cases of TTP. A literature review revealed that mortality in SLE patients with more severe, refractory TTP treated with plasmapheresis and cytotoxics, may not be higher than in patients responding to plasmapheresis alone (who are likely to have milder disease). These data suggest that cytotoxics may have a role in treatment of patients with active SLE and TTP refractory to plasmapheresis.
Development and assessment of a World Wide Web site for systemic lupus erythematosus patient information
Authors: Young S P , Henderson E , Cheseldine D L , Wilson A S , Skan J , Heaton S , Bowman S J , Situnayake D , Bacon P A , Southwood T R , Gordon C
Published: October 2002

Patient education is an important component of the management of chronic diseases such as SLE. We have investigated the value of the World Wide Web as a medium for delivery of SLE patient information.

Volunteers recruited from the clinic and from the website completed interviews and questionnaires aimed at defining their information needs. A new website was then established and its impact on users tested using knowledge questionnaires.

The new website was used extensively (20–30 users each day) over the 24 month period of study until April 2001. A total of 510 participants completed an online questionnaire that showed that for some users it was their first use of the internet to gather lupus information, but the majority (58.9%) accessed it at least monthly for this purpose. We also found that, while most users (56.9%) found current disease information was at an appropriate level, 37.5% thought it was too basic. Knowledge questionnaires from 42 participants before and after using the site showed a significant rise in users’ knowledge of the areas covered by the site.

As far as we are aware this study is the first to show that a patient-oriented website can have a positive effect on disease knowledge. The relative ease with which good quality information can be disseminated via the web suggests that this medium is likely to be less costly and perhaps more educationally effective than printed information, and so is likely to become a primary vehicle for patient education. The website tested can be found at: www.rheumatology.bham.ac.uk/lupus/intro.html
Systemic lupus erythematosus presented as non-inflammatory necrotizing vasculopathy-induced ischemic glomerulopathy and small vessels-related ischemic cardiomyopathy
Authors: Sung J M , Hsu S C , Chen F F , Huang J J
Published: October 2002

The clinical significance of lupus non-inflammatory necrotizing vasculopathy (NINV) is not well established. For example, since lupus renal NINV is usually reported to coexist with proliferative and active glomerulonephritis, it is difficult to demonstrate the role of NINV on renal pathophysiology.

Here we report a 16-year-old SLE boy with renal NINV presenting as ischemic glomerulopathy and small vessels-related ischemic heart failure. The renal biopsy demonstrated mild proliferative glomerulonephritis and NINV initially, and one month later repeated renal biopsy showed NINV with ischemic glomerulopathy. These findings established that NINV, but not proliferative glomerulonephritis, was responsive for his acute renal failure (ARF). Another interesting question is about the pathophysiology of his myocardial dysfunction. This patient presented typical angina and congestive heart failure (CHF). Echocardiograms and ventriculography revealed dilatation of four chambers and low ejection fraction. Serial electrocardiograms demonstrated evolutionary ischemic changes. Coronary angiography revealed no abnormality of large vessels. These findings suggested small vascular lesions-induced myocardial ischemia was the underlying mechanism of dilated cardiomyopathy.

As myocardial biopsy was not done in our case, we could only speculate, but not prove, that the NINV observed in renal biopsy may also involve in cardiac microvascular beds. Nevertheless, this interesting case emphasized the role of obliterative small vascular lesions in the pathophysiologyof ARF and myocardial dysfunction. The patient was treated with high-dose corticosteroid, plasma infusion and hemodialysis. His cardiac function improved gradually, however the renal function did not recover.
Sound barriers: influences of social prestige, peer pressure and teacher (dis)approval on FL oral performance
Authors: Lefkowitz Natalie , Hedgcock John
Published: October 2002

Social pressure and prestige have been viewed as barriers to oral performance in the L2 classroom, but their impact has not been extensively examined in foreign language (FL) contexts. Learner decisions to accept or reject prescriptive pronunciation norms may confer prestige, which may both privilege and marginalize novice classroom learners. This paper examines how adult, monolingual FL learners’ oral performance is affected by the degree to which they associate prestige with classmate and teacher (dis)approval. We explore relationships among the following variables: (1) learners’ views of their own and their peers’ pronunciation skills; (2) values associated with native-like speech; (3) beliefs about social conditions favourable to target-like speech; and (4) the accuracy of learners’ perceptions of desirable pronunciation patterns. Data are drawn from 11 audio-recorded FL class sessions, 10 ethnographic interviews, and questionnaire responses supplied by 282 students in French and Spanish cohorts. Analyses reveal that participants profess a strong desire to attain ‘standard’ pronunciation. However, findings also highlight striking disjunctions between learners’ perceptions and their observed production, reflecting a concern for social status and solidarity. Finally, results expose a tendency to inflate oral performance self-assessments, which may conceal learners’ inability to notice mismatches between their production and target norms.
Psychiatric effects of traumatic brain injury events in Cambodian survivors of mass violence
Authors: Mollica Richard F. , Henderson David C. , Tor Svang
Published: October 2002

Background

The prevalence of brain injury and its effects in populations exposed to war violence has not been studied in recent years.

Aims

To examine the association between traumatic brain injury events and psychiatric symptoms of major depression and post-traumatic stress disorder (PTSD) in Cambodian survivors of mass violence.

Method

The population comprised a multi-stage random sample of Cambodian refugees livingin a Thai refugee camp. The main results analysed the relationship between six categories of trauma events and psychiatric symptoms of depression and PTSD during two time periods.

Results

Almost 15 000 trauma events were reported (n=13481, Pol Pot period;n=1249, past year). Traumatic brain injury was most common in the highly educated and in individuals with the highest levels of cumulative trauma. Of all trauma categories, traumatic brain injury revealed the strongest association with symptoms of depression, and a weaker association with PTSD. Brain injury represented 4% of the total number of traumatic events for both time periods, contributing 20% of the total symptom score for depression and 8% of that for PTSD.

Conclusions

Clinical identification and treatment of traumatic brain injuries in highly traumatised populations must be maintained in order to develop a new public health model for their treatment.
Utility of Troponin I in Patients with Cocaine‐associated Chest Pain
Authors: Kontos Michael C. , Anderson F. Philip , Ornato Joseph P. , Tatum James L. , Jesse Robert L.
Published: October 2002

Baseline electrocardiogram abnormalities and market elevations not associated with myocardial necrosis make accurate diagnosis of myocardial infarction (MI) difficult in patients with cocaine‐associated chest pain. Troponin sampling may offer greater diagnostic utility in these patients. Objective: To assess outcomes based on troponin positivity in patients with cocaine chest pain admitted for exclusion of MI. Methods: Outcomes were examined in patients admitted for possible MI after cocaine use. All patients underwent a rapid rule‐in protocol that included serial sampling of creatine kinase (CK), CK‐MB, and cardiac troponin I (cTnI) over eight hours. Outcomes included CK‐MB MI (CK‐MB ≥ 8 ng/mL with a relative index [(CK‐MB × 100)/total CK] ≥ 4, cardiac death, and significant coronary disease (≥50%). Results: Of the 246 admitted patients, 34 (14%) met CK‐MB criteria for MI and 38 (16%) had cTnI elevations. Angiography was performed in 29 of 38 patients who were cTnI‐positive, with significant disease present in 25 (86%). Three of the four patients without significant disease who had cTnI elevations met CK‐MB criteria for MI, and the other had a peak CK‐MB level of 13 ng/mL. Sensitivities, specificities, and positive and negative likelihood ratios for predicting cardiac death or significant disease were high for both CK‐MB MI and cTnI and were not significantly different. Conclusions: Most patients with cTnI elevations meet CK‐MB criteria for MI, as well as have a high incidence of underlying significant disease. Troponin appears to have an equivalent diagnostic accuracy compared with CK‐MB for diagnosing necrosis in patients with cocaine‐associated chest pain and suspected MI.
Expression of Multidrug Resistance GenesMVP,MDR1, andMRP1Determined Sequentially Before, During, and After Hyperthermic Isolated Limb Perfusion of Soft Tissue Sarcoma and Melanoma Patients
Authors: Stein Ulrike , Jürchott Karsten , Schläfke Matthias , Hohenberger Peter
Published: October 2002

PURPOSE: Isolated, hyperthermic limb perfusion (ILP) with recombinant human tumor necrosis factor alpha and melphalan is a highly effective treatment for advanced soft tissue sarcoma (STS) and locoregional metastatic malignant melanoma. Multidrug resistance (MDR)-associated genes are known to be inducible by heat and drugs; expression levels of the major vault protein (MVP), MDR1, and MDR-associated protein 1 (MRP1) were determined sequentially before, during, and after ILP of patients.

PATIENTS AND METHODS: Twenty-one STS or malignant melanoma patients were treated by ILP. Tumor tissue temperatures were recorded continuously and ranged from 33.4°C initially to peak values of 40.4°C during ILP. Serial true-cut biopsy specimens from tumor tissues were routinely microdissected. Expression analyses for MDR genes were performed by real-time reverse transcriptase polymerase chain reaction and immunohistochemistry.

RESULTS: In 83% of the patients, MVP expression was induced during hyperthermic ILP. MVP-mRNA inductions often paralleled the increase in temperature during ILP. Increased MVP protein expressions either were observed simultaneously with the MVP-mRNA induction or were delayed until after the induction at the transcriptional level. Inductions of MDR1 and MRP1 were observed in only 13% and 27% of the specimens analyzed. Temperatures and drugs applied preferentially led to an induction of MVP and were not sufficient to induce MDR1 and MRP1 in the majority of tumors.

CONCLUSION: This study is the first to analyze the expression of MDR-associated genes sequentially during ILP of patients and demonstrates that treatment might lead to increased levels of MVP, whereas enhanced levels of MDR1 and MRP1 remain rare events.
Symptom Experiences: Perceptual Accuracy Between Advanced-Stage Cancer Patients and Family Caregivers in the Home Care Setting
Authors: Lobchuk Michelle M. , Degner Lesley F.
Published: October 2002

PURPOSE: This study used a comparative descriptive design to compare family caregivers’ and advanced-stage cancer patients’ perceptions of patients’ multidimensional symptom experiences on presence, frequency, severity, and distress.

PATIENTS AND METHODS: A convenience sample of 98 dyads, composed of advanced-stage heterogeneous cancer patients and their caregivers, completed the Memorial Symptom Assessment Scale in the home care setting on a one-time basis. This scale is a 32-item Likert-type scale for assessing the presence, frequency, severity, and distress arising from symptoms in cancer patients.

RESULTS: There was confirmation of trends previously described in related studies where, for example, caregivers tend to overreport on symptom experiences. However, the degree of absolute difference between patient and caregiver responses was normally around 1 unit (on a theoretical range of 0 to 4 units). Levels of patient-caregiver agreement were better on more concrete questions related to symptom frequency, severity, and distress than on broad questions related to the presence of a symptom. Patients and caregivers achieved better levels of agreement on physical versus psychological symptoms.

CONCLUSION: The findings indicated that family caregivers can provide reasonable proxy or complementary reports on patient symptom experiences of frequency, severity, and distress. However, family caregivers have greater difficulty in achieving high levels of accuracy on psychological versus physical symptoms.
Phase I Trial of Intravesical Gemcitabine in Bacillus Calmette-Guérin–Refractory Transitional-Cell Carcinoma of the Bladder
Authors: Dalbagni Guido , Russo Paul , Sheinfeld Joel , Mazumdar Madhu , Tong William , Rabbani Farhang , Donat Machelle S. , Herr Harry W. , Sogani Pramod , dePalma Dominique , Bajorin Dean
Published: October 2002

PURPOSE: The aim of this phase I study was to determine the safety and toxicity profile of gemcitabine administered as an intravesical agent in patients with transitional-cell carcinoma (TCC) of the bladder.

PATIENTS AND METHODS: Patients with superficial bladder cancer refractory to intravesical bacillus Calmette-Guérin (BCG) therapy and refusing a cystectomy were considered eligible for the trial. Gemcitabine was given in the bladder for 1 hour twice weekly in 100 mL sodium chloride for a total of six treatments. After a 1-week break, a second course of six treatments over 3 weeks was given, followed by response assessment. Four dose levels were explored: 500 mg, 1,000 mg, 1,500 mg, and 2,000 mg.

RESULTS: Eighteen patients completed therapy: three at 500 mg, six at 1,000 mg, three at 1,500 mg, and six at 2,000 mg. No grade 3 or 4 toxicity was observed at 500 mg. At 1,000 mg, three patients developed hematuria and one had a skin reaction resembling grade 3 hand-foot syndrome. Three patients at 1,500 mg had no grade 3 or 4 toxicity. Of six patients at 2,000 mg, one had grade 3 thrombocytopenia and neutropenia without infection. Seven patients had a complete response (negative cytology and posttreatment biopsy), and four patients had a mixed response (negative bladder biopsy but positive cytology).

CONCLUSION: Gemcitabine has substantial activity as an intravesical agent in BCG-refractory TCC and warrants further investigation. Therapy given twice weekly was associated with minimal bladder irritation and tolerable myelosuppression. The recommended phase II dose for twice-weekly therapy is 2,000 mg.
Factorial Design Considerations
Authors: Green Stephanie , Liu Ping-Yu , O’Sullivan Janet
Published: October 2002

PURPOSE: Factorial designs may be proposed to test extra questions within a clinical trial. A common approach to sample size and analysis for factorial trials assumes no statistical interactions and does not adjust for multiple testing. This investigation considered the trade-off between potential gains from testing more questions with fewer patients versus how often a factorial trial might arrive at an incorrect conclusion.

METHODS: A simulation study of a 2 × 2 design (observation v chemotherapy v radiation therapy v the combination) was performed under various conditions, including effect of one, both, or neither treatment and absence or presence of statistical interaction (effect of one treatment differed according to the presence of the other). Three analysis approaches were investigated, one assuming no interaction, a second testing first for interaction, and the third testing for interaction as well as adjusting for multiple testing. The approaches were compared with respect to the probability of selecting the correct treatment arm.

RESULTS: No one approach was superior. Testing for interaction was beneficial in some settings but detrimental in others. Under some scenarios, the factorial design improved efficiency, but under others, all three approaches resulted in poor probability of selecting the correct treatment arm at the end of the trial.

CONCLUSION: Extra efficiency is possible, but it is difficult to predict when favorable conditions exist. If a factorial design is used, potential efficiency gains should be weighed against potential loss of power to arrive at the correct conclusion under possible scenarios of interest.
Treatment of Unresectable and Metastatic Hepatoblastoma: A Pediatric Oncology Group Phase II Study
Authors: Katzenstein Howard M. , London Wendy B. , Douglass Edwin C. , Reynolds Marleta , Plaschkes Jack , Finegold Milton J. , Bowman Laura C.
Published: October 2002

PURPOSE: To estimate the disease-response rate, proportion of patients whose tumors can be made resectable, event-free survival (EFS), and toxicity in children with unresectable or metastatic hepatoblastoma (HB) after sequential treatment with the following: (1) carboplatin (CARBO); (2) CARBO, vincristine, and fluorouracil (CARBO-VCR-5-FU); and (3) high-dose cisplatin and etoposide (HDDP-ETOP).

PATIENTS AND METHODS: Thirty-three assessable patients with stage III (n = 22) and stage IV (n = 11) HB were treated sequentially with one course of CARBO (700 mg/m2), followed by three courses of CARBO (700 mg/m2), day 0; 5-FU (1,000 mg/m2/d), by continuous infusion days 0 to 2; and VCR (1.5 mg/m2), days 0, 7, and 14. After that therapy, patients whose tumors were resectable underwent surgery and then received two additional courses of CARBO-VCR-5-FU. Children whose tumors remained unresectable after CARBO-VCR-5-FU or who demonstrated no response or progressive disease during this therapy received two courses of HDDP (40 mg/m2/d), days 1 to 5; and ETOP (100 mg/m2/d), days 2 to 4.

RESULTS: Five-year EFS estimates were 59% ± 11% for stage III disease (n = 22) and 27% ± 16% for stage IV disease (n = 11), respectively (P = .037). Twenty-seven (82%) of 33 patients had at least a partial response to chemotherapy; 18 (55%) of 33 responded to CARBO; 24 (80%) of 30 responded to CARBO and CARBO-VCR-5-FU; and nine (75%) of 12 responded to HDDP-ETOP. Surgical resection was achieved in 19 (58%) of 33 patients, including 15 (68%) of 22 stage III patients and four (36%) of 11 stage IV patients. Five-year EFS for patients whose tumors were completely resected was 79% ± 10%.

CONCLUSION: Patients treated sequentially with CARBO, CARBO-VCR-5-FU, and HDDP-ETOP had response rates and EFS comparable to other therapeutic regimens. This regimen is effective in treating localized, unresectable HB and potentially has less toxicity than other regimens. Novel approaches are needed for patients with metastatic disease.
Phase II Evaluation of Low-Dose Oral Etoposide for the Treatment of Relapsed or Progressive AIDS-Related Kaposi’s Sarcoma: An AIDS Clinical Trials Group Clinical Study
Authors: Evans Scott R. , Krown Susan E. , Testa Marcia A. , Cooley Timothy P. , Von Roenn Jamie H.
Published: October 2002

PURPOSE: Liposomal anthracyclines and paclitaxel are considered the best available cytotoxic therapies for Kaposi’s sarcoma (KS), but relapse is common. To identify new interventions for relapsed or progressive KS, a phase II study of low-dose etoposide to assess its toxicity and efficacy was conducted.

PATIENTS AND METHODS: Thirty-six patients with high-risk KS were treated with oral etoposide 50 mg/d for 7 consecutive days of every 2-week cycle. All patients’ disease had relapsed or progressed after prior combination chemotherapy or anthracycline therapy. For patients without a complete or partial response after two cycles of therapy and no toxicity greater than grade 2, the dose of etoposide was escalated to 100 mg/d orally on days 1 to 7 of each 14-day cycle. Treatment-related and disease-specific quality of life was evaluated using patient reports on the General Health Self-Assessment Form and a KS-specific measure.

RESULTS: One patient achieved a complete response, 12 patients had a partial response (overall response rate, 36.1%), and stable disease was observed in 12 patients (33.3%). Tumor responses were seen in all disease sites. Fourteen patients had their dose escalated, of whom five responded. The median time to response was 17.7 weeks; the median duration of response was 25 weeks. The most frequent hematologic abnormality was neutropenia, which was grade 4 in seven patients and grade 3 in six. Opportunistic infections occurred in eight patients during the treatment period. Both response to treatment and toxicity influenced patient-reported quality of life.

CONCLUSION: We conclude that low-dose oral etoposide at a dose of 50 mg/d is safe and effective for the treatment of refractory or progressed AIDS-related KS and has an overall positive effect on the quality of life of responding patients.
Retinoid X Receptor Dominates the Nuclear Import and Export of the Unliganded Vitamin D Receptor
Authors: Prüfer Kirsten , Barsony Julia
Published: October 2002

Liganded and unliganded vitamin D receptors (VDRs) carry out distinct functions; both types of functions require heterodimerization with retinoid X receptors (RXRs). Our recent studies with fluorescent protein chimeras of VDR and RXR, termed GFP-VDR, YFP-RXR, and RXR-BFP, indicated that RXR regulates VDR functions in part by regulating subcellular localization. Here we explored the mechanisms of this regulation. Photobleaching experiments demonstrated that YFP-RXR and both unliganded and liganded GFP-VDR shuttle constantly between nucleus and cytoplasm. To characterize RXR import, we identified a nuclear localization sequence (NLS) in the DNA-binding domain. Mutations in this NLS caused predominant cytoplasmic localization of nlsYFP-RXR and prevented transcriptional activity. The nlsRXR-BFP retained unliganded GFP-VDR in the cytoplasm and reduced baseline transcriptional activity. After calcitriol exposure, however, both GFP-VDR and nlsRXR-BFP entered the nucleus. We characterized receptor export rates and mechanisms using permeabilization experiments. Mutations in the calreticulin binding region slowed both GFP-VDR and YFP-RXR export. Coexpression of RXR-BFP slowed the export of unliganded GFP-VDR, whereas calcitriol treatment tripled the rate of GFP-VDR export. Treatment with leptomycin B, an inhibitor of CRM-1 receptor-mediated export, inhibited export of unliganded GFP-VDR but did not influence export of liganded GFP-VDR or YFP-RXR. Leptomycin B added before calcitriol similarly decreased hormone-induced luciferase activity but was ineffective when added subsequent to calcitriol. These results indicate that the unliganded and liganded VDR interact differently with the import and export receptors and with RXR. Most likely, the regulation of VDR nuclear import by RXR is essential for ligand-independent functions.
Pituitary Homeobox 1 Activates the Rat FSHβ (rFSHβ) Gene through Both Direct and Indirect Interactions with the rFSHβ Gene Promoter
Authors: Zakaria Marjorie M. , Jeong Kyeong-Hoon , Lacza Charlemagne , Kaiser Ursula B.
Published: October 2002

Molecular mechanisms underlying gonadotrope-specific and hormonal regulation of FSHβ gene expression remain largely unknown. We have studied the role of pituitary homeobox 1 (Ptx1), a transcription factor important for regulation of many pituitary-specific genes, in the regulation of rat FSHβ (rFSHβ) gene transcription. We demonstrate that Ptx1 activates the rFSHβ gene promoter both basally and in synergy with GnRH. The effect of Ptx1 was localized to −140/−50, a region also important for basal activity of the promoter. Two putative Ptx1 binding sites (P1 and P2) homologous to consensus Ptx1 binding elements were identified in this region. We demonstrate specific binding of Ptx1 to the P2 but not to the P1 site. Furthermore, functional studies indicate that the P2 but not the P1 site mediates activation of the promoter by Ptx1. Residual activation of the promoter by Ptx1 was observed independent of the P2 site. However, no additional Ptx1 binding sites were identified in this region, indicating that the residual activation observed is likely independent of direct Ptx1 binding to the promoter. These results identify a functional Ptx1 binding site in the rFSHβ gene promoter and suggest the presence of an additional activating pathway that is independent of direct binding of Ptx1 to the promoter.
Controlled Transdermal Delivery of Propranolol Using HPMC Matrices: Design and In-vitro and In-vivo Evaluation
Authors: Verma P R P , Iyer Sunil S
Published: October 2002

To improve bioavailability and achieve a smoother plasma-concentration profile as compared with oral administration, a matrix-dispersion-type transdermal delivery system was designed and developed for propranolol using different ratios of hydroxypropyl-methylcellulose (HPMC) K4M, K15M and K100M. Formulations were evaluated for in-vitro dissolution characteristics using a Cygnus' sandwich-patch holder.

Drug release followed Higuchi rather than zero-order or first-order kinetics. In-vivo evaluation was carried out on healthy volunteers (21 ± 1.41 years; 60.89 ± 5.35 kg) following the balanced incomplete block design. The dissolution rate constant (k) and data generated from plasma and urine (Cmax, maximum plasma concentration; tmax, time to reach peak plasma concentration; AUC, area under the curve; ke, elimination rate constant; t½e, elimination half-life; ka, absorption rate constant; t½a, absorption half-life) were evaluated statistically by two-way analysis of variance. Statistically excellent correlation was found between the percentage of drug absorbed and Cmax, AUC0–24 and AUC0-∞. A highly significant difference (P < 0.001) was observed when Cmax and AUC0-∞ generated from plasma and urine were compared, but ke, t½e, ka and t½a did not differ significantly (P > 0.1).

We conclude that urinary excretion data may be used as a simpler alternative to blood level data in studying the kinetics of absorption and deriving the absorption parameters.
Effects of Some Non-ionic Surfactants on Transepithelial Permeability in Caco-2 Cells
Authors: Dimitrijevic Dejana , Shaw Andrew J , Florence Alexander T
Published: October 2002

The effects of the non-ionic surfactants polysorbate 20, polysorbate 60, polysorbate 85, cholesteryl poly (24) oxyethylene ether (Solulan C24) and the lanolin-based poly (16) oxyethylene ether (Solulan 16) on the epithelial integrity of monolayers of human intestinal epithelial (Caco-2) cells has been studied using metformin as a model drug. The aim was to identify the surfactants and their optimal concentrations capable of enhancing drug transport while causing no, or only minor, cellular damage. Effects on cell permeability were assessed by measurements of the transport of metformin, a hydrophilic drug, by monitoring transepithelial electrical resistance. Cell viability was determined by the diphenyltetrazolium bromide test (the MTT test).

All the surfactants studied demonstrated concentration-dependent effects on cell permeability and cell viability. The effects on transepithelial electrical resistance correlated with cell viability, i.e. increased transepithelial electrical resistance and increased cell-monolayer permeability for metformin corresponded to decreased cell viability. The results indicate that the Solulan and polysorbate surfactants were active as absorption enhancers, Solulan C24 and 16 being more effective than polysorbates 20, 60 or 85, causing an increase in metformin transport at lower concentrations than the polysorbates. Polysorbate 20 exerted its greatest effect at a concentration of 5%—increasing the flux of metformin after 3h by a factor of around 20 over the control. Large increases in the transport of metformin, especially at surfactant levels of 0.05%, 0.1% and 0.5%, were related to the effect of Solulan C24 and Solulan 16 on the cell permeability.

The Caco-2 cell monolayer experiments confirmed the ability, especially of polysorbate 20, Solulan C24 and Solulan 16, to increase the absorption of metformin. The polysorbates increased permeability as a result of solubilisation of membrane components, while Solulans did so by penetrating and solubilising the membrane. Correlation between increase in membrane permeability and the toxicity of the surfactants towards the cell membrane has been established.
Inhibitory Effects of Glibenclamide on the Contraction of Human Arterial Conduits used in Coronary Artery Bypass Surgery
Authors: Crosbie Alan E , Vuylsteke Alain , Ritchie Andrew J , Latimer Raymond D , Callingham Brian A
Published: October 2002

Glibenclamide has been shown to inhibit prostanoid-induced contraction in a number of blood vessel types. In this study, the effects of glibenclamide on the contraction of human peripheral arteries in response to both prostanoid and non-prostanoid agonists were compared and possible mechanisms of action were investigated.

Segments of left internal mammary artery (LIMA) and radial artery, taken from patients undergoing coronary artery bypass graft (CABG) surgery, were mounted in organ baths containing physiological saline solution aerated with 95% O2/5% CO2 at 37°C. Contractions were obtained by either the use of a thromboxane analogue (U46619), l-phenylephrine, KCl or CaCl2. The effects of glibenclamide on these contractions were observed and pEC50 values were determined after manipulation of a logistic curve-fitting equation. Concentration-dependent relaxation of U46619-contracted LIMA and radial artery was observed in the presence of glibenclamide, with calculated pEC50 values of 4.2±0.17 (n = 7) for LIMA and 3.26 ±0.48 (n = 5) for radial artery. Incubation of both LIMA and radial artery with glibenclamide (50 μm) caused the concentration-response curves for U46619 and l-phenylephrine to shift significantly to the right. Similarly the KCl tension relationship was caused to shift to the right. Finally, glibenclamide (100 μm) also had an inhibitory effect on Ca2+-induced tension in radial artery.

These results show that the inhibitory effects of glibenclamide on human peripheral blood vessels are not restricted to prostanoid-induced contractions. Furthermore, evidence has been provided to suggest that these effects might be mediated through an interaction with voltage-sensitive Ca2+ channels.
Pharmacodynamics of S-2150, a Simultaneous Calcium-blocking and α1-Inhibiting Antihypertensive Drug, in Rats
Authors: Ishibashi Toru , Yano Yoshitaka , Oguma Takayoshi
Published: October 2002

The in-vivo pharmacodynamics of S-2150, a newly developed dual-blocking type antihypertensive drug, was evaluated following intravenous infusion to rats. Previous in-vitro studies showed that the drug has two distinct mechanisms of antihypertensive effect—calcium-channel blocking activity and α1-adrenoceptor antagonism—which could be explained by a combination of two different pharmacodynamic models.

The present in-vivo study showed that S-2150 also displays a complex pharmacodynamic profile (as measured by the decrease in mean blood pressure), which could be described by a combination of two sigmoid Emax models independently connected with the central compartment and the effect compartment.

These results suggested that the dual-blocking mechanism of S-2150, which has been observed in in-vitro experiments, was also evaluated by the pharmacodynamic analysis of in-vivo experimental data.
Anti-inflammatory Effect of FR140423, a Novel Selective Cyclo-oxygenase-2 Inhibitor, in Rat Adjuvant Arthritis Without Gastrointestinal Side Effects
Authors: Ochi Takehiro , Goto Toshio
Published: October 2002

We investigated the effect of FR140423 (3-(difluoromethyl)-1-(4-methoxyphenyl)-5-[4-(methylsulphinyl)phenyl]pyrazole), a novel and selective cyclo-oxygenase (COX)-2 inhibitor, in rat adjuvant arthritis. The results were compared with that of indomethacin.

We tested the inhibitory effects of FR140423 on paw oedema and the formation of the arachidonic acid metabolites prostaglandin (PG) E2 and leukotriene (LT) B4 in inflamed paws immunized with heat-killed and dried Mycobacterium tuberculosis. Oral administration of FR140423 showed a dose-dependent anti-inflammatory effect. This effect was two- to threefold more potent than that of indomethacin. The increase of PGE2 and LTB4 in inflamed paws was associated with the development of paw swelling. FR140423 and indomethacin dose-dependently suppressed the level of PGE2 but not LTB4 in arthritic paws. Unlike indomethacin, FR140423 did not induce gastric lesions even at doses up to 10 mg kg−1 in arthritic rats.

FR140423 has a potent anti-inflammatory effect mediated by inhibition of PGE2 produced by COX-2 in inflamed tissues. The safety profile of FR140423 appears to be an improvement on the safety profile of indomethacin.
Benidipine Inhibits Apoptosis During Ischaemic Acute Renal Failure in Rats
Authors: Yao Kozo , Sato Hitoshi , Ina Yasuhiro , Nagashima Ken , Nishikawa Satoshi , Ohmori Kenji , Ohno Tetsuji
Published: October 2002

We have investigated the effects of benidipine (hydrochloride), a calcium antagonist, against ischaemic acute renal failure in rats. Using histological examination, we studied whether the inhibition of apoptosis was associated with the protective effects of benidipine on the ischaemic renal injury.

Acute renal failure was induced by the unilateral clamping of the left renal artery for 60 min, followed by reperfusion and contralateral nephrectomy. Drugs were given intravenously 5 min before the unilateral clamping. Prophylactic administrations of benidipine (10 μg kg−1, i.v.) significantly ameliorated the development of renal failure as estimated by the measurements of serum creatinine and blood urea nitrogen 24 h after the reperfusion. Amlodipine (besilate, 100 and 300 μg kg−1, i.v.) tended to attenuate renal dysfunction. Lisinopril (300 and 1000 μg kg−1, i.v.), an angiotensin converting enzyme inhibitor, was ineffective in this acute renal failure model. Histological examination using the terminal transferase-mediated dUTP-biotin nick end-labelling (TUNEL) method to detect apoptotic cells revealed that the TUNEL-positive tubular epithelium was prominent in the renal cortex 24 h after the reperfusion. The TUNEL-positive cells were significantly reduced by pretreatment with benidipine.

The results demonstrate that benidipine can ameliorate the ischaemic acute renal failure in rats and suggest that the renoprotective effect of benidipine was at least partly attributable to the reduction of apoptosis in tubular epithelial cells.
Effect of Lamivudine on Uptake of Organic Cations by Rat Renal Brush-Border and Basolateral Membrane Vesicles
Authors: Takubo Takatoshi , Kato Toshihiro , Kinami Junji , Hanada Kazuhiko , Ogata Hiroyasu
Published: October 2002

The effect of lamivudine on uptake of a representative organic cation, tetraethylammonium (TEA), by rat renal brush-border membrane vesicles (BBMV) and basolateral membrane vesicles (BLMV) has been investigated.

The pH-driven uptake of TEA by BBMV (pHin = 60, pHout = 7.5) was inhibited by lamivudine. The IC50 value (concentration resulting in 50% inhibition) for the concentration-dependent effect of lamivudine on TEA uptake by BBMV after 30 s was 2668 μm whereas IC50 values for cimetidine and trimethoprim were <2.5 μm and < 25 μm, respectively. The early uptake of TEA by BLMV was also reduced significantly by lamivudine. The IC50 value for the concentration-dependent effect of lamivudine on uptake of TEA by BLMV at 30 s was > 25 mm, whereas the IC50 values for Cimetidine and trimethoprim were 2116 μm and 445 μm, respectively.

These findings suggest that compared with other cationic drugs, such as trimethoprim and Cimetidine, lamivudine is a weak inhibitor of organic cation transport into the tubules by the brush-border and basolateral membranes of renal epithelial cells. It is unlikely lamivudine will have any significant effect on the excretion of co-administered cationic drugs by the renal tubules.
Reduction of the Potential Anticancer Drug Oracin in the Rat Liver In-vitro
Authors: Szotáková Barbora , Skálová Lenka , Wsól Vladimír , Kvasnièčková Eva
Published: October 2002

Studies on the metabolism of the potential cytostatic drug oracin have shown that a principal metabolite of oracin is 11-dihydrooracin (DHO). We conducted in-vitro experiments to investigate the extent of oracin carbonyl reduction in microsomal or cytosolic fractions and to find out the enzymes involved under these conditions.

Among several inducers of rat cytochrome P450 only 3-methylcholanthrene caused a significant (P < 0.01) stimulation (1.9 times) of DHO production in microsomal fraction and the specific P4501A inhibitor α-naphthoflavone significantly (P < 0.01) decreased (twice) the induced reduction activity. Cytochrome P4501A participates in oracin reduction in microsomes. 18β-Glycyrrhetinic acid, a specific inhibitor of hydroxysteroid dehydrogenase, significantly (P < 0.01) inhibited the production of DHO in the microsomal fraction (>95% inhibition) in comparison with the non-inhibited reaction. Statistically significant (P < 0.01) inhibition (95%) of DHO formation was caused by metyrapone, which is also the substrate of 11β-hydroxysteroid dehydrogenase.

The main microsomal enzyme which catalyses the carbonyl reduction of oracin is probably 11β-hydroxysteroid dehydrogenase. Important oracin reduction to DHO in the cytosolic fraction was found. According to its specific sensitivity towards quercitrin (inhibition by 99%, P < 0.01), the enzyme responsible for DHO formation in the rat liver cytosol is postulated to be carbonyl reductase.
Structure-Activity Relationships for the Ca2+-releasing Activity of 6-Hydroxy-β-carboline Analogues in Skeletal Muscle Sarcoplasmic Reticulum—The Effects of Halogen Substitution at C-5 and C-7
Authors: Seino-Umeda Asami , Ishibashi Masami , Kobayashi Jun'Ichi , Ohizumi Yasushi
Published: October 2002

This study of structure-activity relationships of 6-hydroxy-β-carboline analogues has been performed on the basis of quantitative measurement of Ca2+-releasing activity in the sarcoplasmic reticulum of skinned fibres of skeletal muscle.

Substitution of halogens for hydrogens at the C-5 and C-7 positions and further introduction of a methyl group into the N-9 position of 6-hydroxy-β-carboline resulted in Ca2+-releasing activity. The 50% effective concentrations of 5,7-dibromoeudistomin D, 5,7-dichloroeudistomin D, 5,7-diiodoeudistomin D, 9-methyl-5,7-dibromoeudistomin D, 9-methyl-5,7-dichloroeudistomin D, 9-methyl-5,7-diiodoeudistomin D, and caffeine were 5.6 times 10−6, 6.3 times 10−6, 7.8 times 10−6, 2.1 times 10−6, 2.0 times 10−5, 3.7 times 10−5, and 4.7 times 10−4  m, respectively, indicating that these analogues are 10–200 times more potent than caffeine. Substitution of bromine by chlorine or iodine at the C-5 and C-7 positions markedly reduced the activity of the analogues with a methyl group at the N-9 position.

These results suggest that halogens at the C-5 and C-7 positions in the β-carboline skeleton are essential for Ca2+-releasing activity and that an N-9 methyl group also affects the activity of these analogues. Thus, these 6-hydroxy-β-carboline analogues might become powerful tools for studying the molecular mechanism of Ca2+ release in the sarcoplasmic reticulum.
Antioxidant Properties of Novel Lipophilic Ascorbic Acid Analogues
Authors: Weber Valerie , Coudert Pascal , Rubat Catherine , Duroux Eliane , Leal Fernand , Couquelet Jacques
Published: October 2002

Structural modifications of ascorbic acid by the introduction of lipophilic moieties has led to derivatives with increased stability against thermal and oxidative degradation. Two series of new lipophilic ascorbic analogues were synthesized to obtain antioxidants devoid of autooxidant properties: 4-benzoyl-3-hydroxyfuran-2(5H)-ones (3a-j) and 4-acetyl-5-aryl-3,4-dihydrofuran-2(5H)ones(5a-f).

These compounds were submitted to three different tests: reduction of the stable free radical, 1,1-diphenyl-2-picrylhydrazyl (DPPH); superoxide-anion scavenging assay; and lipid-peroxidation assay. Most compounds interacted with DPPH: at a concentration of 5 times 10−3 M, the reducing activity of 4-benzoyl derivatives, 3c and 3h, was more than 50%; under the same conditions, the rate of inhibition for 4-acetylbutanolides, 5a and 5f, reached 60.6% and 87.3%, respectively; 93.3% inhibition was observed with ascorbic acid. In the superoxide-anion scavenging assay, at a concentration of 1 mg mL−1, 4-benzoyl derivatives, 3g and 3i, exhibited a good activity, with IC50 (dose resulting in 50% inhibition) values of 1.45 and 1.35 times 10−3 M, respectively. 4-Acetylbutanolide, 5f, significantly inhibited the Fe2+/ADP/ascorbate-induced lipid peroxidation of rat liver microsomes with an IC50 of 4.9 times 10−4 M.

This study demonstrates that enol functions in the structure of ascorbic acid analogues are not absolutely essential to bring about antioxidant effects.