Concise formation of 4-benzyl piperidines and related derivatives using a Suzuki protocol.
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Benzyl Compounds↗
Biomedical subjects
J Ford
Publications and source records attributed to J Ford.
Multicenter phase Ib/II trial of the radiation enhancer motexafin gadolinium in patients with brain metastases.
PURPOSE: Motexafin gadolinium is a magnetic resonance imaging (MRI)--detectable redox active drug that localizes selectively in tumor cells and enhances the effect of radiation therapy. This phase Ib/II trial of motexafin gadolinium, administered concurrently with 30 Gy in 10 fractions whole-brain radiation therapy (WBRT), was conducted to determine maximum-tolerated dose (MTD), dose-limiting toxicity, pharmacokinetics, and biolocalization in patients with brain metastases. Additional endpoints were radiologic response rate and survival. PATIENTS AND METHODS: Motexafin gadolinium was administered before each radiation treatment in this open-label, multicenter, international trial. In phase Ib, drug dose was escalated until the MTD was exceeded. In phase II, drug was evaluated in a narrow dose range. RESULTS: In phase Ib, the motexafin gadolinium dose was escalated in 39 patients (0.3 mg/kg to 8.4 mg/kg). In phase II, 22 patients received 5 mg/kg to 6.3 mg/kg motexafin gadolinium. Ten once-daily treatments were well tolerated. The MTD was 6.3 mg/kg, with dose-limiting reversible liver toxicity. Motexafin gadolinium's tumor selectivity was established using MRI. The radiologic response rate was 72% in phase II. Median survival was 4.7 months for all patients, 5.4 months for recursive partitioning analysis (RPA) class 2 patients, and 3.8 months for RPA class 3 patients. One-year actuarial survival for all patients was 25%. CONCLUSION: Motexafin gadolinium was well tolerated at doses up to 6.3 mg/kg, was selectively accumulated in tumors, and, when combined with WBRT of 30 Gy in 10 fractions, was associated with a high radiologic response rate.
Adult↗
Radiotherapy, concomitant protracted-venous-infusion 5-fluorouracil, and surgery for ultrasound-staged T3 or T4 rectal cancer.
BACKGROUND: A prospective study was undertaken to evaluate the response and toxicity of neoadjuvant chemoradiotherapy for ultrasound-staged T3 or T4 rectal cancer. PATIENTS AND METHODS: Since 1995, 30 patients (18 males; median age, 56 (range, 25-83) years) have received preoperative chemoradiotherapy for ultrasound-staged T3 or T4 rectal cancer. All patients underwent an endorectal ultrasound, CT scan, and review in our multidisciplinary Gastrointestinal Tumor Board before treatment. All patients had pathology-demonstrated invasive adenocarcinoma of the rectum. Eleven patients were Stage T3N0, 14 were T3N1, and five were T4N1. Patients received radiotherapy to the primary tumor and draining lymph nodes (45 Gy) followed by a tumor boost (50.4-54 Gy). Protracted-venous-infusion 5-fluorouracil (225 mg/m2 per day, seven days per week) was administered throughout treatment. Surgical resection was performed six to ten weeks after completing chemoradiotherapy. Using endorectal ultrasound measurements, the primary tumor was a median of 4 (range, 0-12) cm from the anal verge, encompassed 50 (range, 20-90) percent of the rectal circumference, and was 6 (range, 3-12) cm in diameter. RESULTS: No Grade 4 toxicity was observed during chemoradiotherapy. Three patients experienced Grade 3 toxicity (diarrhea), and four patients required a treatment interruption of greater than three days. All patients completed at least 90 percent of the prescribed radiotherapy dose. All patients underwent surgical resection. Ninety-four percent had clear surgical margins. All pathologic specimens had significant evidence of necrosis, hyalinization, and fibrosis. Thirty-three percent of the specimens had a complete pathologic response (defined as no evidence of viable tumor cells). Of the 19 patients with ultrasound-staged N1 disease, only five had pathologic evidence of nodal involvement after chemoradiotherapy. Of the 25 patients with ultrasound-staged T3 disease, pathologic staging revealed eight with T0, two with T1, five with T2, and ten with T3 disease. Of the five patients with ultrasound-staged T4 disease, pathologic staging revealed two with T0, one with T2, and two with T3 disease. No patient developed progressive disease while on treatment. Two patients have experienced local failure at 6 and 20 months, and one patient failed in the liver at seven months. Twenty-seven patients remain free of disease with a median follow-up of 20 (range, 3-53) months. CONCLUSION: Our experience suggests that preoperative chemoradiotherapy is well tolerated, down-stages tumors, and sterilizes regional lymph nodes.
Adenocarcinoma↗
Muscarinic agonists and antagonists in the treatment of Alzheimer's disease.
Alzheimer's disease (AD) is a neurodegenerative disease characterized by cognitive impairment and personality changes. The development of drugs for the treatment of the cognitive deficits of AD has focused on agents which counteract loss in cholinergic activity. Although symptoms of AD have been successfully treated with acetylcholinesterase inhibitors (tacrine, donepezil. rivastigmine, galanthamine), limited success has been achieved with direct M1 agonists, probably due to their lack of selectivity versus other muscarinic receptor subtypes. Muscarinic M2 antagonists have been reported to increase synaptic levels of acetylcholine after oral administration to rats (e.g. BIBN-99, SCH-57790), but their selectivity versus other muscarinic receptor subtypes is modest. Exploration of a series of piperidinylpiperidines has yielded the potent and selective M2 antagonist SCH-217443. This antagonist has excellent bioavailability in rats and dogs and shows activity in a rat model of cognition.
Alzheimer Disease↗
Holistic environmental assessment and offshore oil field exploration and production.
According to UK Government surveys, concern for the environment is growing. Environmental regulation of the industry is becoming wider in its scope and tougher in its implementation. Various techniques are available to assess how the industry can drive down its environmental impact and comply with environmental regulation. Environmental Assessments (EA) required by European law do not cover the whole life cycle of the project that they are analysing. Life Cycle Analysis (LCA) was developed to assess the environmental loadings of a product, process or activity over its entire life cycle. It was the first technique used in environmental analysis that adopted what was described as a holistic approach. It fails this approach by not assessing accidental emissions or environmental impacts other than those that are direct. Cost Benefit Analysis (CBA) offers the opportunity to value environmental effects and appraise a project on the basis of costs and benefits. Not all environmental effects can be valued and of those that can there is considerable uncertainty in their valuation and occurrence. CBA cannot satisfactorily measure the total environmental risk of a project. Consequently there is a need for a technique that overcomes the failures of project-level EA, LCA and CBA, and assesses total environmental risk. Many organizations such as, the British Medical Association, the European Oilfield Speciality Chemicals Association, the Royal Ministry of Petroleum and Energy (Norway) and Shell Expro now recognize that a holistic approach is an integral part of assessing total risk. The Brent SPAR case study highlights the interdisciplinary nature required of any environmental analysis. Holistic Environmental Assessment is recommended as such an environmental analysis.
Conservation of Natural Resources↗
Immunoglobulin deficiency in children with a sudden overwhelming infection.
BACKGROUND: A small percentage of previously healthy children develop a sudden overwhelming infection (SOI) that rapidly progresses and results in shock and, occasionally, death. Some of these children may have an undetected Ig deficiency. OBJECTIVE: The aim of this study was to evaluate the incidence of Ig deficiency in children with a SOI. METHODS: A case series study was conducted in a university hospital and included 18 children who either died in the emergency room or required admission to the pediatric intensive care unit secondary to a SOI. Two age-matched control groups included children hospitalized to regular floor beds with an infectious process (infected control group) or a noninfectious process (noninfected control group). Serum left from the initial blood draw, before fluid resuscitation, was collected and stored at -70 degrees C. Total IgG, IgG subclasses, IgM, and IgA were assayed by rate nephelometry in a blinded fashion. RESULTS: In the study group, one of six children under 1 year of age had low Ig levels in comparison with two of nine control patients. In those children over the age of 1 year, 8 of 12 patients (67%) had low Ig levels as compared with 2 of 19 controls (11%) by Fisher's exact test, P = .002. Of those patients with Ig deficiencies, three of eight had isolated IgG deficiency, two of eight had combined IgG and IgA deficiency, three of eight had combined IgG and IgM deficiency. CONCLUSIONS: Children over the age of 1 year who present with a SOI have a significantly higher incidence of Ig deficiencies compared with age-matched controls.
Adolescent↗
Identification of a 70-kDa gastrin-binding protein on DLD-1 human colorectal carcinoma cells.
Gastrin17gly acts as a growth factor for the colonic mucosa. Studies of the receptor involved have generally been restricted to its binding properties, and no investigation of the structure of gastrin17gly receptors on human colorectal carcinoma cell lines has yet been reported. The aim of this study was to optimise the conditions for binding of gastrin17gly to the human colorectal carcinoma cell line DLD-1, and to investigate the structure of the receptor responsible. Binding of 125I[Met15]gastrin17gly to DLD-1 cells was measured in competition experiments with increasing concentrations of either gastrin17gly or gastrin17, or with single concentrations of gastrin receptor antagonists. The molecular weights of the gastrin17gly binding proteins were determined by gel electrophoresis and autoradiography after covalent cross-linking of 125I[Nle15]gastrin2,17gly to cells or membranes with disuccinimidyl suberate. The IC50 value for binding of gastrin17gly to DLD-1 cells was 2.1+/-0.4 microM. Binding was inhibited by the non-selective gastrin/cholecystokinin receptor antagonists proglumide and benzotript, but not by the cholecystokinin-A receptor antagonist L364,718, or the gastrin/cholecystokinin-B receptor antagonist L365,260. The molecular weight of the major gastrin binding protein on DLD-1 cells or membranes was 70,000. We conclude that the major gastrin17gly binding site on the human colorectal carcinoma cell line DLD-1 is clearly distinct from the cholecystokinin-A and gastrin/cholecystokinin-B receptors, but is similar in some respects to the gastrin/cholecystokinin-C receptor.
Autoradiography↗
Radiosurgery and stereotactic radiation therapy of skull base meningiomas: proposal of a grading system.
OBJECTIVE: The development of a grading system to guide treatment selection, and predict treatment difficulty and outcome of skull base meningiomas infiltrating the cavernous sinus which are managed by stereotactic radiosurgery (SRS) and stereotactic radiotherapy (SRT), based on an 8-year experience with stereotactic radiation of skull base meningiomas. METHODS: T1 gadoliniun-enhanced magnetic resonance imaging (MRI) of 40 patients with skull base meningiomas, with or without prior surgery, who underwent radiosurgery or stereotactic radiation therapy from 1991 to 1998 at the UCLA Medical Center were reviewed, and the result of treatment was related to the tumor grade. Grade was based on tumor infiltration of the cavernous sinus and extension into adjacent structures. Treatment was performed with a linac-based system. The dose prescribed to the periphery of the tumor for SRS patients (n = 34) ranged from 12 to 22 Gy, and the maximum dose delivered to the tumor ranged from 24 to 46 Gy. SRT (n = 6). Treatment was planned using a single isocenter, usually prescribed to the 90% isodose volume, bringing the fractionation scheme to the maximal tolerance of the optic apparatus. The periphery dose ranged from 24 to 46 Gy with a maximum dose of 45 to 51 Gy. Clinical and MRI follow-up was performed every six months for the first 3 years and every year thereafter. RESULTS: Grade I meningiomas were restricted to the cavernous sinus (n = 12). Grade II cavernous sinus meningiomas extended to the clivus and/or the petrous bone, without compression of the brainstem (n = 9). Grade III meningiomas had superior and/or anterior extension with compression of the optic nerve or tract (n = 9). Grade IV tumors compressed the brain stem (n = 8), and Grade V were bilateral lesions (n = 2). Tumor control rates were 90% for Grade I, 86% for Grade II, 86% for Grade III, 42% for Grade IV and no control for tumors Grade V. Complications were not related to tumor grade. CONCLUSION: This grading system correlated with outcome and difficulty in planning radiosurgery. Failure of treatment was more likely to occur in patients with higher Grade tumors.
Adult↗
A double-blind, placebo-controlled study of the use of amphetamine in the treatment of aphasia.
BACKGROUND AND PURPOSE: A number of studies suggest that drugs which increase the release of norepinephrine promote recovery when administered late (days to weeks) after brain injury in animals. A small number of clinical studies have investigated the effects of the noradrenergic agonist dextroamphetamine in patients recovering from motor deficits following stroke. To determine whether these findings extend to communication deficits subsequent to stroke, we administered dextroamphetamine, paired with speech/language therapy, to patients with aphasia. METHODS: In a prospective, double-blind study, 21 aphasic patients with an acute nonhemorrhagic infarction were randomly assigned to receive either 10 mg dextroamphetamine or a placebo. Patients were entered between days 16 and 45 after onset and were treated on a 3-day/4-day schedule for 10 sessions. Thirty minutes after drug/placebo administration, subjects received a 1-hour session of speech/language therapy. The Porch Index of Communicative Ability was used at baseline, at 1 week off the drug, and at 6 months after onset as the dependent language measure. RESULTS: Although there were no differences between the drug and placebo groups before treatment (P=0.807), by 1 week after the 10 drug treatments ended there was a significant difference in gain scores between the groups (P=0.0153), with the greater gain in the dextroamphetamine group. The difference was still significant when corrected for initial aphasia severity and age. At the 6-month follow-up, the difference in gain scores between the groups had increased; however, the difference was not significant (P=0.0482) after correction for multiple comparisons. CONCLUSIONS: Administration of dextroamphetamine paired with 10 1-hour sessions of speech/language therapy facilitated recovery from aphasia in a small group of patients in the subacute period after stroke. Neuromodulation with dextroamphetamine, and perhaps other drugs that increase central nervous system noradrenaline levels, may facilitate recovery when paired with focused behavioral treatment.
Adrenergic Uptake Inhibitors↗
The utility of peak flow, symptom scores, and beta-agonist use as outcome measures in asthma clinical research.
STUDY OBJECTIVES: Several methods of utilizing peak expiratory flow (PEF) and other markers of disease activity have been suggested as useful in the management of asthma. It remains unclear, however, as to which surrogate markers of disease status are discriminative indicators of treatment failure, suitable for use in clinical trials. DESIGN: We analyzed the operating characteristics of 66 surrogate markers of treatment failure using a receiver operating characteristic (ROC) curve analysis. PARTICIPANTS: Information regarding FEV(1), symptoms, beta(2)-agonist use, and PEF was available from 313 subjects previously enrolled in two Asthma Clinical Research Network trials, in which 71 treatment failures occurred (defined by a 20% fall in FEV(1) from baseline). INTERVENTIONS: None. MEASUREMENTS AND RESULTS: None of the measures had an acceptable ability to discriminate subjects with a > or % fall in FEV(1) from those without, regardless of the duration of the period of analysis or the criteria for test positivity employed. Areas under the ROC curves generated ranged from 0.51 to 0.79, but none were statistically superior. Sensitivity and specificity combinations were generally poor at all cutoff values; true-positive rates could not be raised without unacceptably elevating false-positive rates concurrently. CONCLUSIONS: Studies that seek to detect treatment failure defined by a significant fall in FEV(1) should not use such individual surrogate measures to estimate disease severity.
Adolescent↗
A pilot study to evaluate a tobacco diversion program.
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Adolescent↗
The visibility of illicit drugs: implications for community-based drug control strategies.
OBJECTIVES: This study examined differences between the visibility of drugs and drug use in more than 2100 neighborhoods, challenging an assumption about drug use in poor, minority, and urban communities. METHODS: A telephone survey assessed substance use and attitudes across 41 communities in an evaluation of a national community-based demand reduction program. Three waves of data were collected from more than 42 000 respondents. RESULTS: Measures of neighborhood disadvantage, population density, and proportion of minority residents explained more than 57% of the variance between census tracts in visibility of drug sales but less than 10% of tract-to-tract variance in drug use. Visible drug sales were 6.3 times more likely to be reported in the most disadvantaged neighborhoods than in the least disadvantaged, while illicit drug use was only 1.3 times more likely. CONCLUSIONS: The most disadvantaged neighborhoods have the most visible drug problems, but drug use is nearly equally distributed across all communities. Thus, efforts to address drug-related problems in poorer areas need to take into account the broader drug market served by these neighborhoods.
Adolescent↗
The impact of age on delivered dose intensity and hospitalizations for febrile neutropenia in patients with intermediate-grade non-Hodgkin's lymphoma receiving initial CHOP chemotherapy: a risk factor analysis.
The purpose of this historical case series study was to evaluate the association of age on delivered dose intensity of initial CHOP (cyclophosphamide/doxorubicin/ vincristine/prednisone) chemotherapy and the occurrence of hospitalizations for febrile neutropenia for patients with intermediate-grade non-Hodgkin's lymphoma (NHL). Findings are reported for 12 managed community and academic practices. Medical records of 930 NHL patients not enrolled on clinical trial protocols were reviewed. We reported on 577 of the study patients (62%) who received initial CHOP chemotherapy. Median age of the patients was 65.1 years. Older patients (age > or = 65 years) had more hospitalizations for febrile neutropenia (28% vs. 16%; P < 0.05) than younger patients (age, 18-64 years). In patients with advanced-stage NHL (stage III/IV), older patients received fewer cycles of CHOP (< 6 cycles, 35% vs. 22%; P < 0.05) than younger patients. Older patients were planned for lower average relative dose intensity (ARDI < or = 80%; P < 0.05) and had more heart disease and comorbid conditions (P < 0.05) than younger patients. Multiple logistic regression models showed that older patients were more likely to receive a lower dose intensity (ARDI < or = 80%; odds ratio = 2.46, 95% confidence interval [CI]: 1.62-3.72) during their first 3 cycles of therapy and to experience more hospitalizations for febrile neutropenia (odds ratio = 2.17, 95% CI: 1.43-3.30). We found the dose intensity of delivered CHOP chemotherapy for elderly patients to be less than standard CHOP therapy and the risk of hospitalizations for febrile neutropenia to be greater than in younger patients. Prospective clinical trials examining supportive care measures, such as colony-stimulating factor, for elderly NHL patients are recommended.
Adult↗
Management and medicine: marriage made in heaven or time for a divorce?
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Education, Graduate↗
Priority setting in health care. Claims are not supported in research literature.
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Health Care Rationing↗
Screening for learning disabilities in preadolescents using psychosocial disability markers-a pilot study.
PURPOSE: Learning disabilities (LD) are among the most common developmental and psychiatric disorders encountered by pediatricians, yet many children are not adequately diagnosed or treated in elementary school when intervention is most effective. Because of the well-known co-morbidity between psychosocial problems and LD, this pilot study sought to utilize psychosocial "markers" to screen for unidentified LD among all fifth graders in three urban/suburb Connecticut elementary schools.METHODS: 115 fifth graders, representing a 71% response rate, agreed to participate in the study and were screened using standardized psychosocial questionnaires administered to parents (Child Behavior Checklist), students (Youth Self Report), and teachers (Teacher Report Form). Psychosocial symptom scores and associated t-scores were obtained for three types of problems; "internalizing," "attention" and "externalizing." 28 students with high levels (t > 60) of internalizing or attention problems, were selected along with a sample of 22 "normal" students with no evidence of psychosocial impairment. These 50 students were given an individually administered battery of ability, performance and cognitive processing tests to determine the presence of unidentified LD. Performance tests included standardized tests of reading, writing and mathematics. All test scores were normed with a mean of 100 and a SD of 15. LD was determined to be present if the student had a 1.5 SD or greater discrepancy between ability and performance in any of the three academic areas, and evidence of a cognitive processing deficit.RESULTS: The results indicated that 14 of the 50 students tested (28%) had evidence of undiagnosed LD. No significant difference was found in the proportion of undiagnosed LD among psychosocially impaired versus normal students. However regression analysis suggested that this finding was misleading. Controlling for ability, attention problems reported by the parent, were found to be significant (p < 0.05) predictors of lowered test scores, whereas internalizing problems were found to be predictive of increased test scores. Students with both internalizing and attention problems did not differ significantly from psychologically unimpaired students.CONCLUSIONS: This pilot study indicates that better screening methods are needed to identify the likely high proportion of elementary school children with undiagnosed learning difficulties and co-morbid psychosocial problems.
Journal Article↗
Pharmacokinetics of carboplatin administered in combination with the bradykinin agonist Cereport (RMP-7) for the treatment of brain tumours.
INTRODUCTION: Cereport (RMP-7) is a novel bradykinin agonist which is being developed as a modulator of the blood-brain barrier (BBB). In order to investigate the pharmacokinetics of carboplatin in combination with Cereport, we performed pharmacological studies in conjunction with early clinical trials. METHODS: Pharmacokinetic samples were collected from eight patients in a phase I study (Cereport 100-300 ng/ kg) and ten patients in a phase II study (Cereport 300 ng/kg). Pharmacokinetic parameters for carboplatin were compared with respect to the dose of Cereport and with historical controls. RESULTS: Cereport combined with carboplatin was well-tolerated, with mild haematological toxicities consistent with the target area under the concentration time curve (AUC) of 7 mg/ml x min. Although the clearance of carboplatin was within the range reported for this drug alone, the addition of Cereport resulted in a higher than expected carboplatin AUC. This effect was related to the dose of Cereport in the phase I study (AUC values 104-133% of target, Spearman rank correlation coefficient = 0.71, P < 0.001). The higher than expected AUC value was confirmed in the phase II study (AUC values 106-189% of target). CONCLUSIONS: Co-administration of Cereport with carboplatin may result in a greater than predicted AUC. The mechanism of this possible interaction remains to be determined, although this did not result in any increased toxicity. Thus, the clinical potential of this combination in the treatment of brain tumours warrants further investigation.
Adolescent↗
Discorhabdin R: a new antibacterial pyrroloiminoquinone from two latrunculiid marine sponges, Latrunculia sp. and Negombata sp.
Two sponges belonging to the family Latrunculiidae (Negombata and Latrunculia sp.) collected during scientific trawling operations in Prydz Bay, Antarctica, and by scuba off Port Campbell, Victoria, have yielded a new antibacterial pyrroloiminoquinone, discorhabdin R (2). The structure was assigned as 2 on the basis of detailed spectroscopic analysis and comparison with the known co-metabolite discorhabdin B (3).
Animals↗