Radioenhancement by cisplatin with accelerated fractionated radiotherapy in a human tumour xenograft

The aim of the present study was to investigate whether cisplatin would enhance the radioresponse of a human tumour xenograft when given in different schedules combined with accelerated fractionated radiation therapy. A human squamous carcinoma of the hypopharynx, FaDu, was grown in the thigh of athymic nude mice. Tumours were exposed to twice-daily 2-Gy fractions, applied 6 h apart over 2 weeks, 5 days a week, alone or combined with cisplatin given at maximally tolerated doses in three different schedules: (1) i.p. as a single bolus (SB) or (2) i.p. as a daily bolus at 30 min before the first daily radiation fraction or (3) s.c. as a continuous infusion through a mini-osmotic pump over 13 days, commencing 24 h prior to the first daily radiation fraction. The end point for the study was tumour growth delay (TGD), calculated as the difference between the delay in regrowth to 200% of the initial tumour size in treated versus control mice. SB cisplatin plus radiation showed only an additive effect on TGD, whereas daily-bolus and continuous-infusion cisplatin demonstrated a greater than additive effect when combined with accelerated fractionated radiation in this human tumour model. Cisplatin appears to be especially beneficial as a radiation enhancer when given throughout the course of radiation. Received: 15 December 1996 / Accepted: 25 March 1997     

Validation of a brief screen for cognitive impairment (BSCI) administered by telephone for use in the medicare population.

The aim of this research was to examine the validity of a brief screen for cognitive impairment (BSCI) consisting of three questions administered by telephone (delayed recall, frequency of help with planning trips for errands, and frequency of help remembering to take medications). The study design was an age and gender matched case-control study. Seventy managed care members, 35 with dementia (cases) and 35 without dementia (controls), were assessed using BSCI embedded within a longer health assessment questionnaire commonly used in Medicare-managed care. A number of measures were used to examine validity of BSCI, including comparisons of the differences between cases and controls in BSCI scores, comparisons of the correlations between patient scores on BSCI and the Mini Mental Status Exam (MMSE, a common screening test for dementia) and the Alzheimer's Disease Assessment Scale (ADAS, a common dementia assessment test), and comparisons of the areas under the receiver operating characteristic (ROC) curves for the three instruments. BSCI scores for cases and controls were significantly different, as were their scores for the MMSE and ADAS. Scores on BSCI were significantly correlated with scores for the MMSE and ADAS using both the Kendall's tau-b and Spearman rank-order correlation; correlations ranged from 0.654 between BSCI and ADAS to -0.83 for the correlation between BSCI and the MMSE (p < 0.001 for both). The areas under the ROC curves ranged from 0.94 to 0.96 for the three tests, meaning that they were equally accurate in discriminating between demented and nondemented patients. BSCI, a brief telephone screen for cognitive impairment due to dementia, discriminates between demented patients and normal controls as well as two standard tests of dementia, and may be considered a valid screen for dementia. Compared to existing screening tests, it has the additional advantages of extreme brevity, and ease of administration and scoring by lay interviewers via telephone. The use of brief screening instruments for dementia, such as the one validated here, will be increasingly important for the effective management of dementia and other chronic diseases where dementia is a coexisting condition.     

Update: Health Insurance and Utilization of Care Among Rural Adolescents

CONTEXT: Adolescence is critical for the development of adult health habits. Disparities between rural and urban adolescents and between minority and white youth can have life-long consequences. PURPOSE: To compare health insurance coverage and ambulatory care contacts between rural minority adolescents and white and urban adolescents. METHODS: Cross-sectional design using data from the 1999-2000 National Health Interview Survey, a nationally representative sample of US households. Analysis was restricted to white, black, and Hispanic children aged 12 through 17 (8,503 observations). Outcome measures included health insurance, ambulatory visit within past year, usual source of care (USOC), and well visit within past year. Independent variables included race, residence, demographics, facilitating/enabling characteristics, and need. RESULTS: Across races, rural adolescents were as likely to have insurance (86.8% vs 87.7%) but less likely to report a preventive visit (60.1% vs 65.5%) than urban children; residence did not affect the likelihood of a visit or a USOC. Minority rural adolescents were less likely than whites to be insured, report a visit, or have a USOC. Most race-based differences were not significant in multivariate analysis holding constant living situation, caretaker education, income, and insurance. Low caretaker English fluency, limited almost exclusively to Hispanics, was an impediment to all outcomes. CONCLUSIONS: Most barriers to care among rural and minority youth are attributable to factors originating outside the health care system, such as language, living situation, caretaker education, and income. A combination of outreach activities and programs to enhance rural schools and economic opportunities will be needed to improve coverage and utilization among adolescents.     

Delivery Complications Associated With Prenatal Care Access for Medicaid-Insured Mothers in Rural and Urban Hospitals

CONTEXT: Pregnancy complications affect many women. It is likely that some complications can be avoided through routine primary and prenatal care of reasonable quality. PURPOSE: The authors examined access to health care during pregnancy for mothers insured by Medicaid. The access indicator is potentially avoidable maternity complications (PAMCs). Potentially avoidable maternity complications are often preventable through routine prenatal care, such as infection screening and treatment. The authors examined the risks of potentially avoidable maternity complications among rural and urban hospital deliveries for groups of mothers defined by race or ethnicity. METHODS: Data are from the year 2000 Nationwide Inpatient Sample (NIS). The stratified sample represents all discharges from 20.5% of community hospitals in the United States. The Nationwide Inpatient Sample identifies hospital locations, but not patients' areas of residence. Analyses, which accounted for the sample design, included calculation of potentially avoidable maternity complication rates by race or ethnicity, chi2, t tests, and multivariate logistic regression. FINDINGS: Within groups defined by race or ethnicity, unadjusted rates for potentially avoidable maternity complications did not differ significantly by hospital location. Holding other factors constant, potentially avoidable maternity complications were less common in rural hospitals than in urban hospitals (odds ratio, 0.78; CI, 0.62 to 0.99). In rural hospitals, African Americans had notably higher risk for potentially avoidable maternity complications than did non-Hispanic whites (odds ratio, 1.72; CI, 1.26 to 2.36). In urban hospitals, risk of potentially avoidable maternity complications was not significantly higher for African Americans. Hispanics and Asians had notably lower risks of potentially avoidable maternity complications in urban hospitals than did non-Hispanic whites. CONCLUSIONS: Providers and policymakers should work to reduce the risks of potentially avoidable maternity complications for African American women in rural areas who are insured by Medicaid.     

Induction of CYP1A in the beagle dog by an inhibitor of kinase insert domain-containing receptor: differential effects in vitro and in vivo on mRNA and functional activity.

Compound I [3-[5-(4-methanesulfonyl-piperazin-1-ylmethyl)-1H-indol-2-yl]-1H-quinolin-2-one] is a potent inhibitor of human kinase insert domain-containing receptor (KDR kinase), which is under investigation for the treatment of cancer. Bile duct-cannulated male beagle dogs were administered 6 mg/kg compound I q.d. for 14 days. There was an approximately 2.5-fold decrease in the mean plasma area under the curve of I on days 7 and 14 (approximately 11.3 microM . h), relative to day 1 (28.2 microM . h). In the dog, compound I was eliminated by metabolism, with a major pathway being aromatic hydroxylation and subsequent sulfation to form the metabolite M3. Metabolic profiling suggested that the pathway leading to the formation of the sulfated conjugate M3 was induced upon multiple dosing of I. Studies conducted in vitro suggested that CYP1A1/2 was responsible for the formation of the hydroxylated metabolite, which is sulfated to yield M3. Additional studies confirmed induction of CYP1A protein and activity in the livers of dogs treated with I. However, studies in a dog hepatocyte model of induction showed a surprising decrease both in CYP1A mRNA and enzymatic activity in the presence of I, emphasizing the need to consider the results from a variety of in vitro and in vivo studies in deriving an understanding of the metabolic fate of a drug candidate. It is concluded that the autoinduction observed after multiple treatments with compound I occurs since compound I is both an inducer and a substrate for dog CYP1A.     

Metabolism and disposition of a potent group II metabotropic glutamate receptor agonist, in rats, dogs, and monkeys.

Metabolism and disposition of MGS0028 [(1R,2S,5S,6S)-2-amino-6-fluoro-4-oxobicyclo[3.1.0]hexane-2,6-dicarboxylic acid monohydrate], a potent group II metabotropic glutamate receptor agonist, were examined in three preclinical species (Sprague-Dawley rats, beagle dogs, and rhesus monkeys). In rats, MGS0028 was widely distributed and primarily excreted in urine as parent and as a single reductive metabolite, identified as the 4R-isomer MGS0034 [(1R,2S,4R,5S,6S)-2-amino-6-fluoro-4-hydroxybicyclo[3.1.0]-hexane-2,6-dicarboxylic acid]. MGS0028 had a low brain to plasma ratio at efficacious doses in rats and was eliminated more slowly in rat brain than in plasma. Exposure increased proportionally (1--10 mg/kg p.o.) in rats, with bioavailability>60% at all doses. However, bioavailability was only approximately 20% in monkeys, and MGS0034 was found in relatively high abundance in plasma. In dogs, oral bioavailability was >60%, and the metabolite was not detected. In vitro metabolism was examined in liver subcellular fractions (microsomes and cytosol) from rat, dog, monkey, and human. Reductive metabolism was observed in rat, monkey, and human liver cytosol incubations, but not in dog liver cytosol incubations. No metabolism of MGS0028 was detected in incubations with liver microsomes from any species. Similar to in vivo results, MGS0028 was reduced in cytosol stereospecifically to MGS0034. The rank order of in vitro metabolite formation (monkey > rat approximately human > dog) was in agreement with in vivo observations in rats, dogs, and monkeys. Based on the observation of species difference in reductive metabolism, rat and monkey were recommended to be the preclinical species for further characterization prior to testing in humans. Finally, allometric scaling predicts that human pharmacokinetic parameters would be acceptable for further development.     

Evaluation of the Washington State National Pharmaceutical Stockpile dispensing exercise, part II--dispensary site worker findings.

On January 24, 2002, the Washington State Department of Health, in collaboration with local and federal agencies, conducted an exercise of the Centers for Disease Control and Prevention's National Pharmaceutical Stockpile dispensing portion of the Washington State plan. This exercise included predrill planning, training, and the orchestration of services of more than 40 dispensary site workers. These workers provided education and post-exposure prophylaxis for over 230 patient volunteers in the aftermath of a simulated exposure to B. anthracis. This article discusses findings of a postdrill questionnaire completed by 90% of these dispensary site workers who provided triage, education, dispensary, security and other services during this exercise. In general, this dispensing drill promoted confidence in the worker participants and provided an opportunity for these participants to coordinate their activities. This mock bioterrorist preparedness exercise allowed worker participants and observers to review and evaluate the Washington State plan for dispensing the National Pharmaceutical Stockpile. This article is apparently the first published account of dispensary site workers' subjective impressions and quantitative analysis of their postdrill opinions following a simulated bioterrorist post-exposure chemoprophylaxis dispensing exercise.     

Goal setting is differentially related to change in fruit, juice, and vegetable consumption among fourth-grade children.

The impact of goal attainment in a dietary change program to increase fruit, 100% juice, and vegetable consumption was assessed among fourth-grade students. At each session, the students were given goals related to increasing fruit, juice, and vegetable consumption. Baseline consumption and postconsumption were assessed with up to 4 days of computerized dietary recalls. Analyses included regression models predicting postconsumption from the numbers of fruit-juice goals, vegetable goals, or total number of general goals attained, respectively. For students with low baseline fruit-juice preferences, attaining more fruit-juice goals resulted in increased post-fruit-juice consumption. Among those with low baseline vegetable consumption, attaining one vegetable goal was related to higher post-vegetable consumption. For boys and those with high baseline fruit, juice, and vegetable consumption, attaining three general goals was related to increased fruit, juice, and vegetable intake. The results show that goal attainment was somewhat effective in promoting dietary change among children.     

Population pharmacokinetic modeling for enterohepatic recirculation in Rhesus monkey.

Enterohepatic recirculation (EHR) occurs via biliary excretion and intestinal reabsorption of a drug. Drug recycling through EHR can lead to a change in pharmacokinetic (PK) properties, such as reduced clearance (CL), extended half-life (T(1/2)) and increased plasma exposure (AUC). As a result, EHR may prolong the pharmacological effect of drugs. In the present study, the compound (Cpd A) was found to exhibit EHR in Rhesus monkeys associated with a reduction in CL (from 3.8 to 0.33 Lh(-1), IV; from 2.3 to 0.4 Lh(-1), PO), and an increase in T(1/2) (from 0.9 to 18 h, IV) and in AUC (from 1.5 to 17.4 microg h/mL, IV; from 2.8 to 16.3 microg h/mL, PO), by comparing the PK in the monkeys via the interruption of EHR (bile-duct cannulation) with that in the intact monkeys. A population four-compartment model was constructed based on recirculation loops incorporating all possible inputs (bile secretion, a lag-time model for gall bladder emptying, routes and amounts of a single dose administration) to fully evaluate the EHR of Cpd A. The plasma concentrations versus time profiles predicted from the model had a good fit to the values observed in the subjects and were further simulated with 90% confidence interval to demonstrate its utility. Thus, the model could be applied as a useful tool to evaluate the drugs or compounds that undergo EHR in different species.