A study examining the relationship between alexithymia and challenging behaviour in adults with intellectual disability.

BACKGROUND: Research suggesting that people with intellectual disabilities (ID) have difficulties in recognising emotions provides a rationale for studying alexithymia in this population. A number of studies have found a relationship between alexithymia and challenging behaviours in various populations and this study aims to discover if this is the case for people with ID. METHOD: Cross-sectional data were collected from 96 participants with ID and 95 of their carers. The service user participants completed an alexithymia questionnaire for children while carers completed the checklist for challenging behaviour and the observer alexithymia scale. Correlational analyses were employed to explore relationships between the variables. RESULTS: The relationship between service user and carer-rated alexithymia was very weak. The analysis did show significant associations between observer-rated alexithymia and challenging behaviour frequency, management difficulty and severity, but there was no significant relationship between challenging behaviour and alexithymia as rated by service users themselves. CONCLUSIONS: This study suggests that observer-rated alexithymia is important in understanding challenging behaviour presented by people with ID. Service user-rated alexithymia had no association with challenging behaviour, in contrast to the results from similar research with other challenging populations.

The UK geochemical environment and cardiovascular diseases: magnesium in food and water.

Cardiovascular diseases (CVDs) contribute approximately one-third to noncommunicable diseases in the UK. The central role of magnesium in CVDs (enzyme activity, cardiac signalling, etc.) is well established. Mortality and morbidity rates for CVDs may be inversely related to water hardness, suggesting a role for environmental magnesium. Published official and quasi-official data sources were evaluated to establish a model magnesium intake for a representative adult: standardised reference individual (SRI), standardised reference male (SRM) or standardised reference female (SRF). For typical dietary constituents, only tap water is probably locally derived and bottled water may not be. Fruits and vegetables are imported from many countries, while meat, dairy and cereal products represent a composite of UK source areas. Alcoholic beverages provide magnesium, there is doubt about its absorptive efficiency, and they are not locally derived. A simple model was devised to examine the effect of varying dietary contributions to total daily intake of magnesium. Omitting tap or bottled water, the combined intake, solid food plus alcoholic beverages, is 10.57 mmol Mg (84.5 % RNI) for the SRM and for the SRF, 8.10 mmol Mg (71.7 % RNI). Consumers drinking water derived from reservoirs or rivers, or supplementing it with the purest bottled water, improve their magnesium intake only slightly compared with water containing no magnesium. Choosing bottled water with high magnesium content when the public supply derives from rivers or reservoirs partially satisfies magnesium needs. Real improvement in SRI magnesium nutrition is seen only where water is hard. However, this conclusion cannot be validated until new measurement technologies for body magnesium become available.

Safety and pharmacokinetics of oseltamivir at standard and high dosages.

Although clinical evidence is currently lacking, opinion in the literature on avian influenza A/H5N1 suggests that increased doses of the oral neuraminidase inhibitor oseltamivir may offer clinical benefits against highly pathogenic influenza where high levels of viral replication and disseminated infection cause severe disease. We assessed the pharmacokinetics and safety/tolerability of oseltamivir at dosages up to 450 mg twice daily. Healthy adult volunteers were randomised to receive placebo or oseltamivir 75, 225 or 450 mg every 12h for 5 days. Volunteers were followed up to Day 7 for pharmacokinetic parameters, vital signs, adverse events and cardiac safety. In total, 391 volunteers were randomised and evaluated. Pharmacokinetics were linear and dose-proportional, with no evidence of accumulation of oseltamivir or its active metabolite at any dosage. Headache was the most common adverse event (16.8-23.7% across groups), but its incidence was unrelated to dosage. Dosage-related events with oseltamivir included nausea (up to 31.3% of volunteers) and vomiting (up to 16.2%), which generally occurred on Day 1 and lasted <1 day, and possibly dizziness (up to 11.3%). Oseltamivir had no relevant effects on vital signs, laboratory parameters or cardiac function. In conclusion, oseltamivir was well tolerated, with dose-proportional pharmacokinetics and no accumulation. Possible clinical benefit in severe influenza infections could be investigated at dosages higher than those currently recommended.

A preliminary electron backscattered diffraction study of sintered NdFeB-type magnets.

This paper reports, for the first time, the use of electron backscattered diffraction (EBSD) to study orientation in sintered NdFeB type magnets. The magnetic properties of NdFeB magnets are greatly improved if a strong crystallographic texture is firstly achieved, namely, the direction of the c-axis is along the direction of magnetization. A systematic survey of sample preparation techniques showed that samples that were mechanically polished and then etched gave the most reliable EBSD data. Analyses were made using both fully automated EBSD scans and by EBSD measurements taken after manual movement of the beam. The EBSD results are presented as secondary electron SEM micrographs, orientation images and 001 pole figures. For the selection of grains investigated, the deviation of the c-axis was shown to be between 10 degrees and 30 degrees from the ideal [001]//magnetization direction. It is demonstrated that EBSD is a valuable tool for characterizing the microstructure and texture relationships and for assessing the performance of the processing routes of NdFeB magnets.

Safety of intravenous gadolinium (Gd-BOPTA) infusion in patients with renal insufficiency.

The safety of gadolinium (Gd-benzyloxypropionictetra-acetate [BOPTA] dimeglumine) infusion was evaluated in 32 patients with severe or moderate chronic renal failure in a prospective, randomized, double-blind, placebo-controlled study. Renal failure was defined as severe if creatinine clearance was between 10 and 29 mL/min, and as moderate if creatinine clearance was between 30 and 60 mL/min. Serum creatinine level and 24-hour urine samples for creatinine clearance were followed up serially for 7 days after the administration of either gadolinium (Gd-BOPTA dimeglumine), 0.2 mmol/kg, or a saline infusion. No patient experienced a significant change in renal function, defined as an increase in serum creatinine level greater than 0.5 mg/dL more than baseline, and no patient required hospitalization or dialysis during the study period. Gadolinium (Gd-BOPTA dimeglumine) appears to be well tolerated in patients with moderate to severe renal failure.

Safety and pharmacokinetic profile of gadobenate dimeglumine in subjects with renal impairment.

RATIONALE AND OBJECTIVES: To determine the safety and pharmacokinetics of gadobenate dimeglumine in a group of subjects with moderate or severe renal impairment. METHODS: The safety and pharmacokinetic profile of gadobenate dimeglumine, a gadolinium (Gd3+) chelate complex in development as a contrast agent for MRI, were evaluated in a placebo-controlled, double-blind, multicenter trial. Subjects with moderate or severe renal impairment (creatinine clearances of 31 to 60 or 10 to 30 mL/min, respectively) received a 0.2-mmol/kg intravenous bolus of Gd3+ or saline placebo. Blood samples (up to 72 hours) and urine and fecal samples (up to 216 hours) were assayed for total Gd3+ content by inductively coupled plasma atomic emission spectroscopy. Gd3+ blood concentration/time data were analyzed nonparametrically and parametrically using the software program WinNonlin VI.1. RESULTS: Mean (SD) values for Gd3+ area under the curve, blood clearance, steady-state volume of distribution, renal clearance, and creatinine clearance for the moderate group were 862 (392) micrograms.h/mL, 56 (25) mL/min, 21 (5) L, 47 (23) mL/min, and 46 (16) mL/min. Values for the severe group were 1347 (366) micrograms.h/mL, 31 (7) mL/min, 19 (6) L, 22 (7) mL/min, and 21 (8) mL/min. No Gd(3+)-related adverse events occurred. Mean values for Gd3+ recovery in urine and feces for moderate and severe groups were 74% and 6%, and 69% and 8% of the dose, respectively. Linear regression analysis demonstrated a significant relation between the level of renal function and blood clearance of Gd3+. CONCLUSIONS: Although mean blood clearance and renal clearance values progressively declined with increasing degree of renal impairment, based on the safety profile and the fact that the administered dose was double the standard dose used for MRI purposes, there appears to be no need for dose reduction in this population.

The pharmacokinetics of topotecan and its carboxylate form following separate intravenous administration to the dog.

PURPOSE: To determine the relationship between topotecan and its ring opened hydrolysis product (SK&F 105,992) following intravenous administration of the two agents separately, and to determine the bio-availability of topotecan in female beagle dogs. METHODS: The pharmacokinetics of topotecan and SK&F 105,992 were determined following separate administration as 30 minute intravenous infusions in a cross-over design. Topotecan was also administered orally to the same dogs. RESULTS: When administered intravenously to dogs, SK&F 105,992 underwent interconversion to topotecan. Plasma concentrations of both topotecan and SK&F 105,992 appeared to decline multi-exponentially following i.v. infusion of either compound. A 2-compartment model was found to adequately characterize the data. CONCLUSIONS: The clearance of topotecan by other routes proceeded at a faster rate than its interconversion to SK&F 105,992, whereas the clearance of SK&F 105,992 by other routes was slower than the rate of its interconversion to topotecan. Any SK&F 105,992 formed in the GI tract did not appear to be well absorbed following oral administration of topotecan to dogs. The steady-state volume of distribution for topotecan was approximately 8- to 9-fold greater than that for SK&F 105,992 in the dog. After intravenous administration of topotecan, the amount of topotecan in the dog was much greater than that of the carboxylate, even though their respective plasma concentrations were similar. The bioavailability of topotecan, calculated from oral topotecan data or from SK&F 105,992 data, was approximately 50%.

Interspecies pharmacokinetics of a novel hematoregulatory peptide (SK&F 107647) in rats, dogs, and oncologic patients.

PURPOSE: To study the pharmacokinetics of SK&F 107647, a novel hematoregulatory agent, in rats, dogs, and patients with non-lymphoid solid tumor malignancy. METHODS: Sprague Dawley rats and beagle dogs (n = 6 each; 3 M, 3 F) were given 25 mg/kg of SK&F 107467 as an iv bolus injection, and patients (n = 6; 4 M, 2 F) received 100 mg/kg as a 2 hour iv infusion. Plasma samples were assayed for drug using either HPLC (rat and dog) or RIA (human). RESULTS: In each species the plasma clearance (CL) of SK&F 107647 was low in relation to hepatic blood flow, and the volume of distribution (Vd ss) was reflective of distribution to extracellular body water. The plasma CL in humans was near that of average glomerular filtration rate. Using allometric equations for interspecies scaling (Y = a.W(b)), body-weight normalized human pharmacokinetic data were reasonably predicted using either the body weight normalized rat or the dog data. The allometric exponents (b) for CL, Vd(ss), and T(1/2) of SK&F 107647 were 0.63, 0.94, and 0.29, respectively. CONCLUSIONS: Use of a limited pool of available animal data allowed for reasonable predictions of human pharmacokinetics of SK&F 107647.

Pharmacokinetics and pharmacodynamics of topotecan given on a daily-times-five schedule in phase II clinical trials using a limited-sampling procedure.

Topotecan is a novel semisynthetic derivative of the anticancer agent camptothecin and inhibits the intranuclear enzyme topoisomerase I. The lactone structure of topotecan, which is in equilibrium with the inactive ring-opened hydroxy acid, is essential for this activity. We performed a pharmacokinetics study as part of phase II clinical trials in patients with various types of solid tumors, giving topotecan at 1.5 mg/m2 per day by 30-min infusion for 5 consecutive days, with courses being repeated every 3 weeks. Previously validated limited-sampling models, using concentration measurements in samples obtained 2 h after infusion, were used to calculate the area under the plasma concentration-time curves (AUCs) for both chemical forms. Samples were obtained from a total of 36 patients over 136 treatment days. The mean AUC of the closed-ring form (AUC(closed)) was 8.74 (range 2.3-16.3 microM min per day, and the mean AUC of the ring-opened form (AUC(open)) was 11.5 (range 3.2-46.0) microM min per day (interpatient variability 34-61%). In each patient the AUC values achieved on the 1st day of administration were similar to and, thus, predictive for those achieved during the following days, with a day-to-day variation of 7.39% being recorded for the AUC(closed) and that of 12.6% for the AUC(open). There was no drug accumulation during the 5 consecutive treatment days of each cycle. However, despite the large interpatient pharmacokinetic variability, the importance of regular drug monitoring on this schedule can be questioned, as the pharmacodynamic variability was relatively small.

Phase I clinical and pharmacokinetic study of topotecan administered by a 24-hour continuous infusion.

PURPOSE: To determine the maximum-tolerable dose (MTD) and to investigate the pharmacokinetics and pharmacodynamics of topotecan in a phase I study. Topotecan is a novel semisynthetic derivative of the anticancer agent camptothecin and inhibits the intranuclear enzyme topoisomerase I. Broad preclinical activity rationalized further clinical evaluation. PATIENTS AND METHODS: In this phase I trial, topotecan was administered by 24-hour continuous infusion every 21 days to patients with solid malignant tumors. RESULTS: A total of 25 eligible patients, of whom 22 were pretreated, entered the study. They received the following dosages of topotecan: 2.5, 3.75, 5.60, 8.4, and 10.5 mg/m2 by 24-hour infusion. Reversible leukopenia and thrombocytopenia were dose-limiting, with mild anemia occurring regularly. Other toxicities, such as alopecia, mucositis, nausea, and vomiting were sporadic and mild. Responses were not observed. However, eight patients had stable disease. The plasma concentration-time curves were not compatible with standard linear pharmacokinetic models, and indications were found for the occurrence of nonlinear (saturation) kinetics at the dosages studied. CONCLUSION: The recommended dose for phase II studies is 8.4 mg/m2 when administered as a 24-hour infusion, which is well tolerated. Further studies will be necessary to account for the putative nonlinear behavior of the drug.

High-performance liquid chromatographic determination of the novel antitumour drug topotecan and topotecan as the total of the lactone plus carboxylate forms, in human plasma.

A sensitive high-performance liquid chromatographic (HPLC) assay has been developed and validated for the quantitation of the novel anticancer agent topotecan and topotecan as the total of its lactone and carboxylate forms in human plasma. Linear response in analyte standard peak area were observed over the concentration range 0.05-10 ng/ml using 100-microliters plasma samples. The instability of the drug in the biological matrix necessitated that the plasma fraction was obtained within 5 min after blood sampling by centrifugation, immediately followed by protein precipitation with cold methanol (-30 degrees C). Stability studies have indicated that topotecan is stable in these methanolic extracts for at least 4.5 months at -30 degrees C and 2 months at -70 degrees C. For the total determination of the lactone plus lactone ring-opened forms of the drug as topotecan, plasma samples were deproteinated with methanol and, subsequently, acidified with 7% (v/v) perchloric acid. Plasma samples for the measurement of total levels of the lactone and the ring-opened forms of topotecan were stable for at least 4.5 months when stored at -30 degrees C. After centrifugation, the supernatants were analysed by HPLC using a Zorbax SB-C18 Stable Bond column and methanol-0.1 M hexane-1-sulfonic acid in methanol-0.01 M N,N,N',N'-tetramethylethylenediamine (TEMED) in distilled water pH 6.0 (25:10:65, v/v) as the mobile phase. Detection was performed fluorimetrically. Within-run and between-run precision was always less than 12.1% in the concentration range of interest (0.05-10.0 ng/ml). The limit of quantitation is 0.05 ng/ml. Accuracy measurements ranged between 87.6 and 113.5%.

Pharmacokinetics and pharmacodynamics of topotecan administered daily for 5 days every 3 weeks.

Topotecan is a novel semisynthetic derivative of the anticancer agent camptothecin and inhibits the intranuclear enzyme topoisomerase I. The lactone structure of topotecan, which is in equilibrium with the inactive ring-opened hydroxy acid, is essential for this activity. The open form predominates at physiological pH. We performed a pharmacokinetic study as part of a phase I study in patients with various types of solid tumors, where topotecan was administered in a 30-min infusion daily on 5 consecutive days every 3 weeks. The plasma kinetics of topotecan could be described best using an open two-compartment model with t1/2(alpha) and t1/2(beta) of 8.1 (range 0.3 to 40.7) min and 132 (range 49 to 286) min, respectively. The plasma concentration-time profiles of the metabolite, however, could be described using a one-compartment model with t1/2(formation) of 29.0 (range 5.6-99.5) min and t1/2 (elimination of 123.2 (range 32-265) min, respectively. The lactone was the predominate form during the first hour from the start of infusion, but was rapidly converted into its ring-opened structure. The elimination rate of topotecan was independent of the dose. There were linear relationships between the dose (mg m-2 day-1), the area under the plasma concentration versus time curve (AUC) of topotecan and its metabolite, the total AUC, peak plasma lactone concentrations, and the time period that the topotecan concentrations remained above 10 nM. Different models were used to correlate pharmacokinetic and pharmacodynamic parameters. The percentage decrease in absolute neutrophil count (ANC) was related to these parameters and plots were well fitted by linear and sigmoidal Emax models.

Distribution of metals in mechanical fractions of soils from a lake catchment in Venezuela.

Soil samples were collected from both the surface and at depth from the lowlands around Lake Valencia and from the adjacent mountains. This paper reports results for Al, Ca, Co, Cr, Cu, Fe, K, Mg, Mn, Na, Ni, Pb and Zn in mechanical fractions of the soils. Lowland soils, developed on lacustrine sediments, show a predominance of medium- to fine-grain size fractions whereas the shallow mountain soils show the highest percentage of particles in the coarse to medium fractions. Concentrations of most of the elements investigated increased toward finer particle sizes. The generally higher metal concentrations in lowland soils compared with mountain soils are consistent with release by weathering in the uplands and accumulation in the lowlands. The presence of carbonates derived from ubiquitous shelly material in the lowland soils may explain increases of Ca and Mg in labile fractions. In the lowland area, there is little evidence for the translocation of metals in the soil profiles, despite the high rainfall of a tropical climate, and the calcareous nature of these soils could account for the immobility of metals.

Trace elements in the human environment: Problems and risks.

Early studies on the possible influences of environmental geochemistry and health were concerned with major diseases such as cancer or multiple sclerosis. They were generally confined to simple comparisons of geochemical and epidemiological maps and corresponding rural areas. Subsequently, studies of dental health produced evidence for the roles of environmental fluoride, selenium, molybdenum and lead in the aetiology of caries. In recent decades lead has been closely studied. Most people in the western world live in urban areas, rather than rural areas, and research on lead has yielded much information on the distribution of the element in streets, parks and gardens of cities and in the home environment. The role of lead in human health has thereby been better understood. Cadmium, selenium and aluminium are good candidates for future study but success will depend on applying appropriate methods of investigation and here the experiences from research on lead are a valuable model to follow.

Leaded windows as a source of lead within homes.

Corrosion of 'cames', i.e., the lead binding or decorative strips in leaded windows, is a significant, but previously unreported source of lead within older homes. Surfaces close to the leaded windows are highly contaminated with lead but the content of lead in dust diminishes rapidly within the first 2 m away from the window and is minimal after 3 m. The dust near the window was identified, using X-ray diffraction, as mainly composed of basic lead carbonate. Condensation water on leaded windows contains appreciable lead whereas for unleaded windows it is negligible. The exterior surface of unleaded windows contains more lead than the interior surface but the converse is true for leaded windows. A laboratory simulation suggested that corrosion by window condensate was likely to be the principal mechanism by which lead entered the home environment.