Summary The pharmacokinetics of the new antifolate CB 3717 were studied in 20 patients during its phase-I clinical evaluation. The drug was administered at doses of 100–550 mg/m2 in 1-h and 12-h infusions, resulting in peak plasma concentrations of CB 3717 of 40–200 M. There was a linear relationship between the dose and both CB 3717 AUC and peak plasma levels. Following a 1-h infusion, drug levels in the plasma decayed biphasically (t1/2=49±9 min, t1/2=739±209 min). 27%±2% of the dose was excreted in urine in the 24-h period after treatment, suggesting that the major route of elimination was via the bile. Furthermore, the parent compound CB 3717 and its desglutamyl metabolite, CB 3751, were found in a faecal collection although the metabolite was not detected in plasma or urine samples. Plasma protein binding of CB 3717 was extensive (97.6%±0.1%). Significant quantities of CB 3717 penetrated into ascitic fluid but not into cerebrospinal fluid.Residual drug was detected in postmortem kidney tissue from a patient who died of progressive disease 8 days after treatment with 330 mg/m2 CB 3717. Thus, dose-limiting renal toxicity (maximum tolerated dose 600 mg/m2) may be due to drug precipitation in the renal tubules. Elevation of liver enzymes, in particular transaminases, occurred frequently as a toxic manifestation of CB 3717 therapy. In 11 patients studied after their first treatment there was a positive correlation between the rise in serum alanine transaminase and peak drug levels (r=0.69, P=0.02)These pharmacokinetic studies have shown that, by analogy with experimental systems, cytotoxic plasma levels of CB 3717 are archieved in man. In addition, they have been valuable in interpreting toxicities observed during phase-I clinical studies.This work was supported by grants from the Medical Research Council and Cancer Research Campaign, U. K. 相似文献
Millions of older people world-wide receive community care services in their home to assist them to live independently. These services often include personal care, domestic assistance and social support which are delivered by non-university trained staff, and are frequently long term. Older people receiving community care services fall 50% more often than individuals of similar age not receiving services. Yet, few ongoing community care services include exercise programs to reduce falls in this population. We conducted an earlier study to examine the feasibility of community care staff delivering a falls prevention program. A critical finding was that while some of the assessment and support staff responsible for service delivery delivered the falls prevention exercise program to one or two clients, others delivered to none. Therefore, the aim of this qualitative sub-study was to understand reasons for this variation. Semi-structured interviews were conducted with 25 participating support staff and assessors from 10 community care organisations. Staff who had successfully delivered the intervention to their clients perceived themselves as capable and that it would benefit their clients. Older clients who were positive, motivated and wanted to improve were perceived to be more likely to participate. Staff who had worked at their organisation for at least 5 years were also more likely to deliver the program compared to those that had only worked up to 2 years. Staff that did not deliver the intervention to anyone were more risk averse, did not feel confident enough to deliver the program and perceived their clients as not suitable due to age and frailty. Experienced staff who are confident and have positive ageing attitudes are most likely to deliver falls prevention programs in a home care organisation. 相似文献
The ongoing Boko Haram insurgency in northeastern Nigeria has depleted the country’s capability to deliver quality healthcare to her citizenry. The ailing health sector is overwhelmed with a rising incidence and prevalence of infectious and non-communicable diseases.
Aim
The aim of this paper was to determine the trend of kidney disease, end-stage renal disease (ESRD), anaemia, malnutrition and human immunodeficiency virus (HIV) in northeastern Nigeria.
Materials and methods
Data covering different periods between 1999 and 2017 were obtained from the University of Maiduguri Teaching Hospital (UMTH), Maiduguri in northeastern Nigeria. This hospital is the largest tertiary healthcare facility in the region. The data were demographic in nature, i.e. sex, age or simply the registered cases. A quadratic model of time-series analysis was used to create the various trends of the respective diseases with the aid of Minitab software (version 18.0). t-Tests and analysis of variance (ANOVA) were also performed, with a p-value of less than or equal to 0.05 being considered significant.
Results
About three out of every five patients treated for kidney disease were male, while three out of every five patients treated for HIV were female. Patients between the ages of 31 and 50 years were at the greatest risk of developing kidney disease. The mean distribution of disease incidence was the same for both sexes for kidney disease, anaemia, malnutrition and HIV. The mean distribution disease incidence was different between age groups for kidney disease but the same for anaemia. The incidence of anaemia and malnutrition reported was almost the same for both sexes. Children under the age of 10 years old were at the most risk of anaemia, with the distribution decreasing with increasing age. The trend analysis of the incidence of kidney disease, ESRD, anaemia and malnutrition showed that these ailments were on the increase, while the number of patients that were on antiretroviral therapy (ART) was on the decline in northeastern Nigeria.
Conclusion
These increasing trends are evidences of the effect of Boko Haram on the public health of the people of northeastern Nigeria and will continue to be a public health concern for the region and the country as a whole.
The natural antibiotic molecules, beta-defensins 1 and 2 (HBD1/2) and secretory leukocyte protease inhibitor (SLPI), have an important role in mucosal defence and are present in the uterus. This study details their regulation in primary endometrial epithelial cells and in two endometrial cell lines (MFE/HES). Cells were treated with proinflammatory molecules and mimics of infection [lipopolysaccharide (LPS) and lipoteichoic acid (LTA)]. mRNA for HBD1, HBD2 and SLPI was detected in primary endometrial epithelial cells using real-time quantitative PCR. HBD1 mRNA was present at very low levels preventing conclusive study of its regulation. However, HBD2 mRNA expression was increased by interferon-gamma, interleukin (IL)-1beta alone and IL-1beta+tumour necrosis factor (TNF)-alpha. SLPI mRNA was not affected by proinflammatory mediators, although protein levels fell in the presence of IL-1beta+TNFalpha. LPS had little effect on antimicrobial expression. However, there was a trend towards increased expression with LTA treatment for 4-8 h. Antimicrobial expression in endometrial cell lines was similar to that in primary cells, although SLPI was increased by IL-1beta+TNFalpha treatment. These results suggest that in endometrium some natural antibiotics (e.g. SLPI) may be constitutively expressed providing a basal level of protection, while others (e.g. HBD2) are inducible allowing maximal antimicrobial activity during infection. Natural antimicrobials will have an important role in endometrium in protecting against infection. 相似文献
Case reports are presented on three patients treated for morbid obesity by vertical gastroplasty. Prior to surgery the patients
had diabetes which required insulin, up to 200 units per day, or oral hypoglycaemics for its control. Six months after surgery
the diabetes had been resolved in all three patients, and they were no longer dependent on medication. Subjective reports
from the patients suggests that their quality of life improved significantly. 相似文献
A prospective study of biochemical changes after vertical banded gastroplasty for morbid obesity, in 94 patients (10 males
and 84 females, ages ranging from 18 to 59 years) has been carried out. Liver function tests and electrolyte estimations were
performed preoperatively, during hospitalisation for surgery, at 6 weeks and at 6 months postoperatively, and demonstrated
no significant changes in liver function in these patients 6 months after surgery. The study concludes that there is no increase
in the risk of liver damage or electrolyte disturbance after vertical gastroplasty, but that there may be subtle hepatic changes
present as gall bladder disease developed in 18 patients postoperation (19%). 相似文献
The pharmacokinetics and pharmacodynamics of prolonged oral etoposide chemotherapy were investigated in 15 women with metastatic breast cancer who received oral etoposide 100 mg as a single daily dose for up to 15 days. There was considerable interpatient variability in the day 1 pharmacokinetic parameters: area under the plasma concentration time curve (AUC) (0–24 h) 1.95±0.87 mg/ml per min (mean ± SD), apparent oral clearance 60.9±21.7 ml/min per 1.73 m2, peak plasma concentration 5.6±2.5 g/ml, time to peak concentration 73±35 min and half-life 220±83 min. However, intrapatient variability in systemic exposure to etoposide was much less with repeated doses. The intrapatient coefficient of variation (CV) of AUC for day 8 relative to day 1 was 20% and for day 15 relative to day 1 was 15%, compared to the day 1 interpatient CV of 45%. Neutropenia was the principal toxicity. Day 1 pharmacokinetic parameters were related to the percentage decrease in absolute neutrophil count using the sigmoidal Emax equation. A good fit was found between day 1 AUC and neutrophil toxicity (R2=0.77). All patients who had a day 1 AUC>2.0 mg/ml per min had WHO grade III or IV neutropenia. The predictive performance of the models for neutrophil toxicity was better for AUC (percentage mean predictive error 5%, percentage root mean square error 18.1%) than apparent oral clearance, peak plasma concentration, or daily dose (mg/m2). A limited sampling strategy was developed to predict AUC using a linear regression model incorporating a patient effect. Data sets were divided into training and test sets. The AUC could be estimated using a model utilizing plasma etoposide concentration at only two time points, 4 h and 6 h after oral dosing (R2=98.9%). The equation AUCpr=–0.376+0.631×C4h+0.336×C6h was validated on the test set with a relative mean predictive error of –0.88% and relative root mean square error of 6.4%. These results suggest monitoring of AUC to predict subsequent myelosuppression as a strategy for future trials with oral etoposide.Division of Haematology and Medical Oncology, Peter MacCallum Cancer Institute, Locked Bag 1, A'Beckett St, Melbourne 3000, Australia 相似文献
Summary The extracellular matrix influences organogenesis by modulating cell behavior. In humans, collagen is the major matrix constituent of the adult intestinal wall and is synthesized by smooth muscle cells. The objective of the current study was to examine collagen production by fetal human intestinal smooth muscle cells isolated during intestinal morphogenesis. Techniques were developed for the isolation and culture of human fetal intestinal smooth muscle cells. The cultured cells were confirmed as muscle by immunohistochemical stains for cytoskeletal filaments and documentation of contractile behavior. In culture, these cells stained for mesenchymal and muscle cytoskeletal proteins: vimentin, actin, and desmin, and did not stain for neural or epithelial markers. The muscle cells contracted in response to acetylcholine, in contrast to human fetal dermal fibroblasts which did not contract appreciably. Collagen production was assayed by the uptake of [3H]-proline into collagenase-digestible protein. Collagen production was greatest at 11 weeks gestation, the youngest age studied. By 20 weeks gestation, collagen production had decreased to adult levels. However, when compared to another matrix-producing fetal mesenchymal cell, the dermal fibroblast, intestinal smooth muscle cells produced twice as much collagen. Collagen types were determined by polyacrylamide slab gel electrophoresis. Smooth muscle cells predominantly produced types I and III collagen chains. Therefore, collagen production is a significant function of human fetal intestinal smooth muscle cells, and probably plays a major role in the development of intestinal structure. The in vitro model presented here provides a means of studying the regulation of this collagen production throughout intestinal organogenesis. 相似文献
We measured performance and event-related brain potential (ERP) map latencies in 12 subjects during four visual discrimination tasks to compare the timing of scopolamine effects on information processing and attention. "Topographic component recognition" found ERP map latencies at times of best fit with a component model map. This "common topography" criterion minimized topographic differences among conditions to facilitate latency interpretations. Scopolamine slowed N1 latency in all tasks, and P3 and reaction time in some tasks. The drug delayed responses to easy targets more than to hard targets. It also induced a disproportionate N1 delay for unilateral high spatial frequency gratings. Both effects reflect a scopolamine-induced impairment when processing targets that usually capture attention. Scopolamine also impaired accuracy for unilateral high spatial frequency gratings, and for gratings presented at probable locations, confirming and extending previous findings. Scopolamine-induced P1 and N1 delays showed that visual processing was affected. Several results were inconsistent with a serial stage model. We suggest that scopolamine both delays selected processes and impairs a processing mode based on automatic capture of attention, inducing more serial processing. 相似文献