Effect of renal impairment on the pharmacokinetics and tolerability of capecitabine (Xeloda) in cancer patients

PURPOSE: The primary objective of this study was to investigate the influence of renal impairment on the pharmacokinetics of capecitabine and its metabolites in cancer patients. Capecitabine (Xeloda) is an orally administered precursor of 5'-deoxy-5-fluorouridine (5'-DFUR), which is preferentially activated to 5-fluorouracil (5-FU) in tumors. METHODS: A total of 27 patients were enrolled, of whom 24 were evaluable for pharmacokinetics (6 with normal renal function, 8 with mild, 6 with moderate, and 4 with severe renal impairment at baseline). Patients received capecitabine orally at the standard dosing regimen (1250 mg/m(2) capecitabine twice daily for 2 weeks followed by a 1-week rest period). On study days 1 and 14, blood samples were collected to evaluate the pharmacokinetics of capecitabine and its metabolites. The relationship between the area under the plasma concentration-time curve (AUC) and creatinine clearance (CL(CR)) was assessed by log-linear regression analysis. RESULTS: The primary pharmacokinetic parameter with respect to the effect of renal dysfunction was systemic exposure to 5'-DFUR, 5-FU and FBAL determined on study day 14. Renal impairment led to an increase in the systemic exposure to 5'-DFUR and FBAL (23% and 109% increase in AUC, respectively) for a 50% reduction in CL(CR). By contrast, renal impairment may lead to decreased exposure to 5'-DFCR. There was no evidence for an effect of renal impairment on systemic exposure to 5-FU or capecitabine. Renal impairment did not have a major effect on peak concentration (C(max)) or elimination half-life (t(1/2)) of capecitabine, 5'-DFCR, 5'-DFUR, and 5-FU. However, in the case of FBAL, moderate or severe renal impairment caused up to a twofold increase in C(max) and prolongation of t(1/2). All patients with severe renal impairment (four patients) had drug-related grade 3 or 4 adverse-events (AEs) and serious AEs. Patients with moderate renal impairment experienced a similar number of grade 3 or 4 AEs (six of nine patients) but had a higher incidence of serious AEs (three of nine patients) when compared with those with normal renal function (four of six patients and one of six patients, respectively). A similar effect was seen in patients with mild renal dysfunction (grade 3 or 4 AEs in four of eight patients; serious AEs in three of eight patients). The relationship between systemic exposure to capecitabine or its metabolites and safety was investigated using logistic regression. This exploratory analysis showed a strong positive relationship between AUC of 5'-DFUR and treatment-related grade 3 or 4 AEs, whereas there was no relationship with exposure to capecitabine, 5'-DFCR, 5-FU or FBAL. CONCLUSIONS: Renal impairment has no effect on the pharmacokinetics of capecitabine or 5-FU, but leads to an increase in the systemic exposure to 5'-DFUR and FBAL. However, only the AUC of 5'-DFUR is correlated with safety. Based on the safety results in patients with severe renal impairment, a dose modification cannot be recommended for these patients and they should not be treated with capecitabine. Additional data from the clinical safety database and pharmacokinetic results from the present study support the recommendation that patients with moderate renal impairment should be treated with 75% of the recommended standard starting dose to achieve systemic exposure comparable to that in patients with normal renal function.     

White matter T(1) relaxation time histograms and cerebral atrophy in multiple sclerosis

T(1) relaxation time (T(1)) provides a quantitative magnetic resonance imaging (MRI) parameter for evaluating tissue damage in the brain. We aimed to measure T(1) in the white matter of patients with multiple sclerosis (MS) and study relationships with cerebral atrophy, T(2) lesion load and clinical parameters. Twenty-six patients with relapsing-remitting MS and sixteen healthy controls were scanned with dual-echo T(2)-weighted, 3-dimensional (3-D) magnetization-prepared rapid acquisition gradient echo and whole brain, multi-slice inversion recovery (IR) sequences. White matter masks were defined on axial T(1) map slices using semi-automated seed growing and normalized 'total white matter' T(1) histograms generated. Atrophy data was obtained using the Cavalieri method of modern design stereology. T(2) lesion volume was also determined using seed growing.T(1) histogram-derived measures (median, peak height, peak position and standard deviation) in MS patients were significantly different (p < 0.0001) from controls. Median T(1) correlated significantly with supratentorial (r = 0.42, p = 0.036), lateral ventricle (r = 0.55, p = 0.004), and T(2) lesion volumes (r = 0.84, p < 0.0001), but not with clinical parameters.Total white matter T(1) provides a robust, quantitative measure of global disease burden in MS, and also correlates significantly with cerebral atrophy. Serial studies are required to determine its potential role as a surrogate marker of disease progression.     

Temporal order memory in patients with Korsakoff's syndrome and medial temporal amnesia

Two groups of patients with global amnesia resulting either from Korsakoff's syndrome (KS) or from medial temporal lobe (MTL) damage were compared with groups of matched healthy control subjects on a list discrimination paradigm. Item recognition memory was matched across the amnesic and control groups in order to determine whether KS, but not MTL amnesics are disproportionately impaired on list discrimination as predicted by Parkin's [Functional significance of etiological factors in human amnesia. In: Squire LR, Butters N, editors. Neuropsychology of memory, 2nd ed. New York: The Guilford Press, 1992] hypothesis. However, both patient groups were impaired disproportionately on the temporal order memory task, which is inconsistent with Parkin's hypothesis. It remains possible that the KS patients are more disproportionately impaired than those with MTL damage because both patient groups performed at floor on the list discrimination task. The results are consistent with theories that postulate a critical role for the hippocampus in the kind of associative memory which underlies memory for temporal order, but not in recognition of single items or arbitrary associations between items of similar kinds.     

Retrieval-induced forgetting in Alzheimer's disease

It is claimed that Alzheimer's disease (AD) patients show reduced inhibitory processing and this has been put forward as a reason why AD patients make intrusion errors at recall. However, the evidence to date has been equivocal, because non-inhibitory mechanisms can account for the pattern of findings. Recently, however, a paradigm has been developed that is claimed to give a purer measure of inhibitory processing in episodic memory, the retrieval-induced forgetting (RIF) paradigm [Inhibitory Processes in Attention, Memory and Language, Academic Press, San Diego, 1994, p. 265; J. Exp. Psychol.: Learning, Memory Cognition 20 (1994) 1063; Psychol. Rev. 102 (1995) 68]. Thus, we were interested whether AD patients would show a deficit in inhibitory processing using this procedure. Participants studied lists of category cue-exemplar pairs (e.g. fruit-orange) then practised retrieval for a subset of items from a subset of categories before taking a final memory test for all studied items. As in previous work, inhibition was measured as the difference between final memory performance for unpractised items from practised categories, and unpractised items from unpractised categories. The results show that AD patients showed normal levels of inhibition with both tests of cued recall and category generation (CG). This suggests that a deficit in inhibitory processes during retrieval is not behind the high levels of intrusion errors made in recall in AD.     

Double-blind placebo-controlled trial of secretin: effects on aberrant behavior in children with autism

Secretin has been proposed as a treatment alternative for autistic spectrum disorders, but empirical support is lacking. A double-blind placebo-controlled study examined the effect of a single dose of synthetic human secretin on aberrant behavior. Parent and teacher data from the Aberrant Behavior Checklist for eight male children were analyzed for reliable change in a clinical replication series. By parent and teacher report, the majority of change occurred either on the placebo trial or reflected deterioration subsequent to secretin infusion. Repeated-measures multivariate analysis of variance results were similar. Results are consistent with other studies, suggesting that secretin may not be an effective treatment option.     

Fluorescent zinc indicators for neurobiology

Mounting evidence indicates that zinc has multiple roles in cell biology, viz. as a part of metalloenzyme catalytic sites, as a structural component of gene regulatory proteins, and (like calcium) as a free signal ion, particularly in the cortex of the brain. While most Zn(II) in the brain is tightly bound, such that free Zn(II) levels extracellularly and intracellularly are likely to be picomolar, a subset of glutamatergic neurons possess weakly bound zinc in presynaptic boutons which is released at micromolar levels in response to a variety of stimuli. Key to further progress in understanding the multiple roles of zinc will be the availability of fluorescent indicator systems that will permit quantitative determination and imaging of zinc fluxes and levels over a broad concentration range both intracellularly and extracellularly using fluorescence microscopy. Towards that end, we have compared a variety of fluorescent indicators for their sensitivity to Zn(II) and Cu(II), selectivity for Zn(II) in the presence of potential interferents such as Ca(II) or Mg(II), and potential for quantitative imaging. The commercially available probes Fura-2, Mag-Fura-5, Newport Green DCF, and FuraZin-1 were compared with the carbonic anhydrase-based indicator systems for selectivity and sensitivity. In addition, intracellular levels of Zn following excitotoxic insult were determined by single pixel fluorescence lifetime microscopy of Newport Green DCF, and extracellular levels of free zinc following stimulus of rat hippocampal slices were determined ratiometrically with a carbonic anhydrase-based indicator system. These results suggest that zinc ion at high nM to microM levels can be accurately quantitated by FuraZin-1 ratiometrically or by Newport Green DCF by fluorescence lifetime; and at levels down to pM by intensity ratio, lifetime, or polarization using carbonic anhydrase-based systems.     

Early expression of thyroid hormone deiodinases and receptors in human fetal cerebral cortex

Thyroid hormones are known to be important for optimal development of the human central nervous system. Classically, maternal thyroid hormones have not been thought to have a major role in defining central nervous system development. However, recent epidemiological evidence has indicated that subtle deficiencies in circulating maternal thyroid hormones in the first trimester of pregnancy are associated with adverse neurodevelopment. We have used real time PCR to quantitate the expression of mRNAs encoding the thyroid receptor isoforms (TR alpha1, alpha2, beta1 and beta2) and thyronine deiodinase subtypes (5'-DI, 5'-DII and 5-DIII) in human fetal cerebral cortex from the first and second trimesters of pregnancy. Deiodinase subtype activities have also been determined in these tissues and compared to 'normal' adult human cerebral cortex. Iodothyronine deiodinase mRNAs were expressed in human fetal cerebral cortex from 7 to 8 weeks of gestation. The expression of 5'-DI mRNA was variable in fetal life but increased relative to adult cortex (P<0.05), whereas the activity of this enzyme was below the level of assay detection. 5'-DII mRNA and activity in fetal cerebral cortex was detectable from as early as 7-8 weeks but not significantly different from that in adult life except at 15-16 weeks when mRNA expression increased (P<0.05). Fetal cortex 5-DIII mRNA expression was present from the early first trimester but less abundant than in adult tissue (P<0.01) and 5-DIII activity appeared greater in fetal cortex (P<0.01) as compared to adults. Only TR alpha1 mRNA was more abundantly expressed in fetal cortex than adult tissues (P<0.01). In contrast, the TR isoforms (alpha2 and beta1) were expressed significantly less than in adult tissues (P<0.05). Only 26% of fetal cerebral cortex samples expressed TR beta 1. There is evidence that the developing fetal brain, as early as the first trimester, expresses TRs and exhibits the mechanisms of pre-receptor control of thyroid hormone supply.     

Asthma Refractory to Glucocorticoids

Asthma is orchestrated by cytokine products of activated T cells. Glucocorticoids are thought to ameliorate asthma at least partly through T cell inhibition. Consequently, other T cell immunomodulatory agents have been assessed for asthma therapy. Since these agents may have serious unwanted effects, attention has been focused on patients with severe asthma refractory to maximal topical, and additional systemic glucocorticoid therapy.Although gold salts show a modest but significant glucocorticoid-sparing effect in severe asthma, lung function is not improved and not all patients respond. The minimum duration of a valid trial of therapy is probably 6 months. Unwanted effects include dermatitis, hepatic dysfunction, proteinuria and interstitial pneumonitis.Meta-analysis of trials of methotrexate in oral glucocorticoid-dependent asthma have confirmed that concomitant weekly methotrexate for a minimum of 3 to 6 months enables significant (approximately 20%) overall reduction in oral glucocorticoid requirements, although only approximately 60% of patients show a significant response. There is little effect on lung function. Blood count and liver function must be monitored. Opportunistic infection is rare but potentially fatal.Cyclosporine, administered for at least 3 months, is effective in only a proportion of patients with oral glucocorticoid-dependent asthma, where it may improve disease severity and/or enable oral glucocorticoid dosage reductions. Regular monitoring of renal function, blood pressure and blood concentrations of cyclosporine is required.The evidence that intravenous immunoglobulin (Ig) is of any benefit in patients with glucocorticoid-dependent asthma is at present equivocal. The therapy is expensive and associated with a high incidence of unwanted effects (fever, aseptic meningitis, urticaria).The macrolides tacrolimus (FK506) and sirolimus (rapamycin) have end effects similar to those of cyclosporine. Brequinar sodium, mycophenolate mofetil and leflunomide are inhibitors of de novo synthesis of pyrimidines and purines, to which T cells are particularly sensitive. Such drugs may in theory be beneficial for therapy of patients with oral glucocorticoid-dependent asthma. Humanized anti-CD4, anti-IgE and anti-interleukin (IL)-5 monoclonal antibodies, and other cytokine inhibitors such as soluble IL-4 receptor have entered early trials.The worth of current immunomodulatory drugs is limited since: (i) not all patients respond, and response cannot be predicted a priori; (ii) the high incidence of unwanted effects makes it difficult to assess overall benefit/risk ratios; (iii) there is increased risk of opportunistic infection and (theoretically) neoplasia; (iv) there are many relative and absolute contraindications to therapy; and (v) there is lack of knowledge about the long-term effects, beneficial or otherwise, of therapy.     

Coeliac disease: more than villous atrophy

A continuing flow of new scientific developments concerning coeliac disease in the last decade asks for the formulation of a new concept of pathophysiology and clinical approach of the coeliac condition. Immunogenetic studies have shown a correlation of the disease to the HLA region on the short arm of chromosome 6. Immunological research has led to the concept of a T-cell driven immunologic response of the small intestine, with the identification of highly sensitive and specific antibodies, and in addition the understanding of the histopathology of coeliac disease has changed dramatically, initiated by the proposition of a spectrum of gluten sensitive enteropathy by Marsh in 1992. Clinical studies report a significant change in patient characteristics and epidemiology. The incidence of the disease has shifted to a majority of adult coeliacs and the disease may present with less severe symptoms of malabsorption while screening studies suggest an overall prevalence of up to 1 in 200-300. In the present paper (an update on histopathology) we specifically describe the work of our group in Arnhem, concerning the identification and validation of the spectrum of intestinal histopathology in gluten sensitive enteropathy, i.e. lymphocytic enteritis (Marsh I lesion), lymphocytic enteritis with crypthyperplasia (Marsh II lesion), and villous atrophy, subdivided in partial villous atrophy (Marsh IIIA), subtotal villous atrophy (Marsh IIIB) and total villous atrophy (Marsh IIIC). Special attention is given to a subgroup of "refractory coeliacs", including the identification of (pre-) malignant aberrant T-cells in the intestinal mucosa of these patients. The new data on immunogenetics, epidemiology, histo-pathology and patient characteristics point to a significant change of views on coeliac disease.