Malignant ascites (MA) is associated with poor prognosis and limited palliative therapeutic options. Therefore, quality of life (QoL) assessment is of particular importance to demonstrate new ...treatment value. Following the demonstration of the superiority of catumaxomab and paracentesis over paracentesis on puncture-free survival, this analysis aimed at comparing deterioration in QoL between both the treatment options.
In a randomised, multicentre, phase II/III study of patients with MA due to epithelial cell adhesion molecule (EpCAM) positive cancer, the QoL was evaluated using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 items (EORTC QLQ-C30) questionnaire at screening, 1, 3 and 7 months after treatment and in the case of re-puncture on the day of paracentesis. Time to first deterioration in QoL was defined as a decrease in the QoL score of at least five points and compared between the catumaxomab (n = 160) and control (n = 85) groups using the log-rank test and Cox proportional hazards models adjusted for baseline score, country and primary tumour type.
Deterioration in QoL scores appeared more rapidly in the control than in the catumaxomab group (median 19–26 days versus 47–49 days). The difference in time to deterioration in QoL between the groups was statistically significant for all scores (P < 0.01). The hazard ratios ranged from 0.08 to 0.24 (P < 0.01).
Treatment with catumaxomab delayed deterioration in QoL in patients with MA. Compared with paracentesis alone, catumaxomab enabled patients to benefit from better QoL for a prolonged survival period.
The small intestinal metabolism of tacrolimus, which is used as an immunosuppressant in transplantation medicine, was investigated in this study. Tacrolimus was metabolized in vitro by isolated ...human, pig, and rat small intestinal microsomes. The metabolites generated were identified by HPLC/MS. Tacrolimus and its metabolites were quantified using HPLC or HPLC/MS. The cytochrome P450 (CYP) enzymes responsible for tacrolimus metabolism in small intestine were identified using specific CYP antibodies and inhibitors. For characterization of the interindividual variability, microsomes were isolated from small intestinal samples of patients who had undergone resection for various reasons. In an in vitro model using pig small intestinal microsomes, 32 drugs were analyzed for their interactions with tacrolimus metabolism. After incubation with human, rat, and pig small intestinal microsomes, the metabolites 13-O-demethyl and 13,15-O-demethyl tacrolimus were identified. The metabolism of tacrolimus by human small intestine was inhibited by anti-CYP3A, troleandomycin, and erythromycin, indicating that, as in the liver, CYP3A enzymes are the major enzymes for tacrolimus metabolism in the human small intestine. Metabolism of tacrolimus by small intestinal microsomes isolated from 14 different patients varied between 24 and 110 pmol/13-O-demethyl tacrolimus/min/mg microsomal protein, with a mean +/- SD of 54.2 +/- 29.2 pmol/min/mg. Of 32 drugs tested, 15 were found to inhibit small intestinal tacrolimus metabolism: bromocryptine, corticosterone, cyclosporine, dexamethasone, ergotamine, erythromycin, ethinyl estradiol, josamycin, ketoconazole, nifedipine, omeprazole, progesterone, rapamycin, troleandomycin, and verapamil. All of these drugs inhibited tacrolimus metabolism by human liver microsomes as well. It is concluded that tacrolimus is metabolized by cytochrome CYP3A enzymes in the small intestine. The rate of the CYP3A enzymatic activities varies about 5 times from patient to patient, and drugs that interfere with the in vitro metabolism of tacrolimus in the liver also inhibit its small intestinal metabolism.
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The macrolide tacrolimus (FK506), used as an immunosuppressant, is a cytochrome P450 (CYP) 3A substrate in the liver. The metabolism of tacrolimus and the transport of its metabolites in the pig ...gut was studied in the Ussing chamber. Tacrolimus and its metabolites were quantified by h.p.l.c./mass spectrometry.
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In the Ussing chamber, demethyl, didemethyl, hydroxy and hydroxy‐demethyl tacrolimus were generated. Their formation was concentration‐ and time‐dependent. The metabolite pattern was not different from that after incubation of tacrolimus with human small intestinal microsomes.
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The metabolite formation was highest in the duodenum and declined in the order duodenum >
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Since tacrolimus metabolism was inhibited by the specific CYP3A inhibitors, troleandomycin and ketoconazole, we concluded that these enzymes are involved in intestinal metabolism of tacrolimus.
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Tacrolimus metabolites re‐entered the mucosa chamber (>90%) and passed through the small intestinal preparation into the serosa chamber.
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It is concluded that tacrolimus is metabolized in the intestine, that the metabolites are able to re‐enter the gut lumen and also enter into the portal vein and that small intestinal metabolism and transport is at least in part responsible for the low oral bioavailability of tacrolimus
Summary
The therapeutic management of the irritable bowel syndrome (IBS) is ineffective and not satisfying either patients or practitioners. Research in functions of the enteric nervous system and ...its interaction with the central nervous system is the basis for the development of emerging pharmaceuticals in therapy of the IBS. These pharmaceuticals include agents such as opioid agonists, psychotropic agents and particularly serotonin receptor modulators. These novel pharmaceuticals aim to provide a more comprehensive approach in the therapy of the IBS and will serve both patients and practitioners. So far, the US Food and Drug Administration has approved two agents specifically for the treatment of the IBS, both belonging to the group of serotonin receptor modulators. However, questions remain whether a single therapy is sufficient in the management of IBS because this disease is influenced by biological and psychological as well as cultural and social factors.
The metabolite patterns of tacrolimus in blood were evaluated in 41 kidney and liver graft recipients. Trough concentrations of tacrolimus and its metabolites were measured by HPLC-mass spectrometry ...and microparticle enzyme immunoassay in parallel. A statistically significant correlation between results of both assays was observed for kidney and liver transplant patients (r = 0.77, P <0.001 and r = 0.71, P <0.001, respectively). The main metabolites in blood were demethyl, demethylhydroxy, didemethyl, didemethylhydroxy, and hydroxy tacrolimus. These metabolites added up to 42% (range 0-145%) of the tacrolimus concentration in liver transplant patients and to 44.8% (range 16-152%) in kidney transplant patients. During episodes of impaired liver function, concentrations of tacrolimus and its metabolites were increased compared with normal liver function, indicating accumulation of metabolites, in particular second-generation metabolites such as didemethyl and didemethylhydroxy tacrolimus. Stepwise regression analysis including tacrolimus, its metabolites, and liver function parameters suggested a model including serum activities of gamma-glutamyltransferase, alkaline phosphatase, and alanine aminotransferase as predictors for increased concentrations of demethyl tacrolimus, didemethyl tacrolimus, and the parent drug.
1. Blood and urine concentrations of the macrolide immunosuppressant FK506 and its metabolites were measured in seven orthotopic liver transplant patients after the first oral dose of FK506 (0.04 +/‐ ...0.02 mg kg‐1) used as primary immunosuppressant. A specific h.p.l.c.‐MS assay was used, allowing the measurement of parent drug and eight metabolites. Results were compared with those obtained using a microparticle enzyme immunoassay (MEIA). 2. Blood drug concentrations were described by an open two compartment model with first‐order absorption giving the following mean data: tmax: 1.9 (h), Cmax: 17.4 (microgram l‐1), AUC: 328.1 (microgram l‐1 h), t1/2,1: 0.74 (h). The terminal elimination half‐life was estimated at about 26 h using the h.p.l.c.‐MS assay. 3. The metabolites found in blood were demethyl‐ FK506 and demethyl‐hydroxy‐FK506, while in urine FK506 and eight of its metabolites were detected.
In this study, a modified, specific assay for measurement of tacrolimus and its metabolites in blood and urine from transplant patients using high-performance liquid chromatography (HPLC) linked to ...mass spectrometry (MS) is described. Samples were prepared for HPLC-MS by modified solid-liquid extraction. The original two-step washing procedure was replaced by a single washing step, and samples were eluted with acetonitrile/water instead of dichloromethane, thus avoiding an evaporation step. Samples were injected automatically every 3 min into the HPLC-MS system. Time-consuming gradient elution was replaced by isocratic elution. This procedure resulted in a lower limit of quantitation of 0.2 microgram/L. The interassay variability was 14.5% for 5 micrograms/L and 15.8% for 25 micrograms/L. The intrassay variability was 11.2% for 5 micrograms/L and 4% for 25 micrograms/L. The recovery for tacrolimus in blood was 90.4% for 1 microgram/L, 78.9% for 10 micrograms/L, and 81.3% for 25 micrograms/L. Measurement of tacrolimus and its metabolites in samples from various transplant patients showed that the main metabolites found in blood and urine are demethyl-tacrolimus, di-demethyl-tacrolimus and demethyl-hydroxy-tacrolimus. Cross validation of the modified HPLC-MS assay with a microparticle enzyme immunoassay showed a significant correlation between the two assays, with r = 0.915.
Community-acquired pneumonia remains a major cause of mortality in developed countries. There is much discrepancy in the literature regarding factors influencing the outcome in the elderly ...population. Data were derived from a multicentre prospective study initiated by the German Competence Network for Community-Acquired Pneumonia. Patients with community-acquired pneumonia (n = 2,647; 1,298 aged < 65 yrs and 1,349 aged > or = 65 yrs) were evaluated, of whom 72.3% were hospitalised and 27.7% treated in the community. Clinical history, residence status, course of disease and antimicrobial treatment were prospectively documented. Microbiological investigations included cultures and PCR of respiratory samples and blood cultures. Factors related to mortality were included in multivariate analyses. The overall 30-day mortality was 6.3%. Elderly patients exhibited a significantly higher mortality rate that was independently associated with the following: age; residence status; confusion, urea, respiratory frequency and blood pressure (CURB) score; comorbid conditions; and failure of initial therapy. Increasing age remained predictive of death in the elderly. Nursing home residents showed a four-fold increased mortality rate and an increased rate of gram-negative bacillary infections compared with patients dwelling in the community. The CURB score and cerebrovascular disease were confirmed as independent predictors of death in this subgroup. Age and residence status are independent risk factors for mortality after controlling for comorbid conditions and disease severity. Failure of initial therapy was the only modifiable prognostic factor.
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