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J P Donnelly

Publications and source records attributed to J P Donnelly.

At least 19 recordsLinked to original sources
PubMed2007

Determining mucosal barrier injury to the oesophagus using CT scan.

INTRODUCTION: Oral mucositis is recognised as one of the most debilitating complications of high-dose cytostatic chemotherapy used to prepare for haematopoietic stem cell transplantation (HSCT), but very little is known about oesophageal mucositis, as endoscopy is not routinely performed. MATERIALS AND METHODS: We incorporate the computed tomography (CT) scan in the diagnostic workup of fever during neutropenia to detect evidence of pulmonary complications. This allowed us to evaluate whether mucosal barrier injury to the oesophagus can be determined. We selected 46 patients without oesophageal cancer or immune suppression (controls), who had a normal oesophagus, and measured the mucosal thickness at the upper part (UP), middle part (MP) and lower part (LP) of the oesophagus. Next, we selected 30 patients having a CT scan done for diagnostic purposes within 14 days after HSCT and measured mucosal thickness at the same levels. We also scored oral mucositis and gut toxicity. RESULTS: The mucosal thickness of the UP, MP and LP, respectively, for the controls (mean +/- SD) was 4.1 mm (+/-1.1), 4.2 mm (+/-1.2) and 4.8 mm (+/-1.3), and the corresponding values for the subjects were 5.9 mm (+/-2.2), 5.9 mm (+/-2.0) and 7.7 mm (+/-3.0). Analysis of variance showed statistically significant differences between subjects and controls at all oesophageal levels. All patients suffered from severe oral mucositis at the time. CONCLUSION: Hence, mucosal barrier injury to the oesophagus can be objectively measured using CT scan.

Adolescent↗
PubMed2006

Pharmacokinetics of itraconazole and hydroxyitraconazole in healthy subjects after single and multiple doses of a novel formulation.

Originally, itraconazole for parenteral administration was licensed in a 40% hydroxypropyl-beta-cyclodextrin (HPBCD) solution for intravenous administration. A novel formulation, the NanoCrystal formulation (NCF), was prepared. NCF consists of drug particles of approximately 200 to 300 nm. The pharmacokinetics of itraconazole and its hydroxy metabolite in healthy subjects were evaluated after single and multiple doses of itraconazole as NCF. In the single-ascending-dose (SAD) study, itraconazole doses were planned to range from 50 to 500 mg, while in the multiple-ascending-dose (MAD) study, itraconazole doses of 100, 200, and 300 mg as NCF were studied, as was one dose level (200 mg) as an HBPCD solution. Samples were collected in heparinized tubes at various time points and were analyzed by high-performance liquid chromatography to allow full pharmacokinetic analysis both after the first dose and on day 7. The results of both the SAD and the MAD studies indicated that there was a dose dependency in the half-life of itraconazole from the novel formulation, increasing from 44 h (100 mg) to more than 150 h (300 mg) once steady state was achieved. Similar dose-dependent effects were observed for the hydroxy metabolite. The areas under the concentration-time curves for itraconazole and hydroxyitraconazole were also dose dependent. The pharmacokinetic profiles after 200-mg doses of itraconazole as NCF and HPBCD formulations were comparable with respect to the terminal half-life, both after a single dose and at steady state. NCF may provide an alternative to the HPBCD solution for the further optimization of antifungal treatment with itraconazole.

Adult↗
PubMed2006

Primary hepatic invasive aspergillosis with progression after rituximab therapy for a post transplantation lymphoproliferative disorder.

We present a case of primary hepatic and possible splenic invasive aspergillosis (IA), which progressed under anti-CD20 B cell treatment for posttransplantation lymphoproliferative disease following allogeneic stem cell transplantation, to highlight the clinical value of a positive galactomannan-antigen test, an intestinal portal of entry of Aspergillus, and the detrimental effect of B lymphocyte depletion in IA.

Antibodies, Monoclonal↗
PubMed2006

Cyclosporine short infusion and C2 monitoring in haematopoietic stem cell transplant recipients.

Blood concentrations of cyclosporine A (CsA) >or=800 microg/l measured 2 h post-dosing, the C2 concentration, is necessary to obtain a maximal pharmacological effect and correlates well with transplant-related complications such as transplant rejection and toxicity. In an open crossover study CsA blood levels were measured during 24 h to generate a pharmacokinetic profile on days 1, 8 and 15 after starting CsA infusion in 21 haematopoietic allogeneic stem cell transplant recipients who were receiving intravenously CsA 3 mg/kg/day either by continuous infusion or by 2 h infusion given every 12 h. C2 levels after the 2 h infusion correlated better than C1 or C3 levels with the area under the concentration-time curve from 0 to 4 h (r2=0.62). C2 levels >or=800 microg/l were also achieved for 20 out of 24 (83%) of cases after the 2 h infusion of CsA without any increase of CsA-related toxicity but for only three of the 23 patients (13%) after continuous infusion. Therefore, we recommend CsA infusions in 2 h during transplant and perform C2 monitoring to obtain therapeutic C2 levels >or=800 microg/l.

Adult↗
PubMed2006

A scoring system for the assessment of oral mucositis in daily nursing practice.

Nurses take care of patients around the clock, so they are in an ideal position to observe and record the signs and symptoms of oral mucositis. This requires a valid, reliable scoring instrument that is easy to use. The objectives of this study were to summarize the scoring instruments that are available, to develop a new Nijmegen Nursing Mucositis Scoring System (NNMSS) and to evaluate this new instrument. A systematic review was undertaken in which 21 scoring instruments were reviewed and compared. None of the instruments studied satisfied the criteria that were established beforehand. The six most common items from the systematic review were selected for the new instrument. To test the NNMSS, pairs of experienced nurses assessed the oral cavity of 26 patients independently. Inter-observer reliability (Kappa), correlation between items (Spearman's rank-order correlations) and internal consistency of the instrument (Cronbach's alpha) were calculated. The usability was evaluated with a questionnaire. Cohen's weighted Kappa was within an acceptable range. Almost all correlations were statistically significant and in the predicted direction. The Cronbach's alpha coefficient indicated sufficient internal consistency. All nurses found the NNMSS user-friendly and suitable for day-to-day care. The NNMSS can be used as a valid, reliable and usable instrument in daily nursing practice.

Humans↗
PubMed2005

A randomised, double-blinded, placebo-controlled, pilot study of parenteral glutamine for allogeneic stem cell transplant patients.

We conducted a prospective, randomised, double-blinded, placebo-controlled pilot study of parenteral nutrition (PN) supplemented with 0.57 g/kg glutamine-dipeptide in a homogeneous group of 32 allogeneic stem cell transplant (SCT) recipients to determine its effect on mucosal barrier injury (MBI). All patients had been prepared with idarubicin, cyclophosphamide and total body irradiation. PN (by continuous infusion) started on SCT day -6 for a median of 19 days. MBI measured by sugar permeability tests, daily mucositis score, daily gut score, and citrulline concentrations was not reduced by glutamine-dipeptide. However, the daily gut score was significantly lower for the glutamine group on SCT +7 (p = 0.001) whilst citrulline was lower (p = 0.03) for the placebo group on SCT day +21. Albumin was significantly lower in the placebo group on SCT day +21 (32+/-4 versus 37+/-3, p = 0.001) whilst CRP was higher (74+/-48 versus 34+/-38, p = 0.003). Other transplant-related complications (infections, acute graft-versus-host disease) were less common although this did not reach statistical significance nor translate into a reduced length of hospital stay or lower mortality. These results indicate that it would be worthwhile conducting a larger trial to see whether or not giving glutamine-dipeptide reduces the 100-day allogeneic transplant-related complications.

Adolescent↗
PubMed2005

[Improved diagnostics in invasive aspergillosis and systematic monitoring in patients at high risk of infection].

Invasive aspergillosis remains an important cause of morbidity and mortality in patients with prolonged and severe immune suppression such as following haematopoietic stem-cell transplantation. Consensus definitions, which allow categorisation of patients based on diagnostic criteria, are an important improvement in uniform registration of invasive mycoses in clinical trials. Prospective monitoring of high-risk patients for the circulating aspergillus cell-wall component galactomannan, results in earlier diagnosis in two-thirds of patients when compared with conventional diagnostic methods. High-resolution CT (HRCT) enables the lesions characteristic of invasive mycoses to be detected earlier and better than by chest radiograph. In addition, invasive mycoses cause characteristic lesions on the HRCT scan including the halo-sign and the air-crescent sign. The pre-emptive management strategy which combines monitoring of patients for surrogate markers with a HRCT scan appears to be a promising approach to the early identification and treatment of patients with invasive aspergillosis.

Aspergillosis↗
PubMed2005

Prospective evaluation of gut mucosal barrier injury following various myeloablative regimens for haematopoietic stem cell transplant.

We determined gut mucosal barrier injury (MBI) among 129 recipients of an allogeneic or autologous haematopoietic stem cell transplant (HSCT) who had been given different myeloablative regimens by measuring integrity using the lactulose/rhamnose (RHA) ratio and absorption using the ratios of rhamnose/3-O-methylglucose and xylose/3-O-methylglucose. Regimens that did not contain idarubicin induced oral mucositis and disturbed gut integrity and absorption earlier than did those containing the anthracycline. By contrast, regimens containing idarubicin induced more severe and prolonged oral and gut MBI. Gut integrity and absorption of most patients were still abnormal at discharge from hospital. These results confirm that the integrity and absorptive capacity of the gut is affected adversely by myeloablative regimens in general, although only two patterns of mucosal injury emerged depending on whether or not idarubicin was used.

Adult↗
PubMed2005

Inflammatory response to mucosal barrier injury after myeloablative therapy in allogeneic stem cell transplant recipients.

We noted a significant increase of interleukin-8 (IL-8), LBP and CRP mirroring the pattern of mucosal barrier injury as measured by gut integrity (lactulose/rhamnose ratio), daily mucositis score (DMS) and serum citrulline concentrations of 32 haematopoietic stem cell transplant (HSCT) recipients following intensive myeloablative therapy. Concentrations of IL-8, LBP and CRP were already significantly elevated before the onset of fever or bacteraemia due to oral viridans streptococci (OVS) in the first week after transplant during profound neutropenia. These markers reached their peak when citrulline concentrations reached their nadir, the highest scores of DMS were attained and when there was significantly decreased gut integrity. This suggests that the degree of mucosal barrier injury rather than bacteraemia due to OVS determines the intensity of the inflammatory response.

Adult↗
PubMed2005

A multi-perspective concept mapping study of problems associated with traumatic brain injury.

OBJECTIVE: To develop a model of the problems of persons with traumatic brain injury that includes multiple perspectives as well as the multi-dimensional nature of the phenomena. DESIGN: Concept mapping, a multi-variate modelling strategy, was employed to produce an exhaustive inventory and concept map of TBI-related problems based on input from patients, family caregivers and professional providers. RESULTS: The eight-cluster concept map included the following dimensions: social competence, intimacy, behavioural, maturity/independence, neurophysiological, mood, executive functions and non-executive functions. CONCLUSIONS: An underlying two-dimensional conceptual model of TBI problems is proposed with relevance for theory, practice and further research.

Adult↗
PubMed2004

Measuring mucosal damage induced by cytotoxic therapy.

We scored oral mucositis and gut toxicity and measured sugar permeability testing among 56 recipients of a haematopoietic stem cell transplant (HSCT) given myeloablative conditioning with idarubicin, cyclophosphamide and TBI, and a group of 18 patients given cytotoxic chemotherapy for newly diagnosed acute myeloid leukaemia (AML) or myelodysplastic syndrome (MDS). Gut integrity was already disturbed in the AML/MDS group as measured by the lactulose/rhamnose ratio (L/R ratio=0.09) before therapy and was severely perturbed (L/R ratio >0.13) for a month after HSCT. Oral mucositis and to a lesser extent gut toxicity was only significantly correlated with disturbed permeability in the transplant group. The data suggest that sugar permeability, oral mucositis and gut toxicity measure different features of mucosal damage after intensive cytotoxic therapy.

3-O-Methylglucose↗
PubMed2004

Citrulline: a potentially simple quantitative marker of intestinal epithelial damage following myeloablative therapy.

We noted a significant decline in the serum concentrations of citrulline of 32 haematopoietic stem cell transplant recipients following intensive myeloablative therapy during the first 3 weeks after transplantation when patients have oral mucositis, a markedly disturbed gut integrity (L/R ratio) and are most at risk of infection and other severe complications. Closer inspection of the citrulline concentrations of 12 patients confirmed that the decline did indeed correspond to the onset of oral mucositis and altered gut integrity. Since serum citrulline is a reliable biochemical marker of small bowel enterocyte mass in humans with villous-atrophy-associated diseases, it may prove a useful marker for intestinal mucosal damage induced by chemotherapy, allowing the relationship between gut mucosal damage and post-transplant complications including infections to be explored more readily.

Adult↗
PubMed2004

Role of curcumin and the inhibition of NF-kappaB in the onset of chemotherapy-induced mucosal barrier injury.

The inhibition of nuclear factor kappa B (NF-kappaB) by, for instance, curcumin is becoming an important new approach in combination with chemotherapy or irradiation for the treatment of a variety of cancers including haematological malignancies. A dose-limiting side effect of anticancer therapy in the gastrointestinal tract is mucosal barrier injury. It is hypothesised that mucosal barrier injury is initiated and amplified by proinflammatory-and NF-kappaB-regulated mediators. Therefore, the effect of NF-kappaB inhibition was studied in the onset of mucosal barrier injury. In response to cytostatic drug treatment (arabinoside cytosine (Ara-C) and methotrexate (MTX)), NF-kappaB was activated in intestinal epithelial cells (IEC-6) resulting in an NF-kappaB-related induction of tumour necrosis factor alpha and monocyte chemoattractant protein-1. NF-kappaB inhibition increased the susceptibility of IEC-6 cells to Ara-C as well as MTX-induced cell death when obtained by the addition of caffeic acid phenethyl ester (CAPE), but not using curcumin. In an animal model for MTX-induced mucosal barrier injury, the induction of NF-kappaB-related cytokines and chemokines was detected upon treatment with MTX. Despite increased susceptibility shown in vitro, the inhibition of NF-kappaB resulted in a partial amelioration of villous atrophy normally seen in the small intestine upon MTX treatment. These results show that the inhibition of NF-kappaB does not increase intestinal side effects of the anticancer treatment, suggesting a safe use of curcumin and CAPE in combination with anticancer treatment.

Animals↗
PubMed2004

The role of itraconazole in preventing and treating systemic fungal infections in immunocompromised patients.

The increasing use of immunosuppressive chemotherapy and allogeneic transplants for haematological malignancies has increased the number of patients at risk of systemic fungal infections (SFIs). A number of antifungal agents are now available. This paper reports the deliberations of an expert panel that considered the role of itraconazole. It concluded that itraconazole has an important role in the prophylaxis and treatment of SFIs whether proven or not.

Drug Interactions↗
PubMed2003

Duration of antifungal treatment and development of delayed complications in patients with candidaemia.

The optimal duration of antifungal treatment of candidaemia is unknown. Prolonged treatment has been advocated to prevent late-onset complications caused by metastatic infectious foci. To evaluate the relationship between duration of antifungal therapy and the development of delayed complications in patients with candidaemia, a retrospective descriptive study was performed in a tertiary care centre. The study included 180 consecutive patients with candidaemia identified by at least one positive blood culture. Development of late-onset complications of candidaemia during long-term follow-up was monitored. Of the patients treated with antifungal agents, 55% completed treatment without apparent complications, 33% died during therapy, 12% developed disseminated disease and one patient continues to receive ongoing treatment. Of the 81 patients who completed treatment as scheduled, 25% received treatment for less than 2 weeks, 31% for 2-4 weeks and 38% for more than 4 weeks; duration of therapy was unknown in 6%. Only three (2%) patients developed delayed complications; in these patients, the duration of antifungal treatment had been 3 weeks, 5 weeks and 22 weeks, respectively. In conclusion, despite theoretical concerns, there seems to be no correlation between the duration of antifungal treatment and the development of late complications in patients with candidaemia. This suggests that treatment of 2 weeks or less may be sufficient, provided the initial response to therapy is favourable.

Adult↗