The pharmacokinetics and metabolism of mitoxantrone in man

Summary An HPLC method using paired-ion chromatography on RP C-18 material was developed. After sample clean up on XAD columns, mitoxantrone (Novantrone^®; dihydroxyanthracenedione) in concentrations below 1 ng/ml in serum and 0.2 ng/ml in urine were measurable with a coefficient of variation <9.3% at a wavelength of 658 nm. Four metabolites were separated in urine. The major metabolite cochromatographed with the synthesized dicarboxylic acid of mitoxantrone. Within 48 hours 4.4% of the administered dose was excreted in urine as mitoxantrone, 0.5% as metabolite 1 and 0.3% as metabolite 2.The pharmacokinetic parameters are adequately described by a three-compartment model with a terminal half-life of 214.8 hours, and a volume of distribution (ss) of 3792 litres. The total body clearance was 358 ml/min and the renal clearance was 26.2 ml/min.     

Calcium-enriched bread for treatment of uremic hyperphosphatemia.

OBJECTIVE: To assess phosphate-binding efficacy of a new food product, bread with unusually high calcium content (Ca-bread). DESIGN AND SETTING: A randomized parallel group trial in the university hospital outpatient dialysis unit. PATIENTS: Fifty-three randomly selected uremic patients who met the following inclusion criteria: (1) required maintenance hemodialysis treatment, (2) were not to receive vitamin D throughout the study, (3) were nondiabetic, and (4) were diagnosed with hyperphosphatemia. INTERVENTION: Fifty-three patients were randomized into 2 groups: control group (n = 26), which received calcium acetate as a phosphate binder throughout the study, and Ca-bread group (n = 27), which, after a 2-week washout period, received Ca-bread containing 2.5% of elemental calcium (by weight), which served as a phosphate binder. Bread was made using wheat flour, calcium carbonate, and fermented buttermilk. The amount of elemental calcium used as a phosphate binder was similar in both groups. Observation of both groups lasted 14 weeks. RESULTS: Mean serum phosphate concentration at randomization was 2.11 +/- 0.14 mmol/L in the control group and 2.20 +/- 0.13 mmol/L in the Ca-bread group. Mean serum calcium concentration at randomization was 2.12 +/- 0.21 mmol/L in the control group and 2.14 +/- 0.11 mmol/L in the Ca-bread group. The Ca-bread group patients' predialysis phosphate concentration decreased to a mean of 1.67 +/- 0.18 mmol/L (P <.05), and their mean calcium concentration increased to 2.27 +/- 0.11 mmol/L (P = NS). In the control group, neither value changed significantly from the original readings. After the hemodialysis session, the mean serum calcium concentration in the control group and the Ca-bread group increased by 7.5% and 7.9%, respectively (P = NS). Mean phosphate concentration simultaneously decreased to nearly 1/2 its original predialysis value in both groups. Ca-bread group patients saw a decrease in the mean phosphate concentration (from predialysis to postdialysis values) that was 13.8% greater than that of the control group (P = NS). CONCLUSION: A new form of calcium-containing phosphate binder was developed: Ca-bread with an elemental calcium content of 2.5%. Ca-bread allows for effective amelioration of hyperphosphatemia without inducing hypercalcemia. Furthermore, patient compliance may increase if hyperphosphatemia can be treated by consuming bread with an elevated calcium content.     

Cavernous hemangioma of the breast: mammographic and sonographic findings and follow-up in a patient receiving hormone-replacement therapy

We report the case of a 78-year-old woman who had been receiving hormone-replacement therapy (HRT) for 6 years and had a 4-month history of a painless nodule in the 9 o'clock position in her right breast. Mammography performed 4 years previously had shown a 4-mm bilobed, ovoid, well-defined nodule in that location; mammography performed 1 year previously had shown that the nodule had increased to 6 mm. We performed mammographic and sonographic examinations, which revealed a 10-mm ovoid nodule in the same 9 o'clock position in the right breast. The imaging findings appeared to indicate benignity, but because of the increasing size of the nodule, we undertook an ultrasound-guided large-core needle biopsy. The histopathologic diagnosis was typical cavernous hemangioma. It was not excised, but HRT was discontinued. Follow-up mammography and sonography 8 months later showed that the nodule had decreased to 6 mm. We believe that the HRT played a contributory role in the increasing size of this patient's cavernous hemangioma. The use of ultrasound-guided large-core needle biopsy is reliable enough to ascertain the benignity of such masses and can thus avoid, if it is clinically appropriate, the need for their surgical removal.     

SOD1 mutation is assosiated with accumulation of neurofilaments in amyotrophic lateral scelaries

Mutations in the Cu/Zn superoxide dismutase (SODl) gene are found in 15 to 20% of patients with familial amyotrophic lateral sclerosis (FALS). Increased levels of neurofilament subunits in transgenic mouse models of ALS also suggests a key role for these proteins in the pathogenesis of the disease. We report the coexistence of an Ile¹¹³ → Thr substitution in exon 4 of the SOD1 gene and marked neurofilamentous pathology in the same FALS patient. These observations suggest that two mechanisms, SOD 1-induced toxicity and neurofilament disruption, are acting together.     

Long-term outcome in patients registered with tuberculosis in Zomba, Malawi: mortality at 7 years according to initial HIV status and type of TB.

SETTING: Zomba Central Hospital, Malawi. OBJECTIVES: To determine the outcome of all adult patients who were registered for tuberculosis (TB) treatment 7 years previously according to initial human immunodeficiency virus (HIV) status and type of TB. DESIGN: A retrospective cohort study of adult patients registered for TB treatment between July and December 1995. Follow-up at patients' homes was performed at the end of treatment, at 32 months and at 84 months (7 years) from the time of TB registration. FINDINGS: Eight hundred and twenty-seven TB patients were registered: 793 had concordant HIV test results, of whom 612 (77%) were HIV-positive. At 7 years, 136 (17%) patients were alive, 539 (65%) had died and 152 (18%) were lost to follow-up. The death rate for all TB patients was 23.7 per 100 person-years of observation. HIV-positive patients had higher death rates than HIV-negative patients (hazard ratio [HR] 2.2, 95% confidence interval [95%CI] 1.7-2.8). Death rates in smear-negative pulmonary TB patients (HR 2.1, 95%CI 1.7-2.6) and in patients with extra-pulmonary TB (HR 1.7, 95% CI 1.3-2.0) were higher than in patients with smear-positive PTB. CONCLUSIONS: There was a high mortality rate in TB patients during and after anti-tuberculosis treatment. Adjunctive treatments to reduce death rates are urgently needed.     

Impact of disaster-related mortality on gross domestic product in the WHO African Region

BACKGROUND: Disaster-related mortality is a growing public health concern in the African Region. These deaths are hypothesized to have a significantly negative effect on per capita gross domestic product (GDP). The objective of this study was to estimate the loss in GDP attributable to natural and technological disaster-related mortality in the WHO African Region. METHODS: The impact of disaster-related mortality on GDP was estimated using double-log econometric model and cross-sectional data on various Member States in the WHO African Region. The analysis was based on 45 of the 46 countries in the Region. The data was obtained from various UNDP and World Bank publications. RESULTS: The coefficients for capital (K), educational enrolment (EN), life expectancy (LE) and exports (X) had a positive sign; while imports (M) and disaster mortality (DS) were found to impact negatively on GDP. The above-mentioned explanatory variables were found to have a statistically significant effect on GDP at 5% level in a t-distribution test. Disaster mortality of a single person was found to reduce GDP by US$0.01828. CONCLUSIONS: We have demonstrated that disaster-related mortality has a significant negative effect on GDP. Thus, as policy-makers strive to increase GDP through capital investment, export promotion and increased educational enrolment, they should always keep in mind that investments made in the strengthening of national capacity to mitigate the effects of national disasters expeditiously and effectively will yield significant economic returns.     

Panel 2.1: assessing impact and needs

This is a summary of the presentations and discussion of Panel 2.1 of the Conference, Health Aspects of the Tsunami Disaster in Asia, convened by the World Health Organization (WHO) in Phuket, Thailand, 04-06 May 2005. The topics discussed included issues related to assessing needs and measuring impact as pertaining to the responses to the damage created by the Tsunami. It is presented in the following major sections: (1) key questions; (2) assessing needs; (3) measuring impact; and (4) lessons learned and recommendations.     

In sympathetic but not sensory neurones, phosphoinositide-3 kinase is important for NGF-dependent survival and the retrograde transport of I-βNGF

The way in which the same ligands and receptors have different functional effects in different cell types must depend on subtle differences in the second messenger cascades. Sensory and sympathetic neurones both retrogradely transport nerve growth factor (NGF) and depend on NGF for their developmental survival. NGF binding to the high affinity tyrosine kinase (TrkA) receptors initiates second messenger signalling cascades, one of which includes the activation of phosphoinositide-3 kinase (P13-kinase). We demonstrate that 100-fold higher concentrations of the P13-kinase inhibitor. Wortmannin, are required to inhibit the survival effects and retrograde axonal transport of NGF in sensory neurones than in sympathetic neurones. Similarly, although less potently than Wortmannin, the P13-kinase inhibitor LY294002 required a 10-fold higher concentration to inhibit the survival effects of NGF in sensory than in sympathetic neurones. Inhibitors of other second messengers, including staurosporine, pertussis and cholera toxins, failed to have an effect on the transport of the NGF receptor complex in both cell types. Also, Wortmannin did not affect the structural integrity of the sympathetic nerve terminals. As P13-kinase is present in both neuronal populations, this suggests that the Wortmannin sensitive isoform of P13-kinase (p110) is essential in sympathetic neurones both for survival and for NGF-TrkA receptor complex trafficking. As sensory neurones also depend on NGF for their developmental survival and endocytose and retrogradely transport the NGF-TrkA receptor complex, this population of neurones may either recruit a different isoform of P13-kinase or utilize P13-kinase independent signalling pathways for these cellular functions.