High levels of morphine-6-glucuronide in street heroin addicts

Rationale In the body, heroin is rapidly transformed to 6-acetylmorphine (6-AM) and then to morphine, that in turn is mainly metabolized to morphine-3-glucuronide (M3G) and, at lesser extent, to morphine-6-glucuronide (M6G). Unlike M3G, M6G is a potent opioid agonist. Intravenous heroin abusers (IHU) are exposed to a wide array of drugs and contaminants that might affect glucuronidation. Objectives We assessed plasma and urine concentrations of M3G and M6G in four groups of subjects: the first two included long-term IHU either exposed to street heroin (n=8) or receiving a single IV injection of morphine (n=4), while the other two groups included non-IHU patients receiving acute IV (n=8) or chronic oral (n=6) administrations of morphine. Methods After solid phase extraction plasma and urine concentrations of morphine metabolites were determined by HPLC analyses. Results M3G accounted for the greater part of morphine glucuronides detected in body fluids of non-IHU patients treated with morphine. This pattern of metabolism remained stable across 15 days of oral administration of incremental doses of morphine. In contrast, the two groups of IHU (street heroin taking or morphine-treated subjects) showed a reduction of blood and urine M3G concentrations in favor of M6G. Consequently, M6G/M3G ratio was significantly higher in the two IHU groups in comparison with the non-IHU groups. Conclusions Chronic exposure to street heroin causes a relative increase in concentrations of the active metabolite, M6G. Since the pattern of M6G action seems closer to heroin than to morphine, the increased synthesis of M6G observed in IHU may prolong the narrow window of heroin effects.     

Monitoring internal exposure to metals and organic substances in workers at a hazardous waste incinerator after 3 years of operation

The potential adverse effects of hazardous waste incinerators (HWI) continue to be a subject of worry. The construction of the first and up till now only HWI in Spain finished in 1999. Twenty-six subjects employed at this HWI were divided into three groups: plant, laboratory and administration. Plasma analyses of HCB, PCBs (28, 52, 101, 138, 153 and 180), and PCDD/Fs, as well as urinary analyses of 2,4- and 2,5-dichlorophenol (DCPs), 2,4,5- and 2,4,6-trichlorophenol (TCPs), pentachlorophenol (PCP), and 1-hydroxypyrene (1-HP) were carried out. Blood concentrations of Be, Mn, Hg and Pb, and urinary levels of Cd, Cr, Ni and V were also determined. In plant workers, the current levels of organic substances and metals in blood and urine did not show any increase for any of the compounds analysed (excepting urinary V). By contrast, plasma levels of PCDD/Fs and PCBs 28, 52, 101, 138 and 153 were significantly lower than the respective baseline concentrations. The current chlorophenol concentrations in urine were similar or lower than the baseline levels, with the exception of 2,5-DCP that showed a significant increase. The concentrations of organic and inorganic substances found in this study do not differ from those corresponding to non-occupationally exposed subjects.     

Results of a phase II multicenter trial of pentostatin and rituximab in patients with low grade B-cell non-Hodgkin's lymphoma: an effective and minimally toxic regimen

This study explored the efficacy and toxicity of the combination of pentostatin and rituximab, effective single agents in low-grade non-Hodgkin's lymphoma (NHL). Sixty patients with previously treated low-grade NHL were enrolled. Except for day 1, both drugs were administered weekly for 4 weeks, with week 5 off. During week 1 (day 1) only rituximab was given; subsequent weekly treatments included both drugs. Patients received a minimum of 2 five-week cycles in order to be evaluable for efficacy. Responses were evaluated on week 5 of cycle 2. If partial response (PR) or stable disease (SD) responses were noted, 2 additional cycles were administered. Final evaluations were done on week 5 of cycle 4. Of 60 patients, 58.3% had an Eastern Cooperative Oncology Group performance status (PS) of 0, and 41.7% had PS of 1; 31.7% and 51.7% had stage III or stage IV disease, respectively. Histology included follicular center, follicular, grade I (45%), II (21.7%), III (1.7%), and small lymphocytic (31.7%). Seventeen patients had prior chemotherapy, but no patients had received prior pentostatin or rituximab. Median age was 60.3 years (range, 32.5-84.7 years). Among 57 evaluable patients, 77% responded (22.3% complete response [CR], 3.5% unconfirmed CR, 35.1% PR, and 10.5% unconfirmed PR); 19.3% had SD, and 8.8% progressive disease (PD). Response rate among previously untreated patients was 83% versus 63% in previously treated patients. Median duration of response was 11 months (range, 2.3-22.2 months); median time to progression was 15 months (range, < 1-25 months). Neutropenia was the only adverse event experienced by >/= 10% of patients. Six deaths were caused by PD, and one death each was caused by acute respiratory distress, possibly related respiratory failure, and cardiac toxicity. These results suggest the combination of pentostatin/rituximab is well tolerated and active in low-grade lymphoma.     

Influence of menstrual cycle on NK activity

Natural killer (NK) cells are CD3⁻ CD56⁺ and/or CD16⁺ cytotoxic lymphocytes that mediate first-line defense against various types of target cells without prior immunization. To assess the effect of the menstrual cycle and gender on NK activity we evaluated 30 healthy women (mean age 28.1 years, range 21–39) in follicular and luteal phases, 29 postmenopausal women (mean age 58.8 years, range 42–72) and 48 healthy men (mean age 31.6 years, range 21–40). In a flow cytometric test of NK activity, peripheral blood mononuclear effector cells were mixed with K562 targets cells labeled with DiO (3,3′-dioctadecyloxacarbocyanine perchlorate) at effector:target cell ratios of 40, 20, 10 and 5:1. Dead cells were stained with propidium iodide and results were expressed as lytic units per 10⁷ cells. In addition, progesterone levels were determined in the luteal phase of the menstrual cycle of healthy women by a chemiluminescence assay. Our results showed that (1) NK cytotoxicity was higher in the follicular than in the luteal phase of the menstrual cycle (P<0.0001); (2) postmenopausal women and men showed NK activity similar to women in the folicular phase but higher than women in the luteal phase of the menstrual cycle (P<0.05); and (3) there was no correlation between NK activity and levels of progesterone. The data suggest that progesterone does not influence NK activity directly and that other factors may explain the reduction of NK activity in the luteal phase of the menstrual cycle.     

Epidemiology of inhibitors and current treatment strategies

The development of inhibitors is currently one of the most serious complications in the treatment of hemophilic children. Prospective studies of previously untreated patients (PUP) showed that up to 52% of patients with severe hemophilia A developed inhibitors during the first 50 exposure days (ED) (>100 for outliers). Inhibitor development is influenced by the type of hemophilia, the severity and the type of mutation. No significant differences in inhibitor incidence were found in prospective studies conducted with plasma-derived or recombinant products. However, no comparative study has been finished yet. A still ongoing prospective, multi-center PUP-study initiated by the German, Austrian and the Swiss Society of Thrombosis and Hemostasis Research (GTH) foresees the direct comparison of different types of concentrates with regard to inhibitor development. Preliminary results (update February 2002) show a slightly higher inhibitor development (p=0.08) in severely affected hemophilia A patients treated with recombinant factor (F) VIII concentrates. However, the groups are very small and statistically reliable statements cannot be made at the moment. In case of inhibitor development rapid inhibitor elimination and immune tolerance induction (ITI) is the preferred way to reduce the high risk of bleeding episodes. In this respect, various therapeutic regimens, such as the administration of high doses of FVIII twice daily (Bonn protocol), or lower doses three times weekly (van Creveld protocol), have been attempted. Elimination of inhibitors from plasma by immune adsorption followed by immune suppression (Malm? protocol) has also been used. The influence of the type of concentrate used for ITI has never been investigated comparatively. A longitudinal study of ITI at our center showed a significantly decreased success rate since the introduction of high purity plasma derived and recombinant FVIII products using the Bonn protocol. In inhibitor patients who showed an unsatisfactory response to treatment with FVIII concentrates with very little or no VWF the change to concentrates containing high amounts of von Willebrand factor (VWF) increased success rates up to 90%. These observations raise the question of whether VWF plays an important role in the induction of immune tolerance.