Regional pharmacokinetics of amifostine in anesthetized dogs: role of the liver, gastrointestinal tract, lungs, and kidneys.

Amifostine is a prodrug in which selectivity is largely determined by the preferential formation and uptake of its cytoprotective metabolite, WR-1065, in normal tissues as a result of differences in membrane-bound alkaline phosphatase activity. In this study, we characterized the sites and extent of organ-specific activation by the liver, gastrointestinal tract, lungs, and kidneys after systemic administrations of amifostine. A total of 10 dogs were infused via the cephalic vein using sequential dose rates of drug at 0.125, 0.500, and 1.00 micro mol/min/kg. Infusion of each dose rate lasted 2 h, at which time steady-state plasma concentrations were obtained (i.e., portal vein, carotid artery, hepatic vein, pulmonary artery, and renal vein). The hepatic arterial, portal venous, and renal arterial blood flows, and cardiac output, were measured. The hepatic and splanchnic extraction of amifostine remained high at 90%, whereas gastrointestinal extraction decreased from 43 to 12 to 15% with increasing dose. Pulmonary extraction of amifostine was low at 7%, whereas renal extraction was intermediate at 57%. Because blood flow measurements were relatively constant during the drug infusions, clearance parameters paralleled that of organ extraction. As a result, saturability was observed in the gastrointestinal blood clearance (i.e., from 9.8 to 2.8-3.3 ml/min/kg) and total body plasma clearance of amifostine (i.e., from 52.6 to about 37.3 ml/min/kg), as the doses increased. Due to the drug's high activation in liver, these findings suggest that amifostine may offer good protection of this organ against the toxicities of chemotherapy and radiation.     

Stereoselective urinary excretion of formoterol and its glucuronide conjugate in human

AIMS: Formoterol is an inhaled beta2-adrenoceptor agonist used as a racemic mixture of the active (R; R)- and inactive (S; S)-enantiomers (rac-formoterol). Glucuronidation is an important route of metabolism in humans which occurs faster for (S; S)-formoterol in human liver microsomes. The aim of this study was to investigate the stereoselectivity of urinary excretion of formoterol and its glucuronide conjugate after oral dosing with rac-formoterol. METHODS: Seven nonsmoking volunteers (six males, one female) were included in the study. After an overnight fast, a single 60 micro g oral dose of rac-formoterol fumarate dihydrate was ingested. Urine samples were collected at 1 h intervals for the first 4 h, and at 6, 8, 12 and 24 h after dosing. Formoterol enantiomers were analysed by chiral h.p.l.c. assay and formoterol glucuronides were determined as formoterol enantiomers after enzymatic cleavage with beta-glucuronidase. RESULTS: The female subject displayed a different pattern of metabolism and statistical analysis was therefore limited to data for the six males. The median (range) of the total urinary excretion of formoterol was 37.8% (20.9-51.2%) of the dose. The medians (ranges) of the amounts of (R; R)- and (S; S)-formoterol and of (R; R)- and (S; S)-formoterol glucuronide excreted were 2.1 (1.0-2.9), 3.5 (2.6-3.8), 21.0 (13.1-31.0) and 10.3 (4.2-14.6)%, respectively, of the dose. Unchanged (S; S)-formoterol excretion was significantly greater than that of unchanged (R; R)-formoterol and (R; R)-formoterol glucuronide excretion was significantly greater than that of (S; S)-formoterol glucuronide. The total RR-formoterol (unchanged drug plus glucuronide) excreted was significantly greater than the total (S; S)-formoterol. CONCLUSIONS: Our study demonstrates that the urinary excretion of formoterol in male humans after oral administration of rac-formoterol is stereoselective with preferential excretion of the active (R; R)-formoterol as unchanged drug and glucuronide. The different pattern of metabolism in the female subject provides impetus for further studies of the effect of gender on the stereoselective metabolism and pharmacokinetics of formoterol.     

An unusual case of intrapulmonary granulocytic sarcoma presenting as interstitial pneumonitis following allogeneic bone marrow transplantation for acute myeloid leukaemia and responding to donor lymphocyte infusion.

We report a 45-year-old female with AML who underwent a T cell-depleted sibling allograft and relapsed a year later with extramedullary disease involving the lung parenchyma and presenting with the clinical and radiological features of interstitial pneumonitis. The patient was treated with donor lymphocyte infusion (DLI) resulting in complete resolution of the radiological signs. The unusual presentation and the management options are discussed.     

Periconceptional nutrient intake and risk for neural tube defect-affected pregnancies.

We investigated whether intakes of nutrients, including folate, by women in the periconceptional period were associated with risks of neural tube defect (NTD)-affected pregnancies. Data were part of a case-control study of fetuses and infants with NTDs among 1989-1991 California births. We conducted interviews with mothers of 409 NTD cases and 420 nonmal-formed controls. Nutrient intake for the 3 months before conception was derived from food frequency questionnaires and from questions to mothers about vitamin/mineral supplement use. We computed NTD risk for each nutrient controlling for the influence of all other studied nutrients and for maternal education, race/ethnicity, height, and prepregnancy weight. Most single nutrients reduced NTD risks when intakes were considered in quartiles and unadjusted for other nutrients. Some of the same nutrients, however, did not provide similar interpretations when we adjusted for other nutrients. Adjusted analyses revealed decreased NTD risks with increased intakes of methionine, lutein, magnesium, zinc, and thiamin for women who did not use vitamin supplements periconceptionally. We observed decreased NTD risks associated with increased intakes of linoleic acid, cysteine, calcium, and zinc for women who used supplements. We also observed increased NTD risks with increased intakes of oleic acid. For users as well as nonusers of vitamin supplements, we observed reduced risks with increased intakes of grains and dairy products. Chance was a likely alternative explanation for many of the observed risk patterns.     

A fatal poisoning from Nicotiana glauca

A young adult male was found dead in a field. No cause of death was apparent at autopsy, and the only positive toxicological finding was the presence of a nicotine-like alkaloid isolated from the liver. Anabasine, the major, highly toxic alkaloid of the shrub, Nicotiana glauca (tree tobacco) was subsequently identified in all body specimens examined using gas chromatography/mass spectrometry. Concentrations of anabasine in blood, urine and other body organs are reported.     

The effectiveness of differing dental health education programmes in improving the oral health of adults with mental handicaps attending Birmingham adult training centres.

There are few published data available relating to dental health in adults with handicaps, or to the effectiveness of dental health education in this group. The present study involved 382 people attending four different adult training centres in Birmingham, UK. Following baseline examinations all participants were given oral hygiene instruction and a scale and polish. Each of the centres was then randomly allocated to one of the four treatment regimens. No specific treatment was provided for the control group; daily supervised toothbrushing was carried out by the participants in the other three groups, with the addition of a three-monthly scale and polish and reinforcement of oral hygiene instruction in group 3 and one-monthly input in group 4. The participants were re-examined after three months and then at six-monthly intervals until 24 months after the baseline examination. The results showed that those people left to their own devices to carry out toothbrushing at home following instruction were not achieving an acceptable standard. Those who were reminded, encouraged and motivated by the adult training centre staff were obviously capable of better standards of oral care. The input of an experienced dental hygienist on a regular basis improved the periodontal condition considerably. Although there were significant differences between the groups throughout the study, particularly in the presence of calculus, the differences between the one-monthly and three-monthly hygienist input were not clinically very apparent after two years, and therefore a one-monthly input would be difficult to justify on a cost benefit basis.     

Superoxide dismutase in the erythrocytes of acute alcoholics during detoxification

The activity of erythrocyte superoxide dismutase in acute alcoholic patients on admission does not form a single population but clusters in two groups either above or below the normal range. The values in both groups revert towards the normal after a week of treatment. The divergent activities of this free radical scavenging enzyme between the two groups could not be explained by differences in age, haematology or liver function tests but are likely to be acute responses, possibly to diverse drinking patterns in the period immediately preceding admission.     

SPLENECTOMY FOR IMMUNE THROMBOCYTOPENIC PURPURA: AUCKLAND EXPERIENCE 1979–87

Of 148 elective splenectomies performed in auckland during 1979-s7, 48 were performed as therapy for immune thrombocytopenic purpura (itp). In all cases medical therapy had either failed to maintain their platelet count (36 patients), or side-effects of medical treatment had made continuation unacceptable (12 patients). The mean age of the group was 31 years and there were 15 males and 33 females. Thirty-four of 48 patients (71%) had a favourable response to splenectomy: platelet count was maintained above 150 × 10⁹/1 and medical therapy was no longer required. There was no operative or inhospital mortality. Seven patienls experienced postoperative complications (mainly infections) of which none were life-threatening. There was no difference in response between males and females (67% and 73% response rate, respectively), and the response rates of europeans and non-europeans were similar (71% and 69%, respectively). By contrast, the average age of the responders ((29 years) was almost 10 years younger than the non-responders (38 years). It is concluded that the use of splenectomy as therapy for patienls with itp. Who have either failed to respond to medical management or for various reasons cannot tolerate the complications associated with steroid therapy, is a safe procedure which in the present series was associated with no operative mortality and an acceptably low rale of morbidity. Younger itp patients (< 30 years) have a better chance of responding favourably to splenectomy than do older patienls (> 40 years).