Summary:Autologous haemopoietic stem cell transplantation (HSCT) represents a potential therapy for severe rheumatoid arthritis (RA). As a prelude to clinical trails, the safety and efficacy of haemopoietic stem cell (HSC) mobilisation required investigation as colony-stimulating factors (CSFs) have been reported to flare RA. A double-blind, randomised placebo-controlled dose escalation study was performed. Two cohorts of eight patients fulfilling strict eligibility criteria for severe active RA (age median 40 years, range 24-60 years; median disease duration 10.5 years, range 2-18 years) received filgrastim (r-Hu-methionyl granulocyte(G)-CSF) at 5 and 10 g/kg/day, randomised in a 5:3 ratio with placebo. Patients were unblinded on the fifth day of treatment and those randomised to filgrastim underwent cell harvesting (leukapheresis) daily until 2 ؋ 10 6 /kg CD34 ؉ cells (haemopoietic stem and progenitor cells) were obtained. Patients were assessed by clinical and laboratory parameters before, during and after filgrastim administration. RA flare was defined as an increase of 30% or more in two of the following parameters: tender joint count, swollen joint count or pain score. Efficacy was assessed by quantitation of CD34 ؉ cells and CFU-GM. One patient in the 5 g/kg/day group and two patients in the 10 g/kg/day group fulfilled criteria for RA flare, although this did not preclude successful stem cell collection. Median changes in swollen and tender joint counts were not supportive of filgrastim consistently causing exacerbation of disease, but administration of filgrastim at 10 g/kg/day was associated with rises in median C-reactive protein and median rheumatoid factor compared with placebo. Other adverse events were well recognised for filgrastim and included bone pain (80%) and increases in alkaline phosphatase (four-fold) and lactate dehydrogenase (two-fold). With respect to efficacy, filgrastim at 10 g/kg/day was more efficient with all patients (n = 5) achieving target CD34 ؉ cell counts with a single leuCorrespondence: Dr JA Snowden, Department of Haematology, Royal Hallamshire Hospital, Sheffield S10 2JF, UK Received 2 May 1998; accepted 21 July 1998 kapheresis (median = 2.8, range = 2.3-4.8 ؋ 10 6 /kg, median CFU-GM = 22.1, range = 4.2-102.9 ؋ 10 4 /kg), whereas 1-3 leukaphereses were necessary to achieve the target yield using 5 g/kg/day. We conclude that filgrastim may be administered to patients with severe active RA for effective stem cell mobilisation. Flare of RA occurs in a minority of patients and is more likely with 10 than 5 g/kg/day. However, on balance, 10 g/kg/day remains the dose of choice in view of more efficient CD34 ؉ cell mobilisation.
SUMMARY The lactulose/breath hydrogen and the sulphasalazine/sulphapyridine methods of assessing orocaecal transit time have been compared. In a two part crossover study in healthy normal subjects the median orocaecal transit time by the SLZ/SP method was 4-84 hours but only 2.92 hours by the lactulose/breath hydrogen method. Coadministration of lactulose and sulphazalazine to nine subjects with assessment of orocaecal transit time by hydrogen breath determination and plasma sulphapyridine assay gave orocaecal transit times of 2.33 and 2.25 hours respectively suggesting that the lactulose reduces transit time and that the lactuloselbreath hydrogen method, which is so convenient to use, gives artificially low transit times. A third experiment was undertaken to compare the orocaecal transit times after 1-5 and 3.0 g sulphazalazine. The orocaecal transit times after the two doses were not statistically different.Traditional methods of investigating upper gastrointestinal transit include radiology, isotopically labelled test meals, and intubation. Intubation has been shown to inhibit gastric emptying and to speed up small bowel transit' and the use of radioopaque materials necessarily dictates meal composition. Isotopically labelled meals are of particular value but the associated radiation may present ethical problems. The presence of flora in the large bowel provides an alternative approach whereby use is made of bacterial metabolism. Thus conversion of lactulose (galactosido-fructose) by large bowel flora to short chain fatty acids together with small quantities of hydrogen gas provides such a method: the hydrogen gas by virtue if its low molecular weight and relative insolubility in water is rapidly absorbed into the blood, transported to the lungs, and exhaled in the breath.23 An alternative method originally described by Kennedy et al' uses the azoreductase producing flora of the large bowel to split the azo link releasing 5-aminosalicylic acid and sulphapyridine from the orally administered sulphasalazine. The sulphapyridine is absorbed into the blood stream and
A new fibrinolytic agent, BRL 26921, a member of the novel class of thrombolytic agents; the acyl enzymes, has been compared with streptokinase. It has been shown that this new agent, which can bind to fibrin before releasing activator, does not result in clinically significant destruction of the haemostatic system when compared to an equivalent dose of streptokinase.
SUMMARY The variability in the orocaecal transit time as measured by the lactulose/breath hydrogen method has been studied for three conditions: lactulose given with a meal, subjects sitting; lactulose given with a meal, subjects semirecumbent; lactulose given in aqueous solution, subjects semirecumbent. Thirty three healthy subjects attended on up to 12 occasions. It was found that administration of the lactulose with a meal significantly reduced the variability (p<005) and that adoption of the semirecumbeut position further reduced variability. A power analysis was used to predict the number of subjects who would be required to show a given percentage change in orocaecal transit time at specified probabilities and powers. A graph and a table for use in the prediction of subject numbers at a probability of 5% and for powers of 50-99% is presented. A dose response curve for metoclopramide using the lactulose/breath hydrogen method is given for doses of 10, 15, and 20 mg.Small bowel transit time may be assessed radiologically, by radioisotope labelling of test meals and by use of intubation techniques, although these methodologies may themselves alter transit times and radiation exposure may present ethical problems. The presence of bacterial flora in the large bowel provides a range of possible alternative approaches. Thus the conversion of sulphasalazine to sulphapyridine by bacterial azoreductase with assay of this metabolite in blood,' the production of hydrogen from the raffinose and stachyose content of a baked bean meal or the hydrogen obtained from sorbitol2 or lactulose (galactosido-fructose) have all been described.The lactulose breath hydrogen (L/BH) test described by Bond and Levitt3'4 is now in widespread use, but only limited application of the method to assess drug activity has been made.5 The orocaecal transit time (OCTT), assessed by the L/BH method, is widely believed to be very variable and so before using this technique as a pharmacological tool, this
The comparative actions of two benzamides; the one metoclopramide, having and the other, BRL 20627, lacking dopamine receptor antagonist properties have been investigated on orocaecal transit time (OCTT) using the lactulose/breath hydrogen method. In addition, the action of codeine, propantheline and domperidone on OCTT has been assessed. Similar quantitative reductions in apparent OCTT were found with metoclopramide and BRL 20627 thus, metoclopramide 20 mg orally and 10 mg i.v. brought about 32.5% and 42% reductions in OCTT. Similar reductions were also found using 20 mg BRL 20627 orally and 10 mg i.v. (31 and 26% respectively). In addition 20 mg domperidone orally was found to cause a 10% reduction. Codeine orally and propantheline i.m. brought about increases in the assessed transit time.
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