Hepatic arterial infusion of mitoxantrone in the treatment of primary hepatocellular carcinoma.

Twenty-three patients (16 male, seven female) with hepatocellular carcinoma (HCC) were treated by hepatic arterial infusion (HAI) of mitoxantrone every 4 weeks. At each treatment, a catheter was inserted percutaneously into the main hepatic artery via the femoral artery under image intensification. Treatment consisted of a 24-hour continuous HAI of mitoxantrone, 6 mg/m2/d X 3 (eight patients) or 10 mg/m2/d X 3 (14 patients) without heparin. Eight patients had only one infusion, nine patients four infusions, five patients three infusions, two patients two infusions, and one patient five infusions. A partial response was seen in six patients, with a median duration of 20 weeks (range, 18 to 38 weeks). Five patients achieved stable disease, with a median duration of 20 weeks (range, 11 to 42 weeks). The median survival of the overall group was 22 weeks. Survivals of responding, stable, and nonresponding patients were 32 weeks, 24 weeks, and 9 weeks, respectively. Complications of catheter placement included asymptomatic dissection of the hepatic artery (one patient), and asymptomatic thrombosis of the hepatic artery (five patients). Three patients experienced mild nausea and vomiting, and six patients had mild to moderate alopecia. Granulocytopenia was frequent at both dose schedules. The granulocyte nadir was greater than 1,000/microL in 34% of evaluable courses, 500 to 1,000/microL in 32%, and less than 500/microL in 34% of courses. Two patients developed neutropenia-associated fever. A platelet nadir below 100,000/microL was seen after only 10% of courses, and only two patients had platelets below 50,000/microL. Seven patients received doxorubicin after progression on mitoxantrone. Four received systemic doxorubicin, 50 mg/m2, and three HAI of doxorubicin, 25 mg/m2, for three days. Two patients achieved partial response (18 weeks and 32 weeks) to HAI doxorubicin. Mitoxantrone has activity in HCC and is well tolerated when administered by HAI. It is not entirely cross-resistant with doxorubicin.

Short report: severe hiccups secondary to doxycycline-induced esophagitis during treatment of malaria.

A 51-year-old man who was treated with quinine and doxycycline for Plasmodium falciparum malaria acquired in West Africa developed hiccups soon after his first dose of antimalarial therapy. Endoscopic examination performed when his hiccups became intractable showed an esophageal erosion and ulcer most likely due to doxycycline. The patient's symptoms resolved on treatment with omeprazole and sucralfate.

Negative impact of Crohn's disease on bone mineral mass.

Prolonged chronic inflammation and corticosteroid therapy increase the risk of osteoporosis in patients with Crohn's disease. It has been estimated that 30% of these patients, who take steroids for prolonged periods, will suffer a vertebral fracture. Patients with Crohn's disease are difficult to wean from corticosteroids and therefore are at risk of developing bone complications. The purpose of this cross-sectional study was to examine the relationship between cumulative steroid dose, duration of the disease and the development of osteopenia in patients with Crohn's disease. We studied 28 patients (17 men, 11 women) with Crohn's disease: eight had one or more bowel resections and all the women were premenopausal. Serum calcium, phosphate, total alkaline phosphatase, immunoreactive parathyroid hormone (iPTH), 25(OH)Vitamin D(3) and 1,25 (OH)(2) Vitamin D(3) were measured by autoanalyser methods or radioimmunoassay. Bone mineral density (BMD) was studied using dual energy X-ray bone absorptiometry of the lumbar spine (L2-L4) and the femoral neck. Of these 28 patients, 27 received an average of 17.3 +/- 21.7 g (range 1 to 80) g of prednisone over a period of 4 to 216 months. Fourteen out of the 28 patients had mildly diminished bone density (z-score >-2.5 SD and < -1 SD) of the spine and 15/28 of the hip. We found a greater decrease in bone density (z-score < -2.5 SD) in 2 out of 28 patients at the spine and in 5 out of 28 at the femoral neck. Those in whom the duration of the disease was less than two years (12 patients) had significantly higher vertebral z-scores (-0.096 +/-0.91) than those who had the disease for over two years (-1.31 +/- 2.37), (p<0.05). We found no significant correlation between lumbar spine and femoral neck z-scores and cumulative steroid therapy. Six out of 28 patients (four women and two men), of mean age 47.2+/-11.7, had one vertebral fracture. The mean cumulative dose of steroids (prednisone or budesonide) in patients with vertebral fractures was higher but not significantly different from that in patients without fractures -20.1+/-18.2 versus 14.1+/-11.2 g of prednisone, respectively (p>0.05). No correlation was found between various serum hormones and other biochemical parameters of bone turnover or bone density. We conclude that a large proportion of patients with Crohn's disease have reduced bone mineral density (58% at the spine and 75% at the femoral neck). The pathogenesis of bone loss is probably multifactorial. Although steroid therapy might be an important contributory factor, we were unable to find a significant correlation between it and bone loss. On the contrary, we observed that the duration of the disease makes a significant contribution to bone loss.

Lupus-like syndrome caused by 5-aminosalicylic acid in patients with inflammatory bowel disease.

BACKGROUND: Although 5-aminosalicylic acid (5-ASA) preparations used to treat inflammatory bowel disease are reported to have fewer side effects than sulphasalazine, increased clinical use of these compounds has resulted in increased reports of significant side effects. OBJECTIVE: To report four patients with antinuclear antibody-positive migratory arthralgias and acute inflammation unrelated to the underlying inflammatory bowel disease, fulfilling the criteria of a drug-induced lupus-like syndrome. SETTING: A university-affiliated teaching hospital. INTERVENTION: Cessation of treatment with 5-ASA compounds. RESULTS: The cases described constitute a drug-induced lupus-like syndrome. All patients improved rapidly after discontinuation of 5-ASA compounds. CONCLUSIONS: Reversible lupus-like syndrome appears to be a rare but significant side effect of 5-ASA compounds. Patients treated with 5-ASA compounds who experience acute inflammatory symptoms or clinical deterioration not related to their gastrointestinal disease should be screened to rule out a lupus-like reaction.

Methyltestosterone-induced night blindness.

A 59-year-old man presented with a 3-month history of night blindness and a 9-month history of steatorrhea. Both symptoms had appeared after he had begun taking methyltestosterone. Investigations revealed low serum levels of carotene (0.1 mmol/L) and vitamin A (0.4 to 0.7 mmol/L), anomalous colour perception, elevation of the rod threshold by 3.5 log units in dark adaptometry, and decreased b-wave amplitudes in photopic and scotopic electroretinograms. No biochemical evidence of cholestasis was elicited. The symptoms and the biochemical and electrophysiologic abnormalities resolved within 9 months of the discontinuation of methyltestosterone.

Review article: a decision-making algorithm for the management of pregnancy in the inflammatory bowel disease patient.

BACKGROUND: Inflammatory bowel disease affects patients who are in their reproductive years. There are many questions regarding the management of IBD patients who are considering or who are already pregnant. These include the effect of the disease and the medications on fertility and on the pregnancy outcome. AIM: To create an evidence-based decision-making algorithm to help guide physicians through the management of pregnancy in the IBD patient. METHODS: A literature review using phrases that include: 'inflammatory bowel disease', 'Crohn's disease', 'ulcerative colitis', 'pregnancy', 'fertility', 'breast feeding', 'delivery', 'surgery', 'immunomodulators', 'azathioprine', 'mercaptopurine', 'biologics', 'infliximab', 'adalimumab', 'certolizumab'. CONCLUSIONS: The four decision-making nodes in the algorithm for the management of pregnancy in the IBD patient, and the key points for each one are as follows: (i) preconception counselling - pregnancy outcome is better if patients remain in remission during pregnancy, (ii) contemplating pregnancy or is already pregnant - drugs used to treat IBD appear to be safe during pregnancy, with the exception of methotrexate and thalidomide, (iii) delivery and (iv) breast feeding - drugs used to treat IBD appear to be safe during lactation, except for ciclosporin. Another key point is that biological agents may be continued up to 30 weeks gestation. The management of pregnancy in the IBD patient should be multi-disciplinary involving the patient and her partner, the family physician, the gastroenterologist and the obstetrician.

Treatment of ulcerative colitis with oral 5-aminosalicylic acid including patients with adverse reactions to sulfasalazine.

Sulfasalazine is an effective drug for maintaining remission in ulcerative colitis, but its use may be precluded by side effects. Eighty-five patients with active ulcerative colitis participated in a prospective open trial to examine the tolerance of the active constituent 5-aminosalicylic acid (5-ASA), coated with an acrylic resin, and its efficacy in inducing and subsequently maintaining a remission. Fifty-one of the patients had previously developed adverse reactions to sulfasalazine. After 4 wk of treatment with 3.2 g 5-ASA daily, a remission was achieved in 23 of 36 patients (64%) with mild or moderate disease, but in none of 43 patients with severe disease. Six patients were withdrawn because of side effects to 5-ASA, but only two of these patients had similar reactions on sulfasalazine. Supplementary corticosteroids for 6 wk or less induced a remission in 27 of the patients who had failed on 5-ASA alone. Fifty patients were therefore eligible for the maintenance phase of the trial, and 39 (78%) had a sustained clinical and endoscopic remission upon 1-yr follow-up. 5-ASA appears to be an effective drug for inducing remission in mild or moderate ulcerative colitis and for the maintenance of remission. It thus represents a valuable addition to the management of patients intolerant to sulfasalazine.

Safety of topical 5-aminosalicylic acid in pregnancy.

OBJECTIVE: To assess the safety and efficacy of topical 5-aminosalicylic acid preparations for therapy of distal colitis during pregnancy. METHODS: Nineteen pregnancies in sixteen consecutive patients with proven distal colitis were identified prospectively at a tertiary care center. All patients were given trials of weaning off medication and all failed. All subjects were on maintenance topical 5-aminosalicylic acid therapy at the time of conception. They were followed throughout their pregnancy and thereafter. Their children were also closely examined and followed by a pediatrician. RESULTS: The mean age at delivery was 25.8 yr, and the mean duration of illness was 4.6 yr. After taking topical therapy, there were no relapses during the pregnancy. There were 19 successful full-term pregnancies with no fetal abnormalities. The mothers and children were followed for more than 6 months. CONCLUSION: In this series, topical 5-aminosalicylic acid appears safe, effective, and well tolerated in the management of pregnant patients with distal colitis.

Rapid purification of human high molecular weight kininogen.

Human high molecular weight kininogen was isolated by a rapid procedure, using anion exchange chromatography on QAE-Sephadex, ammonium sulfate precipitation and cation exchange chromatography on CM-Sephadex. The poor recovery and relatively low specific activity observed in earlier experiments was found to be due to a contaminant, presumably enzymatic, capable of releasing kinin from the kininogen. The "spontaneous" kinin release was blocked by soy bean trypsin inhibitor and by C1-inactivator. The isolated kininogen was stable at different temperatures, did not contain free kinin and was a good substrate for plasma kallikrein and plasmin.

Generation of a vasoactive peptide by a neutral protease of human neutrophil leukocytes.

Neutrophil leukocyte lysosomes contain a neutral protease capable of cleaving a peptide from kininogen. The protease has a molecular weight of about 27,000-28,000, as determined by SDS-disc gel electrophoresis and gel filtration in the presence of guanidine-HCl. Its S-value is 2.7 and the pI 10.0-11.8. Although homogeneous by some criteria (sucrose density gradient ultracentrifugation, gel filtration in Sephadex G-75, SDS-disc gel electrophoresis, immunoelectrophoresis), the protease is heterogeneous by other criteria (cation exchange chromatography, cationic disc gel electrophoresis and isoelectric focusing). The heterogeneity is attributable to charge isomerism. The enzyme is inhibited by DFP and a number of chloromethyl ketone inhibitors. It is also inhibited by the plasma protease inhibitors alpha1-antitrypsin, alpha2-macroglobulin and antithrombin III. The generated peptide has chemical and pharmacological properties similar to the undecapeptide methionyl-lysyl-bradykinin, but probably contains one or two additional amino acids.

Neutral proteases of human PMN leukocytes with kininogenase activity.

A neutral protease with kininogenase activity was isolated from human polymorphonuclear (PMN) leukocytes by cation exchange chromatography and gel filtration. The protease appears heterogeneous by cation exchange chromatography, isoelectric focusing and cationic disc gel electrophoresis, but homogeneous by gel filtration, sucrose density gradient ultracentrifugation, SDS-disc gel electrophoresis and immunoelectrophoresis. By carrying out the electrophoresis of the protease in acrylamide gels of varying concentrations, it was shown that they represent charge isomers. The protease was stable at pH 4-10, but labile to heat, being almost completely inactivated when incubated for 30 min at 70 degrees C. It exhibited proteolytic activity between pH 5 and 9, being maximal at 7.5-8.5. The molecular weight of the PMN protease was estimated to be about 20,000 daltons by gel filtration in aqueous buffer and about 26,000-28,000 daltons by SDS-disc gel electrophoresis and gel filtration in Sepharose 6B in the presence of the dissociating agent guanidine HCl. Its sedimentation coefficient was about 2.7S. Corresponding to the charge heterogeneity, by isoelectric focusing, the kinin-generating and esterolytic activities of the PMN granule lysate focused between pH 6.0 and 11.5, whereas the isolated PMN protease focused between 10.0 and 11.8. With respect to kinin generation, caseinolysis, and alanine esterase activity, the protease was inhibited by DFP and certain chloromethyl ketone inhibitors, as well as the plasma protease inhibitory a1-antitrypsin, a2-macroglobulin and antithrombin III. Both bradykinin and a methionyl-lysyl-bradykinin-like peptide were generated from highly purified kininogens by a lysosomal lysate containing the PMN protease. However, this assay was done with a crude enzyme preparation which contains an aminopeptidase capable of converting lysyl-bradykinin or methionyl-lysyl-bradykinin to bradykinin. When injected intradermally, the protease induced hyperemia, hemorrhage, and moderate enhancement of vascular permeability, but the mixture of the protease and kininogen induced a marked enhancement of vascular permeability.

Cimetidine-resistant Zollinger-Ellison syndrome: successful management with ranitidine.

In a patient with the Zollinger-Ellison syndrome who had undergone vagotomy, pyloroplasty and, later, gastrojejunostomy, epigastric pain and stomal ulceration recurred despite the use of high doses (2700 mg/d) of cimetidine. Ranitidine, a new histamine H2-receptor antagonist, reversed all symptoms and healed the stomal ulcer without side effects, thus obviating the need for further surgery. Ranitidine may prove to be the drug of choice in the medical management of patients with the Zollinger-Ellison syndrome.

Oral 5-aminosalicylic acid for inflammatory bowel disease in pregnancy: safety and clinical course.

BACKGROUND: Oral 5-aminosalicylic acid (5-ASA) has proven an effective maintenance therapy of ulcerative colitis and may also be useful in Crohn's disease, but its safety in pregnancy has not been established. The present study therefore examined the course and outcome of pregnancies in patients with inflammatory bowel disease who continued to take oral 5-ASA. METHODS: Ten patients with ulcerative colitis and 7 patients with Crohn's disease with a total of 19 pregnancies were studied while they were receiving 5-ASA. All patients were previously in remission on 5-ASA, at a mean dose of 1.7 g/day (range, 0.8-2.4 g/day). They continued taking the drug without a change in dose and were followed up throughout their pregnancies and postpartum. RESULTS: Eighteen pregnancies resulted in full-term delivery. No fetal abnormalities were found at delivery, and there were no clinical or biochemical abnormalities in the neonatal period. Four patients had a relapse. One patient required a colectomy but carried on to a full-term pregnancy. One patient had a miscarriage, but she had miscarried on four previous occasions before taking 5-ASA. She subsequently had a successful pregnancy on 5-ASA. CONCLUSIONS: Oral 5-ASA appears to be safe for the management of inflammatory bowel disease during pregnancy.

Kininogen deficiency in Fitzgerald trait: role of high molecular weight kininogen in clotting and fibrinolysis.

Plasma from an asymptomatic person with defects in blood coagulation, release of kinin, and evolution of fibrinolytic activity upon contact with a foreign surface was deficient in kininogen. The coagulation defect was identified as "Fitzgerald trait." A preparation of high molecular weight kininogen repaired the defects in clotting, kinin release and fibrinolysis, but a preparation of low molecular weight kininogen did not. Therefore, Fitzgerald factor appears to be a high molecular weight kininogen. The site of action of the kininogen appears to be after that of activated Hageman factor and kallikrein in the generation of clot-promoting activity through activation of plasma thromboplastin antecedent (PTA).