The quality-of-life effects of interferon beta-1b in multiple sclerosis. An extended Q-TWiST analysis

BACKGROUND: A recombinant form of interferon beta-1b (Betaseron) was given Food and Drug Administration approval for use in the treatment of relapsing-remitting multiple sclerosis in 1993 based on a documented reduction in exacerbation rate. However, its effect on disease progression is less clear. It costs $11,000 per year and has documented adverse effects such as fatigue, feverlike symptoms, and depression. OBJECTIVES: To evaluate a recombinant form of interferon beta-1b in the treatment of relapsing-remitting multiple sclerosis and to discuss treatment trade-offs and comprehensive quality-of-life (QOL) outcomes. METHODS: We present a randomized evaluation of treatment with a recombinant form of interferon beta-1b in 79 patients with multiple sclerosis who participated in a random allocation lottery and were followed up for 12 months, during which data on QOL and clinical outcomes were collected. The data were analyzed using the Extended Quality-Adjusted Time Without Symptoms and Toxicity (Q-TWiST) method, which evaluates treatment trade-offs by incorporating several QOL domains and patient preferences regarding these domains. RESULTS: Over the 12 months of follow-up, the case patients reported 10.6 months of quality-adjusted time, while the control patients reported 10.4 months of quality-adjusted time (P = .50). CONCLUSIONS: Thus, the first year of treatment with interferon beta-1b did not significantly improve or detract from QOL. Results are discussed in terms of acceptable trade-offs depending on the nature of therapy. Future observational and clinical studies should incorporate measures of patient preference.     

Side effect profile and adherence to in the treatment of multiple sclerosis with interferon beta-1a

A 20-year-old woman was admitted complaining of lower abdominal pain. Transabdominal ultrasound revealed a fluid collection in the pouch of Douglas and an irregularly shaped ovary with cystic lesions. Malignant cystic mass of the right ovary was highly suspected from the ultrasound findings. Transvaginal peritoneal centesis yielded a bloody fluid, but the pregnancy test was negative. On the third day of admission, menstruation began. MR examination performed four days after the initial onset of pain showed a subacute hematoma just adjacent to the right ovary, and segmental interruption of the right ovarian cortex. Based on these MR findings and the patient's history, subacute hemorrhage from the right ovarian corpus luteum was suspected, and this was confirmed with surgical exploration.     

Profile of efficacy and safety in the treatment of remittent-recurrent multiple sclerosis with interferon beta-1b

BACKGROUND: Interferon beta 1b (IFN beta-1b) has showed a reduction of exacerbation rate and a decrease in multiple sclerosis activity as evidenced by MRI. After the approval of IFN beta-1b in our country more than 1,000 patients are under treatment, however the experience is limited. The purpose of this study is to describe the clinical results and the tolerance of IFN beta-1b during the postmarketing period in our country. MATERIAL AND METHODS: We studied 95 patients treated with IFN beta-1b. An exhaustive follow-up has been performed in order to assess the tolerance and the efficacy of the drug. We registered the haematological and biochemical abnormalities, secondary effects, relapses, clinical evolution and drop-outs. RESULTS: Mean age was 32.5 +/- 9 years, and the mean follow-up was 13.2 months. Seventy patients (74%) have been followed for more than one year. Haematological abnormalities are frequent, lymphopenia being the most common finding (37%). Flulike symptoms appear in 90% of the patients and skin reaction in the 70%. We have observed a drop-out rate of 7%. One patient developed depressive symptoms and the treatment was temporally discontinued. We have observed a significant decrease in relapses of the disease, however disability has not changed in the first year after treatment. CONCLUSIONS: IFN beta-1b has been well tolerated in the postmarketing period. The profile of secondary effects is similar, although not identical to that reported. The patient awareness of secondary effects and the realistic expectations of the drug are important in order to decrease the drop-out rate.     

Incidence of exacerbations in the first 90 days of treatment with recombinant human interferon beta-1b in patients with relapsing-remitting multiple sclerosis

Interferon beta-1b (IFNbeta-1b) is effective in reducing the frequency of exacerbations in patients with relapsing-remitting multiple sclerosis (RRMS). Recently, a study suggested that treatment with IFNbeta-1b may place MS patients at risk of exacerbations by increasing interferon-gamma (IFNgamma)-secreting cells in the blood early after onset of treatment. We conducted a retrospective study in 192 RRMS patients treated with IFNbeta-1b. We did not observe an increase in the frequency of exacerbations early after the onset of treatment and suggest that the IFNgamma-secreting cell surge linked to the onset of treatment with IFNbeta-1b may not be clinically significant.     

Current treatment of multiple sclerosis with interferon beta

INTRODUCTION: Demonstration of the efficacy of interferon beta IB in the reduction of outbreaks of multiple sclerosis has led to it being used in Spain. DEVELOPMENT: Discussion of the current situation regarding the use of interferon beta IB in Spain, diagnostic criteria, side-effects and future outlook. CONCLUSIONS: Use of interferon beta IB in Spain has followed criteria established by a Committee of Experts, and there is a lower rate of non-completion of treatment than in the U.S.A. New possibilities arise with the appearance of new drugs which are still awaiting evaluation.     

In vitro intercellular adhesion molecule-1 expression on brain endothelial cells in multiple sclerosis

To investigate the origin of intercellular adhesion molecule-1 (ICAM-1) and its expression on brain endothelial cells, we studied the expression in vitro of ICAM-1 on human brain endothelial cells after incubation of T cells from patients with multiple sclerosis (MS) using a histochemical technique and flow cytometry. We determined soluble forms of ICAM-1 (ICAM-1) in the supernatants after mixtures of brain endothelial cells and T cells from patients with MS using an enzyme-liked immunosorbent assay. Flow cytometric analysis showed that a number of ICAM-1-positive cells were significantly increased after incubation of brain endothelial cells with T cells from patients with acute relapsing MS during an exacerbation as compared with those of controls (P < 0.01). Patients with acute relapsing MS during an exacerbation and chronic progressive MS exhibited higher levels of ICAM-1 in the supernatants of mixtures with brain endothelial cells and lymphocytes than those of controls (P < 0.001 and P < 0.01, respectively). These results suggest that lymphocytes from patients with acute relapsing MS during an exacerbation lead to an increased expression of ICAM-1 on the brain endothelial cells and add to evidence involving this adhesion molecule in the pathogenesis of MS.     

In vivo localized NMR proton spectroscopy of normal appearing white matter in patients with multiple sclerosis

Single photon emission computed tomography (SPECT) using I-123 metaiodobenzylguanidine (MIBG) was evaluated for the detection of doxorubicin (DXR) cardiomyopathy in seven patients with malignant lymphoma receiving DXR doses ranging from 70 to 530 mg (DXR group), and 20 normal subjects without hypertension, diabetes mellitus or electrocardiographic abnormalities (control group). The ratio of the heart to mediastinal counts (H/M) and the washout rate (WR) in MIBG SPECT images were compared between the two groups. Correlation of total doses of DXR with H/M and the relationship of H/M to WR were investigated. The H/M of the DXR group was lower than that of the control group (3.00 +/- 0.97 vs 4.90 +/- 1.08, p < 0.001). The WR of the DXR group was higher than that of the control group (30.9 +/- 10.5% vs 16.5 +/- 9.1%, p < 0.001). Total DXR doses were inversely correlated with H/M (r = -0.86), H/M correlated inversely with the WR (r = -0.83) only in the DXR group. Pathological findings of one patient, who died of DXR cardiomyopathy, showed atrophic and fibrotic nerve fibers in the apical inferior segment of the left ventricle where MIBG uptake was reduced markedly. DXR cardiomyopathy can be detected with MIBG SPECT as cardiac sympathetic nervous dysinnervation. The pathological findings correspond to the MIBG SPECT findings.     

Immunoregulatory effects of interferon-beta and interacting cytokines on human vascular endothelial cells. Implications for multiple sclerosis autoimmune diseases

BACKGROUND AND PURPOSE: Radiolabeled immunoglobulin therapy (RIT) can be a selective, effective, low-toxicity outpatient cancer therapy. A consensus on the best approach for the preclinical and clinical development of RIT reagents needs to be developed. We report the M.D. Anderson Cancer Center prior experience in translating RIT from laboratory to clinic for the treatment of Hodgkin's disease and propose a flow diagram for the development of RIT for other malignancies. MATERIAL AND METHODS: Three different animal models are described: nude mice bearing human tumor xenografts, normal beagle dogs, and normal rhesus monkeys. We produced and purified antibodies and prepared chelate-immunoconjugates reactive with six different human tumor-associated antigens. The Igs used were derived from rabbits, mice, and humans (human-derived RIT reagents being less immunogenic in human patients). Eighty patients with refractory Hodgkin's disease were treated with radiolabeled antiferritin. RESULTS: We recommend a two-injection scheme using, (1) an indium-111-labeled radioimmunoconjugate for diagnosis, pharmacokinetic studies, and dosimetry, and (2) a yttrium-90-labeled radioimmunoconjugate for therapy. The animal models provide useful data on tumor targeting, radiotoxicology, and undesirable biodistributions. A 70% response rate is obtained in patients with advanced recurrent Hodgkin's disease. More extensive preclinical testing allows for safer and more effective clinical RIT studies. CONCLUSIONS: We recommend, (1) preclinical optimization of chelation chemistry, Ig size, Ig origin, route of administration, and fractionation, (2) new clinical Phase I-III studies more appropriate for RIT development than the classical Phase I-III studies used for the development of chemotherapeutic agents, and (3) more extensive preclinical testing of RIT reagents.     

Interferon beta-1b inhibits reactive oxygen species production in peripheral blood monocytes of patients with relapsing-remitting multiple sclerosis

To determine if perforation rate is a function of delayed diagnosis or delayed presentation in childhood acute appendicitis we performed a retrospective casenote review of 101 consecutive children undergoing emergency appendicectomy over a 12-month period. The perforation rate was 7% in those children presenting with symptoms of 1 day or less and was significantly greater (33%, Chi 2 = 9.45, P < 0.01) in those who had had symptoms for more than 1 day at presentation. There was no difference in in-hospital delay between the groups. A high perforation rate was found to be a feature of delayed presentation.     

In vivo effects of T helper cell type 2 cytokines on macrophage antigen-presenting cell induction of T helper subsets

SJL mice provide an interesting paradigm to examine the role(s) of APC in the differential induction of Th1 and Th2 cells. Immunization of young male SJL mice results in the preferential induction of Th2 cells, whereas Th1 cells are induced in age-matched female or older male SJL mice. The absence of Th1 responses in young male mice is associated with in vivo IL-4 and IL-10 down-regulating Mac-3+ APC priming of Th1 cells. The present report examines the mechanism of this APC-dependent induction of Th subsets. Examination of the surface expression of MHC class II, adhesion molecules (CD11a, CD11b, CD48, CD54, and CD102) or costimulatory molecules (CD24, CD80, and CD86) showed no differences between male- and female-derived Mac-3+ APC populations. In addition, no differences were detected in IL-1alpha, IL-1beta, IL-18, TNF-alpha, or IL-12 p35 mRNA expression. However, reduced expression of both IL-10 and IL-12 p40 mRNA were found in Mac-3+ cells from male mice compared with those in Mac-3+ cells from female mice. Anti-IL-4 or anti-IL-10 mAb treatment of young male donor mice eliminated the reduction of both IL-10 and IL-12 p40 mRNA, suggesting that the Th2 inducer phenotype is related to a decreased IL-12 secretion. Consistent with this idea, fewer IL-12 p40-secreting Mac-3+ cells were found in male mice compared with female mice, and treatment with rIL-12 resulted in the priming of Th1 cells in male mice. These data suggest that increased Th2 cytokines in vivo before encounter with Ag inhibit APC expression of IL-12, resulting in the preferential induction of Th2 cells in male SJL mice.     

Enhanced spasticity in primary progressive MS patients treated with interferon beta-1b

Spasticity is a disabling symptom of MS that is enhanced during interferon beta-lb (IFNbeta-1b) treatment. Nineteen patients with primary progressive MS were treated with IFNbeta-1b; an additional 19 patients did not receive this treatment. Thirteen of the 19 patients treated with IFNbeta-1b had increased spasticity requiring increased antispasticity drug administration. This observation suggests that further studies are needed before interferons can be so widely used in primary progressive MS patients.     

Copolymer-1 in the treatment of multiple sclerosis

Recent research in the treatment of multiple sclerosis (MS) has yielded new therapies. Specifically, copolymer-1, a mixture of synthetic polypeptides composed of four amino acids has been effective in reducing relapse rates and disability in patients with relapsing-remitting MS. In a two-year multicenter, randomized, double-blind, placebo-controlled trial of 251 patients, copolymer-1 was shown to reduce relapses by an average of 29% when compared with placebo. Sustained disability was also slightly reduced in the copolymer-1-treated group. The results of the clinical trial indicate that copolymer-1 positively alters the course of relapsing-remitting MS. With the present availability of copolymer-1, nurses are challenged to maintain current knowledge of nursing implications, interventions, patient education and goals for treatment.     

Beneficial effects of acetazolamide on paroxysmal attacks of girdle sensation in multiple sclerosis

A 56-year-old woman with a 40-year history of multiple sclerosis (MS) developed paroxysmal attacks of girdle sensation in the Th5-6 dermatomes. The attacks lasted 20-60 minutes and occured up to three times per week. T2-weighted MR imaging of the spinal cord showed high intensity area from Th5 to Th8. Electrocardiography, echocardiography and laboratory findings did not indicate ischemic heart disease; therefore, the paroxysms were attributed to the spinal cord lesions. Attacks were successfully suppressed by acetazolamide 250 mg/day. Although carbamazepine is frequently used to treat paroxysmal attacks in MS, we would like to suggest that acetazolamide may also be beneficial in some patients with paroxysmal symptoms.     

Proinflammatory cytokines regulate antigen-independent T-cell activation by two separate calcium-signaling pathways in multiple sclerosis patients

OBJECTIVE: The study examined the prevalence of low birth weight among biracial infants of black and white parents, by region of the United States. METHODS: Using the national linked live birth-death infant file for 1991, low birth weight (<2,500 g) was examined among 50,980 biracial singleton infants according to parental race (black mother-white father vs. white mother-black father). RESULTS: Nationally, the rate of low birth weight was 31% higher in the black mother-white father group (8.4%) than in the white mother-black father group (6.4%). The difference was smaller in the Northeast, reflecting a high rate (9.8%) for biracial infants of Puerto-Rican white mothers. The difference in the West was larger (75%), due to both a high rate in the black mother-white father group (9.1%) and a low rate for the white mother-black father group (5.2%), and persisted after controlling for parental education and a variety of maternal risk factors. CONCLUSIONS: Further studies are needed to identify the maternal factors involved in the regional differences in the prevalence of low birth weight among biracial infants.     

Managing side effects of interferon-beta in patients with relapsing-remitting multiple sclerosis

In separate clinical trials, two preparations of recombinant interferon (IFN)-beta, IFN beta-1a and IFN beta-1b, reduced exacerbation rates in relapsing-remitting multiple sclerosis (RR-MS). Further, IFN beta-1a slows the progression of disability in patients with RR-MS. Although they are effective in the treatment of MS, use of these drugs is associated with both class-specific and agent-specific side effects. Class-specific side effects include fever, chills, myalgias, arthralgias, and other flulike symptoms beginning 2 to 6 hours after injection and resolving within 24 hours of injection. Transient worsening of preexisting MS symptoms also occurs infrequently. Agent-specific side effects include injection-site reactions with IFN beta-1b. Simple management strategies can be used to minimize these reactions, including patient education; tailoring the dose and time of administration of IFN-beta; and prescribing appropriate combinations of acetaminophen, non-steroidal anti-inflammatory drugs, and steroids. Although side effects tend to diminish with treatment, successful management allows long-term administration of these drugs to achieve a reduction in disease activity and commensurate improvement in outcomes.     

In vitro and in vivo antineoplastic effects of orthovanadate

A liquid chromatographic method for the determination of the macrolide antibiotics, roxithromycin and clarithromycin, in plasma is described. The method is fully automated, employing on-line solid-phase extraction for sample clean-up, using the Prospekt unit. Plasma samples, mixed with internal standard, were injected onto exchangeable CN cartridges. After washing, the compounds were eluted and transferred to a C18 analytical column for separation and electrochemical detection. Clarithromycin was used as internal standard when assaying roxithromycin and vice versa. The recovery of the solid-phase extraction method was 90% and higher, and the relative standard deviation was about 3%. The limit of quantitation was 0.5 mumol/l when 25 microliters of plasma was injected. Comparison with a liquid-liquid extraction method for sample clean-up showed good agreement.     

Determinants of Gd-enhanced MRI response to IFN-beta-1a treatment in relapsing-remitting multiple sclerosis

BACKGROUND: With the prevalence of antibiotic use, the diagnosis and management of Clostridium difficile disease requires assessment. METHODS: In a retrospective review, patients with a positive culture, toxin, or both during 1 year were identified. Recent literature was reviewed. Results of culture and toxin, prior antibiotic use, antibiotic treatment history and cost were analyzed. RESULTS: Of 592 patients tested, 101 were positive; 96 of 101 were available for review. Of those positive tested for both, 45% were positive for toxin and culture. Sixty-two of 96 were treated with antibiotics; metronidazole was used in 90%. Ten of 62 antibiotic treatments were changed (mean 3 days). Ten days of metronidazole is 1/200th the cost of vancomycin. CONCLUSIONS: In 55% of the positive cases in which culture and toxin were obtained, one test was negative. As metronidazole's efficacy and cost compares favorably with vancomycin, metronidazole is the drug of choice. Any changes made to antibiotic regimens occurred prior to the 6 days recommended in the literature.