Weekly administration of 2-chlorodeoxyadenosine in patients with hairy-cell leukemia is effective and reduces infectious complications.
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BACKGROUND AND OBJECTIVE: It has been widely demonstrated that one single 7-day course continuous infusion (c.i.) 2-chlorodeoxyadenosine (2-CdA) at a dose of 0.1 mg/kg daily is dramatically effective in inducing high and prolonged complete remission (CR) rates in patients with hairy-cell leukemia (HCL). However, 2-CdA administration often results in severe neutropenia and lymphocytopenia both responsible for the infectious complications observed in these patients. We previously reported preliminary data regarding the effectiveness and toxicity of a modified protocol of 2-CdA administration (0.15 mg/kg 2 hours infusion once a week for 6 courses) in 25 HCL patients. This treatment schedule produced a similar overall response rate compared to standard 2-CdA regimen and appeared to be followed by a lower incidence of infectious episodes. In the present study we report response rate and toxicity of weekly 2CdA administration in a larger cohort of patients and with a longer follow-up. DESIGN AND METHODS: In a group of HCL patients with a pronounced decrease in neutrophils count (< 1 x 10(9)/L), we modified the standard protocol (0.1 mg/kg daily x 7 days c.i.) by administering 2-CdA at a dose of 0.15 mg/kg 2 hours infusion once a week for 6 courses. Thirty HCL patients, 24 males and 6 females with a median age of 56 years (range 37-76), entered into this protocol. Seventeen out of 30 patients were at diagnosis while the remaining 13 had been previously treated with alpha-interferon (alpha-IFN) (7), or 2-CdA (4) or deoxycoformycin (DCF) (2). RESULTS: Overall, 22/30 (73%) patients achieved CR and 8 (27%) partial remission (PR) with a median duration of response at the time of writing of 35 months, ranging from 6 to 58 months. Five patients (1 CR and 4 PR) have so far progressed. The treatment was very well tolerated. Five out of 30 patients (16%) developed severe neutropenia (neutrophils < 0.5 x 10(9)/L) and only in two of them we did register an infectious complication which required treatment with systemic antibiotics and granulocyte colony-stimulating factor (G-CSF). INTERPRETATION AND CONCLUSIONS: In conclusion, we confirm that weekly administration of 2-CdA at a dose of 0.15 mg/kg for 6 courses appears to be very effective in HCL inducing a high CR rate, similar to that observed with daily c.i. administration. CR durability and relapse/progression rates are also comparable to standard 2-CdA schedule. Moreover this new regimen seems to be safer in pancytopenic patients, markedly reducing life-threatening infectious complications. (+info)
Tolerability and efficacy of carvedilol in patients with New York Heart Association class IV heart failure.
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OBJECTIVES: The purpose of this study was to assess the tolerability and efficacy of carvedilol in patients with New York Heart Association (NYHA) functional class IV symptoms. BACKGROUND: Carvedilol, a nonselective beta-adrenergic blocking drug with alpha-adrenergic blocking and antioxidant properties, has been shown to improve left ventricular function and clinical outcome in patients with mild to moderate chronic heart failure. METHODS: We retrospectively analyzed the outcomes of 230 patients with heart failure treated with carvedilol who were stratified according to baseline functional class: 63 patients were NYHA class IV and 167 were NYHA class I, II or III. Carvedilol was commenced at 3.125 mg b.i.d. and titrated to 25 mg b.i.d. as tolerated. Patients with class IV symptoms were older (p = 0.03), had lower left ventricular fractional shortening (p < 0.001), had lower six-min walk distance (p < 0.001) and were receiving more heart failure medications at baseline compared with less symptomatic patients. RESULTS: Nonfatal adverse events while taking carvedilol occurred more frequently in class IV patients (43% vs. 24%, p < 0.0001), and more often resulted in permanent withdrawal of the drug (25% vs. 13%, p < 0.01). Thirty-seven (59%) patients who were NYHA class IV at baseline had improved by one or more functional class at 3 months, 8 (13%) were unchanged and 18 (29%) had deteriorated or died. Among the less symptomatic group, 62 (37%) patients had improved their NYHA status at 3 months, 73 (44%) were unchanged and 32 (19%) had deteriorated or died. The differences in symptomatic outcome at three months between the two groups were statistically significant (p = 0.001, chi-square analysis). Both groups demonstrated similar significant improvements in left ventricular dimensions and systolic function. CONCLUSIONS: Patients with chronic NYHA class IV heart failure are more likely to develop adverse events during initiation and dose titration when compared with less symptomatic patients but are more likely to show symptomatic improvement in the long term. We conclude that carvedilol is a useful adjunctive therapy for patients with NYHA class IV heart failure; however, they require close observation during initiation and titration of the drug. (+info)
Vascularity in asthmatic airways: relation to inhaled steroid dose.
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BACKGROUND: There is an increase in vascularity in the asthmatic airway. Although inhaled corticosteroids (ICS) are an effective anti-inflammatory treatment in asthma, there are few data on any effects on structural changes. METHODS: Endobronchial biopsy specimens from seven asthmatic subjects not receiving ICS and 15 receiving 200-1500 microg/day beclomethasone dipropionate (BDP) were immunohistochemically stained with an anti-collagen type IV antibody to outline the endothelial basement membrane of the vessels. These were compared with biopsy tissue from 11 non-asthmatic controls (four atopic and seven non-atopic). RESULTS: There was a significant increase in the density of vessels (number of vessels/mm2 of lamina propria) in the asthmatic subjects not on ICS compared with non-asthmatic controls (mean 485 (interquartile range (IQR) 390-597) versus 329 (IQR 248-376) vessels/mm2, p<0.05; 95% CI for the difference 48 to 286). There was no significant difference between asthmatic subjects on ICS and those not on ICS or control subjects in the number of vessels/mm2 (mean 421 (IQR 281-534)). However, patients who received >/=800 microg/day BDP tended to have a reduced number of vessels/mm2 compared with patients not on ICS and those receiving +info)
Morbidity from asthma in relation to regular treatment: a community based study.
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BACKGROUND: The extent to which asthma morbidity in the community occurs in patients who are having relatively little treatment or in those on step 3 or above of the British asthma management guidelines is uncertain. We have looked at this in a community population in southern Nottinghamshire. METHODS: A cross sectional review of treatment in all patients over the age of four with diagnosed asthma was carried out in five large general practices (population 38 865) in 1995/6 using computerised general practice records. The patients' usual treatment was obtained from prescription data and categorised by the appropriate step on the British guidelines on asthma management. Two measures of morbidity, the request for 10 or more short acting beta agonist inhalers a year or the need for a course of oral corticosteroids in the last year, were related to the regular treatment of the patients. RESULTS: Of the 3373 patients (8. 7%) given a diagnosis of asthma, the percentage on steps 1, 2, 3, 4, and 5 of treatment were 54%, 22%, 11%, 3.6%, and 1%, respectively, with a further 8% having had no treatment. During the past year 13. 6% had been prescribed 10 or more beta agonist inhalers and 12.5% had received at least one course of oral corticosteroids. Both measures occurred more frequently in patients taking more prophylactic treatment (step 3 or above). Nevertheless, because most patients were on steps 1 and 2 of the treatment guidelines, more than half the patients requiring high doses of inhaled beta agonists or a course of oral prednisolone came from those taking low dose or no regular inhaled corticosteroid. CONCLUSIONS: Evidence of morbidity from asthma was found in many patients taking little or no prophylactic medication and this should be amenable to improved education. A different approach may be needed for patients with continuing morbidity who are already taking higher doses of prophylactic medication. (+info)
Effect of inhaled corticosteroids on bronchial responsiveness in patients with "corticosteroid naive" mild asthma: a meta-analysis.
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BACKGROUND: Inhaled corticosteroids are the most efficacious anti-inflammatory drugs in asthma. International guidelines also advocate the early introduction of inhaled corticosteroids in corticosteroid naive patients. A study was undertaken to assess the effects of inhaled corticosteroids on bronchial hyperresponsiveness in patients with corticosteroid naive asthma by conventional meta-analysis. METHODS: A Medline search of papers published between January 1966 and June 1998 was performed and 11 papers were selected in which the patients had no history of treatment with inhaled or oral corticosteroids. Bronchial responsiveness to bronchoconstricting agents was considered as the main outcome parameter. Doubling doses (DD) of histamine or methacholine were calculated. RESULTS: The total effect size of inhaled corticosteroids (average daily dose 1000 microg) versus placebo in the 11 studies was +1.16 DD (95% confidence interval (CI) +0.76 to +1.57). When only the eight short term studies (2-8 weeks) were analysed the effect size of the bronchoconstricting agent was +0.91 DD (95% CI +0.65 to +1.16). No relationship was found between the dose of inhaled corticosteroid used and the effect on bronchial responsiveness. CONCLUSION: This meta-analysis in patients with corticosteroid naive asthma indicates that, on average, high doses of inhaled corticosteroids decrease bronchial hyperresponsiveness in 2-8 weeks. It remains unclear whether there is a dose-response relationship between inhaled corticosteroids and effect on bronchial hyperresponsiveness. (+info)
Long-term intensive treatment of type 1 diabetes with the short-acting insulin analog lispro in variable combination with NPH insulin at mealtime.
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OBJECTIVE: To establish whether the short-acting insulin analog lispro can be successfully implemented in long-term intensive insulin therapy in type 1 diabetes, and if so, what its effects are on glycemic control and frequency and awareness of hypoglycemia. RESEARCH DESIGN AND METHODS: We randomized 56 type 1 diabetic patients to treatment with either lispro (n = 28) or human regular insulin (Hum-R; n = 28) as mealtime insulin for 1 year (open design, parallel groups). Lispro was injected at mealtime and Hum-R was given 10-40 min before meals (bedtime NPH was continued on both occasions). With lispro, NPH was added at breakfast (approximately 70/30), lunch (approximately 60/40), and supper (approximately 80/20) (mixing percentage of lispro/NPH) to optimize premeal and bedtime blood glucose. RESULTS: Total daily insulin units were no different in the two treatment groups, but with lispro approximately 30% less short-acting insulin at meals and approximately 30% more NPH was needed versus Hum-R (P < 0.05). The bedtime NPH dosage was no different. With lispro + NPH, the mean daily blood glucose was lower than with Hum-R (8.0 +/- 0.1 vs. 8.8 +/- 0.1 mmol/l; P < 0.05), HbA1c was lower (6.34 +/- 0.10 vs. 6.71 +/- 0.11%, mean value over 1 year; P < 0.002), and hypoglycemia (blood glucose < or = 3.8 mmol/l) was less frequent (7.4 +/- 0.5 vs. 11.5 +/- 0.7 episodes/patient-month) and tended to occur more within 90 min after meals than in the postabsorptive state (P < 0.05 vs. Hum-R). After 1 year, plasma adrenaline and symptom responses to experimental, stepped hypoglycemia improved with lispro and were closer to the responses of 12 nondiabetic control subjects versus Hum-R both in terms of thresholds and magnitude (P < 0.05). CONCLUSIONS: We concluded that mealtime injection of lispro + NPH improves the 24-h blood glucose and the percentage HbA1c as compared with Hum-R. The improvement can be maintained long term. Intensive therapy with lispro + NPH results in less frequent hypoglycemia and better awareness and counterregulation of hypoglycemia. (+info)
Phase II trial of topically applied miltefosine solution in patients with skin-metastasized breast cancer.
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Skin deposits from breast cancer can present serious therapeutic problems, especially when resistant to conventional therapy. Topical application of a cytotoxic drug may represent an attractive new treatment modality devoid of major systemic toxicity. Miltefosine was selected because of its efficacy in breast cancer models. A mixture of alkylated glycerols of various chain lengths and water was used as the pharmaceutical vehicle to dissolve and to further facilitate tissue penetration of miltefosine. In our Institute a phase II study was performed to determine the efficacy and tolerability of topically applied miltefosine in patients with cutaneous metastases from breast cancer. Thirty-three patients in total entered the trial. A 6% miltefosine solution was applied once daily in the first week and twice daily in the following weeks. The planned minimum treatment duration was 8 weeks. We found an overall response rate of 43% for 30 evaluable patients, composed of 23% complete response and 20% partial response. The median response duration was 18 weeks, range 8-68. Toxicity consisted mainly of localized skin reactions, which could be controlled by a paraffin-based skin cream and, where appropriate, by dose modification. No systemic toxicities were observed. We conclude that topical miltefosine is an effective treatment modality in patients with skin metastases from breast cancer. (+info)
Ifosfamide/etoposide alternating with high-dose methotrexate: evaluation of a chemotherapy regimen for poor-risk osteosarcoma.
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Fifteen patients with relapsed osteosarcoma were treated with an intensive combination chemotherapy schedule. Ifosfamide 2.5 g m(-2) daily and etoposide 150 mg m(-2) daily coincidentally for 3 days and high-dose methotrexate 8 g m(-2) (with folinic acid rescue) on days 10-14 in a planned 21 -day cycle. Feasibility, toxicity and response to this alternative combination for the treatment of relapsed osteosarcoma was assessed. There were 98 evaluable cycles for toxicity and tolerability. The majority of cycles were well tolerated. Haematological toxicity of grade 3/4 (common toxicity criteria) was seen in all courses. Renal tubular loss of electrolytes, particularly magnesium, occurred in 71% of cycles. Thirteen per cent of cycles were repeated within 21 days and 61% within 28 days. In the thirteen patients evaluable for response, a partial response rate of 31% was seen after two cycles. However, patients with stable disease continued on therapy, and an overall consequent response rate of 62% was observed. Four patients were alive with no evidence of disease at 8-74 months. Three are alive with disease (at 8-19 months). There were six deaths, all disease related. This regimen exhibits an encouraging response rate in a group of children with poor prognosis disease, with a tolerable toxicity profile. (+info)