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Objectives. To evaluate the efficacy and safety of efalizumab in continuous or interrupted therapy of adults with moderate-to-severe plaque psoriasis who had failed to respond to or were intolerant of other systemic therapies, including methotrexate, ciclosporin and psoralen plus UVA phototherapy, or for whom such therapies were contraindicated.

Methods. Patients received a conditioning dose of efalizumab 0.7 mg/kg followed by once-weekly open-label efalizumab 1.0 mg/kg for 11 weeks. Responders (Physician Global Assessment [PGA] score of “good” or better at Week 12) could continue efalizumab for a further 8 weeks (continuous-treatment period). Nonresponders transitioned to alternative anti-psoriasis medication or stopped treatment. Responders who discontinued efalizumab could restart treatment if symptoms worsened. PGA response was evaluated at Weeks 12 (primary endpoint) and 20, as were the proportions of patients achieving an improvement from baseline of ≥50%, ≥75% and ≥90% in Psoriasis Area and Severity Index (PASI) (PASI 50, PASI 75 and PASI 90, respectively).

Results. A total of 1,255 patients were included in the intention-to-treat population. At Week 12, 68.0% of patients had a PGA rating of “good” or better. Of 688 patients who entered the continuous-treatment period, 79.5% had a PGA rating of “good” or better at Week 20. At Week 12, median improvement in PASI score was 68.4%. PASI 50/75/90 was achieved by 65.5%/35.9%/13.0% of patients at Week 12, and by 78.2%/52.9%/24.3% of responders at Week 20. Of the 127 responders at Week 12 who discontinued efalizumab, 11% experienced rebound and 56.7% relapsed within 8 weeks after stopping therapy. Efalizumab was well tolerated during the study.

Conclusions. Efalizumab provided effective control of psoriasis in the majority of patients during the initial treatment period. The high response rates were maintained in initial responders when treatment was continued beyond 12 weeks.

This post-approval, open-label trial (n = 1266) assessed the efficacy of efalizumab, administered in accordance with the European label at that time, in patients with concomitant nail, scalp or palmoplantar psoriasis. Patients received subcutaneous efalizumab 1.0 mg/kg weekly for up to 20 weeks. By Week 12, an improvement from baseline of 50% or more was observed in 21.4% (181/844) of patients with nail psoriasis, 62.4% (718/1150) of patients with scalp psoriasis, and 51.4% (127/247) of patients with palmoplantar psoriasis. Quality of life improved throughout the trial, with a 50% median improvement in DLQI score after 12 weeks of treatment. Efalizumab showed promising efficacy in the treatment of nail, scalp and palmoplantar psoriasis, which was reflected in improvements in quality of life.

INTRODUCTION: Acute promyelocytic leukemia (APL) is a malignant disorder of the white blood cells. Arsenic trioxide (As(2)O(3)) has been used as a therapeutic agent to treat APL and other tumors. Studies suggest that ascorbic acid (AA) supplementation may improve the clinical outcome of As(2)O(3) for APL patients. Our aim was to use human leukemia (HL-60) APL-cells as an in vitro test model to evaluate the effect of physiologic doses of AA on As(2)O(3)-induced toxicity and apoptosis of HL-60 cells. METHODS: HL-60 cells were treated either with a pharmacologic dose of As(2)O(3) alone and with several physiologic doses of AA. Cell survival was determined by trypan blue exclusion test. The extent of oxidative cell/tissue damage was determined by measuring lipid hydroperoxide concentration by spectrophotometry. Cell apoptosis was measured by flow cytometry using Annexin-V and propidium iodide (PI) staining. RESULTS: AA treatment potentiates the cytotoxicity of As(2)O(3) in HL-60 cells. Viability decreased from (58 +/- 3)% in cells with As(2)O(3) alone to (47 +/- 2)% in cells treated with 100 microM AA and 6 microg/mL As(2)O(3) with P < 0.05. There was a significant (P < 0.05) increase in lipid hydroperoxide concentrations in HL-60 cells co-treated with AA compared to As(2)O(3) alone. Flow cytometry assessment (Annexin V FITC/PI) suggested that AA co-treatment induces more apoptosis of HL-60 cells than did As(2)O(3) alone, but this was not statistically significant. Taken together, our experiment indicates that As(2)O(3) induced in vitro cell death and apoptosis of HL-60 cells. Administration of physiologic doses of AA enhanced As(2)O(3)-induced cytotoxicity, oxidative cell/tissue damage, and apoptosis of HL-60 cells through externalization of phosphatidylserine. CONCLUSIONS: These suggest that AA may enhance the cytotoxicity of As(2)O(3), suggesting a possible future role of AA/As(2)O(3) combination therapy in patients with APL.

INTRODUCTION: Psoriasis is a debilitating, chronic inflammatory systemic disease affecting around 2% of the South American population. Biological therapies offer the possibility of long-term therapy with improved safety and efficacy. METHODS: We conducted a multicentre, open-label, single-arm, Phase IIIb/IV study of adult patients (18-75 years) with moderate-to-severe plaque psoriasis who were candidates for systemic therapy or phototherapy. Patients received efalizumab subcutaneously (1.0 mg/kg/wk). The primary endpoint was the proportion of patients achieving a Physician Global Assessment (PGA) rating of "excellent" or "cleared" at Week 24. Safety outcomes were adverse events (AEs), serious AEs (SAEs) and abnormalities on laboratory tests. RESULTS: Of 189 patients included in the intent-to-treat and safety populations, 104 (55.0%) were of Hispanic or Latino ethnicity. At Week 24, 92/189 (48.7%) patients achieved or maintained a PGA rating of "excellent" or "cleared". AEs were reported by 161/189 (85.2%) patients, SAEs by 21/189 (11.1%). One patient died during the study (meningoencephalitis). Laboratory findings were consistent with previous experience. CONCLUSIONS: Efalizumab demonstrated sustained control of psoriasis up to 24 weeks in patients from Latin America, confirming results seen in Phase III studies conducted in North America and Europe.

Introduction. Non-clinical evaluation of a medication's potential to induce cardiac toxicity is recommended by regulatory agencies. 4-Aminopyridine (fampridine) is a potassium channel blocker with the demonstrated ability to improve walking ability in patients with multiple sclerosis. We evaluated the in vitro effects of 4-aminopyridine on the human ether-à-go-go-related gene (hERG) channel current, since hERG current inhibition is associated with QT interval prolongation—a precursor to torsade de pointes (TdP).

Methods. 4-Aminopyridine was evaluated in concentrations ranging from 0.1 mM to 30 mM in human embryonic kidney 293 cells stably transfected with the hERG gene; terfenadine 60 nM was used as a positive control.

Results and Discussion. We observed concentration-dependent inhibition of hERG current with 4-aminopyridine doses between 0.3 and 30 mM. The concentration of 3.8 mM resulting in 50% inhibition (IC₅₀) is approximately three orders of magnitude higher than expected therapeutic plasma concentrations, suggesting 4-aminopyridine has low potential for prolonging QT interval or inducing TdP.

Aims. Genetic determinants of variability in response to β-blockers are poorly characterized. We defined changes in mRNA expression after a β-blocker to identify novel genes that could affect response and correlated these with inhibition of exercise-induced tachycardia, a measure of β-blocker sensitivity.

Methods. Nine subjects exercised before and after a single oral dose of 25mg atenolol and mRNA gene expression was measured using an Affymetrix GeneChip Human Gene 1.0 ST Array. The area under the heart rate-exercise intensity curve (AUC) was calculated for each subject; the difference between post- and pre-atenolol AUCs (Δ AUC), a measure of β-blocker response, was correlated with the fold-change in mRNA expression of the genes that changed more than 1.3-fold.

Results. Fifty genes showed more than 1.3-fold increase in expression; 9 of these reached statistical significance (P < 0.05). Thirty-six genes had more than 1.3-fold decrease in expression after atenolol; 6 of these reached statistical significance (P < 0.05). Change in mRNA expression of FGFBP2 and Probeset ID 8118979 was significantly correlated with atenolol response (P = 0.03 and 0.02, respectively).

Conclusion. The expression of several genes not previously identified as part of the adrenergic signaling pathway changed in response to a single oral dose of atenolol. Variation in these genes could contribute to unexplained differences in response to β-blockers.

Aims. This paper presents the treatment outcomes for patients intiated on biphasic insulin aspart 30 (BIAsp 30) treatment: BIAsp 30-only, BIAsp 30 + sulphonylureas (SU), BIAsp 30 + biguanides (BI), BIAsp 30 + SU + BI, BIAsp 30 + alpha-glucosidase inhibitors (GI), and BIAsp 30 + BI + thiazolidinediones (TZD) after failing oral antidiabetic drugs (OADs) treatment.

Methods. This was a multi-national, multi-centre, six-month, prospective, open-labelled, uncontrolled, clinical experience evaluation study, with the exception of a three-month study in one country (China) (“all exclude China” and “China”). Initiation and discontinuation of BIAsp 30 treatment were entirely at the discretion of the attending physicians.

Results. Mean HbA_1c, FPG and PPPG were significantly reduced from baseline at three and six months in all groups (P < 0.001). In “all exclude China”, reductions in mean HbA_1c, FPG and PPPG at six months were as follows: BIAsp 30-only group (−2.12 ± 1.76% points; −4.82 ± 3.86 mmol/L; −6.89 ± 4.74 mmol/L), BIAsp 30 + BI group (−2.24 ± 1.77% points; −4.48 ± 3.68 mmol/L; −6.66 ± 4.55 mmol/L), BIAsp 30 + SU group (−1.95 ± 1.59% points; −3.98 ± 3.19 mmol/L; −6.25 ± 4.45 mmol/L) and BIAsp 30 + SU + BI group (−1.78 ± 1.20% points; −3.57 ± 2.78 mmol/L; −5.89 ± 3.98 mmol/L). The only serious adverse drug reaction was reported by the BIAsp 30-only group. In the “China” group, reductions in mean HbA_1c, FPG and PPPG at three months were: BIAsp 30-only group (−2.16 ± 1.52% points; −3.34 ± 2.49 mmol/L; −6.29 ± 3.92 mmol/L), BIAsp 30 + BI group (−2.44 ± 1.52% points; −4.01 ± 2.50 mmol/L; −7.10 ± 3.96 mmol/L), BIAsp 30 + GI group (−2.33 ± 1.41% points; −4.34 ± 2.52 mmol/L; −7.97 ± 3.99 mmol/L) and BIAsp 30 + BI + TZD group (−1.21 ± 1.60% points; −3.50 ± 2.29 mmol/L; −5.97 ± 3.39 mmol/L). No serious ADR were reported in China. The most frequent hypoglycaemic episodes were diurnal and minor in nature.

Conclusions. BIAsp 30 treatment in a clinical setting improved glycaemic control in type 2 diabetes patients failing OADs.

Objectives. Drugs used for the treatment of rheumatoid arthritis (RA) have the potential to affect cardiovascular risk factors. There is concern that corticosteroids, non-steroidal anti-inflammatory drugs (NSAIDs) and COX-2 inhibitors could affect cardiovascular risk adversely, while drugs such as the antimalarial, hydroxychloroquine, may have beneficial effects. However, there is limited information about cardiovascular risk factors in patients with RA receiving different drugs.

Methods. We measured cardiovascular risk factors including systolic and diastolic blood pressure, serum HDL and LDL cholesterol, glucose and homocysteine concentrations and urinary F₂-isoprostane excretion in 169 patients with RA. Risk factors were compared according to current use of corticosteroids, methotrexate, antimalarials, NSAIDs, COX-2 inhibitors, leflunomide and TNF-α blockers. Comparisons were adjusted for age, sex, race, disease activity (DAS28 score), current hypertension, diabetes, smoking status and statin use.

Results. No cardiovascular risk factor differed significantly among current users and non-users of NSAIDs, COX-2 inhibitors, methotrexate and TNF-α blockers. Serum HDL cholesterol concentrations were significantly higher in patients currently receiving corticosteroids (42.2 ± 10.5 vs. 50.2 ± 15.3 mg/dL, adjusted P < 0.001). Diastolic blood pressure (75.9 ± 11.2 vs. 72.0 ± 9.1 mm Hg, adjusted P = 0.02), serum LDL cholesterol (115.6 ± 34.7 vs. 103.7 ± 27.8 mg/dL, adjusted P = 0.03) and triglyceride concentrations (157.7 ± 202.6 vs. 105.5 ± 50.5 mg/dL, adjusted P = 0.03) were significantly lower in patients taking antimalarial drugs. Plasma glucose was significantly lower in current lefunomide users (93.0 ± 19.2 vs. 83.6 ± 13.4 mg/dL, adjusted P = 0.006).

Conclusions. In a cross-sectional setting drugs used to treat RA did not have major adverse effects on cardiovascular risk factors and use of antimalarials was associated with beneficial lipid profiles.

Introduction. The rates of allergic rhinitis, allergic asthma, and atopic eczema range from 6% to 16% globally. Second-generation antihistamines have been shown to be safe and effective for the treatment of symptoms of allergic disease. This study investigated the efficacy and safety of desloratadine, a nonsedating second-generation antihistamine, in the treatment of common allergy symptoms.

Methods. In this open-label, uncontrolled, non-randomized, observational study, subjects (N = 973) with allergy symptoms were given desloratadine 5 mg daily for 3 weeks. Nasal, ocular, and dermal symptom severity was rated as asymptomatic, mild, moderate, or severe; changes in the percentage of subjects in each severity category were assessed. Overall efficacy and tolerability of desloratadine treatment were evaluated separately by physicians and subjects.

Results. Allergic rhinitis was the most frequent diagnosis, occurring in 59.0% of subjects. Approximately 40% of subjects had received previous treatment with other antihistamines, systemic/topical glucocorticosteroids, or beta-sympathicomimetics. Slightly more than half of subjects received concomitant medication during the study; 263 (53.0%) of those used intranasal steroids. A significant reduction in severity scores was observed in all symptom subgroups (P < 0.001). Desloratadine efficacy was judged to be excellent or good by 90.2% of physicians and 88.6% of subjects; 82.5% of investigators and 80.9% of subjects considered it more effective than previous therapy. The tolerability of desloratadine was rated excellent or good by 97.0% of both groups. Thirty-one subjects (3.2%) experienced adverse events.

Conclusions. In an open-label, uncontrolled, non-randomized, observational study allergy symptoms improved significantly in subjects treated with desloratadine.

Objectives. Rifampin is a potent inducer of the cytochrome P450 3A4 isoenzyme (CYP3A4) that metabolizes most protease inhibitor (PI) antiretrovirals. This study was designed to evaluate the steady-state pharmacokinetics and tolerability of the coadministration of the PIs saquinavir and ritonavir (a CYP3A4 inhibitor used as a pharmacoenhancer of other PIs) and rifampin when coadministered in healthy HIV-negative volunteers.

Methods. In an open-label, randomized, one sequence, two-period crossover study involving 28 healthy HIV-negative volunteers, arm 1 was randomized to receive saquinavir/ritonavir 1000/100 mg twice daily while arm 2 received rifampin 600 mg once daily for 14 days. Both arms were then to receive concomitant saquinavir/ritonavir and rifampin for 2 additional weeks. Vital signs, electrocardiography, laboratory analyses, and blood levels of total saquinavir, ritonavir, rifampin, and desacetyl-rifampin, the primary metabolite of rifampin, were measured.

Results. In arm 1, 10/14 (71%) and, in arm 2, 11/14 (79%) participants completed the first study phase; eight participants in arm 1 and nine in arm 2 went on to receive both saquinavir/ritonavir and rifampin. Following substantial elevations (≥ grade 2) in hepatic transaminases in participants receiving the coadministered agents, the study was discontinued prematurely. Two participants in arm 1 displayed moderate elevations after five and four doses of rifampin, respectively. In arm 2, all participants experienced severe elevations within 4 days of initiating saquinavir/ritonavir. Clinical symptoms (e.g., nausea, vomiting, abdominal pain, and headache) were more common and severe in arm 2. Clinical symptoms abated and transaminases normalized following drug discontinuation. Limited pharmacokinetic data suggest a possible relationship between transaminase elevation and elevated rifampin and desacetyl-rifampin concentrations.

Conclusions. Although not confirmed in HIV-infected patients, the data indicate that rifampin should not be coadministered with saquinavir/ritonavir.