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Noncomparative Study (noncomparative + study)
Selected AbstractsInterindividual variability in the concentration,effect relationship of antilymphocyte globulins,a possible influence of Fc,RIIIa genetic polymorphismBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 1 2008David Ternant WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT ,,There is interindividual variability in the antilymphocyte globulin (ALG) effect, but there is no pharmacokinetic,pharmacodynamic study of this subject. ,,In addition, a time dependence of the pharmacokinetics of some therapeutic antibodies has been described. ,,ALGs may partly act by antibody-dependent cellular cytotoxicity (ADCC), but their mechanism of action in humans is not known. WHAT THIS STUDY ADDS ,,Horse ALG pharmacokinetics can be described using a two-compartment model with time-dependent central volume of distribution. ,,After an initial concentration-independent lymphocyte depletion, the concentration,effect relationship can be described using a physiological indirect response model. ,,The genetic polymorphism of Fc,RIIIa at position 158 may influence the ALG concentration,effect relationship and these polyclonal antibodies may therefore act by ADCC. AIMS Polyclonal antilymphocyte globulins (ALGs) are currently used in transplantation, but the sources of interindividual variability of their effect are poorly understood. No pharmacokinetic,pharmacodynamic (PK,PD) study of ALG is available. Moreover, the genetic polymorphism of Fc,RIIIa, a receptor for the Fc portion of immunoglobulins involved in antibody-dependent cellular cytotoxicity (ADCC), may influence their concentration,effect relationship. METHODS Fourteen kidney transplant patients treated by horse ALG were included in a prospective, noncomparative study. A population two-compartment PK model including a time dependence of the central volume of distribution was developed. Total lymphocyte count was used as biomarker of effect. Concentration,effect data were described using a physiological indirect response model, combining concentration-dependent and -independent inhibitions of lymphocyte input into the circulation. In addition, six kidney transplant patients in whom ALG concentrations were not available were included retrospectively. All patients were genotyped for FCGR3A. RESULTS Both the PK and the PK,PD model described the data satisfactorily and showed high interindividual variability. Asymptotic T1/2 -, and T1/2 -,-values were 1.3 and 25 days, respectively. The concentration of ALG leading to a 50% inhibition of lymphocyte input (IC50) was lower in FCGR3A- V carriers than in FCGR3A- F/F patients (383 ± 199 vs. 593 ± 209 mg l,1, P = 0.008). CONCLUSIONS This is the first description of the ALG effect on lymphocyte count using PK,PD modelling. Our results show that part of the variability in their concentration,effect relationship may be explained by Fc,RIIIa genetic polymorphism and therefore that horse ALG may deplete lymphocytes by ADCC. [source] Imiquimod 5% cream for external genital or perianal warts in human immunodeficiency virus-positive patients treated with highly active antiretroviral therapy: an open-label, noncomparative studyBRITISH JOURNAL OF DERMATOLOGY, Issue 4 2009P. Saiag Summary Background, Human immunodeficiency virus (HIV)+ patients have an increased risk of anogenital warts. High-risk (HR) human papillomaviruses (HPVs), especially types 16 and 18, are major risk factors for precancerous and cancerous lesions of the anogenital tract, while low-risk (LR) HPVs are associated with benign lesions. Cure of genital warts with ablative techniques, surgical excision, podophyllotoxin or trichloroacetic acid is frequently difficult. Treatment with imiquimod cream showed a total clearance of external genital or perianal warts in about 50% of immunocompetent subjects. However, total clearance was reduced in HIV+ subjects not treated with highly active antiretroviral therapy (HAART). Objectives, To assess clinically and by monitoring HPV content the efficacy of 5% topical imiquimod to treat anogenital warts in HIV+ subjects with at least partially restored immune functions. Methods, Fifty HIV+ patients successfully treated with HAART (total CD4+ cells , 200 cells mm,3 and plasma HIV RNA load < 104 copies mL,1) with anogenital warts were included. Imiquimod 5% cream was applied on external genital or perianal warts three times weekly for up to 16 weeks. Warts were tested at entry and after treatment for human LR- and HR-HPV DNA. Results, Total wart clearance was observed in 16 of 50 (32%) patients at week 16. At enrolment, HPV DNA was present in more than 90% of lesions with a majority of lesions co-infected by HR- and LR-HPV. At study end, the HPV load decreased or became undetectable in 40% of cases studied. Conclusions, Imiquimod 5% cream did not show safety concerns and is suitable for use in HIV+ subjects with anogenital warts and successful HAART treatment. [source] Efficacy and safety of first- or second-line irinotecan, cisplatin, and mitomycin in mesotheliomaCANCER, Issue 1 2007Dean A. Fennell MD Abstract BACKGROUND. Malignant pleural mesothelioma (MPM) is a rapidly progressive lethal tumor. Treatment options remain limited and the outcome in recurrent disease is poor. METHODS. A Phase II open-label noncomparative study was conducted to assess the safety and efficacy of the triplet combination irinotecan, cisplatin, and mitomycin-C (IPM) chemotherapy in untreated patients and in those with previous exposure to chemotherapy. RESULTS. In 62 patients an objective response rate of 25% was observed. In the first-line setting progression-free survival measured 6.4 months (95% confidence interval [CI]: 4.5,7.3) and overall survival was 10.8 months (95% CI: 7.9,13.7). In the second-line setting progression-free survival was 7.3 months (95% CI: 3.4,11.2) and overall survival was also 7.3 months (95% CI: 4.8,9.8). Psychosocial well-being improved during chemotherapy and the main toxicity observed was neutropenia (40%). CONCLUSIONS. IPM appeared to have a reasonable response rate with an acceptable toxicity profile in the first- and second-line treatment of MPM. Cancer 2007. © 2006 American Cancer Society. [source] Multicenter, noncomparative study of caspofungin in combination with other antifungals as salvage therapy in adults with invasive aspergillosisCANCER, Issue 12 2006Johan Maertens MD Abstract BACKGROUND. Caspofungin inhibits synthesis of ,-1,3-glucan, an essential component of the Aspergillus cell wall. This echinocandin has demonstrated efficacy (45% success) as salvage monotherapy of invasive aspergillosis (IA). Interest remains as to whether caspofungin, in combination with other antifungal classes, can improve the efficacy against IA. METHODS. The study involved 53 adults with documented IA who were refractory to or intolerant of standard antifungal therapy and received caspofungin and 1 other mold-active antifungal agent (at the investigator's discretion). Efficacy was assessed by signs, symptoms, and radiographs at the end of combination therapy and Day 84 after combination therapy initiation. Favorable (complete or partial) responses required significant clinical and radiographic improvement. Diagnoses and outcomes were assessed by an independent expert. RESULTS. Among the 53 patients enrolled the most common underlying diseases were acute leukemia (53%), lymphoma (11%), and chronic leukemia (6%). Pulmonary aspergillosis (81%) was the most common site, and most patients (87%) were refractory to prior therapy. Success at the end of combination therapy and Day 84 was 55% (29/53) and 49% (25/51), respectively. Fifty-seven percent of patients with neutropenia and 54% who received an allogeneic hematopoietic stem cell transplant responded favorably. Survival at Day 84 was 55%. Combination therapy, dosed on average for 31.3 days, was well tolerated. Two (4%) serious drug-related adverse events, both attributed to voriconazole, occurred. None of the patients discontinued caspofungin due to toxicity. CONCLUSIONS. Caspofungin in combination with a triazole or polyene was an effective alternative as salvage therapy for patients with recalcitrant Aspergillus infections. Cancer 2006. © 2006 American Cancer Society. [source] | ||||||||||