Population pharmacokinetics of oral high-dose busulfan in adult patients undergoing hematopoietic stem cell transplantation

Many factors have been reported that contribute to the wide intra- and inter-patient variability of Busulfan [Bu] disposition. The purpose of this study was to develop a population pharmacokinetic model and to determine the covariates affecting the pharmacokinetics [PK] of Bu in Iranian adult patients who received oral high-dose as a conditioning regimen before Hematopoietic Stem Cell Transplantation [HSCT]. A population PK analysis was performed in 30 patients who received an oral Bu and cyclophosphamide regimen before HSCT. Bu was given orally according to the protocol of the institution. In order to prevent seizures caused by Bu, phenytoin was administered orally one hour before each dose of Bu. A total of 180 blood samples were analyzed by HPLC and PK parameters were estimated by the non-linear mixed effect model by MONOLIX 3.1 program. A one-compartment model with an additive error model was used to describe the concentration-time profile of Bu. CL=13.4[1+ [0.141xDisease]], Vd=42.6[1+0.010x [Weight - 63.9]] Patients' disease and weight was found to be the determinant factors for clearance [CL] and the volume of distribution [Vd] according to Monolix analysis. The covariate entered in final model followed by these equations: In this limited study, the age [15-43 years] had no significant effect. For a patient weighting 60 kg, the typical CL and Vd were estimated to be 13.4 l/hr and 42.6 L, respectively. The interindividual variability of CL and Vd were 13.6 and 6.3%, respectively. There was no significant metabolic induction in these four days as is evident by comparing the trough levels of Bu. However it should be mentioned that, one tailed t-test p-values of the days of two and three, two and four and three and four were 0.083, 0.069 and 0.388, respectively. Results of this study showed that the type of disease was a determinant of CL and the weight of patient was a determinant of Vd for Bu population PK parameters. A reliable PK parameters and Css, estimated from only one plasma concentrations [5 hrs after the first dose], were validated. Since these methods require few sampling and are easy to be used, the limited sampling methods might be advantageous in the routine clinical practice

[ effectiveness of non-myeloablative stem cell transplantation and DLI as a selective treatment in class III beta-thalassemic patients]

At present, the only curative treatment for beta-thalassemia major is allogenic bone marrow transplantation accompanied with considerable mortality and morbidity in class III beta-thalassemia. Regarding few case reports on successful non-myeloablative stem cell transplantation in class III beta-thalassemic cases, we evaluated the effectiveness of this type of allogenic stem cell transplantation, considering less toxic non-myeloablative conditioning regimen. In this prospective study in Shariati Hospital bone marrow transplantation center during 2001-3, 13 class III beta-thalassemia patients [on the basis of history and physical examination and liver biopsy] were transplanted with peripheral blood and bone marrow stem cells from their HLA-identical siblings. Non-myeloablative conditioning regimen included fludarabine; busulan; antithymocyte globulin. Graft versus host disease [GVHD] prophylactic regimen was cyclosporin and metothrexate. In the case of the declining chimerism, the patients were treated with donor lymphocyte infusions [DLI]. The conditioning regimen was tolerated well without any considerable toxicity in hematologic, gastrointestinal and pulmonary systems. Five [38.5%] patients had acute and 2[15.4%] had chronic GVHD. Two patients died after transplantation. While two cases had a thalassemia-free survival. Although associated with high graft failure and the recurrence of disease, nonmyeloablative stem cell transplantation may be used as a curative, less toxic posttransplantation treatment for class III beta-thalassemia

[Clinical effects of zataria multiflora essential oil on primary dysmenorrhea]

Dysmenorrhea is one of the most common gynecological complaints in women. The use of Zataria multiflora is recommended in traditional medicine for the relief of dysmenorrhea. The purpose of the study was to determine the efficacy of Zataria multiflora essential oil for the treatment of primary dysmenorrhea. This study was a randomized, double - blind, placebo- controlled, clinical trail. 108 adolescents 18 - 24 years, who complained of primery dysmenorrhea were graded mild, moderate and severe on the basis of a verbal multidimensional scoring system. Subjects were randomly assigned into three groups: The first group [N=36] received placebo, the second group [N=36] received the essence of Zataria multiflora 1% and the third group [N=36] received the essence of Zataria multiflora 2%. The trial medicines were administered as soon as pain feeling [25 drops q 4h orally]. Subjects evaluated for 3 cycles. Intensity of pain was reported by using a 10-point linear analog technique and Multi Dimensional System. Statistical analyses were performed by the paired T- test and Chi - Square and ANOVA test. The accepted level of significant was p < 0.05. After of intervention, Mean of dysmenorrhea severity was decreased from 7.8 +/- 1.6 to 7.4 +/- 1.8 in placebo group, from 7.3 +/- 1.5 to 3.1 +/- 1.5 in Zataria multiflora essential oil 1% group and from 7.5 +/- 1.7 to 2.6 +/- 1.4 in Zataria multiflora essential oil 2% group respectively. A significant difference was observed between two treated groups, and placebo [P<0/001]. The evaluation of treatment is significantly improved in the treated groups compared with placebo, but it was not different between treated groups. In the placebo group, 66.7% of patients needed to use other medication to relief symptoms, but in 1% and 2% Zataria Multiflora essential oil treated groups, 41.8% and 39.9% of patients needed to use other medications, respectively [p< 0/008]. The essence of Zataria multiflora can be used as a effective herbal drug for primary dysmenorrhea

Results of hematopoietic cell transplantation in pediatric leukemia

Hematopoietic cell transplantation [HCT] is an accepted treatment for acute myeloid leukemia [AML] in first remission, the treatment of choice for chronic myeloid leukemia [CML] and high risk groups of ALL who relapse with conventional chemotherapy. We assessed results of HCT for pediatric leukemia in our center. A total of 92 children, 63 with diagnose of AML, 23 with ALL and 6 with CML received allogeneic transplantation from HLA full matched siblings [57.6%] and autologous transplantation [42.4%]. Source of hematopoietic cells were peripheral blood 83.7%, bone marrow 15.2% and cord blood 1.6%. The median transplanted nucleated cells were 6.4 +/- 4.7 X 10[8] /Kg [body weight of patients] and mononuclear cells were 5.5 +/- 2.9 X 10[8]/Kg. The most common conditioning regimens were cyclophosphamide + busulfan. Prophylaxis regimen for GVHD was cyclosporin +/- methotrexate. GVHD occurred in 50 [54.3%] patients. Eighty five of children had engraftment, 26 [28.6%] relapsed and 57 [62%] are alive. The most common cause of death was relapse [68.6%]. Five years overall survival of patients with AML and ALL were 49% and 44% respectively and disease free survival of them were 52% and 49%. One year overall survival and disease free survival of CML was 57%. Overall survival increased with increasing age of patients at transplantation time [P = 0.06]. Longer survival significantly related to earlier WBC and platelet recovery [P < 0.0001 and P = 0.006 respectively]. Considering acceptable overall and disease free survival of patients after HCT, we concluded that is a good modality in treatment of leukemia of children

Useful field of view and risk of accident in simulated car driving

This study investigated the relationship between Useful Field of View and simulator-driving performance measures. Ninety professional drivers, aged 22-65 years from several government organizations voluntarily participated at this study. Useful Field of View was measured by a computerized task was developed at the present study. The participants then performed a driving simulator task and experienced a scenario that could lead to an accident. Reaction time and speed were measured and recorded by simulator and general driving performance and collision events were recorded by examiner. The reduction of Useful Field of View based on subject's error score on Useful Field of View subtests between young and old group statistically was analyzed. Correlation analyses used to examine the relationship among the Useful Field of View as an independent variable and driving performance measures as a dependent variables. A univariate logistic regression analysis was used to determine the extent to which reduction of Useful Field of View predicts risk of accident in simulated car driving. There was a significant and negative correlation between Useful Field of View and simulator performance, on the divided peripheral subtest [Correlation Coefficient-0.28]. Student's t-tests revealed significant differences in peripheral scores of Useful Field of View subtests between accident involved and non-involved groups. The result of logistic regression indicated that 40% reduction of Useftil Field of View, regardless of age, increased risk of accident involvement. Useftil Field of View could be used to predict driving performance and risk of accident. The obtained result can help to identify a high risk driver which is useful to licensing authorities

[Study of the effects of intra venous injection of hyoscine on parturition [labor]]

Despite wide use of hyoscine by midwives and doctors as an adjunct to labor, the obstetrics literature contains few references to the effect of this drug. This study was a double blinded, randomized controlled trial of primigravidas in Iran to determine the effects of hyoscine intravenous injection on parturition [labor]. One hundred primigravidas in uncomplicated spontaneous labor with cervical dilation less than 4 cm and cervical effacement<50% were randomly assigned into two groups; the experimental group [N=50] receiving 20 mg hyoscine and the control group [N=50] receiving placebo, with predetermined codes injected at the beginning of the active phase of labor. The groups were compared for labor progress, fetal tachycardia and bradycardia after 0.5 and 1h of injection, Apgar score and birth weight. Statistical methods for normally distributed variables included 2-tailed student T test and chi-square analysis. The accepted level of significance was p<0.05. The two groups were similar in respect to maternal age, gestational age, initial cervical effacement and dilation and mean birth weight. The mean change in the cervical effacement and dilation after 1 and 2 h of injection was significantly higher in those receiving hyoscine [p<0.0001]. There was a significant difference in the duration of active phase and second stage of labor in the two groups [P<0.0001]. Fetal tachycardia and bradycardia occurred more frequently in patients in the hyoscine group as compared to the control group but the difference was not significant. The difference between the mean first and fifth-minute Apgar score was not significant, too. This small study suggests the benefits of a single dose of hyoscine for labor progress and represents the first attempt to evaluate this medication. However, larger randomized studies are needed to establish the efficacy, safety, and optimal dose of hyoscine

[Early hepatic complication in first year after bone marrow transplantation in major beta thalassemic patients]

Bone marrow transplantation is a good therapeutic modality for beta thalassemia. Liver complications is one of the major causes of morbidity and mortality following BMT. Determination of the factors of liver injury leads to earlier diagnosis after BMT and improves prognosis. We studied 113 major Beta thalassemic patients who have been transplanted from 1990- 2000 in bone marrow transplantation center of Shariati Hospital. 62 were male and 51 were female. 27 patients were class one, 56 were class two and 30 were class three. The median age of each classes were 6.5, 6.3 and 8.7 year. Conditioning regime consisted of busulfan [3.5-4mg/Kg] and cyclophophamide [40-50 mg/kg]. For GVHD prophylaxis we gave cyclosporine +/- metothrexate. Grade of liver fibrosis defined by biopsy in all patients before BMT. All patients and their donors tested for HBsAg, HBsAb, HCVAb, CMVAb with RIA method. We assessed causes of liver dysfunction before and after transplantation and effect of high ferritin level on liver function. Hepatic dysfunction in first year after transplantation were seen in 86 [76%] patients. Causes of liver dysfunction were consisted of 53.1% GVHD, 15.93% cyclosporine hepatotoxicity, 5.3% conditioning regime hepatotoxicity and 1.77% VOD. In all three classes hepatic GVHD, cyclosporine toxicity, death and normal liver function post BMT had significant relation with hepatic dysfunction before BMT [p=0.001]. In patients with ferritin level more than 1000, there were significant hepatotoxicity with conditioning regime [p=0.001]. 17 [15.04%] of patients have been died. In this study we determined incidence and causes of hepatic dysfunction before and after BMT in major beta thalassemic patients. According to our study the incidence of hepatic dysfunction was 76.1% and hepatic GVHD and drug hepotoxicity were the most common causes of hepatic dysfunction in all three classes. Serum ferritin level had not significant relation to GVHD, cyclosporine hepatotoxicity and VOD

Effects of chimerism on graft versus host disease recurrence and survival after HLA identical marrow transplantation in Iran

The co-existence of recipient's hamatopoietic systems after allogeneic marrow transplantation is called mixed chimerism. Chimerism analysis provides a national method of different conditioning regimens, graft-versus-host disease [GVHD], prophylactic regimens, and cellular therapy to promote engraftment. The association of mixed chimerism with acute graft-versus-host disease [GVHD], disease recurrence, survival, and relapse free survival was investigated in 91 patients 12 and 79 of whom underwent either bone or peripheral blood HLA-identical marrow transplantation respectively. Chimerism was assessed using multiplex amplification of shorty tandem repeats [STR-PCR].cases included thalassemics [19 subjects], AML [29], ALL [20], CMT [18] and others [5].Median age was 21 [age range of 3-50]. There were 38 females [41.8%] and 53 males [58.2%]. Conditioning was busulfan plus cyclophosphamide in 34 patients, busulfan plus fludarabin in 51 patients and busulfan plus fludarabin plus anti-thymocyte globulin in 6 patients. Median of follow up was 13 months. Data was analyzed using SPSS statistical software. On day 30 after transplantation, mixed chimerism [MC] was observed in 15 patients [16.5%], complete donor chimerism [CC] in 72 patients [79%], and no chimerism in 4 patients. The incidence of acute GVHD was significantly lower in mixed chimeras that in complete chimeras [p=0.01] but there was no significant difference in acute GVHD grade [I, II vs. III, IV] between two groups. The incidence of relapse and overall survival were 17.6% and 88.9% respectively showing no significant difference between MC and CC. Relapse free survival was 80.2% and significantly different between two groups. Despite some previous reports, we found no significant difference in survival and relapse rate between MC and CC. Relapse free survival was 80.2% and not significantly different between tw ogroup

[Early hepatic complication in frst year after bone marrow transplantation in major beta thalassemic patients]

Bone marrow transplantation is a good therapeutic modality for beta thalassemia. Liver complications is one of the major causes of morbidity and mortality following BMT. Determination of the factors of liver injury leads to earlier diagnosis after BMT and improves prognosis. We studied 113 major Beta thalassemic patients who have been transplanted from 1990- 2000 in bone marrow transplantation center of Shariati Hospital. 62 were male and 51 were female. 27 patients were class one, 56 were class two and 30 were class three. The median age of each classes were 6.5, 6.3 and 8.7 year. Conditioning regime consisted of busulfan [3.5-4mg/Kg] and cyclophophamide [40-50 mg/kg]. For GVHD prophylaxis we gave cyclosporine +/- metothrexate. Grade of liver fibrosis defined by biopsy in all patients before BMT. All patients and their donors tested for HBsAg, HBsAb, HCVAb, CMVAb with RIA method. We assessed causes of liver dysfunction before and after transplantation and effect of high ferritin level on liver function. Hepatic dysfunction in first year after transplantation were seen in 86 [76%] patients. Causes of liver dysfunction were consisted of 53.1% GVHD, 15.93% cyclosporine hepatotoxicity, 5.3% conditioning regime hepatotoxicity and 1.77% VOD. In all three classes hepatic GVHD, cyclosporine toxicity, death and normal liver function post BMT had significant relation with hepatic dysfunction before BMT [p=0.001]. In patients with ferritin level more than 1000, there were significant hepatotoxicity with conditioning regime [p=0.001]. 17 [15.04%] of patients have been died. In this study we determined incidence and causes of hepatic dysfunction before and after BMT in major beta thalassemic patients. According to our study the incidence of hepatic dysfunction was 76.1% and hepatic GVHD and drug hepotoxicity were the most common causes of hepatic dysfunction in all three classes. Serum ferritin level had not significant relation to GVHD, cyclosporine hepatotoxicity and VOD

[Flow cytometric survey of RBC chimerism after bone marrow transplantation]

The aim of the present study was to evaluate red blood cell chimerism after bone marrow transplantation by flow cytometry. In order to perform this assay, FITC labeled antibodies against blood groups ABH, Rh, Kell, Duffy, Kidd, MNS were used.14 hematologic patients under BMT were selected for this study. The required sample was 5 ml peripheral blood that is collected in tubes containing EDTA. At first, donor and recipients red cells phenotypes were identified with the use of both agglutination and flow cytometry methods; then, on post-transplantation days of 15, 30 and 60, only blood samples of the recipients were analyzed by flow cytometry for the antigens differing from donors to recipients. Antibody screening test and titration of ABH Isohemagglutinins were performed on recipients' plasma samples and then repeated on post-transplantation day of 60. After BMT, red cell chimerism was detected in all 14 patients [in 9 patients on post-transplantation day of 15 and in 5 patients on day of 30]. Antibodies against minor blood groups and Rh blood group were not detected at all. The occurrence of chimerism was not inhibited by ABO incompatibility of donors and recipients but in patients who were ABH incompatible with their donors, ABH isohemagglutinins titer following transplantation decreased. Although the presence of isohemagglutinins did not prevent chimerism but it seems these antibodies by attaching to their related antigens on chimeric red cells membrane prevented corresponding antigen detection. Now by using flow cytometry, red cell phenotyping is applicable and reticulocyte analysis is much easier to perform so that chimerism can be detected in patients who have recently experienced blood transfusion. Moreover, through further evaluation of red cell chimerism and detection of recipient autologous red cells, disease relapse can be predicted