scholarly journals Pharmacokinetics and Safety of a 7-Day Administration of Intravenous Itraconazole followed by a 14-Day Administration of Itraconazole Oral Solution in Patients with Hematologic Malignancy

2001 ◽  
Vol 45 (3) ◽  
pp. 981-985 ◽  
Author(s):  
Marc A. Boogaerts ◽  
Johan Maertens ◽  
Ronald Van Der Geest ◽  
Andre Bosly ◽  
Jean-Louis Michaux ◽  
...  
Keyword(s):  
Steady State ◽  
Hematologic Malignancy ◽  
Oral Treatment ◽  
Hematologic Malignancies ◽  
Oral Solution ◽  
Once Daily ◽  
Intravenous Treatment ◽  
Good Safety Profile ◽  
The Mean ◽  
Trough Plasma

ABSTRACT The pharmacokinetics and safety of an intravenous hydroxypropyl-β-cyclodextrin solution of itraconazole administered for 7 days followed by itraconazole oral solution administered at 200 mg once or twice daily for 14 days were assessed in 17 patients with hematologic malignancies. Steady-state plasma itraconazole concentrations were reached by 48 h after the start of intravenous treatment. The mean trough plasma itraconazole concentration at the end of the intravenous treatment was 0.54 ± 0.20 μg/ml. This concentration was not maintained during once-daily oral treatment but increased further in the twice-daily treatment group, with a trough itraconazole concentration of 1.12 ± 0.73 μg/ml at the end of oral treatment. As expected in the patient population studied, all patients experienced some adverse events (mainly gastrointestinal). Biochemical and hematologic abnormalities were frequent, but no consistent changes occurred. In conclusion, 7 days of intravenous treatment followed by 14 days of twice-daily oral treatment with itraconazole solution enables plasma itraconazole concentrations of at least 0.5 μg/ml to be reached rapidly and to be maintained. The regimen is well tolerated and has a good safety profile.

scholarly journals Comparison of Plasma, Epithelial Lining Fluid, and Alveolar Macrophage Concentrations of Solithromycin (CEM-101) in Healthy Adult Subjects

2012 ◽  
Vol 56 (10) ◽  
pp. 5076-5081 ◽  
Author(s):  
Keith A. Rodvold ◽  
Mark H. Gotfried ◽  
J. Gordon Still ◽  
Kay Clark ◽  
Prabhavathi Fernandes
Keyword(s):  
Steady State ◽  
High Performance ◽  
Healthy Adult ◽  
Plasma Concentrations ◽  
Epithelial Lining ◽  
Time Curve ◽  
Epithelial Lining Fluid ◽  
Once Daily ◽  
Drug Concentrations ◽  
The Mean

ABSTRACTThe steady-state concentrations of solithromycin in plasma were compared with concomitant concentrations in epithelial lining fluid (ELF) and alveolar macrophages (AM) obtained from intrapulmonary samples during bronchoscopy and bronchoalveolar lavage (BAL) in 30 healthy adult subjects. Subjects received oral solithromycin at 400 mg once daily for five consecutive days. Bronchoscopy and BAL were carried out once in each subject at either 3, 6, 9, 12, or 24 h after the last administered dose of solithromycin. Drug concentrations in plasma, ELF, and AM were assayed by a high-performance liquid chromatography-tandem mass spectrometry method. Solithromycin was concentrated extensively in ELF (range of mean [± standard deviation] concentrations, 1.02 ± 0.83 to 7.58 ± 6.69 mg/liter) and AM (25.9 ± 20.3 to 101.7 ± 52.6 mg/liter) in comparison with simultaneous plasma concentrations (0.086 ± 0.070 to 0.730 ± 0.692 mg/liter). The values for the area under the concentration-time curve from 0 to 24 h (AUC0–24values) based on mean and median ELF concentrations were 80.3 and 63.2 mg · h/liter, respectively. The ratio of ELF to plasma concentrations based on the mean and median AUC0–24values were 10.3 and 10.0, respectively. The AUC0–24values based on mean and median concentrations in AM were 1,498 and 1,282 mg · h/L, respectively. The ratio of AM to plasma concentrations based on the mean and median AUC0–24values were 193 and 202, respectively. Once-daily oral dosing of solithromycin at 400 mg produced steady-state concentrations that were significantly (P< 0.05) higher in ELF (2.4 to 28.6 times) and AM (44 to 515 times) than simultaneous plasma concentrations throughout the 24-h period after 5 days of solithromycin administration.

Phase II Evaluation of the Tyrosine Kinase Inhibitor MLN518 in Patients with Acute Myeloid Leukemia (AML) Bearing a FLT3 Internal Tandem Duplication (ITD) Mutation.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1792-1792 ◽  
Author(s):  
Daniel J. De Angelo ◽  
Richard M. Stone ◽  
Mark L. Heaney ◽  
Stephen D. Nimer ◽  
Ronald Paquette ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Steady State ◽  
Phase Ii ◽  
Plasma Concentrations ◽  
Remission Induction ◽  
Western Blots ◽  
Adequate Treatment ◽  
The Mean ◽  
Trough Plasma ◽  
Bone Marrow Blasts

Abstract MLN518 is a small molecule inhibitor of FLT3, PDGFR and c-Kit that is currently being evaluated as a therapy for AML. Previous phase I evaluation of MLN518 showed that it inhibits the phosphorylation of both wild-type and ITD-mutated FLT3 in patients’ leukemic blasts with an IC90 in the range of 100–175 ng/mL. Anti-leukemic activity was also observed, with decreases in both peripheral and bone marrow blasts. Dose-limiting toxicity, consisting of reversible general muscular weakness and/or fatigue was associated with trough plasma MLN518 concentrations > 1000 ng/mL. We are now conducting a phase II study of MLN518 in patients with relapsed or refractory AML and in untreated patients with AML considered unfit for standard AML therapies. Eligibility requires demonstration of the FLT3 ITD mutation in the patient’s blasts. All patients are treated with MLN518 at an initial dose of 525 mg po bid, with provision for dose reduction if MLN518-associated weakness occurs. Twenty patients have been treated with MLN518 in this study, eighteen of whom are currently evaluable (2 patients have recently started therapy). Toxicities associated with MLN518 therapy have included weakness/fatigue, QTc prolongation (relationship to MLN518 uncertain), and nausea and vomiting. MLN518 plasma concentration-time data for the first fourteen patients demonstrates that all patients achieved steady-state trough plasma concentrations > 150 ng/mL. Both inter- and intra-subject variability (%CV) in trough steady-state concentrations were < 30%. Assessment of total and phosphorylated FLT3 in leukemic blasts isolated from peripheral blood was possible in 4 patients. Western blots from blasts obtained before and after MLN518 dosing demonstrated either partial or complete inhibition of FLT3 phosphorylation with MLN518 plasma concentrations > 130 ng/mL. Of the eighteen evaluable patients, response could not be assessed in three because intercurrent illness and/or MLN518-associated toxicity precluded adequate treatment with MLN518 (≥ 14 days). Seven patients experienced progressive AML without evidence of any anti-leukemic effect. Two patients had stable disease for ≥ 50 days and subsequently underwent bone marrow transplantation. Although no complete or partial remissions have been observed, 6 patients have demonstrated evidence of an anti-leukemic effect with decreases in both peripheral and bone marrow blasts of 1-3 months duration. In these 6 patients the mean decrease in the absolute peripheral blast count was 92%, with a range of 85–100%. The mean decrease in the bone marrow blast percentage was 62%, with a range of 44–94%. We conclude that MLN518 has anti-leukemic activity in FLT3 ITD-mutated AML and should be further evaluated as a component of remission-induction and/or maintenance therapy in this disease.

scholarly journals Steady-State Plasma and Bronchopulmonary Concentrations of Intravenous Levofloxacin and Azithromycin in Healthy Adults

2003 ◽  
Vol 47 (8) ◽  
pp. 2450-2457 ◽  
Author(s):  
Keith A. Rodvold ◽  
Larry H. Danziger ◽  
Mark H. Gotfried
Keyword(s):  
Steady State ◽  
Intravenous Administration ◽  
Epithelial Lining Fluid ◽  
Once Daily ◽  
Dosing Regimens ◽  
The Mean ◽  
Tract Infections ◽  
Antibiotic Infusion ◽  
Sampling Times ◽  
State Plasma

ABSTRACT The purpose of this study was to compare the concentrations of levofloxacin and azithromycin in steady-state plasma, epithelial lining fluid (ELF), and alveolar macrophage (AM) after intravenous administration. Thirty-six healthy, nonsmoking adult subjects were randomized to either intravenous levofloxacin (500 or 750 mg) or azithromycin (500 mg) once daily for five doses. Venipuncture and bronchoscopy with bronchoalveolar lavage were performed in each subject at either 4, 12, or 24 h after the start of the last antibiotic infusion. The mean concentrations of levofloxacin and azithromycin in plasma were similar to those previously published. The dosing regimens of levofloxacin achieved significantly (P < 0.05) higher concentrations in steady-state plasma than azithromycin during the 24 h after drug administration. The respective mean (± standard deviation) concentrations at 4, 12, and 24 h in ELF for 500 mg of levofloxacin were 11.01 ± 4.52, 2.50 ± 0.97, and 1.24 ± 0.55 μg/ml; those for 750 mg of levofloxacin were 12.94 ± 1.21, 6.04 ± 0.39, and 1.73 ± 0.78 μg/ml; and those for azithromycin were 1.70 ± 0.74, 1.27 ± 0.47, and 2.86 ± 1.75 μg/ml. The differences in concentrations in ELF among the two levofloxacin groups and azithromycin were significantly (P < 0.05) higher at the 4- and 12-h sampling times. The respective concentrations in AM for 500 mg of levofloxacin were 83.9 ± 53.2, 18.3 ± 6.7, and 5.6 ± 3.2 μg/ml; those for 750 mg of levofloxacin were 81.7 ± 37.0, 78.2 ± 55.4, and 13.3 ± 6.5 μg/ml; and those for azithromycin were 650 ± 259, 669 ± 311, and 734 ± 770 μg/ml. Azithromycin achieved significantly (P < 0.05) higher concentrations in AM than levofloxacin at all sampling times. The concentrations in ELF and AM following intravenous administration of levofloxacin and azithromycin were higher than concentrations in plasma. Further studies are needed to determine the clinical significance of such high intrapulmonary concentrations in patients with respiratory tract infections.

scholarly journals Montelukast in Allergic Rhinitis: A Review

2013 ◽  
Vol 24 (2) ◽  
pp. 75-78
Author(s):  
MAN Chowdhury ◽  
MS Uddin ◽  
S Das ◽  
M Hoque
Keyword(s):  
Allergic Rhinitis ◽  
Oral Treatment ◽  
Persistent Asthma ◽  
Ease Of Use ◽  
Once Daily ◽  
New Class ◽  
Good Safety Profile ◽  
Biologic Effect ◽  
Medicine Today ◽  
The U.S

Leukotriene inhibitors are the first new class of medications for the treatment of persistent asthma that have been approved by the U.S food and drug Administration in more than two decades. They also have been approved for the treatment of Allergic Rhinitis. Leukotrienes are inflammatory mediators that are known as the slow-reacting substance of anaphylaxis. Synthesis of these mediators results from the cleavage of arachidonic acid in cell membranes, exert their biologic effect by binding and activating specific adaptors. This occurs in a series of events that lead to their important role in the Allergic Rhinitis. Because agents lead to the production of symptoms, the use of leukotriene inhibitors, particularly montelukast seems appropriate. These classes of drug can block the binding of leukotrienes to CysLT1 receptors and can also result in the prevention of leukotriene activity. Montelukast is the most commonly used inhibitor of the leukotriene pathway because of its ease of use , good safety profile, and once-daily regimen. We conduct a systematic review of studies that have evaluated montelikast in the treatment of Allergic Rhinitis. This review focuses on the pathophysiology and effect of montelukast in Allergic Rhinitis. The purpose of this paper is to provide an overview of the accumulation data concerning these agents in treating Allergic Rhinitis. Montelukast provides an effective and well tolerated oral treatment for Allergic Rhinitis.DOI: http://dx.doi.org/10.3329/medtoday.v24i2.15012 Medicine Today 2012 Vol.24(2): 75-78 

Pharmacokinetics of 5-Azacitidine Administered With Phenylbutyrate in Patients With Refractory Solid Tumors or Hematologic Malignancies

2005 ◽  
Vol 23 (17) ◽  
pp. 3906-3911 ◽  
Author(s):  
Michelle A. Rudek ◽  
Ming Zhao ◽  
Ping He ◽  
Carol Hartke ◽  
Jill Gilbert ◽  
...  
Keyword(s):  
Area Under The Curve ◽  
Hematologic Malignancies ◽  
Pharmacokinetic Data ◽  
Transferase Activity ◽  
Liquid Chromatograph ◽  
Methyl Transferase ◽  
Once Daily ◽  
Average Maximum ◽  
The Mean ◽  
Pharmacokinetic Behavior

PurposeTo characterize the pharmacokinetic behavior of 5-azacitidine (5-AC), a cytidine nucleoside analog, when given with phenylbutyrate, a histone deaceytlase inhibitor.Patients and MethodsPharmacokinetic data were obtained from two trials involving patients with solid tumor and hematologic malignancies. 5-AC at doses ranging from 10 to 75 mg/m2/d was administered once daily as a subcutaneous injection for 5 to 21 days in combination with phenylbutyrate administered as a continuous intravenous infusion for varying dose and duration every 28 or 35 days. Serial plasma samples were collected up to 24 hours after 5-AC administration. 5-AC was quantitated using a validated liquid chromatograph/tandem mass spectrometry method.Results5-AC was rapidly absorbed with the mean Tmaxoccurring at 0.47 hour. Average maximum concentration (Cmax) and area under the curve (AUC0-∞) values increased in a dose-proportionate manner with increasing dose from 10 to 75 mg/m2/d; the mean ± SD Cmaxand AUC0-∞at 10 mg/m2/d were 776 ± 459 nM and 1,355 ± 1,125 h*nM, respectively, and at 75 mg/m2/d were 4,871 ± 1,398 nM and 6,582 ± 2,560 h*nM, respectively. Despite a short terminal half-life of 1.5 ± 2.3 hours, inhibition of DNA methyl transferase activity in tumors of patients receiving 5-AC has been documented.Conclusion5-AC is rapidly absorbed and eliminated when administered subcutaneously. Sufficient 5-AC exposure is achieved to produce pharmacodynamic effects in tumors.

Effectiveness of Darbepoetin alfa Administered Every 3 Weeks on Clinical Outcomes in Patients with Hematologic Malignancies and Chemotherapy-Induced Anemia.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3767-3767 ◽  
Author(s):  
Ralph Vincent Boccia ◽  
Peter T. Silberstein ◽  
Simon Tchekmedyian ◽  
Dianne Tomita ◽  
Greg Rossi ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Darbepoetin Alfa ◽  
Hematologic Malignancy ◽  
Hematologic Malignancies ◽  
Target Range ◽  
Tumor Type ◽  
Open Label ◽  
Serious Adverse Events ◽  
The Mean ◽  
Tumor Types

Abstract Patients (pts) with cancer receiving chemotherapy commonly have chemotherapy-induced anemia (CIA), often resulting in reduced quality of life. The primary objective of this analysis was to summarize the effectiveness of darbepoetin alfa (DA) administered at 300mcg every 3 weeks (Q3W), in achieving and maintaining a hemoglobin (Hb) target range of 11–13g/dL in pts with hematologic malignancies and CIA, versus pts with solid tumors and CIA. Data for all 1493 pts enrolled in this multicenter, open-label, 16-week study who received at least one dose of DA are included in this exploratory analysis stratified by tumor type. Pts ≥18 years of age receiving multicycle chemotherapy and with Hb &lt;11g/dL were eligible for this study. Hb-based endpoints were adjusted for red blood cell transfusions and analyzed with and without imputing missing Hb values. Pt-reported outcomes were assessed using the Functional Assessment of Cancer Therapy-Fatigue (FACT-F) scale. Most pts were white (79%), 61% were female, and the median age was 64 years (range, 19 to 97). At baseline (BL), 31% of pts had Hb &lt;10g/dL and 61% had Hb ≥10g/dL; the mean (SD) was 10.1 (0.7)g/dL. Hematologic malignancy (14%) was the third most common tumor type after breast (29%) and gastrointestinal (24%); 45% of the hematologic malignancies were non-Hodgkin’s lymphoma (NHL) pts. Hb, transfusion, and FACT-F endpoints are shown in the table. A slightly lower percent of NHL pts achieved the Hb target range recommended by current guidelines (11–13g/dL), compared to pts with other hematologic malignancies or with solid tumors. Similar proportions of pts with hematologic malignancies or solid tumors maintained Hb within the target range. The proportion of pts receiving RBC transfusions from week 5 to the end of study (EOS) was similar for pts with hematologic malignancies and for pts with solid tumors. Improvements in FACT-F scores were seen in all groups, although the mean change was lower in NHL pts compared with other tumor types. Serious adverse events were as expected for this patient population. DA Q3W appears to be effective in achieving and maintaining Hb between 11 to 13g/dL in pts with CIA and hematologic malignancies. Since chemotherapy is often administered Q3W, synchronizing DA treatment with pts’ chemotherapy schedules may simplify the treatment of CIA in these pts. Hematologic - NHL N=98 Hematologic - non-NHL N=118 Solid N=1277 All Tumor Types N=1493 *For pts who achieved target. **For pts available at day 29. K-M=Kaplan Meier. CL=confidence limits Mean (95%CL) BL Hb (g/dL) 10.1 (9.9, 10.2) 10.0 (9.8, 10.1) 10.1 (10.1, 10.2) 10.1 (10.1, 10.2) Pts who achieved ≥ Hb 11g/dL. Crude % (95% CL) 74 (66, 83) 82 (75, 89) 79 (77, 81) 79 (77, 81) Proportion of pts maintaining Hb between 11 and 13g/dL after achieving target - n (%)* 51 (70) 68 (70) 739 (73) 858 (73) Time to target Hb (weeks). K-M Median (95% CL) 7 (6, 8) 6 (4, 7) 4 (4, 5) 4 (4, 5) Transfusions from week 5 to EOS. Crude % (95% CL)** 21 (13, 30) 20 (13, 27) 18 (16, 20) 18 (16, 20) Mean change in FACT-F from BL to week 16 (95% CL) 2.8 (−0.9, 6.5) 5.2 (1.8, 8.6) 4.8 (3.9, 5.7) 4.7 (3.9, 5.6)

Non-AIDS-Defining Hematologic Malignancies in HIV-Infected Patients: A Nationwide Epidemiologic Study in Japan

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2183-2183
Author(s):  
Shotaro Hagiwara ◽  
Mihoko Yotsumoto ◽  
Seiji Okada
Keyword(s):  
Complete Remission ◽  
Hiv Infection ◽  
Highly Active Antiretroviral Therapy ◽  
Conflicts Of Interest ◽  
Hematologic Malignancy ◽  
Epidemiologic Study ◽  
Fold Increase ◽  
Hematologic Malignancies ◽  
The Mean ◽  
Hodgkin's Lymphomas

Abstract Abstract 2183 Background. The prevalence of HIV infection is estimated to be less than 0.1% in Japan; however, the number of newly reported HIV-infected persons has gradually increased, and the estimated number of HIV-infected patients now ranges from 6300 to 10000. Since the introduction of highly active antiretroviral therapy (HAART), the morbidity and incidence of AIDS-defining cancers has decreased. However, the incidence of non-AIDS-defining cancers has increased in Japan. To elucidate the incidence and clinical outcome of non-AIDS-defining hematologic malignancies, excluding non-Hodgkin's lymphomas, in HIV-infected patients, we conducted a nationwide epidemiologic study. Methods. We surveyed 429 regional AIDS centers and 497 educational hospitals certified by the Japanese Society of Hematology. Epidemiologic data for HIV was sourced from the Joint United Nations program on HIV/AIDS. Results. We obtained data from 511 institutes (55.4%). From 1991 to 2010, 47 cases of non-AIDS-defining hematologic malignancies were found—19 cases of Hodgkin's lymphoma (HD), 13 of AML, 7 of ALL, 4 of CML, 2 of multiple myeloma, 1 of CLL, and 1 of MDS-RAEB1. The mean age was 49.3 years (21–70 years), and 93.6% patients were male. The mean CD4-positive cell count was 303.7/μL (1–1371/μL). The mean duration from the diagnosis of HIV infection to hematologic malignancy was 45.0 months (0–204 months). Before diagnosis, 68.1% patients had been treated with HAART and 51.1% patients had AIDS. Sixteen of 19 HD patients were treated with ABVD or radiation therapy. Of these, 80% patients achieved complete remission, with a 2-year overall survival of 62.3%. Twelve of AML and 6 of ALL patients were treated with standard induction chemotherapy. Eight of twelve patients (66.7%) with AML and five of six patients (83.3%) achieved complete remission. The median survival for both AML and ALL patients was 16 months, with 42.8% ALL and 30.8% AML patients alive after 4 years. Comparison of the last 2 decades (1991–2000 and 2001–2010) showed a 4.7-fold increase in the incidence of hematologic malignancies (11.5 vs. 54.6/100000 person-years). Conclusion. A nationwide epidemiologic study revealed that HIV-infected patients are at high risk of hematologic malignancies, and that the incidence of hematologic malignancies has increased in the past decade. The prognosis was equivalent to that of HIV-negative patients, and standard chemotherapy may be a feasible treatment option for HIV-infected patients with hematologic malignancies. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Concentrations in plasma and safety of 7 days of intravenous itraconazole followed by 2 weeks of oral itraconazole solution in patients in intensive care units.

1997 ◽  
Vol 41 (12) ◽  
pp. 2714-2718 ◽  
Author(s):  
K Vandewoude ◽  
D Vogelaers ◽  
J Decruyenaere ◽  
P Jaqmin ◽  
K De Beule ◽  
...  
Keyword(s):  
Intensive Care ◽  
Oral Treatment ◽  
Treatment Phase ◽  
Oral Solution ◽  
Severe Illness ◽  
Once Daily ◽  
Oral Itraconazole ◽  
Repeated Administrations ◽  
Trough Concentrations

Pharmacokinetics and safety of a hydroxy-beta-propyl solution of itraconazole were assessed in 16 patients in an intensive care unit. On the first 2 days, four 1-h infusions of 200 mg were given at 0, 8, 24, and 32 h. From day 3 to 7, inclusive, a single 1-h infusion of 200 mg of itraconazole was given daily. The intravenous (i.v.) treatment was directly followed by repeated administrations of an oral solution of itraconazole at a dosage of either 200 mg once daily or 200 mg twice daily (b.i.d.). During i.v. treatment, steady-state concentrations of itraconazole and hydroxy-itraconazole in plasma were reached within 48 and 96 h, respectively. At the end of i.v. treatment, mean (+/- standard deviation) itraconazole and hydroxy-itraconazole trough concentrations in plasma were 0.344 +/- 0.140 and 0.605 +/- 0.205 microg/ml, respectively. After the 2-week oral follow-up of 200 mg once daily the mean trough concentration had decreased to 0.245 microg/ml, whereas after 200 mg b.i.d. it increased to 0.369 microg/ml. Diarrhea during oral treatment appeared to be dose related and may be due to the solvent hydroxypropyl-beta-cyclodextrin. More severe laboratory abnormalities were noted during the i.v. than the oral treatment phase, probably related to more severe illness in that period of intensive care, but none proved clinically important. These results suggest that plasma itraconazole levels above 0.250 microg/ml may be achieved and maintained with the 1-week i.v. schedule followed by b.i.d. oral administration, whereas the once-daily oral follow-up seems to be a suboptimal treatment.

Anticipation in familial hematologic malignancies

Blood ◽  
2011 ◽  
Vol 117 (4) ◽  
pp. 1308-1310 ◽  
Author(s):  
Elizabeth M. Tegg ◽  
Russell J. Thomson ◽  
Jim M. Stankovich ◽  
Annette Banks ◽  
Katherine A. Marsden ◽  
...  
Keyword(s):  
B Cell ◽  
First Generation ◽  
Hematologic Malignancy ◽  
Hematologic Malignancies ◽  
Age At Diagnosis ◽  
Subsequent Generation ◽  
The Third ◽  
Cell Neoplasm ◽  
The Mean ◽  
Insight Into

Abstract We describe a collection of 11 families with ≥ 2 generations of family members whose condition has been diagnosed as a hematologic malignancy. In 9 of these families there was a significant decrease in age at diagnosis in each subsequent generation (anticipation). The mean age at diagnosis in the first generation was 67.8 years, 57.1 years in the second, and 41.8 years in the third (P < .0002). This was confirmed in both direct parent-offspring pairs with a mean reduction of 19 years in the age at diagnosis (P = .0087) and when the analysis was repeated only including cases of mature B-cell neoplasm (P = .0007). We believe that these families provide further insight into the nature of the underlying genetic mechanism of predisposition in these families.

scholarly journals Acyclovir Levels in Serum and Cerebrospinal Fluid after Oral Administration of Valacyclovir

2003 ◽  
Vol 47 (8) ◽  
pp. 2438-2441 ◽  
Author(s):  
Jan Lycke ◽  
Clas Malmeström ◽  
Lars Ståhle
Keyword(s):  
Multiple Sclerosis ◽  
Clinical Trial ◽  
Cerebrospinal Fluid ◽  
Renal Function ◽  
Steady State ◽  
Oral Treatment ◽  
Time Curve ◽  
Minimum Concentration ◽  
Concentration Time ◽  
The Mean

ABSTRACT The possible involvement of herpesviruses in the pathogenesis of multiple sclerosis (MS) was recently investigated in a clinical trial of valacyclovir in patients with MS. As an important part of that survey we performed an independent pharmacokinetic study in order to determine the concentration of acyclovir in cerebrospinal fluid (CSF). The concentrations of acyclovir in serum and CSF were measured at steady state after 6 days of oral treatment with 1,000 mg of valacyclovir three times a day. Samples were obtained from 10 patients with MS. All patients had normal renal function, and none had signs of a damaged blood-CSF barrier. The maximum concentration of acyclovir in serum was reached after 1 to 3 h (mean ± standard deviation [SD], 27.1 ± 5.6 μM), and the minimum concentration in serum was 3.1 ± 1.1 μM (mean ± SD). The acyclovir concentrations in CSF at 2 and 8 h were essentially stable, with the mean ± SD levels being 2.5 ± 0.9 and 2.3 ± 0.7 μM, respectively. Similar levels were recorded in serum and CSF samples from five other MS patients after 6 months of oral treatment with valacyclovir at identical dosages. The area under the concentration-time curve (AUC) for acyclovir in CSF to the AUC for acyclovir in serum (CSF/serum AUC ratio) was approximately 20%. We conclude that the improved bioavailability previously reported for valacyclovir in plasma results in higher concentrations in CSF, while the CSF/serum AUC ratio remains constant.

Sign in / Sign up

Export Citation Format

Share Document