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Dosing Schedule (dosing + schedule)
Selected AbstractsThe Effect of Different Dosing Schedules of UCN-01 on its Pharmacokinetics and Cardiohaemodynamics in DogsJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 11 2000N. KURATA 7-Hydroxy-staurosporine (UCN-01) is now under development as a novel anticancer drug. In clinical studies, different infusion schedules are being investigated in the USA and Japan. To examine the effect of different infusion schedules on the pharmacokinetics and cardiohaemodynamics of UCN-01, dogs were treated with UCN-01 as either a 3-h or a 24-h constant intravenous infusion. Blood pressure and heart rate, together with UCN-01 concentrations during and after infusion, were monitored. To analyse the relationship between the pharmacokinetics and cardiohaemodynamics of UCN-01, the plasma concentration of UCN-01 at the end of infusion (Cend), the area under the plasma concentration versus time curves (AUC0-,) and the mean residence time (MRT) were used. As indices of cardiohaemodynamic changes, the area under decreasing systolic blood pressure and increasing heart rate versus time curves (dAUCpressure and AUCheart rate) were calculated by the trapezoidal method. For the 3-h (0.22 and 0.65 mgkg,1) and 24-h infusion (0.81 to 6.48 mgkg,1), systolic and diastolic blood pressures fell after or during infusions, accompanied by a dose-dependent increase in heart rate for both infusions. During both infusion schedules, the plasma concentrations of UCN-01 gradually increased and Cend showed a dose-proportional increase. After that, UCN-01 was eliminated bi-exponentially with an elimination half-life of 5.14 ± 1.12 to 8.32 ± 1.80 h. The total clearance (CLtotal) ranged from 0.383 to 0.666 ± 0.149L h,1kg,1. There was no significant difference in these parameters among the doses in each infusion schedule, indicating that UCN-01 has a linear pharmacokinetic profile over the dose range examined for each infusion, and there were also no significant differences between the 3-h and 24-h infusion except for MRT. The pharmacokinetic parameters of Cend, AUC0-, and slope0-3h exhibited a degree of correlation with the AUCheart rate in the 3-h infusion and correlated significantly with the dAUCpressure in the 24-h infusion. The MRT did not correlate with cardiohaemodynamic changes during either infusion. In conclusion, the pharmacokinetic profile of UCN-01 after the shorter infusion is similar to that after the longer one. However, a longer dosing period of UCN-01 increased the residence time in comparison with the shorter infusion. This may be due to the effect on the circulatory function in dogs. [source] Botulinum Toxin Type B for Dynamic Glabellar Rhytides Refractory to Botulinum Toxin Type ADERMATOLOGIC SURGERY, Issue 5 2003Tina S. Alster MD Background. Botulinum toxin type B (BTX-B; Myobloc) has recently been introduced for the treatment of dynamic rhytides. This serotype is structurally similar to botulinum toxin type A (BTX-A; Botox) and appears to produce equivalent muscular paralysis. Because of the fact that some patients may become resistant to the effects of BTX-A with its continued use or may require large doses of type A to exert adequate muscular paralysis, the use of BTX-B may prove beneficial in these cases. Objective. To determine the effect of BTX-B on glabellar rhytides refractory or showing decreased clinical effect to treatment with BTX-A. Methods. Twenty females (mean age, 43 years) with vertical glabellar rhytides showing decreased or negligible clinical effect to BTX-A were treated with intramuscular injections of BTX-B. Five standardized intramuscular sites (procerus, inferomedial corrugator muscles, superior middle corrugator muscles) received a total dose of 2,500 U. Patients were evaluated at pretreatment and 48 to 72 hours, 1 week, and 2 and 4 months after injection. Results. All glabellar rhytides improved after treatment with BTX-B injections. Peak clinical effect was noted 1 month after treatment, with 50% of peak effect evident at the 2-month follow-up. Near complete dissolution of effect was seen at 4 months after treatment. Side effects were transient and were limited to moderate injectional pain and rare bruising and frontal brow tightness. Conclusions. BTX-B is an effective treatment modality for glabellar rhytides refractory or exhibiting decreased clinical effect to BTX-A. The duration of effect using the 2,500 U dosing schedule described herein was shorter than that typically achieved after equivalent BTX-A injection. [source] Pharmacoeconomics of factor dosing in the haemophilia populationHAEMOPHILIA, Issue 2006E. BERNTORP Summary., Treatment of haemophilia is extremely costly due to the short biological half-life of infused factor and pricing issues. This paper examines the impact of different dosing schedules on factor consumption, via a review of literature on dosing regimens used for prophylaxis with a focus on pharmacokinetics (PK). Pharmacokinetics were found to have an important role for pharmacoeconomics in factor dosing both for assessment of the treatment and for developing new treatment protocols but the clinical response to treatment must always guide the dosing schedule. In order to better understand pharmacoeconomics during prophylaxis, controlled prospective studies are needed but much can also be learned from studies of existing cohorts that have been treated for decades. [source] Phase II study of arsenic trioxide and ascorbic acid for relapsed or refractory lymphoid malignancies: a Wisconsin Oncology Network study,HEMATOLOGICAL ONCOLOGY, Issue 1 2009JE Chang Abstract Arsenic trioxide (As2O3) has established clinical activity in acute promyelocytic leukaemia and has pre-clinical data suggesting activity in lymphoid malignancies. Cell death from As2O3 may be the result of oxidative stress. Agents which deplete intracellular glutathione, such as ascorbic acid (AA), may potentiate arsenic-mediated apoptosis. This multi-institution phase II study investigated a novel dosing schedule of As2O3 and AA in patients with relapsed or refractory lymphoid malignancies. Patients received As2O3 0.25,mg/kg IV and AA 1000,mg IV for five consecutive days during the first week of each cycle followed by twice weekly infusions during weeks 2,6. Cycles were repeated every 8 weeks. The primary end point was objective response. In a subset of patients, sequential levels of intracellular glutathione and measures of Bcl-2 and Bax gene expression were evaluated in peripheral blood mononuclear cells during treatment. Seventeen patients were enrolled between March 2002 and February 2004. The median age was 71, and the majority of enrolled patients had non-Hodgkin's lymphoma (12/17). Sixteen patients were evaluable, and one patient with mantle cell lymphoma achieved an unconfirmed complete response after five cycles of therapy for an overall response rate of 6%. The trial, which had been designed as a two-stage study, was closed after the first stage analysis due to lack of activity. Haematologic toxicities were the most commonly reported events in this heavily pre-treated population, and comprised the majority of grade 3 and 4 toxicities. Intracellular depletion of glutathione was not consistently observed during treatment. As2O3 and AA in this novel dosing strategy was generally well tolerated but had limited activity in patients with relapsed and refractory lymphoid malignancies. Copyright © 2008 John Wiley & Sons, Ltd. [source] Albinterferon alfa-2b dosed every two or four weeks in interferon-naïve patients with genotype 1 chronic hepatitis C,,HEPATOLOGY, Issue 2 2008Stefan Zeuzem The efficacy and safety of albinterferon alfa-2b (alb-IFN), a novel recombinant protein consisting of interferon alfa-2b genetically fused to human albumin, was evaluated in a phase 2b, open-label study of patients with genotype 1, chronic hepatitis C. In all, 458 IFN-alfa treatment-naïve patients were randomized to 48-week treatment with peginterferon alfa (PEG-IFN,)-2a 180 ,g one time per week (qwk), or alb-IFN 900 or 1,200 ,g once every two weeks (q2wk), or 1,200 ,g once every four weeks (q4wk), administered subcutaneously, plus weight-based oral ribavirin 1,000 or 1,200 mg/day. Hepatitis C virus RNA was measured by real-time polymerase chain reaction (limit of detection: 10 IU/mL). The primary efficacy endpoint was sustained virologic response (hepatitis C virus RNA <10 IU/mL 24 weeks after the end of treatment). By intention-to-treat analysis, sustained virologic response rates were 58.5% (69/118) with alb-IFN 900 ,g q2wk, 55.5% (61/110) with 1,200 ,g q2wk, and 50.9% (59/116) with 1,200 ,g q4wk, and 57.9% (66/114) with PEG-IFN,-2a (P = 0.64 for overall test). Discontinuation rates due to adverse events were 9.3% with alb-IFN 900 ,g q2wk, 18.2% with 1,200 ,g q2wk and 12.1% with 1,200 ,g q4wk, and 6.1% with PEG-IFN,-2a (P = 0.04). Hematologic reductions were lowest in the q4wk group and comparable across other groups. At week 12, mean treatment-associated missed workdays were significantly lower with alb-IFN 900 ,g q2wk versus PEG-IFN,-2a (1.1 versus 4.3 days; P = 0.006). Conclusion: Alb-IFN administered q2wk or q4wk may offer comparable efficacy, with an improved dosing schedule, compared with PEG-IFN,-2a. (HEPATOLOGY 2008;48:407,417.) [source] Evaluation of the off-label usage of rituximab in a large teaching hospital in New South WalesINTERNAL MEDICINE JOURNAL, Issue 8 2007R. Sharma Abstract A retrospective review of patients receiving rituximab off label in a large teaching hospital was conducted between July 2002 and January 2006. The indication, dosing regimen, efficacy and cost of rituximab were evaluated. Rituximab was prescribed for three clinical indications; acute organ transplant rejection, post-transplant lymphoproliferative disease and autoimmune disease. On average, 600 mg of rituximab was prescribed weekly for 4 weeks, costing the hospital $108 739.37. We suggest an initial approval for a limited number of doses with subsequent approval dependent on improvement in predefined clinical or biochemical end-points. Furthermore, we suggest an Australia-wide central database be established to enable delineation of the optimal dosing schedule, as well as monitoring of clinical outcome. [source] Long-term outcome of postoperative interferon-, adjuvant therapy for non-metastatic renal cell carcinomaINTERNATIONAL JOURNAL OF UROLOGY, Issue 5 2004AKINOBU GOTOH Abstract Aim: To investigate the long-term efficacy of postoperative interferon-, (IFN-,) adjuvant therapy in preventing recurrence in non-metastatic renal cell carcinoma treated with radical nephrectomy and to identify related prognostic markers. Methods: Long-term follow-up was conducted to study rates of survival and non-recurrence in 88 subjects following radical nephrectomy for non-metastatic disease. Results: The overall survival rate was 90% at 5 years and 88% at 10, with corresponding non-recurrence rates of 81% and 74%. Survival rates reviewed by preadministration pT stage showed a falling tendency from T1 through to T3 in line with pathological progression; when cases at stage pT1b or below were compared with those at stage pT2 or above, the latter showed a tendency to lower survival rates (P = 0.0966, Breslow-Gehan-Wilcoxon). Similarly, non-recurrence rates tended to fall in line with pathological progression, with a significant difference found in the comparison of cases at stage pT1b or below with those at stage pT2 or above (P = 0.0265, log,rank, Mantel-Cox). Duration of IFN-, administration showed a tendency to positive correlation with long-term survival (P = 0.3765, Breslow-Gehan-Wilcoxon). Non-recurrence rate was not found to differ according to duration of administration. Comparison of groups with normal and abnormal preadministration immunosuppressive acidic protein values showed that the normal group tended to have higher rates of survival and non-recurrence (P = 0.3371, Breslow-Gehan-Wilcoxon). Conclusions: Immunosuppressive acidic protein values appear to be a useful predictive marker for recurrence. A randomized trial, examining long-term outcome according to tumor stage and variables such as duration of administration, dose, administration time, and dosing schedule is required. [source] Ibandronate: A Comparison of Oral Daily Dosing Versus Intermittent Dosing in Postmenopausal OsteoporosisJOURNAL OF BONE AND MINERAL RESEARCH, Issue 10 2001B. J. Riis Abstract The objective of this study was to compare efficacy and safety of continuous versus intermittent oral dosing of ibandronate. Two hundred forty women aged 55,75 years with postmenopausal osteoporosis were randomized to active treatment or placebo. Similar total doses of ibandronate were provided by treatment regimens with either continuous 2.5 mg of ibandronate daily (n = 81) or intermittent 20 mg of ibandronate every other day for the first 24 days, followed by 9 weeks without active drug (n = 78). The placebo group (total, n = 81) was crossed over after 12 months to receive either continuous (n = 37) or intermittent ibandronate (n = 35). By 24 months, bone mineral density (BMD) had increased significantly relative to baseline in both active treatment groups. The continuous and intermittent groups showed statistically equivalent increases in lumbar spine BMD of +5.64% (±0.53) and +5.54% (±0.53) and in total hip of +3.35% (±0.40) and +3.41% (±0.40), respectively (per protocol population). Biochemical markers of bone turnover decreased significantly in both treatment groups. The level of marker suppression was similar, although the intermittent group displayed, as expected, more fluctuation over the treatment period. The frequency of adverse events was similar in the treatment groups. In conclusion, the intermittent and continuous regimens showed equivalent changes in BMD and bone turnover. These results confirm previous preclinical findings indicating that the efficacy of ibandronate depends on the total oral dose given rather than on the dosing schedule. This supports development of new flexible dosing regimens targeted to minimize the frequency of dosing, which are expected to improve convenience and lead to enhanced long-term patient compliance. [source] Valproic acid blocks adhesion of renal cell carcinoma cells to endothelium and extracellular matrixJOURNAL OF CELLULAR AND MOLECULAR MEDICINE, Issue 8b 2009Jon Jones Abstract Treatment strategies for metastatic renal cell carcinoma (RCC) have been limited due to chemotherapy and radiotherapy resistance. The development of targeted drugs has now opened novel therapeutic options. In the present study, anti-tumoral properties of the histone deacetylase inhibitor valproic acid (VPA) were tested in vitro and in vivo on pre-clinical RCC models. RCC cell lines Caki-1, KTC-26 or A498 were treated with various concentrations of VPA to evaluate tumour cell adhesion to vascular endothelial cells or to immobilized extracellular matrix proteins. In vivo tumour growth was conducted in subcutaneous xenograft mouse models. VPA was also combined with low dosed interferon-, (IFN-,) and the efficacy of the combination therapy, as opposed to VPA monotherapy, was compared. VPA significantly and dose-dependently prevented tumour cell attachment to endothelium or matrix proteins, accompanied by elevated histones H3 and H4 acetylation. VPA altered integrin-, and -, subtype expression, in particular ,3, ,5 and ,3, and blocked integrin-dependent signalling. In vivo, VPA significantly inhibited the growth of Caki-1 in subcutaneous xenografts with the 200 mg/kg being superior to the 400 mg/kg dosing schedule. VPA-IFN-, combination markedly enhanced the effects of VPA on RCC adhesion, and in vivo tumour growth was further reduced by the 400 mg/kg but not by the 200 mg/kg VPA dosing schedule. VPA profoundly blocked the interaction of RCC cells with endothelium and extracellular matrix and reduced tumour growth in vivo. Therefore, VPA should be considered an attractive candidate for clinical trials. [source] Influence of dosing schedules on toxicity and antitumour effects of combined cisplatin and docetaxel treatment in miceJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 5 2009Ayumi Kodama Abstract Objectives The combination of cisplatin and docetaxel shows a better cure rate against non-small-cell lung cancer than other drug combinations in clinical studies; however, severe myelosuppression and nephrotoxicity are dose-limiting factors. The purpose of this study was to establish a suitable dosing schedule to reduce adverse effects and improve the antitumour effects. Methods Cisplatin and docetaxel were administered i.p. to male ICR mice simultaneously, or sequentially with either cisplatin or docetaxel first followed by the second drug 12 h later (docetaxel,cisplatin and cisplatin,docetaxel groups). Antitumour effects of these schedules were also tested in C57BL/6N mice bearing Lewis lung carcinomas. Key findings The simultaneous docetaxel/cisplatin group showed the lowest survival rate and the highest blood urea nitrogen (BUN) concentration. Cisplatin concentrations in the plasma and kidney were higher in the simultaneous dosing group than the sequential dosing groups. Antitumour effect was the greatest in the docetaxel,cisplatin group. Conclusions The docetaxel,cisplatin regimen inhibited tumour growth the best and reduced mortality and nephrotoxicity. [source] Use of Malaria Prevention Measures by North American and European Travelers to East AfricaJOURNAL OF TRAVEL MEDICINE, Issue 4 2001Hans O. Lobel Background: The use of preventive measures, including effective chemoprophylaxis, is essential for protection against malaria among travelers. However, data have shown that travelers and medical advisors are confused by the lack of uniform recommendations and numerous prophylactic regimens of varying effectiveness that are used. Methods: To assess the use and type of preventive measures against malaria, we conducted a cross-sectional study in 1997 among travelers departing from the Nairobi and Mombasa airports in Kenya with European destinations. Results: Seventy-five percent of the travelers studied were residents of Europe and 25% were residents of North America; all stayed less than 1 year, and visited malarious areas. Most travelers, 97.1%, were aware of the risk and 91.3% sought pretravel medical advice. Although 95.4% used chemoprophylaxis and/or antimosquito measures, only 61.7% used both regular chemoprophylaxis and two or more antimosquito measures. Compliance with chemoprophylaxis was lowest amongst those who used a drug with a daily, as opposed to, a weekly dosing schedule, stayed more than 1 month, attributed an adverse health event to the chemoprophylaxis, and were less than 40 years of age. Among US travelers, 94.6% of those taking chemoprophylaxis were taking an effective regimen, that is, mefloquine or doxycycline. Only 1.9% used a suboptimal drug regimen, such as chloroquine/proguanil. Among European travelers, 69% used mefloquine or doxycycline, and 25% used chloroquine/proguanil. Notably, 45.3% of travelers from the UK used chloroquine/proguanil. Adverse events were noted by 19.7% of mefloquine users and 16.4% of travelers taking chloroquine/proguanil. Neuropsychologic adverse events were reported by 7.8% of users of mefloquine and 1.9% of those taking chloroquine/proguanil. The adverse events, however, had a lesser impact on compliance than frequent dosing schedule. Conclusions: Health information should be targeted to travelers who are likely to use suboptimal chemoprophylaxis or may be noncompliant with prophylaxis. Uniform recommendations for effective chemoprophylaxis with simple dosing schedules are necessary to reduce rates of malaria among travelers to Africa. [source] Management of drug-to-drug interactions between cyclosporine A and the protease-inhibitor lopinavir/ritonavir in liver-transplanted HIV-infected patientsLIVER TRANSPLANTATION, Issue 7 2004Martin Vogel Highly active antiretroviral therapy (HAART) has improved the life expectancy of HIV-infected patients, allowing orthotopic liver transplantation as a reasonable treatment option for selected patients with terminal liver disease. Both non-nucleoside reverse transcriptase inhibitors and protease inhibitors, key elements of HAART, give rise to substantial drug-to-drug interactions with immunosuppressive drugs such as tacrolimus and cyclosporine A. After studying 12-hour pharmacokinetic profiles in 3 HIV-positive patients after liver transplantation, we describe how dosing of cyclosporine A can be adjusted to maintain effective immunosuppressive drug levels on a daily dosing schedule when ritonavir-boosted indinavir or lopinavir-based antiretroviral therapy is given. To avoid toxic drug levels, we used an orally available cyclosporine A formulation prepared from the commercial available intravenous solution, which enabled dose adjustments in 1-mg increments. Under ritonavir-boosted HAART, cyclosporine A levels showed markedly altered absorption/elimination characteristics with more or less constant blood-levels throughout the dosing interval and prolonged elimination half-lives up to 38 hours. To obtain equivalent areas under the curve of cyclosporine A, daily doses were reduced to 5,20% of the individual standard doses given before initiation of ritonavir-boosted HAART. Because of the flat absorption/elimination profiles under ritonavir-boosted HAART cyclosporine A, dosing could be reliably monitored long term by measuring cyclosporine A trough-levels. (Liver Transpl 2004;10:939,944.) [source] Use of nonsteroidal anti-inflammatory drugs in infants.PEDIATRIC ANESTHESIA, Issue 5 2007A survey of members of the Association of Paediatric Anaesthetists of Great Britain, Ireland Summary Background:, Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used as perioperative analgesics. Many are currently used off label. Diclofenac is currently licensed for use in children over 1 year of age for the treatment of juvenile rheumatoid arthritis, while ibuprofen is licensed for use in children weighing over 7 kg. The dose and interval in children is currently extrapolated from adult studies, as the pharmacokinetic (PK) and pharmacodynamic (PD) data are lacking in infants. Methods:, A postal questionnaire was sent to members of the Association of Paediatric Anaesthetist of Great Britain and Ireland seeking to clarify members' prescribing patterns of NSAIDs, especially in infants. Information regarding the choice of NSAIDS, route of administration, lower age limit, dose interval, dose and practice in two specific perioperative contexts (adenotonsillectomy and open heart surgery) was sought. Results:, The response rate was 80%. NSAIDs are used by 86% of responders in infants. Diclofenac is most commonly used intraoperatively (78%); while ibuprofen (73%) was used more frequently postoperatively. NSAIDs are used by 21% of respondents in ICU. Commonest routes of administration were oral (81%) and rectal (80%), rarely intravenously (9%). The commonest dose for diclofena is 1 mg·kg,1 (59%); the dosing schedule employed being 8 hourly in 53% of cases. NSAIDs are used by 57% of responders as part of their analgesic regime for adenotonsillectomies. Conclusion:, Members of the Association of Paediatric Anaesthetists of Great Britain and Ireland commonly prescribe NSAIDs in infants. This is despite the dearth of PK and PD data in this age group. [source] An open-label, phase 2 trial of denosumab in the treatment of relapsed or plateau-phase multiple myeloma,,AMERICAN JOURNAL OF HEMATOLOGY, Issue 10 2009Ravi Vij RANKL is a key mediator of osteoclast differentiation, activation, and survival. Preclinical data suggest that aberrant production and activation of osteoclasts may influence proliferation of multiple myeloma (MM) cells in the bone marrow. Reports have also shown that inhibiting RANKL may have a direct effect on RANK-expressing myeloma cells and a therapeutic role in treating the disease. In mouse myeloma models, inhibition of RANKL led to reduced serum paraprotein levels and tumor burden. Based on this hypothesis, this proof-of-concept, single-arm study investigated whether RANKL inhibition with denosumab could reduce serum M-protein levels in relapsed or plateau-phase myeloma subjects. All subjects received denosumab monthly, with loading doses on days 8 and 15 of month one, until disease progression or subject discontinuation. Results of this ongoing study demonstrated that no subjects in either cohort met the protocol-defined objective response criteria of complete response (CR) or partial response (PR), but that denosumab effectively inhibited the RANKL pathway regardless of previous exposure to bisphosphonates, as evidenced by suppressed levels of the bone turnover marker, serum C-terminal telopeptide of type 1 collagen (sCTx). Eleven (21%) subjects who relapsed within 3 months before study entry maintained stable disease for up to 16.5 months. Nineteen (46%) subjects with plateau-phase myeloma maintained stable disease for up to 18.3 months. The adverse event (AE) profile for denosumab and its dosing schedule in these populations was consistent with that for advanced cancer patients receiving systemic therapy. Additional controlled clinical studies of denosumab in subjects with both relapsed and plateau-phase MM are warranted. Am. J. Hematol. 2009. © 2009 Wiley-Liss, Inc. [source] The time course of drug effectsPHARMACEUTICAL STATISTICS: THE JOURNAL OF APPLIED STATISTICS IN THE PHARMACEUTICAL INDUSTRY, Issue 3 2009Hesham S. Al-Sallami Abstract This review aims to introduce the concepts and principles underpinning the time course of drug effects. Models describing the time course of drug concentrations (pharmacokinetic models) and the ensuing concentration-effect (pharmacodynamics models) as well as the linked time-effect (pharmacokinetic-pharmacodynamic models) are introduced. Different types of drug time-effects models are discussed with examples which aim to explain the time course of onset, duration, and maximal effect that occurs from any given dosing schedule. These drug effects are also described in relation to disease progression models. Copyright © 2009 John Wiley & Sons, Ltd. [source] Point-of-care reversal treatment in phenprocoumon-related intracerebral hemorrhageANNALS OF NEUROLOGY, Issue 6 2010Timolaos Rizos MD Objective Rapid reversal of the anticoagulatory effect of vitamin K antagonists represents the primary emergency treatment for oral anticoagulant-related intracerebral hemorrhage (OAC-ICH). Predicting the amount of prothrombin complex concentrate (PCC) needed to reverse OAC in individual patients is difficult, and repeated international normalized ratio (INR) measurements in central laboratories (CLs) are time-consuming. Accuracy and effectiveness of point-of-care INR coagulometers (POCs) for INR reversal in OAC-ICH have not been evaluated. Methods In phase 1, the agreement of emergency POC and CL INR measurements was determined. In phase 2, stepwise OAC reversal was performed with PCC using a predetermined dosing schedule. Concordance of POC and CL INR measurements during reversal and time gain due to POC were determined. Results In phase 1 (n = 165), Bland-Altman analysis showed close agreement between POCs and CLs (mean INR deviation 0.04). In phase 2 (n = 26), POCs caused a median initial net time gain of 24 minutes for the start of treatment with PCC. Median time for POC-documented complete OAC reversal was 28 minutes, compared with 120 minutes for CLs. Bland-Altman analysis between POCs and CLs revealed a mean INR deviation of 0.13 during stepwise PCC administration. POCs tended to slightly overestimate the INR, especially at higher INR levels. Remarkably, POC-guided reversal led to a median reduction of 30.5% of PCC dose compared with the a priori dose calculation. Hematomas enlarged in 20% of patients. Interpretation POC INR monitoring is a fast, effective, and economic means of PCC dose-titration in OAC-ICH. Larger studies examining the clinical efficacy of this procedure are warranted. ANN NEUROL 2010;67:788,793 [source] Phase II study of gemcitabine and docetaxel in combination for the treatment of metastatic breast cancerASIA-PACIFIC JOURNAL OF CLINICAL ONCOLOGY, Issue 1 2009Shom GOEL Abstract Aim: Gemcitabine (G) and docetaxel (D) have both shown activity in the treatment of anthracycline-pretreated patients with metastatic breast cancer. This phase II study was designed to evaluate the safety and efficacy of the GD combination. Methods: Patients with measurable locally advanced or metastatic breast cancer who had previously received anthracycline-based therapy were eligible. The patients received D 40 mg/m2 followed by G 800 mg/m2 IV on days 1 and 8 every 3 weeks for a maximum of eight cycles. Results: Thirty patients were enrolled and received a median of five cycles (range 0,8). Of these, 24 were evaluable for efficacy, with an overall response rate of 29.2% (95% CI, 12.6,51.1%). An additional 36.7% had a stable disease for an overall clinical benefit of 65.9%. The median duration of response was 2.1 months (95% CI, 2.0,3.6 months) and the median time to disease progression was 5.5 months (95% CI, 2.0,8.9 months). The median survival time was 16.7 months (95% CI, 7.3,32.0 months). Myelosuppression was the major toxicity, with grade 3/4 neutropenia in 73.3% of patients and febrile neutropenia in 6.7%. Conclusion: Weekly G and D is an active and safe regimen in treating metastatic breast cancer. The response rate was lower than that previously reported for this combination, which may relate to the lower doses used and the weekly D schedule. It may be worthwhile to further explore this combination to determine the optimal dosing schedule. [source] Thromboembolism in children with acute lymphoblastic leukaemia treated on Dana-Farber Cancer Institute protocols: effect of age and risk stratification of diseaseBRITISH JOURNAL OF HAEMATOLOGY, Issue 6 2005Uma H. Athale Summary Children with acute lymphoblastic leukaemia (ALL) are at increased risk for thromboembolism (TE). Identification of a susceptible population is crucial for effective thromboprophylaxis. However, the risk factors for ALL-associated TE are unclear. Concomitant asparaginase (ASP) and steroid therapy has been shown to increase the incidence of TE. Dana-Farber Cancer Institute (DFCI)-ALL protocols use a combination of ASP and steroids during the postinduction intensification phase when high-risk (HR) patients receive thrice the steroid-dose given to standard-risk (SR) patients. We studied prospectively assembled cohorts of children treated on two consecutive DFCI-ALL protocols to define the risk factors for symptomatic TE. Ten (11%) of 91 patients developed symptomatic TE; eight (seven HR) during intensification. Seven (44%) of 16 older patients (,10 years) compared with three of 75 (4%) younger patients developed TE (P < 0·0001). Nine of 35 (26%) HR and one of 56 (2%) SR patients developed TE (P = 0·0006). Gender, ALL-immunophenotype, steroid-type or ASP dosing schedule did not alter the risk but older age and HR-disease were factors predisposing to TE associated with DFCI-ALL protocols. Age-related risk may partly reflect the effect of ALL-risk stratification. Higher dose steroids combined with ASP may lead to an increased risk of TE in HR patients. [source] A phase 1 trial of 2 dose schedules of ABT-510, an antiangiogenic, thrombospondin-1-mimetic peptide, in patients with advanced cancer,CANCER, Issue 12 2008Michael S. Gordon MD Abstract BACKGROUND. ABT-510 is a substituted nonapeptide that mimics the antiangiogenic activity of the endogenous protein thrombospondin-1 (TSP-1). The current study was designed to establish the safety of ABT-510 in the treatment of patients with advanced malignancies on a once-daily (QD) and twice-daily dosing schedule. METHODS. Patients were randomly assigned to 1 of 6 dosing regimens: 20 mg, 50mg, or 100 mg QD or 10 mg, 25 mg, or 50 mg twice daily. ABT-510 was administered by subcutaneous bolus injection in cycles of 28 days. Tumor response and disease progression were monitored at 8-week intervals by computed tomography scan or magnetic resonance imaging. RESULTS. Thirty-six patients were randomly assigned in equal numbers to the 6 study regimens, with an additional 13 patients randomized to the 10-mg-twice-daily and 50-mg-twice-daily ABT-510 regimens. The expected pharmacokinetic target was achieved at all dose levels tested. The majority of adverse events were grade 1 or 2 (according to National Cancer Institute Common Toxicity Criteria [version 2]) and were not found to be dose related. The most frequently reported adverse events that were possibly related to ABT-510 included injection site reactions, asthenia, headache, and nausea. Grade 3 events considered to possibly be related included nausea, dyspnea, bone pain, constipation, vomiting, asthenia, and chills and tremors. One partial response was observed in a patient with carcinosarcoma who received 20 mg QD. The 6-month progression-free survival rate was 6%. Approximately 42% of patients (21 of 50 patients) had stable disease for ,3 months. CONCLUSIONS. ABT-510 can be administered at doses of 20 mg/day to 100 mg/day without significant toxicity. In the current study, minimal antitumor activity was observed, which was similar to observations in other single-agent antiangiogenic trials. Cancer 2008. © 2008 American Cancer Society. [source] Multi-institutional phase II study of temozolomide administered twice daily in the treatment of recurrent high-grade gliomas,CANCER, Issue 5 2008Casilda Balmaceda MD Abstract BACKGROUND. The prognosis for patients with recurrent high-grade gliomas is poor and treatment options are limited. Current chemotherapeutic regimens can improve clinical outcomes, but extend survival by only a few months. Temozolomide is a methylating agent that is typically administered once daily. Because preclinical studies suggested that a twice-daily dosing schedule might be more effective, the safety and efficacy of twice-daily dosing of temozolomide were studied in patients with recurrent gliomas at their first, second, or third recurrence. METHODS. This multi-institutional trial enrolled 120 patients with recurrent glioblastoma multiforme (GBM), anaplastic astrocytoma (AA), or anaplastic oligodendroglioma (AO). An initial oral dose of 200 mg/m2 of temozolomide was followed by 9 consecutive doses of 90-mg/m2 every 12 hours. Treatment cycles were repeated every 28 days. Doses were escalated to 100 mg/m2 twice daily in the absence of unacceptable toxicity or were reduced if unacceptable toxicity occurred. RESULTS. For GBM, AA, and AO patients, respectively, the median progression-free survival (PFS) was 4.2 months, 5.8 months, and 7.7 months, whereas the median overall survival (OS) was 8.8 months, 14.6 months, and 18 months. The overall response rate (partial and complete) for the GBM, AA, and AO patients was 31%, 46%, and 46%, respectively. Grade 3/4 toxicities included neutropenia (1.1%), thrombocytopenia (3.6%), and anemia (0.3%) (graded according to the World Health Organization grading system). CONCLUSIONS. Twice-daily dosing may enhance the efficacy of temozolomide in the treatment of recurrent gliomas without increasing toxicity. This regimen compares favorably with other dosing schedules of temozolomide reported in the literature. Cancer 2008. © 2008 American Cancer Society. [source] Treatment of vulval Crohn's disease with infliximabCLINICAL & EXPERIMENTAL DERMATOLOGY, Issue 3 2006P. W. Preston Summary Anti-tumour necrosis factor-, therapy of Crohn's disease (CD) with infliximab has proved a major advance in the treatment of patients with difficult disease. We report our experience of the use of infliximab in a patient with recalcitrant vulval CD. The introduction of infliximab has improved disease control, although a search for an optimum remittive dosing schedule is ongoing. [source] Pharmacoeconomics of factor dosing in the haemophilia populationHAEMOPHILIA, Issue 2006E. BERNTORP Summary., Treatment of haemophilia is extremely costly due to the short biological half-life of infused factor and pricing issues. This paper examines the impact of different dosing schedules on factor consumption, via a review of literature on dosing regimens used for prophylaxis with a focus on pharmacokinetics (PK). Pharmacokinetics were found to have an important role for pharmacoeconomics in factor dosing both for assessment of the treatment and for developing new treatment protocols but the clinical response to treatment must always guide the dosing schedule. In order to better understand pharmacoeconomics during prophylaxis, controlled prospective studies are needed but much can also be learned from studies of existing cohorts that have been treated for decades. [source] A 6-year follow-up of dosing, coagulation factor levels and bleedings in relation to joint status in the prophylactic treatment of haemophiliaHAEMOPHILIA, Issue 6 2004J. Ahnström Summary., The primary aim of this study was to investigate the possible relationship between coagulation factor level and bleeding frequency during prophylactic treatment of haemophilia after stratification of the patients according to joint scores. The secondary aim was to obtain a systematic overview of the doses of coagulation factors prescribed for prophylaxis at the Malmö haemophilia treatment centre during a 6-year period. A retrospective survey of medical records for the years 1997,2002 and pharmacokinetic study results from the 1990s was complemented by collection of blood samples for coagulation factor assay when needed. Information on the dosing and plasma levels of factor VIII or factor IX, joint scores and incidence of bleedings (joint bleeds and ,other bleeds') was compiled. The patients were stratified by age (0,6, 7,12, 13,18, 19,36 and >36 years) and joint score (0, 1,6 and >6). Individual pharmacokinetic parameters of plasma coagulation factor activities (FVIII:C and FIX:C) were estimated. Trough levels during the treatment were calculated, as well as the number of hours per week of treatment during which plasma FVIII:C/FIX:C fell below a 1, 2 or 3% target level. Fifty-one patients with haemophilia A (two moderate, 49 severe) and 13 with haemophilia B (all severe) were included, yielding data for 364 patient-years of treatment. There was a wide range of dosing schedules, the most common ones being three times a week or every other day for FVIII and twice a week or every third day for FIX. The overall relationship between FVIII:C/FIX:C levels and incidence of joint bleeding was very weak, even after stratification of the patients according to joint score. There was no relationship between coagulation factor level and incidence of other bleeds. In this cohort of patients on high-dose prophylactic treatment, dosing was based more on clinical outcome in terms of bleeding frequency than on the aim to maintain a 1% target level of FVIII:C/FIX:C. Some patients did not bleed in spite of a trough level of <1% and others did in spite of trough levels >3%. The practical implication of our findings is that dosing in prophylactic treatment of haemophilia should be individualized. Thus, proposed standard regimens should be implemented only after careful clinical consideration, with a high readiness for re-assessment and individual dose tailoring. [source] Use of Malaria Prevention Measures by North American and European Travelers to East AfricaJOURNAL OF TRAVEL MEDICINE, Issue 4 2001Hans O. Lobel Background: The use of preventive measures, including effective chemoprophylaxis, is essential for protection against malaria among travelers. However, data have shown that travelers and medical advisors are confused by the lack of uniform recommendations and numerous prophylactic regimens of varying effectiveness that are used. Methods: To assess the use and type of preventive measures against malaria, we conducted a cross-sectional study in 1997 among travelers departing from the Nairobi and Mombasa airports in Kenya with European destinations. Results: Seventy-five percent of the travelers studied were residents of Europe and 25% were residents of North America; all stayed less than 1 year, and visited malarious areas. Most travelers, 97.1%, were aware of the risk and 91.3% sought pretravel medical advice. Although 95.4% used chemoprophylaxis and/or antimosquito measures, only 61.7% used both regular chemoprophylaxis and two or more antimosquito measures. Compliance with chemoprophylaxis was lowest amongst those who used a drug with a daily, as opposed to, a weekly dosing schedule, stayed more than 1 month, attributed an adverse health event to the chemoprophylaxis, and were less than 40 years of age. Among US travelers, 94.6% of those taking chemoprophylaxis were taking an effective regimen, that is, mefloquine or doxycycline. Only 1.9% used a suboptimal drug regimen, such as chloroquine/proguanil. Among European travelers, 69% used mefloquine or doxycycline, and 25% used chloroquine/proguanil. Notably, 45.3% of travelers from the UK used chloroquine/proguanil. Adverse events were noted by 19.7% of mefloquine users and 16.4% of travelers taking chloroquine/proguanil. Neuropsychologic adverse events were reported by 7.8% of users of mefloquine and 1.9% of those taking chloroquine/proguanil. The adverse events, however, had a lesser impact on compliance than frequent dosing schedule. Conclusions: Health information should be targeted to travelers who are likely to use suboptimal chemoprophylaxis or may be noncompliant with prophylaxis. Uniform recommendations for effective chemoprophylaxis with simple dosing schedules are necessary to reduce rates of malaria among travelers to Africa. [source] Pharmacokinetics and pharmacokinetic/pharmacodynamic integration of marbofloxacin in calf serum, exudate and transudateJOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 3 2002F. SHOJAEE ALIABADI Aliabadi, F. S., Lees, P. Pharmacokinetics and pharmacokinetic/pharmacodynamic integration of marbofloxacin in calf serum, exudate and transudate. J. vet. Pharmacol. Therap.25, 161,174. Marbofloxacin is a fluoroquinolone antimicrobial drug used in cattle for the treatment of respiratory infections. In this investigation the pharmacokinetics (PK) of marbofloxacin were determined after intravenous and intramuscular dosing at a dosage of 2 mg/kg. In addition the ex vivo pharmacodynamics (PD) of the drug were determined in serum and three types of tissue cage fluid (transudate, inflammatory exudate generated by carrageenan and exudate generated by lipopolysaccharide). Marbofloxacin PK was characterized by a high volume of distribution after dosing by both routes (1.28 L/kg intravenous and 1.25 L/kg intramuscular). Corresponding area under the concentration,time curve (AUC) and elimination half-life (t½el) values were 9.99 and 10.11 ,g h/mL and 4.23 and 4.33 h, respectively. Values of AUC for carrageenan-induced exudate, lipopolysaccharide-induced exudate and transudate were, respectively, 8.28, 7.83 and 7.75 ,g h/mL after intravenous and 8.84, 8.53 and 8.52 ,g h/mL after intramuscular dosing. Maximum concentration (Cmax) values were similar for the three tissue cage fluids after intravenous and intramuscular dosing. For in vivo PK data values of AUC: minimum inhibitory concentration (MIC) (AUIC) ratio for serum were 250 and 253, respectively, after intravenous and intramuscular dosing of marbofloxacin against a pathogenic strain of Mannheimia haemolytica (MIC=0.04 ,g/mL). For all tissue cage fluids AUIC values were >194 and >213 after intravenous and intramuscular dosing, and Cmax/MIC ratios were 9 or greater, indicating a likely high level of effectiveness in clinical infections caused by M. haemolytica of MIC 0.04 ,g/mL or less. This was confirmed by both in vitro (serum) and ex vivo (serum, exudate and transudate) measurements, which demonstrated a concentration-dependent killing profile for marbofloxacin against M. haemolytica. Ex vivo, after 24-h incubation, virtually all bacteria were killed (<10 cfu/mL) in all samples collected up to 9 h (serum), 24 h (carrageenan-induced exudate and transudate) and 36 h (lipopolysaccharide-induced exudate). Application of the sigmoid Emax equation to the ex vivo antibacterial data provided, for serum, AUIC24 h values of 37.1 for bacteriostasis, 46.3 for bactericidal activity and 119.6 for elimination of bacteria. These data may be used as a rational basis for setting dosing schedules which optimize clinical efficacy and minimize the opportunities for emergence of resistant organisms. [source] The combination of the antitumoural pyridyl cyanoguanidine CHS 828 and etoposide in vitro,from cytotoxic synergy to complete inhibition of apoptosisBRITISH JOURNAL OF PHARMACOLOGY, Issue 4 2002P Martinsson The present study was aimed at elucidating the apoptosis inhibitory properties of the cyanoguanidine CHS 828. CHS 828 exhibits impressive cytotoxic activity in vitro and in vivo. Apoptosis is not its main mode of cytotoxic effect, and we have previously proposed a dual mechanism, where CHS 828 inhibits its own cell death pathways. Etoposide on the other hand, is a well-established anticancer agent with documented effect in a number of malignancies, induces apoptosis through extensively studied caspase dependent pathways. Here we studied the combined effect of the two drugs in the human lymphoma cell line U-937 GTB. Cytotoxicity was evaluated as total viability measured by the fluorometric microculture cytotoxicity assay (FMCA). Caspase activity was assessed by colorimetric detection of specific cleavage products for caspases 3, 8 and 9, respectively. Morphology was evaluated in May-Grünwald/Giemsa stained preparations. Interaction analysis based on FMCA results of simple combination exposure revealed impressive synergistic effect on cell kill. Detailed investigations of the kinetics involved showed that short pre-exposure (0,12 h) to CHS 828 enhanced caspase activation by etoposide, while longer pre-exposure (18,48 h) inhibited both caspase activation and apoptotic morphology otherwise induced by etoposide. The present results support the theory that CHS 828 block specific cell death pathways. The synergistic results are promising for future combination trials in animals, however, different dosing schedules should be considered, in order to investigate whether the above findings translate into the in vivo setting. British Journal of Pharmacology (2002) 137, 568,573. doi:10.1038/sj.bjp.0704888 [source] Multi-institutional phase II study of temozolomide administered twice daily in the treatment of recurrent high-grade gliomas,CANCER, Issue 5 2008Casilda Balmaceda MD Abstract BACKGROUND. The prognosis for patients with recurrent high-grade gliomas is poor and treatment options are limited. Current chemotherapeutic regimens can improve clinical outcomes, but extend survival by only a few months. Temozolomide is a methylating agent that is typically administered once daily. Because preclinical studies suggested that a twice-daily dosing schedule might be more effective, the safety and efficacy of twice-daily dosing of temozolomide were studied in patients with recurrent gliomas at their first, second, or third recurrence. METHODS. This multi-institutional trial enrolled 120 patients with recurrent glioblastoma multiforme (GBM), anaplastic astrocytoma (AA), or anaplastic oligodendroglioma (AO). An initial oral dose of 200 mg/m2 of temozolomide was followed by 9 consecutive doses of 90-mg/m2 every 12 hours. Treatment cycles were repeated every 28 days. Doses were escalated to 100 mg/m2 twice daily in the absence of unacceptable toxicity or were reduced if unacceptable toxicity occurred. RESULTS. For GBM, AA, and AO patients, respectively, the median progression-free survival (PFS) was 4.2 months, 5.8 months, and 7.7 months, whereas the median overall survival (OS) was 8.8 months, 14.6 months, and 18 months. The overall response rate (partial and complete) for the GBM, AA, and AO patients was 31%, 46%, and 46%, respectively. Grade 3/4 toxicities included neutropenia (1.1%), thrombocytopenia (3.6%), and anemia (0.3%) (graded according to the World Health Organization grading system). CONCLUSIONS. Twice-daily dosing may enhance the efficacy of temozolomide in the treatment of recurrent gliomas without increasing toxicity. This regimen compares favorably with other dosing schedules of temozolomide reported in the literature. Cancer 2008. © 2008 American Cancer Society. [source] Increased anterior chamber penetration of topical levofloxacin 0.5% after pulsed dosing in cataract patientsACTA OPHTHALMOLOGICA, Issue 2 2009Karin Sundelin Abstract. Purpose:, This study aimed to investigate the rise in aqueous humour (AH) levels of levofloxacin after a specific perioperative pulsed topical drop regimen. Methods:, Thirty patients undergoing phacoemulsification surgery were administered two preoperative drops of levofloxacin 0.5%, 30 mins apart, and three pulsed drops postoperatively, 5 mins apart. Aqueous humour levels of levofloxacin were measured at the start of surgery and from 5 mins to 90 mins after the last postoperative drop. Samples from individual patients were collected at the time of surgery and at one additional sampling interval by aqueous tap, and analysed using a high-performance liquid chromatography assay. Results:, Aqueous humour levels of levofloxacin continued to rise gradually, reaching a mean peak level (Cmax) of 4.4 ,g/ml (± 2.5) at 60 mins after the last postoperative drop was administered. This level exceeded the minimum inhibitory concentration of common ocular pathogens at least fourfold. At 90 mins after the last drop, mean AH levels remained > 3 ,g/ml. Conclusions:, This is the first study to measure AH levels of levofloxacin after postoperative pulsed dosing in humans. Higher AH levels were found than in previously reported studies in which only preoperative drops were given and levels were measured at the time of surgery. Levels of levofloxacin continued to rise for 60 mins after administration of the last postoperative drop, demonstrating that delivery and maintenance of effective antibiotic levels may be achievable with alternative dosing schedules. [source] | ||||||||||||||||||||||||||||