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Dose Interval (dose + interval)
Selected AbstractsThe role of prophylaxis in bleeding disordersHAEMOPHILIA, Issue 2010E. BERNTORP Summary., The rationale for long-term prophylaxis in more severe forms of von Willebrand's disease (VWD) is obvious, as mucosal bleeding and haemophilia-like joint bleeds resulting in chronic morbidity may occur. However, the experience with prophylactic treatment in this group is scanty. An international VWD Prophylaxis Network (VWD PN) was established in 2006. The VWD PN will investigate prophylaxis with retrospective and prospective studies. Eighteen centres in Europe and North America are recruiting patients and an additional 40 centres are preparing for or evaluating participation. In the absence of randomized prospective studies for most rare bleeding disorders, guidelines for prophylaxis are a subject of controversy. In situations where there is a strong family history of bleeding, long-term prophylaxis is administered in selected cases. Short intervals of prophylaxis can also be given before some surgeries or during pregnancy. The benefits of prophylaxis must be balanced by the risk of side effects. Therefore, it is essential to delineate its management in a specialized comprehensive care environment. In haemophilia, decades of clinical experience and numerous retrospective and, recently, prospective studies clearly demonstrate that prophylactic treatment is superior to on-demand treatment, regardless of whether the outcome is the number of joint- or life-threatening bleeds, arthropathy evaluated by X-ray or MRI, or quality of life measured by generic or haemophilia-specific instruments. Optimal prophylactic treatment should be started early in life (primary prophylaxis) but various options exist for the dose and dose interval. These depend on the objective of treatment in the individual patient, which, in turn, is dependent on resources in the health care system. [source] Prophylactic therapy for haemophilia: early experienceHAEMOPHILIA, Issue 2003E. Berntorp Summary., During the 1960s, it was reported from Sweden that haemophiliacs with factor levels above 1% rarely develop arthropathy. This observation suggested that severe haemophilia could be converted to a milder form by regular infusions with factor concentrate. After several earlier publications, a report was published in 1992 that detailed 25 years' experience with prophylaxis in 60 patients from the Malmö centre. The results showed that starting prophylaxis early in life with a dose regimen that would prevent factor VIII or IX plasma levels from falling below 1% could prevent the development of haemophilic arthropathy. Also, older age groups who had received less intensive treatment, and who started prophylaxis later in life, were still in a much better condition than historic controls. In the 1970s several small but well-controlled studies from the USA, Germany and Italy clearly showed the benefit of prophylaxis in reducing bleeding frequency. Early experience from the Netherlands was published in 1971. Since these early studies, the results have been corroborated from many countries and in a large multinational study. Although the benefits of prophylaxis seem unquestionable, several research questions remain to be better elucidated, such as when to start and when to stop, dosing and dose interval, and how to assess the long-term treatment effects. These issues are of great economic importance, and the need for health economical studies is obvious. [source] Pharmacokinetics of altrenogest in horsesJOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 1 2007M. MACHNIK The Federation Equestre Internationale has permitted the use of altrenogest in mares for the control of oestrus. However, altrenogest is also suspicious to misuse in competition horses for its potential anabolic effects and suppression of typical male behaviour, and thus is a controlled drug. To investigate the pharmacokinetics of altrenogest in horses we conducted an elimination study. Five oral doses of 44 ,g/kg altrenogest were administered to 10 horses at a dose interval of 24 h. Following administration blood and urine samples were collected at appropriate intervals. Altrenogest concentrations were measured by liquid chromatography-tandem mass spectrometry. The plasma levels of altrenogest reached maximal concentrations of 23,75 ng/mL. Baseline values were achieved within 3 days after the final administration. Urine peak concentrations of total altrenogest ranged from 823 to 3895 ng/mL. Twelve days after the final administration concentrations were below the limit of detection (ca 2 ng/mL). [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] More pronounced inhibition of cyclooxygenase 2, increase in blood pressure, and reduction of heart rate by treatment with diclofenac compared with celecoxib and rofecoxibARTHRITIS & RHEUMATISM, Issue 1 2006Burkhard Hinz Objective Recent findings suggest that permanent blockade of cyclooxygenase 2 (COX-2) is one factor contributing to the cardiovascular side effects of selective COX-2 inhibitors (coxibs) and nonsteroidal antiinflammatory drugs (NSAIDs). The present study compared the extent and time course of COX-2 inhibition and the effects on cardiovascular parameters (changes in blood pressure and heart rate) between various antirheumatic doses of diclofenac, celecoxib, and rofecoxib in healthy elderly volunteers. Methods A randomized, parallel-group study was conducted in volunteers receiving 75 mg diclofenac twice daily, 200 mg celecoxib twice daily, or 25 mg rofecoxib once daily for 8 days. Blood samples were obtained predose and at specified time points postdose, on days 1 and 8, for assay of drug plasma concentrations and COX-2 inhibition. Lipopolysaccharide-induced prostaglandin E2 synthesis was measured ex vivo as an index of COX-2 activity in human whole blood. Results COX-2 inhibition was significantly less pronounced after treatment with celecoxib and rofecoxib than with diclofenac. Maximal inhibitions after a single dose and at steady state, respectively, were as follows: 99% and 99% with diclofenac, 70% and 81% with celecoxib, and 56% and 72% with rofecoxib. At steady state, only diclofenac caused virtually complete COX-2 inhibition over the whole dose interval, and this corresponded to the highest increase in systolic blood pressure and greatest reduction in heart rate. Conclusion Diclofenac elicited the most pronounced COX-2 inhibition, blood pressure elevation, and suppression of heart rate. It is assumed that the extent and time course of intravascular COX-2 inhibition may determine the differential profile of cardiovascular side effects associated with NSAIDs and coxibs, but this has to be proven in future studies. [source] Population pharmacokinetics of mycophenolic acid in children and young people undergoing blood or marrow and solid organ transplantationBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 4 2010Lihua Zeng WHAT IS ALREADY KNOWN ABOUT THIS PROJECT? , Mycophenolate mofetil (MMF) is an immunosuppressant drug used for the treatment and prevention of graft vs. host disease in blood or marrow transplantation and acute graft rejection in solid organ transplantation. , Mycophenolic acid (MPA) pharmacokinetics have not been thoroughly studied in paediatric blood or marrow transplant recipients and guidance for optimal dosing of mycophenolic acid in children is lacking. , Mycophenolic acid exhibits considerable inter- and intra-patient pharmacokinetic variability in adults and paediatric transplant recipients. , The AUC of mycophenolic acid over a 12 h dose interval at steady-state is generally agreed to be the most reliable metric associated with the risk of acute rejection. , Population pharmacokinetic analysis can utilize concentration information from both intensive sampling and sparse sampling to provide pharmacokinetic parameter estimates, estimates of inter- individual and intra-individual variability in these parameters and allows patient characteristics explaining inter-individual variability to be quantified. WHAT THIS STUDY ADDS , This study is one of the first investigations in which a population pharmacokinetic modelling approach was applied to assess the pharmacokinetics of both intravenous and oral MMF in children and young people undergoing blood or marrow and solid organ transplantation. , Bodyweight and concomitant ciclosporin were found to influence MPA pharmacokinetics. , This study evaluated current dosing strategies and found that they may be suboptimal for children weighing less than 10 kg. AIMS To characterize the population pharmacokinetics of mycophenolic acid (MPA) and evaluate dose regimens using a simulation approach and accepted therapeutic drug monitoring targets in children and young people undergoing blood or marrow, kidney and liver transplantation. METHODS MPA concentration,time data were collected using an age specific sampling protocol over 12 h. Some patients provided randomly timed but accurately recorded blood samples. Total and unbound MPA were measured by HPLC. NONMEM was employed to analyze MPA pharmacokinetic data. Simulations (n= 1000) were conducted to assess the suitability of the MPA dose regimens to maintain total MPA AUC(0,12 h) within the range 30 and 60 mg l,1 h associated with optimal outcome. RESULTS A two-compartment pharmacokinetic model with first-order elimination best described MPA concentration,time data. Population mean estimates of MPA clearance, inter-compartmental clearance, volumes of distribution in the central and peripheral compartments, absorption rate constant and bioavailability were 6.42 l h,1, 3.74 l h,1, 7.24 l, 16.8 l, 0.39 h,1 and 0.48, respectively. Inclusion of bodyweight and concomitant ciclosporin reduced the inter-individual variability in CL from 54.3% to 31.6%. Children with a bodyweight of 10 kg receiving standard MPA dose regimens achieve an MPA AUC below the target range suggesting they may be at a greater risk of acute rejection. CONCLUSIONS The population pharmacokinetic model for MPA can be used to explore dosing guidelines for safe and effective immunotherapy in children and young people undergoing transplantation. [source] Dose-effect study of domperidone as a galactagogue in preterm mothers with insufficient milk supply, and its transfer into milkBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 2 2008Elise W-X. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT , Domperidone is an effective treatment for some mothers with insufficient milk supply. , However, dose,effect data are not available, and the safety of domperidone use in both mother and infant has been questioned. WHAT THIS STUDY ADDS , Domperidone only increases milk production in about two-thirds of preterm mothers with insufficient milk supply. , On average, the responders showed increasing levels of milk production with dose escalation from 30 mg to 60 mg daily. , The amount of domperidone that transferred into breast milk was very low, and the risk to the breastfed infant is minimal. AIMS To investigate the possibility of a dose,response relationship for the use of domperidone in treating insufficient milk supply in mothers of preterm infants, and to quantify the exposure of the breastfed infant to domperidone. METHODS Six preterm mothers received domperidone (30 mg daily or 60 mg daily) in a double-blind, randomized, crossover trial. Milk production and serum prolactin were measured before and during the trial, and domperidone concentration in milk was measured during drug treatment. RESULTS For milk production, two of the mothers were ,nonresponders', whereas the other four were ,responders' and showed a significant increase in milk production from 8.7 ± 3.1 g h,1 in the run-in phase (mean ± SEM), 23.6 ± 3.9 g h,1 for the 30-mg dose (P = 0.0217) and 29.4 ± 6.6 g h,1 for the 60-mg dose (P = 0.0047). In all participants, serum prolactin was significantly increased for both doses, but the response was not dose dependent. Median (interquartile range) domperidone concentrations in milk over a dose interval at steady-state were 0.28 µg l,1 (0.24,0.43) and 0.49 µg l,1 (0.33,0.72) for the 30-mg and 60-mg doses, respectively. The mean relative infant dose was 0.012% at 30 mg daily and 0.009% at 60 mg daily. CONCLUSION In one-third of mothers, domperidone did not increase milk production. In the remainder, milk production increased at both domperidone doses, and there was a trend for a dose,response relationship. The amount of domperidone that transfers into milk was extremely low, and infant exposure via breastfeeding was not considered to be significant. [source] | ||||||||||