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Dosing Regimen (dosing + regimen)
Kinds of Dosing Regimen Selected AbstractsEfficacy and Safety of Two Dosing Regimens of Tadalafil and Patterns of Sexual Activity in Men with Diabetes Mellitus and Erectile Dysfunction: Scheduled Use vs.THE JOURNAL OF SEXUAL MEDICINE, Issue 3 2006On-Demand Regimen Evaluation (SURE) Study in 14 European Countries ABSTRACT Aim., The aim of this article is to evaluate the efficacy and safety of 20-mg tadalafil taken on demand or three times per week and its effect on the sexual activity of patients with diabetes mellitus and erectile dysfunction (ED). Methods., The scheduled use vs. on-demand regimen evaluation (SURE) was a randomized, crossover, open-label study with 4,262 patients in 14 European countries. The efficacy measures for the 762 patients with diabetes and ED included changes from baseline in the erectile function (EF) domain of the International Index of Erectile Function (IIEF), and the proportion of "yes" responses to patient Sexual Encounter Profile (SEP) questions 2 (SEP2) and 3 (SEP3). The treatment satisfaction was measured with responses to SEP question 4 (SEP4) and SEP question 5 (SEP5), and sexual attempts data were collected. Patient preference for either regimen was determined by the treatment preference question (TPQ). Results., At end point on both regimens, the mean IIEF EF domain score was 22, and >40% of the patients had a normal EF domain score (,26). The proportion of "yes" responses was ,73% for SEP2 (penetration), ,58% for SEP3 (successful intercourse), >46% for SEP4 (hardness of erection), and ,45% for SEP5 (overall satisfaction). Efficacy was maintained up to 36 hours post-dosing. More than 70% of sexual attempts while on the three-times-per-week regimen and approximately 50% of the attempts on the on-demand treatment occurred >4 hours post-dosing. Tadalafil was well tolerated, with dyspepsia and headache as the most frequent adverse events reported. Treatment preference was 57.2% for on demand and 42.8% for three times per week. Conclusions., Tadalafil, when taken on demand or three times per week, is efficacious and safe in men with diabetes and ED. Buvat J, van Ahlen H, Schmitt H, Chan M, Kuepfer C, and Varanese L. Efficacy and safety of two dosing regimens of tadalafil and patterns of sexual activity in men with diabetes mellitus and erectile dysfunction: Scheduled use vs. on-demand regimen evaluation (SURE) study in 14 European countries. J Sex Med 2006;3:512,520. [source] The Pharmacokinetics of Antiepileptic Drugs in Rats: Consequences for Maintaining Effective Drug Levels during Prolonged Drug Administration in Rat Models of EpilepsyEPILEPSIA, Issue 7 2007Wolfgang Löscher Summary:, Rodent models of chronic epilepsy with spontaneous recurrent seizures likely represent the closest parallel to the human condition. Such models may be best suited for therapy discovery for pharmacoresistant epilepsy and for antiepileptogenic or disease-modifying therapeutics. However, the use of such rodent models for therapy discovery creates problems with regard to maintaining effective drug levels throughout a prolonged testing period. This is particularly due to the fact that rodents such as rats and mice eliminate most drugs much more rapidly than humans. Thus, knowledge about elimination rate of a test drug in a laboratory species is essential for development of a treatment paradigm that allows maintaining adequate drug levels in the system over the period of treatment. Currently, the most popular models of epilepsy with spontaneous seizures are poststatus epilepticus models of temporal lobe epilepsy in rats. Such models are both used for studies on antiepileptogenesis and drug resistance. For validation of these models, current antiepileptic drugs (AEDs) have to be used. In this article, the elimination rates of these AEDs and their effective plasma levels in rats are reviewed as a guide for developing treatment protocols for chronic drug testing. The advantages and disadvantages of several technologies for drug delivery are discussed, and some examples for calculation of adequate treatment protocols are given. As shown in this review, because of the rapid elimination of most AEDs in rats, it is no trivial task to maintain effective steady-state AED levels in the plasma throughout the day over multiple days to ensure that there will be adequate levels in the system for the purpose of the experiment. However, the use of an adequate dosing regimen that is based on elimination rate is an absolute prerequisite when using rat models for discovery of new antiepileptogenic therapies or therapies for pharmacoresistant epilepsy, because otherwise such models may lead to erroneous conclusions about drug efficacy. [source] Appraisal of current vitamin K dosing algorithms for the reversal of over-anticoagulation with warfarin: the need for a more tailored dosing regimenEUROPEAN JOURNAL OF HAEMATOLOGY, Issue 6 2006Elizabeth A. Sconce Abstract:, Warfarin is the most commonly prescribed oral anticoagulant in the UK for the treatment and prevention of thromboembolic disorders. Vitamin K administration is an effective way of reversing excessive anticoagulation. Over-anticoagulated patients present with a wide range of international normalized ratio (INR) values and may respond differently to a fixed dose of vitamin K. Current dosing algorithms for vitamin K administration in the non-urgent treatment of over-anticoagulation do not take this variability in response into account. Consequently, over a third of over-anticoagulated patients still remain outside their target INR 24 h after treatment. Such patients are therefore prone to either haemorrhage (if the patient is still over-anticoagulated) or thromboembolism (if the INR reversal is over-corrected). A number of factors such as patient age, body weight, co-morbidity, frailty, warfarin daily dose and CYP2C9 and VKORC1 polymorphism could affect response to vitamin K and thus the rate and extent of INR reversal. There is a need for a more individualized approach to the reversal of over-anticoagulation in asymptomatic or mildly haemorrhagic patients in order to improve the safety of warfarin therapy. [source] Long-Term Protective Effects of Zoledronic Acid on Cancellous and Cortical Bone in the Ovariectomized Rat,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 4 2008Jürg A Gasser PhD Abstract Current bisphosphonate therapies effectively prevent bone loss in postmenopausal women. We studied the effect of a single intravenous dose of ZOL in ovariectomized rats. Protection from bone loss was dose dependent, lasting for up to 32 weeks, supporting the rationale for an annual intravenous dosing regimen of ZOL for treatment of postmenopausal osteoporosis. Introduction: Once-yearly dosing with zoledronic acid (ZOL) 5 mg can increase BMD and reduce fracture rate in postmenopausal women with low BMD. The primary objective of this study was to determine the duration of bone protective effects of a single dose of ZOL in ovariectomized rats, an animal model of postmenopausal osteopenia. Secondary objectives were to determine the effects on bone turnover and mechanical properties. Materials and Methods: Female Wistar rats (10 per group) received single intravenous doses of ZOL 0.8, 4, 20, 100, or 500 ,g/kg, alendronate 200 ,g/kg, or isotonic saline 4 days before bilateral ovariectomy. Sham-operated controls were pretreated with saline. Mass and density of cancellous and cortical bone (pQCT) were measured at 4-wk intervals for 32 wk. Bone architecture (,CT), bone formation dynamics (fluorochrome label-based histomorphometry), and biomechanical strength in compression testing were also assessed at 32 wk. Results: Ovariectomy-associated BMD loss was significantly attenuated for 32 wk by ZOL ,4 ,g/kg for total BMD, ZOL ,20 ,g/kg for cortical BMD, and ZOL ,4 ,g/kg for cancellous BMD (p < 0.01 versus ovariectomized controls). Alendronate 200 ,g/kg was of equivalent potency to ZOL 20 ,g/kg. Ovariectomy-associated decreases in trabecular architectural parameters were dose-dependently attenuated by ZOL. Alendronate 200 ,g/kg was equivalent to ZOL 20 ,g/kg. The bone resorption marker TRACP5b indicated transient suppression of elevated osteoclast activity by ZOL relative to OVX-rats even at the lowest dose of 0.8 ,g/kg, whereas at 100,500 ,g/kg, the effect was significant relative to the OVX control for the entire duration of the study of 32 wk. Bone formation parameters were not significantly affected by ZOL 20 ,g/kg but were significantly reduced by ZOL 100,500 ,g/kg. Alendronate 200 ,g/kg was equivalent to ZOL 100 ,g/kg. ZOL produced dose-related improvements in bone strength parameters after ovariectomy. Alendronate 200 ,g/kg was of similar potency to ZOL 20 ,g/kg. Conclusions: The duration and magnitude of the bone-protecting effect of a single intravenous dose of ZOL in ovariectomized rats is dose dependent and lasts for up to 32 wk. Compared with alendronate, ZOL shows 10-fold higher potency in preventing bone loss. These data support the use of an annual intravenous ZOL dosing regimen for the treatment of osteoporosis. [source] Two-Year Results of Once-Weekly Administration of Alendronate 70 mg for the Treatment of Postmenopausal OsteoporosisJOURNAL OF BONE AND MINERAL RESEARCH, Issue 11 2002R Rizzoli Abstract The aim of this study was to provide confirmation that once-weekly dosing with 70 mg of alendronate (seven times the daily oral dose) and twice-weekly dosing with 35 mg is equivalent to the 10-mg once-daily regimen and to gain more extensive safety experience with this new dosing regimen. Twelve hundred fifty-eight postmenopausal women (aged 42,95 years) with osteoporosis (bone mineral density [BMD] of either lumbar spine or femoral neck at least 2.5 SDs below peak young adult mean or prior vertebral or hip fracture) were assigned to receive oral once-weekly alendronate, 70 mg (n = 519); twice-weekly alendronate, 35 mg (n = 369); or daily alendronate 10 mg (n = 370) for a total of 2 years of double-blind experience. Mean BMD increases from baseline (95% CI) at 24 months in the once-weekly, twice-weekly, and daily treatment groups, respectively, were 6.8% (6.4, 7.3), 7.0% (6.6, 7.5), and 7.4% (6.9, 7.8) at the lumbar spine and 4.1% (3.8, 4.5), 4.3% (3.9, 4.7), and 4.3% (3.9, 4.7) at the total hip. These increases in BMD as well as the BMD increases at the femoral neck, trochanter, and total body and the reductions of biochemical markers of bone resorption (urinary cross-linked N-telopeptides of type I collagen [NTx]) and bone formation (serum bone-specific alkaline phosphatase [BSAP]) were similar for the three dosing regimens. All treatment regimens were well tolerated with a similar incidence of upper gastrointestinal (GI) adverse experiences. The incidence rates of clinical fractures, captured as adverse experiences, were similar among the groups. The 2-year results confirm the conclusion reached after 1 year that once-weekly alendronate is therapeutically equivalent to daily dosing, providing patients with a more convenient dosing option that may potentially enhance adherence to therapy. [source] Emerging Insights in the First-Step Use of Antihypertensive Combination TherapyJOURNAL OF CLINICAL HYPERTENSION, Issue 2007Keith Norris MD The blood pressure (BP) goals set by hypertension management guidelines (<140/90 mm Hg in uncomplicated hypertension; <130/80 mm Hg in type 2 diabetes or kidney disease) are not being achieved in a high proportion of patients, partly because monotherapy is insufficient in many patients. In particular, patients with uncontrolled moderate or severe hypertension and/or associated cardiovascular risk factors remain at high risk for cardiovascular events and hypertensive emergency. In recognition of the urgency of treating moderate and severe hypertension, the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) advocates the initial use of 2-drug therapies in patients with systolic BP levels >20 mm Hg above goal or diastolic BP level >10 mm Hg above goal. Regimens should usually include a thiazide diuretic and, for patients with diabetes or kidney disease, an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker. Recently, clinical trial data have shown that first-step antihypertensive treatment of moderate and severe hypertension with carefully chosen fixed-dose combinations provides a high rate of BP goal achievement, a simplified dosing regimen, and superior tolerability compared with monotherapy. [source] Appropriate dosing of antiarrhythmic drugs in Japan requires therapeutic drug monitoring,JOURNAL OF CLINICAL PHARMACY & THERAPEUTICS, Issue 1 2005M. Takada PhD Summary Objective:, In general, drugs are used in accordance with an approved dosage regimen in expectation of an appropriate balance between efficacy and toxicity. However, dose control of drugs with a narrow therapeutic range and marked intersubject variability in pharmacokinetics should be established through individualization of dosing based on therapeutic drug monitoring (TDM). The purpose of this study was to examine differences between the approved dosage regimen and the doses of antiarrhythmic drugs and digoxin used in clinical practice and to examine the influence of TDM on dosing. Methods:, Prescription research of antiarrhythmic drugs was performed at five national hospitals in Japan. Prescriptions for antiarrhythmic drugs (cibenzoline, disopyramide, pirmenol, mexiletine, aprindine, flecainide, pilsicainide, amiodarone and digoxin) were counted for the study period. The mean dose and dose distribution of the drugs were determined in each hospital. Comparisons were made of mean dose obtained in the study with the dosage approved by the authority. In addition, the percentage of patients that received TDM was determined. Results:, A difference was seen between the approved dosage and the actual dose. For all drugs except flecainide, the mean dose was smaller than the approved dosage. For all drugs except digoxin, remarkable variations were seen in the dose distribution among the hospitals. Digoxin showed a similar dose distribution among the five hospitals. Overall, the percentage of patients that received TDM was low except for Hospital A. However, TDM of digoxin was relatively common at four of the hospitals. Conclusions:, It is concluded that, with the exception of digoxin, the appropriate dosing regimen for antiarrhythmic drugs is not yet established. The establishment of appropriate dosing regimens for antiarrhythmic drugs requires the more widespread adoption of TDM. [source] Gadolinium-based contrast agents and their potential role in the pathogenesis of nephrogenic systemic fibrosis: The role of excess ligandJOURNAL OF MAGNETIC RESONANCE IMAGING, Issue 5 2008Martin A. Sieber PhD Abstract Purpose To investigate the role of excess ligand present in gadolinium (Gd) -based contrast agents in the development of nephrogenic systemic fibrosis (NSF). Using a dosing regimen to simulate the exposure seen in patients with severe renal impairment, we investigated the effect of excess ligand on Gd-deposition and the depletion of endogenous ions. Materials and Methods Gadodiamide and gadoversetamide were formulated with 0%, 5%, and 10% excess ligand. Forty-two, healthy, male Hannover Wistar rats received daily intravenous injections of each formulation over a period of 20 days. At the end of the study, histopathological analysis of the skin was performed and the concentrations of Gd, Zn, and Cu were measured in several tissues. The levels of Zn in the urine were also measured. Results The most severe skin lesions were observed after injection of formulations containing 0% free ligand and in those animals with the highest Gd concentrations in the skin. There were no significant reductions in the levels of Zn or Cu observed in the skin; however, the levels of Zn in the urine were elevated following administration of formulations with the highest amount of excess ligand. Conclusion Our findings suggest that there is an inverse correlation between the amount of excess ligand present in Gd-containing contrast agents and the amount of Gd in the tissue, and further underline the importance of the inherent stability of these agents in the development of NSF. J. Magn. Reson. Imaging 2008;27:955,962. © 2008 Wiley-Liss, Inc. [source] Assessing the antifungal activity and toxicity profile of amphotericin B lipid complex (ABLC; Abelcet®) in combination with caspofungin in experimental systemic aspergillosisJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 6 2004Olena Sivak Abstract The purpose of this study was to assess the antifungal activity and renal and hepatic toxicity of amphotericin B lipid complex (ABLC; Abelcet®) following co-administration of Caspofungin to rats infected with Aspergillus fumigatus. Aspergillus fumigatus inoculum (1.3,2.3,×,107 colony forming units [CFU]) was injected via the jugular vein; 48 h later male albino Sprague,Dawley rats (350,400 g) were administered either a single intravenous (IV) dose of Fungizone® (1 mg AmpB/kg), ABLC (1 or 5 mg AmpB/kg), or an equivalent volume of normal saline (NS) (vehicle control) once daily for 4 days. Rats were further randomized into groups to receive 3 mg/kg Caspofungin or physiologic saline IV once daily for 4 days. To assess antifungal activity, brain, lung, heart, liver, spleen, and kidney sections were homogenized with NS (2 mL; 1 g of each tissue/mL) and a 0.1-mL aliquot was spread plated onto a Sabouraud dextrose agar plate. The plates were incubated for 48 h at 37°C, at which time the numbers of CFU were determined and corrected for tissue weight. To assess renal and hepatic toxicity, serum creatinine and aspartate aminotransferase levels were determined. Fungizone and ABLC at a dosing regimen of 1 mg/kg i.v. once daily for four consecutive days and Caspofungin at a dosing regimen of 3 mg/kg i.v. once daily for four consecutive days had similar effectiveness in decreasing the total number of Aspergillus fumigatus CFUs found in all organs analyzed compared to non-treated controls. A combination of ABLC (1 mg/kg i.v.,×,4 days) and Caspofungin (3 mg/kg i.v.,×,4 days) significantly decreased the total number of Aspergillus fumigatus CFUs found in all organs analyzed compared to Caspofungin alone and non-treated controls. ABLC at a dosing regiment of 5 mg/kg i.v. once daily for four consecutive days was more effective in decreasing the total number of Aspergillus fumigatus CFUs found in all organs analyzed compared to Fungizone or ABLC alone at 1 mg/kg and Caspofungin alone at 3 mg/kg. However, a combination of ABLC (5 mg/kg i.v.,×,4 days) and Caspofungin (3 mg/kg i.v.,×,4 days) was not more effective than ABLC at 5 mg/kg or the combination of ABLC at 1 mg/kg and Caspofungin 3 mg/kg in reducing the total number of Aspergillus fumigatus CFUs compared to controls. Except for non-treated infected control rats, none of the treatment groups tested displayed a greater than 50% increase in serum creatinine concentrations from baseline. In addition, only ABLC at a dosing regimen of 1 mg/kg i.v. once daily for four consecutive days displayed a greater than 50% increase in AST concentration from baseline. Taken together, these findings suggest that ABLC at 5 mg/kg once daily,×,4 days appears to be the best therapeutic choice in this animal model. © 2004 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 93:1382,1389, 2004 [source] Imiquimod 5% cream is an acceptable treatment option for external anogenital warts in uncircumcised malesJOURNAL OF THE EUROPEAN ACADEMY OF DERMATOLOGY & VENEREOLOGY, Issue 1 2002RD Maw Abstract Objectives To determine the safety and efficacy of imiquimod (AldaraÔ) 5% cream in the treatment of prepuce-associated warts in uncircumcised males. Methods An open-label study in six UK medical centres with 35 uncircumcised males with prepuce-associated warts treated with imiquimod 5% cream three times per week for up to 16 weeks. Other anogenital warts were also treated. Results Three times weekly application of imiquimod was found to be safe, with erythema as the most commonly reported local skin reaction. Forty per cent of patients had complete clearance of anogenital warts within 16 weeks. Conclusions Imiquimod cream at a dosing regimen of three times per week, is effective and has an acceptable safety profile in the treatment of prepuce associated warts and other external anogenital warts in uncircumcised males. [source] Treatment of ulcerative colitis from the patient's perspective: a survey of preferences and satisfaction with therapyALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 10 2009J. R. GRAY Summary Background, Data available regarding patient perspectives on ulcerative colitis (UC) and their preferences and satisfaction with therapy are limited. Aims, To examine the preferences of UC patients to understand better what they look for in a therapy when managing their disease, as this may influence overall medication adherence. Methods, The study surveyed 100 Canadian UC patients on topics including educational resources used to learn about the disease, medication attributes that are most valued and preferred by the patient and satisfaction with current therapy. Results, Overall, efficacy- and safety-related medication attributes were rated by patients to be more important than those related to dosing regimen (e.g. dosing frequency, number of pills), cost and formulary coverage. In pair-wise comparisons of specific medication attributes, UC patients rated speed of symptom relief and few side effects as the most important factors when considering a UC medication (preferred on average 84% and 74% of the time respectively). Conclusion, This study provides insight into UC patient preferences and satisfaction with therapy that may be important when counselling on treatment options, and generates relevant discussions on adherence. Larger studies may be warranted to examine further how these findings can be extrapolated to broader UC populations. [source] Administration of adalimumab in the treatment of Crohn's disease of the ileal pouchALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 5 2009B. SHEN Summary Background, Crohn's disease (CD) of the pouch can develop in patients with ileal pouch-anal anastomosis (IPAA). Scant data are available on the treatment of this disease entity. Aim, To evaluate efficacy and safety of adalimumab in treating CD of the ileal pouch. Methods, From June 2007 to June 2008, 17 IPAA patients with inflammatory (n = 10), fibrostenotic (n = 2) or fistulizing (n = 5) CD of the pouch treated with adalimumab were evaluated. Inclusion criteria were CD of the pouch who failed medical therapy and were otherwise qualified for permanent pouch diversion or excision. All qualified patients received the standard dosing regimen of subcutaneous injection adalimumab (160 mg at week 0, 80 mg at week 1, and 40 mg every other week thereafter). Complete clinical response was defined as resolution of symptoms. Partial clinical response was defined as improvement in symptoms. Endoscopic inflammation before and after therapy was recorded, using the Pouchitis Disease Activity Index (PDAI) endoscopy subscores. Results, The median age was 36 years with 12 patients (70.6%) being male. At 4 weeks, seven patients (41.2%) had a complete symptom response and 6 (35.3%) had a partial response. There was also a significant improvement in the PDAI endoscopy subscores at week 4 (P < 0.05). At the last follow-up (median of 8 weeks), eight patients (47.1%) had a complete symptom response and 4 (23.5%) had a partial response. Four patients (23.6%) developed adverse effects. Three patients (17.7%) eventually had pouch failure after failing to respond to adalimumab therapy. Conclusion, Adalimumab appeared to be well-tolerated and efficacious in treating CD of the pouch in this open-labelled induction study. [source] Investigation of Japanese quail (Coturnix japonica) as a pharmacokinetic model for cockatiels (Nymphicus hollandicus) and Poicephalus parrots via comparison of the pharmacokinetics of a single intravenous injection of oxytetracycline hydrochlorideJOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 6 2005A. OSOFSKY The purpose of this study was to determine whether Japanese quail (Coturnix japonica) would serve as a pharmacokinetic animal model for two small companion parrots: cockatiels (Nymphicus hollandicus) and Poicephalus parrots. Oxytetracycline (OTC) was the pharmacologic agent chosen for this study as it is eliminated primarily by renal glomerular filtration and undergoes minimal metabolism. A single intravenous injection of 20 mg/kg oxytetracycline hydrochloride was administered to the three study groups and blood samples were obtained at 5, 10, 15, and 30 min post-OTC injection as well as 1, 2, 4, 8, 12 and 24 h post-OTC injection. Quantification of plasma OTC was accomplished using a standardized microbial inhibition assay. Naïve-pooled data (NPD) analysis of the plasma concentration,time profile of OTC best fit a two-compartment open model for all three avian species. Noncompartmental analysis of the mean data yielded the following parameters for quail, cockatiels and Poicephalus parrots respectively: ,z = 3.14, 4.57, 3.71 h; AUC = 38.9, 42.7, 49.6 ,g·h/mL; and Cl = 514, 468, 403 mL/h/kg. Based on the similarity of these pharmacokinetic parameters, it appears that quail could be used as a model species to predict the appropriate OTC dosing regimen for small psittacine birds. A bootstrap procedure was also applied to these sparse data sets for both compartmental and noncompartmental analysis. The bootstrap procedure allowed for the calculation of variability of parameters; however, the estimates of the parameters were very similar to those calculated using the NPD and the data mean values. [source] Clinical trial: sodium phosphate tablets are preferred and better tolerated by patients compared to polyethylene glycol solution plus bisacodyl tablets for bowel preparationALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 10 2007G. R. LICHTENSTEIN Summary Background, Patient acceptance of bowel preparation can affect colon cancer screening compliance. Aim, To compare patient acceptance, preference and tolerability of 32-sodium phosphate tablets vs. 2L polyethylene glycol solution plus 4 bisacodyl tablets for bowel preparation. Methods, A prospective, randomized, investigator-blinded, multicentre trial was performed. Results were based on responses to a patient questionnaire. Results, 411 patients (205 sodium phosphate; 206 polyethylene glycol plus bisacodyl) completed the study preparation and patient questionnaire prior to colonoscopy. More patients receiving sodium phosphate vs. polyethylene glycol plus bisacodyl found it easy to take (77% vs. 42%), reported it to be without taste (47% vs. 6%), found it easy to take with respect to volume of liquid prescribed (72% vs. 27%) and indicated they would take the same preparation again in the future (96% vs. 74%, P < 0.0001 for all). Fewer patients receiving sodium phosphate vs. polyethylene glycol plus bisacodyl had to take time off work or change ordinary activities to take the study preparation (18% vs. 52%, P < 0.0001). Nausea, vomiting, bloating and abdominal pain were reported less frequently with sodium phosphate (P < 0.0013). Conclusion, The 32-tablet sodium phosphate dosing regimen was easier to take and better tolerated, when compared to 2L polyethylene glycol plus bisacodyl tablets for bowel preparation. [source] Maintenance of Crohn's disease over 12 months: fixed versus flexible dosing regimen using budesonide controlled ileal release capsulesALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 9 2001J. R. B. Green Background: It may be possible to achieve more effective management of Crohn's Disease by introducing a flexible dosage regimen sensitive to patients' needs. Aim: Comparison of the efficacy and tolerability of a fixed vs. flexible budesonide controlled ileal release treatment regimen for the prevention and management of relapse in Crohn's disease patients. Budesonide controlled ileal release is an oral formulation which delivers drug directly to disease sites in the ileum and ascending colon, by preventing more proximal release and absorption. Methods: A randomized, double-blind comparison of a fixed dose of budesonide controlled ileal release (6 mg o.m.) and a flexible dose of budesonide controlled ileal release (3, 6 or 9 mg o.m.) for 12 months, in 143 patients in remission from ileal or ileo,caecal Crohn's Disease. Results: Very low rates of clinical relapse in Crohn's disease were achieved with budesonide controlled ileal release 6 mg o.m. There was no significant difference between the treatment groups with respect to the survival estimate of percentage of treatment failures (flexible group 15%, fixed group 19%; P=0.61). The average consumed dose of budesonide was comparable in both groups (5.8 mg flexible, 6.0 mg fixed). Similar proportions of patients reported adverse events (flexible 100%, fixed 97%). There were 33 serious adverse events (flexible 19, fixed 14) and 13 withdrawals due to significant adverse events (flexible 9, fixed 4). Conclusion: Maintenance treatment with budesonide controlled ileal release 6 mg o.m. is well-tolerated and is associated with low rates of clinical relapse in stable Crohn's disease over 12 months. Flexible dosing remains an option for individual patients, but this study has shown no advantage over a standard fixed dosing regimen. [source] FDA report: Ferumoxytol for intravenous iron therapy in adult patients with chronic kidney disease,,§AMERICAN JOURNAL OF HEMATOLOGY, Issue 5 2010Min Lu On June 30, 2009, the United States Food and Drug Administration (FDA) approved ferumoxytol (FerahemeÔ injection, AMAG Pharmaceuticals), an iron-containing product for intravenous (IV) administration, for the treatment of iron deficiency anemia in adult patients with chronic kidney disease (CKD). The safety and efficacy of ferumoxytol were assessed in three randomized, open-label, controlled clinical trials. Two trials evaluated patients with nondialysis dependent CKD and a third trial assessed patients undergoing hemodialysis. Randomization was either to ferumoxytol or oral iron. Ferumoxytol was administered as two 510 mg IV injections, separated by 3,8 days. Oral iron, Ferro-Sequels®, was administered at a dose of 100 mg twice daily for 21 days. In all three clinical trials, ferumoxytol administration increased the mean blood hemoglobin (Hgb) concentrations by ,1.0 g/dL over the 35 day period, a mean increase that was greater than what was observed in patients receiving oral iron. Patients receiving ferumoxytol also had increases in blood transferrin saturation (TSAT) and ferritin values. For the proposed ferumoxytol dosing regimen, 4.9% of patients had serum ferritin ,800 ng/mL and TSAT ,50% post-treatment. The most important ferumoxytol safety concerns were hypersensitivity reactions and/or hypotension. Anaphylaxis or anaphylactoid reactions were reported in 0.2% of subjects, and other adverse reactions potentially associated with hypersensitivity (e.g., pruritus, rash, urticaria, or wheezing) were reported in 3.7%. Hypotension was observed in 1.9%, including three patients with serious hypotensive reactions. Ferumoxytol administration may transiently affect the diagnostic ability of magnetic resonance imaging and the drug label provides further information regarding this effect. Am. J. Hematol. 2010. Published 2010 Wiley-Liss, Inc. [source] High-risk adenovirus-infected pediatric allogeneic hematopoietic progenitor cell transplant recipients and preemptive cidofovir therapyPEDIATRIC TRANSPLANTATION, Issue 2 2008Evan J. Anderson Abstract:, ADV has emerged as an important pathogen in children undergoing allogeneic HPCT. A prospective study of the epidemiology of ADV infection and preemptive therapy of high risk ADV infections in children undergoing HPCT was undertaken. Cultures of throat, urine, and stool for viral pathogens and plasma for ADV PCR were obtained prior to transplantation, weekly for the first 100 days, and then monthly for one yr. Children developing high-risk ADV infections were treated preemptively with cidofovir 1 mg/kg/day given three times weekly for three wk. A case-controlled study was performed to identify risk factors for high-risk ADV infections. Seven (18%) of the 38 subjects developed high-risk ADV infections usually within 100 days of HPCT and were preemptively treated with i.v. cidofovir at a dose of 1 mg/kg/dose three times weekly for nine doses. High-risk ADV infections resolved in all seven patients without renal toxicity. CMV viremia occurred in two of seven patients during or shortly after therapy with cidofovir. A case,control study did not identify any risk factors that achieved statistical significance. Treatment with a modified dosing regimen of cidofovir was well-tolerated and high-risk ADV infections resolved in all patients. [source] A Phase II intra-patient dose-escalation trial of weight-based darbepoetin alfa with or without granulocyte-colony stimulating factor in myelodysplastic syndromes,AMERICAN JOURNAL OF HEMATOLOGY, Issue 1 2009Jason Gotlib This Phase II study evaluated darbepoetin alfa (DA) in 24 patients with predominantly low or intermediate-1 risk myelodysplastic syndrome (MDS). Intra-patient dose escalation of DA was undertaken in three 6-week dose cohorts until a major erythroid response was achieved: 4.5 mcg/kg/week, 9 mcg/kg/week, and 9 mcg/kg/week plus granulocyte-colony stimulating factor (G-CSF) 2.5 mcg/kg twice weekly. Patients with refractory anemia with ringed sideroblasts (RARS) commenced DA at 9 mcg/kg/week. The weight-based dosing regimen translated into a median starting DA dose of 390 mcg/week. Erythroid responses were observed in 16/24 patients (67%; 12 major and 4 minor), with a median response duration of 11 months in major responders. Addition of G-CSF generated a major erythroid response in 7/15 patients (47%) who suboptimally responded to DA alone. DA was well tolerated, except for worsening of baseline mild hypertension and renal insufficiency in one patient with diabetes. IPSS score <0.5 and RBC transfusions <2 units/month increased the probability of an erythroid response. A minority of subjects (12%) developed low-level non-neutralizing anti-DA antibodies. Our data indicate that weekly weight-based dosing of DA, with the addition of G-CSF in selected individuals, can be an effective erythropoietic option in a high proportion of lower-risk MDS patients. Am. J. Hematol, 2009. © 2008 Wiley-Liss, Inc. [source] Treatment with inhaled corticosteroids in asthma is too often discontinued,PHARMACOEPIDEMIOLOGY AND DRUG SAFETY, Issue 4 2008Nancy S. Breekveldt-Postma PhD Abstract Purpose To study persistence with inhaled corticosteroids (ICS) and its determinants in asthma-patients. Methods From the PHARMO database, asthma-patients (age,<,35 years) with a first dispensing for ICS in 1999,2002 and,,,2 dispensings in the first year were included. Persistence during the first year was defined as the number of days from start to time of first failure to continue renewal of the initial ICS. Potential determinants of persistence were assessed at ICS-start and 1 year before. Results The study-cohort included 5563 new users of single ICS and 297 of fixed-combined ICS. Less than 10% of patients using single ICS and 15% of patients using fixed-combined ICS were persistent at 1 year. Similar persistence-rates were observed when stratified for age (children/adolescents: 0,18 years and adults: 19,34 years). Increased persistence with single ICS was observed with the type of ICS (budesonide), prescriber (specialist), prior use of long-acting beta-agonists, previous hospitalization for asthma, metered-dose inhaler, low starting-dose and once-daily dosing regimen at start. Persistence with fixed combined ICS-treatment increased with younger age and was decreased in patients having high starting-dose of ICS and prior use of antibiotics. Conclusion New users of both single and fixed combined ICS have alarming low persistence rates with ICS-treatment in the first year of follow-up. Persistence was mainly related to patient factors, such as severity of disease, and to treatment-related factors, such as once-daily dosing frequency. Copyright © 2008 John Wiley & Sons, Ltd. [source] Safety, Efficacy, and Pharmacokinetic Overview of Low-Dose Daily Administration of TadalafilTHE JOURNAL OF SEXUAL MEDICINE, Issue 7 2009Rebecca Wrishko PhD ABSTRACT Introduction., Several phosphodiesterase type 5 (PDE5) inhibitors are commercially available for the treatment of erectile dysfunction (ED). Development of the first once-daily alternative dosing regimen with a PDE5 inhibitor was motivated by the behavioral complexities associated with sexual intimacy. Aim., To provide an alternative dosing option for certain men who may benefit from the removal of the temporal linkage between administration of an ED therapy and sexual intimacy or for men and their partners who anticipate at least twice-weekly sexual activity. Methods., Pharmacokinetic predictions of tadalafil plasma concentrations were generated based upon empirical data following 20-mg, single-dose administration coupled with tadalafil usage patterns from as-needed clinical trials. To support the pharmacokinetic simulations and pharmacodynamic assumptions, clinical trials were conducted to demonstrate the efficacy and safety of once-daily, low-dose tadalafil 2.5 and 5 mg. Main Outcome Measures., Simulated tadalafil plasma concentrations and comparison with safety and efficacy measures from clinical trials. Results., Based upon pharmacodynamic and pharmacokinetic data, once-daily doses of tadalafil 5 mg were predicted to provide therapeutic concentrations that would be maintained throughout the 24-hour dosing interval. Additionally, for a subgroup of men who anticipate at least twice-weekly sexual activity and are currently taking tadalafil 20 mg, a reduction in daily tadalafil exposure was predicted. To support the hypothesis that low-dose, once-daily tadalafil may be a safe and effective treatment alternative, clinical trials were conducted to demonstrate the safety and efficacy of once-daily tadalafil 2.5 and 5 mg. These results were similar to those of historical as-needed studies evaluating tadalafil 10 and 20 mg. Conclusions., Consistent with pharmacokinetic predictions, data from clinical trials indicate that once-daily use of low-dose tadalafil is a safe and effective treatment for men with ED. Wrishko R, Sorsaburu S, Wong D, Strawbridge A, and McGill J. Safety, efficacy, and pharmacokinetic overview of low-dose daily administration of tadalafil. J Sex Med 2009;6:2039,2048. [source] Mycophenolic acid area under the curve correlates with disease activity in lupus patients treated with mycophenolate mofetilARTHRITIS & RHEUMATISM, Issue 7 2010Noël Zahr Objective Mycophenolic acid (MPA) is the active metabolite of mycophenolate mofetil (MMF), which is widely used to treat systemic lupus erythematosus (SLE). In transplantation, MPA area under the plasma concentration,time curve from 0 to 12 hours (MPA AUC0,12) is correlated with clinical outcome. We undertook the present study to assess possible relationships between SLE activity and MPA AUC0,12. Methods Using a Bayesian estimator, MPA AUC0,12 was determined in 71 consecutive SLE patients (61 women and 10 men; mean ± SD age 34 ± 10 years) receiving a stable MMF dose. On the same day, SLE activity was assessed using the SLE Disease Activity Index (SLEDAI; active disease defined as a SLEDAI score ,6) and the British Isles Lupus Assessment Group (BILAG) index (active disease defined as BILAG A or B). Results Two groups were studied: patients with active SLE (mean ± SD SLEDAI score 11.6 ± 4.4; n = 26) and patients with inactive SLE (mean ± SD SLEDAI score 1.9 ± 1.6; n = 45). MPA AUC0,12 correlated weakly with the dose of MMF (r = 0.33, P = 0.005). Mean ± SD MPA AUC0,12 in the group with active SLE was significantly lower than that in the group with inactive SLE (26.8 ± 13.6 ,g.hour/ml versus 46.5 ± 16.3 ,g.hour/ml; P < 0.0001). MPA AUC0,12 was negatively correlated with the SLEDAI (r = ,0.64, P < 0.0001). In multivariate analysis, MPA AUC0,12 was the sole parameter associated with SLE activity (odds ratio 0.89 [95% confidence interval 0.83,0.96], P = 0.002). The MPA AUC0,12 threshold value of 35 ,g.hour/ml was associated with the lowest risk of active SLE. Conclusion Our data show that SLE activity is strongly correlated with MPA AUC0,12. An individualized dosing regimen of MMF, with a target AUC0,12 of 35 ,g.hour/ml, should be considered for SLE patients. [source] Tocilizumab in systemic lupus erythematosus: Data on safety, preliminary efficacy, and impact on circulating plasma cells from an open-label phase I dosage-escalation study,ARTHRITIS & RHEUMATISM, Issue 2 2010Gabor G. Illei Objective To assess the safety of interleukin-6 receptor inhibition and to collect preliminary data on the clinical and immunologic efficacy of tocilizumab in patients with systemic lupus erythematosus (SLE). Methods In an open-label phase I dosage-escalation study, 16 patients with mild-to-moderate disease activity were assigned to receive 1 of 3 doses of tocilizumab given intravenously every other week for 12 weeks (total of 7 infusions): 2 mg/kg in 4 patients, 4 mg/kg in 6 patients, or 8 mg/kg in 6 patients. Patients were then monitored for an additional 8 weeks. Results The infusions were well tolerated. Tocilizumab treatment led to dosage-related decreases in the absolute neutrophil count, with a median decrease of 38% in the 4 mg/kg dosage group and 56% in the 8 mg/kg dosage group. Neutrophil counts returned to normal after cessation of treatment. One patient was withdrawn from the study because of neutropenia. Infections occurred in 11 patients; none was associated with neutropenia. Disease activity showed significant improvement, with a decrease of ,4 points in the modified Safety of Estrogens in Lupus Erythematosus National Assessment version of the Systemic Lupus Erythematosus Disease Activity Index score in 8 of the 15 evaluable patients. Arthritis improved in all 7 patients who had arthritis at baseline and resolved in 4 of them. Levels of anti,double-stranded DNA antibodies decreased by a median of 47% in patients in the 4 mg/kg and 8 mg/kg dosage groups, with a 7.8% decrease in their IgG levels. These changes, together with a significant decrease in the frequency of circulating plasma cells, suggest a specific effect of tocilizumab on autoantibody-producing cells. Conclusion Although neutropenia may limit the maximum dosage of tocilizumab in patients with SLE, the observed clinical and serologic responses are promising and warrant further studies to establish the optimal dosing regimen and efficacy. [source] Time-dependent clearance and hematological pharmacodynamics upon erythropoietin multiple dosing in ratsBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 5-6 2010Sihem Ait-Oudhia Abstract The pharmacokinetics (PK) and pharmacodynamics (PD) of recombinant human erythropoietin (rHuEPO) upon its repeated administrations were investigated. Two groups (A and B) of normal Wistar rats received rHuEPO intravenously at 450 or 1350,IU/kg thrice weekly for 2 and 6 weeks. PK studies were conducted following days 0 and 4 for group (A) and days 0, 17 and 28 for group (B), then, washout PK were assessed on days 11 and 36 for both groups. Reticulocytes (RET), red blood cells (RBC) and hemoglobin (Hb) were evaluated daily until day 14, then every 2 days until day 30 for group (A) and 59 for group (B). The total clearance CLTotal increased with the dose but decreased over time. Its decay reached 20% and 55% between the first and last full PK in both treatment arms. RET peaked on day 5 and were 77.6% and 87.3% higher than baselines for the two dosing regimen. Their nadirs occurred on days 22 and 55 and were 37.9% and 47.3% below normal values. Hb peaked on days 10 and 34 and was 28.9% and 38.6% above the baseline level, its nadirs occurred on days 25 and 57 and were 13.1% and 16% below baselines. Control animals showed stable baselines over the study but with moderate variability. In conclusion, rHuEPO exhibits a nonlinear PK with a time-dependent decrease of its CLTotal. During exposure, RET, RBC and Hb showed a tolerance effect. After exposure, the rebound was characterized for RET, RBC, but not Hb. Copyright © 2010 John Wiley & Sons, Ltd. [source] Pharmacodynamics of glucose regulation by methylprednisolone.BIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 1 2009Abstract Mechanisms related to the adverse effects of corticosteroids on glucose homeostasis were studied. Five groups of adrenalectomized (ADX) rats were given methylprednisolone (MPL) intravenously at 10 and 50,mg/kg, or a continuous 7 day infusion at rates of 0, 0.1, 0.3,mg/kg/h via subcutaneously implanted Alzet mini-pumps. Plasma concentrations of MPL, glucose and insulin were determined at various time points up to 72,h after injection or 336,h after infusion. The pharmacokinetics of MPL was captured with a two-compartment model. The Adapt II software was used in modeling. Injection of MPL caused a temporary glucose increase over 6,h by stimulating gluconeogenesis. The glucose changes stimulated pancreatic ,-cell secretion yielding a later insulin peak at around 10,h. In turn, insulin can stimulate glucose disposition. However, long-term MPL treatment caused continuous hyperglycemia during and after infusion. Insulin was increased during infusion, and immediately returned to baseline after the infusion was terminated, despite the almost doubled glucose concentration. A disease progression model incorporating the reduced endogenous glucose disposition was included to capture glucose homeostasis under different treatments. The results exemplify the importance of the steroid dosing regimen in mediating pharmacological and adverse metabolic effects. This mechanistic pharmacokinetic/pharmacodynamic (PK/PD) model quantitatively describes the induction of hyperglycemia and provides additional insights into metabolic disorders such as diabetes. Copyright © 2009 John Wiley & Sons, Ltd. [source] Complete bioavailability and lack of food-effect on pharmacokinetics of gliclazide 30 mg modified release in healthy volunteersBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 4 2002P. Delrat Abstract A new modified release (MR) formulation containing 30 mg of gliclazide was developed to obtain a better predictable release of the active principle and to allow once-daily dosing regimen. An absolute bioavailability study was carried out to characterise the performance of the new formulation and the food-effect was also investigated in a separate study. Both studies were single dose, randomised, open label, two way cross over studies with a wash out period between doses. For the bioavailability study, each volunteer received 30 mg of gliclazide given either as a 1 h intravenous infusion or as a 30 mg MR tablet. For the food-effect study, the treatment was given either fasted or 10 min after the start of a standardised Melander breakfast. Blood samples were collected up to 72 h after administrations and plasma samples assayed for gliclazide concentrations using a reverse-phase HPLC method with UV detection. Mean absolute bioavailability of gliclazide was 97% and ranged between 79 and 110% showing complete absorption. A similar moderate to low variability was observed after IV and oral administration showing the MR formulation did not add to the overall variability which is solely due to the disposition parameters, in particular metabolism of gliclazide. No significant difference was observed in tmax, t1/2z, Cmax and AUC of gliclazide after administration of the 30 mg MR tablet under fasted and fed conditions. In conclusion, after single oral administration of a 30 mg MR tablet, gliclazide was completely absorbed both under fasted and fed conditions. A consistent and optimal release of gliclazide from this formulation leads to a low to moderate overall variability of its pharmacokinetic parameters. Diamicron 30 mg MR can be given without regards to meals i.e. before, during or after breakfast. Copyright © 2002 John Wiley & Sons, Ltd. [source] Vancomycin dosing assessment in intensive care unit patients based on a population pharmacokinetic/pharmacodynamic simulationBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 2 2010Natalia Revilla WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT , Despite the frequent use of vancomycin in intensive care unit (ICU) patients, few studies aimed at characterizing vancomycin population pharmacokinetics have been performed in this critical population. , Population pharmacokinetics coupled with pharmacodynamic analysis, in order to optimize drug exposure and hence antibacterial effectiveness, has been little applied in these specific patients. WHAT THIS STUDY ADDS , Our population model characterized the pharmacokinetic profile of vancomycin in adult ICU patients, higher distribution volume values (V) being observed when the patient's serum creatinine (CrSe) was greater than 1 mg dl,1. , Age and creatinine clearance (CLcr) were identified as the main covariates explaining the pharmacokinetic variability in vancomycin CL. , Our pharmacokinetic/pharmacodynamic (PK/PD) simulation should aid clinicians to select initial vancomycin doses that will maximize the rate of response in the ICU setting, taking into account the patient's age and renal function as well as the susceptibility of Staphylococcus aureus. AIM To estimate the vancomycin pharmacokinetic profile in adult ICU patients and to assess vancomycin dosages for increasing the likelihood of optimal exposure. METHODS Five hundred and sixty-nine concentration,time data from 191 patients were analysed using a population pharmacokinetic approach (NONMENÔ). External model evaluation was made in 46 additional patients. The 24 h area under the concentration,time curve (AUC(0,24 h)) was derived from the final model. Minimum inhibitory concentration (MIC) values for S. aureus were obtained from the EUCAST database. AUC(0,24 h) : MIC , 400 was considered as PK/PD efficacy index. The probability of different dosages attaining the target considering different strains of S. aureus and patient subgroups was estimated with Monte Carlo simulation. RESULTS Vancomycin CL showed a significant dependence on patient age and renal function whereas CrSe > 1 mg dl,1 increased V more than twofold. For our representative ICU patient, 61 years, 73 kg, CrSe= 1.4 mg dl,1, measured CLCr= 74.7 ml min,1, the estimated values were CL = 1.06 ml min,1 kg,1 and V= 2.04 l kg,1. The cumulative fraction of response for a standard vancomycin dose (2 g day,1) was less than 25% for VISA strains, and 33% to 95% for susceptible S. aureus, depending on patient characteristics. CONCLUSIONS Simulations provide useful information regarding the initial assessment of vancomycin dosing, the conventional dosing regimen probably being suboptimal in adult ICU patients. A graphic approach provides the recommended dose for any selected probability of attaining the PK/PD efficacy target or to evaluate the cumulative fraction of response for any dosing regimen in this population. [source] Hormonal and metabolic effects of morning or evening dosing of the dipeptidyl peptidase IV inhibitor vildagliptin in patients with type 2 diabetesBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 1 2010Yan-Ling He WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT , Vildagliptin is an orally active, potent inhibitor of dipeptidyl peptidase IV and was developed for the treatment of type 2 diabetes. , In clinical trials, once or twice daily dosing with vildagliptin (up to 100 mg day,1) has been shown to reduce endogenous glucose production and fasting plasma glucose in patients with type 2 diabetes. , The comparative efficacy of vildagliptin under a morning vs. evening dosing regimen has not previously been determined. WHAT THIS STUDY ADDS , Once daily dosing with vildagliptin 100 mg for 28 days improved glycaemic control in patients with type 2 diabetes independent of whether vildagliptin was administered in the morning or evening. , Morning or evening dosing with vildagliptin had similar effects on 24 h glycaemic control and plasma concentrations of the hormones insulin, glucagon and glucagon-like peptide 1. AIM This randomized, double-blind, crossover study compared post-prandial hormonal and metabolic effects of vildagliptin, (an oral, potent, selective inhibitor of dipeptidyl peptidase IV [DPP-4]) administered morning or evening in patients with type 2 diabetes. METHODS Forty-eight patients were randomized to once daily vildagliptin 100 mg administered before breakfast or before dinner for 28 days then crossed over to the other dosing regimen. Blood was sampled frequently after each dose at baseline (day ,1) and on days 28 and 56 to assess pharmacodynamic parameters. RESULTS Vildagliptin inhibited DPP-4 activity (>80% for 15.5 h post-dose), and increased active glucagon-like peptide-1 compared with placebo. Both regimens reduced total glucose exposure compared with placebo (area under the 0,24 h effect,time curve [AUE(0,24 h)]: morning ,467 mg dl,1 h, P= 0.014; evening ,574 mg dl,1 h, P= 0.003) with no difference between regimens (P= 0.430). Reductions in daytime glucose exposure (AUE(0,10.5 h)) were similar between regimens. Reduction in night-time exposure (AUE(10.5,24 h) was greater with evening than morning dosing (,336 vs.,218 mg dl,1 h, P= 0.192). Only evening dosing significantly reduced fasting plasma glucose (,13 mg dl,1, P= 0.032) compared with placebo. Insulin exposure was greater with evening dosing (evening 407 µU ml,1 h; morning 354 µU ml,1 h, P= 0.050). CONCLUSIONS Both morning and evening dosing of once daily vildagliptin 100 mg significantly reduced post-prandial glucose in patients with type 2 diabetes; only evening dosing significantly decreased fasting plasma glucose. Although evening dosing with vildagliptin 100 mg tended to decrease night-time glucose exposure more than morning dosing, both regimens were equally effective in reducing 24 h mean glucose exposure (AUE(0,24 h)) in patients with type 2 diabetes. [source] Pharmacokinetics and pharmacodynamics of LC15-0444, a novel dipeptidyl peptidase IV inhibitor, after multiple dosing in healthy volunteersBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 6 2009Kyoung Soo Lim WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT , The importance of efficient drug development using biomarkers has been increasingly emphasized, from preclinical studies to clinical trials. , However, as yet few ,validated' or ,qualified' biomarkers are used in early-stage drug development in terms of clinical pharmacology and disease pathophysiology. WHAT THIS STUDY ADDS , This first-time-in-human study provides evidence of the pharmacological activity of LC15-0444 in humans, by using dipeptidyl peptidase IV activity and active glucagon-like peptide-1 concentrations. , LC15-0444 possesses pharmacokinetic and pharmacodynamic characteristics that support a once-daily dosing regimen. AIMS LC15-0444 is a selective and competitive inhibitor of dipeptidyl peptidase (DPP) IV with potential for the treatment of Type 2 diabetes. The aim was to investigate the pharmacokinetic (PK) and pharmacodynamic (PD) profiles after multiple oral ascending doses of LC15-0444 in healthy male subjects. METHODS A dose block-randomized, double-blind, placebo-controlled, parallel group study was performed in three groups with 10 subjects (eight for active drug; two for placebo) per group; each group received 200, 400 or 600 mg of LC15-0444 once daily for 10 days. Blood and urine samples were collected up to 24 h after the first dosing and up to 72 h after the last dosing. RESULTS The LC15-0444 concentration,time profiles exhibited characteristics of multicompartment disposition. No dose- or time-dependent change in PK parameters was observed. Mean elimination half-life was in a range 16.6,20.1 h in the dose groups. Mean renal clearance and fraction of unchanged drug excreted in urine was 18.6,21.9 and 0.40,0.48 l h,1, respectively. In the steady state, mean accumulation ratios by dose groups were between 1.22 and 1.31. More than 80% inhibition of DPP IV activity from baseline was sustained for >24 h in all dose groups. CONCLUSIONS This study provides evidence of the pharmacological activity of LC15-0444 in humans. LC15-0444 possesses PK and PD characteristics that support a once-daily dosing regimen. [source] Development of a drug,disease simulation model for rituximab in follicular non-Hodgkin's lymphomaBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 4 2009David Ternant WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT , Serum concentrations of rituximab influence its clinical efficacy in follicular lymphoma (FL), but its concentration,effect relationship has not been described by pharmacokinetic,pharmacodynamic (PK,PD) modelling. , The genetic polymorphism of FCGR3A influences rituximab efficacy and its in vitro concentration,effect relationship. , Increasing rituximab dose and/or number of infusions may lead to a better clinical response in FL. WHAT THIS PAPER ADDS , This study is the first to describe the concentration,effect relationship of rituximab in populations of FL patients. , This PK,PD model relates progression-free survival with rituximab concentrations and takes into account the influence of FCGR3A polymorphism. , Clinical trials testing new dosing regimens of rituximab can be designed using this PK,PD model. AIM Rituximab has dramatically improved the survival of patients with non-Hodgkin's lymphomas (NHL), but the dosing regimen currently used should be optimized. However, the concentration,effect relationship of rituximab has never been described by pharmacokinetic,pharmacodynamic (PK,PD) modelling, precluding the simulation of new dosing regimens. The aim of this study was to develop a PK,PD model of rituximab in relapsed/resistant follicular NHL (FL). METHODS A model describing the relationship between rituximab concentrations and progression-free survival (PFS) was developed using data extracted from the pivotal study, which evaluated 151 relapsed/resistant FL patients. The influence of FCGR3A genetic polymorphism on the efficacy of rituximab was quantified using data from 87 relapsed/resistant FL patients. The predictive performance of the model was analysed using two independent datasets: a study that evaluated rituximab combined with chemotherapy [rituximab, cyclophosphamide, vincristine, adriamycin and prednisone (R-CHOP)] in 334 relapsed/resistant FL patients and a study that evaluated rituximab monotherapy in 47 asymptomatic FL patients with known FCGR3A genotype. RESULTS For R-CHOP, observed and model-predicted PFS (90% confidence interval) at 24 months were 0.50 and 0.48 (0.40, 0.56), respectively, for the observation arm, and 0.62 and 0.59 (0.50, 0.65), respectively, for the rituximab maintenance arm. For rituximab monotherapy, observed and predicted PFS at 24 months were 0.67 and 0.63, respectively, for FCGR3A -V/V patients, and 0.41 and 0.36 (0.25, 0.49), respectively, for FCGR3A -F carriers. CONCLUSIONS Our model provides a satisfactory prediction of PFS at 24 months. It can be used to simulate new dosing regimens of rituximab in populations of FL patients and should improve the design of future clinical trials. [source] Assessment of the effect of dextromethorphan and ketamine on the acute nociceptive threshold and wind-up of the second pain response in healthy male volunteersBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 6 2002A. M. Hughes Aims, The aim of this study was to assess the efficacy of dextromethorphan and ketamine relative to placebo on the acute nociceptive threshold and wind-up of second pain response in healthy male volunteers. Methods, The trial was a randomized, double-blind, placebo-controlled, three period crossover, double dummy design in 12 healthy male volunteers. During each of the three periods (which were separated by a 1 week washout period) each volunteer received either a single oral dose of 0.7 mg kg,1 dextromethorphan and placebo to ketamine, or placebo to dextromethorphan followed by a single intravenous injection of 0.375 mg kg,1 ketamine, or placebo to both dextromethorphan and ketamine. The trial did not schedule administration of both ketamine and dextromethorphan together. Acute nociceptive thresholds and wind-up of second pain were measured in the skin of the thenar eminence of the ventral surfaces of the right and left hands, using a SOMEDICTM thermotest apparatus, before and at the estimated tmax for dextromethorphan (i.e. 2.15 h). Blood pressure and heart rate were also monitored before dosing and after the dosing regimen. Results, Neither dextromethorphan nor ketamine had any significant effect on acute nociceptive thresholds on either hand (P>0.05). Moreover, dextromethorphan was without any significant effect (P>0.05) on the wind-up of the second pain response on either hand. The lsmean number of stimuli tolerated vs placebo (95% confidence intervals of the difference in number of stimuli in parentheses) were 15.84 vs 16.48 (,5.52, 4.24) and 11.75 vs 15.25 (,11.89, 4.90) for left- and right-hand, respectively, following dextromethorphan administration. In contrast ketamine produced significant reductions in wind-up to second pain in both the left and right hands (P=0.0002 and 0.0386, respectively). The lsmean numbers of stimuli tolerated vs placebo (95% confidence intervals of the difference in number of stimuli in parentheses) were 28.41 vs 16.48 (6.60, 17.25) and 25.00 vs 15.25 (0.58, 18.93) for left- and right-hand, respectively. Conclusions, Wind-up of second pain induced by noxious heat is sensitive to intervention by ketamine, which is known to block the NMDA receptor. These data infer that the wind-up phenomenon evoked by noxious heat involves the activation of NMDA receptors. This volunteer model of pain may have utility in the evaluation of agents that modulate their antinociceptive actions via NMDA mechanisms. [source] | ||||||||||||||||||||||||||||||||||||||||