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Kinds of Subjects Terms modified by Subjects Selected AbstractsMEGESTROL ACETATE USE FOR ANOREXIA IN THE OLDER SUBJECTJOURNAL OF AMERICAN GERIATRICS SOCIETY, Issue 1 2006Anupam Suneja MBBS No abstract is available for this article. [source] TWO NOTIONS OF TRANSCENDENCE: CONFUCIAN MAN AND MODERN SUBJECTJOURNAL OF CHINESE PHILOSOPHY, Issue 3 2009GUOPING ZHAO First page of article [source] PRICING EQUITY DERIVATIVES SUBJECT TO BANKRUPTCYMATHEMATICAL FINANCE, Issue 2 2006Vadim Linetsky We solve in closed form a parsimonious extension of the Black,Scholes,Merton model with bankruptcy where the hazard rate of bankruptcy is a negative power of the stock price. Combining a scale change and a measure change, the model dynamics is reduced to a linear stochastic differential equation whose solution is a diffusion process that plays a central role in the pricing of Asian options. The solution is in the form of a spectral expansion associated with the diffusion infinitesimal generator. The latter is closely related to the Schrödinger operator with Morse potential. Pricing formulas for both corporate bonds and stock options are obtained in closed form. Term credit spreads on corporate bonds and implied volatility skews of stock options are closely linked in this model, with parameters of the hazard rate specification controlling both the shape of the term structure of credit spreads and the slope of the implied volatility skew. Our analytical formulas are easy to implement and should prove useful to researchers and practitioners in corporate debt and equity derivatives markets. [source] POWER IN SOCIAL ORGANIZATION AS THE SUBJECT OF JUSTICEPACIFIC PHILOSOPHICAL QUARTERLY, Issue 1 2005AARON JAMES This rationale for assessment of social justice equally applies to legally optional or informal social practices. But it does not apply to individual conduct. Indeed, it follows that principles of social justice cannot provide a basis for the assessment and guidance of individual choice. The paper develops this practice-based conception of the subject of justice by rejoining G. A. Cohen's influential critique of Rawls' focus on the "basic structure" of society. [source] KNOWLEDGE, SPEAKER AND SUBJECTTHE PHILOSOPHICAL QUARTERLY, Issue 219 2005Stewart Cohen I contrast two solutions to the lottery paradox concerning knowledge: contextualism and subject-sensitive invariantism. I defend contextualism against an objection that it cannot explain how ,knows' and its cognates function inside propositional attitude reports. I then argue that subject-sensitive invariantism fails to provide a satisfactory resolution of the paradox. [source] SUBJECT, OBJECT, MIMESIS: THE AESTHETIC WORLD OF THE BECHERS' PHOTOGRAPHYART HISTORY, Issue 5 2009SARAH E. JAMES This paper will examine the critical relationship between subjectivity and objecthood established in Bernd and Hilla Bechers' photography. Building upon existing readings by Blake Stimson and Michael Fried, I argue that Adorno's aesthetic thought, and especially his category of mimesis, offers a way in which both to frame the politics of the subject and object experiences in the Bechers' photography, and to situate these culturally, contextualizing their work within a critical juncture in German history. The Bechers' rejection of the subject and the pursuit of an objective photography are explored in relation to the ,post-Auschwitz taboo on beauty' and the anti-ideology that dominated West Germany of the 1950s. The Bechers' attempt to redeem expression by presenting the frail objectivity and historicity of things is examined in relation to the negative dialectical framework and desubjectifying model of aesthetics formulated by Adorno. [source] Prescribing pattern of anti-epileptic drugs in an Italian setting of elderly outpatients: a population-based study during 2004,07BRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 4 2010Alessandro Oteri WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT , In the last years there has been a growing trend in anti-epileptic drug (AED) use, particularly in elderly patients, but few data concerning indication of use are available in general practice. , Various AEDs, including newer agents, have been approved for indications other than epilepsy and are increasingly also used for unlicensed indications. , No data about the impact of re-imbursement restrictions on the choice of anti-epileptic drugs in general practice are available. WHAT THIS STUDY ADDS , In general practice, a rapid increase of AED prescriptions in the elderly was observed, principally due to the use of newer AEDs for indications other than epilepsy. , Re-imbursement restrictions influenced newer AED use, particularly pregabalin and gabapentin prescriptions. , Phenobarbital, accounting for more than 50% of total AED volume, was the most prescribed medication during the entire study period. This finding should be considered in light of the potential risks associated with phenobarbital use in the geriatric population. AIMS The aims of the study were to assess the trend of older and newer anti-epileptic drugs (AEDs) in the elderly population and to analyze the effects of a health-policy intervention with regard to AED use in general practice in a setting in Southern Italy. METHODS Data were extracted from the ,Caserta-1' Local-Health-Unit Arianna database in the years 2004,07. Patients aged over 65 years, receiving at least one AED prescription and registered in the lists of 88 general practitioners, were selected. The use of older and newer AEDs was calculated as 1 year prevalence and incidence of use and defined daily dose (DDD) per 1000 inhabitants day,1. Sub-analyses by gender, age and indication of use were performed. RESULTS Most of AED users were treated because of neuropathic pain (64.8%). However, the main indication of use for older AEDs (57.8%) was epilepsy, whereas newer AEDs (79.5%) were used for neuropathic pain. Prevalence and incidence of newer AED use increased until 2006, followed by a reduction in 2007. Newer AEDs, particularly gabapentin and pregabalin, were used in the treatment of more patients than older AEDs. However phenobarbital, accounting for more than 50% of total AED volume, was the most prescribed medication during the entire study period. CONCLUSIONS An increasing use of AEDs has been observed during 2004,07, mostly due to the prescription of newer compounds for neuropathic pain. The fall in the use of newer AEDs during 2007 coincides with revised re-imbursement criteria for gabapentin and pregabalin. The large use of phenobarbital in the elderly should be considered in the light of a risk of adverse drug reactions. [source] Proteome mapping of overexpressed membrane-enriched and cytosolic proteins in sodium antimony gluconate (SAG) resistant clinical isolate of Leishmania donovaniBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 4 2010Awanish Kumar WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT Over 60% of patients with visceral leishmaniasis (VL) in India and Sudan have become unresponsive to treatment with pentavalent antimonials, the first line of drugs for over 60 years. The drug resistance mechanism, studied so far in in vitro selected laboratory strains, has been attributed to various biochemical parameters. The resistance to Sb (V) in Leishmania field isolates is still unexplored. WHAT THIS STUDY ADDS In order to elucidate for the first time the mechanism of drug resistance in field isolates, this study was done in those clinically relevant field isolates which were either responsive or non responsive to SAG. A comparison of proteome profiles of membrane-enriched as well as cytosolic protein fractions of these isolates has pinpointed the multiple overexpressed proteins in resistant isolates. This study has indicated their possible essential role in antimony resistance of the parasite and provides a vast field to be exploited to find much needed novel treatment strategies against VL. AIMS This study aimed to identify differentially overexpressed membrane-enriched as well as cytosolic proteins in SAG sensitive and resistant clinical strains of L. donovani isolated from VL patients which are involved in the drug resistance mechanism. METHODS The proteins in the membrane-enriched as well as cytosolic fractions of drug-sensitive as well as drug-resistant clinical isolates were separated using two-dimensional gel electrophoresis and overexpressed identified protein spots of interest were excised and analysed using MALDI-TOF/TOF. RESULTS Six out of 12 overexpressed proteins were identified in the membrane-enriched fraction of the SAG resistant strain of L. donovani whereas 14 out of 18 spots were identified in the cytosolic fraction as compared with the SAG sensitive strain. The major proteins in the membrane-enriched fraction were ABC transporter, HSP-83, GPI protein transamidase, cysteine,leucine rich protein and 60S ribosomal protein L23a whereas in the cytosolic fraction proliferative cell nuclear antigen (PCNA), proteasome alpha 5 subunit, carboxypeptidase, HSP-70, enolase, fructose-1,6-bisphosphate aldolase, tubulin-beta chain have been identified. Most of these proteins have been reported as potential drug targets, except 60S ribosomal protein L23a and PCNA which have not been reported to date for their possible involvement in drug resistance against VL. CONCLUSION This study for the first time provided a cumulative proteomic analysis of proteins overexpressed in drug resistant clinical isolates of L. donovani indicating their possible role in antimony resistance of the parasite. Identified proteins provide a vast field to be exploited for novel treatment strategies against VL such as cloning and overexpression of these targets to produce recombinant therapeutic/prophylactic proteins. [source] Influence of methotrexate exposure on outcome in patients treated with MBVP chemotherapy for primary central nervous system lymphomaBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 3 2010Hélčne Blasco WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT Although treated using the same high-dose methotrexate (HD-MTX)-based multiagent chemotherapy, patients with primary central nervous system lymphoma (PCNSL) have significant differences in outcome. However, little information has been published about factors influencing outcome in PCNSL. As it is known that the pharmacokinetics of MTX vary considerably between subjects leading to different exposure in patients receiving the same dose, it is important to evaluate its role in response to chemotherapy. WHAT THIS STUDY ADDS This study is the first to evaluate the exposure,response relationship in patients treated with MBVP chemotherapy. We found that patients who were early non-responders to MBVP chemotherapy had poor survival, whatever the salvage regimen. Tumour response at early evaluation was not associated with MTX pharmacokinetics and increasing the dose would probably not improve results. AIMS Although the standard treatment for primary central nervous system lymphoma (PCNSL) consists of three cycles of MBVP (methotrexate, BCNU, VP16, methylprednisolone) and radiotherapy, early failure of treatment may require modification of the treatment. However, our understanding of the outcome in such patients and of the factors involved in early failure of treatment is poor. In addition to known prognostic factors, we evaluated the influence of methotrexate (MTX) exposure on the response to MBVP chemotherapy in patients treated for PCNSL after the first two cycles. METHODS We retrospectively analyzed all patients with PCNSL treated with the MBVP regimen over the previous 10 years. Clinical, personal data and known prognostic factors were studied. The parameters of MTX exposure were estimated using a population pharmacokinetic approach with NONMEM. Objective response (OR), overall survival (OS) and failure-free survival (FFS) were evaluated in all patients. RESULTS Thirty-seven patients were studied. We observed lower FFS and OS (0.49 years) in patients who were not able to receive the planned treatment (group 1, n= 12) than in those who received three cycles (8.04 years) (group 2, n= 25). Known prognostic factors were comparable in both groups, but mean dose of MTX and mean AUC tended to be lower in patients who failed prematurely or showed no response after two cycles. CONCLUSIONS We found that patients who were early non-responders to MBVP chemotherapy had poor survival, without major influence of MTX exposure. It is thus probably unlikely that increasing the dose of MTX would improve outcome. [source] Perceived adverse drug reactions among non-institutionalized children and adolescents in GermanyBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 3 2010Hildtraud Knopf WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT Drug safety in paediatric medication is a public health concern. According to previous studies, the incidence of adverse drug reactions (ADRs) varies greatly from 0.7% to 2.7% among paediatric outpatients and from 2.6% to 18.1% among paediatric inpatients. Little has been reported on the risks of drug use in the general child population. WHAT THIS STUDY ADDS Our study showed that the prevalence of perceived ADRs in Germany was 0.9% among non-institutionalized children in general and 1.7% among children who had used at least one medicine within the 7 days before the medical interview. Perceived ADRs in the general child population were clustered with gastrointestinal disorders and subcutaneous tissue disorders. They appeared to be mild and at the lower limits of the range reported in other studies. Health surveys covering the use of a diverse range of drugs might be suitable for computing ADR prevalence and for identifying risk factors among non-institutionalized children. They should be taken into account together with other pharmacovigilance systems. AIMS Little has been reported on the risks of drug use in the general child population. This study investigated perceived adverse drug reactions (ADRs) among non-institutionalized children in Germany. METHODS All medicines used in the last 7 days before the medical interview were recorded among the 17 450 children aged 0,17 years who participated in the 2003,06 German Health Interview and Examination Survey for Children and Adolescents (KiGGS). Perceived ADRs were reported by the children's parents and confirmed by trained medical professionals during the medical interview. RESULTS One hundred and fifty-seven medicines were involved in the occurrence of 198 perceived ADRs in 153 patients. This corresponded to 1.1% of total used drugs, 0.9% (95% confidence intervals 0.7, 1.1%) of all children, and 1.7% (1.4, 2.1%) of children treated with medications. About 40% of all perceived ADRs involved gastrointestinal disorders and 16% involved skin tissue disorders. Perceived ADRs were most frequently reported in relation to drugs acting on the nervous system (25.8%), followed by systemic anti-infectives (18.7%) and drugs acting on the respiratory system (16.2%). Risk factors for perceived ADRs included older age groups, polypharmacy (,2) and a poor health status. CONCLUSION Perceived ADRs in the general child population were clustered with gastrointestinal disorders and subcutaneous tissue disorders. They appeared to be mild and at the lower limits of the range reported in other studies. Health surveys covering the use of a diverse range of drugs might be suitable for computing ADR prevalence and identifying risk factors among non-institutionalized children. They should be taken into account together with other pharmacovigilance systems. [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] Absence of large intragenic rearrangements in the DPYD gene in a large cohort of colorectal cancer patients treated with 5-FU-based chemotherapyBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 2 2010Laia Paré WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT , Dihydropyrimidine dehydrogenase (DPD) is the enzyme responsible for the elimination of approximately 80% of the administered dose of 5-fluorouracil (5-FU). , Mutations in the DPD-coding gene have been shown to increase the risk of severe toxicity in 5-FU treated patients. , The IVS14+1G>A is the most common DPYD mutation. WHAT THIS STUDY ADDS , The intragenic rearrangements of DPYD using multiplex ligation-dependent probe amplification (MLPA) were studied for the first time in a large series of 234 colorectal cancer patients treated with 5-FU-containing chemotherapy. , No deletions or duplications of one or more DPYD exons were detected. The presence of the IVS14+1G>A mutation was also excluded. , These data show that neither the large genomic rearrangements in the DPYD gene nor the IVS14+1G>A mutation are responsible for the serious toxicity associated with a 5-FU containing regimen in this cohort of Spanish patients. AIMS To study the relationship between the toxicity associated with a 5-FU-based therapy and the presence of (i) the large intragenic rearrangements in the DPYD gene and (ii) the IVS14+1G>A mutation. METHODS We used the multiplex ligation-dependent probe amplification technique (MLPA) to study genomic DNA from 234 colorectal cancer patients treated with 5-FU-based chemotherapy. RESULTS We did not detect any deletion/duplication in the DPYD gene. The presence of the IVS14+1G>A mutation was also excluded. CONCLUSIONS Neither the large genomic rearrangements in the DPYD gene nor the IVS14+1G>A mutation play a significant role in the development of serious toxicity associated with a 5-FU containing regimen. [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] Exposure to oral oxycodone is increased by concomitant inhibition of CYP2D6 and 3A4 pathways, but not by inhibition of CYP2D6 aloneBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 1 2010Juha Grönlund WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT , Oxycodone is an opioid analgesic that is metabolized mainly in the liver by cytochrome P450 (CYP) 2D6 and 3A4 enzymes. , So far, the effects of CYP2D6 or CYP3A4 inhibitors on the pharmacokinetics of oxycodone in humans have not been systematically studied. WHAT THIS STUDY ADDS , Drug interactions arising from CYP2D6 inhibition most likely have minor clinical importance for oral oxycodone. , When both of CYP2D6 and CYP3A4 pathways are inhibited, the exposure to oral oxycodone is increased substantially. AIM The aim of this study was to find out whether the inhibition of cytochrome P450 2D6 (CYP2D6) with paroxetine or concomitant inhibition of CYP2D6 and CYP3A4 with paroxetine and itraconazole, altered the pharmacokinetics and pharmacological response of orally administered oxycodone. METHODS A randomized placebo-controlled cross-over study design with three phases was used. Eleven healthy subjects ingested 10 mg of oral immediate release oxycodone on the fourth day of pre-treatment with either placebo, paroxetine (20 mg once daily) or paroxetine (20 mg once daily) and itraconazole (200 mg once daily) for 5 days. The plasma concentrations of oxycodone and its oxidative metabolites were measured for 48 h, and pharmacological (analgesic and behavioural) effects were evaluated. RESULTS Paroxetine alone reduced the area under concentration,time curve (AUC(0,0,48 h)) of the CYP2D6 dependent metabolite oxymorphone by 44% (P < 0.05), but had no significant effects on the plasma concentrations of oxycodone or its pharmacological effects when compared with the placebo phase. When both oxidative pathways of the metabolism of oxycodone were inhibited with paroxetine and itraconazole, the mean AUC(0,,) of oxycodone increased by 2.9-fold (P < 0.001), and its Cmax by 1.8-fold (P < 0.001). Visual analogue scores for subjective drug effects, drowsiness and deterioration of performance were slightly increased (P < 0.05) after paroxetine + itraconazole pre-treatment when compared with placebo. CONCLUSIONS Drug interactions arising from CYP2D6 inhibition most likely have minor clinical importance for oral oxycodone if the function of the CYP3A4 pathway is normal. When both CYP2D6 and CYP3A4 pathways are inhibited, the exposure to oral oxycodone is increased substantially. [source] Effects of woohwangcheongsimwon suspension on the pharmacokinetics of bupropion and its active metabolite, 4-hydroxybupropion, in healthy subjectsBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 1 2010Hyunmi Kim WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT , Woohwangcheongsimwon suspension has traditionally been used for the treatment and prevention of stroke, hypertension, palpitations, convulsions and unconsciousness in various Asian countries. , Woohwangcheongsimwon suspensions showed an inhibitory effect on CYP2B6 activity in vitro. Two terpenoids, borneol and isoborneol, are major constituents of woohwangcheongsimwon suspension, and show a competitive inhibition of CYP2B6 with Ki values of 9.5 and 5.9 µm, respectively. , Bupropion undergoes metabolic transformation to the active metabolite, 4-hydroxybupropion, primarily via CYP2B6 both in vivo and in vitro. It is often used as a CYP2B6 substrate for clinical drug,drug interaction studies. , Drug interactions may occur between woohwangcheongsimwon suspension and bupropion. WHAT THIS STUDY ADDS , Co-administration with woohwangcheongsimwon suspension did not alter the pharmacokinetics of bupropion or its metabolite, 4-hydroxybupropion. , Dosage adjustment of bupropion is unnecessary in patients concomitantly administered the highest recommended daily dose of woohwangcheongsimwon suspension. AIMS To examine the effects of woohwangcheongsimwon suspension on the pharmacokinetics of bupropion and its active metabolite, 4-hydroxybupropion, formed via CYP2B6 in vivo. METHODS A two-way crossover clinical trial with a 2 week washout period was conducted in 14 healthy volunteers. In phases I and II, subjects received 150 mg bupropion with or without woohwangcheongsimwon suspension four times (at ,0.17, 3.5, 23.5 and 47.5 h, with the time of bupropion administration taken as 0 h) in a randomized balanced crossover order. Bupropion and 4-hydroxybupropion plasma concentrations were measured for up to 72 h by LC-MS/MS. Urine was collected up to 24 h to calculate the renal clearance. In addition, the CYP2B6*6 genotype was also analyzed. RESULTS The geometric mean ratios and 90% confidence interval of bupropion with woohwangcheongsimwon suspension relative to bupropion alone were 0.976 (0.917, 1.04) for AUC(0,,) and 0.948 (0.830,1.08) for Cmax, respectively. The corresponding values for 4-hydroxybupropion were 0.856 (0.802, 0.912) and 0.845 (0.782, 0.914), respectively. The tmax values of bupropion and 4-hydroxybupropion were not significantly different between the two groups (P > 0.05). The pharmacokinetic parameters of bupropion and 4-hydroxybupropion were unaffected by woohwangcheongsimwon suspension. CONCLUSIONS These results indicate that woohwangcheongsimwon suspension has a negligible effect on the disposition of a single dose of bupropion in vivo. As a result, temporary co-administration with woohwangcheongsimwon suspension does not seem to require a dosage adjustment of bupropion. [source] The ,apparent clearance' of free phenytoin in elderly vs. younger adultsBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 1 2010Daniel F. B. Wright WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT , The clearance of many drugs is reduced in the elderly, but the data regarding phenytoin are conflicting. Most studies have estimated phenytoin metabolic clearance using total drug concentrations (bound plus unbound), which may be confounded by protein binding effects. Free phenytoin concentrations are independent of protein binding and should more accurately reflect true metabolic clearance changes in elderly patients. WHAT THIS STUDY ADDS , The two studies reported in this paper suggest a trend towards reduced free phenytoin ,apparent clearance' in the elderly, although statistically significant results were not found. Other published studies have largely found similar trends, suggesting an age effect. AIMS To test the hypothesis that the ,apparent clearance' of free phenytoin is reduced in elderly patients. METHODS Two separate studies were conducted comparing free phenytoin ,apparent clearance' in elderly vs. younger adults. The first study was a retrospective analysis of free phenytoin concentrations measured at Christchurch Hospital from 1997 to 2006. In the second study free phenytoin concentrations were measured prospectively in ambulatory subjects who were taking phenytoin regularly. RESULTS In the retrospective study (n= 29), free phenytoin ,apparent clearance' was 0.27 ± 0.04 l kg,1 day,1 (95% CI 0.19, 0.34) in the elderly cohort vs. 0.37 ± 0.06 l kg,1 day,1 (95% CI 0.22, 0.52) in younger adults, but the difference was not statistically significant. In the prospective study, free phenytoin ,apparent clearance' showed a non-significant trend to being reduced in the elderly patients (0.12 ± 0.02 l kg,1 day,1, 95% CI 0.07, 0.17) compared with the younger cohort (0.18 ± 0.07 l kg,1 day,1, 95% CI 0.09, 0.26) in those not taking interacting drugs (n= 21). CONCLUSIONS This research does not prove the hypothesis that the ,apparent clearance' of free phenytoin is reduced in the elderly. However, the trends found in these two studies are supported by trends in the same direction in other published studies, suggesting an age effect. [source] Pharmacokinetics, immunogenicity and bioactivity of the therapeutic antibody catumaxomab intraperitoneally administered to cancer patientsBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 6 2010Peter Ruf WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT , The trifunctional antibody catumaxomab is a highly effective anti-cancer therapeutic that is administered to patients suffering from malignant ascites intraperitoneally (i.p.) in microgram (µg) doses. So far, no clinical pharmacokinetic data are available. WHAT THIS STUDY ADDS , Catumaxomab attains effective local concentrations in the ascites fluid and shows low systemic exposure with an acceptable safety profile confirming the appropriateness of the i.p. application scheme. AIMS Catumaxomab is the first EMEA approved trifunctional anti-EpCAM×anti-CD3 antibody for the treatment of cancer patients with malignant ascites. A phase II pharmacokinetic study was conducted to determine local and systemic antibody concentrations and anti-drug antibody (ADA) development. METHODS Thirteen cancer patients with symptomatic malignant ascites were treated with four ascending doses of 10, 20, 50, and 150 µg catumaxomab intraperitoneally (i.p.) infused on days 0, 3, 6 or 7 and 10. The pharmacokinetics of catumaxomab were studied by implementation of supportive data from a non clinical mouse tumour model. Additionally, ADA development was monitored. RESULTS Ten out of 13 patients were evaluable for pharmacokinetic analysis. Catumaxomab became increasingly concentrated in ascites during the course of treatment, attaining effective concentrations in the ng ml,1 range. Catumaxomab remained immunologically active even after several days in the circulation. The observed systemic catumaxomab exposure was low (<1%), with a maximal median plasma concentration (Cmax) of 403 pg ml,1. The mean elimination half-life in the plasma was 2.13 days. All patients developed ADA, but not before the last infusion. High observed inter-individual variability and low systemic exposure may be explained by the inverse correlation between tumour burden, effector cell numbers and systemic antibody bioavailability as demonstrated in a defined mouse tumour model. CONCLUSIONS Based on the high and effective local concentrations, low systemic exposure and acceptable safety profile, we confirmed that the i.p. application scheme of catumaxomab for the treatment of malignant ascites is appropriate. [source] Risk of diarrhoea in a long-term cohort of renal transplant patients given mycophenolate mofetil: the significant role of the UGT1A8*2 variant alleleBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 6 2010Jean-Baptiste Woillard WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT , Mycophenolate mofetil (MMF), the most widely used drug in allograft transplantation, is subject to hepatic and intestinal glucuronidation and entero-hepatic cycling. , Diarrhoea is its most frequent adverse event leading to non-compliance, treatment interruption and ultimately to an increased rate of acute rejection. , Cyclosporin reduces the biliary excretion of mycophenolate metabolites, presumably by inhibiting the efflux transporter MRP2. , When combined with MMF, cyclosporin reduces the incidence of diarrhoea, suggesting the role played by biliary excretion of mycophenolate glucuronides in this adverse event. WHAT THIS STUDY ADDS , In a long-term cohort of renal transplant patients on MMF, the two factors significantly associated with a reduced incidence of diarrhoea were the co-medication with cyclosporin (as opposed to tacrolimus or sirolimus) and the *2 variant allele of the intestinal UGT1A8. , Polymorphisms in the other UDP-glucuronosyl-transferases and MRP2 were not significant. AIM In renal transplant patients given mycophenolate mofetil (MMF), we investigated the relationship between the digestive adverse events and polymorphisms in the UGT genes involved in mycophenolic acid (MPA) intestinal metabolism and biliary excretion of its phase II metabolites. METHODS Clinical data and DNA from 256 patients transplanted between 1996 and 2006 and given MMF with cyclosporin (CsA, n = 185), tacrolimus (TAC, n = 49) or sirolimus (SIR, n = 22), were retrospectively analysed. The relationships between diarrhoea and polymorphisms in UGT1A8 (*2; 518C>G, *3; 830G>A), UGT1A7 (622C>T), UGT1A9 (,275T>A), UGT2B7 (,840G>A) and ABCC2 (,24C>T, 3972C>T) or the co-administered immunosuppressant were investigated using the Cox proportional hazard model. RESULTS Multivariate analysis showed that patients on TAC or SIR had a 2.8 higher risk of diarrhoea than patients on CsA (HR = 2.809; 95%CI (1.730, 4.545); P < 0.0001) and that non-carriers of the UGT1A8*2 allele (CC518 genotype) had a higher risk of diarrhoea than carriers (C518G and 518GG genotypes) (HR = 1.876; 95%CI (1.109, 3.175); P = 0.0192). When patients were divided according to the immunosuppressive co-treatment, a significant effect of UGT1A8*2 was found in those co-treated with CsA (HR = 2.414; 95%CI (1.089, 5.354); P = 0.0301) but not TAC or SIR (P = 0.4331). CONCLUSION These results suggest that a possible inhibition of biliary excretion of MPA metabolites by CsA and a decreased intestinal production of these metabolites in UGT1A8*2 carriers may be protective factors against MMF-induced diarrhoea. [source] Population pharmacokinetics of intravenously and orally administered docetaxel with or without co-administration of ritonavir in patients with advanced cancerBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 5 2010Stijn L. W. Koolen WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT , Docetaxel is an approved drug for the treatment of cancer of various primary origins. , An oral docetaxel regimen is warranted because of patient convenience and the opportunity to investigate more schedule intensive treatment regimens. , Co-administration of ritonavir significantly enhanced the apparent oral bioavailability of docetaxel. WHAT THIS STUDY ADDS , This study demonstrates that ritonavir increased the absorption of docetaxel after oral administration. , Furthermore, we showed that the clearance of docetaxel was inhibited in a concentration dependent manner. , The developed model will be used for further development of an oral docetaxel regimen. AIM Docetaxel has a low oral bioavailability due to affinity for P-glycoprotein and cytochrome P450 (CYP) 3A4 enzymes. Inhibition of the CYP3A4 enzymes by ritonavir resulted in increased oral bioavailability. The aim of this study was to develop a population pharmacokinetic (PK) model and to evaluate and quantify the influence of ritonavir on the PK of docetaxel. METHODS Data from two clinical trials were included in the data analysis, in which docetaxel (75 mg m,2 or 100 mg) had been administered intravenously or orally (10 mg or 100 mg) with or without co-administration of oral ritonavir (100 mg). Population modelling was performed using non-linear mixed effects modelling. A three-compartment model was used to describe the i.v. data. PK data after oral administration, with or without co-administration of ritonavir, were incorporated into the model. RESULTS Gut bioavailability of docetaxel increased approximately two-fold from 19 to 39% (CV 13%) with ritonavir co-administration. The hepatic extraction ratio and the elimination rate of docetaxel were best described by estimating the intrinsic clearance. Ritonavir was found to inhibit in a concentration dependent manner the intrinsic clearance of docetaxel, which was described by an inhibition constant of 0.028 µg ml,1 (CV 36%). A maximum inhibition of docetaxel clearance of more then 90% was reached. CONCLUSIONS A PK model describing both the PK of orally and intravenously administered docetaxel in combination with ritonavir, was successfully developed. Co-administration of ritonavir lead to increased oral absorption and reduced elimination rate of docetaxel. [source] Intracellular and plasma steady-state pharmacokinetics of raltegravir, darunavir, etravirine and ritonavir in heavily pre-treated HIV-infected patientsBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 5 2010Rob Ter Heine WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT , The combination of raltegravir, etravirine and ritonavir boosted darunavir is a potent antiretroviral regimen for patients who have been heavily pre-treated for HIV-infection. All these agents have to exert their action intracellularly. However, only little is known about the cellular pharmacology of these agents. WHAT THIS STUDY ADDS , We investigated the steady-state plasma and cellular pharmacokinetics of raltegravir, etravirine, darunavir and ritonavir and the observed distinct intracellular accumulation ratios indicated that these antiretroviral drugs have different affinity for the cellular compartment. AIM To study the steady-state plasma and intracellular pharmacokinetics of raltegravir, etravirine, darunavir and ritonavir in heavily pre-treated patients. METHODS Patients on a salvage regimen containing raltegravir, etravirine, darunavir and ritonavir were eligible for inclusion. During a 12 h dosing interval plasma and peripheral blood mononuclear cells were collected. Drug concentrations were measured using a validated LC-MS/MS assay and pharmacokinetic analysis was performed using non-linear mixed effect modelling. RESULTS Irregular absorption was observed with raltegravir and darunavir, which may be caused by enterohepatic cycling. Relative bioavailability of ritonavir was low, when compared with other ritonavir regimens. Raltegravir plasma pharmacokinetics showed wide interpatient variability, while intracellular raltegravir concentrations could not be detected (<0.001 mg l,1 in cell lysate). The intracellular to plasma ratios for etravirine, darunavir and ritonavir were 12.9, 1.32 and 7.72, respectively, and the relative standard error of these estimates were 16.3%, 12.3% and 13.0%. CONCLUSIONS The observed distinct intracellular accumulation indicated that these drugs have different affinity for the cellular compartment. The relatively high intracellular accumulation of etravirine may explain its efficacy and its previously described absence of PK,PD relationships in the therapeutic concentration range, when compared with other non-nucleoside reverse transcriptase inhibitors. Lastly, the intracellular concentrations of ritonavir seem sufficient for inhibition of viral replication in the cellular compartment in PI-naive patients, but not in patients with HIV harbouring PI resistance. [source] Co-administration of the JAK inhibitor CP-690,550 and methotrexate is well tolerated in patients with rheumatoid arthritis without need for dose adjustmentBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 2 2010Stanley Cohen WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT , CP-690,550 is a novel JAK inhibitor in development as a therapy for rheumatoid arthritis. , Methotrexate is the cornerstone of combination treatment for rheumatoid arthritis. , The safety and tolerability of co-administration of CP-690,550 with methotrexate have not been addressed to date. WHAT THIS STUDY ADDS , This study in patients with rheumatoid arthritis shows that there are no clinically relevant effects on the pharmacokinetics of either drug following short-term co-administration. , Co-administration of CP-690,550 and methotrexate was safe and well tolerated. AIMS To investigate the effects of methotrexate (MTX) on the pharmacokinetics (PK) of CP-690,550, a novel Janus kinase (JAK) inhibitor in development as a therapy for rheumatoid arthritis (RA), to determine the effects of multiple doses of CP-690,550 on the PK of MTX, and to evaluate the short-term safety and tolerability of co-administration of CP-690,550 and MTX. METHODS This was a fixed-dose drug,drug interaction study. Twelve patients diagnosed with RA for at least 6 months were enrolled in a Phase I, open-label study of the PK of multiple doses of CP-690,550 (30 mg b.i.d.) and single doses of MTX (15,25 mg per week). RESULTS All patients completed the study and were evaluated for PK and safety. CP-690,550 exposure was not affected by co-administration with MTX; AUC12 ratio (CP-690,550 + MTX/CP-690,550) was 103.06% [90% confidence interval (CI) 99.00, 107.29]. MTX exposure decreased by 10%; AUC12 ratio (CP-690,550 + MTX/MTX) was 89.53% (90% CI 77.38, 103.57), which was not considered clinically significant. Co-administration of CP-690,550 and MTX was safe and well tolerated. There were no serious adverse events or withdrawals from the study and there was no trend in the incidence or severity of adverse events across treatments. CONCLUSIONS Co-administration of CP-690,550 and MTX was safe and well tolerated. There was no clinically significant effect on the PK profile of either drug. Therefore, dose adjustments should not be required when co-administering CP-690,550 and MTX. [source] Effects of nicotine on cytochrome P450 2A6 and 2E1 activitiesBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 2 2010Janne Hukkanen WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT , Smoking slows the metabolism of nicotine and accelerates the metabolism of chlorzoxazone. , Nicotine is a useful probe for phenotyping cytochrome P450 2A6 activity and chlorzoxazone is a frequently used probe for CYP2E1 activity. , The tobacco smoke constituents responsible for the reduced CYP2A6 and increased CYP2E1 activities are unknown. WHAT THIS PAPER ADDS , This study demonstrates that CYP2A6 and CYP2E1 activities are not affected by nicotine dosing. , High-dose nicotine treatment has a low potential of interaction with CYP2A6 and CYP2E1 substrates. , The mechanisms of tobacco smoke-elicited changes in CYP2A6 and CYP2E1 activities are yet to be determined. AIMS Smoking slows the metabolism of nicotine and accelerates the metabolism of chlorzoxazone, which are probe reactions for cytochrome P450 2A6 (CYP2A6) and CYP2E1 activities, respectively. We aimed to determine the role of nicotine in these metabolic effects of cigarette smoking. METHODS The study had a single-blind, randomized, crossover two-arm design. Twelve healthy smokers were given two transdermal patches with 42-mg nicotine a day or placebo patches, each for 10 days. The subjects abstained from smoking during the study arms. Oral chlorzoxazone was given on day 7 and deuterium-labelled nicotine-d2 and cotinine-d4 infusion on day 8. RESULTS There was no significant influence of transdermal nicotine administration on pharmacokinetic parameters of nicotine-d2 or on the formation of cotinine-d2. Nicotine decreased the volume of distribution (62.6 vs. 67.7 l, 95% confidence interval of the difference ,9.7, ,0.6, P= 0.047) of infused cotinine-d4. There were no significant differences in disposition kinetics of chlorzoxazone between the treatments. CONCLUSIONS CYP2A6 and CYP2E1 activities are not affected by nicotine. The tobacco smoke constituents responsible for the reduced CYP2A6 and increased CYP2E1 activities remain unknown. [source] Superior palatability of crushed lercanidipine compared with amlodipine among childrenBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 2 2010Gregorio Milani WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT , Among children, medication palatability is crucial for adherence to therapeutic regimen. , Since there is a lack of appropriate formulations for children prescribed drugs originally designed for adults, parents crush available tablets and administer the medication mixed with solid food or a palatable drink. , Crushed amlodipine, a very popular calcium channel blocker, is bitter and unpalatable. WHAT THIS STUDY ADDS , From the perspective of the child with arterial hypertension, the taste of pulverized lercanidipine is superior to that of pulverized amlodipine. AIMS To compare the taste of equivalent doses of pulverized amlodipine and lercanidipine, two calcium channel blockers, among children with kidney disease. METHODS Each child received a test dose of 1 mg of amlodipine besylate and 2 mg of lercanidipine in a single-blinded fashion. Children indicated their preference by pointing to the appropriate face on a visual analogue scale (VAS) that depicts five degrees of pleasure. RESULTS The VAS palatability score assigned to lercanidipine was higher than that assigned to amlodipine both in nine children 4,7 years of age (P < 0.005) and in 10 children 8,11 years of age (P < 0.005). The preference for lercanidipine was statistically significant in both girls (P < 0.02) and boys (P < 0.001) and in both children initially presented amlodipine (P < 0.005) and children initially presented lercanidipine (P < 0.005). CONCLUSIONS There is a lack of appropriate formulations for children prescribed drugs originally designed for adults, such as calcium channel blockers. Parents therefore crush available tablets and administer the medication mixed with solid food or a palatable drink. From the perspective of the child, the taste of pulverized lercanidipine is superior to that of pulverized amlodipine. [source] Population pharmacokinetic analysis of cilostazol in healthy subjects with genetic polymorphisms of CYP3A5, CYP2C19 and ABCB1BRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 1 2010Hee-Doo Yoo WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT , The interindividual variability of the pharmacokinetic parameters of cilostazol is relatively large. , Cilostazol undergoes extensive hepatic metabolism via the P450 enzymes, primarily CYP3A and, to a lesser extent, CYP2C19. , Indeed, <1% of the administered dose of cilostazol is excreted unchanged in the urine. WHAT THIS STUDY ADDS , A population pharmacokinetic analysis of cilostazol was conducted to evaluate the impact of CYP3A, CYP2C19 and ABCB1 polymorphisms on cilostazol disposition in vivo. , Genetic polymorphisms of CYP3A5 and CYP2C19 explain the substantial interindividual variability in the pharmacokinetics of cilostazol. , ABCB1 genotypes do not to appear to be associated with the disposition of cilostazol. AIMS To investigate the influence of genetic polymorphisms in the CYP3A5, CYP2C19 and ABCB1 genes on the population pharmacokinetics of cilostazol in healthy subjects. METHODS Subjects who participated in four separate cilostazol bioequivalence studies with the same protocols were included in this retrospective analysis. One hundred and four healthy Korean volunteers were orally administered a single 50- or 100-mg dose of cilostazol. We estimated the population pharmacokinetics of cilostazol using a nonlinear mixed effects modelling (nonmem) method and explored the possible influence of genetic polymorphisms in CYP3A (CYP3A5*3), CYP2C19 (CYP2C19*2 and CYP2C19*3) and ABCB1 (C1236T, G2677T/A and C3435T) on the population pharmacokinetics of cilostazol. RESULTS A two-compartment model with a first-order absorption and lag time described the cilostazol serum concentrations well. The apparent oral clearance (CL/F) was estimated to be 12.8 l h,1. The volumes of the central and the peripheral compartment were characterized as 20.5 l and 73.1 l, respectively. Intercompartmental clearance was estimated at 5.6 l h,1. Absorption rate constant was estimated at 0.24 h,1 and lag time was predicted at 0.57 h. The genetic polymorphisms of CYP3A5 had a significant (P < 0.001) influence on the CL/F of cilostazol. When CYP2C19 was evaluated, a significant difference (P < 0.01) was observed among the three genotypes (extensive metabolizers, intermediate metabolizers and poor metabolizers) for the CL/F. In addition, a combination of CYP3A5 and CYP2C19 genotypes was found to be associated with a significant difference (P < 0.005) in the CL/F. When including these genotypes, the interindividual variability of the CL/F was reduced from 34.1% in the base model to 27.3% in the final model. However, no significant differences between the ABCB1 genotypes and cilostazol pharmacokinetic parameters were observed. CONCLUSIONS The results of the present study indicate that CYP3A5 and CYP2C19 polymorphisms explain the substantial interindividual variability that occurs in the metabolism of cilostazol. [source] Adherence level of antihypertensive agents in coronary artery diseaseBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 1 2010Sylvie Perreault WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT , Non-adherence is probably an important source of preventable cardiovascular morbidity and mortality. , However, until now there have been very few large effectiveness studies assessing the relationship between adherence levels to antihypertensive medication and major cardiovascular outcomes for primary prevention of cardiovascular disease. WHAT THIS STUDY ADDS , The study results suggest that there is an association between better adherence to antihypertensive agents and a relative risk reduction of coronary artery disease. , Adherence to antihypertensive agents needs to be improved so that patients can benefit from the full protective effects of antihypertensive therapies. AIMS Antihypertensive (AH) agents have been shown to reduce the risk of cardiovascular events, including coronary artery disease (CAD). Previous surveys have shown that a substantial number of patients with diagnosed hypertension remain uncontrolled. Non-adherence to AH agents may reduce the effectiveness. The aim was to evaluate the impact of better adherence to AH agents on the occurrence of CAD in a real clinical setting. METHODS A cohort of 83 267 patients was reconstructed using the Régie de l'assurance maladie du Québec databases. Patients were eligible if they were between 45 and 85 years of age without indication of cardiovascular disease, and had been newly treated with AH agents between 1999 and 2004. A nested case,control design was used to study the incidence of CAD. Every case of CAD was matched for age and duration of follow-up to up to 15 randomly selected controls. The adherence level was measured by calculating the medication possession ratio. Cases' adherence was calculated from the start of follow-up to the time of the CAD (index date). For controls, adherence was calculated from the start of follow-up to the time of selection (index date). Rate ratios of CAD were estimated by conditional logistic regression adjusting for covariables. RESULTS The mean patient age was 65 years, 37% were male, 8% had diabetes and 18% had dyslipidaemia. High adherence level (96%) to AH therapy compared with lower adherence level (59%) was associated with a relative risk reduction of CAD events (rate ratios 0.90; 0.84, 0.95). Risk factors for CAD were male gender, diabetes, dyslipidaemia and developing a cardiovascular condition disease during follow-up. CONCLUSION Our study suggests that better adherence to AH agents is associated with a risk reduction of CAD. Adherence to AH agents needs to be improved so that patients can benefit from the full protective effects of AH therapies. [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] Pharmacokinetic assessment of a five-probe cocktail for CYPs 1A2, 2C9, 2C19, 2D6 and 3ABRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 6 2009Sandrine Turpault WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT , Numerous cocktails using concurrent administration of several cytochrome P450 (CYP) isoform-selective probe drugs have been reported to investigate drug,drug interactions in vivo. , This approach has several advantages: characterize the inhibitory or induction potential of compounds in development toward the CYP enzymes identified in vitro in an in vivo situation, assess several enzymes in the same trial, and have complete in vivo information about potential CYP-based drug interactions. WHAT THIS STUDY ADDS , This study describes a new cocktail containing five probe drugs that has never been published. , This cocktail can be used to test the effects of a new chemical entity on multiple CYP isoforms in a single clinical study: CYP1A2 (caffeine), CYP2C9 (warfarin), CYP2C19 (omeprazole), CYP2D6 (metoprolol), and CYP3A (midazolam) and was designed to overcome potential liabilities of other reported cocktails. AIMS To assess the pharmacokinetics (PK) of selective substrates of CYP1A2 (caffeine), CYP2C9 (S-warfarin), CYP2C19 (omeprazole), CYP2D6 (metoprolol) and CYP3A (midazolam) when administered orally and concurrently as a cocktail relative to the drugs administered alone. METHODS This was an open-label, single-dose, randomized, six-treatment six-period six-sequence William's design study with a wash-out of 7 or 14 days. Thirty healthy male subjects received 100 mg caffeine, 100 mg metoprolol, 0.03 mg kg,1 midazolam, 20 mg omeprazole and 10 mg warfarin individually and in combination (cocktail). Poor metabolizers of CYP2C9, 2C19 and 2D6 were excluded. Plasma samples were obtained up to 48 h for caffeine, metoprolol and omeprazole, 12 h for midazolam, 312 h for warfarin and the cocktail. Three different validated liquid chromatography tandem mass spectrometry methods were used. Noncompartmental PK parameters were calculated. Log-transformed Cmax, AUClast and AUC for each analyte were analysed with a linear mixed effects model with fixed term for treatment, sequence and period, and random term for subject within sequence. Point estimates (90% CI) for treatment ratios (individual/cocktail) were computed for each analyte Cmax, AUClast and AUC. RESULTS There was no PK interaction between the probe drugs when administered in combination as a cocktail, relative to the probes administered alone, as the 90% CI of the PK parameters was within the prespecified bioequivalence limits of 0.80, 1.25. CONCLUSION The lack of interaction between probes indicates that this cocktail could be used to evaluate the potential for multiple drug,drug interactions in vivo. [source] Population pharmacokinetic analysis of varenicline in adult smokersBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 5 2009Patanjali Ravva WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT? , Several clinical pharmacology studies have characterized the pharmacokinetics of varenicline in young adult and elderly smokers and subjects with impaired renal function. , Varenicline pharmacokinetics is linear over the recommended dose range. , Varenicline total clearance is linearly related to its renal clearance. , Both are progressively reduced as renal function declines, which results in a progressive increase in varenicline systemic exposure and prolonged half-life. WHAT THIS STUDY ADDS? , This work provides an integrated model-based analysis of varenicline pharmacokinetics across multiple studies in the target patient population. , The model describes the impact of patient-specific covariates, such as renal function, and provides a rationale for dose adjustment. , The resulting model also provides a means to predict individual-specific drug exposures to clinical responses in subsequent analyses. AIMS To characterize the population pharmacokinetics of varenicline and identify factors leading to its exposure variability in adult smokers. METHODS Data were pooled from nine clinical studies consisting of 1878 subjects. Models were developed to describe concentration,time profiles across individuals. Covariates were assessed using a full model approach; parameters and bootstrap 95% confidence intervals (CI) were estimated using nonlinear mixed effects modelling. RESULTS A two-compartment model with first-order absorption and elimination best described varenicline pharmacokinetics. The final population parameter estimates (95% CI) were: CL/F, 10.4 l h,1 (10.2, 10.6); V2/F, 337 l (309, 364); V3/F, 78.1 l (61.9, 98.9); Q/F, 2.08 l h,1 (1.39, 3.79); Ka, 1.69 h,1 (1.27, 2.00); and Alag, 0.43 h (0.37, 0.46). Random interindividual variances were estimated for Ka[70% coefficient of variation (CV)], CL/F (25% CV), and V2/F (50% CV) using a block covariance matrix. Fixed effect parameters were precisely estimated [most with % relative standard error < 10 and all with % relative standard error < 25], and a visual predictive check indicated adequate model performance. CL/F decreased from 10.4 l h,1 for a typical subject with normal renal function (CLcr = 100 ml min,1) to 4.4 l h,1 for a typical subject with severe renal impairment (CLcr = 20 ml min,1), which corresponds to a 2.4-fold increase in daily steady-state exposure. Bodyweight was the primary predictor of variability in volume of distribution. After accounting for renal function, there was no apparent effect of age, gender or race on varenicline pharmacokinetics. CONCLUSIONS Renal function is the clinically important factor leading to interindividual variability in varenicline exposure. A dose reduction to 1 mg day,1, which is half the recommended dose, is indicated for subjects with severe renal impairment. [source] Influence of CYP2C19 polymorphism on the pharmacokinetics of nelfinavir and its active metaboliteBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 5 2009Bharat D. Damle WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT , The true influence of CYP2C19*2 mutation on the pharmacokinetics of nelfinavir and its active metabolite, M8, is not clear. , Often, published studies have combined *2 hetero- and homozygous poor metabolizers (PMs) and/or have very limited data from *2 homozygotes, which contributes to the lack of clarity. WHAT THIS STUDY ADDS , The pharmacokinetics of nelfinavir was delineated using pharmacogenomic data from 66 healthy subjects. , The exposure of nelfinavir was elevated, whereas that of M8 was reduced, in heterozygous and homozygous PMs in an incremental manner consistent with the loss of functional alleles. , However, the exposure of active moiety was only modestly elevated in hetero- and homozygous PMs. AIMS This study reports the pharmacokinetics of nelfinavir, its active metabolite, M8, and active moiety (nelfinavir + M8) in volunteers genotyped for CYP2C19 as extensive metabolizer (*1*1; n = 38), heterozygous poor metabolizer (PM) (*1*2; n = 22) and homozygous PM (*2*2; n = 6). METHODS Subjects received nelfinavir at normal dose (3.5 days of 1250 mg q12h) or high dose (1250 mg q12h for 3 days and single dose of 3125 mg on day 4). Steady-state plasma samples were analysed by high-performance liquid chromatography/ultraviolet assay to determine pharmacokinetics. RESULTS At steady state, the mean Cmax was 42% [95% confidence interval (CI) 19, 69] and 63% (95% CI 20, 122) higher, and mean AUC was 51% (95% CI 24, 83) and 85% (95% CI 32, 159) higher for *1*2 and *2*2 compared with *1*1 subjects, respectively. For M8, the mean Cmax and AUC were 35% (95% CI 6, 55) and 33% (95% CI ,3, 56), respectively, lower for *1*2 compared with *1*1 subjects. M8 was not detectable in *2*2 subjects. The mean Cmax and AUC values for the active moiety were higher by 30,35% for the *1*2 and *2*2 compared with *1*1 subjects. CONCLUSIONS Mutation in CYP2C19 increased the systemic exposure of nelfinavir and reduced the exposure of M8. No significant differences were noted among the heterozygous (*1*2) and homozygous (*2*2) PMs. These changes are not considered to be clinically relevant and hence the use of nelfinavir does not require prior assessment of CYP2C19 genotype. [source] Inhaled tiotropium bromide and risk of strokeBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 5 2009Anthony Grosso WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT , Conflicting studies have raised uncertainty over the vascular effects of the long-acting anticholinergic, tiotropium bromide. WHAT THIS STUDY ADDS , Our results show no increased risk of stroke with tiotropium bromide, or with inhaled anticholinergics in general. AIMS A recent communication from the United States Food and Drug Administration highlighted a possible increased risk of stroke associated with use of the relatively new inhaled anticholinergic drug, tiotropium bromide. Using the United Kingdom General Practice Research Database, we set out to assess the risk of stroke in individuals exposed to inhaled tiotropium bromide and two other inhaled treatments for airways disease. METHODS We used the self-controlled case-series that reduces confounding and minimizes the potential for biases in the quantification of risk estimates. RESULTS Of 1043 people with a diagnosis of incident stroke who had had at least one prescription for tiotropium bromide, 980 satisfied inclusion criteria. The age-adjusted incidence rate ratio for all-cause stoke in individuals exposed to tiotropium bromide (n= 980), ipratropium bromide (n= 4181) and fluticasone propionate/salmeterol xinafoate (n= 1000) was 1.1 [95% confidence interval (CI) 0.9, 1.3], 0.8 (95% CI 0.7, 0.9) and 1.0 (95% CI 0.9, 1.2), respectively. CONCLUSIONS We found no evidence of an increased risk of all-cause stroke for individuals exposed to commonly prescribed inhaled treatments for chronic obstructive pulmonary disease. [source] | |||||||||||||||||||||||||||||||||||||||||||||||||