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Dose Regimen (dose + regimen)

Distribution by Scientific Domains

Medical Sciences	95%

Distribution within Medical Sciences

Hematology	13%
Dermatology	9%
10 Other Subdomains	38%

Selected Abstracts

Accelerating drug development: methodology to support first-in-man pharmacokinetic studies by the use of drug candidate microdosing

DRUG DEVELOPMENT RESEARCH, Issue 1 2007
Matthew A. McLean
Abstract Microdosing of experimental therapeutics in humans offers a number of benefits to the drug development process. Microdosing, conducted under an exploratory Investigational New Drug (IND) application, entails administration of a sub-pharmacological dose of a new chemical entity (NCE) that allows for early evaluation of human pharmacokinetics. Such information can be pivotal for: (1) selecting a compound for full drug development from a small group of candidates; (2) defining the amount of material needed for early development; and (3) setting the initial Phase I dose regimen in humans. Appropriate safety studies must be conducted to support microdosing in humans, but the requirements are generally less extensive than those needed to support a traditional IND. To date, microdosing has not been broadly applied by the pharmaceutical industry due to concerns about analytical sensitivity and the possibility of non-linear pharmacokinetics at extremely low doses. The primary method for detecting analytes following microdosing until now has been accelerator mass spectrometry, which is expensive, not generally available, and requires test agents to be radiolabeled. Presented in this report is an example of pharmacokinetics analysis using LC/MS/MS following microdosing of an experimental agent in cynomolgus monkeys. The results show good linearity in plasma pharmacokinetics for oral doses of 10,mg/kg (therapeutic dose) and 0.0005,mg/kg (microdose) of the test agent. The results also demonstrate the feasibility of applying standard laboratory analytics to support microdosing in humans and raise the possibility of establishing an animal model to screen for compounds having non-linear pharmacokinetics at low dose levels. Drug Dev. Res. 68:14,22, 2007. © 2007 Wiley-Liss, Inc. [source]

A breath test to assess compliance with disulfiram

ADDICTION, Issue 12 2006
Keron Fletcher
ABSTRACT Aims To evaluate the ability of a hand-held breath analyser, the Zenalyser® (Zenics Medical), to identify alcohol-dependent patients receiving disulfiram therapy and to assess the sensitivity and specificity of the instrument at different time intervals post-disulfiram dosing. Design Breath samples were taken from two groups of alcohol-dependent patients, one group on a daily disulfiram regimen and one group receiving no disulfiram. The breath samples were analysed for the combined concentration of carbon disulphide and acetone produced from the metabolism of disulfiram. From these data, two reference ranges were prepared and used for sensitivity and specificity assessments. Setting Breath samples for the reference ranges were obtained from patients at Shelton Hospital, Shrewsbury. Breath samples used to assess the sensitivity and specificity of the instrument were obtained from patients at the Edinburgh Alcohol Problems Clinic. Participants Twenty in-patients from Shelton Hospital receiving a daily 200 mg disulfiram regimen and 20 in-patients receiving no disulfiram. At the Edinburgh Clinic, 54 patients taking a thrice-weekly disulfiram regimen and 22 patients not on disulfiram. Measurements A total of 489 breath samples from Shelton Hospital and 391 breath samples from the Edinburgh Clinic were analysed for the combined concentrations of carbon disulphide and acetone. Findings The breath analyser produced results that distinguished between the disulfiram-treated and untreated groups (P < 0.001). At 1 day post-dose, the sensitivity was 100% and the specificity was 100%. At 2 and 3 days post-dose, the sensitivities and specificities were 84.6% and 100% and 88.2% and 100%, respectively. Conclusion The breath analyser can improve the assessment of the compliance status of patients receiving a daily dose regimen of disulfiram, but is less useful for this purpose if disulfiram is taken on a thrice-weekly regimen. [source]

Inhibition of endogenous pancreatic enzyme secretion by oral pancreatic enzyme treatment

EUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 1 2003
J. Walkowiak
Abstract Background ,The existence of a feedback mechanism for exocrine pancreatic secretion in humans is controversial. Exclusion of proteases from the duodenum stimulates exocrine pancreatic secretion. Conversely, addition of exogenous enzymes could reduce the enzyme secretion. Further investigation of the feedback mechanism should be performed under the most physiological conditions. In the present study we investigated exocrine pancreatic function by measuring fecal enzyme output in healthy volunteers consuming a normal diet, before and during a time course of exogenous pancreatic enzyme supplementation. Material and methods ,Twenty-five healthy subjects (HS) were given two different doses (30 and 60 FIP proteases kg,1 d,1) divided by the number of meals. In all subjects, fecal elastase-1 (E1) concentrations and chymotrypsin (ChT) activities were measured without and with enzyme supplements after 7 days of treatment. In eight subjects, E1 concentrations and ChT activities were measured daily for 10 consecutive days. The subjects were given a dose regimen of 100 FIP proteases kg,1 d,1 (divided by the number of meals) for the first 7 days. Results ,Oral pancreatic treatment dose-dependently inhibited endogenous pancreatic secretion measured with the use of E1 concentrations. In both regimen groups, the differences were statistically significant. The exogenous enzymes, which interfere with colorimetric method for ChT, dose-dependently increased ChT output. However, only the higher dose resulted in a statistically significant difference. In the subgroup of eight HS, time-dependent changes of fecal enzyme output occurred with a decrease of E1 concentrations and an increase of ChT activity from the second up to eighth or ninth day of the experiment. Conclusion ,Exogenous applied pancreatic enzymes, dose- and time-dependently inhibited endogenous pancreatic secretion. The obtained results strongly support the existence of a protease mediated feedback mechanism in humans. [source]

Risk factors for inhibitor formation in haemophilia: a prevalent case,control study

HAEMOPHILIA, Issue 5 2009
M. V. RAGNI
Summary., Inhibitor formation is a major complication of haemophilia treatment. In a prevalent case,control study, we evaluated blood product exposure, genotype and HLA type on haemophilia A inhibitor formation. Product exposure was extracted from medical records. Genotype was determined on stored DNA samples by detection of virtually all mutations-SSCP (DOVAM-S) and subcycling PCR. HLA typing was performed by PCR amplification and exonuclease-released fluorescence. Cases experienced higher intensity factor, 455 vs. 200 U per exposure, P < 0.005, more frequent central nervous system (CNS) bleeding, seven of 20 (35.0%) vs. one of 57 (1.7%), P = 0.001 and more commonly from inhibitor families, seven of 20 (35.0%) vs. zero of 57 (0%), P < 0.001, and African-American, 12 of 63 (19.0%) vs. six of 117 (5.1%), P = 0.015. Among the latter, CNS bleeding was more commonly the initial bleed, 60% vs. 0%, P < 0.001, and survival was shorter, 14 vs. 38 yr, P = 0.025. Inhibitor formation was uncommon in those with missense mutations, two of 65 (3.1%) vs. 31 of 119 (26.0%), P = 0.008, and unrelated to factor VIII immunogenic epitope, P = 0.388, or HLA type, P > 0.100. Genotype was not associated with race. Time to immune tolerance was shorter for titres <120 vs. ,120 BU/mL, six vs. 16 months, P < 0.01, but unaffected by tolerizing dose regimen, P > 0.50. Inhibitor formation is associated with high intensity product exposure, CNS bleeding, African-American race and low frequency of missense mutations. The ideal time to initiate prophylaxis to reduce CNS bleeding and inhibitor formation will require prospective studies. [source]

Prophylactic therapy for haemophilia: early experience

HAEMOPHILIA, Issue 2003
E. Berntorp
Summary., During the 1960s, it was reported from Sweden that haemophiliacs with factor levels above 1% rarely develop arthropathy. This observation suggested that severe haemophilia could be converted to a milder form by regular infusions with factor concentrate. After several earlier publications, a report was published in 1992 that detailed 25 years' experience with prophylaxis in 60 patients from the Malmö centre. The results showed that starting prophylaxis early in life with a dose regimen that would prevent factor VIII or IX plasma levels from falling below 1% could prevent the development of haemophilic arthropathy. Also, older age groups who had received less intensive treatment, and who started prophylaxis later in life, were still in a much better condition than historic controls. In the 1970s several small but well-controlled studies from the USA, Germany and Italy clearly showed the benefit of prophylaxis in reducing bleeding frequency. Early experience from the Netherlands was published in 1971. Since these early studies, the results have been corroborated from many countries and in a large multinational study. Although the benefits of prophylaxis seem unquestionable, several research questions remain to be better elucidated, such as when to start and when to stop, dosing and dose interval, and how to assess the long-term treatment effects. These issues are of great economic importance, and the need for health economical studies is obvious. [source]

Partial and transient modulation of the CD3,T-cell receptor complex, elicited by low-dose regimens of monoclonal anti-CD3, is sufficient to induce disease remission in non-obese diabetic mice

IMMUNOLOGY, Issue 1 2010
Devangi S. Mehta
Summary It has been established that a total of 250 ,g of monoclonal anti-mouse CD3 F(ab,)2 fragments, administered daily (50 ,g per dose), induces remission of diabetes in the non-obese diabetic (NOD) mouse model of autoimmune diabetes by preventing , cells from undergoing further autoimmune attack. We evaluated lower-dose regimens of monoclonal anti-CD3 F(ab,)2 in diabetic NOD mice for their efficacy and associated pharmacodynamic (PD) effects, including CD3,T-cell receptor (TCR) complex modulation, complete blood counts and proportions of circulating CD4+, CD8+ and CD4+ FoxP3+ T cells. Four doses of 2 ,g (total dose 8 ,g) induced 53% remission of diabetes, similarly to the 250 ,g dose regimen, whereas four doses of 1 ,g induced only 16% remission. While the 250 ,g dose regimen produced nearly complete and sustained modulation of the CD3 ,TCR complex, lower doses, spaced 3 days apart, which induced similar remission rates, elicited patterns of transient and partial modulation. In treated mice, the proportions of circulating CD4+ and CD8+ T cells decreased, whereas the proportions of CD4+ FoxP3+ T cells increased; these effects were transient. Mice with greater residual ,-cell function, estimated using blood glucose and C-peptide levels at the initiation of treatment, were more likely to enter remission than mice with more advanced disease. Thus, lower doses of monoclonal anti-CD3 that produced only partial and transient modulation of the CD3,TCR complex induced remission rates comparable to higher doses of monoclonal anti-CD3. Accordingly, in a clinical setting, lower-dose regimens may be efficacious and may also improve the safety profile of therapy with monoclonal anti-CD3, potentially including reductions in cytokine release-related syndromes and maintenance of pathogen-specific immunosurveillance during treatment. [source]

Paliperidone palmitate , review of the efficacy, safety and cost of a new second-generation depot antipsychotic medication

INTERNATIONAL JOURNAL OF CLINICAL PRACTICE, Issue 2 2010
L. Citrome
Summary Objective:, To describe the efficacy, safety and cost of paliperidone palmitate, a depot antipsychotic medication recently approved for the treatment of schizophrenia. Data sources:, A literature search was conducted by querying the websites http://www.pubmed.gov, http://www.fda.gov, http://www.accessdata.fda.gov/scripts/cder/drugsatfda and http://www.clinicaltrials.gov for the search term ,paliperidone palmitate'. Cost information was obtained from the pharmaceutical vendor servicing a local state-operated psychiatric facility. Study selection:, All available reports of studies were identified. Product labelling provided additional information. Data extraction:, Descriptions of the principal results and calculation of the number needed to treat (NNT) and number needed to harm (NNH) for relevant dichotomous outcomes were extracted from the study reports and synopses. Additional safety outcomes subject to NNH analysis were obtained from product labelling. Data synthesis:, Paliperidone palmitate is a newly available depot formulation of paliperidone (the 9-OH metabolite of risperidone). Upon injection into the deltoid or gluteal muscle, the release of the drug starts as early as day 1, reaches maximum plasma concentrations at 13 days and lasts for as long as 126 days. Maximum concentration following deltoid injection is approximately 28% higher compared with injection into the gluteal muscle, and thus paliperidone palmitate requires initiation by two initial deltoid injections spread 1 week apart to achieve therapeutic concentrations rapidly. Subsequent injections are at 4-week intervals. Acute efficacy was evidenced by four short-term double-blind, randomised, placebo-controlled, fixed-dose studies of acutely relapsed adult inpatients who met DSM-IV criteria for schizophrenia. NNT for a 30% or greater decrease in the Positive and Negative Syndrome Scale total score compared with placebo was consistently lower for the higher dose strengths of 156 and 234 mg, suggesting a therapeutic dose,response. Treatment with paliperidone palmitate at doses between 39 and 156 mg significantly delayed the time to recurrence of symptoms of schizophrenia after 24 weeks of maintained symptom stability. The NNT vs. placebo to avoid a recurrence of symptoms was 5 (95% CI 4,7). Overall, paliperidone palmitate was reasonably well tolerated, with low rates of extrapyramidal symptoms or body weight gain; however, these may be more common at higher doses. Injection site reactions occurred at a rate ranging from 4% to 10%, depending on the dose regimen, compared with 2% for the pooled placebo arms. The acquisition cost of a maintenance dose of paliperidone palmitate calculated on a per day basis is similar to that for risperidone microspheres, but about double the cost for oral paliperidone and approximately 19 times the cost of oral generic risperidone. Conclusions:, Paliperidone palmitate is efficacious for the acute and maintenance treatment of schizophrenia and is reasonably well tolerated. It offers several advantages over other available second-generation depot antipsychotics: it comes in prefilled syringes in a number of different dosage strengths; it does not require refrigeration; it does not require supplementation with oral antipsychotics; it can be administered once monthly; it can be administered with a very small bore needle; the injection volume is small; the injection site can be either the deltoid or gluteal muscles; it does not require an additional precautionary observation period after the injection. For patients for whom oral risperidone or paliperidone is otherwise effective, paliperidone palmitate offers a guaranteed delivery system that enhances adherence. However, the high acquisition cost of paliperidone palmitate will likely be an important obstacle to its routine use. [source]

Predictors of the efficacy of interferon therapy for patients with chronic hepatitis C before and during therapy: how does this modify the treatment course?

JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, Issue 2000
Yasushi Shiratori
Antiviral therapy for hepatitis C virus (HCV) infection should be based on the natural history of HCV infection; there is a sequential, but slow, progression from chronic hepatitis to cirrhosis, leading to death from either liver failure or hepatocellular carcinoma (HCC). The risk of HCC development increases in association with the advance of fibrosis, and antiviral therapy can reduce this risk. More than 30 indices have been proposed as ,predictors' of favourable response to IFN therapy: host factors (age, gender, duration of HCV-infection, alcohol intake, hepatic iron stores, platelet count, histological staging of the liver disease), viral factors (HCV RNA levels in serum, HCV subtype, diversity of the hypervariable region, mutation of non-structure 5A gene), and IFN factors (dose, duration of treatment, type, treatment regimens i.e. every day vs three times a week, escalating dose regimen). Before starting IFN therapy, HCV subtype and pretreatment HCV RNA load, as well as the fibrotic stage of the liver, should be determined. The response to IFN therapy should be monitored by the HCV RNA status in serum during therapy, and the treatment regimen modified, or discontinued as required. A sustained virological response should be checked at more than 3 months after the completion of therapy. Even though the risk of HCC is markedly reduced in sustained responders, it is possible to develop HCC several years after completion of IFN therapy. [source]

Golimumab, a new human anti,tumor necrosis factor , antibody, administered intravenously in patients with active rheumatoid arthritis: Forty-eight,week efficacy and safety results of a phase III randomized, double-blind, placebo-controlled study ,

ARTHRITIS & RHEUMATISM, Issue 4 2010
Joel Kremer
Objective To assess the efficacy and safety of intravenous administration of golimumab in patients with rheumatoid arthritis (RA). Methods Adult patients with RA in whom disease activity was persistent despite treatment with methotrexate (MTX) at a dosage of 15,25 mg/week for ,4 weeks were randomized to receive intravenous infusions of placebo plus MTX or intravenous infusions of golimumab at a dose of 2 mg/kg or 4 mg/kg, with or without MTX, every 12 weeks through week 48. Patients with <20% improvement in the swollen and tender joint counts could enter early escape and receive additional active treatment (week 16) or could have their dose regimen adjusted (week 24). The primary end point was the proportion of patients achieving a 50% response according to the American College of Rheumatology improvement criteria (ACR50) at week 14. Results The primary study end point was not met (at week 14, an ACR50 response was observed in 21% of the patients treated with golimumab plus MTX compared with 13% of the patients treated with placebo plus MTX [P = 0.051]). By week 24, significantly more patients treated with golimumab plus MTX had achieved an ACR50 response. Differences in the proportion of patients achieving an ACR50 response between the group receiving golimumab monotherapy and the group receiving placebo plus MTX were not significant at either week 14 (16% versus 13%) or week 24 (10% versus 9%). At week 48, the proportions of patients achieving ACR20 and ACR50 responses were highest among those who had received golimumab 4 mg/kg plus MTX (70% and 48%, respectively). Concomitant treatment with MTX was associated with a lower incidence of antibodies to golimumab. The most commonly reported adverse events through week 48 were infections (48% of patients treated with golimumab with or without MTX and 41% of patients receiving placebo plus MTX). Conclusion The primary end point was not met. However, intravenously administered golimumab plus MTX appears to have benefit in the longer-term reduction of RA signs/symptoms in MTX-resistant patients, with no unexpected safety concerns. [source]

Pharmacokinetics and tissue distribution of the anticholinergics tiotropium and ipratropium in the rat and dog

BIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 5 2001
A. Leusch
Abstract Ipratropium, a current treatment for chronic obstructive pulmonary disease (COPD) and tiotropium, a longer acting anticholinergic bronchodilator currently being developed for COPD are structurally related to atropine. In this study, the intravenous (i.v.), oral (p.o.) and intratracheal (i.tr.) single dose pharmacokinetics (PK) of tiotropium and ipratropium were determined in rat and dog. In rats, concentration,time profiles of tiotropium and ipratropium after single i.v. bolus administration of 7,8 mg kg,1 are similar. Both drugs are highly cleared (Cl between 87 and 150 ml min,1 kg,1) and extensively distributed into tissues (volume of distribution Vss between 3 and 15 l kg,1). In dogs, this holds also true for both drugs (Cl between 34 and 42 ml min,1 kg,1, Vss between 2 and 10 l kg,1), although different dose regimen were applied (i.v. bolus of 0.08 mg kg,1 vs. infusion of 0.1 mg kg,1 h,1 for 3 h). Tiotropium plasma concentrations increased linearly in rats over a wide dose range following single i.v. administration. Both ipratropium and tiotropium showed a comparable terminal elimination half-life in rat urine (21,24 h) after single i.v. administration, which was much longer than the corresponding half-life in plasma (6,8 h). Whole body autoradiography in rats revealed a broad and rapid tissue distribution of [14C]tiotropium radioactivity after single i.v. administration. A comparable distribution pattern has also been reported earlier for ipratropium. Copyright © 2001 John Wiley & Sons, Ltd. [source]

A systematic review of phase-II trials of thalidomide monotherapy in patients with relapsed or refractory multiple myeloma

BRITISH JOURNAL OF HAEMATOLOGY, Issue 5 2006
Axel Glasmacher
Summary The activity of thalidomide in relapsed or refractory multiple myeloma is widely accepted but not yet demonstrated in a randomised-controlled trial. A systematic review of the published clinical trials of these patients could reduce the possible bias of single phase-II studies. A systematic search identified 42 communications reporting on 1674 patients. Thirty-two trials used an escalating dosing regimen and four a fixed dose regimen (one dose with 50 mg/d, three doses with 200 mg/d). The target dose in the dose escalating trials was 800 mg/d in 17 trials, 400,600 mg/d in 10 and 200 mg/d in one trial. The intention-to-treat population for efficacy was 1629 patients with a median age of 62 years. The complete and partial (>50% reduction in monoclonal protein) response rate was 29·4% (95%-confidence interval, 27,32%). The rates for minor responses or stable disease were 13·8% (12,16%) and 11·0% (9,13%). Progressive disease was reported in 9·9% (8,11%). The median overall survival from all trials was reported at 14 months. Severe adverse events (grade III,IV) included somnolence 11%, constipation 16%, neuropathy 6%, rash 3%, thrombo-embolism 3%, cardiac 2%. In conclusion, thalidomide monotherapy achieved complete and partial responses in 29·4% of patients with relapsed or refractory multiple myeloma. [source]

Establishing the dose of the oral NK1 antagonist aprepitant for the prevention of chemotherapy-induced nausea and vomiting

CANCER, Issue 9 2003
Sant P. Chawla M.D.
Abstract BACKGROUND The neurokinin-1 antagonist aprepitant (EMENDÔ; Merck Research Laboratories, West Point, PA) has been shown to reduce chemotherapy-induced nausea and vomiting when it is given with a 5-hydroxytryptamine-3 receptor antagonist and dexamethasone. The current study sought to define the most appropriate dose regimen of oral aprepitant. METHODS This multicenter, randomized, double-blind, placebo-controlled study was conducted in patients with cancer who were receiving initial cisplatin (, 70mg/m2) and standard antiemetic therapy (intravenous ondansetron plus oral dexamethasone). Patients were randomized to receive standard therapy plus either aprepitant 375 mg on Day 1 and 250 mg on Days 2,5, aprepitant 125 mg on Day 1 and 80 mg on Days 2,5, or placebo. Due to an apparent interaction with dexamethasone suggested by pharmacokinetic data obtained while the study was ongoing, the aprepitant 375/250 mg dose was discontinued and replaced with aprepitant 40 mg on Day 1 and 25 mg on Days 2,5, and a new randomization schedule was generated. Patients recorded nausea and emesis in a diary. The primary endpoint was complete response (no emesis and no rescue therapy), which was analyzed using an intent-to-treat approach with data obtained after the dose adjustment. Treatment comparisons were made using logistic regression models. Tolerability was assessed by reported adverse events and physical and laboratory assessments, and included all available data. RESULTS The percentages of patients who achieved a complete response in the overall study period were 71.0% for the aprepitant 125/80-mg group (n = 131 patients), 58.8% for the aprepitant 40/25-mg group (n = 119 patients), and 43.7% for the standard therapy group (n = 126 patients; P < 0.05 for either aprepitant regimen vs. standard therapy). Rates for Day 1 were 83.2% for the aprepitant 125/80-mg group, 75.6% for aprepitant 40/25-mg group, and 71.4% for the standard therapy group (P < 0.05 for aprepitant 125/80 mg vs. standard therapy), and rates on Days 2,5 were 72.7% for the aprepitant 125/80-mg group, 63.9% for the aprepitant 40/25-mg group, and 45.2% for the standard therapy group (P < 0.01 for either aprepitant group vs. standard therapy). The efficacy of the aprepitant 375/250-mg regimen was similar to that of the aprepitant 125/80-mg regimen. The overall incidence of adverse events was generally similar across treatment groups: 85% in the aprepitant 375/250-mg group (n = 34 patients), 76% in the aprepitant 125/80-mg group (n = 214 patients), 71% in the aprepitant 40/25-mg group (n = 120 patients), and 72% in the standard therapy group (n = 212 patients), with the exception of a higher incidence of infection in the aprepitant 125/80-mg group (13%) compared with the standard therapy group (4%). CONCLUSIONS When it was added to a standard regimen of intravenous ondansetron and oral dexamethasone in the current study, aprepitant reduced chemotherapy-induced nausea and vomiting and was generally well tolerated, although increases in infection were noted that were assumed to be due to elevated dexamethasone levels as a result of the pharmacokinetic interaction. The aprepitant 125/80-mg regimen had the most favorable benefit:risk profile. Cancer 2003;97:2290,300. © 2003 American Cancer Society. DOI 10.1002/cncr.11320 [source]

Prediction of cure and risk of hypothyroidism in patients receiving 131I for hyperthyroidism

CLINICAL ENDOCRINOLOGY, Issue 1 2009
K. Boelaert
Summary Context, There is little consensus regarding the most appropriate dose of radioiodine (131I) to be administered to patients with hyperthyroidism. Objective, To compare the efficacy of fixed dose regimens of 131I in curing hyperthyroidism and to define simple clinical and biochemical factors that predict outcome in individual patients. Design, Consecutive series of hyperthyroid subjects treated with 131I. Setting, Single Secondary/Tertiary Care Hospital Clinic. Participants, A total of 1278 patients (1013 females and 262 males, mean age 49·7 years) presenting with hyperthyroidism between 1984 and 2006. Intervention, Treatment with 131I using a fixed dose regimen. Main outcome measures, Probability of cure and risk of development of hypothyroidism following a single dose of 131I. Results, Patients given a single dose of 131I of 600 MBq (n = 485) had a higher cure rate (84·1%) compared with those receiving either 370 MBq (74·9%, P < 0·001) or those given 185 Bq (63%, P < 0·001). An increased incidence of hypothyroidism by 1 year was evident with higher doses (600 MBq: 60·4%; 370 MBq: 49·2%, P = 0·001; 185 Bq: 38·1%, P < 0·001). Binary logistic regression analysis identified a 600 Bq dose of 131I [adjusted odds ratio, AOR 3·33 (2·28,4·85), P < 0·001], female gender [AOR 1·75 (1·23,2·47), P = 0·002], lower presenting serum free T4 concentration [AOR 1·01 (1·01,1·02), P < 0·001] and absence of a palpable goitre [AOR 3·33 (2·00,5·56), P < 0·001] to be independent predictors of cure. Similarly, a 600 MBq dose [AOR 3·79 (2·66,5·38), P < 0·001], female gender [AOR 1·46 (1·05,2·02), P = 0·02], younger age [AOR 1·03 (1·02,1·04), P < 0·001], absence of a palpable goitre [AOR 3·85 (2·38,5·88), P < 0·001] and presence of ophthalmopathy [AOR 1·57 (1·06,2·31), P = 0·02] were identified as independent factors predicting the probability of development of hypothyroidism at one year. Based on these findings, formulae to indicate probability of cure and risk of hypothyroidism for application to individual patients were derived. Conclusions, Simple clinical/biochemical criteria can be used to predict outcome after 131I treatment. These factors determine that males, those with severe biochemical hyperthyroidism, and those with a palpable goitre require larger doses (600 MBq) in order to achieve cure. [source]

Clinical experience with infliximab among Filipino patients with rheumatic diseases

INTERNATIONAL JOURNAL OF RHEUMATIC DISEASES, Issue 2 2006
Sandra V. NAVARRA
Abstract Aim:, To describe the clinical experience with infliximab among Filipino patients with rheumatic diseases, specifically disease indications, dose regimens, clinical response, and adverse events. Methods:, We reviewed the data on Filipino patients who were given infliximab by rheumatologists for a rheumatic disease indication. The case report form included demographic profile, underlying rheumatic disease, comorbidities, concurrent medications, dose and frequency of infliximab, physicians' assessment of clinical response, and adverse events. The frequency of doses, intervals between doses, and discontinuation status were recorded. Results:, Included were 64 patients (35 females), with a mean age of 44 years. Most (41%) had rheumatoid arthritis, followed by psoriasis/psoriatic arthritis (31.2%) and ankylosing spondylitis (17.2%). Average disease duration from diagnosis to initiation of infliximab therapy was 7.6 years ± 6.7 SD. Among 35 patients, the interval between maintenance infusions ranged from 6 to 13.6 weeks, with a mean of 8.27 weeks. Clinical response was good to excellent in more than 80% of patients. Discontinuation rate was 10.9% and 28.1% at 3 and 12 months, respectively. Infusion-related adverse events were mild and transient, and 14 (21.8%) cases of infection resolved with appropriate therapy. Infliximab was temporarily withheld in five (7.8%) patients with active tuberculosis. Summary:, These findings substantiate the superior clinical efficacy of infliximab and manageable adverse events among Filipinos with rheumatic diseases. It also demonstrates dose regimens in clinical practice in a third world setting with limited resources. [source]

Effect of Cadmium and Aluminum Intake on the Antioxidant Status and Lipid Peroxidation in Rat Tissues

JOURNAL OF BIOCHEMICAL AND MOLECULAR TOXICOLOGY, Issue 4 2001
Shohda A. El-Maraghy
Abstract This work aimed to study the relationship between the accumulation of cadmium (Cd) or aluminum (Al) in certain tissues and the levels of lipid peroxides as well as tissue antioxidants. To carry out such investigations, CdCl2 was given to rats in two dose levels; 0.5 or 2.0 mg/kg i.p for 1 day or daily repeated doses for 2 weeks. Al was given as AlCl3 either in a single dose of 100 mg/kg or daily repeated doses of 20 mg/kg for 2 and 4 weeks. The measured parameters were tissue malondialdehyde (MDA, index of lipid peroxidation) and reduced glutathione (GSH) levels as well as the activities of glutathione peroxidase (GSH-PX), glutathione reductase (GSSG-R), and glucose-6-phosphate dehydrogenase (G-6-PDH) enzymes. Liver and kidney functions were assessed by measuring serum alanine aminotransferase (ALT) and alkaline phosphatase (ALP) activities as well as serum urea and creatinine concentrations. Cd and Al concentrations in the studied tissues were also measured. Results indicated that tissue Cd was significantly increased after administration of either Cd doses. After a single dose of 0.5 or 2.0 mg/kg CdCl2, the increase in tissue Cd levels were accompanied by an increase in MDA and a decrease in GSH levels. On the other hand, after repeated administration of Cd, tissue Cd accumulation was accompanied by increased hepatic and renal GSH levels with decrease in MDA content and a decrease in GSH-PX activity in liver. Liver function was affected at all dose regimens, whereas kidney function was affected only after 2 weeks administration of the higher dose. In Al treated rats, Al concentration was shown to be increased in liver much more than in brain. This was accompanied by a slight decrease in hepatic GSH level after 2 weeks and a decrease in GSH-PX activity after 4 weeks. Liver function was affected only after repeated injection of Al for 2 or 4 weeks. In general, Al administration exhibited safer pattern than Cd. © 2001 John Wiley & Sons, Inc. J Biochem Mol Toxicol 15:207,214, 2001 [source]

A qualitative systematic review of peri-operative dextromethorphan in post-operative pain

ACTA ANAESTHESIOLOGICA SCANDINAVICA, Issue 1 2006
T. H. Duedahl
Background:, The N -methyl- d -aspartate (NMDA) receptor antagonist, dextromethorphan (DM), has received interest as an adjunctive agent in post-operative pain management. Clinical trials have been contradictory. This systematic review aims to evaluate the available literature examining the analgesic efficacy of DM in post-operative patients. Methods:, Twenty-eight randomized, double-blind, clinical studies, with 40 comparisons, including a variety of dosing regimens comparing DM treatment with placebo, were included. Meta-analysis was intended but deemed to be inappropriate because of the substantial difference in methodology and reporting between trials. The outcome measures (pain scores at rest, time to first analgesic request and supplemental analgesic consumption) were evaluated qualitatively by significant difference (P < 0.05) as reported in the original investigations. Results:, DM did not reduce the post-operative pain score with a clinically significant magnitude. The time to first analgesic request was significantly prolonged in most comparisons with DM. Significant decreases in supplemental opioid consumption were observed in the majority of parenteral DM studies and in about one-half of the oral studies. The decreases were of questionable clinical importance in most comparisons, although a relationship between a decrease in opioid consumption and opioid-related side-effects was established in some studies. Conclusion:, Based on the studies available, DM has the potential to be a safe adjunctive agent to opioid analgesia in post-operative pain management, but the consistency of the potential opioid-sparing and pain-reducing effect must be questioned. Consequently, it is not possible to recommend dose regimens or routine clinical use of DM in post-operative pain. The route of administration may be important for the beneficial effect. [source]

Praziquantel efficacy in mice infected with PZQ non-susceptible S. mansoni isolate treated with artemether: parasitological, biochemical and immunohistochemical assessment

APMIS, Issue 9 2010
Sanaa S. Botros
Botros SS, Hammam O, Mahmoud M, Bergquist R. Praziquantel efficacy in mice infected with PZQ non-susceptible S. mansoni isolate treated with artemether: parasitological, biochemical and immunohistochemical assessment. APMIS 2010; 118: 692,702. Based on the fact that artemether (ART) affects immature schistosomes and that the effect of praziquantel (PZQ) mainly targets mature schistosomes, this work investigates the possible enhanced efficacy of PZQ in combination with ART in mice harboring a PZQ non-susceptible Schistosoma mansoni isolate. Associated schistosomal, inflammatory, hepatic histopathological changes have been investigated by examining the tissue markers expressing apoptosis using FAS (CD95), anti-apoptosis (Bcl2) and angiogenesis [vascular endothelial growth factor (VEGF)]. A batch of Swiss albino mice infected with a PZQ non-susceptible (EE10) S. mansoni isolate was divided into 12 groups. Animals of the first group were left without treatment as infected controls, while groups 2,6 received PZQ in increasing doses. The animals of group 7 received ART in double doses. Those comprising groups 8,12 received combined therapy of PZQ and ART in the same doses and at the same timings postinfection (PI) as those belonging to groups 2,6. Parasitological parameters, liver function, and histopathological and immunohistochemical studies of FAS, Bcl2 and VEGF antibodies were assessed. Combined administration of ART and PZQ reduced the ED50 (the dose at which the worm burden was decreased by 50%) of PZQ. Typical granulomas were not seen in animals treated with ART alone and combined with PZQ, with least expression of FAS and VEGF and increased expression of Bcl2. The minimal histopathological changes recorded in mice treated with both ART and PZQ could be related to a synergistic/additive effect of ART, markedly reducing the intensity of infection. Improved liver function tests support the less severe histopathological changes under the influence of this treatment protocol. This study encourages human trials especially in areas where malaria is not endemic, and differing combination doses should be investigated in view of the antagonistic effect noticed with some dose regimens. [source]

Population pharmacokinetics of mycophenolic acid in children and young people undergoing blood or marrow and solid organ transplantation

BRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 4 2010
Lihua Zeng
WHAT IS ALREADY KNOWN ABOUT THIS PROJECT? , Mycophenolate mofetil (MMF) is an immunosuppressant drug used for the treatment and prevention of graft vs. host disease in blood or marrow transplantation and acute graft rejection in solid organ transplantation. , Mycophenolic acid (MPA) pharmacokinetics have not been thoroughly studied in paediatric blood or marrow transplant recipients and guidance for optimal dosing of mycophenolic acid in children is lacking. , Mycophenolic acid exhibits considerable inter- and intra-patient pharmacokinetic variability in adults and paediatric transplant recipients. , The AUC of mycophenolic acid over a 12 h dose interval at steady-state is generally agreed to be the most reliable metric associated with the risk of acute rejection. , Population pharmacokinetic analysis can utilize concentration information from both intensive sampling and sparse sampling to provide pharmacokinetic parameter estimates, estimates of inter- individual and intra-individual variability in these parameters and allows patient characteristics explaining inter-individual variability to be quantified. WHAT THIS STUDY ADDS , This study is one of the first investigations in which a population pharmacokinetic modelling approach was applied to assess the pharmacokinetics of both intravenous and oral MMF in children and young people undergoing blood or marrow and solid organ transplantation. , Bodyweight and concomitant ciclosporin were found to influence MPA pharmacokinetics. , This study evaluated current dosing strategies and found that they may be suboptimal for children weighing less than 10 kg. AIMS To characterize the population pharmacokinetics of mycophenolic acid (MPA) and evaluate dose regimens using a simulation approach and accepted therapeutic drug monitoring targets in children and young people undergoing blood or marrow, kidney and liver transplantation. METHODS MPA concentration,time data were collected using an age specific sampling protocol over 12 h. Some patients provided randomly timed but accurately recorded blood samples. Total and unbound MPA were measured by HPLC. NONMEM was employed to analyze MPA pharmacokinetic data. Simulations (n= 1000) were conducted to assess the suitability of the MPA dose regimens to maintain total MPA AUC(0,12 h) within the range 30 and 60 mg l,1 h associated with optimal outcome. RESULTS A two-compartment pharmacokinetic model with first-order elimination best described MPA concentration,time data. Population mean estimates of MPA clearance, inter-compartmental clearance, volumes of distribution in the central and peripheral compartments, absorption rate constant and bioavailability were 6.42 l h,1, 3.74 l h,1, 7.24 l, 16.8 l, 0.39 h,1 and 0.48, respectively. Inclusion of bodyweight and concomitant ciclosporin reduced the inter-individual variability in CL from 54.3% to 31.6%. Children with a bodyweight of 10 kg receiving standard MPA dose regimens achieve an MPA AUC below the target range suggesting they may be at a greater risk of acute rejection. CONCLUSIONS The population pharmacokinetic model for MPA can be used to explore dosing guidelines for safe and effective immunotherapy in children and young people undergoing transplantation. [source]

A multiparameter flow cytometric analysis of the effect of bexarotene on the epidermis of the psoriatic lesion

BRITISH JOURNAL OF DERMATOLOGY, Issue 3 2003
M.E.J. Franssen
Summary Background A new retinoid, bexarotene (Targretin®), was recently investigated in a large multicentre trial for its efficacy and safety in psoriasis. Bexarotene is a novel retinoid X receptor (RXR)-selective ligand. Objectives The aim was to study the effect of bexarotene in psoriasis by analysing markers for epidermal differentiation, proliferation and inflammation in epidermal single cell suspensions from lesions of patients with psoriasis treated with various doses of bexarotene. Methods Thirty-four patients with moderate to severe plaque psoriasis participated in this study and were assigned in sequence to four different dose regimens: 0·5, 1, 2 and 3 mg kg,1 once daily. Before and after 12 weeks of bexarotene treatment, punch biopsies were taken from lesional skin from which epidermal single cell suspensions were prepared using an optimized thermolysin protocol. A sum of scores was determined for each biopsy site, based on a four-point scale for erythema, induration and desquamation. An improved multiparameter flow cytometric assay was used that enabled simultaneous assessment of epidermal proliferation, various aspects of differentiation and epidermal inflammation. The following variables were measured simultaneously: relative DNA content, relative cell size, keratin (K) 10, K6 and vimentin expression. Results The psoriasis area and severity index (PASI) and sum of scores for the individual psoriatic lesion each showed a statistically significant decrease of 28% after 12 weeks of bexarotene treatment (P < 0·001). However, no significant dose,response effect was found. The total percentage of K10+ cells showed a significant increase of 43% (P < 0·01). The total population of K6 expressing cells did not show significant changes. Regarding the subpopulations of K6 single, K10 single and K6 and 10 co-expressing cells, a significant increase of 77% was seen in the K10+ K6, cells (P < 0·05), a significant decrease of 33% in K10, K6+ cells (P < 0·01), and no significant changes in the remaining population of K10+ K6+ cells. After 12 weeks of treatment with bexarotene no significant changes in epidermal proliferation and inflammation were shown. Conclusions The present study indicates a direct effect of RXR activation by bexarotene on the transition of proliferation-associated keratinization into normal keratinization. Although no direct effect of bexarotene on DNA content in the total K10, cells was shown, further studies on subpopulations within the germinative layer such as stem cells and transit amplifying cells might be worthwhile. [source]

Systemic immunosuppressant therapy in childhood

CLINICAL & EXPERIMENTAL DERMATOLOGY, Issue 4 2002
David Atherton
The indications for systemic immunosuppressant therapy are much the same in children as in adults. Perhaps the most important difference is the need in a child to consider more carefully the patient's likely future therapy requirements. This need reflects a justifiable anxiety concerning the longer-term toxicity associated with some of these drugs. It is obvious that special attention should be paid to the dosage regimens that are appropriate in children. However, otherwise the principles of treatment are essentially the same as in adults. This talk will focus on the use of azathioprine in atopic eczema, methotrexate in psoriasis and linear morphoea, and intravenous methylprednisolone in severe muco-cutancous erythema multiforme and toxic epidermal necrolysis. The value of azathioprine as a treatment for severe childhood eczema was greatly increased by the elucidation of the metabolic pathways for this drug, and by the development of an assay for thiopurine methyl transferase to allow detection of those at greatest risk of myelosuppression. We now treat children with normal TPMT levels with 3 mg/kg per day with gratifying therapeutic response and limited requirement for monitoring of blood counts and liver function. More recently we have successfully treated TPMTHL heterozygotes with doses of around 1.5 mg/kg per day. We now consider azathioprine as superior to cyclosporin as a systemic therapy for atopic eczema. The value of methotrexate in adults with plaque psoriasis and generalized pustular psoriasis is well established. It is equally useful in children with these disorders, and the most appropriate dosage appears to be in the region of 0.3,0.4 mg/kg as a single weekly dose. Children generally tolerate oral therapy well. Methotrexate also appears helpful in arresting the progression of linear morphoea, both in the case of coup de sabre lesions and progressive hemi-facial atrophy, and in limb lesions that are interfering with joint mobility or are causing profound lipoatrophy. Intravenous methylprednisolone appears to be of value in several acute dermatoses in childhood, but is most commonly used at Great Ormond Street Hospital in the hope of arresting progression of severe muco-cutaneous erythema multiforme and toxic epidermal necrolysis. Various dose regimens are used in children, but in our unit we use a dose of 20,30 mg/kg per day, up to a maximum of 500 mg, for 3 successive days. Each dose is given over period of 2 h with frequent monitoring of vital signs, particularly blood pressure. [source]