Home About us Contact
|
Home About us Contact | ||
|
|
||
Therapeutic Doses (therapeutic + dose)
Selected AbstractsTherapeutic doses of glucocorticoids: implications for oral medicineORAL DISEASES, Issue 5 2006SK Baid Glucocorticoids can cause adverse systemic side-effects ranging from iatrogenic Cushing's syndrome during treatment, to hypothalamic,pituitary,adrenal axis suppression and clinically significant adrenal insufficiency when the agents are discontinued. While the oral route of administration is most often implicated, it is now becoming more apparent that inhaled and topical administration also can cause these effects. Given the high therapeutic value of glucocorticoids, the ability to prescribe these agents while maintaining a low risk-to-benefit ratio for patients is critical. The aim of this review is to provide oral healthcare practitioners with a practical guide to commonly used glucocorticoids, their adverse effects, and perioperative use. [source] Lamotrigine does not prolong QTc in a thorough QT/QTc study in healthy subjectsBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 3 2008Ruth Dixon WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT , Drugs that inhibit the human cardiac delayed rectifier potassium current may lead to prolongation of the cardiac QT interval and are associated with a fatal, polymorphic, ventricular tachycardia known as torsades de pointes. , Lamotrigine is indicated in the treatment of epilepsy and the prevention of mood episodes in patients with bipolar disorder. , Lamotrigine inhibits the human cardiac delayed rectifier potassium current in vitro, and it has been hypothesized that QT prolongation may contribute to the risk of sudden unexpected death in epilepsy patients. WHAT THIS STUDY ADDS , This is the first reported thorough QT/QTc study with lamotrigine conducted to International Conference on Harmonization guidelines. , The mean QTc interval was not prolonged by lamotrigine in healthy subjects, as assessed by the standard heart rate correction methods (Fridericia's and Bazett's). , The in vitro inhibition of the delayed rectifier potassium current does not translate into an effect on QT in man. AIM To characterize the effects of lamotrigine on QT interval in healthy subjects. METHODS Healthy subjects received a single oral dose of moxifloxacin (400 mg) or placebo in crossover design, followed by a dose-escalating regimen of lamotrigine (n = 76) over a 77-day period, or matched placebo (n = 76). Blood samples were taken for determination of moxifloxacin and lamotrigine concentrations and digital 12-lead ECGs were recorded. The relationships between individual QT values and respective individual moxifloxacin or lamotrigine concentrations were explored using population pharmacokinetic,pharmacodynamic (PK,PD) modelling. RESULTS Moxifloxacin was associated with a maximum mean increase from baseline in QTcF of 14.81 ms [90% confidence interval (CI) 13.50, 16.11] 2.5 h after dosing. Steady-state exposure to lamotrigine (50, 150 or 200 mg b.d.) was not associated with an increase in QTc interval. Small reductions in QTcF (maximum mean difference from placebo ,7.48 ms, 90% CI ,10.49, ,4.46) and small increases in heart rate (maximum mean difference from placebo 5.94 bpm, 90% CI 3.81, 8.06) were observed with lamotrigine 200 mg b.d. vs. placebo. No effect of lamotrigine on QRS duration or blood pressure was observed. No outliers with QTcF > 450 ms, or with an increase from baseline of >60 ms were observed in the lamotrigine group. PK,PD modelling indicated statistically significant decreases in individually corrected QT intervals for lamotrigine and statistically significant increases in individually corrected QT intervals for moxifloxacin over the concentration ranges studied. CONCLUSIONS Therapeutic doses of lamotrigine (50,200 mg b.d.) were not associated with QT prolongation in healthy subjects. [source] Accelerating drug development: methodology to support first-in-man pharmacokinetic studies by the use of drug candidate microdosingDRUG DEVELOPMENT RESEARCH, Issue 1 2007Matthew 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] New metabolic and pharmacokinetic characteristics of thiocolchicoside and its active metabolite in healthy humansFUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 4 2004M. Trellu Abstract Thiocolchicoside (TCC) has been prescribed for several years as a muscle relaxant drug, but its pharmacokinetic (PK) profile and metabolism still remain largely unknown. Therefore, we re-investigated its metabolism and PK, and we assessed the muscle relaxant properties of its metabolites. After oral administration of 8 mg (a therapeutic dose) of 14C-labelled TCC to healthy volunteers, we found no detectable TCC in plasma, urine or faeces. On the other hand, the aglycone derivative obtained after de-glycosylation of TCC (M2) was observed and, in addition, we identified, as the major circulating metabolic entity, 3-O-glucuronidated aglycone (M1) obtained after glucuro-conjugation of M2. One hour after oral administration, M1 plus M2 accounted for more than 75% of the circulating total radioactivity. The pharmacological activity of these metabolites was assessed using a rat model, the muscle relaxant activity of M1 was similar to that of TCC whereas M2 was devoid of any activity. Subsequently, to investigate the PK profile of TCC in human PK studies, we developed and validated a specific bioanalytical method that combines liquid chromatography and ultraviolet detection to assay both active entities. After oral administration, TCC was not quantifiable with an lower limit of quantification set at 1 ng/mL, whereas its active metabolite M1 was detected. M1 appeared rapidly in plasma (tmax = 1 h) and was eliminated with an apparent terminal half-life of 7.3 h. In contrast, after intramuscular administration both active entities (TCC and M1) were present; TCC was rapidly absorbed (tmax = 0.4 h) and eliminated with an apparent terminal half-life of 1.5 h. M1 concentration peaked at 5 h and this metabolite was eliminated with an apparent terminal half-life of 8.6 h. As TCC and M1 present an equipotent pharmacological activity, the relative oral pharmacological bioavailability of TCC vs. intramuscular administration was calculated and represented 25%. Therefore, to correctly investigate the PK and bioequivalence of TCC, the biological samples obtained must be assayed with a bioanalytical method able to specifically analyse TCC and its active metabolite M1. [source] Paliperidone palmitate , review of the efficacy, safety and cost of a new second-generation depot antipsychotic medicationINTERNATIONAL JOURNAL OF CLINICAL PRACTICE, Issue 2 2010L. 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] Pharmacokinetics of a novel transdermal rivastigmine patch for the treatment of Alzheimer's disease: a reviewINTERNATIONAL JOURNAL OF CLINICAL PRACTICE, Issue 5 2009A. Kurz Summary Background:, Cholinesterase inhibitors have all been available in oral formulations, but a rivastigmine transdermal patch has now been developed and is approved in many countries worldwide for the treatment of mild-to-moderate Alzheimer's disease (AD) (including the USA, Latin America, Europe and Asia). Objectives:, To review the available pharmacokinetic data that supported the rationale behind the development of the rivastigmine transdermal patch and its clinical effects in dementia therapy. This article will also discuss how the patch may alter the treatment paradigm for patients with AD. Results:, The 9.5 mg/24 h rivastigmine patch was shown to provide comparable exposure to the highest recommended doses of capsules (12 mg/day) with significantly lower maximum plasma concentration (Cmax 8.7 vs. 21.6 ng/ml) and slower absorption rate (tmax 8.1 vs. 1.4 h). In a clinical trial of 1195 AD patients, this translated into similar efficacy with three times fewer reports of nausea and vomiting (7.2% vs. 23.1%, and 6.2% vs. 17.0% respectively). Consequently, more patients in the 9.5 mg/24 h patch group achieved their target therapeutic dose at the end of the study, compared with those in the 12 mg/day capsule group (95.9% vs. 64.4%). Conclusion:, The rivastigmine patch provides continuous drug delivery over 24 h and similar efficacy to the highest recommended dose of oral rivastigmine with improved tolerability. This may allow patients to achieve optimal therapeutic doses and to benefit from a longer duration of treatment. [source] Continuation and long-term maintenance treatment with Hypericum extract WS® 5570 after successful acute treatment of mild to moderate depression , rationale and study designINTERNATIONAL JOURNAL OF METHODS IN PSYCHIATRIC RESEARCH, Issue 3 2004Chairman, S. Kasper Professor Abstract Unipolar major depression is often a chronic disease that may require lifelong prophylaxis. Recovery from an acute episode is followed by 4-6 months of relapse prevention. After that, long-term maintenance treatment is administered to avoid recurrence. We present the rationale and design of an ongoing double-blind, randomized, placebo-controlled trial investigating the efficacy of Hypericum extract WS® 5570 in relapse prevention in recurrent unipolar depression. An estimated sample of 425 adults with recurrent, mild to moderate major depression (ICD-10 and DSM-IV criteria), ,3 previous episodes (last 5 years) and a total score ,20 points on the 17-item Hamilton Rating Scale for Depression (HAMD) will be included. After a one-week wash out patients receive 3 × 300 mg/day WS® 5570 single-blind for 6 weeks. Responders are randomized to 26 weeks of double-blind continuation treatment with 3 × 300 mg/day WS® 5570 or placebo. Patients completing continuation treatment without relapse enter 52 weeks of double-blind maintenance treatment, where those treated with WS® 5570 are re-randomized to 3 × 300 mg/day WS® 5570 or placebo. The primary outcome measure is the time to relapse during continuation treatment (HAMD ,16, clinical diagnosis of depression, or premature treatment termination for inefficacy). Hypericum extract, with its favourable tolerability profile, could be an interesting option for long-term prophylaxis. The trial was designed according to current consensus and guidance. Notably, it includes long-term prophylactic treatment with the same drug and the same therapeutic dose applied during acute treatment, uses well-defined outcome measures and provides a clear distinction between relapse and recurrence. Copyright © 2004 Whurr Publishers Ltd. [source] Kinetic analysis of oxytetracycline residues in Chinese mitten crab, Eriocheir sinensis, muscle following intramuscular administrationJOURNAL OF FISH DISEASES, Issue 8 2010Q Feng Abstract Crab culture is a very important economic industry in China. An epidemic of tremor disease of Chinese mitten crabs, Eriocheir sinensis, has become a serious problem in recent years. A spiroplasm has been proved to be the causative agent of this disease. Oxytetracycline (OTC) is used widely in aquaculture and was confirmed to be very effective against this pathogen. In this study, the distribution and depletion patterns of OTC in crab muscle were evaluated following single intramuscular doses of 2, 8 and 40 mg kg,1 body weight. OTC was detected with a validated HPLC method. Concentration,time profiles were well described by a three-compartment model with first-order absorption after a single dose of 8 and 40 mg kg,1. For comparison, a non-compartment model was employed. A withdrawal time of 48.29 and 55.92 days was suggested prior to consumption after receiving 8 and 40 mg kg,1. A recommended therapeutic dose of OTC in theory was calculated to be 36.37 mg kg,1. OTC was distributed well throughout the body. The elimination of OTC in muscle was slower compared with fish and other crustaceans. A dose of 40 mg kg,1 is suggested for practical use. [source] STAT3 activation in photoreceptors by leukemia inhibitory factor is associated with protection from light damageJOURNAL OF NEUROCHEMISTRY, Issue 3 2008Yumi Ueki Abstract Members of the interleukin-6 cytokine family, including leukemia inhibitory factor (LIF), signal through gp130. The neuroprotective role of gp130 activation has been widely demonstrated in both CNS and PNS, but the mechanism by which this is accomplished is not well established. We investigated temporal and cell-specific activation of signaling pathways induced by LIF in the mature mouse retina. Intravitreal injection of LIF preserved photoreceptor function and prevented photoreceptor cell death from light-induced oxidative damage in a dose-dependent manner (2 days post-injection). A therapeutic dose of LIF induced rapid and sustained activation of signal transducer and activator of transcription (STAT) 3. Activated STAT3 was localized to all the retinal neurons and glial cells, including photoreceptors. Activation of extracellular signal-regulated kinase 1 and 2 was robust but transient in Müller glial cells, and undetectable at the time of light exposure. Akt was not activated by LIF. We also show that at the time of neuroprotection, STAT3 but not extracellular signal-regulated kinase 1 and 2 or the Akt pathways was active in LIF-treated retinas, and activated STAT3 was clearly localized in transcriptionally active areas of photoreceptor nuclei. Our data suggest that photoreceptor protection in response to LIF can be directly mediated by activation of STAT3 in photoreceptors. [source] Prospective observational cohort study of bioaccumulation of dalteparin at a prophylactic dose in patients with peritoneal dialysisJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 4 2010P. SCHMID See also Schmid P, Brodmann D, Odermatt Y, Fischer AG, Wuillemin WA. Study of bioaccumulation of dalteparin at a therapeutic dose in patients with renal insufficiency. J Thromb Haemost 2009; 7: 1629,32. [source] Laboratory and clinical outcomes of pharmacogenetic vs. clinical protocols for warfarin initiation in orthopedic patientsJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 10 2008P. A. LENZINI Summary.,Background:,Warfarin is commonly prescribed for prophylaxis and treatment of thromboembolism after orthopedic surgery. During warfarin initiation, out-of-range International Normalized Ratio (INR) values and adverse events are common. Methods:,In orthopedic patients beginning warfarin therapy, we developed and prospectively validated pharmacogenetic and clinical dose refinement algorithms to revise the estimated therapeutic dose after 4 days of therapy. Results:,The pharmacogenetic algorithm used the cytochrome P450 (CYP) 2C9 genotype, smoking status, peri-operative blood loss, liver disease, INR values and dose history to predict the therapeutic dose. The R2 was 82% in a derivation cohort (n = 86) and 70% when used prospectively (n = 146). The R2 of the clinical algorithm that used INR values and dose history to predict the therapeutic dose was 57% in a derivation cohort (n = 178) and 48% in a prospective validation cohort (n = 146). In 1 month of prospective follow-up, the percent time spent in the therapeutic range was 7% higher (95% CI: 2.7,11.7) in the pharmacogenetic cohort. The risk of a laboratory or clinical adverse event was also significantly reduced in the pharmacogenetic cohort (Hazard Ratio 0.54; 95% CI: 0.30,0.97). Conclusions:,Warfarin dose adjustments that incorporate genotype and clinical variables available after four warfarin doses are accurate. In this non-randomized, prospective study, pharmacogenetic dose refinements were associated with more time spent in the therapeutic range and fewer laboratory or clinical adverse events. To facilitate gene-guided warfarin dosing we created a non-profit website, http://www.WarfarinDosing.org. [source] Safety of plasmin in the setting of concomitant aspirin and heparin administration in an animal model of bleedingJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 12 2003S. Sadeghi Summary., Plasmin is a direct thrombolytic which has been shown to have a strikingly favorable benefit to risk profile in comparison with plasminogen activators, notably tissue plasminogen activator (t-PA). As heparin is known to increase the risk of hemorrhage when co-administered with a plasminogen activator, we asked whether adjunct antithrombotic agents such as aspirin and heparin would affect the safety of plasmin. Three groups of rabbits were administered plasmin at a dose (4 mg kg,1) designed to induce significant decreases in antiplasmin, fibrinogen and factor (F)VIII, to about 25, 40 and 40%, respectively, of baseline values, but not cause prolongation of the ear puncture bleeding time. In a blinded and randomized trial, the results show that an intravenous aspirin bolus plus heparin administered as a bolus followed by a maintenance continuous infusion did not significantly prolong the bleeding time during plasmin infusion. These data indicate that in the rabbit, concomitant use of aspirin plus heparin does not affect the safety of a therapeutic dose of plasmin. [source] Recombinant Human Thyrotropin Administration Enhances Thyroid Uptake of Radioactive Iodine in Hyperthyroid CatsJOURNAL OF VETERINARY INTERNAL MEDICINE, Issue 6 2008I. Van Hoek Background: Hyperthyroidism is the most diagnosed endocrine disorder in cats and radioiodine (131I) is the treatment of choice. The dose emission rate and radioactivity in urine, saliva, and on hair and paws are determined by the dose of administered 131I. A dose reduction of therapeutic 131I could possibly be achieved after recombinant human thyrotropin (rhTSH) administration as in humans with nodular goiter. Hypothesis: rhTSH will increase radioiodine uptake in hyperthyroid cats. Animals: Five hyperthyroid cats. Methods: Twenty-five micrograms rhTSH (day 1) or 2 mL 0.9% sodium chloride (NaCl) (day 9) was injected IV. One hour later, 11.4 ± 4.1 (mean ± SD) MBq 123I was injected IV. Radioactive iodine uptake (RAIU) was measured 6, 12, and 24 hours after rhTSH (RAIU-rhTSH) or NaCl (RAIU-blanco) injection. Blood samples for measurement of TT4 were taken before injection of rhTSH or NaCl (TT40) and at the time of imaging. Results: Percentages of RAIU-rhTSH (and RAIU-blanco) at 6, 12, and 24 hours after administration of rhTSH were 34 ± 18 (31 ± 21), 46 ± 20 (38 ± 18), and 47 ± 15 (36 ± 14). There was a statistically significant effect of rhTSH administration on RAIU (P= .043) but not on serum TT4 concentration. Baseline serum TT40 concentration influenced RAIU-rhTSH significantly at 6 hours (P= .037). Conclusion and Clinical Importance: The increased RAIU observed after rhTSH administration in hyperthyroid cats could lead to a lower therapeutic dose of 131I after rhTSH administration in hyperthyroid cats and decreased risk of environmental and owner contamination during and after hospitalization. [source] Population pharmacokinetics of pyrazinamide in elephantsJOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 5 2005M. ZHU This study was undertaken to characterize the population pharmacokinetics (PK), therapeutic dose, and preferred route of administration for pyrazinamide (PZA) in elephants. Twenty-three African (Loxodonta africana) and Asian (Elephas maximus) elephants infected with or in contact with others culture positive for Mycobacterium tuberculosis were dosed under treatment conditions. PZA was dosed daily at 20,30 mg/kg via oral (fasting or nonfasting state) or rectal (enema or suppository) administration. Blood samples were collected 0,24 h postdose. Population PK was estimated using nonlinear mixed effect modeling. Drug absorption was rapid with Tmax at or before 2 h regardless of the method of drug administration. Cmax at a mean dose of 25.6 (±4.6) mg/kg was 19.6 (±9.5 ,g/mL) for PZA given orally under fasting conditions. Under nonfasting conditions at a mean dose of 26.1 ± 4.2 mg/kg, Cmax was 25% (4.87 ± 4.89 ,g/mL) and area under concentration curve (AUC) was 30% of the values observed under fasting conditions. Mean rectal dose of 32.6 ± 15.2 mg/kg yielded Cmax of 12.3 ± 6.3 ,g/mL, but comparable AUC to PZA administered orally while fasting. Both oral and rectal administration of PZA appeared to be acceptable and oral dosing is preferred because of the higher Cmax and lower inter-subject variability. A starting dose of 30 mg/kg is recommended with drug monitoring between 1 and 2 h postdose. Higher doses may be required if the achieved Cmax values are below the recommended 20,50 ,g/mL range. [source] Polychromatic Light Similar to the Terrestrial Solar Spectrum Without its UV Component Stimulates DNA Synthesis in Human Peripheral Blood Lymphocytes In Vivo and In VitroPHOTOCHEMISTRY & PHOTOBIOLOGY, Issue 5 2006Natalya A. Zhevago ABSTRACT Immunosuppressive effects of the minor component of the terrestrial solar spectrum, UV radiation, have been substantiated over the past several years. This raises the question of what influence the dominant part of the solar spectrum,visible and IR light,would have on the human immune system. In the present randomized, placebo-controlled double-blind study a small area of the body surface of volunteers was irradiated with polychromatic light (480,3400 nm), simulating the significant part of the terrestial sunlight irradiance spectrum and its power density. An average 2.5-fold to three-fold increase in spontaneous and phytohemagglutinin-induced DNA synthesis in peripheral blood lymphocytes (Lym) was revealed at 0.5,24 h after irradiation at a therapeutic dose (12 J/cm2) in subjects with low preirradiation levels of both processes. The in vivo findings were echoed in parallel in vitro experiments, when blood drawn from the same subjects was directly irradiated (2.4 J/cm2), or when the irradiated blood was mixed 1:10 with nonirradiated autolo-gous blood to model events in the circulation following transcutaneous blood photomodification. Our data suggest that exposure of the human body to polychromatic visible + IR light may photomodify blood in the dermal vasculature of the irradiated area to lead to an immediate transfer of the light-induced effects to Lym of the entire circulating blood, which can result in modulation of Lym functional state at the systemic level. [source] Valproate in children with newly diagnosed idiopathic generalized epilepsyACTA NEUROLOGICA SCANDINAVICA, Issue 3 2010K. D. Holland Holland KD, Monahan S, Morita D, Vartzelis G, Glauser TA. Valproate in children with newly diagnosed idiopathic generalized epilepsy. Acta Neurol Scand: 2010: 121: 149,153. © 2009 The Authors Journal compilation © 2009 Blackwell Munksgaard. Objectives,,, Sparse information on dose,response characteristics for initial antiepileptic drug monotherapy in children with idiopathic generalized epilepsy (IGE) is available. The aim of this study is to characterize the therapeutic dose of valproate in children with newly diagnosed IGE. Materials and methods,,, Effect of initial valproate monotherapy and doses associated with seizure freedom were examined in consecutive children with IGE identified from a New Onset Seizure Clinic. Results,,, Of 84 patients identified, 48 (57%) became seizure-free on valproate monotherapy and another 10 patients became seizure-free but discontinued VPA because of adverse effects. The mean dose in seizure-free children was 15.7 mg/kg/day and over 95% of IGE patients will respond below 25 mg/kg/day. Conclusions,,, Half of children became seizure-free on valproate monotherapy and did so at modest doses. [source] Intra-hepatic arterial administration with miriplatin suspended in an oily lymphographic agent inhibits the growth of human hepatoma cells orthotopically implanted in nude ratsCANCER SCIENCE, Issue 1 2009Mitsuharu Hanada Miriplatin is a lipophilic platinum complex which contains myristates as leaving groups and diaminocyclohexane as a carrier ligand. In order to examine in vivo the antitumor activities of miriplatin suspended in an oily lymphographic agent (Lipiodol Ultra-Fluide®, LPD) against human hepatocellular carcinoma (HCC) after the intra-hepatic arterial administration, we have developed a novel orthotopic model of HCC in which the human hepatoma cell line Li-7 was successively implanted and maintained in the liver of nude rats. Li-7 tumors established in nude rat livers displayed a trabecular structure similar to their original morphology, and were exclusively supplied by the hepatic artery, suggesting that they exhibited in part the conditions of human HCC. Miriplatin suspended in LPD (miriplatin/LPD) administered into the hepatic artery of this model dose-dependently inhibited the growth of Li-7 tumors without markedly enhancing body weight loss and caused a significant reduction in the growth rate at a dose of 400 µg/head compared to LPD alone. In addition, at the therapeutic dose, miriplatin/LPD as well as cisplatin suspended in LPD (400 µg/head) was shown to be more active than zinostatin stimalamer suspended in LPD (20 µg/head) against Li-7 tumors after a single intra-hepatic arterial administration. These results suggest miriplatin to be a suitable candidate for use in transarterial chemoembolization (Cancer Sci 2009; 100: 189,194) [source] The prefrontal cortex: a target for antipsychotic drugsACTA PSYCHIATRICA SCANDINAVICA, Issue 1 2010F. ArtigasArticle first published online: 14 DEC 200 Objective:, At therapeutic doses, classical antipsychotic drugs occupy a large proportion of subcortical dopamine D2 receptors, whereas atypical antipsychotics preferentially occupy cortical 5-HT2 receptors. However, the exact cellular and network basis of their therapeutic action is not fully understood. Method:, To review the mechanism of action of antipsychotic drugs with a particular emphasis on their action in the prefrontal cortex (PFC). Results:, The PFC controls a large number of higher brain functions altered in schizophrenia. Histological studies indicate the presence of a large proportion of PFC neurons expressing monoaminergic receptors sensitive to the action of atypical- and to a lesser extentclassical antipsychotic drugs. Functional studies also indicate that both drug families act at PFC level. Conclusion:, Atypical antipsychotic drugs likely exert their therapeutic activity by a preferential action on PFC neurons, thus modulating the PFC output to basal ganglia circuits. Classical antipsychotics also interact with these PFC targets in addition to blocking massively striatal D2 receptors. [source] Topiramate Loading for Refractory Status Epilepticus in ChildrenEPILEPSIA, Issue 6 2006M. Scott Perry Summary:,Purpose: To describe three cases of refractory status epilepticus (RSE) in children responsive to topiramate (TPM). Methods: Patients with SE refractory to therapeutic doses of at least two antiepileptic medications were given TPM, 10 mg/kg/d, for 2 consecutive days, followed by maintenance doses of 5 mg/kg/d. Results: This protocol has been used in three cases of RSE at our institution. In each case, SE was aborted within 21 h of the initial dose of TPM. Two patients avoided pharmacologic coma, and one was rapidly weaned from continuous benzodiazepine infusion. Conclusions: Our experience indicates that TPM loading can be effective in the treatment of RSE in children. [source] Saliva DHEA and cortisol responses following short-term corticosteroid intakeEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 2 2010L. Jollin Eur J Clin Invest 2010; 40 (2): 183,186 Abstract Background, Given the high correlation between the serum and saliva hormone values demonstrated at rest, saliva provides a convenient non-invasive way to determine dehydroepiandrosterone (DHEA) and cortisol concentrations. However, to our knowledge, pituitary adrenal recovery following short-term suppression with corticosteroids has never been investigated in saliva. The aim of this study was therefore to examine how steroid hormone concentrations in saliva are influenced by short-term corticosteroid administration. Materials and methods, We studied saliva DHEA and cortisol concentrations before, during (day 1,day 7) and following (day 8,day 16) the administration of oral therapeutic doses of prednisone (50 mg daily for 1 week) in 11 healthy recreationally trained women. Results, Mean saliva DHEA and cortisol concentrations decreased immediately after the start of prednisone treatment (P < 0·05). Three days after concluding prednisone administration, both saliva DHEA and cortisol had returned to pretreatment levels. Conclusions, These data are consistent with previous studies on blood samples and suggest that non-invasive saliva samples may offer a practical approach to assessing pituitary-adrenal function continuously during and after short-term corticosteroid therapy. [source] Coronary Vasoconstrictor Potential of Triptans: A Review of In Vitro Pharmacologic DataHEADACHE, Issue 2004Antoinette MaassenVanDenBrink PhD This article reviews the in vitro pharmacology of the triptans in human isolated coronary arteries. As expected, based on their similar pharmacologic profiles, the triptans cannot be easily differentiated with respect to effects at human isolated coronary arteries. Furthermore, the data show that at therapeutically relevant concentrations, triptans have little potential to cause clinically significant constriction of nondiseased coronary arteries. These data, considered in the context of clinical findings reviewed elsewhere in this supplement, support the conclusion that, while all triptans have the potential to produce small contractions of human isolated coronary arteries, their craniovascular selectivity, when used at therapeutic doses, renders them unlikely to cause serious adverse coronary events in patients with healthy coronary arteries. [source] Mitochondrial protection by the JNK inhibitor leflunomide rescues mice from acetaminophen-induced liver injury,HEPATOLOGY, Issue 2 2007Calivarathan Latchoumycandane Acetaminophen (APAP) is a widely used analgesic and antipyretic drug that is safe at therapeutic doses but which can precipitate liver injury at high doses. We have previously found that the antirheumatic drug leflunomide is a potent inhibitor of APAP toxicity in cultured human hepatocytes, protecting them from mitochondria-mediated cell death by inhibiting the mitochondrial permeability transition. The purpose of this study was to explore whether leflunomide protects against APAP hepatotoxicity in vivo and to define the molecular pathways of cytoprotection. Male C57BL/6 mice were treated with a hepatotoxic dose of APAP (750 mg/kg, ip) followed by a single injection of leflunomide (30 mg/kg, ip). Leflunomide (4 hours after APAP dose) afforded significant protection from liver necrosis as assessed by serum ALT activity and histopathology after 8 and 24 hours. The mechanism of protection by leflunomide was not through inhibition of cytochrome P450 (CYP),catalyzed APAP bioactivation or an apparent suppression of the innate immune system. Instead, leflunomide inhibited APAP-induced activation (phosphorylation) of c-jun NH2 -terminal protein kinase (JNK), thus preventing downstream Bcl-2 and Bcl-XL inactivation and protecting from mitochondrial permeabilization and cytochrome c release. Furthermore, leflunomide inhibited the APAP-mediated increased expression of inducible nitric oxide synthase and prevented the formation of peroxynitrite, as judged from the absence of hepatic nitrotyrosine adducts. Even when given 8 hours after APAP dose, leflunomide still protected from massive liver necrosis. Conclusion: Leflunomide afforded protection against APAP-induced hepatotoxicity in mice through inhibition of JNK-mediated activation of mitochondrial permeabilization. (HEPATOLOGY 2007.) [source] Lack of effects between rupatadine 10,mg and placebo on actual driving performance of healthy volunteersHUMAN PSYCHOPHARMACOLOGY: CLINICAL AND EXPERIMENTAL, Issue 5 2007Eric Vuurman Abstract Introduction Rupatadine fumarate is a potent, selective, histamine H1 -receptor antagonist and PAF inhibitor with demonstrated efficacy for the relief of allergic rhinitis. Rupatadine does not easily cross the blood,brain barrier and is believed to be non-sedating at therapeutic doses. Consequently, rupatadine should show no impairment on car driving. Objective This study compared the acute effects of rupatadine, relative to placebo and hydroxyzine (as an active control), on healthy subjects' driving performance. Methods Twenty subjects received a single dose of rupatadine 10,mg, hydroxyzine 50,mg, or placebo in each period of this randomized, double-blind, three-way crossover study. Two hours postdosing, subjects operated a specially instrumented vehicle in tests designed to measure their driving ability. Before and after the driving tests ratings of sedation were recorded. Results There was no significant difference between rupatadine and placebo in the primary outcome variable: standard deviation of lateral position (SDLP); however, hydroxyzine treatment significantly increased SDLP (p,<,0.001 for both comparisons). Objective (Stanford sleepiness scale) and subjective sedation ratings (Visual Analogue Scales) showed similar results: subjects reported negative effects after hydroxyzine but not after rupatadine. Conclusion Rupatadine 10,mg is not sedating and does not impair driving performance. Copyright © 2007 John Wiley & Sons, Ltd. [source] Evaluation of the cognitive, psychomotor and pharmacokinetic profiles of rupatadine, hydroxyzine and cetirizine, in combination with alcohol, in healthy volunteersHUMAN PSYCHOPHARMACOLOGY: CLINICAL AND EXPERIMENTAL, Issue 1 2006Manuel J. Barbanoj Abstract Introduction The Central Nervous System (CNS) impairment induced by moderate alcohol (ALC) ingestion may be enhanced if other drugs are taken simultaneously. Rupatadine (RUP) is a new H1 -antihistamine which also inhibits platelet activating factor (PAF) release in inflammatory reactions. Objective The main aim of the study was to assess the effects of ALC 0.8,g/Kg on RUP (10,mg and 20,mg) CNS effects. An evaluation of alcohol and RUP pharmacokinetics was also attained. Methods Eighteen healthy young volunteers of both sexes participated in a phase I, randomised, crossover, double-blind, placebo-controlled study. At 2-week intervals they received six treatments: (a) placebo (PLA), (b) ALC alone and ALC in combination with: (c) hydroxyzine 25,mg (HYD), (d) cetirizine 10,mg (CET), (e) RUP 10,mg or (f) RUP 20,mg. At baseline and several times thereafter, seven psychomotor performance tests (finger tapping, fine motoric skills, nystagmus, temporal estimation, critical-flicker-fusion frequency, ,d2' cancellation, simple reaction) and eleven subjective self-reports (drunkenness, sleepiness, alertness, clumsiness, anger, inattentiveness, efficiency, happiness, hostility, interest and extraversion) were carried out. Two-way (treatment, time) ANOVAs for repeated measures to each variable together with a multivariate non-parametric approach were applied. Plasma concentrations of alcohol, and of RUP and its metabolites, were quantified by validated immunofluorescence and LC/MS/MS methods, respectively. Plasma-time curves for all compounds were analysed by means of model-independent methods. Results The combination of alcohol with HYD, CET and RUP 20,mg produced more cognitive and psychomotor impairment as compared to alcohol alone, being the combination of alcohol and HYD the one which induced the greatest deterioration. The combination of alcohol and RUP 10,mg could not be differentiated from ALC alone. Subjective self-reports reflect effects on metacognition after the combination of alcohol with HYD and CET i.e. the increased objective impairment observed was not subjectively perceived by the subjects. No significant differences were obtained when comparing alcohol plasma concentrations assessed after the treatments evaluated. RUP showed a lineal kinetic relationship after 10 and 20,mg with a higher exposition to both metabolites assayed. Conclusions Present results showed that single oral doses of rupatadine 10,mg in combination with alcohol do not produce more cognitive and psychomotor impairment than alcohol alone. Higher doses of rupatadine, in combination with alcohol, may induce cognitive and psychomotor deterioration as hydroxyzine and cetirizine at therapeutic doses. Copyright © 2006 John Wiley & Sons, Ltd. [source] Cardiovascular mortality and morbidity in chronic obstructive pulmonary disease: the impact of bronchodilator treatmentINTERNAL MEDICINE JOURNAL, Issue 2 2010R. Wood-Baker Abstract Chronic obstructive pulmonary disease (COPD) is a substantial health burden. Cardiovascular disease (CVD), the leading cause of death, frequently coexists with COPD, an effect attributed to high individual disease prevalences and shared risk factors. It has long been recognized that COPD, whether stable or during acute exacerbations, is associated with an excess of cardiac arrhythmias. Bronchodilator medications have been implicated in the excess CVD seen in COPD, either as an intrinsic medication effect or related to side-effects. Despite the theory behind increased pro-arrhythmic effects in COPD, the reported results of trials investigating this for inhaled formulations at therapeutic doses are few. Methodological flaws, retrospective analysis and inadequate adjustment for concomitant medications, including short-acting ,relief' bronchodilators and non-respiratory medications with known arrhythmia propensity, mar many of these studies. For most bronchodilators at therapeutic levels in stable COPD, we can be reassured of their safety from current studies. The exception to this is ipratropium bromide, where the current data indicate an association with increased cardiovascular adverse effects. Moreover, there is no proven benefit from combining short-acting beta-agonists with short-acting anticholinergics at high doses in the acute setting, and although this practice is widespread, it is associated with increased cardiovascular risk. [source] Effects of lithium carbonate on rat seminiferous tubules: an ultrastructural studyINTERNATIONAL JOURNAL OF ANDROLOGY, Issue 6 2006O. Zarnescu Summary Lithium salts are commonly used for treatment of bipolar disorder but prolonged treatment with therapeutic doses induces substantial toxic effects. In the present study we examined the effects of lithium carbonate on the ultrastructure of rat seminiferous tubules. Rats were exposed to lithium carbonate at doses of 35 mg/kg/day for 21 days. After lithium treatment, the tunica propria widened and folded together with convolutions of the basement membrane, myoid cells and lymphatic endothelium. In the seminiferous epithelium loss of germ cell attachment and appearance of expanded intercellular spaces between spermatogenic cells were observed. Early stages of spermatogenic cells showed nuclear protrusions or swellings because of an extensive enlargement of the outer nuclear membrane. Round spermatids exhibited abnormally shaped acrosomes and dilation of the subacrosomal space. Many abnormal, degenerated late spermatids with random orientation were seen towards the basal and adluminal compartments of the seminiferous epithelium. In addition, spermatids exhibited alteration in F-actin bundle ectoplasmic specialization and contained many mitochondria-associated granular bodies. [source] CNTO 859, a humanized anti-tissue factor monoclonal antibody, is a potent inhibitor of breast cancer metastasis and tumor growth in xenograft modelsINTERNATIONAL JOURNAL OF CANCER, Issue 6 2007Cam V. Ngo Abstract Thromboembolic complications are frequently associated with advanced cancer. Interestingly, one of the major initiators of blood coagulation, tissue factor (TF), is reported to be overexpressed in several tumor types and can be found on both tumor cells and tumor vasculature. Although the exact mechanisms have yet to be elucidated, TF expressed on tumor cells can trigger intracellular signaling events through various pathways that can lead to tumor angiogenesis, proliferation, and metastasis. There exists preclinical evidence that disruption of TF dependent signaling can effectively inhibit tumor cell migration, metastasis, and angiogenesis. Here, we report for the first time that an antibody to tissue factor can also prevent tumor growth in vivo. Prophylactic administration of CNTO 859, a humanized anti-human TF antibody, was shown to inhibit experimental lung metastasis of MDA-MB-231 human breast carcinoma cells by over 99% compared to a control antibody. Furthermore, therapeutic doses of CNTO 859 were shown to reduce tumor incidence and growth of orthotopically implanted MDA-MB-231 cells. © 2006 Wiley-Liss, Inc. [source] Pharmacokinetics of a novel transdermal rivastigmine patch for the treatment of Alzheimer's disease: a reviewINTERNATIONAL JOURNAL OF CLINICAL PRACTICE, Issue 5 2009A. Kurz Summary Background:, Cholinesterase inhibitors have all been available in oral formulations, but a rivastigmine transdermal patch has now been developed and is approved in many countries worldwide for the treatment of mild-to-moderate Alzheimer's disease (AD) (including the USA, Latin America, Europe and Asia). Objectives:, To review the available pharmacokinetic data that supported the rationale behind the development of the rivastigmine transdermal patch and its clinical effects in dementia therapy. This article will also discuss how the patch may alter the treatment paradigm for patients with AD. Results:, The 9.5 mg/24 h rivastigmine patch was shown to provide comparable exposure to the highest recommended doses of capsules (12 mg/day) with significantly lower maximum plasma concentration (Cmax 8.7 vs. 21.6 ng/ml) and slower absorption rate (tmax 8.1 vs. 1.4 h). In a clinical trial of 1195 AD patients, this translated into similar efficacy with three times fewer reports of nausea and vomiting (7.2% vs. 23.1%, and 6.2% vs. 17.0% respectively). Consequently, more patients in the 9.5 mg/24 h patch group achieved their target therapeutic dose at the end of the study, compared with those in the 12 mg/day capsule group (95.9% vs. 64.4%). Conclusion:, The rivastigmine patch provides continuous drug delivery over 24 h and similar efficacy to the highest recommended dose of oral rivastigmine with improved tolerability. This may allow patients to achieve optimal therapeutic doses and to benefit from a longer duration of treatment. [source] Ranolazine Exerts Potent Effects on Atrial Electrical Properties and Abbreviates Atrial Fibrillation Duration in the Intact Porcine HeartJOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY, Issue 7 2009KAPIL KUMAR M.D. Introduction: In vitro studies and ambulatory ECG recordings from the MERLIN TIMI-36 clinical trial suggest that the novel antianginal agent ranolazine may have the potential to suppress atrial arrhythmias. However, there are no reports of effects of ranolazine on atrial electrophysiologic properties in large intact animals. Methods and Results: In 12 closed-chest anesthetized pigs, effects of intravenous ranolazine (,9 ,M plasma concentration) on multisite atrial effective refractory period (ERP), conduction time (CT), and duration and inducibility of atrial fibrillation (AF) initiated by intrapericardial acetylcholine were investigated. Ranolazine increased ERP by a median of 45 ms (interquartile range 29,50 ms; P < 0.05, n = 6) in right and left atria compared to control at pacing cycle length (PCL) of 400 ms. However, ERP increased by only 28 (24,34) ms in right ventricle (P < 0.01, n = 6). Ranolazine increased atrial CT from 89 (71,109) ms to 98 (86,121) ms (P = 0.04, n = 6) at PCL of 400 ms. Ranolazine decreased AF duration from 894 (811,1220) seconds to 621 (549,761) seconds (P = 0.03, n = 6). AF was reinducible in 1 of 6 animals after termination with ranolazine compared with all 6 animals during control period (P = 0.07). Dominant frequency (DF) of AF was reduced by ranolazine in left atrium from 11.7 (10.7,20.5) Hz to 7.6 (2.9,8.8) Hz (P = 0.02, n = 6). Conclusions: Ranolazine, at therapeutic doses, increased atrial ERP to greater extent than ventricular ERP and prolonged atrial CT in a frequency-dependent manner in the porcine heart. AF duration and DF were also reduced by ranolazine. Potential role of ranolazine in AF management merits further investigation. [source] Paracetamol hepatotoxicity at therapeutic dosesJOURNAL OF INTERNAL MEDICINE, Issue 2 2003S. Vitols First page of article [source] | |||||||||||||||||||||||||||||||||||||