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Maintenance Dose (maintenance + dose)
Selected AbstractsAbuse liability of intravenous buprenorphine/naloxone and buprenorphine alone in buprenorphine-maintained intravenous heroin abusersADDICTION, Issue 4 2010Sandra D. Comer ABSTRACT Background Sublingual buprenorphine is an effective maintenance treatment for opioid dependence, yet intravenous buprenorphine misuse occurs. A buprenorphine/naloxone formulation was developed to mitigate this misuse risk. This randomized, double-blind, cross-over study was conducted to assess the intravenous abuse potential of buprenorphine/naloxone compared with buprenorphine in buprenorphine-maintained injection drug users (IDUs). Methods Intravenous heroin users (n = 12) lived in the hospital for 8,9 weeks and were maintained on each of three different sublingual buprenorphine doses (2 mg, 8 mg, 24 mg). Under each maintenance dose, participants completed laboratory sessions during which the reinforcing and subjective effects of intravenous placebo, naloxone, heroin and low and high doses of buprenorphine and buprenorphine/naloxone were examined. Every participant received each test dose under the three buprenorphine maintenance dose conditions. Results Intravenous buprenorphine/naloxone was self-administered less frequently than buprenorphine or heroin (P < 0.0005). Participants were most likely to self-administer drug intravenously when maintained on the lowest sublingual buprenorphine dose. Subjective ratings of ,drug liking' and ,desire to take the drug again' were lower for buprenorphine/naloxone than for buprenorphine or heroin (P = 0.0001). Participants reported that they would pay significantly less money for buprenorphine/naloxone than for buprenorphine or heroin (P < 0.05). Seven adverse events were reported; most were mild and transient. Conclusions These data suggest that although the buprenorphine/naloxone combination has intravenous abuse potential, that potential is lower than it is for buprenorphine alone, particularly when participants received higher maintenance doses and lower buprenorphine/naloxone challenge doses. Buprenorphine/naloxone may be a reasonable option for managing the risk for buprenorphine misuse during opioid dependence treatment. [source] Methadone doses of 100 mg or greater are more effective than lower doses at suppressing heroin self-administration in opioid-dependent volunteersADDICTION, Issue 10 2005Eric C. Donny ABSTRACT Aims Methadone maintenance has been an effective pharmacotherapy for the treatment of heroin dependence for nearly four decades. Recent clinical research suggests that methadone doses larger than those used in most clinics are more effective at suppressing illicit heroin use. This greater efficacy may result from greater cross-tolerance to the reinforcing effects of heroin. Design The purpose of this double-blind, within-subject study was to examine the relationship between methadone maintenance dose and the reinforcing effects of heroin. Setting Participants were stabilized on 50, 100 and 150 mg methadone (ascending order) during separate outpatient periods before being admitted to an inpatient research unit for testing at each maintenance dose. Participants Five opiate-dependent volunteers completed the study. Measurements During each 4-week inpatient testing period, participants sampled three doses of heroin (0, 10, or 20 mg; random order; one dose per week) and were subsequently allowed seven opportunities to choose between another injection of that week's heroin dose and varying amounts of money ($2,38). Findings The number of heroin injections chosen decreased as methadone dose was increased. Larger alternative monetary reinforcers were required to suppress heroin self-administration during maintenance on 50 compared to 100 or 150 mg methadone. Larger methadone doses also completely blocked the subjective effects of heroin and produced greater withdrawal suppression during the outpatient periods. Conclusions These results support other clinical and laboratory-based research indicating that persistent heroin use may be reduced by providing larger methadone maintenance doses that produce more effective cross-tolerance to heroin. [source] Catechol-O-methyltransferase val108/158met genotype and response to antipsychotic medication in schizophreniaHUMAN PSYCHOPHARMACOLOGY: CLINICAL AND EXPERIMENTAL, Issue 4 2007Ari Illi Abstract Catechol-O-methyltransferase (COMT) gene has been investigated as a possible candidate gene in schizophrenia. The most studied polymorphism has been the functional val108/158met polymorphism of this COMT gene. There is also some evidence that this polymorphism could be related to drug response to antipsychotics in schizophrenia. COMT enzyme inactivates dopamine and noradrenaline. Based mainly on the original dopamine theory of schizophrenia, our primary hypothesis was that the maintenance dose of antipsychotics would be higher in patients with the low activity COMT genotype. In this study we evaluated the current daily dosage of antipsychotics in 180 patients with schizophrenia in connection with the COMT genotype. We could not demonstrate any clearly significant effect of this particular COMT genotype in relation to the daily maintenance dosages of antipsychotics in patients with schizophrenia. Copyright © 2007 John Wiley & Sons, Ltd. [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] Severe antibody-mediated agranulocytosisINTERNATIONAL JOURNAL OF LABORATORY HEMATOLOGY, Issue 1 2008H. JOHNSEN Summary A 56-year-old female with Crohn's disease was admitted to the hospital with malaise, fever, and a low white blood cell count (0.8 × 109/l) with no granulocytes or myeloid precursor cells in the bone marrow. The leucopenia was initially thought to be the result of an infection and she was treated with antibiotics and granulocyte colony-stimulating factor (G-CSF, filgrastim). However, the bacterial cultures and viral tests were all negative. The patient's condition deteriorated and she became morbidly ill, but recovered after high dose steroid treatment. Six weeks later she relapsed whilst receiving 7.5 mg daily dose of prednisolone. She recovered quickly after being given high dose methylprednisolone in combination with filgrastim. A high maintenance dose of prednisolone was tapered over 5 months. She has not relapsed since and is currently well. Antibodies to the human neutrophil antigen (HNA)-3a were detected, but these antibodies could not easily explain her agranulocytosis as she had a HNA-3a negative phenotype. It seems plausible that her agranulocytosis was immune mediated through autoantibodies directed towards the early myeloid cells. [source] Effects of dexmedetomidine or methylprednisolone on inflammatory responses in spinal cord injuryACTA ANAESTHESIOLOGICA SCANDINAVICA, Issue 8 2009M. CAN Background: The aim of this study was to compare the anti-inflammatory response of methylprednisolone and the ,2-agonist dexmedetomidine in spinal cord injury (SCI). Methods: Twenty-four male adult Wistar albino rats, weight 200,250 g, were included in the study. The rats were divided into four groups as follows: the control group (n: 6) received only laminectomy; the SCI group (n: 6) with trauma alone; the SCI+methylprednisolone group (n: 6) with trauma and 30 mg/kg methylprednisolone, followed by a maintenance dose of 5.4 mg/kg/h; and the SCI+dexmedetomidine group (n: 6) with trauma and 10 ,g/kg dexmedetomidine treatment intraperitoneally. Twenty-four hours after the trauma, spinal cord samples were taken for histopathological examination and serum samples were collected for interleukin-6 (IL-6) and tumor necrosis factor (TNF)-, measurement. Results: TNF-, (P=0.009) and IL-6 (P=0.009) levels were significantly increased in the SCI group. TNF-, and IL-6 levels were significantly decreased with methylprednisolone (P=0.002, 0.002) and dexmedetomidine (P=0.002, 0.009) treatment, respectively. Methylprednisolone and dexmedetomidine treatment reduced neutrophils' infiltration in SCI. Conclusions: The current study does not clarify the definitive mechanism by which dexmedetomidine decreases inflammatory cytokines but it is the first study to report the anti-inflammatory effect of dexmedetomidine in SCI. Further studies are required to elucidate the effects of dexmedetomidine on the inflammatory response. [source] Effect of an increased clopidogrel maintenance dose or lansoprazole co-administration on the antiplatelet response to clopidogrel in CYP2C19-genotyped healthy subjectsJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 3 2010J.-S. HULOT First page of article [source] The pharmacokinetics and pharmacodynamics of alfaxalone in cats after single and multiple intravenous administration of Alfaxan® at clinical and supraclinical dosesJOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 6 2008T. WHITTEM This study aimed to determine the pharmacokinetic parameters and pharmacodynamics of alfaxalone in a 2-hydroxypropyl-,-cyclodextrin alfaxalone formulation (Alfaxan®, Jurox Pty Ltd, Rutherford, NSW, Australia) in cats after single administration at clinical and supraclinical dose rates and as multiple maintenance doses. First, a prospective two-period cross-over study was conducted at single clinical and supraclinical doses. Second, a single group multiple dose study evaluated the effect of maintenance doses. Eight (five female and three male) domestic cats completed the cross-over experiment and six female cats completed the multiple dose study. In the first experiment, alfaxalone was administered intravenously (IV) at 5 or 25 mg/kg with a washout period of 14 days. In the second experiment, alfaxalone was administered IV at 5 mg/kg followed by four doses each of 2 mg/kg, administered at onset of responsiveness to a noxious stimulus. Blood was collected at prescribed intervals and analysed by LCMS for plasma alfaxalone concentration. Noncompartmental pharmacokinetics were used to analyse the plasma alfaxalone data. The plasma clearance of alfaxalone at 5 and 25 mg/kg differed statistically at 25.1 and 14.8 mL/kg/min respectively. The elimination half lives were 45.2 and 76.6 min respectively. Alfaxalone has nonlinear pharmacokinetics in the cat. Nevertheless, for cats dosed with sequential maintenance doses, a regression line through their peak plasma concentrations indicated that there was no clinically relevant pharmacokinetic accumulation. The duration of nonresponsiveness after each maintenance dose was similar at approximately 6 min, indicating a lack of accumulation of pharmacodynamic effect. The cardiovascular and respiratory parameters measured in cats after administration of the labelled doses of Alfaxan® were stable. In conclusion, the pharmacokinetics of alfaxalone in cats are nonlinear. At clinical dose rates, however, neither alfaxalone nor its effects accumulated to a clinically relevant extent. Further, in the un-premedicated cat the induction and maintenance of surgical anaesthesia was free of untoward events after a dose of 5 mg alfaxalone/kg body weight followed by four sequential doses of 2 mg/kg as needed (i.e., approximately 7 to 8 mg/kg/h). [source] EU Forum: The CREATE Project: development of certified reference materials for allergenic products and validation of methods for their quantificationALLERGY, Issue 3 2008R. Van Ree Allergen extracts have been used for diagnosis and treatment of allergy for around 100 years. During the second half of 20th century, the notion increasingly gained foothold that accurate standardization of such extracts is of great importance for improvement of their quality. As a consequence, manufacturers have implemented extensive protocols for standardization and quality control. These protocols have overall IgE-binding potencies as their focus. Unfortunately, each company is using their own in-house reference materials and their own unique units to express potencies. This does not facilitate comparison of different products. During the last decades, most major allergens of relevant allergen sources have been identified and it has been established that effective immunotherapy requires certain minimum quantities of these allergens to be present in the administered maintenance dose. Therefore, the idea developed to introduce major allergens measurements into standardization protocols. Such protocols based on mass units of major allergen, quantify the active ingredients of the treatment and will at the same time allow comparison of competitor products. In 2001, an EU funded project, the CREATE project, was started to support introduction of major allergen based standardization. The aim of the project was to evaluate the use of recombinant allergens as reference materials and of ELISA assays for major allergen measurements. This paper gives an overview of the achievements of the CREATE project. [source] Effect of grass pollen immunotherapy with Alutard SQ® on quality of life in seasonal allergic rhinoconjunctivitisALLERGY, Issue 11 2007R. J. Powell Background:, Treatment of allergic rhinitis with subcutaneous allergen immunotherapy is effective in terms of reductions in symptoms and seasonal use of reliever medication. Its effect on quality of life (QoL), reflecting the impact of symptoms on work/school performance and leisure activities is, however, important and often overlooked. Aims of the study:, To assess effect on QoL of specific immunotherapy with two doses of Alutard SQ®Phleum pratense in patients with moderately to severe seasonal allergic rhinoconjunctivitis inadequately controlled by standard drug therapy. Methods:, Double-blind, randomized, placebo-controlled study of 410 patients with seasonal allergic rhinoconjunctivitis. Participants were randomized (2 : 1 : 1) to receive Alutard SQ®P. pratense (ALK-Abelló) at maintenance doses of 100 000 SQ-U (203 subjects), 10 000 SQ-U (104 subjects) or placebo (103 subjects) given by subcutaneous injections. The groups were well matched for demographics and baseline symptoms. Quality of life was assessed using the Rhinoconjunctivitis Quality of Life Questionnaire which covers seven domains of health before and in the peak of the pollen season. Results:, While all domain scores were significantly improved when comparing 100 000 SQ-U with placebo, two domain scores were significantly improved when comparing 10 000 SQ-U with placebo. When comparing 100 000 SQ-U with 10 000 SQ-U, four domain scores were significantly improved. Conclusion:, Treatment with Alutard SQ® significantly improved the seasonal QoL of patients suffering from allergic rhinoconjunctivitis. The improvement was more pronounced and wider ranging in patients who received the higher 100 000 SQ-U maintenance dose. [source] Association of age, gender, and weight on maintenance dose of intravenous unfractionated heparin,AMERICAN JOURNAL OF HEMATOLOGY, Issue 8 2010Siddharth Verma No abstract is available for this article. [source] Latest news and product developmentsPRESCRIBER, Issue 21 2008Article first published online: 2 DEC 200 Osteoporosis guideline A new guideline on the management of osteoporosis in men over 50 and post-menopausal women has been published by the National Osteoporosis Guideline Group (www.shef.ac.uk/NOGG), a group of organisations representing health professionals and patients, with funding from several pharmaceutical companies. The guideline recommends using the FRAX tool (www.shef.ac.uk/FRAX) to assess the 10-year fracture risk in individuals with risk factors to facilitate targeting DXA scans to measure bone mineral density. Patients who have already sustained a fragility fracture should be treated without risk assessment. Treatment recommendations are similar to those published in draft NICE guidance on primary and secondary prevention, selecting alendronate as the drug of first choice for most patients. Efalizumab efficacy A multicentred postapproval trial has demonstrated long-term efficacy and a favourable safety profile for efalizumab (Raptiva) in moderate to severe chronic plaque psoriasis. The CONTROL II study, presented in September at the 17th EADV congress in Paris, was conducted at 170 sites in 18 European countries and involved 1255 patients who had failed to respond to traditional systemic therapies. In this non-blinded study, 68 per cent of participants achieved the primary efficacy end-point and showed improvement within the first 12 weeks; control was maintained in responding patients who continued treatment. Adverse effects were graded as mild or moderate and similar to those reported in earlier studies. There was no evidence of an increase in malignancies or infections. New oral anticoagulant Rivaroxaban (Xarelto), an oral factor Xa inhibitor, has been introduced for the prevention of venous thrombo-embolism in patients undergoing elective hip or knee replacement surgery. Compared with the low molecular weight heparin enoxaparin (Clexane), rivaroxaban has been shown to reduce the risk of venous thrombosis by 70 per cent after hip replacement and by 49 per cent after knee replacement; the risk of bleeding was similar. At the recommended dose of 10mg once daily, prophylaxis after hip surgery lasts five weeks and costs £157; prophylaxis after knee surgery lasts two weeks and costs £63. New products UCB Pharma has introduced lacosamide (Vimpat) as adjunctive treatment of partial-onset epilepsy with or without secondary generalisation in patients aged 16 and over. A month's treatment at the recommended maintenance dose of 100-200mg twice daily costs approximately £73-£140. A new non-nucleoside reverse transcriptase inhibitor (NNRI) is available for the treatment of HIV-1 infection in combination with a boosted protease inhibitor (PI) and other antiretrovirals in treatment-experienced adults. Etravirine (Intelence) costs approximately £320 for one month's treatment at the recommended dose of 200mg twice daily. Voltarol Pain-Eze (diclofenac) 12.5mg tablets are now available without prescription; a pack of 18 tablets costs £5.99. Atypicals and EPS risk Atypical antipsychotics are not associated with a significantly lower risk of extra-pyramidal symptoms than first-generation agents such as perphenazine (Fentazin), a new analysis of the CATIE study has shown (Br J Psychiatry 2008;193:279,88). CATIE was a large trial comparing the efficacy and safety of antipsychotics in the treatment of schizophrenia in which perphenazine was a representative first-generation agent (Am J Psychiatry 2006;163:611,22). This analysis found no differences in the risk of parkinsonism, dystonia, akathisia or tardive dyskinesia between perphenazine and the newer antipsychotics; use of antiparkinsonian medication was higher with risperidone and lower with quetiapine (Seroquel). Mental health website A new website offering information about mental illnesses and drug treatment has been launched by the United Kingdom Psychiatric Pharmacy Group (UKPPG), the College of Mental Health Pharmacists (CMHP), the Pharmaceutical Schizo-phrenia Initiative (PSI) and the National Institute for Mental Health in England (NIMHE). www.choiceandmedication.org.uk includes information about 17 mental illnesses and a large number of drug treatments. It offers links to other sites offering information and downloadable leaflets, help to identify the local mental health trust and downloadable charts comparing treatments for each indication. [source] Pharmacokinetic interaction of nelfinavir and methadone in intravenous drug usersBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 2 2006Poe-Hirr Hsyu Abstract The effect of nelfinavir 1250 mg twice daily (b.i.d.) on the pharmacokinetics of methadone was determined in 14 HIV-negative methadone users. Design: The methadone dose (20,140 mg/day) was stabilized and fixed for at least 1 month before nelfinavir (1250 mg b.i.d. for 8 days) was added to the regimen. The concentrations of methadone enantiomers were measured before and during nelfinavir treatment, and the concentrations of nelfinavir and its active metabolite, AG1402, were measured during nelfinavir treatment. Adverse events and withdrawal/intoxication symptoms were monitored throughout the study. Results: Nelfinavir reduced the area under the concentration-time curve of R-methadone, and S-methadone by 43% and 51%, respectively. Nelfinavir and AG1402 concentrations were within the normal range of historical data, and no subject experienced withdrawal symptoms during the study or required dose adjustment during or after the study. Conclusions: Although nelfinavir reduced the plasma concentrations of both R- and S-methadone, it seems to have no impact on the maintenance dose of methadone. A routine reduction of methadone dose is not recommended when coadministered with nelfinavir. Copyright © 2005 John Wiley & Sons, Ltd. [source] A phase II trial of arsenic trioxide in patients with metastatic melanomaCANCER, Issue 8 2005Kevin B. Kim M.D. Abstract BACKGROUND Arsenic trioxide induces growth inhibition and apoptosis in human melanoma cell lines. Therefore, a Phase II trial was conducted to evaluate the efficacy and toxicity of single-agent arsenic trioxide in patients with Stage IV melanoma. METHODS Twenty patients, 10 with metastatic melanoma of cutaneous origin and 10 with metastatic melanoma of choroidal origin, received arsenic trioxide 0.25 mg/kg/day for 5 days, followed by a maintenance dose of 0.35 mg/kg/day twice a week. All patients with melanoma of cutaneous origin and four patients with melanoma of choroidal origin had received prior therapy. RESULTS Single-agent arsenic trioxide did not induce clinical response in this patient population. Eight patients (five with melanoma of cutaneous origin, and three with melanoma of choroidal origin) had disease stabilization for at least six weeks. The median overall survival duration for patients with melanoma of cutaneous origin was 7.9 months, and that of patients with melanoma of choroidal origin has not been reached at a median follow-up duration of 11.8 months. Grade 3 toxicity included neutropenia, fatigue, abdominal pain, and arthralgia. Grade 4 toxicity did not occur. CONCLUSIONS Single-agent arsenic trioxide was generally well tolerated; however, no tumor regression was observed in this patient population. Future clinical trials should evaluate arsenic trioxide in combination with other anticancer drugs that may improve its clinical activity in melanoma. Cancer 2005. © 2005 American Cancer Society. [source] Use of inhaled nitric oxide in the new born period: results from the European inhaled nitric oxide registryACTA PAEDIATRICA, Issue 6 2010Chris Dewhurst Abstract Aims:, The aim of this study was to present data relating to the use of inhaled nitric oxide (iNO) in newborn infants included in the European Inhaled Nitric Oxide Registry. Methods:, Demographic, clinical and therapeutic data from seven European centres are reported. Univariate analyses were performed to identify factors associated with acute response to iNO and survival without extra corporeal membrane oxygenation (ECMO). Results:, A total of 112 newborn infants received iNO, with 40% being less than 34 weeks gestational age. The commonest indication for iNO was secondary pulmonary hypertension. Acute response to iNO was more common in infants with a higher oxygenation index (median OI 32.7 vs 22.6, p = 0.040), although acute response did not predict survival without ECMO. Infants who survived without ECMO had a lower OI prior to therapy (median OI 24 vs 43, p = 0.009), were commenced on a higher starting dose (median dose 20 ppm vs 10 ppm p = 0.013) and received a lower maintenance dose (median dose 10 vs 17 ppm, p = 0.027) than those who died or received ECMO. Conclusion:, Collating and reporting data about iNO therapy in neonates across a number of European centres using a web-based system is feasible. These data may be used to monitor the clinical use of iNO, identify adverse effects, generate research hypotheses and promote high standards in the clinical use of iNO. [source] Antiplatelet Strategies: Evaluating Their Current Role in the Setting of Acute Coronary SyndromesCLINICAL CARDIOLOGY, Issue S1 2008Eugene Braunwald Abstract Numerous clinical trials have established the value of antiplatelet therapies for acute coronary syndromes (ACS). Aspirin (ASA), thienopyridines (i.e., clopidogrel and ticlopidine) and GP IIb/IIIa antagonists comprise the major classes of antiplatelet therapies demonstrated to be of benefit in the treatment of ACS and for the prevention of thrombotic complications of percutaneous coronary intervention (PCI). Clopidogrel is beneficial when administered before and after PCI, and is more effective when combined with either ASA or GP IIb/IIIa inhibitors in preventing post-PCI complications, coronary subacute stent thrombosis, and thrombotic events in general. It is currently unclear whether a higher loading dose of clopidogrel (600 mg) is better than the standard loading dose (300 mg), how long therapy should continue, and which maintenance dose is optimal. The role of the GP IIb/IIIa antagonists in ACS is less clear due to conflicting data from several studies with different patient populations. Currently, it appears that the use of GP IIb/IIIa antagonists might be most beneficial in high-risk ACS patients scheduled to undergo PCI, who demonstrate non-ST-segment elevation myocardial infarction and elevated troponin levels. Copyright © 2008 Wiley Periodicals, Inc. [source] Tolerability, Safety, and Efficacy of ,-Blockade in Black Patients With Heart Failure in the Community Setting: Insights From a Large Prospective ,-Blocker RegistryCONGESTIVE HEART FAILURE, Issue 1 2007William T. Abraham MD Heart failure (HF) clinical trials suggest different responses of blacks and whites to ,-blockers. Differences between clinical trial and community settings may also have an impact. The Carvedilol Heart Failure Registry (COHERE) observed experience with carvedilol in 4280 patients with HF in a community setting. This analysis compares characteristics, outcomes, and carvedilol dosing of blacks and whites in COHERE. Compared with whites (n=3433), blacks (n=523) had more severe HF symptoms despite similar systolic function. At similar carvedilol maintenance doses, symptoms improved in 33% of blacks vs 28% of whites, while worsening in 10% and 11%, respectively (both nonsignificant), and HF hospitalization rates were reduced comparably in both groups (,58% vs ,56%, respectively; both P<.001). Incidence and hazard ratios of death were similar in blacks and whites (6.9% vs 7.5%, hazard ratio 1.2 vs 1.0, P=.276). Thus carvedilol was similarly effective in blacks and whites with HF in the community setting, consistent with carvedilol clinical trials. [source] Abuse liability of intravenous buprenorphine/naloxone and buprenorphine alone in buprenorphine-maintained intravenous heroin abusersADDICTION, Issue 4 2010Sandra D. Comer ABSTRACT Background Sublingual buprenorphine is an effective maintenance treatment for opioid dependence, yet intravenous buprenorphine misuse occurs. A buprenorphine/naloxone formulation was developed to mitigate this misuse risk. This randomized, double-blind, cross-over study was conducted to assess the intravenous abuse potential of buprenorphine/naloxone compared with buprenorphine in buprenorphine-maintained injection drug users (IDUs). Methods Intravenous heroin users (n = 12) lived in the hospital for 8,9 weeks and were maintained on each of three different sublingual buprenorphine doses (2 mg, 8 mg, 24 mg). Under each maintenance dose, participants completed laboratory sessions during which the reinforcing and subjective effects of intravenous placebo, naloxone, heroin and low and high doses of buprenorphine and buprenorphine/naloxone were examined. Every participant received each test dose under the three buprenorphine maintenance dose conditions. Results Intravenous buprenorphine/naloxone was self-administered less frequently than buprenorphine or heroin (P < 0.0005). Participants were most likely to self-administer drug intravenously when maintained on the lowest sublingual buprenorphine dose. Subjective ratings of ,drug liking' and ,desire to take the drug again' were lower for buprenorphine/naloxone than for buprenorphine or heroin (P = 0.0001). Participants reported that they would pay significantly less money for buprenorphine/naloxone than for buprenorphine or heroin (P < 0.05). Seven adverse events were reported; most were mild and transient. Conclusions These data suggest that although the buprenorphine/naloxone combination has intravenous abuse potential, that potential is lower than it is for buprenorphine alone, particularly when participants received higher maintenance doses and lower buprenorphine/naloxone challenge doses. Buprenorphine/naloxone may be a reasonable option for managing the risk for buprenorphine misuse during opioid dependence treatment. [source] Cardiac function and antiepileptic drug treatment in the elderly: A comparison between lamotrigine and sustained-release carbamazepineEPILEPSIA, Issue 8 2009Erik Saetre Summary Purpose:, To investigate the comparative effects of carbamazepine (CBZ) and lamotrigine (LTG) on electrocardiography (ECG) parameters in elderly patients with newly diagnosed epilepsy. Methods:,, The study was conducted in the Norwegian subcohort (n = 108) of an international randomized double-blind 40-week trial, which compared the efficacy and tolerability of LTG and sustained-release CBZ in patients aged 65 and older with newly diagnosed epilepsy. Target maintenance doses were 400 mg/day for CBZ and 100 mg/day for LTG, with adjustments based on clinical response. Patients with significant unpaced atrioventricular (AV) conduction defect were excluded. Resting 12-lead ECG recordings were made under standardized conditions at pretreatment (baseline) and at the 40-week study visit (treatment visit). Changes in QRS interval (primary endpoint), heart rate (HR), PQ, and QTc (HR-corrected QT) intervals were assessed and compared between groups. Results:, Of the 108 patients randomized, 33 discontinued prematurely because of adverse events (n = 24, none of which was cardiac) or other reasons (n = 9), and 15 were nonevaluable due to incomplete ECG data. None of the assessed ECG parameters differed significantly between groups at baseline. No significant ECG changes were recorded between baseline and treatment visit for QRS duration and QTc intervals, whereas HR fell and PQ intervals increased slightly on both treatments. However, there were no differences between groups in changes from baseline to treatment visit. There were no significant relationships between individual ECG changes and serum drug concentrations, except for QTc intervals, which decreased slightly with increasing CBZ concentrations. The proportion of patients with ECG parameters outside the normal range at treatment visit was similar to that recorded at baseline. Discussion:, Clinically significant ECG changes are not common during treatment with CBZ or LTG in elderly patients with no preexisting significant AV conduction defects. [source] Methadone doses of 100 mg or greater are more effective than lower doses at suppressing heroin self-administration in opioid-dependent volunteersADDICTION, Issue 10 2005Eric C. Donny ABSTRACT Aims Methadone maintenance has been an effective pharmacotherapy for the treatment of heroin dependence for nearly four decades. Recent clinical research suggests that methadone doses larger than those used in most clinics are more effective at suppressing illicit heroin use. This greater efficacy may result from greater cross-tolerance to the reinforcing effects of heroin. Design The purpose of this double-blind, within-subject study was to examine the relationship between methadone maintenance dose and the reinforcing effects of heroin. Setting Participants were stabilized on 50, 100 and 150 mg methadone (ascending order) during separate outpatient periods before being admitted to an inpatient research unit for testing at each maintenance dose. Participants Five opiate-dependent volunteers completed the study. Measurements During each 4-week inpatient testing period, participants sampled three doses of heroin (0, 10, or 20 mg; random order; one dose per week) and were subsequently allowed seven opportunities to choose between another injection of that week's heroin dose and varying amounts of money ($2,38). Findings The number of heroin injections chosen decreased as methadone dose was increased. Larger alternative monetary reinforcers were required to suppress heroin self-administration during maintenance on 50 compared to 100 or 150 mg methadone. Larger methadone doses also completely blocked the subjective effects of heroin and produced greater withdrawal suppression during the outpatient periods. Conclusions These results support other clinical and laboratory-based research indicating that persistent heroin use may be reduced by providing larger methadone maintenance doses that produce more effective cross-tolerance to heroin. [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] Pharmacokinetics and pharmacodynamics of prasugrel in subjects with moderate liver diseaseJOURNAL OF CLINICAL PHARMACY & THERAPEUTICS, Issue 5 2009D. S. Small PhD Summary Background and Objective:, Prasugrel is a thienopyridine antiplatelet agent under investigation for the prevention of atherothrombotic events in patients with acute coronary syndrome who undergo percutaneous coronary intervention. Patients with chronic liver disease are among those in the target population for prasugrel. As hepatic enzymes play a key role in formation of prasugrel's active metabolite, hepatic impairment could affect the safety and/or efficacy of prasugrel in such patients. Methods:, This was a parallel-design, open-label, multiple dose study of 30 subjects, 10 with moderate hepatic impairment (Child-Pugh Class B) and 20 with normal hepatic function. Prasugrel was administered orally as a 60-mg loading dose (LD) and daily 10-mg maintenance doses (MDs) for 5 days. Pharmacokinetic parameters (AUC0,t, Cmax and tmax) and maximal platelet aggregation (MPA) by light transmission aggregometry were assessed after the LD and final MD. Results and Discussion:, Exposure to prasugrel's active metabolite was comparable between healthy subjects and those with moderate hepatic impairment. Point estimates for the ratios of geometric least square means for AUC0,t and Cmax after the LD and last MD ranged from 0·91 to 1·14. MPA to 20 ,m ADP was similar between subjects with moderate hepatic impairment and healthy subjects for both the LD and MD. Prasugrel was well tolerated by all subjects, and adverse events were mild in severity. Conclusion:, Moderate hepatic impairment appears to have no effect on exposure to prasugrel's active metabolite. Furthermore, MPA results suggest that moderate hepatic impairment has little or no effect on platelet aggregation relative to healthy controls. Overall, these results suggest that a dose adjustment would not be required in moderately hepatically impaired patients taking prasugrel. [source] European Federation of Neurological Societies/Peripheral Nerve Society Guideline on management of chronic inflammatory demyelinating polyradiculoneuropathy: Report of a joint task force of the European Federation of Neurological Societies and the Peripheral Nerve Society , First RevisionJOURNAL OF THE PERIPHERAL NERVOUS SYSTEM, Issue 1 2010Joint Task Force of the EFNS, the PNS Background: Consensus guidelines on the definition, investigation, and treatment of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) have been published (J Peripher Nerv Syst 2005; 10: 220,228, Eur J Neurol 2006; 13: 326,332). Objectives: To revise these guidelines. Methods: Disease experts, including a representative of patients, considered references retrieved from MEDLINE and Cochrane Systematic Reviews published between August 2004 and July 2009 and prepared statements that were agreed in an iterative fashion. Recommendations: The Task Force agreed on Good Practice Points to define clinical and electrophysiological diagnostic criteria for CIDP with or without concomitant diseases and investigations to be considered. The principal treatment recommendations were: (i) intravenous immunoglobulin (IVIg) (Recommendation Level A) or corticosteroids (Recommendation Level C) should be considered in sensory and motor CIDP; (ii) IVIg should be considered as the initial treatment in pure motor CIDP (Good Practice Point); (iii) if IVIg and corticosteroids are ineffective, plasma exchange (PE) should be considered (Recommendation Level A); (iv) if the response is inadequate or the maintenance doses of the initial treatment are high, combination treatments or adding an immunosuppressant or immunomodulatory drug should be considered (Good Practice Point); (v) symptomatic treatment and multidisciplinary management should be considered (Good Practice Point). [source] The pharmacokinetics and pharmacodynamics of alfaxalone in cats after single and multiple intravenous administration of Alfaxan® at clinical and supraclinical dosesJOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 6 2008T. WHITTEM This study aimed to determine the pharmacokinetic parameters and pharmacodynamics of alfaxalone in a 2-hydroxypropyl-,-cyclodextrin alfaxalone formulation (Alfaxan®, Jurox Pty Ltd, Rutherford, NSW, Australia) in cats after single administration at clinical and supraclinical dose rates and as multiple maintenance doses. First, a prospective two-period cross-over study was conducted at single clinical and supraclinical doses. Second, a single group multiple dose study evaluated the effect of maintenance doses. Eight (five female and three male) domestic cats completed the cross-over experiment and six female cats completed the multiple dose study. In the first experiment, alfaxalone was administered intravenously (IV) at 5 or 25 mg/kg with a washout period of 14 days. In the second experiment, alfaxalone was administered IV at 5 mg/kg followed by four doses each of 2 mg/kg, administered at onset of responsiveness to a noxious stimulus. Blood was collected at prescribed intervals and analysed by LCMS for plasma alfaxalone concentration. Noncompartmental pharmacokinetics were used to analyse the plasma alfaxalone data. The plasma clearance of alfaxalone at 5 and 25 mg/kg differed statistically at 25.1 and 14.8 mL/kg/min respectively. The elimination half lives were 45.2 and 76.6 min respectively. Alfaxalone has nonlinear pharmacokinetics in the cat. Nevertheless, for cats dosed with sequential maintenance doses, a regression line through their peak plasma concentrations indicated that there was no clinically relevant pharmacokinetic accumulation. The duration of nonresponsiveness after each maintenance dose was similar at approximately 6 min, indicating a lack of accumulation of pharmacodynamic effect. The cardiovascular and respiratory parameters measured in cats after administration of the labelled doses of Alfaxan® were stable. In conclusion, the pharmacokinetics of alfaxalone in cats are nonlinear. At clinical dose rates, however, neither alfaxalone nor its effects accumulated to a clinically relevant extent. Further, in the un-premedicated cat the induction and maintenance of surgical anaesthesia was free of untoward events after a dose of 5 mg alfaxalone/kg body weight followed by four sequential doses of 2 mg/kg as needed (i.e., approximately 7 to 8 mg/kg/h). [source] Effect of grass pollen immunotherapy with Alutard SQ® on quality of life in seasonal allergic rhinoconjunctivitisALLERGY, Issue 11 2007R. J. Powell Background:, Treatment of allergic rhinitis with subcutaneous allergen immunotherapy is effective in terms of reductions in symptoms and seasonal use of reliever medication. Its effect on quality of life (QoL), reflecting the impact of symptoms on work/school performance and leisure activities is, however, important and often overlooked. Aims of the study:, To assess effect on QoL of specific immunotherapy with two doses of Alutard SQ®Phleum pratense in patients with moderately to severe seasonal allergic rhinoconjunctivitis inadequately controlled by standard drug therapy. Methods:, Double-blind, randomized, placebo-controlled study of 410 patients with seasonal allergic rhinoconjunctivitis. Participants were randomized (2 : 1 : 1) to receive Alutard SQ®P. pratense (ALK-Abelló) at maintenance doses of 100 000 SQ-U (203 subjects), 10 000 SQ-U (104 subjects) or placebo (103 subjects) given by subcutaneous injections. The groups were well matched for demographics and baseline symptoms. Quality of life was assessed using the Rhinoconjunctivitis Quality of Life Questionnaire which covers seven domains of health before and in the peak of the pollen season. Results:, While all domain scores were significantly improved when comparing 100 000 SQ-U with placebo, two domain scores were significantly improved when comparing 10 000 SQ-U with placebo. When comparing 100 000 SQ-U with 10 000 SQ-U, four domain scores were significantly improved. Conclusion:, Treatment with Alutard SQ® significantly improved the seasonal QoL of patients suffering from allergic rhinoconjunctivitis. The improvement was more pronounced and wider ranging in patients who received the higher 100 000 SQ-U maintenance dose. [source] Usefulness of specific immunotherapy in patients with atopic dermatitis and allergic sensitization to house dust mites: a multi-centre, randomized, dose,response studyALLERGY, Issue 2 2006T. Werfel Background:, The effect of specific immunotherapy (SIT) on eczema in atopic dermatitis is not known. Therefore, a multi-centre, randomized dose,response trial, double-blind with respect to the efficacy of a biologically standardized depot house dust mite preparation was performed. Methods:, Eighty-nine adults with a chronic course of atopic dermatitis, SCORAD ,40 and allergic sensitization to house dust mites [CAP-FEIA ,3] were included, of whom 51 completed the study. Subcutaneous SIT with a house dust mite preparation (Dermatophagoides pteronyssinus/D. farinae) applying maintenance doses of 20, 2000 and 20 000 SQ-U in weekly intervals for 1 year. The main outcome measures addressed the change of the SCORAD as average of the values after 9 and 12 months of SIT in comparison with the value at baseline. Results:, The SCORAD declined in the three dose groups in a dose-dependent manner (P = 0.0368, Jonckheere,Terpstra test) and was significantly lower in the two high-dose groups (2000, 20000 SQ-U) compared with the low-dose group of 20 SQ-U (P = 0.0379, U -test) after 1 year of SIT. The use of topical corticosteroids was significantly reduced with higher doses (P = 0.0007, Mantel,Haenszel chi-square test). Conclusions:, Allergen-SIT for 1 year with a house dust mite preparation is able to improve the eczema in patients with atopic dermatitis who are sensitized to house dust mite allergens and reduces the need for topical corticosteroids. SIT may be valuable in the treatment of this chronic skin disease. [source] Pilot Study: Noninvasive Monitoring of Oral Flecainide's Effects on Atrial Electrophysiology during Persistent Human Atrial Fibrillation Using the Surface ElectrocardiogramANNALS OF NONINVASIVE ELECTROCARDIOLOGY, Issue 2 2005Daniela Husser M.D. Background: The relation between flecainide's plasma level and its influence on human atrial electrophysiology during acute and maintenance therapy of atrial fibrillation (AF) is unknown. Therefore, this study determined flecainide plasma levels and atrial fibrillatory rate obtained from the surface ECG during initiation and early maintenance of oral flecainide in patients with persistent lone AF and assessed their relationship. Methods and Results: In 10 patients (5 males, mean age 63 ± 14 years, left atrial diameter 46 ± 3 mm) with persistent lone AF, flecainide was administered as a single oral bolus (day 1) followed by 200,400 mg/day (days 2,5). The initial 300 mg flecainide bolus resulted in therapeutic plasma levels in all patients (range 288,629 ng/ml) with no side effects. Flecainide plasma levels increased on day 3 and remained stable thereafter. Day 5 plasma levels were lower (508 ± 135 vs 974 ± 276 ng/ml, P = 0.009) in patients with daily mean flecainide doses of 200 mg compared to patients with higher maintenance doses. Fibrillatory rate obtained from the surface electrocardiogram measuring 378 ± 17 fpm at baseline was reduced to 270 ± 18 fpm (P < 0.001) after the flecainide bolus but remained stable thereafter. Fibrillatory rate reduction was independent of flecainide plasma levels or clinical variables. Conclusion: A 300 mg oral flecainide bolus is associated with electrophysiologic effects that are not increased during early maintenance therapy in persistent human lone AF. In contrast to drug plasma levels, serial analysis of fibrillatory rate allows monitoring of individual drug effects on atrial electrophysiology. [source] UR-3216: A Manageable Oral GPIIb/IIIa AntagonistCARDIOVASCULAR THERAPEUTICS, Issue 1 2001Kosuke Baba ABSTRACT UR-3216, a prodrug, is a novel, selective, and orally active platelet surface glycoprotein GPIIb/IIIa) receptor antagonist. The most important property of UR-3216 is the very tight binding of its active metabolite to platelets (Ki for resting platelets is <1 nM). UR-2992, the active form of UR-3216, binds to platelets for a long period of time, while the unbound drug is rapidly cleared. Therefore, after an initial loading dose of 0.1 mg/kg, only once daily repeated low maintenance doses of UR-3216 (<0.05 mg/kg p.o.) are required. This regimen maintains a high level of inhibition of platelet aggregation and, due to a small peak-to-trough ratio, severe bleeding is avoided. The therapy with UR-3216 is easy to manage, because it has low peak-to-trough ratio and high efficacy (>80% inhibition of platelet aggregation). In addition, UR-3216 does not produce excessive bleeding or thrombocytopenia and does not interact with abciximab. UR-3216 is excreted mostly in bile, so that it will not accumulate in patients with chronic renal dysfunction. UR-2316 has the following abciximab-like features: (a) its half-lives for residence on platelets, inhibition of platelets aggregation and bleeding time prolongation are 60 to 80 h, 24, and 2 h, respectively; (b) its receptor binding occupancy is similar to that of abciximab (Mab1 is inhibited and Mab2 is unaltered). In conclusion, UR-3216 is a promising, orally active GPIIb/IIIa antagonist for the treatment of cardiovascular diseases. [source] | |||||||||||||||||||||||||