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Long Half-life (long + half-life)
Selected AbstractsInsulin analogues: have they changed insulin treatment and improved glycaemic control?DIABETES/METABOLISM: RESEARCH AND REVIEWS, Issue S1 2002Sten Madsbad Abstract To improve insulin therapy, new insulin analogues have been developed. Two fast-acting analogues with a more rapid onset of effect and a shorter duration of action combined with a low day-to-day variation in absorption rate are now available. Despite this favourable time,action profile most studies have not been able to show any improvement in overall glycaemic control with the fast-acting analogues. A reduced post-prandial increase in blood glucose has been found in all studies, whereas between 3 and 5,h after the meal and during the night an increased blood glucose level is the normal course. This is probably the main explanation for the absence of improvement in overall glycaemic control when compared with regular human insulin. A tendency to a reduction in hypoglycaemic events during treatment with fast-acting analogues has been observed in most studies. Recent studies have indicated that NPH insulin administered several times daily at mealtimes can improve glycaemic control without increasing the risk of hypoglycaemia. The fast-acting analogues are now also available as insulin mixed with NPH. Insulin glargine is a new long-acting insulin which is soluble and precipitates after injection, resulting in a long half-life with a residual activity of about 50% 24,h after injection. Insulin glargine is a peakless insulin and studies in both type 1 and type 2 diabetic patients indicate that glargine improves fasting blood glucose control and reduces the incidence of nocturnal hypoglycaemia. Surprisingly, the new fast,acting analogues have not achieved the expected commercial success, which emphasises the need for new strategies for basal insulin supplementation, exercise, diet and blood glucose monitoring. Copyright © 2002 John Wiley & Sons, Ltd. [source] Clinical issues in using buprenorphine in the treatment of opiate dependenceDRUG AND ALCOHOL REVIEW, Issue 3 2000Dr A. Chadderton MB Abstract This paper looks at the current role of buprenorphine in the treatment of opiate dependence. It suggests that buprenorphine is a useful alternative to methadone and that in at least some cases it may be the preferred option. Buprenorphineis a partial agonist and a partial antagonist with a ceiling of opiate activity probably approximately equal to 30mg methadone. It achieves this at a dose of 10-12mg, although there is considerable individual variation. Because of its ceiling effect it has a good safety profile compared to full agonists such as methadone although some overdose deaths, particularly in conjunction with benzodiazepine abuse, have been reported in France. Induction of buprenorphine may take slightly longer than for methadone and there is a higher dropout rate compared to methadone in the first 2 weeks. This is probably due to the antagonist action of buprenorphine causing more withdrawal symptoms in comparison to methadone. Also, the ceiling effect for buprenorphine means that some clients do not experience sufficient opiate activity to satisfy them. Buprenorphine has a long half-life and dissociates slowly from opiate receptors. Most clients can be dosed second-daily but some find this unacceptable due to mood swings and/or withdrawal symptomson the second day. For these clients daily dosing is required. Transferring from buprenorphine to methadone is straightforward and well tolerated by clients. Transferring from methadone to buprenorphine, however, is more difficult because of the partial antagonist action of buprenorphine. Clients experience withdrawal symptoms that can take up to 2 weeks to settle. Most clients find these symptoms unacceptable when transferring from doses of over 30mg of methadone. The optimum method for transferring from methadone to buprenorphine is still to be determined. Withdrawal from buprenorphine appears to be relatively easier than from methadone. This is presumably due to buprenorphine's partial agonist effect at mureceptors. It is expected that during 2000 buprenorphine will be approved for use in Australia for the treatment of opiate dependence. It may well becomea first-line choice for opiate replacement in heroin dependence. It is also likely to be useful in assisting detoxification fromboth methadone and heroin. [source] Radon (222Rn) in Ground Water of Fractured Rocks: A Diffusion/Ion Exchange ModelGROUND WATER, Issue 4 2004Warren W. Wood Ground waters from fractured igneous and high-grade sialic metamorphic rocks frequently have elevated activity of dissolved radon (222Rn). A chemically based model is proposed whereby radium (226Ra) from the decay of uranium (238U) diffuses through the primary porosity of the rock to the water-transmitting fracture where it is sorbed on weathering products. Sorption of 226Ra on the fracture surface maintains an activity gradient in the rock matrix, ensuring a continuous supply of 226Ra to fracture surfaces. As a result of the relatively long half-life of 226Ra (1601 years), significant activity can accumulate on fracture surfaces. The proximity of this sorbed 226Ra to the active ground water flow system allows its decay progeny 222Rn to enter directly into the water. Laboratory analyses of primary porosity and diffusion coefficients of the rock matrix, radon emanation, and ion exchange at fracture surfaces are consistent with the requirements of a diffusion/ion-exchange model. A dipole-brine injection/withdrawal experiment conducted between bedrock boreholes in the high-grade metamorphic and granite rocks at the Hubbard Brook Experimental Forest, Grafton County, New Hampshire, United States (42°56,N, 71°43,W) shows a large activity of 226Ra exchanged from fracture surfaces by a magnesium brine. The 226Ra activity removed by the exchange process is 34 times greater than that of 238U activity. These observations are consistent with the diffusion/ion-exchange model. Elutriate isotopic ratios of 223Ra/226Ra and 238U/226Ra are also consistent with the proposed chemically based diffusion/ion-exchange model. [source] Once-daily nevirapine dosing: a pharmacokinetics, efficacy and safety reviewHIV MEDICINE, Issue 1 2007CL Cooper In the context of attempts to simplify treatment regimens and enhance adherence, there is great interest in once-daily dosing regimens for the treatment of HIV-1 infection. Nevirapine has a long half-life and achieves high steady-state plasma concentrations relative to the concentration required to inhibit 50% viral replication in vitro (IC50) in patients. For this reason, it has been considered as a once-daily antiretroviral. Pharmacokinetic and efficacy data support the use of this dosing approach, but excess rash and lingering concerns over liver toxicity preclude use of once-daily dosed nevirapine at this time. Tolerance to high nevirapine concentrations may develop when dose escalation is used during initiation of therapy. It is theoretically possible that the benefits of once-daily dosing may be achieved without excess toxicity by switching to once-daily nevirapine following several months of twice-daily administration. This dosing strategy is currently under evaluation. [source] The normal circadian pattern of blood pressure: implications for treatmentINTERNATIONAL JOURNAL OF CLINICAL PRACTICE, Issue 2004J. Redon Summary Blood pressure fluctuates over 24 h following a circadian rhythm that reaches a peak in the morning shortly after awakening. The onset of many acute cardiovascular and cerebrovascular events shows a synchronous cyclical pattern, with the highest incidence of morbidity and mortality in the early morning hours. Strong, although circumstantial, evidence suggests that the early morning surge in blood pressure may contribute to the onset of acute cardiovascular episodes. Sustained blood pressure control that blunts the early morning blood pressure surge may help to reduce the incidence of these events. Antihypertensive agents are needed that provide smooth and sustained blood pressure control for the full 24 h, including the risky early morning hours. The angiotensin II receptor blocker telmisartan given once daily, because of its long half-life and mechanism of action, is likely to confer benefit in terms of 24-h blood pressure control and may reduce cardiovascular risk at the time of greatest patient vulnerability. [source] Circadian Variation in Blood Pressure: Dipper or NondipperJOURNAL OF CLINICAL HYPERTENSION, Issue 2002Pierre Larochelle MD Awareness of an increased incidence of cardiovascular events shortly after awakening has heightened interest in the chronopathology of cardiovascular diseases. Blood pressure varies according to cycles characterized by a reduction during sleep and an increase on awakening. The surge in blood pressure coincides with the circadian nature of various endocrine and hematologic parameters that also have a putative role in triggering the onset of cardiovascular events. The nighttime decrease is absent or blunted in some hypertensive patients (termed "nondippers"), an effect associated with increased morbidity. Drugs can influence the effect of these circadian patterns. Research efforts are focused on clarifying an underlying pathophysiologic process that could be modified by pharmacologic or other means. Long-acting angiotensin II receptor blockers have an effect on blood pressure over 24 hours due to their long half-life, but could also limit the morning surge in blood pressure through an effect on the renin-angiotensin-aldosterone and noradrenergic systems. [source] Blood ribavirin concentration in high-dose ribavirin for adenovirus-induced haemorrhagic cystitis , a case reportJOURNAL OF CLINICAL PHARMACY & THERAPEUTICS, Issue 1 2008M. Homma PhD Summary Blood ribavirin concentration was monitored after the administration of high-dose oral ribavirin in a case of adenovirus-induced haemorrhagic cystitis post-stem-cell transplantation. Combination use of intravenous gamma immunoglobulin (15 g/3 days) and high-dose ribavirin (RBV; 9000 mg/4 days) provided plasma ribavirin concentration of 24·3 ,m and achieved virus eradication. High level of erythrocyte ribavirin (1085 ,m; mostly as phosphorylated metabolites) with long half-life (15 days) caused severe anaemia, which required several blood transfusions for 2 weeks after the cessation of the ribavirin treatment. It was suggested that blood transfusion and intensive haemoglobin level monitoring is necessary for at least 4 weeks after the RBV, because of the high accumulation of phosphorylated ribavirin in erythrocytes even after stopping ribavirin administration. [source] Development and Evaluation of an Ozonated Water System for Antimicrobial Treatment of Durum WheatJOURNAL OF FOOD SCIENCE, Issue 7 2009B. Dhillon ABSTRACT:, Ozonated water is reported to be effective in reducing the microbial load in foods such as fruits, vegetables, and grains. Ozonated water may be an effective alternative to chlorinated water in treating durum wheat before milling. Therefore, durum wheat was washed with ozonated water and analyzed for yeast and mold count (YMC) and aerobic plate count (APC). A system for producing and monitoring ozonated water was developed. The effect of water quality (tap, distilled, and ultra-pure), temperature (7, 15, and 25 °C), and pH (2, 4, and 6.5) was evaluated on the following: steady-state dissolved ozone concentration, ozone decay constant, half-life, mass transfer coefficient, equilibrium ozone concentration, and solubility ratio. The study of these parameters was important to attain a stable, high dissolved ozone concentration at the outset of washing and to have information for system improvement and scale-up. A 1% acetic acid solution (pH 2) at 15 °C resulted in high dissolved ozone concentration (21.8 mg/L) and long half-life (9.2 min). Subsequently, wheat was washed with 5 wash water types: distilled water, ozonated water (16.5 mg/L), chlorinated water (700 mg/L), acetic acid solution (1%), and acetic acid + ozonated water (1%, 20.5 mg/L). The treated samples were analyzed for YMC and APC. The acetic acid + ozonated water treatment was the most effective, with a reduction of 4.1 and 3.2 log10 colony forming units/g in YMC and APC, respectively. Though ozonated water was not very effective alone, it was useful in combination with acetic acid. [source] Antithrombotic properties of a direct thrombin inhibitor with a prolonged half-life and AT-mediated factor Xa inhibitory activityJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 9 2003G. M. T. Vogel Summary., Rebound thrombin generation after successful thrombolysis might be related to (i) too short-term anticoagulant therapy and to (ii) the inability of heparin derivatives to inhibit clot-bound thrombin. To meet these shortcomings, a compound was synthesized, which consists of a pentasaccharide conjugated to a direct thrombin inhibitor. This compound (Org 42675) has a 10 times longer half-life compared with the original half-life of the direct thrombin inhibitor, while the thrombin inhibitory activity is maintained. An extra advantage of this product is the inhibitory activity on thrombin generation via antithrombin III (AT)-mediated factor (F)Xa inhibition. Org 42675 inhibited in vitro clot-bound thrombin with similar activity to the direct thrombin inhibitor argatroban. In experimental models in rats, Org 42675 showed on a molar base similar antithrombotic activity to unfractionated heparin, was more active than argatroban and was more active than fondaparinux sodium (AT-mediated FXa inhibitor) in arterial thrombosis. Finally, Org 42675 was far more active than the three reference compounds in an experimental thrombolysis model in rabbits. These properties of Org 42675, with its FXa and (clot-bound) thrombin inhibitory activity in combination with its long half-life, make this compound a powerful drug that is likely to be effective in the prevention of re-occlusion after successful thrombolysis in man. [source] Pharmacokinetics and bioavailability of imidocarb dipropionate in swineJOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 4 2007D. SU A two-way crossover study was performed in eight healthy young pigs to determine the pharmacokinetics of imidocarb dipropionate (IMDP) following intravenous (2 mg/kg b.w.) and intramuscular (2 mg/kg b.w.) administrations. Each animal received one intravenous and one intramuscular injection with a 30-day washout period between the two-treatments. Plasma concentrations were measured by high-performance liquid chromatography (HPLC) assay with UV detector at regular intervals for up to 24 h post-injection. Intravenous plasma concentration profiles best fit a three-compartmental model yielding a mean system clearance (Cl(s)) of 558 mL/kg·h and a mean half-life of 13.91 h. Mean imidocarb AUC(0,,) (,g·h/mL), Vc (L/kg), Vd(area)(L/kg) and MRT(0-t) (h) values were 3.58, 0.11, 14.36 and 1.46, respectively. Compartmental modeling of imidocarb, after intramuscular administration produced best fit for two-compartmental model yielding mean K, (h,1), Cmax (,g/mL), tmax (h), and bioavailability (%) of 3.89, 2.02, 0.54, and 86.57 for the 2 mg/kg dose level. The present studies showed that IMDP was rapidly absorbed, widely distributed, and slowly eliminated. No adverse effects were observed in any of the pigs after i.v. and i.m. administrations of IMDP. The favorable PK behavior, such as the long half-life, acceptable bioavailability indicated that it is likely to be effective in pigs. [source] Pharmacokinetic,pharmacodynamic integration of danofloxacin after intravenous, intramuscular and subcutaneous administration to rabbitsJOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 1 2007E. FERNÁNDEZ-VARÓN The pharmacokinetics of danofloxacin was studied following intravenous (i.v.), intramuscular (i.m.) and subcutaneous (s.c.) administration of 6 mg/kg to healthy rabbits. Danofloxacin concentration were determined by high-performance liquid chromatography assay with fluorescence detection. Minimal inhibitory concentrations (MICs) assay of danofloxacin against 30 strains of Staphylococcus aureus from several European countries was performed in order to compute pharmacodynamic surrogate markers. The danofloxacin plasma concentration versus time data after i.v. administration could best be described by a two-compartment open model. The disposition of i.m. and subcutaneously administered danofloxacin was best described by a one-compartment model. The terminal half-life for i.v., i.m. and s.c. routes was 4.88, 6.70 and 8.20 h, respectively. Clearance value after i.v. dosing was 0.76 L/kg·h. After i.m. administration, the absolute bioavailability was mean (±SD) 102.34 ± 5.17% and the Cmax was 1.87 mg/L. After s.c. administration, the absolute bioavailability was mean (±SD) 96.44 ± 5.95% and the Cmax was 1.79 mg/L. Danofloxacin shows a favourable pharmacokinetics profile in rabbits reflected by parameters such as a long half-life and a high bioavailability. However, in consideration of the low AUC/MIC indices obtained, its use by i.m. and s.c. route against the S. aureus strains assayed in this study cannot be recommended given the risk for selection of first mutant subpopulations. [source] Orbofiban: An orally active GPIIb/IIIa platelet receptor antagonistMEDICINAL RESEARCH REVIEWS, Issue 3 2001Nancy S. Nicholson Abstract A key role has been established for platelet activation and thrombus formation in the pathogenesis of acute coronary syndromes, and restenosis after percutaneous interventions. Antiplatelet agents that have a wider spectrum of activity than aspirin, and clopidogrel would be expected to provide improved antithrombotic protection. Preclinical studies were used to predict clinical efficacy of orally active GPIIb/IIIa antagonists such as xemilofiban, sibrafiban, lefradafiban, and orbofiban. While clinical trials have shown potent and sustained platelet inhibition, outcomes of trials with these first generation GPIIb/IIIa compounds have been disappointing. The active moiety of orbofiban is a potent and specific inhibitor of fibrinogen binding to GPIIb/IIIa, leading to inhibition of platelet aggregation to a wide variety of agonists. Studies comparing inhibition of aggregation and bleeding suggest that chronic inhibition of platelet aggregation can be achieved without major bleeding side effects. Thrombus formation is prevented in canine models of thrombosis. Orbofiban is approximately 28% bioavailable with a t1/2 of 18,hr. The high bioavailability, long half-life, and potential safety suggest orbofiban would be suitable for chronic oral administration. Clinical data demonstrate that orally administered orbofiban has the desired pharmacodynamic effect of inhibiting platelet aggregation but does not demonstrate clinical benefit when examined in large-scale trials. © 2001 John Wiley & Sons, Inc. Med Res Rev, 21, No. 3, 211,226, 2001 [source] Variability among nonsteroidal antiinflammatory drugs in risk of upper gastrointestinal bleedingARTHRITIS & RHEUMATISM, Issue 6 2010Elvira L. Massó González Objective Traditional nonsteroidal antiinflammatory drugs (NSAIDs) increase the risk of upper gastrointestinal (GI) bleeding/perforation, but the magnitude of this effect for coxibs in the general population and the degree of variability between individual NSAIDs is still under debate. This study was undertaken to assess the risk of upper GI bleeding/perforation among users of individual NSAIDs and to analyze the correlation between this risk and the degree of inhibition of whole blood cyclooxygenase 1 (COX-1) and COX-2 in vitro. Methods We conducted a systematic review of observational studies on NSAIDs and upper GI bleeding/perforation published between 2000 and 2008. We calculated pooled relative risk (RR) estimates of upper GI bleeding/perforation for individual NSAIDs. Additionally, we verified whether the degree of inhibition of whole blood COX-1 and COX-2 in vitro by average circulating concentrations predicted the RR of upper GI bleeding/perforation. Results The RR of upper GI bleeding/perforation was 4.50 (95% confidence interval [95% CI] 3.82,5.31) for traditional NSAIDs and 1.88 (95% CI 0.96,3.71) for coxibs. RRs lower than that for NSAIDs overall were observed for ibuprofen (2.69 [95% CI 2.17,3.33]), rofecoxib (2.12 [95% CI 1.59,2.84]), aceclofenac (1.44 [95% CI 0.65,3.2]), and celecoxib (1.42 [95% CI 0.85,2.37]), while higher RRs were observed for ketorolac (14.54 [95% CI 5.87,36.04]) and piroxicam (9.94 [95% CI 5.99,16.50). Estimated RRs were 5.63 (95% CI 3.83,8.28) for naproxen, 5.57 (95% CI 3.94,7.87) for ketoprofen, 5.40 (95% CI 4.16,7.00) for indomethacin, 4.15 (95% CI 2.59,6.64) for meloxicam, and 3.98 (95% CI 3.36,4.72) for diclofenac. The degree of inhibition of whole blood COX-1 did not significantly correlate with RR of upper GI bleeding/perforation associated with individual NSAIDs (r2 = 0.34, P = 0.058), but a profound and coincident inhibition (>80%) of both COX isozymes was associated with higher risk. NSAIDs with a long plasma half-life and with a slow-release formulation were associated with a greater risk than NSAIDs with a short half-life. Conclusion The results of our analysis demonstrate that risk of upper GI bleeding/perforation varies between individual NSAIDs at the doses commonly used in the general population. Drugs that have a long half-life or slow-release formulation and/or are associated with profound and coincident inhibition of both COX isozymes are associated with a greater risk of upper GI bleeding/perforation. [source] Benzodiazepines in epilepsy: pharmacology and pharmacokineticsACTA NEUROLOGICA SCANDINAVICA, Issue 2 2008J. Riss Benzodiazepines (BZDs) remain important agents in the management of epilepsy. They are drugs of first choice for status epilepticus and seizures associated with post-anoxic insult and are also frequently used in the treatment of febrile, acute repetitive and alcohol withdrawal seizures. Clinical advantages of these drugs include rapid onset of action, high efficacy rates and minimal toxicity. Benzodiazepines are used in a variety of clinical situations because they have a broad spectrum of clinical activity and can be administered via several routes. Potential shortcomings of BZDs include tolerance, withdrawal symptoms, adverse events, such as cognitive impairment and sedation, and drug interactions. Benzodiazepines differ in their pharmacologic effects and pharmacokinetic profiles, which dictate how the drugs are used. Among the approximately 35 BZDs available, a select few are used for the management of seizures and epilepsy: clobazam, clonazepam, clorazepate, diazepam, lorazepam and midazolam. Among these BZDs, clorazepate has a unique profile that includes a long half-life of its active metabolite and slow onset of tolerance. Additionally, the pharmacokinetic characteristics of clorazepate (particularly the sustained-release formulation) could theoretically help minimize adverse events. However, larger, controlled studies of clorazepate are needed to further examine its role in the treatment of patients with epilepsy. [source] Engineered therapeutic antibodies with improved effector functionsCANCER SCIENCE, Issue 9 2009Tsuguo Kubota In the past decade, more than 20 therapeutic antibodies have been approved for clinical use and many others are now at the clinical and preclinical stage of development. Fragment crystallizable (Fc)-dependent antibody functions, such as antibody-dependent cell-mediated cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and a long half-life, have been suggested as important clinical mechanisms of therapeutic antibodies. These functions are primarily triggered through direct interaction of the Fc domain with its corresponding receptors: Fc,RIIIa for ADCC, C1q for CDC, and neonatal Fc receptor for prolongation of the clearance rate. However, current antibody therapy still faces the critical issues of insufficient efficacy and the high cost of the therapeutic agents. A possible solution to these issues could be to engineer antibody molecules to enhance their antitumor activity, leading to improved therapeutic outcomes and reduced doses. Here, we review advanced Fc engineering approaches for the enhancement of effector functions, some of which are now ready for evaluation of their effectiveness in clinical trials. (Cancer Sci 2009; 100: 1566,1572) [source] | |||||||||||||