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Longer Half-life (longer + half-life)
Selected AbstractsTreatment of congestive heart failure , current status of use of digitoxinEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue S2 2001G. G. Belz Digitalis glycosides exert a positive inotropic effect, i.e. an increase in myocardial contractility associated with a prolongation of relaxation period, and glycosides lower the heart rate (negative chronotropic), impede stimulus conduction (negative dromotropic) and promote myocardial excitability (positive bathmotropic). They seem to influence the activities of both the vagal and the sympathetic systems. Digitalis glycosides that belong to different substance classes are closely comparable concerning pharmacodynamics but differ substantially in regard to pharmacokinetics. Digoxin and its derivatives are less lipophilic, show lower protein binding and shorter half-life, are mainly eliminated via the kidney and accumulate rather rapidly in cases of insufficient kidney function. Digitoxin is highly lipophilic and extensively bound to plasma proteins, has a longer half-life, is mainly eliminated in the metabolized state via urine and faeces and does not accumulate in kidney dysfunction. As a result of a more stable pharmacokinetic profile, the incidence of toxic side effects seems to be lower with digitoxin than with digoxin. Since the beginning of the 1990s, the antagonists of the RAAS qualified as the standard treatment for congestive heart failure, often in combination with diuretics, vasodilators or ,-antagonists. However, the important role of digitalis glycosides as therapeutic comedication or alternative was never denied, especially in atrial fibrillation with tachycardia. The PROVED and RADIANCE trials proved a detrimental effect of the withdrawal of digoxin therapy on exercise capacity, left-ventricular ejection fraction and clinical symptoms. The DIG trial revealed that digoxin comedication in sinus rhythm patients with congestive heart failure was associated with a lower morbidity (as taken from death or hospitalization because of worsening heart failure) and an unchanged overall mortality , being a unique feature among the available inotropic drugs. Comparable studies for digitoxin have not yet been performed but, because of its higher pharmacological stability, it might well be associated with even more advantages in this regard than digoxin. [source] Gene therapy for haemophilia,yes, but,with non-viral vectors?HAEMOPHILIA, Issue 3 2009A. LIRAS Summary., High-purity plasma-derived and recombinant factors are currently safe and efficient treatment for haemophilia. The mid-term future of haemophilia treatment will involve the use of modified recombinant factors to achieve advantages such as decreased immunogenicity in inhibitor formation and enhanced efficacy as a result of their longer half-life. In the long-term, gene therapy and cell therapy strategies will have to be considered. Achievements in cell therapy to date have been using embryonic stem cells and hepatic sinusoidal endothelial cells. Current gene therapy strategies for haemophilia are based on gene transfer using adeno-associated viruses and non-viral vectors. Gene therapy for haemophilia is justified because it is a chronic disease and because a very regular factor infusion is required that may involve fatal risks and because it is very expensive. Haemophilia is a very good candidate for use of gene therapy protocols because it is a monogenic disease, and even low expression is able to achieve reversion from a severe to a moderate phenotype. The current trends in haemophilia using adeno-associated viral vectors are safe but also involve immunogenicity problems. The other alternatives are non-viral vectors. There have been in recent years relevant advances in non-viral transfection that raise hope for considering this possibility. Several research groups are opting for this experimental alternative. An expression over 5%, representing a moderate phenotype, for a few months with a high safety, regarding vector, transfected cells, and implantation procedure, would already be a great success. This may represent an intermediate protocol in which the expression levels and times obtained are lower and shorter respectively as compared to viral vectors, but which provide a potential greater patient safety. This may more readily win acceptance among both patients and haematologists because fatal events in the past due to HIV/HCV infection may constrain the implementation of viruses as vectors. [source] Cluster headache: aetiology, diagnosis and management.HEADACHE, Issue 3 2003K Ekbom Drugs. 2002;62(1):61-69 Cluster headache is characterised by repeated attacks of strictly unilateral pain in the orbital region associated with local autonomic symptoms or signs. The attacks are brief but of a very severe, almost excruciating intensity. For unknown reasons males are affected more often than females. Recent studies suggest that an autosomal dominant gene has a role in some families with cluster headache. Hormonal studies indicate a dysfunction in the central nervous system. Neuroimaging has revealed primary defects in the hypothalamic grey matter. Local homolateral dilatation in the intracranial segment of the internal carotid and ophthalmic arteries during attacks is the result of a generic neurovascular activation, probably mediated by trigeminal parasympathetic reflexes. Sumatriptan 6mg subcutaneously is the drug of choice in the treatment of acute attacks. Inhalation of 100% oxygen can also be recommended. In the prophylactic treatment, verapamil is the first option. Other drugs that can be considered are corticosteroids, which may induce a remission of frequent, severe attacks, and lithium. Oral ergotamine tartrate may be sufficient for patients with night attacks and/or short, rather mild to moderately severe cluster headache periods. Third line drugs are serotonin inhibitors (methysergide and pizotifen) and valproic acid. Patients should be encouraged to keep headache diaries and be carefully instructed about the nature and treatment of the headaches. Alcohol can bring on extra attacks and should not be consumed during active periods of cluster headache. Comment: A useful review of clinical options. Given the effectiveness of injectable sumatriptan and the prophylactic use of ergotamine mentioned, one might speculate that the new intranasal formulations of triptans (eg, zolmitriptan) and triptans with a longer half-life (eg, frovatriptan) may prove to be effective in the treatment of cluster headache. DSM [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] Trex-1 deficiency in rheumatoid arthritis synovial fibroblastsARTHRITIS & RHEUMATISM, Issue 9 2010Michel Neidhart Objective To explore whether the increased expression of long interspersed nuclear element 1 (LINE-1; L1) messenger RNA (mRNA) and protein in rheumatoid arthritis synovial fibroblasts (RASFs) is associated with decreased expression of Trex-1, an exonuclease involved in the metabolization of L1 DNA:RNA hybrids. Methods Chromatin immunoprecipitation was used to detect L1-related p40 protein (L1-ORF1p) binding sequences in RASFs. Luciferase activity was measured in the synovial fibroblasts following cotransfection of the episomal plasmid with pJM105 expressing L1-ORF1p and pGL3-TS3 carrying the target sequence for L1-ORF1p. This luciferase reporter assay was used to compare the activity between RASFs and osteoarthritis synovial fibroblasts (OASFs) and to assess correlations of luciferase activity with the expression of Trex-1 measured by flow cytometry. The expression of Trex-1 mRNA and protein was also compared using real-time polymerase chain reaction, immunohistochemistry, and Western blot analyses. The role of Trex-1 in the L1-ORF1p,mediated luciferase activity assay was studied using interfering RNAs (iRNA) and a Trex-1 expression vector. Results Increased luciferase activity occurred after cotransfection of synovial fibroblasts with pJM105 and pGL3-TS3. L1-ORF1p activity was increased in RASFs as compared with OASFs, and this was correlated inversely with the expression of Trex-1. Levels of Trex-1 mRNA and protein were lower in RASFs than in OASFs. After transfection of the L1 expression plasmid, Trex-1 mRNA levels increased in OASFs, but not in RASFs. The addition of iRNA against Trex-1, however, resulted in an enhancement of L1-ORF1p activity in OASFs to the levels measured in RASFs. Overexpression of Trex-1 inhibited 5-azacytidine,induced expression of p38, MAPK, a gene carrying the TS3 sequence. Conclusion The deficiency of Trex-1 in RASFs allows a longer half-life of gene products encoded by active endogenous L1 retrotransposons. This pathway may play a role in diseases in which the cells exhibit a "spontaneous" aggressive behavior. [source] Anticonvulsant activity, teratogenicity and pharmacokinetics of novel valproyltaurinamide derivatives in miceBRITISH JOURNAL OF PHARMACOLOGY, Issue 4 2003Nina Isoherranen The purpose of this study was to synthesize novel valproyltaurine (VTA) derivatives including valproyltaurinamide (VTD), N -methyl-valproyltaurinamide (M-VTD), N,N -dimethyl-valproyltaurinamide (DM-VTD) and N -isopropyl-valproyltaurinamide (I-VTD) and evaluate their structure,pharmacokinetic,pharmacodynamic relationships with respect to anticonvulsant activity and teratogenic potential. However, their hepatotoxic potential could not be evaluated. The metabolism and pharmacokinetics of these derivatives in mice were also studied. VTA lacked anticonvulsant activity, but VTD, DM-VTD and I-VTD possessed anticonvulsant activity in the Frings audiogenic seizure susceptible mice (ED50 values of 52, 134 and 126 mg kg,1, respectively). VTA did not have any adverse effect on the reproductive outcome in the Swiss Vancouver/Fnn mice following a single i.p. injection of 600 mg kg,1 on gestational day (GD) 8.5. VTD (600 mg kg,1 at GD 8.5) produced an increase in embryolethality, but unlike valproic acid, it did not induce congenital malformations. DM-VTD and I-VTD (600 mg kg,1 at GD 8.5) produced a significant increase in the incidence of gross malformations. The incidence of birth defects increased when the length of the alkyl substituent or the degree of N -alkylation increased. In mice, N-alkylated VTDs underwent metabolic N-dealkylation to VTD. DM-VTD was first biotransformed to M-VTD and subsequently to VTD. I-VTD's fraction metabolized to VTD was 29%. The observed metabolic pathways suggest that active metabolites may contribute to the anticonvulsant activity of the N-alkylated VTDs and reactive intermediates may be formed during their metabolism. In mice, VTD had five to 10 times lower clearance (CL), and three times longer half-life than I-VTD and DM-VTD, making it a more attractive compound than DM-VTD and I-VTD for further development. VTD's extent of brain penetration was only half that observed for the N-alkylated taurinamides suggesting that it has a higher intrinsic activity that DM-VTD and I-VTD. In conclusion, from this series of compounds, although VTD caused embryolethality, this compound emerged as the most promising new antiepileptic drug, having a preclinical spectrum characterized by the highest anticonvulsant potential, lowest potential for teratogenicity and favorable pharmacokinetics. British Journal of Pharmacology (2003) 139, 755,764. doi:10.1038/sj.bjp.0705301 [source] Characterization of the anticonvulsant profile and enantioselective pharmacokinetics of the chiral valproylamide propylisopropyl acetamide in rodentsBRITISH JOURNAL OF PHARMACOLOGY, Issue 4 2003Nina Isoherranen Propylisopropyl acetamide (PID) is a new chiral amide derivative of valproic acid. The purpose of this study was to evaluate the anticonvulsant activity of PID in rodent models of partial, secondarily generalized and sound-induced generalized seizures which focus on different methods of seizure induction, both acute stimuli, and following short-term plastic changes as a result of kindling, and to assess enantioselectivity and enantiomer,enantiomer interactions in the pharmacokinetics and pharmacodynamics of racemic PID and its pure enantiomers in rodents. Anticonvulsant activity of (S)-PID, (R)-PID and racemic PID was evaluated in the 6 Hz psychomotor seizure model in mice, in the hippocampal kindled rat, and in the Frings audiogenic seizure susceptible mouse. The pharmacokinetics of (S)-PID and (R)-PID was studied in mice and rats. In mice (S)-PID, (R)-PID and racemic PID were effective in preventing the 6 Hz seizures with (R)-PID being significantly (P<0.05) more potent (ED50 values 11 mg kg,1, 46 mg kg,1 and 57 mg kg,1 at stimulation intensities of 22, 32 and 44 mA, respectively) than (S)-PID (ED50 values 20 mg kg,1, 73 mg kg,1 and 81 mg kg,1 at stimulation intensities of 22, 32 and 44 mA, respectively). (S)-PID, (R)-PID and racemic PID also blocked generalized seizures in the Frings mice (ED50 values 16 mg kg,1, 20 mg kg,1 and 19 mg kg,1 respectively). In the hippocampal kindled rat a dose of 40 mg kg,1 of (R)- and (S)-PID prevented the secondarily generalized seizure, whereas racemic PID also blocked the expression of partial seizures following an i.p. dose of 40 mg kg,1. Racemic PID also significantly increased the seizure threshold in this model. Mechanistic studies showed that PID did not affect voltage-sensitive sodium channels or kainate-, GABA- or NMDA- evoked currents. The pharmacokinetics of PID was enantioselective following i.p. administration of individual enantiomers to mice, with (R)-PID having lower clearance and longer half-life than (S)-PID. In rats and mice, no enantioselectivity in the pharmacokinetics of PID was observed following administration of the racemate, which may be due to enantiomer,enantiomer interaction. This study demonstrated that PID has both enantioselective pharmacokinetics and pharmacodynamics. The better anticonvulsant potency of (R)-PID in comparison to (S)-PID may be due to its more favorable pharmacokinetic profile. The enhanced efficacy of the racemate over the individual enantiomers in the kindled rat may be explained by a pharmacokinetic enantiomer,enantiomer interaction in rats. This study also showed the importance of studying the pharmacokinetics and pharmacodynamics of chiral drugs following administration of the individual enantiomers as well as the racemic mixture. British Journal of Pharmacology (2003) 138, 602,613. doi:10.1038/sj.bjp.0705076 [source] Pharmacokinetics and tolerability of intranasal diazepam and midazolam in healthy adult volunteersACTA NEUROLOGICA SCANDINAVICA, Issue 5 2009V. D. Ivaturi Objective,,, The purpose of this pilot study was to determine the pharmacokinetics and tolerability of an investigational diazepam (DZP) formulation and a parenteral midazolam (MDZ) formulation following intranasal (i.n.) administration for the efficient treatment of seizure emergencies. Methods,,, Each subject received 5 mg of DZP and MDZ via both i.n. and intravenous routes in a four-way, randomized crossover trial. Blood samples were collected over 48 h. DZP and MDZ concentrations were measured using HPLC. Using analog scales, subjects rated tolerability (0 = no change from normal; 10 = maximum intolerability) and pain (0 = no pain; 4 = extreme pain) prior to and 0, 5, 15, 60 min, and 8 h after administration. Results,,, The Cmax and Tmax values for i.n. DZP and MDZ were 179.2 ng/ml and 28.8 min vs 62.8 ng/ml and 21.6 min, respectively. Immediately following i.n. administration, subjects reported tolerability scores of 6.75 and 6.0, and identical pain scores, 3.2, for DZP and MDZ, respectively. Conclusion,,, Both formulations were rapidly absorbed following i.n. administration with transient discomfort. DZP had a longer half-life, which may result in an extended duration of action. Further studies in large patient populations to evaluate the safety after long term use, efficacy and pharmacokinetics of i.n. DZP are warranted. [source] | ||||||||||