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Useful Drug (useful + drug)
Selected AbstractsValproate Suppresses Status Epilepticus Induced by 4-Aminopyridine in CA1 Hippocampus RegionEPILEPSIA, Issue 11 2003Eduardo D. Martín Summary:,Purpose: We investigated the effects of valproate (VPA) on an in vivo model of status epilepticus (SE) induced by intrahippocampal application of 4-aminopyridine (4-AP). Methods: To induce continuous epileptiform activity without a clinical component, 4-AP (100 mM) was slowly injected in the hippocampus of adult rats. Extracellular field potential from the CA1 region of the rat hippocampus was recorded to assess abnormal epileptiform activity. Once the SE seizures were induced by 4-AP, the test drug was injected. In some experiments to test the ability of a drug to prevent the induction of SE, the drug was administered before 4-AP injection. Results: Intrahippocampal injection of 4-AP induced continuous epileptic activity without a clinical component that lasted >60 min. The intravenous injection of 400,600 mg/kg VPA rapidly (,100 s) abolished the SE, and this effect persisted for ,4 h in our experimental model. The intravenous injection of 100,300 mg/kg VPA did not abolish previously induced SE, but prevented the appearance of SE when applied before the induction of SE. The intravenous injection of 80 mg/kg phenytoin or carbamazepine did not abolish or prevent SE. Conclusions: We conclude that 4-AP,induced SE was suppressed by VPA at 400,600 mg/kg, whereas minor doses (100,300 mg/kg) only prevent the 4-AP,induced SE. Present results suggest the revisiting of VPA as a useful drug for the treatment of SE. [source] Cetirizine in horses: pharmacokinetics and effect of ivermectin pretreatmentJOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 3 2007L. OLSÉN The pharmacokinetics of the histamine H1 -antagonist cetirizine and the effects of pretreatment with the antiparasitic macrocyclic lactone ivermectin on the pharmacokinetics of cetirizine were studied in horses. After oral administration of cetirizine at 0.2 mg/kg bw, the mean terminal half-life was 3.4 h (range 2.9,3.7 h) and the maximal plasma concentration 132 ng/mL (101,196 ng/mL). The time to reach maximal plasma concentration was 0.7 h (0.5,0.8 h). Ivermectin (0.2 mg/kg bw) given orally 1.5 h before cetirizine did not affect its pharmacokinetics. However, ivermectin pretreatment 12 h before cetirizine increased the area under the plasma concentration,time curve by 60%. The maximal plasma concentration, terminal half-life and mean residence time also increased significantly following the 12 h pretreatment. Ivermectin is an inhibitor of P-glycoprotein, which is a major drug efflux transporter in cellular membranes at various sites. The elevated plasma levels of cetirizine following the pretreatment with ivermectin may mainly be due to decreased renal secretion, related to inhibition of the P-glycoprotein in the proximal tubular cells of the kidney. The pharmacokinetic properties of cetirizine have characteristics which are suitable for an antihistamine, and this substance may be a useful drug in horses. [source] Pharmacokinetics of ceftiofur in red deer (Cervus elaphus)JOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 1 2004Mark L. Drew Twelve adult female red deer (Cervus elaphus) were given 250 mg of ceftiofur sodium by intramuscular injection (i.m.) and ballistic implant in a crossover design. Blood samples were taken from an in-dwelling jugular catheter prior to drug administration and at 0.25, 0.5, 1, 2, 4, 8, 12, 24, 36, 48, and 72 h postadministration of the drug. Samples were centrifuged and plasma kept frozen at ,70 °C until analysis for ceftiofur and active metabolites using an HPLC method. The pharmacokinetics of ceftiofur and metabolites after i.m. dosing and following ballistic implant were quite different. Absorption after i.m. injection was rapid; whereas following ballistic implant there was a lag-time until concentrations were detectable in plasma. The maximum concentration reached in plasma was higher following injection compared with ballistic implant, however the AUC calculated after ballistic implant was almost identical to the mean AUC found after i.m. dosing. The results indicate that i.m. administration of ceftiofur maintains adequate plasma levels for most susceptible bacterial pathogens for at least 12 h; therefore twice daily administration is needed in red deer. Ballistic implants produced plasma concentrations above the MIC for most bacterial pathogens from 4 to 24 h in most animals after administration; however, absorption of the drug was variable and some did not maintain effective concentrations for more than a few hours. Ceftiofur is a useful drug in red deer and twice daily i.m. administration dosing should allow treatment for susceptible bacterial pathogens. [source] Usefulness and pharmacokinetic study of oral terbinafine for hyperkeratotic type tinea pedisMYCOSES, Issue 1 2008Izumi Kikuchi Summary To study and establish an optimal administration method of oral antifungal, terbinafine (TBF), for hyperkeratotic type tinea pedis, from the pharmacokinetic point of view, 20 patients with hyperkeratotic type tinea pedis were given TBF 125 mg once daily for 4 weeks and observed over time for improvement in dermatological symptoms and mycological efficacy. Targeting five of the patients, TBF concentration in the stratum corneum was measured using the liquid chromatography/tandem mass spectrometry (LC-MS/MS) method. TBF was detected in the stratum corneum of the sole 1 week after beginning the treatment in some cases and reached its peak 1 week after the completion of the treatment with a concentration of 247.8 ng g,1, which was approximately more than 50 times higher than its minimal inhibitory concentration against dermatophytes. TBF was not detected at 8 weeks post-treatment, although its concentration was 50.73 ng g,1 at 6 weeks post-treatment. Its effectiveness rate (effective + markedly effective) was 95% (19/20) with no adverse reactions, including abnormal changes in the laboratory test values, in any patient. These results suggest that TBF is a useful drug to treat hyperkeratotic tinea pedis from the pharmacokinetic point of view. [source] Long-term posaconazole treatment and follow-up of rhino-orbital-cerebral mucormycosis in a diabetic girlPEDIATRIC DIABETES, Issue 4 2009Luigi Tarani Abstract:, To demonstrate that the 2-yr clinical follow-up of our patient strongly suggests that long-term therapy with posaconazole (POS) is safe and beneficial in treatment and prevention of relapses of, otherwise fatal, central nervous system mucormycosis. Mucormycosis is a very rare opportunistic mycotic infection of diabetic children. We present the 30-month follow-up of a 12-yr-old girl affected by diabetic ketoacidotic coma, complicated by rhinocerebral mucormycosis and successfully treated with POS at the initial daily dose of 5 mg/kg t.i.d. with fatty food for 3 wk, followed by a daily dose of 10 mg/kg in four doses for 2 months and then 20 mg/kg/d in four doses for 16 months and in two doses for further 5 months. The previous amphotericin B, granulocyte colony-stimulating factor, hyperbaric oxygen and nasal and left maxillary sinus surgical debridement therapy was ineffective in stopping the progression of the infection to the brain. The patient improved within 10 d with reduced ocular swelling and pain, and 6 months after therapy stop, she is in good health and cultures are sterile. This article demonstrates that POS may be a useful drug in mucormycosis in children. We also strongly draw the attention to the main preventive procedure against invasive fungal infection that is the correct management of antidiabetic therapy that prevents the predisposing temporary neutrophils activity deficit, contributing to a better survival rate of diabetic children. [source] Oral R115866 in the treatment of moderate to severe facial acne vulgaris: an exploratory studyBRITISH JOURNAL OF DERMATOLOGY, Issue 1 2007C.J. Verfaille Summary Background, R115866 (RambazoleTM; Barrier Therapeutics NV, Geel, Belgium), a new-generation retinoic acid metabolism-blocking agent, is a nonretinoid compound enhancing intracellularly the endogenous levels of all- trans -retinoic acid by blocking its catabolism. By virtue of this property, and the proven positive effects of retinoids in the treatment of acne, R115866 could potentially be a useful drug for acne. Objectives, To explore the efficacy, safety and tolerability of systemic R115866 in male patients with moderate to severe facial acne vulgaris (at least 15 papules and/or pustules and at least two nodulocystic lesions). Methods, In this exploratory trial, 17 patients were treated with oral R115866 1 mg once daily for 12 weeks, followed by a 4-week treatment-free period. Results, At the end of treatment (week 12, n = 16) a mean reduction in inflammatory lesion count of 77ˇ4% (P < 0ˇ001), in noninflammatory lesion count of 58ˇ3% (P < 0ˇ001) and in total lesion count of 76ˇ0% (P < 0ˇ001) was observed as compared with baseline. All lesion counts were significantly reduced from week 4 onwards. Mild side-effects were reported occasionally. Conclusions, The current data indicate that treatment with oral R115866 1 mg once daily for 12 weeks in patients with moderate to severe facial acne vulgaris is efficacious and well tolerated and merits further investigation. [source] [Gly14]-Humanin improved the learning and memory impairment induced by scopolamine in vivoBRITISH JOURNAL OF PHARMACOLOGY, Issue 8 2001Takayoshi Mamiya Humanin is a very recently discovered 24 amino acid linear polypeptide, which protects against cell death induced by either familial Alzheimer's disease mutant of amyloid precursor protein, presenilin-1 or presenilin-2 in vitro. However, it has remained uncertain whether humanin is a useful drug for the animal model of learning and memory deficit. In this study, we evaluated the effects of [Gly14]-humanin, a more potent humanin analogue, on the scopolamine HBr (1 mg kg,1 s.c.)-induced impairment of spontaneous alternation behaviour in the Y-maze, an index of short-term memory in mice. [Gly14]-Humanin (1000 pmol 5 ,l,1 i.c.v.) reversed the impairment without affecting the number of arm entries. These results suggest that (I) [Gly14]-humanin is a beneficial drug for the impairment of learning and memory and (II) it modulates the learning and memory function mediated via cholinergic systems in mice. British Journal of Pharmacology (2001) 134, 1597,1599; doi:10.1038/sj.bjp.0704429 [source] The Novel Antiarrhythmic Drug Dronedarone: Comparison with AmiodaroneCARDIOVASCULAR THERAPEUTICS, Issue 3 2005Sven Kathofer ABSTRACT Dronedarone is a noniodinated benzofuran derivative that has been developed to overcome the limiting iodine-associated adverse effects of the commonly used antiarrhythmic drug, amiodarone. It displays a wide cellular electrophysiological spectrum largely similar to amiodarone, inhibiting the potassium currents Ikr, IKs, IKI, IKACh, and Isus, as well as sodium currents and L-type calcium currents in isolated cardiomyocytes. In addition, dronedarone exhibits antiadrenergic properties. In vivo, dronedarone has been shown to be more effective than amiodarone in several arrhythmia models, particularly in preventing ischemia- and reperfusion-induced ventricular fibrillation and in reducing mortality. However, an increased incidence of torsades de pointes with dronedarone in dogs shows that possible proarrhythmic effects of dronedarone require further evaluation. The clinical trails DAFNE, EURIDIS, and ADONIS indicated safety, antiarrhythmic efficacy and low proarrhythmic potential of the drug in low-risk patients. In contrast, the increased incidence of death in the dronedarone group of the discontinued ANDROMEDA trial raises safety concerns for patients with congestive heart failure and moderate to severe left ventricular dysfunction. Dronedarone appears to be effective in preventing relapses of atrial fibrillation and atrial flutter. Torsades de pointes, the most severe adverse effect associated with amiodarone, has not yet been reported in humans with dronedarone. Unlike amiodarone, dronedarone had little effect on thyroid function and hormone levels in animal models and had no significant effects on human thyroid function in clinical trials. In conclusion, dronedarone could be a useful drug for prevention of atrial fibrillation and atrial flutter relapses in low-risk patients. However, further experimental studies and long-term clinical trials are required to provide additional evidence of efficacy and safety of dronedarone. [source] Molecular mechanisms underlying inflammatory lung diseases in the elderly: Development of a novel therapeutic strategy for acute lung injury and pulmonary fibrosis,GERIATRICS & GERONTOLOGY INTERNATIONAL, Issue 3 2005Takahide Nagase In the elderly, inflammatory lung diseases, including acute lung injury and pulmonary fibrosis, are significant in terms of both mortality and difficulty in management. Acute respiratory distress syndrome (ARDS) is an acute lung injury and the mortality rate for ARDS ranges from 40 to 70% despite intensive care. Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal disorder of the lung parenchyma. No useful drugs are currently available to treat IPF. However, molecular mechanisms underlying these lung diseases are little understood and the development of a novel therapeutic strategy is urgently needed. Platelet-activating factor (PAF) and metabolites of arachidonic acid, i.e. eicosanoids, are lipid mediators that have various biological effects. A key enzyme for the production of these inflammatory mediators, including eicosanoids and PAF, is phospholipase A2. In particular, cytosolic PLA2 (cPLA2) is especially important. The purpose of this article is to report novel findings regarding the role of PAF and cPLA2 in lung inflammatory diseases, especially, acute lung injury and pulmonary fibrosis. To address this question, we used mutant mice, i.e. PAFR transgenic mice, PAFR gene-disrupted mice and cPLA2 gene-disrupted mice. We have shown that PAF and eicosanoids, downstream mediators of cPLA2, may be involved in the pathogenesis of ARDS and IPF, which are important diseases in the elderly. Although there exist extreme differences in clinical features between ARDS and IPF, both diseases are fatal disorders for which no useful drugs are currently available. On the basis of recent reports using mutant mice, cPLA2 might be a potential target to intervene in the development of pulmonary fibrosis and acute lung injury in the elderly. [source] Development of a single-tube PCR-pyrosequencing method for the simultaneous and rapid detection of four variant alleles of CYP2C9 gene polymorphismJOURNAL OF CLINICAL PHARMACY & THERAPEUTICS, Issue 2 2008Y. Okada MS Summary Background and Objective:, CYP2C9 is a polymorphic enzyme that has been reported to metabolize several clinically useful drugs such as warfarin, phenytoin and non-steroidal anti-inflammatory drugs. We designed a rapid single-tube multiplex assay to detect four variant alleles of the CYP2C9 in a single polymerase chain reaction (PCR) and a single pyrosequencing reaction. Methods:, A multiplex PCR was designed to amplify two fragments simultaneously, one containing 430C>T (CYP2C9*2) polymorphism and other containing 1075A>C (CYP2C9*3), 1076T>C (CYP2C9*4) and 1080C>G (CYP2C9*5) polymorphisms. Results:, Four variants of the CYP2C9 gene could be simultaneously detected using only two varieties of pyrosequencing primers in a single-tube. The success rate for the four SNPs (*2, *3,*4 and *5) was high. Genotypes obtained by the multiplex reaction were 100% concordant with genotypes obtained using direct DNA sequencing (n = 96). The analysis time was halved, compared with existing simplex pyrosequencing. The system allowed high-throughput analysis of over 384 samples per hour. Discussion:, Our method reduces running cost and halves analysis time, compared to simplex pyrosequencing. Another advantage of this method is that it analyses and determines multiple bases around the polymorphic site thereby reducing the possibility of scoring a truncated PCR product. [source] Conformational Study of Short Peptoid Models for Future Applications as Potent Antimicrobial CompoundsMACROMOLECULAR THEORY AND SIMULATIONS, Issue 3 2007Fateh Singh Nandel Abstract Development of peptides as clinically useful drugs is limited by their poor metabolic stability and low bioavailability. Recent progresses in chemical synthesis and design have led to several strategies for producing potent mimetics. This study aims to analyze sequence/structure requirements and composition for antimicrobial peptoid designs, as use of peptoids is one of the most representative approaches to meet the goal of biomimicry. Analysis of the designs showed that for maximum activity and minimum hemolysis, the plane of the aromatic residues should be at an angle between 0 and 90,° with respect to membranes, cationic residues need not be at the terminal position, and central positions should be uniform in NIle, NLys, and NPhe residues. [source] ,,,-Cyclopentaneglycine Dipeptides Capped with Biaryls as Tachykinin NK2 Receptor AntagonistsCHEMMEDCHEM, Issue 7 2008Marina Porcelloni Dr. Abstract The NK2 receptor belongs to the family of tachykinin neurotransmitters. It has been reported to be involved in several pathological conditions, and selective antagonists are potentially useful drugs for the treatment of asthma, irritable bowel syndrome, cystitis, and depression. Starting from in-house capped dipeptide libraries, we were able to identify a number of molecules with sub-nanomolar binding affinity for the hNK2 receptor. All were characterized by a rigid core structure with a strong constraint induced by an ,,,-cyclopentaneglycine fragment. Herein we report the further elaboration of three initial basic structures. The planar benzothiophene group was substituted with a series of biphenyl and heterobiphenyl moieties that are well tolerated in terms of receptor affinity. The new compounds also maintained good antagonist potency in an in,vitro functional assay, and a number of them showed significant in,vivo activity after intravenous administration in our guinea pig model. [source] | |||||||||||||||||||