Search

The objective of this study was to analyze the relationship between CYP2D6 genotype and pharmacokinetics and pharmacodynamics of risperidone. Seventy-one healthy volunteers (36 women and 35 men) received a 1-mg single oral dose of risperidone. Six major CYP2D6 polymorphisms (CYP2D6*3, *4, *5, *6, *7, and *9) and the duplication were detected. Subjects were classified into 4 phenotypic groups: 6 ultrarapid (UMs), 34 extensive (EMs), 25 intermediate (IMs), and 6 poor metabolizers (PMs). There was a clear relationship between the number of active alleles and the pharmacokinetic parameters for risperidone and 9-hydroxyrisperidone, but there were no differences for total active moiety. Area under the curve and half-life of risperidone were significantly higher in PMs and IMs compared with EMs and UMs, which showed higher area under the curve of 9-hydroxyrisperidone. Risperidone produced a small decrease in blood pressure, a mild increase in QTc and a quick increase in prolactin, without significant differences between groups. Surprisingly, the incidence of adverse reactions was lower in PMs (50%) than in other subjects (78%). In conclusion, metabolism of risperidone depends on the number of active CYP2D6 alleles. So, PM subjects show higher concentrations of risperidone and very low concentrations of 9-hydroxyrisperidone. On the contrary, EM and UM subjects show low concentrations of risperidone and high concentrations of 9-hydroxyrisperidone. However, no major pharmacodynamic differences are observed between CYP2D6 genotypes, presumably because of the similar pharmacological activity of parent drug and metabolite.

Cytosolic Ca2+ signals are followed by mitochondrial Ca2+ uptake, which, in turn, modifies several biological processes. Mg2+ is known to inhibit Ca2+ uptake by isolated mitochondria, but its significance in intact cells has not been elucidated. In HEK293T cells, activation of purinergic receptors with extracellular ATP caused cytosolic Ca2+ signals associated with parallel changes in cytosolic [Mg2+]. Neither signals were affected by omitting bivalent cations from the extracellular medium. The effect of store-operated Ca2+ influx on cytosolic Mg2+ concentration ([Mg2+]c) was negligible. Uncaged Ca2+ displaced Mg2+ from cytosolic binding sites, but for an equivalent Ca2+ signal, the change in [Mg2+] was significantly smaller than that measured after adding extracellular ATP. Inositol 1,4,5-trisphosphate mobilized Ca2+ and Mg2+ from internal stores in permeabilized cells. The increase of [Mg2+] in the range that occurred in ATP-stimulated cells inhibited mitochondrial Ca2+ uptake in permeabilized cells without affecting mitochondrial Ca2+ efflux. Therefore, the Mg2+ signal generated by Ca2+ mobilizing agonists may attenuate mitochondrial Ca2+ uptake.

(i) To define the incidence of alleles CYP2C8*1 to *5 in a Spanish population; (ii) to test the impact of such alleles, and those of CYP2C9, on the metabolism of racemic ibuprofen, R-ibuprofen and S-ibuprofen; and (iii) to discern whether those metabolic alterations have safety implications.Data from three phase I clinical trials with 69 healthy volunteers taken ibuprofen were analyzed. Genotyping were performed by PCR. Pharmacokinetic parameters were determined in studies 1 and 2 by non-compartmental analysis. Levels of COX-1, COX-2, eNOS and iNOS were determined by Western Blots in gastric biopsies of study 3.Allelic frequencies were 0.80, 0.02, 0.11, 0.07 and 0 for CYP2C8*1, *2, *3, *4 and *5. CYP2C9*3 allele had a decreased racemic ibuprofen metabolism, leading to a 30% augmentation of AUC(0-infinity) and a 30% reduction of clearance compared to CYP2C9*1 (p0.05). CYP2C8*3 had a 20% augmentation of clearance compared to CYP2C8*1 (p0.05) of R-ibuprofen. CYP2C9*3 had a 45% reduction of clearance, as well as a 87% and 47% augmentation of AUC(0-infinity) and t(1/2) with respect to CYP2C9*1 of S-ibuprofen and a 30% reduction of clearance of R-ibuprofen. A decreased iNOS expression was found in CYP2C8*3 compared to wild type (p0.05). Adverse events in CYP2C8*3 (20%) and *4 (20%) were fewer than in CYP2C8*1 (77%).This study suggest an impaired metabolism of racemic, S-ibuprofen and R-ibuprofen in CYP2C9*3; an increased R-ibuprofen metabolism in CYP2C8*3; and fewer adverse events in CYP2C8*3 volunteers; that correlates with a decreased expression of iNOS.

Donepezil, rivastigmine, and galantamine are three drugs with acetylcholinesterase (AChE)-inhibiting activity that are currently being used to treat patients suffering from Alzheimer's disease. We have studied the neuroprotective effects of these drugs, in comparison with nicotine, on cell death caused by beta-amyloid (Abeta) and okadaic acid, two models that are relevant to Alzheimer's pathology, in the human neuroblastoma cell line SH-SY5Y. Galantamine and donepezil showed a U-shaped neuroprotective curve against okadaic acid toxicity; maximum protection was achieved at 0.3 microM galantamine and at 1 microM donepezil; at higher concentrations, protection was diminished. Rivastigmine showed a concentration-dependent effect; maximum protection was achieved at 3 microM. When apoptosis was induced by Abeta25-35, galantamine, donepezil, and rivastigmine showed maximum protection at the same concentrations: 0.3, 1, and 3 microM, respectively. Nicotine also afforded protection against Abeta- and okadaic acid-induced toxicity. The neuroprotective effects of galantamine, donepezil, and nicotine were reversed by the alpha7 nicotinic antagonist methyllycaconitine but not by the alpha4beta2 nicotinic antagonist dihydro-beta-erythroidine. The phosphoinositide 3-kinase (PI3K)-Akt blocker 2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one hydrochloride (LY294002) reversed the protective effects of galantamine, donepezil, and nicotine but not that of rivastigmine. In contrast, the bcl-2 antagonist ethyl[2-amino-6-bromo-4-(1-cyano-2-ethoxy-2-oxoethyl)]-4H-chromene-3-carboxylate (HA 14-1) reversed the protective effects of the three AChE inhibitors and that of nicotine. Our results show that galantamine, donepezil, and rivastigmine afford neuroprotection through a mechanism that is likely unrelated to AChE inhibition. Such neuroprotection seemed to be linked to alpha7 nicotinic receptors and the PI3K-Akt pathway in the case of galantamine and donepezil but not for rivastigmine.

Aims: This study was conducted to assess the bioequivalence between two 10-mg amlodipine tablet formulations. As secondary objectives, sex-related differences and tolerability profile were evaluated. Methods: Thirty-six healthy volunteers (18 males and 18 females; age 20–32 years, weight 49.5–98.0 kg) were included in a randomised crossover study. Subjects were administered a single 10-mg oral dose of each formulation separated by a 14-day washout period. Plasma amlodipine levels were determined by a high performance liquid chromatographic method with tandem mass spectrometry detection. Results: All subjects completed the study and 90% confidence intervals for relevant pharmacokinetic parameters were within the ranges defined by European and US Regulatory Authorities: the geometric mean and the 90% confidence interval test/reference ratios calculated from log-transformed values were 104.54 (101.46–107.72%) for AUC 0–∞ and 100.32 (97.41–103.33%) for C max . There were no serious or severe adverse events. The tolerability profile appeared to be comparable for the two products. On average, bioavailability of amlodipine was slightly higher in females than in males, but these differences could be explained by the lower body weight of women. There were no sex-related differences in drug clearance. Bioequivalence was also demonstrated within each gender group. Amlodipine treatment produced a slight decrease of systolic blood pressure and an increased in heart rate, which were more pronounced in women. The incidence of adverse events was similar in men and women. Conclusions: The two formulations were considered bioequivalent. Although there were no relevant gender-related differences in the pharmacokinetics of amlodipine, women reached higher amlodipine concentrations most likely because of their lower body weight, and therefore, the reported pharmacodynamic effects were higher within this gender group.

The aim of this study was to evaluate the effect of ibuprofen on gastric mucosa and enzymes involved in gastroprotection in healthy volunteers. Twenty-four Helicobacter pylori-negative subjects were randomized to treatment with ibuprofen or ibuprofen-arginate (each 600 mg/6 hr during 3 days). Endoscopies were performed 1 week before and after treatment. Biopsies were taken from the gastric antrum and corpus for determination of prostaglandin E2 (PGE2) by ELISA and cyclooxygenase (COX-1 and COX-2) and nitric oxide synthase (eNOS and iNOS) by western blot. All subjects had at least one gastric lesion except for two individuals taking ibuprofen-arginate. Ibuprofen-arginate caused a lower rate of clinical adverse reactions than ibuprofen. Subjects with gastric lesions or adverse reactions had lower PGE2 levels. COX-1, COX-2, eNOS, and iNOS were detectable in all subjects. The constitutive enzymes (COX-1 and eNOS) did not change after treatment. COX-2 was higher in corpus than antrum and it increased after ibuprofen treatment. iNOS tended to increase mildly in the corpus in subjects with adverse reactions or endoscopic lesions. There were no significant differences between ibuprofen and ibuprofen-arginate in PGE2, or enzymes.

Background: The new local anesthetic IQB-9302 is an amide derivative bearing a cyclopropyl group, with remarkable long duration of action and relative low toxicity. In trying to characterize further its safety profile, the current study compared the hemodynamic effects of different concentrations of bupivacaine and IQB-9302 with saline. Methods: Two groups of eight anesthetized Sprague–Dawley rats were given 0.1, 0.3, 1, 3, and 10 mg/kg of intravenous (i.v.) IQB-9302 or bupivacaine at 20-min intervals; control animals received saline only. Arterial blood pressure and heart rate were monitored during the following 20 min. Results: Both bupivacaine and IQB-9302 reduced heart rate: for bupivacaine, −73.8 beats per min (bpm) (SD: 103.8) and −132.5 bpm (SD: 140.7) at 1 and 3 mg/kg, respectively; for IQB-9302, the reduction amounted to −40.8 bpm (SD: 14.2) and −113.5 bpm (SD: 94.2) at 1 and 3 mg/kg, respectively (baseline range, 318.7–438.2 bpm). The two drugs also produced a comparable increase in the mean arterial blood pressure; bupivacaine increased it by 8.7 mmHg (SD: 6.6) and 12.6 mmHg (SD: 15.4) at 1 and 3 mg/kg, respectively, and IQB-9302, 18.7 mmHg (SD: 21.1) and 20.7 mmHg (SD: 20.5) at 1 and 3 mg/kg, respectively (baseline range, 47.4–134.1 mmHg). All rats treated with 10 mg/kg of either drug died after a drop in heart rate and mean arterial blood pressure. Conclusion: IQB-9302 had hemodynamic effects similar to those of bupivacaine in anesthetized rats. The clinical relevance of these effects warrants further investigation.

This study was undertaken to assess the bioequivalence between a new formulation of propofol 2% and the commercially available product Diprivan. Secondary objectives were to compare the times to onset of and emergence from hypnosis, the hemodynamic effects, and the safety profiles. Twelve healthy male volunteers were included in a randomized crossover study. Subjects were administered a 2-mg/kg single bolus injection of each formulation separated by a 7- to 10-day washout period. Plasma propofol was determined by reversed-phase liquid chromatography with fluorescence detection. Eleven subjects completed the study, and both formulations were considered bioequivalent. There were no serious or severe adverse events. The concentration-time profiles of all the subjects could adequately be described using a three-compartment model. The mean times to cessation of counting out loud (17 vs. 18 s) and to eye opening (245 vs. 244 s) were not statistically different between treatment groups. Moreover, they seem to show some degree of pharmacodynamic bioequivalence, although a higher number of subjects are necessary to unequivocally demonstrate it.

Genetically encoded calcium indicators allow monitoring subcellular Ca2+ signals inside organelles. Most genetically encoded calcium indicators are fusions of endogenous calcium-binding proteins whose functionality in vivo may be perturbed by competition with cellular partners.We describe here a novel family of fluorescent Ca2+ sensors based on the fusion of two Aequorea victoria proteins, GFP and apo-aequorin (GAP). GAP exhibited a unique combination of features: dual-excitation ratiometric imaging, high dynamic range, good signal-to-noise ratio, insensitivity to pH and Mg2+, tunable Ca2+ affinity, uncomplicated calibration, and targetability to five distinct organelles. Moreover, transgenic mice for endoplasmic reticulum-targeted GAP exhibited a robust long-term expression that correlated well with its reproducible performance in various neural tissues. This biosensor fills a gap in the actual repertoire of Ca2+ indicators for organelles and becomes a valuable tool for in vivo Ca2+ imaging applications., This work was supported by grants from the European Research Area Net (ERA-Net) program, the Spanish Ministerio de Economía y Competitividad (SAF2008-03175-E, BFU2010-17379), and the Instituto de Salud Carlos III (RD06/0010/0000).

El sistema renina-angiotensina desempena un papel fundamental en la fisiopatologia de la hipertension arterial. El eprosartan es un antagonista de los receptores de angiotensina de nueva generacion que bloquea de forma selectiva los receptores de la angiotensina II del subtipo 1, tanto postsinapticos (vasculares) como presinapticos (neuronales), por lo que ademas disminuye la actividad simpatica. Se elimina por via biliar y renal y habitualmente no es necesario ajustar la dosis inicial en pacientes con insuficiencia hepatica o renal. Como en su metabolismo no interviene el citocromo P450, es poco probable que produzca interacciones con otros farmacos, lo que favorece su utilizacion en terapia combinada y en pacientes polimedicados. Los resultados de varios ensayos clinicos ha demostrado que eprosartan (habitualmente 400-800 mg/dia como una dosis o dividido en dos dosis) posee una eficacia antihipertensiva superior al placebo y al menos tan buena como enalapril o losartan. Es un farmaco bien tolerado y a diferencia del enalapril no produce tos. Tambien se ha demostrado que es eficaz y seguro en pacientes mayores de 65 anos.

7 páginas, 5 figuras.-- El pdf del artículo es la versión post-print., CALHM1 (calcium homoeostasis modulator 1), a membrane protein with similarity to NMDA (N-methyl-D-aspartate) receptor channels that localizes in the plasma membrane and the ER (endoplasmic reticulum) of neurons, has been shown to generate a plasma-membrane Ca2+ conductance and has been proposed to influence Alzheimer's disease risk. In the present study we have investigated the effects of CALHM1 on intracellular Ca2+ handling in HEK-293T [HEK (human embryonic kidney)-293 cells expressing the large T-antigen of SV40 (simian virus 40)] cells by using targeted aequorins for selective monitorization of Ca2+ transport by organelles. We find that CALHM1 increases Ca2+ leak from the ER and, more importantly, reduces ER Ca2+ uptake by decreasing both the transport capacity and the Ca2+ affinity of SERCA (sarcoplasmic/endoplasmic reticulum Ca2+-ATPase). As a result, the Ca2+ content of the ER is drastically decreased. This reduction in the Ca2+ content of the ER triggered the UPR (unfolded protein response) with induction of several ER stress markers, such as CHOP [C/EBP (CCAAT/enhancer-binding protein)-homologous protein], ERdj4, GRP78 (glucose-regulated protein of 78 kDa) and XBP1 (X-box-binding protein 1). Thus CALHM1 might provide a relevant link between Ca2+ homoeostasis disruption, ER stress and cell damage in the pathogenesis of neurodegenerative diseases., This work was supported by grants from the EU-ERA-Net program, the Spanish Ministerio de Ciencia e Innovación (MICINN; SAF2008-03175-E, BFU2007-60157 and BFU2010-17379), the Instituto de Salud Carlos III (RD06/0010/0000) and the Junta de Castilla y León (gr175). Sonia Gallego-Sandín was supported by a postdoctoral JAE contract from the Spanish National Research Council (CSIC).

Transient receptor potential vanilloid type 1 (TRPV1) is a plasma membrane Ca2+ channel involved in transduction of painful stimuli. Dorsal root ganglion (DRG) neurons express ectopic but functional TRPV1 channels in the endoplasmic reticulum (ER) (TRPV1ER). We have studied the properties of TRPV1ER in DRG neurons and HEK293T cells expressing TRPV1. Activation of TRPV1ER with capsaicin or other vanilloids produced an increase of cytosolic Ca2+ due to Ca2+ release from the ER. The decrease of [Ca2+]ER was directly revealed by an ER-targeted aequorin Ca2+ probe, expressed in DRG neurons using a herpes amplicon virus. The sensitivity of TRPV1ER to capsaicin was smaller than the sensitivity of the plasma membrane TRPV1 channels. The low affinity of TRPV1ER was not related to protein kinase A- or C-mediated phosphorylations, but it was due to inactivation by cytosolic Ca2+ because the sensitivity to capsaicin was increased by loading the cells with the Ca2+ chelator BAPTA. Decreasing [Ca2+]ER did not affect the sensitivity of TRPV1ER to capsaicin. Disruption of the TRPV1 calmodulin-binding domains at either the C terminus (Δ35AA) or the N terminus (K155A) increased 10-fold the affinity of TRPV1ER for capsaicin, suggesting that calmodulin is involved in the inactivation. The lack of TRPV1 sensitizers, such as phosphatylinositol 4,5-bisphosphate, in the ER could contribute to decrease the affinity for capsaicin. The low sensitivity of TRPV1ER to agonists may be critical for neuron health, because otherwise Ca2+ depletion of ER could lead to ER stress, unfolding protein response, and cell death. © 2009 by The American Society for Biochemistry and Molecular Biology, Inc.

Altered calcium homeostasis and increased cytosolic calcium concentrations ([Ca2+]c) are linked to neuronal apoptosis in epilepsy and in cerebral ischemia, respectively. Apoptotic programmed cell death is regulated by the antiapoptotic Bcl2 family of proteins. Here, we investigated the role of Bcl2 on calcium (Ca2+) homeostasis in PC12 cells, focusing on L-type voltage-dependent calcium channels (VDCC). Cytosolic Ca2+ transients ([Ca2+]c) and changes of mitochondrial Ca2+ concentrations ([Ca2+]m) were monitored using cytosolic and mitochondrially targeted aequorins of control PC12 cells and PC12 cells stably overexpressing Bcl2. We found that: (i) the [Ca2+]c and [Ca2+]m elevations elicited by K+ pulses were markedly depressed in Bcl2 cells, with respect to control cells; (ii) such depression of [Ca2+]m was not seen either in digitonin-permeabilized cells or in intact cells treated with ionomycin; (iii) the [Ca2+]c transient depression seen in Bcl2 cells was reversed by shRNA transfection, as well as by the Bcl2 inhibitor HA14-1; (iv) the L-type Ca2+ channel agonist Bay K 8644 enhanced K(+)-evoked [Ca2+]m peak fourfold in Bcl2, and twofold in control cells; (v) in current-clamped cells the depolarization evoked by K+ generated a more hyperpolarized voltage step in Bcl2, as compared to control cells. Taken together, our experiments suggest that the reduction of the [Ca2+]c and [Ca2+]m transients elicited by K+, in PC12 cells overexpressing Bcl2, is related to the reduction of Ca2+ entry through L-type Ca2+ channels. This may be due to the fact that Bcl2 mitigates cell depolarization, thus diminishing the recruitment of L-type Ca2+ channels, the subsequent Ca2+ entry, and mitochondrial Ca2+ overload.

The aim of the present investigation was to compare the pharmacokinetics of two tablet formulations of 600 mg of racemic ibuprofen obtained using enantiospecific and non-enantiospecific assays, in order to explore if chiral assays should be employed in bioequivalence studies of chiral active substances. The stereoselective assay showed that, for both formulations, there was an initial phase where (R)-ibuprofen was the predominant enantiomer followed by a final phase where (S)-ibuprofen was the predominant one. Results from both analytical methods proved that the two formulations were bioequivalent. However, the chiral bioanalytical method detected a larger difference in the eutomer than that showed by the nonchiral bioanalytical method. In conclusion, although the exposure ratios of enantiomers are near unity, the measurement of unresolved ibuprofen alone is not an adequate measure of bioequivalence since it may mask the actual difference in the eutomer exposure among formulations.

Serum albumin protects against cell death elicited by various cytotoxic agents; however, conflicting views on the protective mechanism still remain. Hence, we have studied the ability of serum albumin to prevent apoptosis of human neuroblastoma SH-SY 5 Y cells elicited by four compounds known to release Ca(2+) from the endoplasmic reticulum, i.e. dotarizine, flunarizine, thapsigargin and cyclopiazonic acid. Spontaneous basal apoptosis, after 24 h incubation in Dulbecco's Modified Eagle Medium (DMEM) containing 10% serum, was 5%. Dotarizine (30--50 microM) enhanced basal apoptosis to 18--43%, flunarizine (30--50 microM) to 15%, thapsigargin (1--10 microM) to 21--35%, and cyclopiazonic acid (100 microM) to 10%. Serum deprivation augmented basal apoptosis to 20%. Under serum-free medium, 30 microM dotarizine or flunarizine drastically enhanced apoptosis to 63% and 68%, respectively; the increase was milder with 1 microM thapsigargin (37%) and 30 microM cyclopiazonic acid (27%). In serum-free medium, albumin (29 or 49 mg/ml) fully prevented the apoptotic effects of dotarizine, flunarizine and cyclopiazonic acid. The four compounds increased the cytosolic Ca(2+) concentration ([Ca(2+)](c)) in fluo-4 loaded cells; such increase developed slowly to reach a plateau after several minutes, followed by a slow decline. Albumin did not modify the kinetic parameters of such increase. In the absence of serum, dotarizine, flunarizine, thapsigargin, and cyclopiazonic acid caused mitochondrial depolarization in tetramethylrhodamine ethyl ester (TMRE)-loaded cells; depolarization was inhibited by cytoprotective concentrations of albumin. These results suggest that albumin protects cells from entering into apoptosis by preventing mitochondrial depolarization. They also suggest that inhibition of mitochondrial depolarization might become a target to develop new anti-apoptotic compounds with therapeutic neuroprotective potential in stroke, Alzheimer's disease, and other neurodegenerative diseases.

A progressive 69% increase in sales of hydrocortisone tablets was observed in Spain from 1988 to 1995. But there were no data suggesting an increase in the number of adrenal insufficiency cases. We aimed to assess the hydrocortisone prescription habits of physicians in 1996 in Madrid (Spain). An anonymous mail questionnaire was sent to 6130 randomly selected physicians (3345 generalists and 2785 specialists) of Madrid. Five hundred and forty-six questionnaires (8.8%) were returned. Three hundred and eighteen physicians (58.2%) sometimes prescribed oral hydrocortisone. 70.8% of these physicians prescribed hydrocortisone for chronic adrenal insufficiency, 17.3% for acute adrenal insufficiency, 7.9% for congenital adrenal hyperplasia, and 30.2% for inflammatory diseases (asthma, allergic diseases, urticaria, rheumatic diseases, ulcerative colitis). Prescription for inflammatory diseases was more frequent in male physicians, physicians older than 40 years, and general practitioners. We can conclude that the main indication for hydrocortisone prescription was chronic adrenal insufficiency but there was a significant number of physicians that used the drug in inflammatory diseases. As a drastic increase in prevalence of adrenal insufficiency seems unlikely, the augmentation in sales of hydrocortisone could be explained by its prescription for other pathologies.

Summary. Aims. The course of mild cognitive impairment (MCI) involves a slight loss of memory without any significant effects on other cognitive functions. Around 12% of these patients advance annually toward Alzheimer’s disease, and for this reason it is important to search for medications that can prevent or slow down the evolution to dementia. Memory training programs, with relaxation techniques, the repetition of facts, information or pictures, categorizing information and the use of mnemonic rules can be effective. Drugs that can improve the cognitive faculties include piracetam, selegiline, vitamin E, Ginkgo biloba extract, estrogens, nonsteroidal antiinflammatory drugs (NSAIDs), acetylcholinesterase inhibitors and memantine. The aim of this study is to evaluate whether citilcoline can be effective in this clinical situation. Method. It has been shown in several animal models that citicoline improves scoring in learning and memory tests. Likewise, citicoline has been shown to improve memory and other cognitive functions in patients with chronic cerebrovascular disease or dementia and in old people suffering from memory defici t without dementia. Furthermore, a meta-analysis of 12 clinical trials conducted by the Cochrane Collaboration, researchers reached the conclusion that citicoline improves memory, behaviour and the overall clinical impression in old people suffering from chronic brain diseases. Conclusion. Citicoline could be effective in the treatment of MCI, although more studies are needed in order to check whether the effect continues in the long term and whether it manages to slow down the progression to dementia . [REV NEUROL 2002; 35: 675-82]

Introduction Citicoline has a neuroprotector effect since it reduces the lesions of nerve membranes, by increase in the synthesis of phospholipids, and reduces the levels of free fatty acids. In this study we review the existing data on the efficacy of citicoline in the treatment of acute ischemic cerebrovascular disease and its sequelae, both in animals and in clinical trials involving patients. Development In various animal models citicoline reduces the volume of cerebral infarction and neurological sequelae and also potentiates the effects of other neuroprotector drugs. On analysis of the literature, we found six randomised clinical trials, double-blind and placebo-controlled in which the effect of citicoline was evaluated in patients who had acute ischemic cerebrovascular accidents. In all of these it was found that citicoline reduced the neurological sequelae. The finding of a broad therapeutic window (24-48 hours) gives this an advantage over the fibrinolytic agents, which have to be given within the first three to six hours. In further controlled trials carried out in patients with sequelae of cerebrovascular disease different degrees of neurological improvement were found, although studies of greater duration are required to see improvement in a longer term. Conclusions With the data available, we may affirm that citicoline is a safe, effective drug, although clinical trials are still underway in larger populations of patients. In these trials not only the neurological state but also the area of infarction are assessed to confirm their efficacy.