[Show abstract][Hide abstract] ABSTRACT: Hepatic encephalopathy (HE) is a common complication of cirrhosis, of largely reversible impairment of brain function occurring in patients with acute or chronic liver failure or when the liver is bypassed by portosystemic shunts. The mechanisms causing this brain dysfunction are still largely unclear. The need to avoid complications caused by late diagnosis has attracted interest to understand the mechanisms underlying neuronal damage in order to find markers that will allow timely diagnosis and to propose new therapeutic alternatives to improve the care of patients. One of the experimental approaches to study HE is microdialysis; this technique allows evaluation of different chemical substances in several organs through the recollection of samples in specific places by semi-permeable membranes. In this review we will discuss the contributions of microdialysis in the understanding of the physiological alterations in human hepatic encephalopathy and experimental models and the studies to find novel alternative therapies for this disease.
International Journal of Molecular Sciences 01/2013; 14(8):16184-206. · 2.46 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: It is estimated that at least 100 million people worldwide will suffer from epilepsy at some point in their lives. This neurological disorder induces brain death due to the excessive liberation of glutamate, which activates the postsynaptic N-methyl-D-aspartic acid (NMDA) receptors, which in turn cause the reuptake of intracellular calcium (excitotoxicity). This excitotoxicity elicits a series of events leading to nitric oxide synthase (NOS) activation and the generation of reactive oxygen species (ROS). Several studies in experimental models and in humans have demonstrated that certain antiepileptic drugs (AEDs) exhibit antioxidant effects by modulating the activity of various enzymes associated with this type of stress. Considering the above-mentioned data, we aimed to compile evidence elucidating how AEDs such as valproic acid (VPA), oxcarbazepine (OXC), and topiramate (TPM) modulate oxidative stress.
Oxidative Medicine and Cellular Longevity 01/2013; 2013:598493.
[Show abstract][Hide abstract] ABSTRACT: Oxidative stress, a state of imbalance in the production of reactive oxygen species and nitrogen, is induced by a wide variety of factors. This biochemical state is associated with systemic diseases, and diseases affecting the central nervous system. Epilepsy is a chronic neurological disorder with refractoriness to drug therapy at about 30%. Currently, experimental evidence supports the involvement of oxidative stress in seizures, in the process of their generation, and in the mechanisms associated with refractoriness to drug therapy. Hence, the aim of this review is to present information in order to facilitate the handling of this evidence and determine the therapeutic impact of the biochemical status for this pathology.
International Journal of Molecular Sciences 01/2013; 14(1):1455-76. · 2.46 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The bacteriostatic agent 4,4'-diaminodiphenylsulfone or dapsone (DDS) and some of its N,N'-dialkylated analogs have shown anticonvulsant and neuroprotective properties in different experimental models. In this study, we tested the ability of five DDS analogs (N,N'-dimethyldapsone, N,N'-diethyldapsone, N,N'-dipropyldapsone, N,N'-dibutyldapsone and N,N'-ditosyldapsone) to attenuate quinolinic acid-induced toxicity in vivo. Male Wistar rats were treated with either DDS or analogs (12.5mg/kg and equimolar doses respectively) 30min before quinolinic acid intrastriatal stereotaxic injection (240nmol/μl). Six days after injury, circling behavior was evaluated by counting ipsilateral turns for 1h after apomorphine challenge (1mg/kg, sc). Twenty-four hours later, rats were sacrificed and their corpora striata were dissected out to determine GABA content. Hemotoxicity of the analogs was assessed as the ability to produce methemoglobin (MHb) in vivo. Blood was sampled from tail vein within 18h after drugs administration. Methemoglobin levels were determined by visible spectrophotometry and mean profiles of MHb-percentage versus time were obtained. All of the analogs tested decreased the number of ipsilateral turns/hour, reducing up to 67% the turns counting (p<0.05) when compared to those induced in animals receiving quinolinic acid with no treatment. N,N'-dimethylated, N,N'-diethylated and N,N'-dibutylated analogs significantly prevented the decrease of intrastriatal GABA content (p<0.05). Methemoglobin produced by the administration of analogs was significantly lower than the levels of the group receiving dapsone (p<0.05). The neuroprotective effect of analogs and their diminished hemotoxicity make them potential candidates for therapeutic applications.
[Show abstract][Hide abstract] ABSTRACT: Neurodegenerative diseases constitute a worldwide health problem. Metals like iron and copper are essential for life, but they are also involved in several neurodegenerative mechanisms such as protein aggregation, free radical generation and oxidative stress. The role of Fe and Cu, their pathogenic mechanisms and possible therapeutic relevance are discussed regarding four of the most common neurodegenerative diseases, Alzheimer's, Parkinson's and Huntington's diseases as well as amyotrophic lateral sclerosis. Metal-mediated oxidation by Fenton chemistry is a common feature for all those disorders and takes part of a self-amplifying damaging mechanism, leading to neurodegeneration. The interaction between metals and proteins in the nervous system seems to be a crucial factor for the development or absence of neurodegeneration. The present review also deals with the therapeutic strategies tested, mainly using metal chelating drugs. Metal accumulation within the nervous system observed in those diseases could be the result of compensatory mechanisms to improve metal availability for physiological processes.
[Show abstract][Hide abstract] ABSTRACT: Valproic acid has been associated with a highly variable intersubject absorptive phase; therefore, magnesium salt (magnesium valproate [MgV]) was developed to diminish variation during enteric absorption.
The aims of this study were to assess the pharmacokinetics of single oral doses of MgV 500-mg solution, suspension, and enteric-coated tablets in a healthy Mexican population, and to compare formulation-related differences.
This was a randomized, single-dose, 3-period, 6-sequence crossover study in healthy Mexican volunteers aged 18 to 45 years. In each period, subjects received single oral doses of 500-mg MgV solution, suspension, and enteric-coated tablet formulations, with a 7-day washout period between each dosing period. Serial blood samples were collected at 0 hour (prior to MgV administration) and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 9, 12, 24, 48, and 72 hours after dosing. Valproate was measured by a new method of ultraperformance liquid chromatography coupled with mass spectrometry. Pharmacokinetic parameters of interest were C(max), T(max), AUC(0-72), AUC(0-infinity), t(1/2), V(d)/F, CL/F, and mean residence time (MRT). Formulation-related differences were assayed in accordance with the Mexican regulatory bioequivalence criteria. Log-transformed values of C(max) and AUC were used to construct a classic 90% CI. Bioequivalence was established if the 90% CI for the mean test:reference ratio of log-transformed C(max) and AUC were within the range of 0.80 to 1.25. Tolerability was assessed based on subject interview, vital sign monitoring, and clinical assessment.
A total of 24 healthy volunteers (12 women and 12 men; mean [SD] age, 28.79 [6.5] years; height, 164 [9.8] cm; weight, 65.42 [8.95] kg; and body mass index, 24.28 [2.11] kg/m(2)) were included. For the MgV solution, the mean (SD) pharmacokinetic parameters of C(max), T(max), AUC(0-72), AUC(0-infinity), t(1/2), V(d)/F, CL/F, and MRT were 59.75 (8.24) microg/mL, 0.542 (0.14) hours, 1099.67 (241.70) microg h/mL, 1156.30 (264.01) microg h/mL, 16.19 (2.36) hours, 9633.68 (1892.70) mL, 418.35 (92.01) mL/h, and 18.36 (1.44) hours, respectively. For the MgV suspension, the mean (SD) pharmacokinetic parameters of C(max), T(max), AUC(0-72), AUC(0-infinity), t(1/2), V(d)/F, CL/F, and MRT were 55.04 (7.72) microg/mL, 0.773 (0.51) hour, 1057.76 (223.37) microg h/mL, 1111.09 (245.07) microg h/mL, 16.32 (2.20) hours, 1069.05 (1775.64) mL, 435.43 (99.59) mL/h, and 18.41 (1.43) hours, respectively. For the MgV enteric-coated tablets, the mean (SD) pharmacokinetic parameters of C(max), T(max), AUC(0-72), AUC(0-infinity), t(1/2), V(d)/F, CL/F, and MRT were 54.88 (6.73) microg/mL, 2.79 (0.89) hours, 1100.79 (216.70) microg h/mL, 1163.61 (238.36) microg h/mL, 16.48 (2.10) hours, 9675.15 (1659.36) mL, 412.36 (85.24) mL/h, and 19.95 (1.53) hours, respectively. The 90% CIs for the tablets:solution ratio were 82.15 to 95.44, 94.60 to 105.39, and 95.43 to 105.95 for C(max), AUC(0-72), and AUC(0-infinity), respectively. The 90% CIs for the suspension:solution ratio were 84.79 to 98.50, 88.89 to 99.02, and 89.15 to 98.97, respectively. The 90% CIs for the tablets:suspension ratio were 89.90 to 104.43, 100.84 to 112.34, and 101.60 to 112.80, respectively.
This single-dose study found that the 3 formulations (solution, suspension, and enteric-coated tablets) of MgV met the regulatory criteria for bioequivalence in these healthy, fasting, Mexican volunteers.
[Show abstract][Hide abstract] ABSTRACT: The aim of the present work was to develop a chromatographic technique coupled with mass spectrometry for the measurement of lamotrigine in plasma. Lamotrigine and guanabenz (internal standard) were measured by selected reaction monitoring. The method was validated and applied in a bioequivalence trial on 26 female volunteers. Lamotrigine chewable tablets (100 mg) were administered and monitored for up to 96 h.
The method was linear between 0.05 and 5.0 µg/ml, with acceptable stability, accuracy and precision. Mean maximum plasma concentration was 1.37 µg/ml and was reached at 1.6 h postdose. Elimination half-life was 32.7 h.
Lamotrigine tablets were bioequivalent. Ultra-performance liquid chromatography with tandem mass spectrometry represents a powerful tool in terms of sensitivity, specificity and high-throughput analysis.
[Show abstract][Hide abstract] ABSTRACT: Sildenafil extemporaneous formulations, used to treat pulmonary arterial hypertension (PAH) in hospitalised children, must be also stable and uniform in content. In this study, we determined content uniformity, stability and therapeutic efficacy of sildenafil in gelatine capsules containing 5 mg from three brands (Viagra ® , Maxifort ® and Apodefil ®). The powder from crushed tablets was distributed into 32 gelatine capsules for each brand. Content uniformity and stability at 25 and 40°C were analysed by HPLC-UV (µ µ µ µBondapack C 18 column, H 2 KPO 4 35 mM (pH 6.0)/ acetonitrile (53:47 v/v), 0.8 ml/min). Therapeutic efficacy of unitary doses was assessed in 25 patients (14 boys and 11 girls), according to clinical improvement and systolic pulmonary arterial pressure (SPAP) decrease, before and after taking sildenafil. Unitary doses showed content uniformity (4.93 ± 0.327 ≈ 5 mg) and were stable for 30 days at 25 and 40°C. SPAP values decreased to normal in 64% of the patients. Dyspnoea disappeared in 85% (11/13) and cyanosis in 67% (6/9). Two children (8%) showed no therapeutic response. Individualised doses of sildenafil in gelatine capsules are stable, uniform in content, and therapeutically effective, being an alternative to treat PAH in hospitalised and ambulatory patients.
[Show abstract][Hide abstract] ABSTRACT: The purpose of the present work was to study the pharmacokinetics of ketorolac, a poorly metabolized drug, in experimental cirrhosis. Cirrhosis was induced by bile duct ligation (BDL) for four weeks in male Wistar rats. Ketorolac was given intravenously (1 mg/kg ) or orally (3.2 mg/kg) to control (sham-operated) and BDL-rats. Determination of ketorolac in plasma was carried out by HPLC and estimation of pharmacokinetic parameters was performed by non-compartmental analysis. Indicators of liver damage and liver fibrosis were significantly increased (p < 0.05) in BDL compared to control rats. Experimental cirrhosis did not induce any significant alteration in intravenous ketorolac pharmacokinetics. Volume of distribution, clearance, AUC and t1/2 were similar in BDL and control animals. Notwithstanding, oral ketorolac bioavailability was significantly altered in BDL rats. AUC and Cmax were reduced, while tmax was prolonged, suggesting that both, the extent and the rate of ketorolac absorption were decreased. Results show that liver cirrhosis may result in significant pharmacokinetic alterations, even for poorly bio-transformed drugs, but that alterations may vary with the route of administration. In conclusion, uncritical generalizations on the effect of liver damage on drug kinetics should be avoided and systematic studies for every drug and every route of administration are thus recommended.
Annals of hepatology: official journal of the Mexican Association of Hepatology 2(4):175-81. · 1.67 Impact Factor