Therapeutic Monitoring of Anticonvulsants: Use of Saliva as Biological Fluid

Plasma drug concentration is not homogeneous within the intravascular space, being the arterial (PA) concentrations higher or lower than that in veins (PV) depending on whether the samples are taken during the drug absorption or the elimination phases, respectively. However, blood samples are currently withdrawn from peripheral veins and total (bound plus unbound) plasma drug concentration is assayed. Despite the fact that free plasma drug levels (PfV) are not determined in routine therapeutic drug monitoring (TDM), they could be assayed for research purposes. Salivary drug concentrations (S) approximate to their free plasma levels in the arteries of the great circulation. Saliva is recommended to be collected with stimulation to minimize the difference between the pHs of both fluids (saliva and blood), and thus, artery/vein-free drug concentration ratios (PfA/PfV) could be surrogated by the stimulated saliva/free-plasma in vein drug concentration ratios (SS/PfV). It is possible in this way not only to assess this S/P ratio but also to infer the brain (B)/PfV ratio, which is actually the most relevant for antiepileptic drugs (AEDs). Different cases of AEDs are considered in this review, taking into account their physiochemical properties and their ability to be transported by membrane carriers

Pharmacotherapy of Chronic Pain

In the past two decades, many preclinical works have been carried out assisting in our understanding of the underlying pathophysiological mechanisms that cause chronic pain. Chronic pain involves multiple pathophysiological mechanisms with peripheral and central components. This research in basic and clinical research has greatly expanded the options for analgesic pharmacotherapy. This chapter gives information regarding the major classes of medication used to assist in the management of chronic pain, including nonopioids analgesics such as NSAIDs and acetaminophen, opioids analgesics, antidepressants and anticonvulsants and an emerging area as the field of cannabinoids is. Importantly, chronic pain treatment encompasses multiple agents to take advantage of synergistic mechanism of actions, but drug‐drug interactions have to be taken into account in order to avoid lack of efficacy or toxicity

Current State and Future Perspectives in QSAR Models to Predict Blood Brain Barrier penetration in Central Nervous System Drug R&D

The blood brain barrier (BBB) is a physical and biochemical barrier that restricts the entry of certain drugs to the Central Nervous System (CNS), while allowing the passage of others. The ability to predict the permeability of a given molecule through the BBB is a key aspect in CNS drug discovery and development, since neurotherapeutic agents with molecular targets in the CNS should be able to cross the BBB, whereas peripherally acting agents should not, to minimize the risk of CNS adverse effects. In this review we examine and discuss QSAR approaches and current availability of experimental data for the construction of BBB permeability predictive models, focusing on the modeling of the biorelevant parameter unbound partitioning coefficient (Kp,uu) . Emphasis is made on two possible strategies to overcome the current limitations of in silico models: considering the prediction of brain penetration as a multifactorial problem, and increasing experimental datasets through accurate and standardized experimental techniques.Facultad de Ciencias Exacta

Assessment of the release of metals from cigarette butts into the environment

Cigarette butts are known to contain toxic metals which pose a potential threat to the environment and human health. The seriousness of this threat is largely determined by the leachability of these toxic metals when the butts are exposed to aqueous solutions in the environment. The aims of this study were to determine the presence and mobility of toxic and non-toxic elements found in discarded cigarette butts; to relate this mobility to two different contact situations with leaching liquids: tumbling and trampling (batch test) and percolation in a static position (column test); and finally, to verify possible variations in solubility by simulating different environmental systems. Five leachants with different pH values were used to simulate various environmental conditions The concentrations of the solubilized metals were determined by inductively coupled plasma-atomic emission spectrometry (ICP-AES) and inductively coupled plasma-mass spectrometry (ICP-MS). CH3COOH pH 2.5 showed the greatest capacity to dissolve many elements. On the contrary, weakly acidic or alkaline environments did not favor the leachability of the elements. The best extraction capacity of the column with respect to the batch is statistically significant (p <0.05) for the elements Al, Fe, Ni and Zn, while the batch for P, Si, S. Pb, Cd, As were not detectable in cigarette butts, while Hg had an average concentration of 0.0502 μg/g. However, Hg was < LOD in all different leachants

Active Pharmacovigilance in Epileptic Patients: A Deep Insight into Phenytoin Behaviour

Despite the introduction of new and more expensive anticonvulsant drugs, phenytoin (PHT) is still a first-line medication for common types of epilepsy such as tonic-clonic and complex partial seizures but not for absence seizures. PHT shows a nonlinear kinetics and a narrow therapeutic range, thus a fine balance must be found between efficacy and toxic effects. Since the free (unbound) drug is responsible for producing the pharmacological effect, the concentration in a novel biological fluid more closely related to arterial free plasma drug concentration—saliva—is used in this study as part of the monitoring strategy. Therefore, in order to optimize therapy in epileptic patients under PHT treatment, plasma and saliva concentrations of PHT were measured, and adverse drug reactions were registered during a 2-year follow-up. CYP2C9, CYP2C19, and epoxide hydrolase polymorphisms (enzymes involved in PHT metabolism) were also analyzed using, in this way, pharmacogenetics for drug safety. The two PHT brands commercially available in our country and used in this study demonstrated similar pattern of efficacy and safety

Sex-related <em>in vitro/in vivo</em> and PK/PD correlations after oral single dose furosemide administration

Background: The goal of this study was to develop an in vivo-in vitro (IVIV) correlation, both in men and women, which allows constructing a model to predict bioequivalence assessments for drugs with narrow absorption windows. Besides, pharmacokinetic and pharmacodynamic equivalences were also investigated. Furosemide was chosen as a prototype.Methods: Twelve healthy Caucasian volunteers (8 women and 4 men) participated in a relative bioavailability study. Two oral formulations [Lasix® (Reference, R) and Furosemide EFA® (Test, T)] were administered under fasting conditions. Urinary excretion of unchanged drug (PK), and of chloride, sodium and potassium (PD) wasmonitored throughout time. PK and PD parameters were calculated from each respective excretion rate versus time curve. In vitro dissolution testing of both formulations was carried out using the USP apparatus 2 and 4 with fixed and variable dissolution media.Results: T and R could be considered bioequivalent since the 90% confidence intervals for the T/R ratio of geometric means for the area under the urinary drug excretion rate versus time curve and for the maximum excretion rate were within the 0.80-1.25 bioequivalence interval. However, T had faster initial absorption and higher levels in women, while R displayed such characteristics in men. Closer IVIV correlations in women were obtained when apparatus 4 with variable biorelevant dissolution media were used [going from fasting state simulated gastric fluid to fasting state simulated intestinal fluid]. Since R had faster disintegration time than T, a shorter stay of R under gastric conditions was required in order to obtain a good IVIV correlation in men. Saluretic effect displayed a typical clockwise hysteresis loop for the PKPD correlation assessed through chloride-versus-furosemide urinary excretion rates. Even though a higher amount of furosemide was excreted with the urine in men, differences in the excretion of electrolytes between sexes were almost negligible.Conclusions: Sex-differences in the gastrointestinal transit of formulations, under fasting conditions, determined the extent and the rate of furosemide absorption. The prolongation of the absorption process by mean of slowing the gastric emptying would make the formulation more effective. The USP-4 apparatus with variable dissolution media was able to discriminate the formulations even between sexes, becoming a promissory in vitro dissolution testing to predict bioequivalence.<br/

Revisiting Pharmacokinetics and Pharmacogenetics of Methadone in Healthy Volunteers

Methadone acts as a μ opioid agonist, a serotonin and norepinephrine reuptake inhibitor, and a noncompetitive N-methyl-D-aspartate receptor antagonist. These actions altogether are responsible for its efficacy in the management of chronic pain. It is available as a racemic mixture of (R)- and (S)-methadone, both being stereoisomers responsible for its analgesic effect. Methadone elimination occurs mainly through metabolism in the liver by CYP3A4, CYP2B6, and CY2C19 and to a lesser extent by CYP2D6 and in the intestine by CYP3A4. The relative intestinal content of CYP2B6 and CY2C19 is unknown but it seems that CYP2B6 is not present at the intestine. CYP3A4, CYP2B6, and CYP2C19 convert methadone mainly into 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine(EDDP). CYP2B6 and CYP2C19 are stereoselective to S- and R-enantiomer, respectively. The pharmacokinetic study carried out in healthy volunteers by our research group confirmed that MTD undergoes recirculation via gastric secretion and intestinal reabsorption and revealed that the drug is extensively metabolized in the liver but intestinal metabolism is not only relevant but also stereoselective. Polymorphisms of the CYP2B6 and CYP2C19 isoenzymes and their relationship with the pharmacokinetics of MTD were also assessed

Sex- and smoke-related differences in gastrointestinal transit of cyclosporin A microemulsion capsules

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