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/

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

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

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

The use of drug calendars for the diagnosis of cutaneous drug eruptions in the age of electronic medical records

A morbilliform drug eruption is the most common condition leading to a dermatology consultation for a patient in the hospital. Timing is an important diagnostic tool since the onset of a skin rash usually takes place within days-to-weeks of the start of the implicated drug. A comprehensive, thorough, and reliable drug history by the clinician is essential. Therefore, to assist in the task of determining the causative medication of a new skin rash in a hospitalized patient, the creation of a drug calendar is recommended. The development of an electronic version of the drug calendar offers several benefits over the manual version. As the use of electronic medical records continues to become the standard in medicine, the electronic drug calendar will serve as an invaluable tool for the diagnosis of drug hypersensitivity

INFESTAZIONE DI PLUSIA (CHRYSODEIXIS) CHALCITES ESP. SU FAGIOLINO COLTIVATO IN SERRA

L'A. ha constatato violenti attacchi di Plusia chalcites Esp. in una serra, coltivata a fagiolino, della Facoltà di Agraria di Bari. Vengono descritti i danni causati dalla larva sulle foglie e sui baccelli. Sono stati evidenziati numerosi parassiti della Plusia chalcites Esp.: l'Imenottero Calcidide endofago Litomastix truncatellus Dalm., l'lcneumonide Ctenochares instructor F. ed un Dittero, la Sturmia bella Meig.  The Author refers strong attacks of Plusia chalcites Esp. in a glass-house, cultured with gren beans, of the Faculty of Agriculture in Bari. There are described the damages caused by the larva on the leaves and pods. There are three parasites endofagous in the Plusia chalcites Esp.: Litomastix truncatellus Dalm. (Hymenoptera - Calcididae), Ctenochares instructor F. (Hymenoptera - Icheumonidae), Sturmia bella Meig. (Diptera)

Monitoreo de vancomicina administrada intraventricularmente en lactantes durante el tratamiento de ventriculitis

The objective of this study was to establish guidelines for the monitoring of intraventricularly administeredVancomycin in infants.Eleven patients with ventriculo-peritoneal shunts who developed ventriculitis were included in the study.All patients were given an intraventricular (IVT) dose of Vancomycin. Cerebrospinal fluid (CSF)samples were analysed and pharmacokinetic parameters: elimination rate constant (ke) and distributionvolume (Vd) were calculated in order to adjust the dose. Mean values of Vd and elimination half-lifefor these patients were 244 (± 162) mL and 37.1 (±23.3) hours respectively.A great variability in the Vd was observed in some patients. This change in Vd correlates with problemsin the ventricle size or with septated ventricles. In all cases a new dose was suggested according to thecalculated parameters.Due to variations in the system throughout therapy, a protocol for CSF samples collection was proposedin order to individualise Vancomycin dosage according to pharmacokinetic parameters.El objetivo de este estudio fue establecer pautas para el monitoreo de Vancomicina cuando la misma esadministrada intraventricularmente en lactantes.En este estudio se incluyeron once pacientes con derivaciones ventrículo-peritoneal. Todos los pacientesrecibieron una dosis de Vancomicina intraventricular (IVT). Las muestras de líquido cefalorraquídeo(LCR) fueron analizadas y se calcularon los parámetros farmacocinéticos: constante de velocidad deeliminación (ke) y volumen de distribución (Vd) para poder llevar a cabo un ajuste posológico. Lasmedias referidas al Vd y a la semivida de eliminación para estos pacientes fueron de 244(±162) mL y37.1(±23.3) horas respectivamente.En algunos pacientes se observó una gran variabilidad en el Vd. Este cambio en Vd se correlacionó conproblemas en el tamaño ventricular o con ventrículos septados. En todos los casos, se propuso una nuevadosis de acuerdo a los parámetros calculados.Debido a variaciones en el sistema a lo largo de la terapia, se propuso un protocolo para la recolecciónde muestras de LCR de forma tal de individualizar la dosis de Vancomicina con los parámetros farmacocinéticosobtenidos