Drug exposure during pregnancy in primary care: an algorithm and observational study from SIDIAP database, Catalunya, Spain.

OBJECTIVES: To develop an algorithm to identify pregnancy episodes in women at childbearing age using SIDIAP (Information System for the Improvement of Research in Primary Care) data (Catalunya, Spain).To describe drugs dispensed during gestation. DESIGN: Construction of an algorithm to identify all pregnancy episodes occurred from January 2011 to June 2020 in women aged 12-50. The variables used to create the algorithm include first day of last menstrual period, reasons for pregnancy termination and diagnoses registered in the primary healthcare records. Population-based cohort study including the pregnancy episodes identified by the algorithm. SETTING: Catalonia, Spain. PARTICIPANTS: All women aged 12-50 with at least one pregnancy episode occurred during January 2011-June 2020. INTERVENTIONS: No interventions performed. PRIMARY AND SECONDARY OUTCOME MEASURES: Identification of pregnancy episodes through an algorithm and description of drug exposure. RESULTS: We identified 327 865 pregnancy episodes in 250 910 people with a mean age of 31.3 years. During the study period, 83.4% of the episodes were exposed to at least one drug. The most frequent groups dispensed were iron preparations (48% of pregnancy episodes), iodine therapy (40.2%), analgesics and antipyretics (28%), penicillins (19.8%), vitamin B12 plus folic acid (19.7%) and non-steroidal anti-inflammatory drugs (NSAIDs, 15.1%). The supplements were more frequently dispensed at least twice, and the drugs for acute conditions were mainly dispensed only once during the pregnancy episode. CONCLUSIONS: We developed an algorithm to automatically identify the pregnancy periods in SIDIAP.We described prescription drugs used during pregnancy. The most used ones were supplements, analgesics, NSAID or antibiotics.SIDIAP might be an efficient database to study drug safety during pregnancy and the consequences of drug use in the offspring. TRIAL REGISTRATION NUMBER: EUPAS37675.

Quantitative systems pharmacology Model to characterize valproic acid-induced hyperammonemia and the effect of L-carnitine supplementation.

Valproic acid (VPA) is a short-chain fatty acid widely prescribed in the treatment of seizure disorders and epilepsy syndromes, although its therapeutic value may be undermined by its toxicity. VPA serious adverse effects are reported to have a significant and dose-dependent incidence, many associated with VPA-induced hyperammonemia. This effect has been linked with reduced levels of carnitine; an endogenous compound involved in fatty acid's mitochondrial ß-oxidation by facilitation of its entrance via the carnitine shuttle. High exposure to VPA can lead to carnitine depletion causing a misbalance between the intra-mitochondrial ß-oxidation and the microsomal ω-oxidation, a pathway that produces toxic metabolites such as 4-en-VPA which inhibits ammonia elimination. Moreover, a reduction in carnitine levels might be also related to VPA-induced obesity and lipids disorder. In turn, L-carnitine supplementation (CS) has been recommended and empirically used to reduce VPA's hepatotoxicity. The aim of this work was to develop a Quantitative Systems Pharmacology (QSP) model to characterize VPA-induced hyperammonemia and evaluate the benefits of CS in preventing hyperammonemia under both chronic treatment and after VPA overdosing. The QSP model included a VPA population pharmacokinetics model that allowed the prediction of total and unbound concentrations after single and multiple oral doses considering its saturable binding to plasma proteins. Predictions of time courses for 2-en-VPA, 4-en-DPA, VPA-glucuronide, carnitine, ammonia and urea levels, and for the relative change in fatty acids, Acetyl-CoA, and glutamate reflected the VPA induced changes and the efficacy of the treatment with L-carnitine. The QSP model was implemented to give a rational basis for the L-carnitine dose selection to optimize CS depending on VPA dosage regime and to assess the currently recommended L-carnitine rescue therapy after VPA overdosing. Results show that a L-carnitine dose equal to the double of the VPA dose using the same interdose interval would maintain the ammonia levels at baseline. The QSP model may be expanded in the future to describe other adverse events linked to VPA-induced changes in endogenous compounds.

Effect of a single vectored thermal pulsation treatment of Meibomian gland dysfunction patients under controlled environmental conditions.

To assess the prophylactic effect of LipiFlow treatment in Meibomian gland dysfunction (MGD) patients exposed to an adverse environmental humidity. MGD patients were exposed to normal (23 °C; 50% relative humidity; 30 min) and adverse (23 °C; 10% relative humidity; 2 h) controlled environments consecutively during baseline and follow-up visits (3, 6, and 12 months) after a single LipiFlow treatment. Ocular Surface Disease Index (OSDI), lipid layer thickness (LLT), fluorescein tear break-up time (TBUT), corneal and conjunctival staining, change in dry eye symptoms questionnaire (CDES-Q), and Meibomian gland yielding liquid secretion (MGYLS), were assessed. Linear mixed-effects and cumulative logit mixed models were fitted to assess the effect of the LipiFlow treatment over time and within the controlled environments. Seventeen females and 4 males (59.6 ± 9.4 years) completed the study. LLT and TBUT did not vary significantly (p > 0.05) after LipiFlow treatment. OSDI, corneal and conjunctival staining, and MGYLS scores were improved (p ≤ 0.01) 12 months after treatment. After the adverse exposure, corneal staining increased at all visits (p = 0.01), and there was no significant improvement in CDES-Q scores after LipiFlow treatment (p ≥ 0.07). One LipiFlow treatment improved objective and subjective outcomes in MGD disease for at least one year. Further studies are needed to support that LipiFlow might also help as an adjuvant to avoid acute flares against an adverse environmental humidity.

The role of efflux transporters and metabolizing enzymes in brain and peripheral organs to explain drug-resistant epilepsy.

Drug-resistant epilepsy has been explained by different mechanisms. The most accepted one involves overexpression of multidrug transporters proteins at the blood brain barrier and brain metabolizing enzymes. This hypothesis is one of the main pharmacokinetic reasons that lead to the lack of response of some antiseizure drug substrates of these transporters and enzymes due to their limited entrance into the brain and limited stay at the sites of actions. Although uncontrolled seizures can be the cause of the overexpression, some antiseizure medications themselves can cause such overexpression leading to treatment failure and thus refractoriness. However, it has to be taken into account that the inductive effect of some drugs such as carbamazepine or phenytoin not only impacts on the brain but also on the rest of the body with different intensity, influencing the amount of drug available for the central nervous system. Such induction is not only local drug concentration but also time dependent. In the case of valproic acid, the deficient disposition of ammonia due to a malfunction of the urea cycle, which would have its origin in an intrinsic deficiency of L-carnitine levels in the patient or by its depletion caused by the action of this antiseizure drug, could lead to drug-resistant epilepsy. Many efforts have been made to change this situation. In order to name some, the administration of once-daily dosing of phenytoin or the coadministration of carnitine with valproic acid would be preferable to avoid iatrogenic refractoriness. Another could be the use of an adjuvant drug that down-regulates the expression of transporters. In this case, the use of cannabidiol with antiseizure properties itself and able to diminish the overexpression of these transporters in the brain could be a novel therapy in order to allow penetration of other antiseizure medications into the brain.

Therapeutic Instruments Targeting Meibomian Gland Dysfunction.

The most prevalent type of meibomian gland dysfunction (MGD), which is obstructive, is the main cause of evaporative dry eye and is characterized by changes in the meibum composition and duct obstruction. Eyelid hygiene has usually been the most common clinical approach. However, alternative therapies for MGD are emerging on the market. Some warming and humidity devices have led to an improvement in the signs and symptoms in MGD patients. Likewise, eyelid massaging and cleaning devices are also beneficial for ocular signs and symptoms; however, patients usually need more than one session to maintain the therapeutic effect. Thermal pulsation has been reported to be more efficient than other strategies, and the effects can last up to 12 months. Moreover, intense pulsed light therapy has been demonstrated to improve ocular signs and symptoms alone and in combination with other therapies. Proper counseling of clinicians considering MGD status and patient compliance will help patients to undergo the adequate technique that best suits their condition.

Potential Therapeutic Role of Carnitine and Acetylcarnitine in Neurological Disorders.

BACKGROUND: Current therapy of neurological disorders has several limitations. Although a high number of drugs are clinically available, several subjects do not achieve full symptomatic remission. In recent years, there has been an increasing interest in the therapeutic potential of L-carnitine (LCAR) and acetyl-L-carnitine (ALCAR) because of the multiplicity of actions they exert in energy metabolism, as antioxidants, neuromodulators and neuroprotectors. They also show excellent safety and tolerability profile. OBJECTIVE: To assess the role of LCAR and ALCAR in neurological disorders. METHODS: A meticulous review of the literature was conducted in order to establish the linkage between LCAR and ALCAR and neurological diseases. RESULTS: LCAR and ALCAR mechanisms and effects were studied for Alzheimer's disease, depression, neuropathic pain, bipolar disorder, Parkinson's disease and epilepsy in the elderly. Both substances exert their actions mainly on primary metabolism, enhancing energy production, through ß-oxidation, and the ammonia elimination via urea cycle promotion. These systemic actions impact positively on the Central Nervous System state, as Ammonia and energy depletion seem to underlie most of the neurotoxic events, such as inflammation, oxidative stress, membrane degeneration, and neurotransmitters disbalances, present in neurological disorders, mainly in the elderly. The impact on bipolar disorder is controversial. LCAR absorption seems to be impaired in the elderly due to the decrease of active transportation; therefore, ALCAR seems to be the more effective option to administer. CONCLUSION: ALCAR emerges as a simple, economical and safe adjuvant option in order to impair the progression of most neurological disorders.

L-Carnitine supplementation to reverse hyperammonemia in a patient undergoing chronic valproic acid treatment: A case report.

Valproic acid is a broad-spectrum anticonvulsant that has also gained attention in the psychiatric setting. With respect to safety, valproic acid may induce a seemingly rare condition, hyperammonemia, which can induce a wide variety of symptoms ranging from irritability to coma. The proposed mechanism of hyperammonemia involves depletion of carnitine and overproduction of a toxic metabolite, 4-en-valproic acid, both of which impair the urea cycle and thus ammonia elimination. Carnitine is a commonly used antidote for acute intoxication of valproic acid, but is not a therapeutic option for management of chronic adults with adverse effects related to valproic acid. We herein report a case involving a woman with epilepsy who developed hyperammonemia after a change in her anticonvulsant therapy. She reported increased seizures and gastrointestinal disturbances. Her ammonia, valproic acid, 4-en-valproic acid, and carnitine levels were monitored. Her ammonia level was elevated and her carnitine level was at the inferior limit of the population range. She was supplemented with carnitine at 1 g/day. After 1 month, her ammonia level decreased, her carnitine level increased, and her seizures were better controlled. Carnitine supplementation was useful for reversal of her hyperammonemia, allowing her to continue valproic acid for seizure control.

Antiepileptic drugs: Energy-consuming processes governing drug disposition.

Diffusion is not the main process by which drugs are disposed throughout the body. Translational movements of solutes given by different energy-consuming mechanisms are required in order to dispose them efficiently. Membrane transportation and cardiac output distribution are two effective processes to move the molecules among different body sites. Gastrointestinal-blood cycling constitutes a supplementary way to regulate the distribution of molecules between the non-hepatic organs and the liver. Any change in the relative supply of drug molecules among eliminating organs could modify their clearance from the body. Either the nonlinear phenytoin (PHT) pharmacokinetic response or the influence that carbamazepine (CBZ) exerts on PHT exposure could be explained throughout their efflux transporter inducer abilities. Cardiac output distribution difference between the individuals might also explain the dual CBZ-over-PHT interaction response. Finally, valproic acid (VPA) pharmacokinetics can be understood by adding to these mechanisms of transportation its ability to cross the mitochondrial membrane of the hepatocyte.

Hyperammonemia associated with valproic acid concentrations.

Valproic acid, a branched short-chain fatty acid, has numerous action mechanisms which turn it into a broad spectrum anticonvulsant drug and make its use possible in some other pathologies such as bipolar disorder. It is extensively metabolized in liver, representing ß -oxidation in the mitochondria one of its main metabolic route (40%). Carnitine is responsible for its entry into the mitochondria as any other fatty acid. Long-term high-dose VPA therapy or acute VPA overdose induces carnitine depletion, resulting in high levels of ammonia in blood. As a high correlation between salivary valproic acid levels and plasma ultrafiltrate levels was found in humans, saliva becomes a promising monitoring fluid in order to study valproic acid pharmacokinetics and its toxic effect. Extended-release (twice daily) formulations of valproic acid or carnitine supplementation are the proposed two therapeutic strategies in order to reverse hyperammonemia.

Experiencia Uruguaya en Atención Farmacéutica activa en la comunidad / Uruguayan experience in community-wide active pharmaceutical care

Objetivo: realizar una actividad de difusión a la población sobre el uso racional de medicamentos, mediante la inserción de los estudiantes en el equipo de salud y analizar los datos farmacoterapéuticos obtenidos de esta actividad educativa. Métodos: en la vía pública se instaló una carpa de Atención Farmacéutica durante tres días donde participaron químicos farmacéuticos y médicos, quienes impartieron charlas sobre diferentes temas de salud preponderantes en la población uruguaya. Asimismo, los alumnos de Atención Farmacéutica, como parte de su formación práctica, participaron de esta actividad mediante la realización de entrevistas a los transeúntes, llenado de fichas de perfiles farmacoterapéuticos y de consumo de plantas medicinales, elaboradas para este fin, y la entrega de folletos informativos. A partir de las fichas farmacoterapéuticas se desarrolló un trabajo de investigación. Resultados: los alumnos del curso participaron de forma activa en el llenado de las fichas farmacoterapéuticas y mantuvieron una comunicación fluida con los asistentes a la carpa y con los profesionales de la salud. Se completaron 117 fichas farmacoterapéuticas (90 mujeres y 27 hombres). El 60 por ciento de los entrevistados consumía plantas medicinales. Sesenta personas recibían cuatro o más especialidades farmacéuticas. Las drogas antihipertensivas resultaron las más utilizadas. Veintitrés personas presentaban hipotiroidismo y dos personas de este grupo recibían litio para trastorno bipolar. Entre el grupo de mujeres: 18 tomaban ansiolíticos, 12 antidepresivos, 7 hipnóticos y 2 antisicóticos. Diecinueve personas manifestaron tener colesterol alto y 14 recibían medicación. Catorce presentaban artrosis y 10 estaban en tratamiento con analgésicos. Nueve personas presentaban gastritis, grupo este con un alto consumo de café y mate. Seis mujeres mayores de 50 años, declararon tener osteoporosis y solo tres recibían medicación a base de calcio y vitamina D. Conclusiones: la experiencia tuvo aceptación por el público y muestra una vez más la necesidad de la población de una educación sanitaria responsable(AU)

Objective: to conduct a health promotion activity for the population on the rational use of drugs, in which students participate with the rest of the health team and to analyze pharmacotherapeutic data collected in this educational activity. Methods: a pharmaceutical care tent was put up on a public area for three days where physicians and pharmacists participated, giving talks on various prevailing health issues that affect the Uruguayan population. Also, a number of pharmaceutical care students, as part of their practical training, participated in this activity by interviewing passers-by, filling out forms of pharmacotherapeutic profiles and of consumption of herbal medicines and giving people some information leaflets. A research study was carried out from the data collected in these pharmacotherapeutic forms. Results: the students actively participated in filling out the pharmacotherapeutic profiles and keeping fluent communication with the audience and with health professionals. One hundred and seventeen pharmacotherapeutic forms were completed (90 women and 27 men). Sixty percent of the interviewed people consumed herbal medicines. Sixty people received four or more medicines. Antihypertensive drugs were the most commonly used. Twenty three people had hypothyroidism and two people in this group were treated with lithium for bipolar disorder. In the female group 18 took anxiolytics, 12 antidepressants, 7 hypnotic drugs and 2 antipsychotic drugs. Nineteen people reported high cholesterol condition and 14 of them took medication. Fourteen had osteoarthritis and 10 were under painkiller treatment. Nine people had gastritis and this group showed high consumption rates of coffee and mate. Six women over 50 years old reported having osteoporosis and only 3 of them took calcium-based medication and vitamin D. Conclusions: the experience was well-accepted by the public and once again, the need for responsible health education of the population was demonstrated(AU)

In vitro study of intestinal transport of inorganic and methylated arsenic species by Caco-2/HT29-MTX cocultures.

This study characterizes intestinal absorption of arsenic species using in vitro system Caco-2/HT29-MTX cocultures in various proportions (100/0 to 30/70). The species assayed were As(V), As(III), monomethylarsonic acid [MMA(V)], monomethylarsonous acid [MMA(III)], dimethylarsinic acid [DMA(V)], and dimethylarsinous acid [DMA(III)]. The results show that the apparent permeability (P(app)) values of pentavalent species increase significantly in the Caco-2/HT29-MTX cocultures in comparison with the Caco-2 monoculture, probably because of enhancement of paracellular transport. For MMA(III) and DMA(III), P(app) decreases in the Caco-2/HT29-MTX cell model, and for As(III), there is no change in P(app) between the two culture models. Transport studies of arsenic solubilized from cooked foods (rice, garlic, and seaweed) after applying an in vitro gastrointestinal digestion showed that arsenic absorption also varies with the model used, increasing with the incorporation of HT29-MTX in the culture. These results show the importance of choosing a suitable in vitro model when evaluating intestinal arsenic absorption processes.

Systemic and presystemic conversion of carbamazepine to carbamazepine-10, 11-epoxide during long term treatment / Conversão da carbamazepina para 10, 11-epóxido-carbamazepina no tratamento prolongado

INTRODUCTION: Carbamazepine (CBZ) undergoes biotransformation, being CYP3A4 the major cytocrome P450 (CYP) enzyme catalyzing the carbamazepine-10,11-epoxide (EPOX) formation, which is quantitatively the most important pathway in CBZ metabolism. There is evidence of dose-dependent elimination of this drug due to its autoinduction capacity. Moreover, published data showed an incomplete bioavailability of CBZ since its absorption increases when grapefruit juice was administered. Both CYP3A4 and MRP2 (located in the enterocyte) are autoinduced during long term use of CBZ. As the other enzymes involved in CBZ metabolism are negligible in the gut, presystemic biotransformation through CYP3A4 could be responsible for the bioavailability of the drug as well as EPOX formation. OBJECTIVE: The purpose of our study was to assess the importance of presystemic formation of EPOX during the autoinduction of CBZ versus the daily administered dose. PATIENTS AND METHODS: 40 adults (average age: 28 years) and 29 children (average age: 9 years) receiving CBZ as monotherapy were included in the study. CBZ and EPOX plasma concentrations were analyzed by a previous validated HPLC method. RESULTS AND CONCLUSION: The results obtained confirmed the metabolic induction after chronic administration and provided new elements to suggest a strong contribution of dose-dependent bioavailability in the non linear kinetics of CBZ.

Uso del árnica homeopática como antiinflamatorio en los edemas traumáticos faciales / Use of homeopathic arnica as anti-inflammatory agent in facial edema from trauma

Se trataron 45 pacientes de uno y otro sexos en edades comprendidas entre 16 a 49 años que acudieron al Servicio de Cirugía Máxilo-Facial con el diagnóstico clínico de edema facial traumático. A 30 de ellos (grupo de estudio) se le administró árnica homeopática con el propósito de evaluar la eficiencia de este medicamento como antiinflamatorio. A los 15 restantes (grupo control) se le administró piroxicam como antiinflamatorio. El tratamiento con árnica consistió en suministrar 10 gotas con una dinamización a la 6, 30 y 200 CH, mientras con piroxicam, 40 mg diarios divididos en 2 dosis. Los pacientes se evaluaron al tercer, quinto y séptimo días. De acuerdo con la remisión del edema en el tiempo se evaluaron de bien, regular y mal. El árnica homeopática fue efectiva en el 96,6 por ciento y el piroxicam en el 66,7 por ciento de los pacientes estudiados(AU)

Uso del árnica homeopática como antiinflamatorio en los edemas traumáticos faciales / Use of homeopathic arnica as anti-inflammatory agent in facial edema from trauma

Se trataron 45 pacientes de uno y otro sexos en edades comprendidas entre 16 a 49 años que acudieron al Servicio de Cirugía Máxilo-Facial con el diagnóstico clínico de edema facial traumático. A 30 de ellos (grupo de estudio) se le administró árnica homeopática con el propósito de evaluar la eficiencia de este medicamento como antiinflamatorio. A los 15 restantes (grupo control) se le administró piroxicam como antiinflamatorio. El tratamiento con árnica consistió en suministrar 10 gotas con una dinamización a la 6, 30 y 200 CH, mientras con piroxicam, 40 mg diarios divididos en 2 dosis. Los pacientes se evaluaron al tercer, quinto y séptimo días. De acuerdo con la remisión del edema en el tiempo se evaluaron de bien, regular y mal. El árnica homeopática fue efectiva en el 96,6 por ciento y el piroxicam en el 66,7 por ciento de los pacientes estudiados