A Chinese medicine called Danggui Longhui may be a new clinically relevant clozapine inducer: Two case reports identified by therapeutic drug monitoring.

BACKGROUND: Danggui Longhui is a traditional Chinese medicine made from the dried root of Angelica sinensis. It is used in psychiatric patients in China to reduce associated constipation. In a population pharmacokinetic model in olanzapine patients from Beijing Anding Hospital, we demonstrate that dangguilonghui tablets doubled olanzapine clearance, indicating the induction of olanzapine metabolism. Olanzapine metabolism is similar to clozapine metabolism. METHODS: Two cases of possible clozapine induction using dangguilonghui tablets 4 g/day were identified in Beijing Anding Hospital. Dividing the minimum therapeutic concentration of 350 ng/mL by the concentration-to-dose (C/D) ratio provides the minimum therapeutic dose. RESULTS: Case 1 was a female smoker on clozapine for 415 days. The mean of 6 clozapine C/D ratios associated with smoking provided a minimum therapeutic dose of 267 mg/day. There were 6 steady-state concentrations on the combination of valproic acid and dangguilonghui tablets, which provided a much higher minimum therapeutic dose of 833 mg/day. Four steady-state clozapine C/D ratios based on smoking and valproate after 4 months of carbamazepine 200 mg/day provided a minimum therapeutic dose of 603 mg/day. Case 2 was a female non-smoker on clozapine for 58 days. She had 3 clozapine C/D ratios on dangguilonghui tablets with a mean of 0.30 ng/mL providing a minimum therapeutic dose of 1167 mg/day. CONCLUSION: Future clinical studies with repeated measures need to replicate the possibility that dangguilonghui tablets are a moderate-to-strong inducer of clozapine metabolism as suggested by these two limited cases.

Etiquetado frontal de advertencia nutricional de alimentos y bebidas pre-envasados. Postura intersectorial de expertos en Centro América y República Dominicana / Front-of-package warning labelling system for pre-packaged foods and beverages: an intersectoral position of expertsin Central American and Dominican Republic

La región latinoamericana ha sido pionera en la implementación del etiquetado frontal de advertencia nutricional (EFAN), mismo que ha demostrado su eficacia y efectividad para identificar correctamente cuando un producto contiene cantidades excesivas de nutrientes asociados a Enfermedades no transmisibles (ENT). Sin embargo, ningún país del Sistema de la Integración Centroamericana (SICA); que incluye a Belice, Costa Rica, El Salvador, Guatemala, Honduras, Nicaragua, Panamá y República Dominicana, lo ha adoptado. Por esta razón, el Instituto de Nutrición de Centro América y Panamá, convocó a un grupo de expertos de la academia y la sociedad civil con el objetivo de establecer una postura técnica, basada en la mejor evidencia científica, en relación al etiquetado frontal para los nutrientes críticos de alimentos y bebidas pre- envasados en la región centroamericana. Se presenta evidencia específica de la región del SICA que demuestran la superioridad del EFAN frente a otros etiquetados como las Guías Diarias de Alimentación (GDA), el semáforo y el Nutriscore para seleccionar opciones más saludables. Dentro del marco de los derechos de la niñez y de los consumidores, se brindan argumentos y se hace un llamado a los gobiernos para la pronta adopción del EFAN como una política costo-efectiva para la prevención de ENT. Además, se proveen recomendaciones para su monitoreo y evaluación, así como recomendaciones de otras políticas costo-efectivas como la regulación de la publicidad de alimentos no saludables dirigido a la niñez y adolescencia, entre otros, para la prevención de las ENT y la creación de ambientes y sistemas alimentarios más saludables y sostenibles(AU)

The Latin American region has been a pioneer in the implementation of a front- of-pack warning labeling system (FOPWL), which has demonstrated its efficacy and effectiveness in correctly identifying when a product contains excessive amounts of nutrients associated with Non-Communicable Diseases (NCDs). However, countries of the Central American Integration System (SICA); which includes Belize, Costa Rica, El Salvador, Guatemala, Honduras, Nicaragua, Panama and the Dominican Republic, have no adopted it. For this reason, the Institute of Nutrition of Central America and Panama convened a group of experts from academia and civil society with the aim of establishing an evidence-based technical position, in relation to front-of-pack labelling for critical nutrients of pre-packaged foods and beverages in the Central American region. Specific evidence from the SICA region demonstrating the superiority of FOPWL over other labels such as the Guideline Daily Amount (GDA), the traffic light and Nutriscore to select healthier choices is presented. Within the framework of children's and consumer rights, arguments are provided, and a call is made to governments for the prompt adoption of FOPWL as a cost-effective policy for the prevention of NCDs. In addition, recommendations for its monitoring and evaluation are provided, as well as recommendations for other cost-effective policies such as the regulation of unhealthy food advertising aimed at children and adolescents, among others, for the prevention of NCDs and the creation ofhealthier and more sustainable environments and food systems(AU)

The Impact of Smoking, Sex, Infection, and Comedication Administration on Oral Olanzapine: A Population Pharmacokinetic Model in Chinese Psychiatric Patients.

BACKGROUND AND OBJECTIVE: Prior olanzapine population pharmacokinetic (PPK) models have focused on the effects of sex and smoking on olanzapine clearance. This PPK model in Chinese adult psychiatric patients also investigated the influence of comedications and co-occurrence of infections on olanzapine clearance, and explored how to personalize oral olanzapine dosage in the clinical setting. METHODS: A total of 1546 serum concentrations from 354 patients were collected in this study. A one-compartment model with first-order absorption was employed to develop the PPK model using a nonlinear mixed-effects modeling approach. Covariates included demographic parameters, co-occurrence of infection and concomitant medications (including dangguilonghui tablets, a Chinese herbal medicine for constipation). Bootstrap validation (1000 runs) and external validation of 50 patients were employed to evaluate the final model. Simulations were performed to explore the personalization of olanzapine dosing after stratification by sex, smoking, and comedication with valproate. RESULTS: Typical estimates for the absorption rate constant (Ka), apparent clearance (CL/F), and apparent distribution volume (V/F) were 0.30 h-1, 12.88 L/h, and 754.41 L, respectively. Olanzapine clearance was increased by the following variables: 1.23-fold by male sex, 1.23-fold by smoking, 1.23-fold by comedication with valproate, 1.16-fold by sertraline, and 2.01-fold by dangguilonghui tablets. Olanzapine clearance was decreased by the following variables: 0.75-fold by co-occurrence of infection, 0.70-fold by fluvoxamine, and 0.78-fold by perphenazine. The model evaluation indicated that the final model's performance was good, stable, and precise. CONCLUSION: This study contributes to the personalization of oral olanzapine dosing, but further studies should be performed to verify the effects of infection and comedications, including valproate and dangguilonghui.

This study included a total of 1546 serum olanzapine concentrations from 354 Chinese adult psychiatric patients that were analyzed by a complex mathematical model. The goal was to explore how oral olanzapine is eliminated from the body in Chinese psychiatric patients and how to personalize its dosing. Prior studies using similar complex mathematical models only studied the effects of sex and smoking on olanzapine elimination. This study also investigated the influence of co-occurrence of infection and comedications, including dangguilonghui tablets. This is a Chinese herbal medicine used to treat constipation, including constipation secondary to olanzapine treatment. Olanzapine elimination was increased by the following variables: 1.23-fold by male sex, 1.23-fold by smoking, 1.23-fold by comedication with valproate, 1.16-fold by sertraline, and 2.01-fold by dangguilonghui tablets. Olanzapine elimination was decreased by the following variables: 0.75-fold by co-occurrence of infection, 0.70-fold by fluvoxamine, and 0.78-fold by perphenazine. This study contributes to the improvement of oral olanzapine dosing personalization, but further studies are needed to verify the effects of infection and comedications, including valproate and dangguilonghui.

Measuring individual benefits of psychiatric treatment using longitudinal binary outcomes: Application to antipsychotic benefits in non-cannabis and cannabis users.

We present and evaluate a method for predicting individual treatment benefits based on random effects logistic regression models of binary outcomes that change over time. The method uses empirical Bayes predictors based on patients' characteristics and responses to treatment. It is applicable to both 1-dimentional and 2-dimentional personalized medicine models. Comparisons between predicted and true benefits for simulated new patients using correlations, relative biases and mean-squared errors were used to evaluate prediction performance. The predicted benefits had relatively small biases and relatively high correlations with the true benefits in the simulated new patients. The predictors also captured estimated overall population trends in the evolution of individual benefits. The proposed approach can be used to retrospectively evaluate patients' responses in a clinical trial, or to retrospectively or prospectively predict individual benefits of different treatments for new patients using patients' characteristics and previous responses. The method is used to examine changes in the disorganized dimension of antipsychotic-naïve patients from an antipsychotic randomized clinical trial. Retrospective prediction of individual benefits revealed that more cannabis users had slower and lower responses to antipsychotic treatment as compared to non-cannabis users, revealing cannabis use as a negative prognostic factor for psychotic disorders in the disorganized dimension.

Exploring the Prevalence of Clozapine Phenotypic Poor Metabolizers in 4 Asian Samples: They Ranged Between 2% and 13.

PURPOSE/BACKGROUND: Clozapine clearance is influenced by sex, smoking status, ethnicity, coprescription of inducers or inhibitors, obesity, and inflammation. In 126 Beijing inpatients, we measured repeated trough steady-state serum concentrations and identified 4% (5/126) who were phenotypical poor metabolizers (PMs); none were ultrarapid metabolizers (UMs). They were defined as being 2 SDs beyond the means of total clozapine concentration/dose ratios stratified by sex and smoking. Using this definition, this study explores the prevalence of PMs and UMs using data from 4 already published Asian samples. Three samples were East Asian (Beijing 2, Taipei, and Seoul); one was from South India (Vellore). FINDINGS/RESULTS: The prevalence of phenotypical PMs ranged from 2% to 13%, but inflammation was not excluded. The prevalence was 7% (14/191) for Beijing 2, 11% (8/70) for Taipei, 13% (9/67) for Seoul, and 2% (2/101) for the Vellore sample. Five phenotypic PMs appeared to be associated with extreme obesity. Phenotypic UM prevalence ranged from 0% to 1.6% but may be partly explained by lack of adherence. A Vellore phenotypic UM appeared to be associated with induction through high coffee intake. IMPLICATIONS/CONCLUSIONS: Approximately 10% of Asians may be clozapine PMs and may need only 50 to 150 mg/d to get therapeutic concentrations. Future studies combining gene sequencing for new alleles with repeated concentrations and careful control of confounders including inhibitors, inflammation, and obesity should provide better estimations of the prevalence of phenotypic clozapine PMs across races. Clozapine UM studies require excluding potent inducers, careful supervision of compliance in inpatient settings, and multiple serum concentrations.

Clinically Significant Drug-Drug Interactions with Agents for Attention-Deficit/Hyperactivity Disorder.

This article provides an overview of the pharmacokinetic drug-drug interactions (DDIs) for agents prescribed for attention-deficit/hyperactivity disorder (ADHD). Polypharmacy in the treatment of patients with ADHD leads to high exposures to DDIs and possibly adverse safety outcomes. We performed a systematic search of DDI reports for ADHD agents in Embase and Medline. We also searched for agents in the pharmacological pipeline, which include (1) mazindol, molindone and viloxazine, which were previously prescribed for other indications; (2) centanafadine and AR-08, never before approved; and (3) two extracts (Polygala tenuifolia extract and the French maritime pine bark extracts). The identified literature included case reports, cross-sectional, cross-over and placebo-controlled studies of patient cohorts and healthy volunteers. The DDIs were classified as follows: ADHD agents acting as perpetrators, i.e., affecting the clearance of co-prescribed agents (victim drugs), or ADHD agents being the victim drugs, being affected by other agents. Ratios for changes in pharmacokinetic parameters before and after the DDI were used as a rough estimate of the extent of the DDI. Alcohol may increase plasma dextroamphetamine concentrations by presystemic effects. Until studies are done to orient clinicians regarding dosing changes, clinicians need to be aware of the potential for cytochrome P450 (CYP) 2D6 inhibitors to increase amphetamine levels, which is equivalent to increasing dosages. Atomoxetine is a wide therapeutic window drug. The CYP2D6 poor metabolizers who do not have CYP2D6 activity had better atomoxetine response, but also an increased risk of adverse effects. CYP2D6 inhibitors have been used to increase atomoxetine response in CYP2D6 extensive metabolizers. Guanfacine is mainly metabolized by CYP3A4, which can be induced and inhibited. The package insert recommends that in guanfacine-treated patients, after adding potent CYP3A4 inducers, the guanfacine dose should be doubled; after adding potent CYP3A4 inhibitors the guanfacine dose should be halved. Based on a phenobarbital case report and our experience with CYP3A4-metabolized antipsychotics, these correction factors may be too low. According to two case reports, carbamazepine is a clinically relevant inducer of methylphenidate (MPH). A case series study suggested that MPH may be associated with important elevations in imipramine concentrations. Due to the absence of or limitations in the data, no comments for clinicians can be provided on the pharmacokinetic DDIs for clonidine, centanafadine, mazindol, molindone, AR-08, P. tenuifolia extract and the French maritime pine bark extracts. According to currently available data, clinicians should not expect that ADHD drugs modify each other's serum concentrations. A summary table for clinicians provides our current recommendations on pharmacokinetic DDIs of ADHD agents based on our literature review and the package inserts; whenever it was possible, we provide information on serum concentrations and dose correction factors. There will be a need to periodically update these recommendations and these correction factors as new knowledge becomes available.

Ethnopsychopharmacology study of patients' beliefs regarding concerns about and necessity of taking psychiatric medications.

OBJECTIVE: The aim of this study was to examine whether or not cultural differences influence beliefs about the necessity of taking prescribed psychiatric drugs and concern about their adverse effects in psychiatric outpatients in Spain, Argentina, and Venezuela. METHODS: This cross-sectional study included 1,372 adult psychiatric outpatients using 2,438 psychotropic drugs and was designed to assess outpatients' beliefs about their prescribed medication. Patients completed sociodemographic, clinical questionnaires, and the Beliefs about Medicines Questionnaire Specific Scale and registered scores ranging from 1 to 5 on each of two subscales: concern and necessity. A "necessity-concern differential" was obtained by calculating the difference (range -4 to +4). RESULTS: The global score, including all drugs in the total sample, had a mean necessity score of 3.50 ± 0.95, a mean concern score of 2.97 ± 0.99, and a mean differential score of 0.54 ± 1.42. The concern and necessity mean scores varied significantly across these three culturally Hispanic countries, probably across drug classes, and were associated with treatment duration. On the other hand, age and education played a very limited role. CONCLUSIONS: Understanding the diverse effects of culture and society on these attitudes is highly relevant for the development of responsive mental health services in multicultural societies.

Effect of stevia and citric acid on the stability of phenolic compounds and in vitro antioxidant and antidiabetic capacity of a roselle (Hibiscus sabdariffa L.) beverage.

Plant infusions are consumed due to their beneficial effects on health, which is attributed to their bioactive compounds content. However, these compounds are susceptible to degradation during processing and storage. The objective of this research was to evaluate the effect of stevia and citric acid on the stability of phenolic compounds, antioxidant capacity and carbohydrate-hydrolysing enzyme inhibitory activity of roselle beverages during storage. The optimum extraction conditions of roselle polyphenolic compounds was of 95 °C/60 min, which was obtained by a second order experimental design. The incorporation of stevia increased the stability of colour and some polyphenols, such as quercetin, gallic acid and rosmarinic acid, during storage. In addition, stevia decreased the loss of ABTS, DPPH scavenging activity and α-amylase inhibitory capacity, whereas the incorporation of citric acid showed no effect. These results may contribute to the improvement of technological processes for the elaboration of hypocaloric and functional beverages.

La selección de la potencia en la prescripción homeopática / The selection of the power in homeopathic prescribing

La prescripción del medicamento homeopático no se limita a la observación detallada de los síntomas del paciente ni a la habilidad para identificar al remedio más semejante. En cumplimiento a lo dicho por el doctor Samuel Hahnemann, en cuanto a que el tratamiento homeopático tiene el objetivo de producir una enfermedadartificial ligeramente más fuerte que la enfermedad natural que se pretende curar, el médico debe apegarse a ciertas consideraciones para elegir la potencia correcta que le permita restablecer la salud del paciente de la manera más rápida, suave y duradera posible.En este artículo se exponen aspectos teóricos y reflexiones basadas en la práctica que ayudarán a que el médico homeópata se forme un criterio más amplio sobre el uso de potencias bajas, medias y altas, de acuerdo con los principios desemejanza e individualidad. (AU)

The prescription of homeopathic medicine is not limited to the detailed observation of the patient’s symptoms or the ability to identify the most similar remedy. In compliance with the said by Dr. Samuel Hahnemann, in that homeopathic treatment aims to produce a slightly stronger artificial disease that natural disease to be cured, the physician must adhere to certain considerations to choose the correct power that restores the health of the patient as quickly, soft and durable as possible. In this article theoretical and practice-based reflections that will help the homeopath a broader view on the use of low, medium and high, according to the principles of similarity and individuality powers to form aspects are discussed. (AU)

La selección de la potencia en la prescripción homeopática / The selection of the power in homeopathic prescribing

La prescripción del medicamento homeopático no se limita a la observación detallada de los síntomas del paciente ni a la habilidad para identificar al remedio más semejante. En cumplimiento a lo dicho por el doctor Samuel Hahnemann, en cuanto a que el tratamiento homeopático tiene el objetivo de producir una enfermedadartificial ligeramente más fuerte que la enfermedad natural que se pretende curar, el médico debe apegarse a ciertas consideraciones para elegir la potencia correcta que le permita restablecer la salud del paciente de la manera más rápida, suave y duradera posible.En este artículo se exponen aspectos teóricos y reflexiones basadas en la práctica que ayudarán a que el médico homeópata se forme un criterio más amplio sobre el uso de potencias bajas, medias y altas, de acuerdo con los principios desemejanza e individualidad.

The prescription of homeopathic medicine is not limited to the detailed observation of the patient’s symptoms or the ability to identify the most similar remedy. In compliance with the said by Dr. Samuel Hahnemann, in that homeopathic treatment aims to produce a slightly stronger artificial disease that natural disease to be cured, the physician must adhere to certain considerations to choose the correct power that restores the health of the patient as quickly, soft and durable as possible. In this article theoretical and practice-based reflections that will help the homeopath a broader view on the use of low, medium and high, according to the principles of similarity and individuality powers to form aspects are discussed.