Pharmacological Interaction Between Cannabidiol and Tramadol on Experimental Diabetic Neuropathic Pain: An Isobolographic Analysis.

Introduction: Diabetic neuropathies are the most prevalent chronic complications of diabetes, characterized by pain and substantial morbidity. Although many drugs have been approved for the treatment of this type of pain, including gabapentin, tramadol (TMD), and classical opioids, it is common to report short-term results or potentially severe side effects. TMD, recommended as a second-line treatment can lead to unwanted side effects. Cannabidiol (CBD) has been gaining attention recently due to its therapeutic properties, including pain management. This study aimed to characterize the pharmacological interaction between CBD and TMD over the mechanical allodynia associated with experimental diabetes using isobolographic analysis. Materials and Methods: After diabetes induction by streptozotocin (STZ), diabetic rats were systemically treated with CBD or TMD alone or in combination (doses calculated based on linear regression of effective dose 40% [ED40]) and had the mechanical threshold evaluated using the electronic Von Frey apparatus. Both experimental and theoretical additive ED40 values (Zmix and Zadd, respectively) were determined for the combination of CBD plus TMD in this model. Results: Acute treatment with CBD (3 or 10 mg/kg) or TMD (2.5, 5, 10, or 20 mg/kg) alone or in combination (0.38+1.65 or 1.14+4.95 mg/kg) significantly improved the mechanical allodynia in STZ-diabetic rats. Isobolographic analysis revealed that experimental ED40 of the combination (Zmix) was 1.9 mg/kg (95% confidence interval [CI]=1.2-2.9) and did not differ from the theoretical additive ED40 2.0 mg/kg (95% CI=1.5-2.8; Zadd), suggesting an additive antinociceptive effect in this model. Conclusions: Using an isobolographic analysis, these results provide evidence of additive pharmacological interaction between CBD and TMD over the neuropathic pain associated with experimental diabetes induced by STZ.

Several reasons why ketamine as a neuroplastic agent may have failed to prevent postoperative delirium: Implications for future protocols.

Ketamine exerts anti-inflammatory, neuroprotective and neuroplastic activity, therefore it may counteract the neurotoxic processes underlying postoperative delirium. However, the majority of studies in this field failed. We identified several pharmacological reasons why these studies may have failed, together with suggestions of how to remediate them. Among them, the interaction with intravenous general anesthetics exerting the opposite effect on GABA interneurons than ketamine may be of principal importance. We suggest biomarkers which may elucidate the influence of this interaction on the different steps of neuroplastic pathways. We hypothesize that administering ketamine before or after general anesthesia could both prevent the interactions and strengthen the effect of ketamine by timing surgery within the climax of ketamine-induced neuroplastic changes or by stabilizing AMPA receptors. It is vital to deal with these questions because the protocols of ongoing studies are based again on the administration of ketamine during general anesthesia (the major identified pitfall).

Structure-based virtual screening discovers novel kidney-type glutaminase inhibitors.

Glutaminase (GLS) serves a critical bioenergetic role for malignant tumor growth and has become a valuable therapeutic target for cancer treatment. Herein, we performed a structure-based virtual screening to discover novel GLS inhibitors and provide information for developing new GLS inhibitors. We identified critical pharmacological interactions in the GLS1 binding site by analyzing the known GLS1 inhibitors and selected potential inhibitors based on their docking score and pharmacological interactions. The inhibitory effects of compounds were further confirmed by enzymatic and cell viability assays. We treated colorectal cancer and triple-negative breast cancer cells with the selected candidates and measured the inhibitory efficacy of hit compounds on cell viability. In total, we identified three GLS1 inhibitors. The compounds identified from our structure-based virtual screening methodology exhibited great anticancer potential as a lead targeting glutamine metabolism.

In vivo evaluation of pharmacokinetic drug-drug interactions between fluorinated pyrimidine anticancer drugs, 5-fluorouracil and capecitabin, and an anticoagulant, warfarin.

Warfarin is a common anticoagulant and has demonstrated interactions with several drugs. Among them, as a serious adverse event, a case of death due to the enhanced warfarin action owing to its combined use with a fluoropyrimidine anticancer drug has been reported, but the detailed mechanism has not been elucidated.Some reports have advocated that fluorinated pyrimidine anticancer drugs reduce cytochrome P450 2C9 expression, leading to the enhanced pharmacological effects of warfarin.The purpose of this study was to clarify the mechanisms of drug-drug interactions between warfarin and 5-fluorouracil (5-FU) and capecitabine in vivo using rats. Rats were administered warfarin in combination with 5-FU (15 mg/kg/d) or capecitabine (15 mg/kg/d) for 7 d. Prothrombin time (PT) and activated partial thromboplastin time were significantly prolonged in the warfarin plus 5-FU or capecitabine groups compared with those in the warfarin alone group. No significant difference was observed in the area under the plasma concentration-time curve of the warfarin alone group compared with the warfarin with 5-FU or capecitabine groups.These data suggest that the enhancement of warfarin efficacy caused by the combination of 5-FU or capecitabine was due to a pharmacological interaction rather than a pharmacokinetic interaction.

Análisis de las interacciones farmacológicas y recomendaciones terapéuticas asociadas a la utilización de isavuconazol / Analysis of drug interactions and therapeutic recommendations associated with the use of isavuconazole

Objetivos: Identificar, describir las interacciones farmacológicas potenciales de isavuconazol, estudiar el impacto clínico de aquellas más relevantes y establecer recomendaciones terapéuticas para las encontradas en pacientes ingresados.Métodos: Estudio observacional descriptivo retrospectivo que incluyó todos los pacientes tratados con isavuconazol desde su comercialización hasta diciembre 2019.Se recogieron variables demográficas y fármacos concomitantes a isavuconazol durante más de 48 horas que recibió el paciente. Se revisaron los tratamientos con Lexicomp® para detectar interacciones potenciales, se analizó su mecanismo de acción y se relacionó con los fármacos implicados, estableciéndose recomendaciones terapéuticas.Para establecer el impacto clínico, se revisaron las historias clínicas de los pacientes con interacciones de mayor gravedad (D y X de Lexicomp®). En el caso de hallar alguna reacción adversa, se aplicó el algoritmo de Horn para establecer la probabilidad de que el efecto esté producido por la interacción farmacológica.Resultados: Se analizaron 84 ingresos en 59 pacientes. Se produjeron 209 interacciones potenciales en el 84,5% de los ingresos. La mayoría, 84,7% fueron de carácter moderado (categoría C), la más frecuente con tacrolimus. El principal mecanismo de acción fue el efecto inhibidor sobre el citocromo CYP3A4 de isavuconazol (82,8%). Se detectó una paciente con aumento de fosfatasa alcalina coincidente con el inicio concomitante de isavuconazol y claritromicina. Al aplicar el algoritmo de Horn, se consideró la interacción como posible.Conclusiones: Se detectaron interacciones farmacológicas potenciales graves en un porcentaje inferior al 10% de los ingresos y solo se detectó una posible reacción adversa asociada a esta interacción, no pudiéndose clasificar como definitiva. (AU)

Objetive: Identify, describe the potential pharmacological interactions of isavuconazole, study the clinical impact of the most relevant ones and establish therapeutic recommendations for those found in hospitalized patients.Methods: Retrospective descriptive observational study that included all patients treated with isavuconazole from its marketing until December 2019.Demographic variables and drugs concomitant to isavuconazole for more than 48 hours received by the patient were collected. The treatments with Lexicomp® were reviewed to detect possible interactions, its mechanism of action was analyzed and it was related to the drugs involved, establishing therapeutic recommendations.To establish the clinical impact, the medical records of the patients with more severe interactions (D and X for Lexicomp®) were reviewed. In the case of finding any adverse reaction, Horn’s algorithm was applied to establish the probability that the effect is produced by the pharmacological interaction.Results: 84 admissions in 59 patients were analyzed. There were 209 potential interactions in 84.5% of the admissions. The majority, 84.7%, were of a moderate nature (category C), the most frequent with tacrolimus. The main mechanism of action was the inhibitory effect on cytochrome CYP3A4 of isavuconazole (82.8%).A patient with an increase in alkaline phosphatase coinciding with the concomitant initiation of isavuconazole and clarithromycin was detected. When applying Horn’s algorithm, the interaction is considered as possible.Conclusions: Potential serious drug interactions were detected in less than 10% of admissions and only one possible adverse reaction associated with this interaction was detected, and it could not be classified as definitive. (AU)

Quercetin decreases the antinociceptive effect of diclofenac in an arthritic gout-pain model in rats.

OBJECTIVE: To analyse the antinociceptive interaction between quercetin (QUER) and diclofenac (DIC) in experimental arthritic gout-pain. METHODS: The antinociceptive effect of DIC and QUER alone and in combination were evaluated using an arthritic gout-pain model. Pain was induced through intra-articular administration of uric acid in the rats and the treatments were administered 2 h later. Additionally, the cyclooxygenase (COX) activity was determined in rats treated with DIC, QUER and their combination. KEY FINDINGS: DIC induced a maximal effect of 69.7 ± 2.7% with 3.1 mg/kg; whereas QUER only produced 17.6 ± 2.6% with the maximal dose (316 mg/kg). Ten of twelve DIC + QUER combinations showed a lesser antinociceptive effect than DIC alone did (P < 0.05). Moreover, DIC reduced total-COX (70.4 ± 1.3 versus 52.4 ± 1.8 and 77.4 ± 9.0 versus 56.1 ± 1.3, P < 0.05) and COX-2 (60.1 ± 1.0 versus 42.4 ± 1.8 and 58.1 ± 2.4 versus 48.7 ± 1.3, P < 0.05) activity after 1 and 3 h, respectively. Nevertheless, only the COX-2 activity induced by DIC was prevented in the presence of QUER (63.2 ± 3.0 versus 60.1 ± 1.0 and 56.6 ± 1.3 versus 58.1 ± 2.4 at 1 and 3 h, respectively). CONCLUSIONS: All these data demonstrated that the simultaneous administration of QUER + DIC produces an unfavorable interaction on the antinociceptive effect of DIC. Therefore, this combination might not be recommendable to relieve arthritic gout-pain.

Increasing the Effectiveness of Pharmacotherapy in Psychiatry by Using a Pharmacological Interaction Database.

Recent studies have shown that the knowledge of pharmacological interaction databases in global psychiatry is negligible. The frequency of hospitalizations in the case of patients taking new psychoactive substances along with other drugs continues to increase, very often resulting in the need for polypharmacotherapy. The aim of our research was to make members of the worldwide psychiatric community aware of the need to use a pharmacological interaction database in their daily work. The study involved 2146 psychiatrists from around the world. Participants were primarily contacted through the LinkedIn Recruiter website. The surveyed psychiatrists answered 5 questions concerning case reports of patients taking new psychoactive substances along with other drugs. The questions were answered twice, i.e., before and after using the Medscape drug interaction database. The mean percentage of correct answers given by the group of psychiatrists who were studied separately in six individual continents turned out to be statistically significantly higher after using the pharmacological interaction database (p < 0.001). This also applies to providing correct answers separately, i.e., to each of the five questions asked concerning individual case reports (p < 0.001). Before using the drug interaction database, only 14.1% of psychiatrists stated that they knew and used this type of database (p < 0.001). In the second stage of the study, a statistically significant majority of subjects stated that they were interested in using the pharmacological interaction database from that moment on (p < 0.001) and expressed the opinion that it could be effective in everyday work (p < 0.001). Using a pharmacological interaction database in psychiatry can contribute to the effectiveness of pharmacotherapy.

Statin use and incident cardiovascular events in renal transplant recipients.

BACKGROUND: Statins achieve potent LDL lowering in the general population leading to a significant cardiovascular (CV) risk reduction. In renal transplant recipients (RTR) statins are included in treatment guidelines, however, conclusive evidence of improved cardiovascular outcomes has not been uniformly provided and concerns have been raised about simultaneous use of statins and the immunosuppressant cyclosporine. This study aimed to elucidate the effect of statins on a compound CV endpoint, comprised of ischaemic CV events and CV mortality in RTR, with subgroup analysis focussing on cyclosporine users. METHOD: 622 included RTR (follow-up 5.4 years) were matched based on propensity scores and dichotomized by statin use. Survival analysis was conducted. RESULTS: Cox regression showed that statin use was not significantly associated with the compound CV endpoint in a fully adjusted model (HR = 0.81, 95% CI = 0.53-1.24, P = .33). Subgroup analyses in RTR using cyclosporine revealed a strong positive association of statin use with the CV compound outcome in a fully adjusted model (HR = 6.60, 95% CI 1.75-24.9, P = .005). Furthermore, statin use was positively correlated with cyclosporine trough levels (correlation coefficient 0.11, P = .04). CONCLUSION: In conclusion, statin use does not significantly decrease incident CV events in an overall RTR cohort, but is independently associated with CV-specific mortality and events in cyclosporine using RTR, possibly due to a bilateral pharmacological interaction.

Interactions of clinical relevance associated with concurrent administration of prescription drug and food or medicinal plants: a systematic review protocol.

BACKGROUND: An inadequate combination of prescription drugs with food or medicinal plants could cause adverse effects in patients or produce negative therapeutic results. Therefore, this generic systematic review protocol aims to identify and synthesize the literature on clinical characteristics and safety issues of these types of pharmacological interactions occurring in children, adolescents, adults, pregnant/lactating women, and older adults. METHODS/DESIGN: This generic protocol follows the stated guidelines from the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols (PRISMA-P) statement. A literature search will be performed in PubMed, Scopus, and Virtual Health Library (VHL) electronic databases from 1960 till present for studies reporting clinical characteristics and safety issues associated with pharmacological interactions occurring between prescription drugs and food or medicinal plants in participants from birth-age to ≥ 65-year-old, including pregnant/lactating women. Lateral searching will be carried out in PubMed via related citation. Two reviewers will carry out an independent evaluation of eligible studies as well as the corresponding data extraction of the selected ones. Subsequently, the methodological quality evaluation of the selected articles will be completed using the corresponding Joanna Briggs Institute Checklists. Moreover, the quality of evidence will be graded according to the criteria of the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) Working Group. Quantitative research in humans comprising clinical trials and clinical, comparative and, observational studies will be included. The main outcomes of this protocol involve reported potential food-drug and herb-drug interactions, associated safety issues, and adverse reactions along with the generic name of the prescribed drug and the scientific name of the food and medicinal plants involved in these types of pharmacological interactions. Finally, findings extracted from the selected studies will be summarized in a narrative synthesis. DISCUSSION: This generic systematic review protocol seeks to synthesize and critically evaluate current knowledge besides to identify any comprehension gaps in the concurrent administration of prescription drugs with food and herbs. By achieving a better understanding of this topic, this information will allow healthcare professionals to develop useful strategies to recognize, manage, and prevent these types of pharmacological interactions at different age stages, including pregnant/lactating women. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42018117308.

Período de latência, progressão e duração do bloqueio da anestesia epidural com lidocaína, bupivacaína ou sua associação em cães / Period of latency, progression and duration of blockade of epidural anesthesia with lidocaine, bupivacaine or its association in dogs

O objetivo deste estudo foi avaliar latência, duração do efeito, progressão cranial da lidocaína e da bupivacaína isoladas, ou em associação, pela via epidural, em cães, além de mensurar a pressão média do canal epidural antes e após a realização dela. Utilizaram-se 18 cães, alocados em três grupos, os quais receberam, por via epidural: lidocaína 2% (GL) 0,25mL/kg; bupivacaína 0,5% (GB) no mesmo volume, ou a associação de ambas (GLB) na proporção de 1:1. Avaliaram-se as frequências cardíaca e respiratória e a pressão arterial sistólica (PAS) previamente aos tratamentos (M0) e até 60 minutos após a anestesia epidural. Ainda, avaliou-se a pressão no canal epidural antes e após a administração dos tratamentos, o período de latência, a progressão e a duração do bloqueio pelo pinçamento interdigital e do panículo paravertebral. Houve redução de 12% da PAS no GL em todos os momentos e de 16% aos 30 minutos no GLB quando comparados ao basal. A pressão média no espaço epidural antes e após a anestesia epidural foi de -1,5 (±3,9) e 41 (±16) mmHg; 55% apresentaram pressão negativa no espaço epidural. O período de latência não diferiu entre os grupos (GL: 3,5±1,6; GB: 4,5±4,5; e GLB: 2,4±1 minutos) e a duração do bloqueio foi maior no GB em relação ao GL (GL: 125±24; GB: 176±24; e GLB: 153±35 minutos). A progressão máxima dos anestésicos foi até L1-T13 no GL, L4-L3 no GB e L3-L2 no GLB. Conclui-se que a associação de lidocaína com bupivacaína não apresenta vantagens em relação ao uso dos fármacos isolados pela via epidural, tendo a lidocaína progredido mais cranialmente em relação à bupivacaína ou à associação. A lidocaína promoveu redução da PAS, mesmo quando associada à bupivacaína, permanecendo dentro dos valores de referência. Apenas 55% dos cães apresentaram pressão média negativa no espaço epidural antes da administração dos fármacos, dessa forma o teste da gota pendente pode não ser eficiente para localização do espaço epidural em todos os animais.(AU)

The objective of this study was to evaluate the latency, duration of the effect, and cranial progression of lidocaine and bupivacaine alone or in combination, by epidural route in dogs, and measuring the average pressure of the epidural channel before and after the completion thereof. Eighteen dogs were allocated in three groups, which received epidural: lidocaine 2% (GL) 0.25ml / kg; bupivacaine 0.5% (GB) in the same volume, or the association of both (GLB) in a 1: 1 ratio. Heart and respiratory rates and systolic blood pressure (SBP) were evaluated before treatment (M0) and up to 60 minutes after epidural anesthesia. In addition, the pressure in the epidural canal was evaluated before and after the administration of the treatments, latency period, progression and duration of the block by interdigital and paravertebral pannicus clamping. There was a 12% decrease in SBP in the GL at all times and 16% at 30 minutes in GLB when compared to the baseline. The mean pressure in the epidural space before and after epidural anesthesia was -1.5 (±3.9) and 41 (±16) mmHg), 55% presented negative pressure in the epidural space. The latency period did not differ between groups (GL: 3.5±1.6; GB: 4.5±4.5; and GLB: 2.4±1 minutes) and the duration of blockade was higher in GB (GL: 125±24, GB: 176±24, and GLB: 153±35 minutes). The maximum progression of anesthetics was up to L1-T13 in GL, L4-L3 in GB and L3-L2 in GLB. It is concluded that the association of lidocaine with bupivacaine does not present advantages in relation to the use of the drugs isolated by the epidural route, with lidocaine progressing more cranially in relation to bupivacaine or the association. Lidocaine promoted the reduction of SBP, even when associated with bupivacaine, remaining within the reference values. Only 55% of the dogs presented negative mean pressure in the epidural space before administration of the drugs, so the drop test may not be efficient for locating the epidural space in all animals.(AU)

Multi-target antidiabetic mechanisms of mexicanolides from Swietenia humilis.

BACKGROUND: Swietenia humilis seeds are consumed in Mexico to treat type 2 diabetes; the antihyperglycemic effect of this species was previously demonstrated and related to the presence of tetranortriterpenoids of the mexicanolide class. PURPOSE AND STUDY DESIGN: The present investigation was conducted to determine the mechanism of action of selected mexicanolides, including 2-hydroxy-destigloyl-6-deoxyswietenine acetate (1), methyl-2-hydroxy-3-ß-tigloyloxy-1-oxomeliac-8(30)-enate (2) and humilinolide H (3), using in vivo experiments with hyperglycemic mice, and cell-based models. METHODS: Nicotinamide-streptozotocin hyperglycemic mice (50-130 mg/kg, i.p.) were used to build antihyperglycemic drug-response curves using an oral glucose tolerance test model. In vitro studies were carried out on INSE1, H4IIE and C2C12 cells to assess insulin secretion, glucose-6-phosphatase inhibition, glucose uptake and mitochondrial bioenergetics, respectively. RESULTS: The combination of the decoction of S. humilis or 2-hydroxy-destigloyl-6-deoxyswietenine acetate (mexicanolide 1) with glibenclamide resulted in a reduction of the antihyperglycemic effect while a significant increase was observed when they were dosed with metformin. These effects were related to KATP SUR blockade, insulin secretion in INSE1 cells, and modulation of 5-HT2 receptors. Furthermore, mexicanolides 1-3 inhibited glucose-phosphatase in H4IIE cells, and enhanced glucose uptake and spare respiratory capacity in C2C12 myotubes. CONCLUSION: S. humilis mexicanolides interact with pharmacological targets at pancreas (KATP channels), liver (glucose-6-phosphatase), and skeletal muscle (mitochondria and possibly glucose transporters) to modulate glucose homeostasis, and could be a promising resource to treat type 2 diabetes.

Pharmacological interaction between NSAIDS with clomipramine and risperidone in mice visceral pain.

Nonsteroidal anti-inflammatory drugs (NSAIDs) possess as primary action mechanism the inhibition of cyclooxygenases (COX-1, COX-2, and COX-3), thus producing a decreasing prostaglandin synthesis. This study was designed to evaluate whether the antinociception induced by NSAIDs could be modulated by clomipramine or risperidone using a chemical model of inflammatory acute visceral pain, the abdominal acetic acid induced a writhing test in mice. Dose-response curves, intraperitoneal, or intrathecal for the antinociceptive activity displayed by ketoprofen, piroxicam, nimesulide, parecoxib, and paracetamol were analyzed in order to obtain the ED50 of each drug. Pretreatment of mice with either clomipramine or risperidone, increased antinociceptive potency of ketoprofen, piroxicam, nimesulide, parecoxib, and paracetamol, expressed by a decrease in the values of antinociceptive ED50. The results that were obtained are in line with those where the inhibition of COXs provides a justification for most of the pharmacological actions. Nevertheless, several findings suggest other molecular mechanisms, among which may be mentioned, L-selecting shedding; inhibition of i-NOS; inhibition of NF-Kappa B; suppression metaloproteinasas; inhibition of ß2 integrin activation; activation of α2 -adrenoceptor; increase of IL-1ß; upregulation IL-6. In conclusion, the data generated in this study demonstrated that risperidone and clomipramine, separately, increase antinociceptive potency of NSAIDs in a chemical model of inflammatory acute visceral tonic pain.

A Novel Selective JAK2 Inhibitor Identified Using Pharmacological Interactions.

The JAK2/STAT signaling pathway mediates cytokine receptor signals that are involved in cell growth, survival and homeostasis. JAK2 is a member of the Janus kinase (JAK) family and aberrant JAK2/STAT is involved with various diseases, making the pathway a therapeutic target. The similarity between the ATP binding site of protein kinases has made development of specific inhibitors difficult. Current JAK2 inhibitors are not selective and produce unwanted side effects. It is thought that increasing selectivity of kinase inhibitors may reduce the side effects seen with current treatment options. Thus, there is a great need for a selective JAK inhibitor. In this study, we identified a JAK2 specific inhibitor. We first identified key pharmacological interactions in the JAK2 binding site by analyzing known JAK2 inhibitors. Then, we performed structure-based virtual screening and filtered compounds based on their pharmacological interactions and identified compound NSC13626 as a potential JAK2 inhibitor. Results of enzymatic assays revealed that against a panel of kinases, compound NSC13626 is a JAK2 inhibitor and has high selectivity toward the JAK2 and JAK3 isozymes. Our cellular assays revealed that compound NSC13626 inhibits colorectal cancer cell (CRC) growth by downregulating phosphorylation of STAT3 and arresting the cell cycle in the S phase. Thus, we believe that compound NSC13626 has potential to be further optimized as a selective JAK2 drug.

Cutaneous Adverse Drug Reactions: How to Identify the Trigger. / Reacciones cutáneas adversas a medicamentos: cómo identificar el desencadenante.

It is estimated that 10% to 15% of medicated patients develop adverse drug reactions (ADR). Despite the high prevalence of ADR, the identification of the trigger drugs remains a medical challenge, mainly in polymedicated patients. Our goal is to update the diagnostic tools to identify enhancer drugs of type B-ADR that compromise the skin and /or mucous membranes, in order to optimize patients' follow-up and improve their quality of life. We develop the review in two stages: I- we review the pathophysiological mechanisms of the ADR; II- we developed the clinical approach for the identification of the triggering drug.

Reacciones adversas causadas por quimioprofilaxis con doxiciclina / Adverse reactions caused by chemoprophylaxis with doxicicline

Se realizó un estudio descriptivo y prospectivo de 86 trabajadores del Puerto Guillermón Moncada de Santiago de Cuba, quienes recibieron tratamiento quimioprofiláctico con doxiciclina y presentaron reacciones adversas asociadas a dicho tratamiento, en noviembre del 2015, con vistas a caracterizarles y determinar la relación de causalidad existente entre la administración del medicamento, la aparición de efectos indeseables y las posibles interacciones farmacológicas. En esta serie, las reacciones adversas resultaron leves y no graves; las relaciones de causalidad, definitivas en la mayoría de los afectados (65,1 por ciento), aunque se determinaron algunas como probables y posibles, en tanto, las reacciones más frecuentes se presentaron en la esfera gastrointestinal

A descriptive and prospective study of 86 workers from Guillermón Moncada Port was carried out in Santiago de Cuba. They received chemoprophylactic treatment with doxicicline and presented adverse reactions associated with this treatment, in November, 2015, aimed at characterizing them and determining the relationship of causation existing between the administration of medication, emergence of undesirable effects and possible pharmacological interactions. In this series, the adverse reactions were light and no severe; the causation relationships, were definitive in most of the affected patients (65.1 percent), although some were determined as probable and possible, while, the most frequent reactions were presented in the gastrointestinal sphere

Brexpiprazole: A Partial Dopamine Agonist for the Treatment of Schizophrenia.

BACKGROUND: Schizophrenia is a chronic and debilitating mental disorder that affects the patient's and their family's life. The disease remains a complicated disorder that is challenging to treat, despite there being a large antipsychotic armamentarium. Brexpiprazole acts both as a partial agonist at the serotonin 5-HT1A and dopamine D2 receptors and as an antagonist at the serotonin 5- HT2A and noradrenaline alpha1B and alpha2C receptors, all with similar potency. This balanced receptor profile may produce promising antipsychotic effects on positive, negative and cognitive symptoms in schizophrenia with minimal adverse effects. METHODS: This review summarizes the pharmacodynamics and pharmacokinetic profile of brexpiprazole and the clinical trial information pertaining to its effectiveness and safety and tolerability, discusses its best clinical use, and compares its clinical profile to those of other widely used antipsychotic agents. RESULTS: Brexpiprazole demonstrated significant clinical efficacy and had good safety and tolerability in well-designed trials with patients with schizophrenia. This agent may be a useful treatment alternative. CONCLUSION: However, it will be valuable to consider a long-term observational study that includes an active comparator, especially other second-generation antipsychotics (SGAs), to further evaluate the efficacy and safety of brexpiprazole in the treatment of schizophrenia.

Pharmacokinetic drug evaluation of anacetrapib for the treatment of dyslipidemia.

INTRODUCTION: While some cholesteryl ester transfer protein inhibitors have had their clinical study interrupted because of no or adverse effects on cardiovascular disease, anacetrapib (MK-0859) is being evaluated in Phase III cardiovascular outcomes trials. We review its pharmacokinetic properties. Areas covered: The apparent anacetrapib terminal elimination half-life after a single dose is 9-62 h in the fasted state and 42-83 h in the fed state. After repeat administrations, a biphasic elimination profile with a long terminal elimination phase (~60-80 h) was observed, although the effective half-life was ~20 h. The steady state appeared to be reached after ~7 days of dosing with 0.85- to 2.8-fold accumulation for AUC0-24 and Cmax, respectively. The unchanged drug is mainly eliminated with feces; renal impairment does not seem be a limitation to the use of the drug. However, liver impairment could cause an increase in the anacetrapib level, especially when associated with CYP3A4 inhibitors, since it is a moderately sensitive CYP3A substrate. Expert opinion: Given the interesting pharmacokinetic profile, and if the preliminary data on cardiovascular outcomes is confirmed, anacetrapib could find a relevant role as a moderately expensive drug between standard lipid-lowering treatment and the new expensive PCKS9 inhibitors.

Metabolic complete response with vinflunine as second-line therapy in a kidney-transplanted patient with advanced urothelial carcinoma: a case report.

BACKGROUND: Patients undergone kidney transplantation present higher risk of Urothelial Carcinoma (UC) development and represent a subgroup of special interest. To date, vinflunine is the only drug approved in Europe for the treatment of advanced UC after failure of platinum-based chemotherapy. However, to our knowledge, no data on the concomitant administration of vinflunine and immunosuppressive agents are available. CASE PRESENTATION: The patient, a 45 years old Caucasian male, presented poorly differentiated UC of the bladder recurred after initial cystectomy with abdominal lymphadenopathies evidenced by FDG-PET/CT. Previously, at the age of 22, he had post-glomerulonephritis renal failure and underwent kidney transplantation from deceased donor. Since then, he has been in treatment with immunosuppressive therapy. At the time of UC recurrence, he was on treatment with cyclosporine. After progression to platinum-based chemotherapy, he received second-line therapy with vinflunine resulting in a complete metabolic response after two cycles. However, despite several dose reductions, the patient experienced severe hematologic toxicity. The pharmacological interaction between vinflunine and cyclosporine, both metabolized by CYP 3A4, may explain the excellent result and the concomitant severe toxicity. CONCLUSIONS: Vinflunine is active on UC developed in kidney transplanted patients. However, special attention should be paid to concomitant administration with immunosuppressive agents that could result in increased toxicity.

Antacid attenuates the laxative action of magnesia in cancer patients receiving opioid analgesic.

OBJECTIVE: This study was designed to investigate pharmacological interaction between magnesium laxative and antacid in patients receiving opioid analgesic. METHODS: Data obtained from a total of 441 eligible patients receiving opioid analgesic for the first time were retrospectively analysed. The incidence of constipation, defined as stool-free interval of 3 days and more within the first week of opioid intake, was compared between patients who took laxative alone and those who received laxative in combination with antacid. KEY FINDINGS: Laxatives were prescribed in 74% of patients, among them 61% received antacids such as proton pump inhibitor and H2 receptor blocker. Magnesia was the most commonly used laxative (89%). Constipation occurred in 21% and 55% of patients with and without laxatives, respectively. Antacids reversed the laxative action of lower doses (<2000 mg/day) but not higher doses (>2000 mg/day) of magnesia without affecting the effects of other laxatives. Therefore, it is suggested that both acid-dependent and acid-independent mechanisms may operate in the laxative action of magnesia, in which the former may be involved in the action of lower doses of magnesia. CONCLUSION: Care should be taken to avoid the unfavourable pharmacological interaction between low doses of magnesia and antacid.