Population pharmacokinetics of duloxetine in Japanese pediatric patients with major depressive disorder.

The objectives of this analysis were to characterize the pharmacokinetics of duloxetine in Japanese pediatric patients aged 9-17 years with major depressive disorder (MDD) and to explore potential intrinsic factors affecting its pharmacokinetics. A population pharmacokinetic (PK) model was developed with plasma steady-state duloxetine concentrations from Japanese pediatric patients with MDD in an open-label long-term extension trial in Japan (ClinicalTrials.gov Identifier: NCT03395353). Duloxetine pharmacokinetics in Japanese pediatric patients was well described by a one-compartment model with first-order absorption. The population mean estimates of CL/F and V/F of duloxetine were 81.4 L/h and 1170 L, respectively. Patient intrinsic factors were assessed for their potential influence on duloxetine apparent clearance (CL/F). Only sex was identified as a statistically significant covariate of duloxetine CL/F. Duloxetine pharmacokinetic parameters and model-predicted duloxetine concentrations at steady state in the Japanese pediatric population were compared with those in Japanese adults. The mean duloxetine CL/F in pediatrics is slightly higher than adults, it is, however, expected that comparable steady-state duloxetine exposure in pediatric patients can be achieved with the approved dose regimen for adults. The population PK model provides useful information to understand the pharmacokinetic characteristics of duloxetine for Japanese pediatric patients with MDD. CLINICALTRIALS.GOV IDENTIFIER: NCT03395353.

Simultaneous determination of duloxetine and 4-hydroxy duloxetine glucuronide in human plasma and back-conversion study.

Aim: To develop an LC-MS/MS method for simultaneous determination of duloxetine and its metabolite, 4-hydroxy duloxetine glucuronide (4HDG) in human plasma and to investigate the potential back-conversion of 4HDG to duloxetine using stability study. Materials & methods: The LC-MS/MS method was validated according to the EMA and USFDA Bioanalytical Method Validation Guidelines and applied to pilot bioequivalence study. Results & conclusion: The method validation results were within the acceptance limits. The stability study and incurred sample reanalysis results ruled out the occurrence of back-conversion. The study highlighted the conduct of back-conversion test and the advantages of LC-MS/MS method in terms of sensitivity, specificity and low consumption of organic solvents.

Bioaccumulation of therapeutic drugs by human gut bacteria.

Bacteria in the gut can modulate the availability and efficacy of therapeutic drugs. However, the systematic mapping of the interactions between drugs and bacteria has only started recently1 and the main underlying mechanism proposed is the chemical transformation of drugs by microorganisms (biotransformation). Here we investigated the depletion of 15 structurally diverse drugs by 25 representative strains of gut bacteria. This revealed 70 bacteria-drug interactions, 29 of which had not to our knowledge been reported before. Over half of the new interactions can be ascribed to bioaccumulation; that is, bacteria storing the drug intracellularly without chemically modifying it, and in most cases without the growth of the bacteria being affected. As a case in point, we studied the molecular basis of bioaccumulation of the widely used antidepressant duloxetine by using click chemistry, thermal proteome profiling and metabolomics. We find that duloxetine binds to several metabolic enzymes and changes the metabolite secretion of the respective bacteria. When tested in a defined microbial community of accumulators and non-accumulators, duloxetine markedly altered the composition of the community through metabolic cross-feeding. We further validated our findings in an animal model, showing that bioaccumulating bacteria attenuate the behavioural response of Caenorhabditis elegans to duloxetine. Together, our results show that bioaccumulation by gut bacteria may be a common mechanism that alters drug availability and bacterial metabolism, with implications for microbiota composition, pharmacokinetics, side effects and drug responses, probably in an individual manner.

Brain Targeting of Duloxetine HCL via Intranasal Delivery of Loaded Cubosomal Gel: In vitro Characterization, ex vivo Permeation, and in vivo Biodistribution Studies.

PURPOSE: Duloxetine (DLX) is dual serotonin and norepinephrine reuptake inhibitor suffering from limited bioavailability (≈ 40%) due to extensive hepatic metabolism. This work aims to formulate and evaluate DLX intranasal thermoreversible cubosomal gels to enhance its bioavailability and ensure efficient brain targeting. MATERIALS AND METHODS: Cubo-gels were prepared by 33 central composite design with three independent factors, lipid ratio (glycerol monooleate: glycerol tripalmitate), Pluronic F127%, and Pluronic F68%. The prepared formulations were evaluated for their particle size (PS), gelling temperature (GT), entrapment efficiency (EE%), and in vitro release. The cubo-gel with the highest desirability (0.88) was chosen as the optimized formulation. DLX cubo-gel was evaluated using differential scanning calorimetry, Fourier-transform infrared spectroscopy, X-ray powder diffraction, and transmission electron microscopy. Cytotoxicity study, ex vivo permeation study and in vivo bio-distribution study were conducted to evaluate the safety and efficacy of brain targeting. RESULTS: The optimum cubo-gel was composed of 3.76 lipid ratio, 20% w/v PF127, and 5% w/v PF68. It had PS of 265.13 ± 9.85 nm, GT of 32 ± 0.05°C, EE% of 98.13 ± 0.50%, and showed controlled release behavior where 33% DLX was released within 6 hrs. The plain in situ cubo-gel had a significantly higher IC50 compared to DLX solution and DLX-loaded in situ cubo-gel. The ex vivo permeation study showed 1.27 enhancement in the drug permeation from DLX in situ cubo-gel. According to the in vivo bio-distribution study in plasma and brain, the intranasal DLX in situ cubo-gel showed a 1.96 fold improvement in brain bioavailability compared to the intranasal solution. Its BTE% and DTP% were 137.77 and 10.5, respectively, indicating efficient brain targeting after intranasal administration. CONCLUSION: Accordingly, intranasal DLX in situ cubo-gel can be considered as an innovative nano-carrier delivery system for bioavailability enhancement and efficient brain targeting of DLX to maximize its effect.

Impact of Polymorphism of CYP2D6 on Equilibrium Concentration of Duloxetine in Patients Suffering from Major Depressive Disorder.

Introduction: Duloxetine is commonly prescribed to patients with recurrent depressive disorder. Some part of patients in this group do not respond adequately to treatment regimen containing duloxetine, while many of them experience dose-dependent adverse drug reactions. Previous research investigated that CYP2D6 is involved in the biotransformation of duloxetine, the activity of which is highly dependent on the polymorphism of the gene encoding it. Objective: The objective of this study was to evaluate the influence of 1846G > A polymorphism of the CYP2D6 gene on the concentration/dose indicator of duloxetine, using findings on enzymatic activity of CYP2D6 (as evaluated by the 6M-THBC/pinoline ratio measurement) and on CYP2D6 expression level obtained by measuring the hsa-miR-370-3p plasma concentration levels in patients suffering from recurrent depressive disorder. Material and Methods: This study enrolled 118 patients with recurrent depressive disorder (average age - 40.6±17.1 years). Therapy included duloxetine in an average daily dose of 103.7±37.1 mg per day. Treatment efficacy was assessed using the international psychometric scales. Therapy safety was assessed using the UKU Side-Effect Rating Scale. For genotyping we performed the real-time polymerase chain reaction (PCR Real-time). Therapeutic drug monitoring has been performed using HPLC-MS/MS. Results: Our findings revealed the statistically significant results in terms of the treatment efficacy evaluation (HAMD scores at the end of the treatment course): (GG) 9.0 [7.0; 10.0] and (GA) 11.0 [8.5; 14.0], p < 0.001; at the same time, the statistical significance in the safety profile was obtained (the UKU scores): (GG) 3.0 [3.0; 4.0] and (GA) 4.0 [3.0; 4.0], p = 0.007. We revealed a statistical significance for concentration/dose indicator of duloxetine in patients with different genotypes: (GG) 0.776 [0.529; 1.067] and (GA) 1.388 [0.942; 1.732], p < 0.001. Conclusion: Thus, the effect of genetic polymorphism of the CYP2D6 gene on the efficacy and safety profiles of duloxetine was demonstrated in a group of 118 patients with recurrent depressive disorder.

Application of an Inter-Species Extrapolation Method for the Prediction of Drug Interactions between Propolis and Duloxetine in Humans.

Duloxetine (DLX) is a potent drug investigated for the treatment of depression and urinary incontinence. DLX is extensively metabolized in the liver by two P450 isozymes, CYP2D6 and CYP1A2. Propolis (PPL) is one of the popular functional foods known to have effects on activities of CYPs, including CYP1A2. Due to the high probability of using DLX and PPL simultaneously, the present study was designed to investigate the potent effect of PPL on pharmacokinetics (PKs) of DLX after co-administration in humans. A PK study was first conducted in 18 rats (n = 6/group), in which the plasma concentration of DLX and its major metabolite 4-hydroxy duloxetine (4-HD) with or without administration of PPL was recorded. Population PKs and potential effects of PPL were then analyzed using NONMEM software. Lastly, these results were extrapolated from rats to humans using the allometric scaling and the liver blood flow method. PPL (15,000 mg/day) exerts a statistically significant increase in DLX exposures at steady state, with a 20.2% and 24.6% increase in DLX C m a x , s s and the same 28.0% increase in DLX A U C s s when DLX (40 or 60 mg) was administered once or twice daily, respectively. In conclusion, safety issues are required to be attended to when individuals simultaneously use DLX and PPL at high doses, and the possibility of interactions between DLX and PPL might be noted.

Eficacia de pregabalina, gabapentina y duloxetina en el dolor neuropático verificado por el análisis de la curva-p / Efficacy of pregabalin, gabapentin and duloxetine in neuropathic pain verified by the p-curve analysis

INTRODUCCIÓN: Existe una preocupación creciente entre los clínicos y los investigadores de que muchos resultados publicados en revistas científicas se tratan de falsos positivos. OBJETIVO: Determinar el valor de evidencia o integridad del cuerpo de la literatura publicada sobre la eficacia de pregabalina, gabapentina y duloxetina en el tratamiento del dolor neuropático. MÉTODOS: Se realizó una búsqueda bibliográfica seleccionando ensayos clínicos aleatorizados que evaluaban la eficacia de pregabalina, gabapentina y duloxetina en dolor neuropático. Se aplicó el análisis de curva-p de los estudios con resultados estadísticamente significativos para estudiar su distribución. RESULTADOS: Se demostró que existía una asimetría significativa a la derecha en la curva-p de los tres fármacos (test continuo p < 0,0001) confirmando el valor de evidencia de los estudios. CONCLUSIONES: Los clínicos, los científicos y las publicaciones científicas deben ser conscientes del problema creciente con el "p-hacking" y sus efectos perjudiciales. Todas las partes comparten la responsabilidad en mantener la integridad científica de la literatura publicada

INTRODUCTION: There is a growing concern among clinicians and researchers that many results published in scientific journals are false positives. OBJECTIVE: To determine the value of evidence or integrity of the body of the published literature on the efficacy of pregabalin, gabapentin and duloxetine in the treatment of neuropathic pain. METHODS: A literature search was conducted selecting randomized clinical trials that evaluated the efficacy of pregabalin, gabapentin and duloxetine in neuropathic pain. The p-curve analysis of the studies with statistically significant results was applied to study their distribution. RESULTS: It was demonstrated that there was a significant asymmetry to the right in the p-curve of the three drugs (continuous test p <0.0001) confirming the value of evidence from the studies. CONCLUSIONS: Clinicians, scientists and scientific publications should be aware of the growing problem with "p-hacking" and its harmful effects. All parties share the responsibility to maintain the scientific integrity of the published literature

The Effect of Food on the Single-Dose Bioavailability and Tolerability of the Highest Marketed Strength of Duloxetine.

Duloxetine is a combined serotonin and norepinephrine reuptake inhibitor indicated in adults for the treatment of major depressive disorder, diabetic peripheral neuropathic pain, and generalized anxiety disorder. The aim of these studies was to evaluate the effect of food on the pharmacokinetics and safety of duloxetine 60-mg gastroresistant hard capsules following single-dose administration. The data were obtained from 2 phase 1 bioequivalence studies, 1 in a fasting state and the other under fed conditions. Both studies have shown that, when administered as a single dose in the same prandial state, the test and reference duloxetine treatments were bioequivalent and exhibited similar safety profiles. The mean fed and fasting pharmacokinetic parameters and drug-related adverse events from the 2 studies were compared in order to assess the effect of food on the duloxetine bioavailability and respectively, tolerability. Administration of duloxetine in fed conditions increased peak plasma concentration by up to 30% and delayed mean time to peak concentration by an average of 1.15 hours while having an insignificant effect on extent of absorption (area under the plasma concentration-time curve in fed state within ±6% as compared with fasting conditions). Even though peak plasma levels were substantially higher in the fed state, there was no negative impact on the drug's safety profile. Actually, administration with food resulted in a lower average number of adverse events per single dose exposure. The negligible variation in overall systemic exposure suggests that efficacy remains unchanged irrespective of administration conditions; however, a better tolerability of the 60-mg dose is expected when the drug is taken with food.

Development and Evaluation of Optimized Thiolated Chitosan Proniosomal Gel Containing Duloxetine for Intranasal Delivery.

Proniosomes offer excellent potential for improved drug delivery, through versatile routes, by overcoming the permeation barriers faced by several drugs. The study was aimed to develop a thiomer gel containing duloxetine proniosomes for the intranasal delivery, improving its bioavailability and brain delivery through olfactory system. Duloxetine-loaded proniosomes were optimized through Design-Expert Software, prepared by coacervation phase separation method and then characterized in vitro for different vesicle features, and permeation enhancement potential using various techniques. The formulation F2, out of all the trials, fulfilled the maximum requisite of highest entrapment efficiency (76.21 ± 1.24%) and minimum vesicle size (223.91 ± 11.07 nm). The F2 was embedded in thiolated chitosan gel rendering it mucoadhesive and further characterized. The in vitro release showed a sustained drug release from the mucoadhesive proniosomal gel with only 54% drug release as compared to that of 71% from proniosome over 8 h, following Higuchi drug release model. Ex vivo permeation studies showed the enhancement ratio for the mucoadhesive proniosomal gel to be 1.86-fold greater than proniosomes, indicating a significant improvement in transmucosal permeation. The results suggest that incorporation of proniosomes into thiolated gel can significantly improve its mucoadhesion and retention time in the nasal cavity for providing a sustained drug release. Thus, gel formulation could be considered as a promising approach for efficient intranasal drug delivery of duloxetine. Graphical Abstract.

Physiologically-Based Pharmacokinetic Modeling for the Prediction of CYP2D6-Mediated Gene-Drug-Drug Interactions.

The aim of this work was to predict the extent of Cytochrome P450 2D6 (CYP2D6)-mediated drug-drug interactions (DDIs) in different CYP2D6 genotypes using physiologically-based pharmacokinetic (PBPK) modeling. Following the development of a new duloxetine model and optimization of a paroxetine model, the effect of genetic polymorphisms on CYP2D6-mediated intrinsic clearances of dextromethorphan, duloxetine, and paroxetine was estimated from rich pharmacokinetic profiles in activity score (AS)1 and AS2 subjects. We obtained good predictions for the dextromethorphan-duloxetine interaction (Ratio of predicted over observed area under the curve (AUC) ratio (Rpred/obs ) 1.38-1.43). Similarly, the effect of genotype was well predicted, with an increase of area under the curve ratio of 28% in AS2 subjects when compared with AS1 (observed, 33%). Despite an approximately twofold underprediction of the dextromethorphan-paroxetine interaction, an Rpred/obs of 0.71 was obtained for the effect of genotype on the area under the curve ratio. Therefore, PBPK modeling can be successfully used to predict gene-drug-drug interactions (GDDIs). Based on these promising results, a workflow is suggested for the generic evaluation of GDDIs and DDIs that can be applied in other situations.

A three-pronged formulation approach to improve oral bioavailability and therapeutic efficacy of two lipophilic drugs with gastric lability.

The aim of present study was to co-administer curcumin (CRM) liquisolid pellets and coated duloxetine hydrochloride (DXH) pellets in rats to treat neuropathic pain (NP) associated with chronic constriction injury (CCI). To formulate liquisolid pellets of CRM, it was first dissolved in Tween-80 and then adsorbed on the porous surface of MCC PH102 and Syloid XDP that were used as carrier and coating materials, respectively. Central composite design was used to optimize the liquisolid formulation. The results of powder X-ray diffraction studies, differential scanning calorimetry, and scanning electron microscopy showed complete solubility of drug in Tween-80 followed by its complete adsorption on the porous surface of Syloid XDP and MCC PH102. Both DXH and liquisolid CRM powders were converted into pellets using extrusion-spheronization. DXH pellets were further coated with Eudragit S100 to bypass the gastric pH. About 32.31-fold increase in dissolution rate of CRM present in liquisolid formulation was observed as compared to its unprocessed form. Similarly, the dissolution profile in 0.1 N HCl for Eudragit S100-coated DXH showed complete protection of drug for 2 h and complete release after its introduction in buffer medium (0.2 M phosphate buffer pH 6.8). he pharmacokinetic studies carried out on rats revealed 7.3-fold increase in bioavailability of CRM present in liquisolid pellets and 4.1-fold increase in bioavailability of DXH present in coated pellets was observed as compared to their unprocessed pellets. This increase in bioavailability of drugs caused significant amelioration of CCI-induced pain in rats as compared to their unprocessed forms. The histological sections showed better improvement in regeneration of nerve fibers in rats.

A rapid LC-MS/MS method for simultaneous determination of quetiapine and duloxetine in rat plasma and its application to pharmacokinetic interaction study.

Combinations of new antidepressants like duloxetine and second-generation antipsychotics like quetiapine are used in clinical treatment of major depressive disorder, as well as in forensic toxicology scenarios. The drug-drug interaction (DDI) between quetiapine and duloxetine is worthy of attention to avoid unnecessary adverse effects. However, no pharmacokinetic DDI studies of quetiapine and duloxetine have been reported. In the present study, a rapid and sensitive liquid chromatography tandem mass spectrometry (LC-MS/MS) method was developed for simultaneous determination of quetiapine and duloxetine in rat plasma. A one-step protein precipitation with acetonitrile was applied for sample preparation. The analytes were eluted on an Eclipse XDB-C18 column using the mixture of acetonitrile and 2 mM ammonium formate containing 0.1% formic acid at a gradient elution within 6.0 min. Quantification was performed in multiple-reaction-monitoring mode with the ion transitions m/z 384.4 â†’ 253.2 for quetiapine, m/z 298.1 â†’ 154.1 for duloxetine and m/z 376.2 â†’ 165.2 for IS (haloperidol), respectively. Good linearity was obtained in the range of 0.50-100 ng/mL for quetiapine (r2 = 0.9972) and 1.00-200 ng/mL for duloxetine (r2 = 0.9982) using 50 µL of rat plasma, respectively. The method was fully validated with accuracy, precision, matrix effects, recovery and stability. The validated data have met the acceptance criteria in FDA guideline. The method was applied to a pharmacokinetic interaction study and the results indicated that quetiapine had significant effect on the enhanced plasma exposure of duloxetine in rats under combination use. This study could be readily applied in therapeutic drug monitoring of major depressive disorder patients receiving such drug combinations.

Effects of Magnesium Oxide on the Serum Duloxetine Concentration and Antidepressant-Like Effects of Duloxetine in Rats.

Duloxetine is a serotonin/noradrenaline reuptake inhibitor that is used as an antidepressant. However, it is known to cause constipation as a side effect. Magnesium compounds, such as magnesium oxide and magnesium hydroxide aqueous solution, are often combined with duloxetine to ameliorate the constipation caused by duloxetine. However, there is concern that these magnesium compounds might alter the effects of duloxetine via physicochemical interactions. In this study, we attempted to clarify the interactions that take place between duloxetine and magnesium oxide using in vivo and in vitro experiments. We evaluated the influence of magnesium oxide on in vitro duloxetine concentrations using HPLC. In addition, we examined the in vivo antidepressant-like effects and serum concentrations of duloxetine in rats. In the in vitro experiment, the duloxetine concentration was significantly decreased by co-treatment with magnesium oxide. In the in vivo experiment, the antidepressant-like effects of duloxetine were not affected by the combined oral administration of magnesium oxide and a duloxetine formulation although the serum duloxetine level was significantly decreased. However, the antidepressant-like effects of a duloxetine reagent were significantly attenuated by the co-administration of magnesium oxide. These results suggest that duloxetine and magnesium oxide directly interact and that such interactions affect the absorption and antidepressant-like effects of duloxetine.

Duloxetine loaded-microemulsion system to improve behavioral activities by upregulating serotonin and norepinephrine in brain for the treatment of depression.

Duloxetine is a well-known antidepressant molecule which is used in the treatment of depression but due to poor solubility it suffers with the drawback of low oral bioavailability. The objective of present work was to formulate and characterize duloxetine loaded microemulsion to enhance the oral bioavailability. Prepared microemulsion was studied for droplet size, zeta potential, refractive index, polydispersity index (PDI), percentage transmittance, viscosity and in vitro release study. Optimized microemulsion (D1) showed spherical droplets with mean diameter of 35.40 ±â€¯3.11 nm, PDI of 0.170 and zeta potential values of -25.8 mV. Formulation showed good transmittance (greater than 99%), viscosity (0.205 Pa s) and refractive index (1.43 ±â€¯0.01). Increased duloxetine release was obtained with microemulsion in comparison to drug suspension. Behavioral tests like mobility test, tail suspension test and forced swimming test performed in depressed and treated rats with duloxetine microemulsion significantly improved the behavioral activities in comparison to duloxetine suspension. Pharmacokinetic studies showed that microemulsion exhibited 1.8 times increment in bioavailability in comparison to duloxetine suspension.

Pharmacokinetic profiles contribute to the differences in behavioral pharmacology of 071031B enantiomers as novel serotonin and norepinephrine reuptake inhibitors.

Our previous study indicated that a chiral compound 071031B was a novel serotonin and noradrenaline reuptake inhibitor with superior antidepressant activity compared to duloxetine. The present study aimed to investigate chiral pharmacology differences of 071031B enantiomers, S-071031B and R-071031B, and disclose mechanisms underlying the behavioral differences based on target profiles and pharmacokinetic profiles. In vivo behavioral tests indicated that S-071031B was more potent than R-071031B in two depression models (the forced swimming test in mice and rats) and two pain models (the acetic acid-induced writhing and formalin tests in mice). In vitro assays revealed that both S-071031B and R-071031B showed high affinity for human serotonin transporters and norepinephrine transporters with equal potency, and showed consistently equipotent inhibitory effects on serotonin and norepinephrine uptake. Pharmacokinetic studies demonstrated that oral availability and hepatic metabolism, rather than pH stability, intestinal transport, and plasma binding, contributed to enantiomers' behavioral differences. Based on these findings, it is suggested that S-071031B is a more active enantiomer, and the differential pharmacokinetic profiles, but not target affinity, contribute to differences of S-071031B and R-071031B in behavioral pharmacology. Moreover, current PK-PD study may provide positive exploration for chiral antidepressants development.

[Desvenlafaxine and neuropathic pain: additional clinical benefits of a second generation serotonin-noradrenaline reuptake inhibitor]. / Desvenlafaxina y dolor neuropatico: beneficios clinicos adicionales de un inhibidor de la recaptacion de serotonina-noradrenalina de segunda generacion.

INTRODUCTION: Desvenlafaxine is the third antidepressant within the group of serotonin-norepinephrine reuptake inhibitors. The latest clinical practice guidelines consulted agree that tricyclic antidepressants, dual (venlafaxine/duloxetine) and gabapentin/pregabalin antiepileptics, are the first-line drugs in the treatment of neuropathic pain, being tramadol, lidocaine 5% patches and capsaicin 8% patches of second-line drugs, while strong opioids constitute a third line treatment. The interaction between the binomial pain and depression is very frequent, being the psychological complication more frequent in patients with chronic pain. DEVELOPMENT: Following a literature search, this article summarizes the most relevant pharmacological data of desvenlafaxine and its usefulness in clinical practice, as well as the specific literature of this drug in neuropathic pain and chronic pain. CONCLUSIONS: Although evidence of desvenlafaxine in neuropathic pain is scarce, it presents some interesting pharmacokinetic properties, as it is not substrate or have activity on P-glycoprotein, and have a metabolism which practically does not depend on cytochrome P450 system, which limits the risk of pharmacokinetic interactions and potential problems associated tolerability when administered with drugs that are CYP2D6 moderate or potent inhibitors or other substrates of this isoenzyme. These characteristics make desvenlafaxine a different antidepressant especially useful in some subgroups of patients with chronic pain (as polypharmacy and patients with liver failure), where comorbid depression is frequent.

TITLE: Desvenlafaxina y dolor neuropatico: beneficios clinicos adicionales de un inhibidor de la recaptacion de serotonina-noradrenalina de segunda generacion.Introduccion. La desvenlafaxina es el tercer antidepresivo incluido entre los inhibidores de la recaptacion de serotonina y noradrenalina. Las ultimas guias de practica clinica consultadas coinciden en señalar que los antidepresivos triciclicos, los duales (venlafaxina/duloxetina) y los antiepilepticos gabapentina y pregabalina constituyen los farmacos de primera linea en el tratamiento del dolor neuropatico. El tramadol, los apositos de lidocaina al 5% y los parches de capsaicina al 8% son los farmacos de segunda linea, mientras que los opioides potentes constituirian una tercera linea de tratamiento. La interaccion entre el binomio dolor y depresion es muy habitual y representa la complicacion psicologica mas frecuente en los pacientes con dolor cronico. Desarrollo. Tras una busqueda bibliografica, en este articulo se resumen los datos farmacologicos mas relevantes de la desvenlafaxina y su utilidad en la practica clinica, asi como la bibliografia especifica de este farmaco en el dolor neuropatico y el dolor cronico. Conclusiones. Aunque la evidencia de la desvenlafaxina en el dolor neuropatico es escasa, presenta unas caracteristicas farmacocineticas interesantes, como son no ser sustrato ni actuar sobre la glicoproteina P y tener un metabolismo que practicamente no depende del sistema del citocromo P450, lo que limita el riesgo de interacciones farmacocineticas y los potenciales problemas de tolerabilidad asociados cuando se administra con farmacos que sean inhibidores moderados o potentes del CYP2D6 o con otros sustratos de esta isoenzima. Estas caracteristicas hacen de la desvenlafaxina un antidepresivo distinto y especialmente util en algunos subgrupos de pacientes con dolor cronico (como polimedicados y pacientes con insuficiencia hepatica), donde la depresion comorbida es frecuente.

Utilidad de la desvenlafaxina en dolor crónico / Desvenlafaxine utility in chronic pain

Aunque la evidencia de la desvenlafaxina en dolor neuropático es escasa, presenta unas características farmacocinéticas interesantes, como son no ser sustrato ni tener actividad sobre la glicoproteína P, y tener un metabolismo que prácticamente no depende del sistema del citocromo P450, lo que limita el riesgo de interacciones farmacocinéticas y los potenciales problemas de tolerabilidad asociados cuando se administra con fármacos que sean inhibidores moderados o potentes del CYP2D6 o con otros sustratos de esta isoenzima. Estas características hacen de la desvenlafaxina un antidepresivo distinto y especialmente útil en algunos subgrupos de pacientes con dolor crónico (como polimedicados y pacientes con insuficiencia hepática), donde la depresión comórbida es frecuente (AU)

Although evidence of desvenlafaxine in neuropathic pain is scarce, it presents some interesting pharmacokinetic properties, as it is not substrate or have activity on P-glycoprotein, and have a metabolism which practically does not depend on cytochrome P450 system, which limits the risk of pharmacokinetic interactions and potential problems associated tolerability when administered with drugs that are CYP2D6 moderate or potent inhibitors or other substrates of this isoenzyme. These characteristics make desvenlafaxine a different antidepressant especially useful in some subgroups of patients with chronic pain (as polypharmacy and patients with liver failure), where comorbid depression is frequent (AU)

Duloxetine in elderly major depression disorder: effectiveness and drug plasma level evaluation.

OBJECTIVE: The aim of this open-label naturalistic study was to assess clinical outcomes and the predictive value of duloxetine plasma levels in major depressive disorder in the elderly. METHODS: This naturalistic, open-label design involved 35 outpatients aged between 65 and 87 years. Duloxetine plasma levels were collected in 24 patients after the first month. Patients were evaluated using 21-item Hamilton Rating Scales for Depression, Hamilton Rating Scales for Anxiety, the Clinical Global Impression Severity, Mini Mental State Examination, Cumulative Illness Rating Scale, Barthel Index and Beck's Depression Inventory. RESULTS: Duloxetine plasma levels at T2 ranged from 4.9 to 201.9 ng/mL without a significant correlation between duloxetine dose and plasma levels. A significant improvement in mean 21-item Hamilton Rating Scales for Depression total scores at T2,T3, T4, T9 and T12 and a progressive significantly decrease of the mean Hamilton Rating Scales for Anxiety scores from T3 to T12 were observed. CONCLUSIONS: The levels of duloxetine in plasma do not correlate with a greater clinical improvement, indeed appear to adversely affect the improvement of the Beck Depression Inventory and Hamilton Rating Scales for Anxiety. This could be explained by an increase in side effects that may aggravate the discomfort felt by the patient. Copyright © 2016 John Wiley & Sons, Ltd.

Duloxetine enters the brain - But why is it not found in the cerebrospinal fluid.

BACKGROUND: Antidepressants enter the brain to reach their site of action in a different extent. However, there has been no study to date about duloxetine's ability to enter the brain and cerebrospinal fluid. Aim of this study was to measure blood and cerebrospinal fluid concentrations of duloxetine and to account for the distribution between the two compartments. METHODS: Concentrations of duloxetine were measured in blood serum and cerebrospinal fluid of 19 patients treated with daily doses of 30-120mg. Daily doses were correlated with serum and cerebrospinal fluid concentrations and serum concentrations were correlated with concentrations in cerebrospinal fluid. RESULTS: Serum concentrations of duloxetine showed a moderate but significant correlation with the applied daily dose, r=+0.473, p=0.04. Duloxetine concentrations in the cerebrospinal fluid above the designated limit of quantification of 2.0ng/mL were only found in three of the 19 patients. CONCLUSIONS AND LIMITATIONS: Contrasting to own preceding studies on venlafaxine, mirtazapine and citalopram with comparably high concentrations in cerebrospinal fluid, the here presented findings indicate that duloxetine shows a very different distribution pattern. Very low concentrations in the cerebrospinal fluid may be due to the fact that the drug crosses the blood-cerebrospinal fluid barrier much worse than other antidepressants do, suggesting a low ability of duloxetine to enter the brain. Alternatively, low drug concentrations may be interpreted in a sense of a missing residence time in cerebrospinal fluid due to active transport mechanisms out of this environment either back into the bloodstream or into the brain.