Milnacipran Research Articles

A Pharmacovigilance Study of Drug-Induced Glaucoma Utilizing the Japanese Adverse Event Reporting System.

Clinically, glaucoma is a serious problem because it is asymptomatic until a relatively late stage in most cases, which can lead to delays in the diagnosis and treatment of the disease. The purpose of this study was to clarify the rank-order of the association of glaucoma with the causative drugs using a spontaneous reporting system database. Data were extracted from the Japanese Adverse Drug Event Report database of the Pharmaceuticals and Medical Devices Agency (Japan). Based on reports of glaucoma caused by all drugs, we calculated the reporting odds ratio (ROR) and 95% confidence interval (CI) for glaucoma. Among 609 reports of adverse events corresponding to glaucoma (46%, women), the most frequently implicated drug were steroids (prednisolone, betamethasone sodium phosphate, triamcinolone acetonide, and fluorometholone), pregabalin, ranibizumab, crizotinib, tacrolimus hydrate, darbepoetin alfa, and foscarnet sodium hydrate. Among 207 reports involved in angle-closure glaucoma (86%, women), anticholinergic drug and antidepressants ranked high and showed signals. Signals were also detected in bromazepam (ROR, 69.7; 95% CI, 30.9-157.5), oral brotizolam (ROR, 16.6; 95% CI, 6.18-44.8), and oral milnacipran hydrochloride (ROR, 22.8; 95% CI, 8.46-61.4) for angle-closure glaucoma. A national pharmacovigilance database enabled us to identify the drugs that frequently induce glaucoma. The likelihood of the reporting of glaucoma varied among the drugs, which should be used carefully in clinical practice to avoid it.

Miniaturized Chip Integrated Ecological Sensor for the Quantitation of Milnacipran Hydrochloride in the Presence of Its Impurities in Dosage Form and Human Plasma

The sensitivity and selectivity of potentiometric sensors towards their targets in various matrices have been challenging for analysts since their development. Modifications of the sensor composition provide the sensitivity and selectivity of potentiometric sensors towards their targets in various matrices have been challenging for analysts since their development. Modifications of the sensor composition provide a way to achieve the utmost sensitivity and selectivity. Molecular imprinting, together with conducting polymers and graphite derivatives, represents a robust composite that attains better sensor performance. Besides, the miniaturization of potentiometric sensors is advantageous to the sensitivity and greenness of the developed sensors due to their smaller portable size, lower sample volume, and lower waste. These advantages provide these sensors with a fast track toward developing wearable versions of ion-selective sensors, which are valuable in point-of-care services in different clinical settings. Here, we report on the first recyclable on-chip miniaturized potentiometric sensors integrated by a printed Ag/AgCl quasi-reference electrode for the quantitation of milnacipran hydrochloride (MLN) in its dosage form and human plasma in the presence of its impurities. The sensing module of the sensor is modified by a molecularly imprinted conducting polymer (polyaniline), which is computationally optimized to achieve maximum selectivity towards MLN in the presence of its impurities. Moreover, the designated sensor composition is optimized by a self-validated ensemble modeling experimental design seeking the composition leading to optimal sensor performance. The proposed on-chip sensor successfully achieved a LOD value of (7.94 × 10−7 M) and a linear range of (1 × 10−6 − 1 × 10−2 M) with a green analytical profile as redeemed from the Agree assessment score.

Gut microbe-derived milnacipran enhances tolerance to gut ischemia/reperfusion injury

There are significant differences in the susceptibility of populations to intestinal ischemia/reperfusion (I/R), but the underlying mechanisms remain elusive. Here, we show that mice exhibit significant differences in susceptibility to I/R-induced enterogenic sepsis. Notably, the milnacipran (MC) content in the enterogenic-sepsis-tolerant mice is significantly higher. We also reveal that the pre-operative fecal MC content in cardiopulmonary bypass patients, including those with intestinal I/R injury, is associated with susceptibility to post-operative gastrointestinal injury. We reveal that MC attenuates mouse I/R injury in wild-type mice but not in intestinal epithelial aryl hydrocarbon receptor (AHR) gene conditional knockout mice (AHRflox/flox) or IL-22 gene deletion mice (IL-22-/-). Collectively, our results suggest that gut microbiota affects susceptibility to I/R-induced enterogenic sepsis and that gut microbiota-derived MC plays a pivotal role in tolerance to intestinal I/R in an AHR/ILC3/IL-22 signaling-dependent manner, revealing the pathological mechanism, potential prevention and treatment drugs, and treatment strategies for intestinal I/R.

Milnacipran Ameliorates Executive Function Impairments following Frontal Lobe Traumatic Brain Injury in Male Rats: A Multimodal Behavioral Assessment.

Traumatic brain injuries (TBIs) affect more than 10 million patients annually worldwide, causing long-term cognitive and psychosocial impairments. Frontal lobe TBIs commonly impair executive function, but laboratory models typically focus primarily on spatial learning and declarative memory. We implemented a multi-modal approach for clinically relevant cognitive-behavioral assessments of frontal lobe function in rats with TBI and assessed treatment benefits of the serotonin-norepinephrine reuptake inhibitor, milnacipran (MLN). Two attentional set-shifting tasks (AST) evaluated cognitive flexibility via the rats' ability to locate food-based rewards by learning, unlearning, and relearning sequential rule sets with shifting salient cues. Adult male rats reached stable pre-injury operant AST (oAST) performance in 3-4 weeks, then were isoflurane-anesthetized, subjected to a unilateral frontal lobe controlled cortical impact (2.4 mm depth, 4 m/sec velocity) or Sham injury, and randomized to treatment conditions. Milnacipran (30 mg/kg/day) or vehicle (VEH; 10% ethanol in saline) was administered intraperitoneally via implanted osmotic minipumps (continuous infusions post-surgery, 60 μL/h). Rats had a 10-day recovery post-TBI/Sham before performing light/location-based oAST for 10 days and, subsequently, odor/media-based digging AST (dAST) on the last test day (26-27 days post-injury) before sacrifice. Both AST tests revealed significant deficits in TBI+VEH rats, seen as elevated total trials and errors (p < 0.05), which generally normalized in MLN-treated rats (p < 0.05). This first simultaneous dual AST assessment demonstrates oAST and dAST are sufficiently sensitive and robust to detect subtle attentional and cognitive flexibility executive impairments after frontal lobe TBI in rats. Chronic MLN administration shows promise for attenuation of post-TBI executive function deficits, thus meriting further investigation.

Drug-drug eutectic mixtures of celecoxib with tapentadol and milnacipran which could improve analgesic and antidepressant efficacy

Eutectic mixtures had been developed as an approach to enhance physicochemical properties and oral bioavailability of drugs. Moreover, drug-drug eutectics mixtures with synergetic effects had been used to improve pharmacodynamic properties. In this study, two eutectic mixtures of celecoxib (CEL) with milnacipran hydrochloride (MIN) and tapentadol hydrochloride (TAP) were designed and prepared. The differential scanning calorimetry (DSC) data of mixtures prepared from 0.1 to 0.9 M ratios were applied to construct binary phase diagrams to determine the eutectic molar ratio. The CEL and TAP eutectics (CEL-TAP-EU) system formed a eutectic at a CEL mole fraction of 0.6, and for CEL and MIN eutectics (CEL-MIN-EU) system was at a CEL mole fraction of 0.5. Eutectic mixtures were further characterized by powder x-ray diffraction (PXRD) Fourier Transform infrared spectroscopy(FTIR), Raman spectra, and solid-state nuclear magnetic resonance (SS-NMR) to verify the formation of the eutectic system. Scanning electron microscope (SEM) techniques depict the actual morphology difference between eutectic mixtures and CEL, TAP, and MIN. The disk intrinsic dissolution rate test (DIDR) and powder dissolution test indicated that CEL from CEL-TAP-EU and CEL-MIN-EU had improved dissolution properties comparing CEL alone and their physical mixture, while the dissolution of TAP and MIN dramatically reduced. The pharmacokinetics study suggested that the CEL in the eutectic mixtures had higher oral bioavailability and earlier plasma concentration peak time. The acetic induced writhing test of CEL-TAP-EU indicated an analgesic efficacy enhancement while the forced swimming test of CEL-MIN-EU suggested an improved antidepressant efficacy. The solubility, pharmacokinetics, and pharmacodynamic properties enhancements made the CEL-TAP-EU and CEL-MIN-EU potential candidates for further pharmaceutical products development.

The Effect of Serotonin-Norepinephrine Reuptake Inhibitor Milnacipran on Anxiety-like Behaviors in Diabetic Mice

Background: Diabetes mellitus is a chronic disease that causes neuronal plasticity and increased hypothalamic pituitary adrenal (HPA) axis of stress disorders. The change in metabolism is reportedly associated with inadequate response to antianxiety and antidepressant agents. Objective: This study aimed to determine the effect of milnacipran antidepressants on anxiety-like behavior in mice with diabetes mellitus. Methods: Male ICR mice were divided into naive, stress, diabetes mellitus (DM), DM + stress groups to measure anxiety-like behavior. Diabetes mellitus was induced using alloxan, and electric footshock stress was used as a stressor for 14 consecutive days. Anxiety-like behavior was measured using the light-dark box (LDB) and elevated plus maze (EPM) test at days 0, 7 and 14. The antidepressant milnacipran (MIL) was given for 7 days, on days 8 to 14. On day 14, evaluation of anxiety-like behavior after administration of MIL was carried out in all groups using LDB and EPM tests. Results: The results showed that administration of milnacipran effectively ameliorated anxiety-like behavior in the non-DM, but not in the DM group, using the LDB test. A similar result was demonstrated in the EPM test showing the non-DM group's attenuation after milnacipran administration. Conclusion: The present results indicate that there is an inadequate attenuation of the anxiety-like behavior after treatment with milnacipran in diabetes conditions.

Formulation and Evaluation of Oral Controlled Release Tablets of Milnacipran Hydrochloride

Formulation and Evaluation of Oral Controlled Release Tablets of Milnacipran Hydrochloride

All-Solid-State Disposable Polymeric Ion Selective Electrode for Determination of Milnacipran in Pharmaceutical Dosage Form

Screen printing technology offers a simple and cost-effective methodology for large scale production of electrochemical sensors with high reproducibility. Herein, a novel polymeric all-solid-state screen printed ion selective electrode is developed for determination of milnacipran (MLN) in pharmaceutical formulation. The morphology of the electrode was characterized by Scanning Electron Microscopy (SEM). The electrode response was optimized with regard to the membrane composition, type of the plasticizer and the ion exchanger. Optimal potentiometric response was obtained with a membrane containing milnacipran-phosphomolybdate (MLN-PMA) ion associate as ion exchanger and tricresyl phosphate as a plasticizer. The electrode exhibited a Nernstian response of 57.2±1 mV/decade (n = 3) over the concentration range from $1.0 \times 10^{-5}$ to $1.0 \times 10^{-2}$ M of MLN (r=0.9998) with a detection limit of $2.0 \times 10^{-6}$ M. The electrode showed a fast potentiometric response time ( $\le 10\text{s}$ ) with a high potential stability ( $\Delta \text{E}/\Delta \text{t}~\le 1.3~\mu \text{V}$ /s over 40 min of continuous monitoring). The electrode response is independent of pH in the range from 2.5 to 7.0. The electrode is selective to MLN over common pharmaceutical excipients, inorganic cations and amino acids. The electrode was used for determination of MLN in pharmaceutical dosage form with high accuracy (average recovery = 99.30%) and precision (RSD≤2%, n = 5).

A new sensitive approach for spectrofluorimetric assay of Milnacipran and Amisulpride in real plasma and pharmaceutical preparations via complexation with Eosin Y dye.

An accurate, economic, rapid, reliable spectrofluorimetric assay was developing for the assay of definite anti-depressant drugs namely Amisulpride and Milnacipran hydrochloride, in those pharmaceutical preparation and biological fluid. The suggested method was established on the detection of quenching process resulting from the action of AMS and MCN to the native fluorescent EosinY. A binary complex between selected medications and Eosin Y was established in acetate buffer (0.2 M) at pH 3.3 & 4.0 for AMS and MCN respectively. The relative fluorescence capacity was determined at λex = 301.8 nm and λem = 542.7 nm. The calibration graphs had been linear through extent from 0.02 to 0.3 and 0.1-1 μg mL-1, to both dugs respectively. Detection limits have been 0.0047 & 0.0188 μg mL-1 while quantitation limits have been 0.0141 & 0.0569 μg mL-1 to AMS & MCN respectively. Developed assay has been validated in agreement with ICH recommendations. Due to high sensitivity of the described assay, it allows the quantitation of anti-depressant drugs through biological fluid.

An experimental ninhydrin design approach for the sensitive spectrofluorimetric assay of milnacipran in human urine and plasma

Women are the most ones who susceptible to a common syndrome called fibromyalgia syndrome, up to 90% of all people with fibromyalgia are women. It affects mainly muscles and soft tissue and cause for them muscle pain, sleep problems and painful tender points. Milnacipran is acting as a serotonin–norepinephrine reuptake inhibitor (SNRI) therefore, it is recommended for the treatment of this syndrome. The widespread use of this compound in our market requires the development and validation of a simple, sensitive, cheap, fast and reproducible spectrofluorimetric method for the assay of milnacipran hydrochloride in its pure state, pharmaceutical tablets and spiked human urine and plasma. In the current work ninhydrin and phenylacetaldehyde in Teorell and Stenhagen buffer (pH 7) reacts with the amino moiety of milnacipran through a sensitive condensation reaction resulting in formation of a fluorescent product, which exhibits its fluorescence emission intensity at 465 nm after excitation at 390 nm. It is observed that, in the concentration range 0.5 to 3.0 μgmL−1, the constructed calibration curve was linear with a good correlation coefficient (0.9998). The condensation reaction was successfully applied for the assay of the studied drug in Avermilan® tablets, spiked human urine and plasma without interference from the components of the sample matrix with average percentage recoveries of 101.73 ± 0.56 and 100.55 ± 0.64 for urine and plasma, respectively.

DEVELOPMENT AND EVALUATION OF MODIFIED RELEASE MATRIX TABLETS OF MILNACIPRAN HCL USING MELT GRANULATION TECHNIQUE

The objective of the present study was to identify critical formulation parameters affecting the drug release from modified release wax matrix tablet of milnacipran hydrochloride employing the concept of design of experiments.The optimized amount of Compritol 888 ATO(intragranular) (X1), lactose (X2) and Compritol 888ATO (extragranular)(X3) were determined employing simplex latticedesign. The tablets were prepared using melt granulation technique. The in vitro drug release study was carried out in an acidic medium (pH 1.2) for 2 h and thereafter the dissolution study was conducted in phosphate buffer (pH 6.8).The selected dependent variables were the cumulative percentage of milnacipran hydrochloride dissolved at 1 (Y1), 8 (Y8), 16 (Y16) and 24 h (Y24). Mathematical models, correlating the independent variables with dependent variables were evolved. Optimization was performed for the three independent variables using the stated target ranges; Y1≤20%; Y8=45±5%; Y16=72±5%; Y24=100%. The optimized amounts of Compritol ATO888 (intragranular)(X1), lactose (X2) and Compritol 888ATO (extragranular)(X3), were found to be 60, 55 and 30 mg, respectively.The optimized formulation showed a release profile that was close to the predicted values. The drug was released by anomalous diffusion from the optimized formulation. Compritol 888ATO (intragranular) (X1), lactose (X2) and Compritol 888ATO(extragranular) (X3) were identified as critical variables.

Utility of the chromogenic and fluorogenic properties of benzofurazan for the assay of milnacipran in human urine and plasma.

Our article presents the development and validation of two simple, very sensitive, and low-cost spectroscopic methods for the assay of milnacipran hydrochloride in bulk form, pharmaceutical tablets and spiked human urine and plasma. Spectroscopic methods (spectrophotometric and spectrofluorimetric techniques) were dependent on the chromogenic and fluorogenic properties of the 4-chloro-7 nitrobenzofurazan (NBD-Cl) reagent. The reaction product, resulting from the interaction between NBD-Cl and milnacipran in the presence of borate buffer pH 8.5, was measured spectrophotometrically at 465 nm and spectrofluorimetrically at 510 nm after excitation at 465 nm. The absorbance–concentration plot was rectilinear over the range of 1.5–12 μg mL−1 with a limit of quantitation 1.09 μg mL−1, while the fluorescence–concentration plot was rectilinear over the range of 0.03–0.5 μg mL−1 with a limit of quantitation 0.02 μg mL−1. Influential parameters affecting the development and stability of the reaction product were studied and optimized. Assurance of the cited drug in its tablets by our proposed methods was successfully completed without obstruction from the presence of the basic excipients with average percentage recoveries of 99.27 ± 1.18 and 99.44 ± 0.69 for the spectrophotometric and spectrofluorimetric methods, respectively. The spectrofluorimetric method was additionally adopted as a preliminary in vitro study for the assay of the cited drug in spiked human urine and plasma with average percentage recoveries of 101.52 ± 1.01 and 100.38 ± 1.57 for spiked urine and plasma, respectively.

Assessment of clinical manifestations and treatment of post-stroke depression in young patients with ischemic stroke

To consider clinical manifestations and treatment of post-stroke depression in young patients with carotid ischemic stroke. Forty patients, 24 women and 16 men, aged from 18 to 45 years old, diagnosed with ICD-10 post-stroke depression were examined. All patients underwent neurological examination, brain MRI and MR-angiography of cerebral vessels. The following psychometric tests were used: MMSE, Hamilton depression scale, CES-D depression scale, a questionnaire on nocturnal sleep assessment, and Epworth Sleepiness Scale. The Recovery Locus of Control Questionnaire was administered to evaluate motivation level for the post-stroke recovery. Patients were divided into two groups: group 1 (n=22) received basic treatment including milnacipran hydrochloride (ixel) in dose 1 capsule twice a day during 3 months, group 2 received only basic treatment. Psychometric testing was performed 2 month after stroke before the treatment and 3 month after the end of treatment. Patients demonstrated positive (melancholy, anxiety, intellectual and motor inhibition) and negative affectation (apathy, dysphoria) accompanied by somatic/autonomic disorders, in particular, sleep deficiency. A marked therapeutic effect of ixel was shown in group 1. The number of patients with depression decreased significantly after treatment compared to group 2. Sleep improvement and increased motivation levels for recovery were observed as well.

Development of Bioanalytical HPLC Method for Estimation of Milnacipran Hydrochloride in Rabbit Plasma Using Solid Phase Extraction Technique and its Application in Pharmacokinetic Investigation

Background: The availability of a low-cost bioanalytical method, easy to transfer and to set up, represents an advantage in therapeutic drug monitoring and industrial research. Objective: A simple, sensitive and rapid high performance liquid chromatographic (HPLC) method is developed and validated for quantitative determination of milnacipran hydrochloride in rabbit plasma. Method: Simple and effective solid phase extraction technique was performed for sample treatment and it has resulted in consistent and high recoveries (93–95%) at all concentrations studied. Efficient chromatographic separation has been performed on a LiChrospher® C18 column using a mobile phase consisting of a mixture of phosphate buffer, acetonitrile and methanol (65:25:10; v/v/v) at a flow rate of 0.8 mL/min. Results: The method has demonstrated linearity from 25 ng to 2000 ng/mL with a regression coefficient of 0.9998. The accuracy was found to be very high (99.31 to 101.44 %). %RSD values for inter-day and intra-day variation were not more than 3.58. The method has demonstrated high sensitivity with a lower limit of quantification of 25 ng/mL and excellent stability of milnacipran in rabbit plasma. The method was applied for pharmacokinetic investigation of immediate release and controlled release milnacipran tablets. The in-vivo study results indicated that developed HPLC method was sensitive to accurately quantify the concentration of milnacipran in plasma, which is an essential requirement for determination of pharmacokinetic parameters for drug formulation studies as well as future bioavailability or bioequivalence studies. Conclusion: A simple and sensitive bioanalytical HPLC method was developed, validated and applied for pharmacokinetic studies. Keywords: Milnacipran, liquid chromatography, solid phase extraction, rabbit plasma, pharmacokinetic investigation.

An Efficient Synthesis of Milnacipran Hydrochloride via Reductive Amination of Aldehyde

An efficient synthesis of milnacipran hydrochloride has been accomplished. The important application of this paper is the reductive amination of aldehyde to primary amine with water soluble reagents. This method provides a high yield of primary amine as the major product, reduces the number of steps, and discourages by-products.

Simple and Sensitive Colorimetric Method for the Determination of Milnacipran in Bulk and Swellable Matrix Tablets

Milnacipran, a serotonin and adrenaline reuptake inhibitor used to treat fibromyalgia and major depression, is difficult to quantify analytically at shorter UV wavelengths. This necessitates the development of a sensitive, precise and accurate colorimetric method for the determination of milnacipran hydrochloride in bulk and swellable matrix tablets. The drug was derivatized with ninhydrin reagent prepared by two methods using direct heating on flame and in glycerol bath at 110°C. The drug -(milnacipran)- ninhydrin complex (Ruhemman’s Purple) showed an absorbance maximum at 570 nm. The method exhibited linearity in a concentration range of 4 to 400 μg/mL with a correlation coefficient of 0.9999. As per ICH guidelines, the method showed good sensitivity (LOD = 0.550 μg/mL and LOQ = 1.667 μg/mL), intraday accuracy and precision (4.713%), and interday accuracy and precision (2.569%). The method was applied to determine the drug in swellable matrix tablets. The obtained results indicate that the proposed method of milnacipran hydrochloride determination in bulk and swellable matrix tablets is simple, accurate and precise, and can be used in less equipped laboratories.

Does milnacipran improve pain in adults with fibromyalgia?

Does milnacipran improve pain in adults with fibromyalgia?

Is the Efficacy of Milnacipran in Fibromyalgia Predictable? A Data-Mining Analysis of Baseline and Outcome Variables.

Objectives:Minalcipran has been approved for the treatment of fibromyalgia in several countries including Australia. Australian agency considered that the overall efficacy is moderate, although clinically significant, and could be translated into a real and strong improvement in some patients. The determination of the characteristics of patients who could benefit the most from milnacipran (MLN) is the primary objective of this manuscript.Materials and Methods:Data from the 3 pivotal phase 3 clinical trials of the Australian submission dossier were assembled into a database. A clustering method was implemented to exhibit natural groupings of homogeneous observations into clusters of efficacy outcomes and individual patients. Next, baseline characteristics were investigated using a data-mining method to determine the clinical features that may be predictive of a substantially improved effect of MLN on a set of efficacy outcomes.Results:The clustering analysis reveals 3 symptom domains: “Pain and global,” “Mood and central status,” and “Function.” We show that improvement in “Fatigue” goes with improvement in “Function.” Furthermore, the predictive data-mining analysis exhibits 4 single baseline characteristics that are associated with a substantially improved effect of MLN on efficacy outcomes. These are high pain intensity, low anxiety or catastrophizing level, absence of major sleeping problems, and physical limitations in the daily life effort.Discussion:Clustering and predictive data-mining methods provide additional insight about fibromyalgia, its symptoms, and treatment. The information is useful to physicians to optimize prescriptions in the daily practice and to regulatory bodies to refine indications.

Evaluation of oral antidepressant drugs for adaptation to the simple suspension method

Objective: Gavage administration of antidepressant drugs is required for some depressed patients with dysphagia. In the recent years, a simple suspension method has drawn increasing attention as a method that prevents changes in the stability and safety of various drugs. However, only 59 of the 354 orally administered antidepressant drugs (16.7%) approved in Japan by April 2013 have been examined with this method. In this study, we investigated whether 44 oral antidepressant drugs, which have not previously been tested for effi cacy through gavage, could be adapted to the simple suspension method. Materials and Methods: Adaptability of antidepressants to the simple suspension method was assessed by incubating at room temperature a drug in 20 mL of warm water (at 55°C) in a 30 mL-syringe for 5 and 10 min. The ability of the decayed drugs to pass through the tubing was also examined. Results: Most of the 44 oral antidepressant drugs tested could be adapted to the simple suspension method. Unexpectedly, fl uvoxamine maleate tablets, milnacipran hydrochloride tablets, and Cymbalta® capsules required 10 min or longer to decay. Conclusion: We were able to qualitatively assess all 44 oral antidepressant drugs. These results provide useful information for administration of oral antidepressant drugs to depressed patients using a simple suspension method. Key words: Difficulty swallowing, gavage administration, generic drugs, oral antidepressant drugs, simple suspension method.

Comparative Pharmacokinetic Evaluation of Controlled Release Matrix Tablet of Milnacipran Hydrochloride in Rabbit

Comparative Pharmacokinetic Evaluation of Controlled Release Matrix Tablet of Milnacipran Hydrochloride in Rabbit