Nortriptyline Research Articles

Analysis of the anti-Candida activity of tricyclic antidepressants in association with amphotericin B and their antifungal mechanisms.

Candida species are among the priority pathogens in the area of research and development. Due to the problems associated with resistance to antifungals, new therapeutic alternatives are necessary. In this regard, drug repositioning has gained prominence. The objective of this study was to evaluate the activity of three tricyclic antidepressants (TCAs) - amitriptyline (AMT), nortriptyline (NOR) and clomipramine (CLO) - isolated or associated with antifungals against strains of Candida spp., as well as to analyze the possible mechanism of action. Among the methods used were broth microdilution tests, tolerance level assessment, checkerboard assays, flow cytometry and fluorescence microscopy. Furthermore, Candida cells were visualized after treatments by scanning electron microscopy (SEM). AMT presented MIC 50% in the range of 16 to 128µg/mL, NOR from 8 to 128µg/mL, and CLO from 8 to 64µg/mL, with all three TCAs having a fungicidal inhibitory action profile. For these TCAs, there was synergism with amphotericin B (AMB) in 100% of the isolates. In association with fluconazole (FLC) and itraconazole (ITR), there were mostly indifferent interactions. TCAs isolated and associated with AMB reduced cell viability, promoted DNA fragmentation and damage, caused mitochondrial depolarization, externalization of phosphatidylserine, produced reactive oxygen species (ROS), decreased reduced glutathione (GSH) and increased carbonyl protein levels, causing morphological changes. The results suggest the antifungal mechanism of the TCAs works via the apoptotic pathway.

MDB-93. A TRANSCRIPTOME-BASED APPROACH TO DRUG REPURPOSING FOR AGGRESSIVE GROUP 3 MEDULLOBLASTOMAS

Abstract BACKGROUND Medulloblastoma (MB) is the most common malignant brain tumor in children, representing 20% of pediatric brain tumors. International consensus has identified molecular subgroups: WNT, SHH, group 3 (G3), and group 4 (G4). Current treatments, guided by histologic tumor grade and stage, do not fully harness these subgroups, resulting in varying prognoses. G3MB particularly faces challenges with rapid recurrence and aggressive disease, necessitating focused intervention. METHODS We conducted differential expression analysis on MB patient datasets (GSE148389, GSE164677) to generate a G3MB gene expression signature. This gene expression signature was analyzed against the LINCS database, yielding candidate antineoplastic compounds. Candidates were filtered for blood-brain barrier permeability and FDA approval. Functional assays evaluated drug effects on cytotoxicity, clonogenicity, wound healing, cell cycle, and apoptosis in G3MB cell lines (HDMB03 and D425). RNA sequencing of treated cells identified differentially regulated pathways to infer mechanism, followed by in vitro validation. Mitochondrial function and membrane potential were measured by Seahorse and TMRM assays, respectively. RESULTS Eighty-one candidates passed filtering. The leading drug class identified was antidepressants. Based on MTT assays, the top four candidates were nortriptyline, simvastatin, fluoxetine, and sertraline. Nortriptyline (NT) emerged as the lead compound, with IC50 values of ~7uM (HDMB03) and ~11uM (D425). Amongst the four drugs, NT induced consistent anti-neoplastic effects on wound healing, colony formation, medullosphere generation, and apoptosis. Mechanistically, NT induced mitochondrial stress, escalated mitochondrial superoxide, and decreased mitochondrial membrane potential. CHRM3, a receptor antagonized by NT and upregulated in G3MB samples was downregulated by NT treatment. Western blotting confirmed the inhibition of CHRM3 downstream effectors. CONCLUSIONS Our pipeline identified cytotoxic compounds against G3MB, including NT, which we hypothesize induces mitochondrial stress via CHRM3 modulation. This approach offers repurposable FDA-approved candidates for high-risk G3MB, potentially reducing current treatment toxicity and improving outcomes.

Transformation mechanisms of antidepressants in biological wastewater treatment: Removal kinetic, transformation products and pathways

The extensive detection of antidepressants in wastewater has raised increasing concerns for human beings. During biological wastewater treatment processes, antidepressants cannot be completely removed and mineralized, which caused the formation of transformation products (TPs). To date, knowledges on TPs that participated in the transformation processes of antidepressants were scarce. To fill this gap, molecular networking nontarget screening based on lab-scale batch assays were employed to explore the removal and transformation of five antidepressants (amitriptyline (AMI), clomipramine (CLO), duloxetine (DUL), nortriptyline (NOR) and paroxetine (PAR)). The removal rate constants per unit of biomass (kbio) of the five antidepressants were found to range from 0.29 to 0.56 L/(gMLSS*d). Comparatively, clomipramine was removed more slowly than other antidepressants, which attributed to its lower electrophilic properties. Subsequently, 22 TPs were tentatively identified, among which 19 ones were newly found in the present study. The proposed transformation pathways indicated that demethylation, N-formylation, N-acetylation, N-succinylation, N-hydroxylation, dealkylation, hydrolysis and nitrosation participated in the transformation of antidepressants in wastewater. Particularly, N-acylation and N-hydroxylation were found as characteristics reactions for antidepressants in wastewater and these reactions consistently occurred at the site of amino functional group, where high electrophilic activity was the dominant causes for the observed characteristics reactions. In silico results revealed that TPs formed during biological wastewater treatment generally had lower toxicity, lower bioaccumulation and higher bioavailability than their parent compounds. Collectively, the present study provides insights into the transformation processes of antidepressants in wastewater, indicating that characteristic transformation reactions occur across different antidepressants, which is theoretically useful to effectively remove pharmaceuticals from wastewater.

Nortriptyline hydrochloride, a potential candidate for drug repurposing, inhibits gastric cancer by inducing oxidative stress by triggering the Keap1-Nrf2 pathway

Effective drugs for the treatment of gastric cancer (GC) are still lacking. Nortriptyline Hydrochloride (NTP), a commonly used antidepressant medication, has been demonstrated by numerous studies to have antitumor effects. This study first validated the ability of NTP to inhibit GC and preliminarily explored its underlying mechanism. To begin with, NTP inhibits the activity of AGS and HGC27 cells (Human-derived GC cells) in a dose-dependent manner, as well as proliferation, cell cycle, and migration. Moreover, NTP induces cell apoptosis by upregulating BAX, BAD, and c-PARP and downregulating PARP and Bcl-2 expression. Furthermore, the mechanism of cell death caused by NTP is closely related to oxidative stress. NTP increases intracellular reactive oxygen species (ROS) and malondialdehyde (MDA) levels, decreasing the mitochondrial membrane potential (MMP) and inducing glucose (GSH) consumption. While the death of GC cells can be partially rescued by ROS inhibitor N-acetylcysteine (NAC). Mechanistically, NTP activates the Kelch-like ECH-associated protein (Keap1)—NF-E2-related factor 2 (Nrf2) pathway, which is an important pathway involved in oxidative stress. RNA sequencing and proteomics analysis further revealed molecular changes at the mRNA and protein levels and provided potential targets and pathways through differential gene expression analysis. In addition, NTP can inhibited tumor growth in nude mouse subcutaneous tumor models constructed respectively using AGS and MFC (mouse-derived GC cells), providing preliminary evidence of its effectiveness in vivo. In conclusion, our study demonstrated that NTP exhibits significant anti-GC activity and is anticipated to be a candidate for drug repurposing.

Impact of pH and membrane nature on distribution and permeability processes of nortriptyline hydrochloride

Partitioning/distribution and permeability are key parameters determining successful drug absorption. In the present work the distribution thermodynamics of nortryptiline hydrochloride (NTT) - an antidepressant drug of BCS II class was studied in the three partition systems: 1-octanol/buffer, n-hexane/buffer and isopropyl myristate (IPM)/buffer (pH 2.0, pH 4.0, and pH 6.8). The studies revealed rather low values of DappOrg/buf attributed to the ionized state of the majority of the NTT molecules. The following sequence of the distribution coefficients in all the systems was estimated: DappOrg/buf(pH6.8)>DappOrg/buf(pH4.0)>DappOrg/buf(pH2.0). Thermodynamic calculations disclosed the entropy as the main driving force for the buffer → 1-octanol and buffer pH 6.8 → IPM transfer. In order to select the optimal membrane for simulating the cells of different tissues, three artificial barriers were tested for NTT permeability: cellulose (RC), PermeaPad (PP) and polydimethylsiloxane-polycarbonate (PDS). A 4.7-fold enhancing effect of IPM as a known “percutaneous permeability enhancer” was demonstrated on PDS membrane. The distribution-permeability interrelations were discussed. We expected the results to be applicable for the improvement of tricyclic antidepressants peroral and transdermal use.

Formulation and In-Vitro evaluation of Nortriptyline Hydrochloride mucoadhesive buccal films

This contemporaneous research was aimed to formulate buccal mucoadhesive DDS to enhance bioavailability and avoid pre systemic metabolism. The mucoadhesive film was fabricated by solvent casting method with base polymer chitosan and a combination of hydrophilic polymer like PVP or Gelatin. The films were then evaluated. All the formulations were found to have optimum strength to withstand folding endurance. The films' consistent size, thickness, and weight variation were discovered. The drug content uniformity of films was exceptionally well. Given that the film's surface pH falls between 6.6 and 6.7, buccal administration is appropriate for it. The pH near to the neutral region decreases the chances of mucosal irritation. The invitro adhesion ability of the formulations were affected by the composition of chitosan and PVP or Gelatin. The lower and higher concentration of chitosan was not sufficient for invitro adhesion of films. The formulation having chitosan and hydrophilic polymers in the ratio 1:1.5 showed strong invitro adhesion. The invitro bioadhesion time of the formulations containing chitosan and gelatin or PVP was less due to poor ionization of gelatin. On increasing the concentration of hydrophilic polymers, the invitro bioadhesion time increased. The highest concentration of the polymers decreased the adhesion time. The formulation NF5 with chitosan and gelatin within the proportion of 1:1.5 exhibited drug release of 98.1% at 6 hours. The sole purpose of this work is to adhere the buccal film with the mucosa, hence formulation NF5 was selected as best formulation. Thus, current investigation's goal to develop a buccal mucoadhesive drug delivery was fulfilled.
 Keywords: Buccal film, Nortriptyline HCl, depression, in vitro studies, mucoadhesive

Cyclodextrin's Effect on Permeability and Partition of Nortriptyline Hydrochloride.

Cyclodextrin-based delivery systems have been intensively used to improve the bioavailability of drugs through the modification of their pharmaceutically relevant properties, such as solubility, distribution and membrane permeation. The present work aimed to disclose the influence of HP-β-CD and SBE-β-CD on the distribution and permeability of nortriptyline hydrochloride (NTT•HCl), a tricyclic antidepressant drug. To this end, the distribution coefficients in the 1-octanol/buffer and n-hexane/buffer model systems and the coefficients of permeability through the cellulose membrane and lipophilic PermeaPad barrier were determined at several cyclodextrin concentrations. The results demonstrated a dramatic decrease in both the distribution and the permeability coefficients as the cyclodextrin concentration rose, with the decrease being more pronounced in SBE-β-CD due to the charge-charge attraction and electrostatic interactions between NTT and SBE-β-CD. It is these interactions that were shown to be responsible for the greater value of the constant of NTT's association with SBE-β-CD than that with HP-β-CD. The findings of this study revealed similar trends in the 1-octanol/buffer 6.8 pH distribution and permeability through the PermeaPad barrier in the presence of CDs. These results were attributed to the determinative role of the distribution coefficient (serving as a descriptor) in permeation through the PermeaPad barrier modeling the lipophilic nature of biological barriers.

Mixed micellization analysis of tri-substituted SAIL and amphiphilic drug mixture in aqueous/salt media at diverse temperatures

Abstract The present work aimed to study the mixed micellar behaviour of a tri-substituted imidazolium based surface-active ionic liquid (SAIL), 1-tetradecyl-2,3-dimethylimidazolium bromide [C14bmim][Br], with a drug Nortriptyline hydrochloride (NOT) in the water/salt (Na2SO4) medium using surface tension measurements (298.15 K) alongwith conductivity measurements (298.15K–313.15K). Lower experimentally obtained cmc values compared to their ideal values suggest that the investigated amphiphiles interact strongly. The values of micellar mole fraction (X 1) based on the several proposed models (Rubingh, Motomura, and Rodenas) and the ideal micellar mole fraction (X id ) were assessed, and the predicted outcomes indicate that NOT has a significant contribution to the formation of mixed micelles, which increases as the [C14bmim][Br] mole fraction is increased. The negative values of micellization’s Gibbs free energy (ΔGm 0) between the examined amphiphiles were an indication of spontaneous mixed micelle formation. Micellar changes in entropy (ΔSm 0) and enthalpy (ΔHm 0) were also computed and discussed. Using surface tension measurements, surface-active parameters like surface tension at cmc (γ cmc ), minimum surface area per IL molecule (A min), maximum surface excess concentration (τ max), effectiveness of surface tension reduction (π cmc ), and cmc of mixed system have been estimated. The results showed an improved adsorption and micellization properties of these mixtures which will surely contribute to the tremendous rise of these mixed systems in drug delivery applications.

In-situ growth of covalent organic framework on stainless steel needles as solid-phase microextraction probe coupled with electrospray ionization mass spectrometry for rapid and sensitive determination of tricyclic antidepressants in biosamples

Tricyclic antidepressants (TCAs) including amitriptyline (AT), doxepin (DOX) and nortriptyline (NT) are the first-line drugs for the clinical treatment of depression; however, monitoring TCA concentrations in biological fluids and tissues is necessary to improve therapeutic effect and determine the cause of death in patients. It is of great significance to develop a rapid and sensitive method for real-time monitoring of TCAs in various biosamples. In this work, we fabricated a novel covalent organic framework (COF) based solid-phase microextraction (SPME) probe by an in-situ step-by-step strategy, which was obtained by sequentially modifying 1,3,5-tri (4-aminophenyl) benzene (TPB) and 2, 5-divinylbenzaldehyde (DVA) on the surface of polydopamine layer. The TPB-DVA-COF-SPME probe possessed high specific surface area (1244 m2·g − 1), regular pores (3.23 nm), good hydrophobicity and stability, resulting in efficient enrichment for TCAs. Furthermore, the combination of TPB-DVA-COF-SPME probe and ambient electrospray ionization mass spectrometry system (ESI/MS) was firstly proposed for rapid and sensitive determination of TCAs in biosamples. As a result, the developed method exhibited low limits of detection (LODs) (0.1–0.5 μg∙L − 1), high enrichment factors (39–218), and low relative standard deviations (RSDs) for one probe (1.2–3.8%) and probe-to-probe (2.0–3.7%). Benefiting from these outstanding performance, TPB-DVA-COF-SPME probe was further successfully applied to biosamples (i.e., serum, liver, kidney, and brain) with excellent reusability, indicating the promising applicability of the TPB-DVA-COF-SPME-ESI/MS as a powerful tool for drug monitoring.

A green microfluidic method for the simultaneous extraction of polar and non-polar basic compounds in biological samples

Microfluidic devices as sample treatment have showed significant advancements in recent years, becoming an important tool in pharmaceutical analysis. In this work, a green microfluidic method for the simultaneous extraction of basic polar and non-polar compounds is proposed for the first time, offering a new and more sustainable and environmentally friendly alternative. A mixture of camphor:menthol 1:1 is presented as a new green supported liquid membrane (SLM) for the simultaneous extraction of a wide log P range for basic compounds (0.4 < log P < 5): verapamil hydrochloride (VRP), tyramine (TYR), atenolol (ATN), metopropol (MTP) and nortriptyline (NRP). Different SLMs were investigated to offer new other green alternatives for polar or non-polar basic drugs. Microfluidic operational parameters were also optimized at pH 1.5, pH 11.5 and 1 µL min−1 as acceptor phase, donor phase and donor flow rate, respectively. Camphor:menthol 1:1 showed good stability and reproducibility (RSD < 5%) in human urine samples. It was found to be an attractive alternative to traditional toxic organic solvents applied in microextraction techniques. The green microfluidic method offered good recoveries between 50 and 100% for all compounds in urine sample after 7 min extraction, using only 3 µL of Ca:Me 1:1 and showing a good long-term stability system up to 6 consecutive extraction in real samples. A relative standard deviation (n = 3) was below 6 % for all compounds with and without replacing the membrane of the system.

Antinociceptive effects of nortriptyline and desipramine hydrochloride in Speke's hinge-back tortoise (Kinixys Spekii).

Some of the most commonly used analgesic drugs in animals are of questionable efficacy or present adverse side effects among the various species of reptiles. Tricyclic antidepressants have been demonstrated to have antinociceptive effects in several animal models of pain and could be a good alternative for use in reptiles. The aim of the study was to investigate the antinociceptive effects of nortriptyline and desipramine hydrochloride in Speke's hinge-back tortoise. A total of 24 animals weighing 600-1000 g were used for nociceptive tests, i.e., formalin, capsaicin, and hot plate tests. Drugs were administered intracoelomically 30 min before starting the tests. The time spent in nocifensive behavior and the associated observable effects during the tests were recorded. Only the highest dose of 40 mg/kg of nortriptyline hydrochloride caused statistically significant decrease in nocifensive behavior in both the formalin and the capsaicin test. Desipramine hydrochloride at doses of 20 and 40 mg/kg caused statistically significant decrease in nocifensive behavior in the formalin test. Also, desipramine hydrochloride at doses of 15, 20, and 60 mg/kg caused statistically significant decrease in nocifensive behavior in the capsaicin test. None of the doses used for both drugs had any statistically significant effect on nocifensive behavior in the hot plate test. The results show that nortriptyline and desipramine hydrochloride have significant antinociceptive effects in the chemical but not thermal inflammatory pain-related behavior in the Speke's hinge-back tortoise. The most common associated side effect following administration of the higher doses of either of the drugs is excessive salivation.

Four Greenness Evaluations of Two Chromatographic Methods: Application to Fluphenazine HCl and Nortriptyline HCl Pharmaceutical Combination in Presence of Their Potential Impurities Perphenazine and Dibenzosuberone

Nowadays, when analysts develop a new method, they are taking into consideration the green aspects of the developed method. Two chromatographic methods were developed for the determination of antidepressant pharmaceutical combination nortriptyline hydrochloride and fluphenazine hydrochloride in presence of their potential impurities and the methods were assessed using four tools; eco-scale, analytical greenness profile (AGP), analytical greenness metric approach (AGREE), and green analytical procedure index (GAPI). Method (A) was RP-HPLC, in which the separation was carried out on C18 column (250 × 4.5 mm, 5 µm) by gradient elution using mobile phase consisting of a mixture of water containing 0.1% H3PO4 (pH 2.25) and methanol, at a flow rate of 2 mL/min with DAD detection at 254 nm. Method (B) was TLC, in which the separation was carried out on silica gel TLC F254 plates. The mobile phase used was a mixture of methanol and acetone (9:1, v/v) with UV detection at 245 nm. The proposed methods agreed with ICH guidelines of method validation and were successfully applied for determination of the proposed components in their dosage form and the results were compared statistically to those obtained by the reported RP-HPLC method with no significant difference; which suggests the application of the developed methods for routine quality control analysis of these drugs.

DEVELOPMENT AND VALIDATION OF RP-HPLC METHOD FOR DETERMINATION OF NORTRIPTYLINE HYDROCHLORIDE IN BULK AND DOSAGE FORM

The present work reports a validated reverse phase-HPLC method for determination of nortriptyline hydrochloride (NORH) in bulk and in its pharmaceutical dosage form. Chromatographic separation was performed on Waters C-18, (250×4.6mm, 5µm) stationary phase using a mixture of 50 mM KH2 PO4 pH 3.0 phosphate buffer: methanol: acetonitrile in the proportion of 50: 10: 40 V/V/V as mobile phase components at 1.0 mL min-1 flow rate. Detection of drug was carried out in isocratic mode at 235 nm. The validation of the method was carried out as per ICH guidelines. The LOD and LOQ for NORH was 0.22 µg mL-1 and 0.69 µg mL-1, respectively. NORH showed linearity range of 5-50 µg mL-1 and correlation coefficient (r2 ) value, 0.9937. The method was tested for assay of NORH in tablet dosage form.

The Usefulness of In Vitro Percutaneous Absorption Experiments Applying the Infinite Dose Technique to Predict In Vivo Plasma Levels: Comparison of Model-Predicted and Observed Plasma Concentrations of Nortriptyline in Rats.

The aims of this study were to evaluate the feasibility of a nortriptyline (NT) formulation for transdermal administration and to assess the usefulness of an estimated kinetic parameter (kout) using the in vitro infinite dose technique to predict in vivo plasma levels when used in combination with pharmacokinetic parameters. To do so, a simple one-compartment model was used to describe the transport of a permeant across a membrane (skin). This model provides relatively simple expressions for the amount of permeant in the skin, the cumulative amount of permeant that crosses the skin, and the flux of permeant, for both the infinite and the finite dose regimens. Transdermal administration of the formulated NT gel to rats resulted in plasma levels of approximately 150 ng/mL between 8 and 30 h post-administration. These levels were higher than the minimum concentration of 40 ng/mL recommended for smoking cessation therapy and slightly higher than the upper limit of the therapeutic range for the treatment of depression in humans. The one-compartment model used to describe transport across the skin was connected to a two-compartment pharmacokinetic model used to predict NT plasma concentrations in rats using the kout determined in vitro and the values of other pharmacokinetic parameters obtained in vivo. The predicted concentrations were close to the observed plasma levels and the time profiles were similar for both types of data. These results show the usefulness of the kout parameter determined in vitro to predict plasma concentrations of drugs administered percutaneously.

Development and Validation of RP-HPLC Method for the Simultaneous Estimation of Gabapentin and Nortriptyline Hydrochloride in Bulk and Tablet Dosage Form

Published on:June 2022 Journal of Young Pharmacists, 2022; 14(2):187-191 Original Article | doi:10.5530/jyp.2022.14.35 Authors: V. S. Thiruvengadarajan*, N. Arunkumar, Rajasekaran Aiyalu, Ponnilavarasan I, N. Tamilselvi Department of Pharmaceutical Analysis, KMCH College of Pharmacy, Coimbatore, Tamil Nadu, INDIA. Abstract: Background: According to ICH requirements, a simple isocratic RPHPLC technique for the simultaneous estimation of gabapentin (GAB) and nortriptyline HCl (NOR) in pharmaceutical dosage forms has been developed and validated. Methods: On a reversed phase, separation is accomplished Phenomenex Luna C18 Column (5μm, 250 × 4.60 mm) as a stationary phase using two solvents (Solvent A: buffer 0.2 % Triethylamine adjusted to pH 5.5 with orthophosphoric acid and Solvent B: Acetonitrile) as a mobile phase. The ratio of Solvent A: Solvent B was 50:50 v/v. The flow rate was 1.2 ml/min with UV detection at 210 nm. Results: The retention time for Gabapentin and Nortriptyline HCl was found to be 1.96 and 4.54 min respectively with runtime of 15 min, theoretical plate for GAB and NOR were 3936 and 3912 respectively, with a resolution of 8.5. Linearity of GAB and NOR was found in the range of 200-1000 μg/ml and 5-25 μg/ ml. The correlation coefficient for GAB and NOR were 0.9995 and 0.9998. The LOD values for GAB and NOR were 62.729 and 0.8727 μg/ml. The LOQ values for GAB and NOR were 190.09 and 2.6447 μg/ml respectively. The percentage of GAB and NOR in pharmaceutical dosage form was found to be 99.79 % and 99.75 %. Conclusion: This demonstrates that the developed method is simple, precise, rapid, selective, accurate and reproducible for simultaneous estimation of GAB and NOR tablet dosage form.Key words: Dosage formulation, Gabapentin, Method validation, RP-HPLC, Nortriptyline HCl UV detection.

MEDB-87. Transcriptome-driven drug repurposing in group 3 medulloblastoma

Across the molecular spectrum of medulloblastoma (MB), group 3 (G3) tumors are the most aggressive with <50% five-year survival, the lowest of all MB subgroups. G3 MB tumors are characterized by frequent metastases at diagnosis, unique methylation profiles, MYC amplification, and i17q, but these unique molecular features have yet to be exploited for therapeutic purposes despite their contribution to the disease process. As such, we sought to address this gap in survivorship by identifying FDA-approved compounds with the potential to inhibit cellular processes critical to G3 MB tumor proliferation and metastasis, aiming to exploit the unique molecular pathogenesis of G3 tumors. Guided by analysis of RNA-sequencing data from locally obtained, patient-derived MB samples against the LINCS chemical perturbagens database, we identified nortriptyline (NT), a tricyclic antidepressant, as a candidate MB therapeutic due to: 1) its ability to revert the transcriptomic signature of G3 MB to a normal cerebellum-like state and 2) its ability to cross the blood-brain barrier. We first identified the IC50 of NT in D425 and HDMB03 cells as 28μM and 20μM, respectively. Then, we observed that NT increased apoptosis of HDMB03 cells 3-fold by flow cytometry and confirmed our observations with Western blotting of apoptotic markers. Additionally, NT treatment resulted in abrogation of colony formation, impairment of wound healing, and inhibition of cell migration and invasion in vitro in HDMB03 cells. In all, transcriptome-driven drug repurposing holds great promise, as identifying novel uses for compounds with a known safety profile can deliver effective treatments into the hands of both patients and physicians in an expedited manner when compared to traditional means.

A rapid and versatile microfluidic method for the simultaneous extraction of polar and non-polar basic pharmaceuticals from human urine

In sample preparation, simultaneous extraction of analytes of very different polarity from biological matrixes represents a challenge. In this work, verapamil hydrochloride (VRP), amitriptyline (AMP), tyramine (TYR), atenolol (ATN), metopropol (MTP) and nortriptyline (NRP) were used as basic model analytes and simultaneously extracted from urine samples by liquid-phase microextraction (LPME) in a microfluidic device. The model analytes (target compounds) were pharmaceuticals with 0.4 < log P < 5. Different organic solvents and mixtures of them were investigated as supported liquid membrane (SLM), and a mixture of 2:1 (v/v) tributyl phosphate (TBP) and dihexyl ether (DHE) was found to be highly efficient for the simultaneous extraction of the non-polar and polar model analytes. TBP reduced the intrinsic hydrophobicity of the SLM and facilitated extraction of polar analytes, while DHE served to minimize trapping of non-polar analytes. Sample and acceptor phase composition were adjusted to pH 12 and pH 1.5, respectively. Urine samples were pumped into the microfluidic system at 1 μL min-1 and the extraction was completed in 7 min. Recoveries exceeded 78% for the target analytes, and the relative standard deviation (n = 4) was below 7% in all cases. Using five microliters of SLM, the microfluidic extraction system showed good long-term stability, and the same SLM was used for more than 18 consecutive extractions.

Application of Antisolvent Precipitation Method for Formulating Excipient-Free Nanoparticles of Psychotropic Drugs

The aim of the present study was to systematically examine the effects of variations in the process parameters of the antisolvent precipitation method employed in the preparation of excipient-free pure nanoparticles of five existing/potential psychotropic drugs, namely amitriptyline hydrochloride (AMI), coumarin 6 (COU), curcumin (CUR), nortriptyline hydrochloride (NOR), and prochlorperazine dimaleate (PRO). In the preparation protocols employed, AMI and NOR were expected to be charged enough to be identified as surface-active molecules. Through the employment of five different preparation protocols, the effects of varying the flow rate, the compound concentration in the solvent solution , the solvent:antisolvent ratio (SAS-ratio), and pH of the antisolvent on the final size of the particles were investigated in detail and the results were explained using available theories for the antisolvent precipitation method. We found that increased with the average of the octanol-water partition coefficients (logP)av of the compound. Moreover, the average of the final particle sizes increased linearly with (logP)av. These findings are useful for predicting the size of nanodrugs prepared through the antisolvent precipitation method.

Polymer-mediated electrospun nanofibrous mats on supramolecular assembly of nortriptyline in the β-cyclodextrin medium for antibacterial study

With the thought and strong hope of uniqueness and challenging characteristic highlights and importance of nanofibrous mats (NFMs) along with cyclodextrins (CDs) that having a significant opportunity, chances and handling a vital role in hostile to bacterial activities. For the most part, CDs are utilized to upgrade the antibacterial activity through the improvement of solubility, stability, and etc., to any molecule which can bring inside the CDs cavity via the formation of inclusion complexes. Polymer-mediated electrospun nanofibrous mats (PAN NFMs) are utilized as a nanocarrier for antibacterial activity in this article, utilizing nortriptyline (NP) as a reference molecule. As a result, NP forms an inclusion complex with β-Cyclodextrin (β-CD). As a result, the PAN NFMs are able to absorb it, thereby consolidating the complex NP on the nanofibrous surface. Additionally, the soaking of PAN NFMs in NP solution without β-CD was performed for comparison. To characterize the nanofibrous mats of NP/PAN and NP:β-CD-ICs/PAN NFMs, UV absorption, FTIR, Raman, XRD, and SEM techniques were used. The antibacterial activity of NP and NP:β-CD-ICs have been tried against positive control antibiotics by the disc diffusion method. Thus, the action has been improved for NP:β-CD-ICs/PAN NFMs over NP/PAN NFMs because of the solubility upgraded for the NP by the complexation of β-CD.

Volumetric, acoustic and viscometric studies of solute-solute and solute-solvent interactions of glycine and its peptides in aqueous solutions of an antidepressant drug at different temperatures

From the density (ρ), speed of sound (u) and viscosity (η) measurements, the interactions of glycine, glycylglycine and glycylglycylglycine with antidepressant drug, nortriptyline hydrochloride have been investigated in aqueous medium at temperatures, T = (293.15–313.15) K and experimental pressure p = 0.1 MPa. From the experimental density measurements, apparent molar volume (VΦ), limiting apparent molar volume (VoΦ) and partial molar volumes of transfer (VoΦ,tr) have been determined for various solutions of glycine, glycylglycine and glycylglycylglycine in aqueous nortriptyline hydrochloride. In addition, using speed of sound data, apparent molar isentropic compression (Ks,Φ), limiting apparent molar isentropic compression (Kos,Φ) and partial molar isentropic compression of transfer (Kos,Φ,tr) have been calculated. Pair and triplet interaction coefficients are also determined from VoΦ,tr values using McMillan-Mayer theory. Further, apparent molar expansibility (EoΦ) and Hepler's constant values ∂EoΦ∂TP have been evaluated to assist the interpretations earned from the volumetric and acoustic analysis. The viscosity coefficients A and B, viscosity B-coefficient of transfer (Btr) and temperature derivative of B-coefficients (dB/dT) have been determined from viscosity data. The results were interpreted in terms of different kinds of intermolecular interactions present in the ternary systems (amino acid/peptides + water + nortriptyline hydrochloride) through a cosphere overlap model. The Hepler’s constant and temperature derivative of B-coefficients (dB/dT) confirms the structure breaking nature of the solute.