Engineered exosome-targeted delivery of duloxetine hydrochloride and its antidepressant effects

Schizophrenia is a chronic, complex and severs psychiatric disorder that impacts men and women globally. The combined use of atypical antipsychotics; risperidone (RSP), and antidepressants medications; duloxetine hydrochloride (DLX), has grown more clinical significance in cutting edge treatments of complex psychiatric conditions like schizophrenia. This research targets to develop an environmentally harmonious, selective, and accurate TLC method to measure the levels of both DLX and RSP in spiked human plasma samples. A mixture of methanol, ethylacetate, and 33% ammonia solution (6: 4: 0.2, by volume) was successfully utilized as a solvent system to separate the proposed components. A UV-scanning wavelength of 230 nm was used for detection. An internal standard; propranolol (PRP); was used to account for small variations in the samples. The resulting retardation factors (Rf) were 0.02, 0.32, 0.46 and 0.59 for plasma, DLX, PRP and RSP, respectively. The linearity ranges were 0.04–0.4 and 0.1–0.6 µg band− 1 for DLX and RSP, respectively. The suggested method’s environmental safety was evaluated using five tools and the results showed good greenness and blueness method’s characteristics. Additionally, the method’s figures of merits were within the accepted criteria, according to the US-FDA bio-analytical guidelines. Furthermore, drug-drug interactions (DDI) evaluation was conducted using web-based DDI tool to examine the interaction manifestations and to verify safety and therapeutic effectiveness of this combination.Graphical abstract

Major Depressive Disorder (MDD), a leading global health challenge, urgently requires advanced therapeutics to mitigate its widespread impact. In this study, a series of duloxetine (DLX) analogs were designed and evaluated using a comprehensive in silico workflow incorporating quantum chemical calculations, ADMET profiling, molecular docking, and molecular dynamics (MD) simulations. Density Functional Theory (DFT) calculations at the B3LYP/6-311G level were performed to assess electronic properties such as the HOMO–LUMO energy gap, dipole moment, electronegativity, and chemical softness. Among the designed compounds, DLX48 demonstrated superior quantum descriptors while retaining the electronic characteristics of the parent molecule. ADMET predictions using ADMETlab 3.0 and ProTox-II revealed that DLX48 complies with major drug-likeness rules (Lipinski, Pfizer), exhibits improved aqueous solubility (Log S = − 3.21), optimal lipophilicity (Log P = 2.87), and shows no predicted hepatotoxicity or genotoxicity. Molecular docking against the LeuBAT (Δ13 mutant) transporter revealed a significant increase in binding affinity for DLX48 (–12.45 kcal/mol), with an inhibition constant (Ki) of 742.09 pM—indicating markedly enhanced target engagement compared to DLX. Long-timescale MD simulations (300 ns) confirmed the thermodynamic stability and favorable dynamic behavior of the DLX48–LeuBAT complex, supported by lower RMSD/RMSF values, persistent hydrogen bonding, reduced solvent exposure, and constrained conformational fluctuations. Collectively, these in silico findings nominate DLX48 as a promising central nervous system (CNS)-active lead compound with enhanced pharmacological efficacy and a reduced toxicity profile, warranting further preclinical investigation for the treatment of depression and anxiety disorders.

Objective To develop and validate a novel ultraviolet (UV)-Vis spectrophotometric method for the simultaneous determination of pregabalin (PG) and duloxetine (DL), addressing PG’s non-chromophoric nature through selective derivatisation and ensuring a sustainable, cost-effective approach suitable for routine quality control. Material and Methods PG was derivatised with ninhydrin in ethanol at 100°C for 5 minutes, forming a stable Ruhemann’s purple complex measured at 580 nm. DL, possessing a native naphthalene chromophore, was directly quantified at 230 nm. The distinct wavelengths eliminated mutual interference. Method validation was performed according to international council for harmonisation(ICH) Q2(R1) guidelines, assessing linearity, accuracy, precision, sensitivity, and specificity. Sustainability was evaluated using AGREE, GAPI, NEMI, Eco-scale, and BAGI tools. Results The method demonstrated excellent linearity (r 2 ≥ 0.9996), high accuracy (mean recovery: 100.57% for PG, 100.58% for DL), and precision (%RSD < 1.2%). Sensitivity was confirmed by low limits of detection (0.549 µg/mL for PG, 0.243 µg/mL for DL). Specificity was verified in synthetic mixtures, and statistical comparison with a reference method confirmed equivalence. The green profile was affirmed by multiple sustainability assessment tools. Conclusion The proposed UV-Vis spectrophotometric method is simple, selective, accurate, precise, and environmentally friendly. Its validated performance and sustainability profile make it highly suitable for routine quality control of PG and DL in pharmaceutical analysis.

Pregabalin (PGB) and duloxetine (DLX) are commonly used first-line medications in the clinical management of painful diabetic neuropathy (PDN), yet high-quality comparative evidence is limited. This meta-analysis evaluates the comparative efficacy and safety of PGB versus DLX, focusing on efficacy outcomes such as pain reduction and mental health, and safety outcomes including adverse events in PDN patients. We searched electronic databases for relevant studies assessing the efficacy and safety of PGB and DLX in PDN. The primary outcomes were the mean change of the visual analog scale (VAS) and the improvement ratio for patients achieving ≥ 50% pain reduction. Secondary outcomes, including the numeric rating scale (NRS) for pain, the short form 12 health survey (SF-12), and related adverse events. A random-effects meta-analysis was performed to evaluate these outcomes. We analyzed 19 studies involving 4,483 patients. PGB significantly reduced VAS scores at 24 weeks (MD = -0.38; 95% CI [-0.45, -0.31], P < 0.0001) and decreased the mental component of SF-12 compared to DLX (MD = -3.36; 95% CI [-6.64, -0.07], P = 0.05) and lower rates of achieving >50% pain reduction (RR = 0.88; 95% CI [0.79, 0.98], P = 0.03). Regarding safety, PGB showed a lower incidence of several adverse events, including anorexia, decreased appetite, diarrhea, nausea, and vomiting. However, no significant differences in VAS scores were observed between PGB and DLX at 1 week, 2 weeks, 4 weeks, 6 weeks, 8 weeks, and 12 weeks, with similar results observed in NRS. We found that PGB and DLX showed similar efficacy in relieving PDN. Ultimately, the two drugs' similar effectiveness and different safety profiles highlight the importance of considering patient-specific factors when choosing the appropriate treatment.

Introduction: Duloxetine Hydrochloride is a selective serotonin and norepinephrine reuptake inhibitor (SSNRI) commonly prescribed for the treatment of depression and anxiety dis-orders. Despite its efficacy, frequent dosing can lead to poor patient compliance and increased side effects. This study aims to develop sustained-release liposomal formulations of Duloxetine Hydrochloride to enhance therapeutic efficacy, reduce dosing frequency, and improve patient ad-herence. Methods: Two formulation techniques-physical dispersion and ether injection-were utilized to prepare Duloxetine Hydrochloride-loaded liposomes. Soya lecithin and cholesterol were used as key lipid components to facilitate sustained release. Organic solvents, including chloroform, ether, and methanol, were used in the drug loading process. Phosphate buffer (pH 6.8) served as the hydration medium. The formulations were evaluated for morphology, particle size, entrap-ment efficiency, and in vitro drug release. Results: Both methods successfully produced liposomes with sustained-release properties. The ether injection method resulted in more uniform and stable vesicles with higher entrapment effi-ciency. Drug release studies showed prolonged release profiles for both techniques, with the ether injection method demonstrating a more controlled release pattern. Discussion: While both formulation methods proved effective for sustained drug delivery, the ether injection method offered superior entrapment efficiency and drug release control. The phys-ical dispersion method, however, showed acceptable stability and may be preferred for simpler preparation processes. Conclusion: This comparative study suggests that the ether injection method is more suitable for achieving extended release of Duloxetine Hydrochloride. In contrast, the physical dispersion method remains a viable alternative for preparing stable liposomes. These findings support the potential of liposomal delivery systems in enhancing the pharmacokinetic profile of antidepres-sants. other: Not applicable

A sensitive spectrofluorimetric approach was developed for simultaneous measurement of duloxetine (DUL) and mirtazapine (MIR) in pharmaceutical dosage forms and human plasma as well. The method depends on first-derivative synchronous spectrofluorometric scan where DUL and MIR were measured at 272 and 336 nm, respectively using Δλ of 60 nm. Both drugs are co-administered in resistant depression. The linearity was attained over the ranges of 0.1-1.3 μg/mL and 0.1-1.5 μg/mL for DUL and MIR, respectively. The limit of detection was found to be 0.013, while the limit of quantitation was found to be 0.042 for both drugs. The method gives high percentage recoveries of 98.27%-101.29% for DUL and 99.55%-101.69% for MIR when determining both analytes in their dosage forms. The two analytes were estimated in human plasma using the described approach achieving excellent percentage recoveries ranging from 98% to 101.33%. This is so important for quality control laboratories and pharmacokinetic studies. ICH criteria were used to validate the adopted procedure. The method's sustainability is evaluated by applying different tools,namely, Analytical Green Star Area (AGSA), Multi-Color Assessment (MA) Tool, analytical eco-scale, the Analytical Greenness Calculator (AGREE), Green Analytical Procedure Index (GAPI) and Blue Applicability Grade Index (BAGI).

Background/Objectives: The purpose of this preclinical pilot study was to explore the potential of green tea extract (GTE) to mitigate and/or prevent oxaliplatin-induced allodynia and axonal damage in rats, when compared to duloxetine (DLX), an ASCO-recommended treatment for established neuropathic pain. Methods: Using a randomized, placebo-controlled experimental design, Sprague Dawley rats (N = 41) received 4 intraperitoneal oxaliplatin (2 mg/kg) injections every other day over 7 days. One week prior to the first oxaliplatin dose, animals began 1 of 4 interventions (saline; GTE 100 mg/kg; DLX 3 mg/kg; GTE 100 mg/kg + DLX 3 mg/kg). A naïve group (n = 6) that received no neurotoxic oxaliplatin or intervention was added to serve as a baseline measure for sNfL. Interventions were administered daily for 4 weeks. Mechanical sensitivity (allodynia) was measured 3 times per week using von Frey testing to determine paw withdrawal thresholds. Von Frey testing began one day prior to the start of interventions to establish baselines and continued through Day 35. Groups were compared to their respective baselines to calculate changes in paw withdrawal thresholds. To measure axonal damage, alterations in serum levels of neurofilament light (sNfL) protein were measured at Day 35 using ELISA. Group differences were identified using two-way analysis of variance (ANOVA). Pearson correlation coefficient was used for correlation analysis between paw withdrawal thresholds and sNfL levels at Day 35. Partial eta-squared and Hedges’ g were used to measure effect sizes. Statistical significance was assigned at P ≤ 0.05 with a 95% confidence interval. Results: Overall, the saline group showed significant reductions in mean paw withdrawal thresholds across experimental timepoints, denoting more severe allodynia caused by oxaliplatin. Conversely, intervention groups exhibited mean paw withdrawal thresholds that were significantly greater than the saline group, indicating less allodynia. The average level of sNfL was also significantly higher in the saline group (113.58 ± 43.84 pg/mL) compared to GTE100 (72.75 ± 26.85), DLX3 (59.93 ± 20.57), and DLX3 + GTE100 (77.04 ± 24.35) intervention groups, suggesting less oxaliplatin-induced axonal damage in these groups. The naïve group exhibited the lowest levels of sNfL (45.69 ± 14.64) when compared to the oxaliplatin-receiving groups (saline and intervention). There were large effect sizes between the saline group, naïve (g = 1.88), GTE100 (g = 1.123), DLX3 (g = 1.157), and DLX3 + GTE100 (g = 1.030) groups. There was also a moderate negative correlation [r(30) = −0.38, p = 0.04] between sNfL levels and paw withdrawal thresholds. Conclusions: The preliminary findings from this pilot study suggest that GTE may be an effective, nutraceutical intervention for mitigating OIPN-associated neuropathic pain, warranting further investigation as an intervention to mitigate chemotherapy-associated neurotoxicities like OIPN.

Duloxetine's potential dual antitumor and immunomodulatory role in apoptosis and autophagy signaling pathways in cancer: In Vitro and In Vivo evidence.

Gabapentin fails to provide analgesia while duloxetine remains effective in an attention deficit hyperactivity disorder rat model with neuropathic pain.

Cisplatin (CIS)-induced peripheral neuropathy and associated comorbidities have a detrimental effect on the lives of cancer patients. Currently, there are no effective therapies to alleviate these symptoms. Duloxetine (DULO) is a recommended treatment, but it is linked with important side effects, thus making it essential to explore novel approaches. We examined the impact of a prophylactic treatment with a low dose of DULO combined with hydrogen-rich water (HRW) on CIS-injected C57BL/6 male and female mice as a possible therapy for allodynia, muscle and body weight deficits, and emotive syndromes accompanying this type of chemotherapy. The prophylactic treatment with DULO and HRW prevented mechanical allodynia caused by CIS in both sexes and had greater effects than either treatment given individually. The combined treatment also prevented cold allodynia in male mice but only reduced it in females. Moreover, the coadministration of DULO with HRW avoided muscular deficits in both sexes. Furthermore, the body weight reduction induced by CIS in both sexes was not entirely mitigated by the combined therapy. However, all treatments avoided the anxiety- and depressive-like behaviors elicited by CIS. The antiallodynic actions and prevention of muscular deficits produced by the combined treatment might be explained by the inhibition of oxidative stress, inflammatory responses, and plasticity alterations provoked by CIS in the dorsal root ganglia of these subjects. This study proposes, for the first time, the cotreatment of DULO with HRW as an effective therapy for CIS-induced peripheral neuropathy and reveals the influence of sex on these actions.

To describe and examine, in a sample of depressed outpatients, the relationship between level of response to a previous SSRI or SNRI antidepressant trial and subsequent response to duloxetine hydrochloride. Experimental Design: Data collected from a multicenter trial that evaluated the safety and efficacy of duloxetine for the treatment of major depressive disorder were analyzed to determine the relationship between response to previous antidepressant treatment and degree of response to duloxetine. Eighty-two patients, with documented antidepressant usage history, were included in the analysis. Participants were required, at baseline of the duloxetine treatment protocol, to be 18 years of age and meet criteria for major depressive disorder. Patients, whose data were included in these analyses, were classified as belonging to one of the three groups based on the most recent antidepressant treatment received: nonresponders, partial responders, and responders without remission. Time to first response, first remission, sustained response, and sustained remission during the first 12 weeks of duloxetine treatment were compared across patient groups. Principal Observations: Response and remission with duloxetine treatment ranged between 57 and 68% and 29 and 57%, respectively, and did not differ significantly across previous response levels. An additional analysis, collapsing the partial responder and responder without remission groups, indicated significantly lower rates of remission in those patients who demonstrated inadequate prior response to an SSRI or SNRI compared to responders.

To describe and examine, in a sample of depressed outpatients, the relationship between level of response to a previous SSRI or SNRI antidepressant trial and subsequent response to duloxetine hydrochloride. Experimental Design: Data collected from a multicenter trial that evaluated the safety and efficacy of duloxetine for the treatment of major depressive disorder were analyzed to determine the relationship between response to previous antidepressant treatment and degree of response to duloxetine. Eighty-two patients, with documented antidepressant usage history, were included in the analysis. Participants were required, at baseline of the duloxetine treatment protocol, to be 18 years of age and meet criteria for major depressive disorder. Patients, whose data were included in these analyses, were classified as belonging to one of the three groups based on the most recent antidepressant treatment received: nonresponders, partial responders, and responders without remission. Time to first response, first remission, sustained response, and sustained remission during the first 12 weeks of duloxetine treatment were compared across patient groups. Principal Observations: Response and remission with duloxetine treatment ranged between 57 and 68% and 29 and 57%, respectively, and did not differ significantly across previous response levels. An additional analysis, collapsing the partial responder and responder without remission groups, indicated significantly lower rates of remission in those patients who demonstrated

Chronic neuropathic pain increases basal noradrenaline (NA) concentrations in the spinal cord and brain. Spinal NA further increased by duloxetine (DLX) alleviates neuropathic pain, however, the roles of basal and DLX induced NA in brain regions have not been well investigated. α2-adrenoceptor antagonist, atipamezole, to the medial prefrontal cortex (mPFC) produced anti-allodynia at 6 weeks following spinal nerve ligation (SNL6W) but produced no effects in the earlier phase of SNL animals (SNL2W). The anti-allodynia effect of intraperitoneal DLX is attenuated in SNL6W, and the combination of intraperitoneal DLX and atipamezole to the mPFC enhanced the anti-allodynia in SNL6W. Intrathecal atipamezole in SNL6W reduced DLX analgesia. Microdialysis experiments revealed that DLX increased NA in the mPFC and spinal cord in the same manner in both SNL6W and SNL2W. These results suggested that the basal mPFC NA maintains neuropathic pain in SNL6W. The spinal NA increased by DLX produces analgesia, but NA in mPFC may counteract the action of spinal NA. In the locus coeruleus (LC), DLX increased NA around LC and decreased the pERK immunoreactivity to restore noxious stimuli induced analgesia. These results suggest that reduced LC activity may lead to the restoration of stimulus responsive activity.

Genome-wide association study -Driven drug repositioning for the treatment of insomnia.

Examining green analytical chemistry approach for development of a gradient HPLC protocol for the simultaneous analysis of pregabalin and duloxetine hydrochloride in capsule dosage form

Antidepressant drugs, particularly selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) are known to induce sexual dysfunction as a side effect. Duloxetine (DLX) and Tadalafil (TDL) are simultaneously determined in their pure state and laboratory-prepared mixtures by two novel, environmentally friendly, and accurate spectrophotometric methods. The first method based on second order derivatives while the second method is based on first derivative dual-wavelength detection. In method I, the linearity range was found to be 0.5–9 μg/mL and 1–14 μg/mL with limit of detection 0.15 μg/mL and 0.23 μg/mL for DLX and TDL, respectively, with a good correlation coefficient of 9998. In method II, the linearity range was found to be 1–10 μg/mL and 1–12 μg/mL with limit of detection 0.25 μg/mL and 0.20 μg/mL for DLX and TDL, respectively, with a good correlation coefficient of 0.9997 for DLX and 0.9998 for TDL. The validation of these methods followed the guidelines set by the International Council for Harmonization (ICH). The methods are accurate and precise. The proposed methods can be used for simultaneous determination of DLX and TDL in synthetic mixture. Additionally, the suggested method's greenness was assessed by means of four up-to-date ecological tools, namely the Eco-Scale, the National Environmental Method Index (NEMI), the Green Analytical Procedure Index (GAPI), and the Analytical Greenness metric approach and software (AGREE). The sustainability characteristics of the proposed method were also assessed using the Blue Applicability Grade Index (BAGI), a recently developed metric for assessing the practicality (blueness) of procedures.

Antidepressant drugs, particularly selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) are known to induce sexual dysfunction as a side effect. Duloxetine (DLX) and Avanafil (AVN) are simultaneously determined in their pure state and laboratory-prepared mixtures by two novel, environmentally friendly spectrophotometric methods. The first method was based on second order derivatives while the second method is based on first derivative dual-wavelength. In method I, the linearity range was found to be 0.5–12 µg/mL and 1–12 µg/mL with limit of detection 0.15 µg/mL and 0.27 µg/mL for DLX and AVN, respectively. In method II, the linearity range was found to be 1–10 µg/mL for both drugs with limit of detection 0.18 µg/mL and 0.21 µg/mL for DLX and AVN, respectively. The validation of these approaches meets the International Council for Harmonization’s (ICH) standards. Furthermore, three current ecological tools namely the Eco-Scale, GAPI, and AGREE were used to evaluate the proposed method’s greenness. The sustainability characteristics of the proposed method were also assessed using the Blue Applicability Grade Index (BAGI), a recently developed metric for assessing the practicality (blueness) of procedures.

The fixed-dose combination of pregabalin and duloxetine hydrochloride is mainly used in the treatment of neuropathic pain. Sensitive determination of drugs like pregabalin is challenging by chromatographic methods using UV detection due to their nonchromophoric nature. This study presents the development of a validated high-performance thin-layer chromatography (HPTLC) method for the simultaneous determination pregabalin and duloxetine hydrochloride in formulation. Because pregabalin has a weak chromophoric system, it was visualized using a derivatization reagent containing ninhydrin. Optimum separation of pregabalin and duloxetine hydrochloride was achieved on silica gel 60 F254 plates using methanol:dichloromethane:acetone:ammonia (8:1:1:0.2, v/v/v/v). Good resolution was achieved with Rf values of 0.34 ± 0.02 and 0.52 ± 0.02 for duloxetine hydrochloride and pregabalin, respectively. The method was validated as per the ICH Q2(R1) guidelines. Linearity range was found between 200 and 450 ng/band for duloxetine and 500 and 1125 ng/band for pregabalin. Low %RSD values shows that the developed method is precise. Greenness assessment of the developed method was evaluated using three different assessment tools, namely, Analytical Eco-Scale, GAPI, and AGREE This is the first validated derivatization-based HPTLC method for simultaneous analysis of duloxetine hydrochloride and pregabalin.

Thermodynamic Studies of Binary and Ternary Mixtures of Duloxetine Hydrochloride and <i>myo</i>-Inositol: A Volumetric, Acoustic, and Viscometric Approach