Effect of regulated add-on sodium chloride intake on stabilization of serum lithium concentration in bipolar disorder: A randomized controlled trial.

OBJECTIVE: Lithium-induced natriuresis may lead to lithium retention and fluctuation of lithium levels during maintenance therapy. Therefore, the present study was conducted to evaluate the effect of add-on sodium chloride on serum lithium levels in bipolar disorder. METHODS: This RCT was conducted in 60 patients with type I bipolar disorder who were randomized into the control group that received lithium carbonate with the advice not to take additional salt (at the table) and the test group that received sachets of sodium chloride (1 g/d) as an add-on to lithium carbonate and were advised to restrict their additional salt intake (at the table) to 1 g/d. After baseline assessments, all patients were followed up at 4 weeks, 8 weeks, and 12 weeks when serum lithium, sodium, and potassium were estimated. Serum creatinine and aldosterone were repeated at 12 weeks. The percentage of patients showing fluctuations in serum lithium level (serum lithium <0.6 mEq/L or >0.8 mEq/L) was considered as the primary outcome measure. RESULTS: In the test group, the fluctuation rate in serum lithium (26.7%) was significantly (p = 0.01) lower than that in the control group (63.3%). Serum lithium values varied significantly across sampling times in the control group but not in the test group. There was a significant difference in serum lithium between the groups at 8 and 12 weeks of follow-up. There were no significant differences in the change in serum sodium, potassium, creatinine, aldosterone, creatinine clearance, and blood pressure within the group and between the groups. A significant positive correlation was found between serum lithium and aldosterone at baseline. CONCLUSIONS: Intake of add-on sodium chloride (1 gm/day) may reduce the fluctuations in serum lithium during the maintenance phase of lithium therapy in type I bipolar disorder. GOV IDENTIFIER: NCT04222816.

Paroxysmal dystonia and psychotic exacerbations in chronic psychosis: Diagnostic dilemmas and preliminary treatment approaches.

Patients with chronic psychosis on prolonged antipsychotic therapy may present with paroxysmal dystonia along with an exacerbation of their psychotic symptoms: paroxysmal dystonia and psychotic exacerbations (PDPE). The interindividual variability in the clinical presentations of PDPE can pose challenges in its diagnosis and treatment. The objectives of this work are to (i) discuss this rare phenomenon through a series of 10 patients and a relevant literature review, (ii) conceptualize its neurobiological underpinnings, and (iii) explore the preliminary treatment approaches for its management. Acute stress and/or a dysfunctional gamma-aminobutyric acid (GABA) ergic or dopaminergic system may be implicated in the pathogenesis of PDPE. The episodes respond acutely to parenteral benzodiazepines, while long-term management can be achieved by reducing antipsychotic doses, switching to clozapine or using central GABA enhancers. This article is the first attempt at conceptualizing and exploring treatment options for the rare condition PDPE and intends to guide future research in this regard.

Tinospora cordifolia Leaves Derived Carbon dots for Cancer Cell Bioimaging, Free radical Scavenging, and Fe3+ Sensing Applications.

Herein, we report the fabrication of Tinospora cordifolia leaves-derived carbon dots (TCLCDs) from aqueous extract of leaves as carbon source via simple, environmentally friendly, hydrothermal carbonization (HTC) technique. The synthesized TCLCDs were characterized for their physicochemical properties and further explored for in-vitro cancer cell bioimaging, radical scavenging, and metal ion sensing. The synthesized TCLCDs showed excitation-dependent emission property with maximum emission at 435 nm under the excitation of 350 nm. The High-Resolution Transmission Electron Microscopy (HRTEM) results revealed a roughly spherical shape with an average diameter of 5.47 nm. The diffused ring pattern of Selected Area Electron Diffraction (SAED) and halo diffraction pattern of X-ray diffraction (XRD) disclosed their amorphous nature. The Energy Dispersive X-ray (EDX) showed the existence of C, N, and O. The Fourier-transform infrared spectroscopy (FTIR) revealed the presence of -OH, -NH, -CN, and -CH groups. The TCLCDs showed excellent cellular biocompatibility with dose-dependent bioimaging results in melanoma (B16F10) and cervical cancer (SiHa) cell lines. Also, they exhibited excellent scavenging of free radicals with an IC50 value of 0.524 mg/mL & selective Fe3+ ion sensing with a detection limit of 0.414 µM. Further, they exerted excellent bacterial biocompatibility, photostability, and thermal stability. The overall results reflected their potential for in-vitro cancer cell bioimaging, free radical scavenging, and selective Fe3+ ion sensing.

Exploring the potential of solid dispersion for improving solubility, dissolution & bioavailability of herbal extracts, enriched fractions, and bioactives.

Most drugs' poor aqueous solubility has emerged as a significant challenge in achieving proper therapeutic response following oral administration. Herbal drugs are being used from time immemorial to prevent, mitigate, and cure multiple diseases. However, most of the bioactives phytoconstituents possess limited aqueous solubility & poor oral bioavailability. Solid dispersion (SD) has been realised as an efficient formulation to overcome hydrophobic candidates' solubility issues and improve their oral bioavailability. The current review mainly explores the potential of SD for improving solubility, dissolution & bioavailability of herbal extracts, enriched fractions, and isolated bioactives. Hence, basics of SD, selection of excipients, need for SD of plant products, SD of plant products, selection of preparation method, the chemistry of phytoconstituent-excipient interaction, and hurdles associated with SD of herbal extract/enriched fraction were explored in this review. The SD has the potential to overcome solubility, dissolution, and oral bioavailability issues of poorly soluble phytoconstituents.

Multi-Functional Carbon Dots from an Ayurvedic Medicinal Plant for Cancer Cell Bioimaging Applications.

The combination of an Ayurvedic wisdom and nanotechnology may help us to resolve the complex healthcare challenges. A facile and economical one-pot hydrothermal synthesis method has been adopted for preparing a blue fluorescent carbon dots (CDs) with a quantum yield of 15.10% from an Ayurvedic medicinal plant Andrographis paniculata (AP). The Andrographis paniculata derived CDs (AAPCDs) were then characterized using different techniques. Through High Performance Thin Layer Chromatography (HPTLC) profiling of the AP extract and the CDs, it was found that some of the phytoconstituents are retained as such while others may have been converted into their derivatives during the process of formation of CDs. The CDs are designed to possess cellular imaging of human breast carcinoma cells (MCF-7), apart from free radicals sensing and scavenging capabilities. AAPCDs showed minimal cytotoxicity in Multi Drug Resistant clinically isolated strains of gram positive and gram negative bacteria which may be employed for microbiology oriented experiments. These results suggest potential of multi-functional AAPCDs as nano-probes for various pharmaceutical, biomedical and bioengineering applications.

Nanovesicular ultraflexible invasomes and invasomal gel for transdermal delivery of phytopharmaceuticals.

Tweetable abstract Invasomes and invasomal gel are ultraflexible, soft vesicular, phospholipid based nanocarriers with deeper skin penetration ability for transdermal applications of drugs and phytopharmaceuticals.

Efficacy and safety of add-on sarcosine in patients with major depressive disorder: A randomized controlled trial.

The main hurdles with current therapies for major depressive disorder (MDD) include lack of efficacy, therapeutic latency, and adverse drug reactions. Add-on therapy to conventional antidepressants may result in better therapeutic outcomes to overcome these obstacles. Sarcosine (N-methyl glycine), an endogenous amino acid that acts by modulating the NMDA receptor, is available as a dietary supplement. So, the present study was planned to evaluate the efficacy and safety of add-on sarcosine to SSRIs in MDD. In the present randomized, double-blind clinical trial (NCT04975100), 60 eligible participants with MDD were randomly assigned to either the test group (SSRI + sarcosine) or the control group (SSRI + placebo). Clinical and biochemical parameters like MADRS, CGI, serum BDNF, and serum glycine were assessed at baseline and eight weeks. The mean reduction in MADRS score was significant in both the control (-8.7, 95% CI: -11.0 to -6.4, p < 0.001) and the test group (-13.3, 95% CI: -14.9 to -11.7, p < 0.001), but the change in the test group was significantly greater (-4.6, 95% CI: -7.5 to -1.7, p = 0.003). The test group had a significantly higher response rate (p = 0.007) and remission rate (p = 0.038) compared to the control group. There was a significant increase in serum BDNF in both groups; however, the change in the test group was significantly higher than in the control group (p = 0.041). Similarly, the test group had a significantly higher increase in serum glycine than the control group (p < 0.001). Sarcosine may be considered an efficacious and safe add-on therapy to standard SSRIs in the management of MDD. ClinicalTrial.gov IdentifierNCT04975100.

Efficacy and safety of monoamine reuptake inhibitors in attention deficit hyperactivity disorder: A Bayesian network meta-analysis.

The use of first-line drugs in clinical practice for attention deficit hyperactivity disorder (ADHD) is limited by their adverse effects. Many novel monoamine reuptake inhibitors (MRIs) with better safety profiles and comparable efficacy are also being tried for ADHD. This network meta-analysis (NMA) has evaluated the efficacy and safety of MRIs in ADHD. The data was extracted from 31 relevant clinical trials after a literature search on MEDLINE/PubMed, Embase, Scopus, Cochrane databases, and clinical trial registries. Quality assessment was performed using the risk of bias assessment tool (RoB2) by Cochrane Collaboration, and the random-effects model was used to estimate the effect size. Standardised mean difference (SMD) and 95% credible interval(95%CrI) were reported for the reduction in ADHD rating scale score. Network geometry was visualised, and node splitting was done for the closed triangles. Meta-regression was done for the duration of therapy. PRISMA-NMA guidelines were followed in selecting, analyzing, and reporting findings. The drugs showing significant reduction on the ADHD rating scale as compared to placebo are bupropion (SMD: 0.33; 95%CrI: 0.60,-0.059), dasotraline(SMD: 0.49; 95%CrI: 0.82,-0.16), venlafaxine(SMD: 0.71; 95%CrI: 1.3,-0.15), viloxazine(SMD: 0.45; 95%CrI: 0.77,-0.12). Other drugs (centanafadine, duloxetine, edivoxetine, reboxetine, tipepidine, vortioxetine) were no better than placebo in reducing symptom severity of ADHD. The efficacy of none of the drugs was found to be significantly different as compared to methylphenidate. Among all, duloxetine (OR:15; 95%CrI:1.8130) showed significantly more treatment-emergent adverse events than methylphenidate. In conclusion, venlafaxine, viloxazine, and bupropion are the most efficacious MRIs for ADHD symptom reduction as compared to placebo with high certainty of evidence.

Repurposing of dextromethorphan as an adjunct therapy in patients with major depressive disorder: a randomised, group sequential adaptive design, controlled clinical trial protocol.

BACKGROUND: Therapeutic latency, lack of efficacy and adverse drug reactions are the major concerns in current antidepressant therapies. To overcome these treatment hurdles, add-on therapy to conventional antidepressant medications may lead to better therapeutic outcomes. The present randomised controlled trial has been planned to evaluate the efficacy and safety of add-on dextromethorphan to selective serotonin reuptake inhibitors (SSRIs) in major depressive disorder (MDD). METHODS AND ANALYSIS: A randomised, double-blind, add-on, placebo-controlled, group sequential design clinical trial will be conducted on patients with MDD who will be randomly assigned to the control and the test group in a 1:1 ratio. Patients in the test group will get dextromethorphan 30 mg once daily, whereas patients in the control group will receive a placebo once daily as an add-on to ongoing SSRI treatment for 8 weeks. All patients will be evaluated for the primary outcome (change in the Montgomery-Åsberg Depression Rating Scale score) and secondary outcomes (treatment response rate, remission rate, Clinical Global Impression, serum brain-derived neurotrophic factor, serum dextromethorphan and treatment-emergent adverse events) over the period of 8 weeks. Intention-to-treat analysis will be done for all parameters using suitable statistical tools. ETHICS AND DISSEMINATION: This study was approved by the Institutional Ethics Committee of All India Institute of Medical Sciences, Bhubaneswar, India, and the study conformed to the provisions of the Declaration of Helsinki and ICMR's ethical guidelines for biomedical research on human subjects (2017). Written informed consent will be obtained from the participants before recruitment. The results of this study will be published in peer-reviewed publications. TRIAL REGISTRATION NUMBER: NCT05181527.

Quality-by-design-based microemulsion of disulfiram for repurposing in melanoma and breast cancer therapy.

Aim: The current study aims to develop and optimize microemulsions (ME) through Quality-by-Design (QbD) approach to improve the aqueous solubility and dissolution of poorly water-soluble drug disulfiram (DSF) for repurposing in melanoma and breast cancer therapy.Materials & methods: The ME was formulated using Cinnamon oil & Tween® 80, statistically optimized using a D-optimal mixture design-based QbD approach to develop the best ME with low vesicular size (Zavg) and polydispersity index (PDI).Results: The DSF-loaded optimized stable ME showed enhanced dissolution, in-vitro cytotoxicity and improved cellular uptake in B16F10 and MCF-7 cell lines compared with their unformulated free DSF.Conclusion: Our investigations suggested the potential of the statistically designed DSF-loaded optimized ME for repurposing melanoma and breast cancer therapy.

Identifying new medicinal uses of an existing marketed drug can save both money and time in the process of drug development. From many of the recently reported literature, disulfiram (a drug used for alcoholism) has shown its activity against various cancers, including breast and skin cancer. However, it possesses poor water solubility and absorption, leading to low medicinal activity. The current study aims to develop a novel microemulsion dosage form through a statistical design approach to enhance the solubility, dissolution and anticancer activity for repurposing in melanoma and breast cancer treatment. The novel microemulsion was prepared, statistically analyzed and optimized. The optimized microemulsion was found to be stable and showed improved medicinal activity against breast and skin cancer compared with the pure drug. Our research showed the potential of the developed microemulsion of the disulfiram for its new therapeutic use in skin cancer and breast cancer.

Pharmacological interventions for antipsychotic-induced weight gain in schizophrenia: A network meta-analysis.

OBJECTIVE: Antipsychotic-induced weight gain (AIWG) is a significant but frequently neglected adverse effect of first- and second-generation antipsychotic therapy, which may lead to cardiovascular disturbances. The present network meta-analysis (NMA) was conducted to evaluate and compare the effects of available treatment options in antipsychotic-induced weight gain (AIWG). METHODS: The data was extracted from 68 relevant clinical trials after a literature search on MEDLINE/PubMed, Embase, Scopus, Cochrane databases and clinical trial registries. Random-effects Bayesian NMA was done to pool the effects across the interventions for the change in body weight from baseline. A network graph was built, a consistency model was run, node split analysis was performed, treatments were ranked as per the SUCRA score and meta-regression was done for the duration of therapy, baseline body weight and treatment strategy as the predictor variables. Finally, the results were sorted based on the certainty of evidence. RESULTS: The drugs showing significant reduction in body weight in order of magnitude of effect size include sibutramine 10 mg (-8.0 kg; -16. to -0.21), metformin 750 mg + lifestyle modification (-7.5 kg; -12 to -2.8), topiramate 200 mg (-7 kg; -10 to -3.4), metformin 750 mg (-5.7 kg; -9.3 to -2.1), topiramate 100 mg (-5.7 kg; -8.8 to -2.5), topiramate 50 mg (-5.2 kg; -10 to -0.57), liraglutide 1.8 mg (-5.2 kg; -10., -0.080), sibutramine 15 mg (-4.5 kg; -8.9 to -0.59), nizatidine 300 mg (-3.0 kg; -5.9 to -0.23) and metformin 1000 mg (-2.3 kg; -4.6 to -0.0046). There was no effect of duration of follow-up, baseline body weight and, preventive versus therapeutic strategy on weight reduction in AIWG. CONCLUSION: Metformin 750 mg with lifestyle modification was the most effective treatment for AIWG, followed by topiramate 200 mg, metformin 750 mg, and topiramate 100 mg with moderate certainty of evidence.

Psychometric properties and factor structure of the suicidal narrative inventory in major depression: A multicentric evaluation.

BACKGROUND: The Suicidal Narrative Inventory (SNI) is a 38-item self-report measure developed to assess elements of the suicidal narrative, a subacute, predominantly cognitive, presuicidal construct. Our objectives were to assess the factor structure, validity, and reliability of the SNI-38 among adults with major depressive disorder (MDD). METHODS: Using a cross-sectional design, we administered the Hindi version of the SNI along with other self-report measures to adults with MDD, recruited from 24 tertiary care hospitals across India. Confirmatory factor analysis (CFA) was performed to assess the factor structure of SNI-38. Reliability (internal consistency) was assessed using Cronbach's alpha (α). Convergent, discriminant, and criterion validity of the SNI-38 were tested by comparing it against other appropriate measures. RESULTS: We collected usable responses from 654 Hindi-speaking participants (Mean age = 36.9 ± 11.9 years, 50.2% female). The eight-factor solution of the SNI showed good model fit indices (χ2[637] = 3345.58, p <.001, CFI =.98, and RMSEA =.08). Internal consistencies for the SNI subscale scores were good to excellent, α ranging from .73 to.92. While most subscales significantly converged with other measures, associations were comparatively weaker and inconsistent for the 'thwarted belongingness' and 'goal reengagement' subscales. CONCLUSION: Consistent with prior data, our study confirmed an eight-factor solution and demonstrated adequate psychometric properties for the Hindi version of the SNI-38 in our sample. These findings provide empirical support for the use of SNI to assess the suicidal narrative among Indian adults with MDD.

Efficacy and safety of tramadol in the treatment of opioid withdrawal: A meta-analysis of randomized controlled trials.

BACKGROUND: Pharmacotherapeutic options for the treatment of opioid withdrawal are limited by abuse potential, adverse effects, and lack of availability of existing drugs. The results from previous clinical trials on tramadol are contradictory and non-conclusive; hence the present meta-analysis was conducted to evaluate the efficacy and safety of tramadol in the treatment of opioid withdrawal. METHODS: Reviewers extracted data from eight relevant clinical trials after a literature search on MEDLINE/PubMed, Cochrane databases, and clinical trial registries. Quality assessment was done using the risk-of-bias assessment tool, and the random-effects model was used to estimate effect size in frequentist and Bayesian approaches. Subgroup analysis, meta-regression, and sensitivity analysis were done as applicable. PRISMA guidelines were followed in reporting findings. RESULTS: Tramadol significantly reduced opioid withdrawal scale score (SMD: -0.44; 95%CI: -0.76 to -0.13; PI: -1.54 to 0.71; p = 0.006) when all comparators were considered together in the frequentist approach but the reduction was non-significant in Bayesian approach. However, the subgroup analysis revealed no significant difference between tramadol and comparators like placebo (SMD: -1.12; 95%CI: -2.69 to 0.45) buprenorphine (SMD: -0.21; 95%CI: -0.43 to 0.01), clonidine (SMD: -0.26; 95%CI: -0.55 to 0.02) and methadone (SMD: -0.84; 95%CI: -1.78 to 0.10). Meta-regression showed non-significant associations between the SMD in opioid withdrawal score with the duration and dose of tramadol therapy. There were no significant differences in treatment retention at the end of studies between tramadol and comparators. Safety data in the individual studies were inadequate to analyze. CONCLUSION: Authors conclude that the efficacy of tramadol in reducing opioid withdrawal symptoms is not significantly different from comparators with low certainty of evidence against placebo, moderate against methadone, whereas with high certainty of evidence against buprenorphine and clonidine.

Quality-by-design-based development of ultradeformable nanovesicular transgelosome of standardized Piper longum extract for melanoma.

Background: Melanoma is the most aggressive and deadly form of skin cancer. The stratum corneum of the skin is a major obstacle to dermal and transdermal drug delivery. Ultradeformable nanovesicular transferosome has the capacity for deeper skin penetration and its incorporation into hydrogel forms a transgelosome that has better skin permeability and patient compliance. Method: Here, the quality-by-design-based development and optimization of nanovesicular transgelosome of standardized Piper longum fruit ethanolic extract (PLFEE) for melanoma therapy are reported. Results: Compared with standardized PLFEE-loaded plain gel, the transgelosome displayed optimal pharmaceutical properties and improved ex vivo skin permeability and in vivo tumor regression in B16F10 melanoma-bearing C57BL/6 mice. Conclusion: The results reflect the potential of transgelosome for melanoma therapy.

Melanoma is a deadly form of skin cancer that originates from melanocytes in the skin. Skin is a major barrier to drug delivery. Transferosome is a liquid nanoformulation that has the capacity for deeper skin penetration. The transferosome was prepared from standardized Piper longum fruit ethanolic extract (PLFEE) and loaded into gel to form a transgelosome for improved skin application and patient compliance. Compared with extract-loaded plain gel, the transgelosome showed good pharmaceutical properties with better activity in melanoma (B16F10)-bearing female C57BL/6 mice. The therapeutic activity of the standard anticancer drug dacarbazine was improved with the prepared PLFEE transgelosome.

Tracing the Anti-cancer Mechanism of Pleurotus osteratus by the Integrative Approach of Network Pharmacology and Experimental Studies.

The present study identified the probable mechanism behind the anti-cancer activity of the hexane fraction of Pleurotus osteratus (HFPO) using network pharmacology and experimental validation. HFPO myco-metabolites targets and targets related to the cancer were mined from the online web server, and overlapping targets were screened. Out of the 74 overlapping targets, 33 targets were identified in the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway of cancer. Furthermore, the main active myco-metabolites and hub targets were identified by network analysis of the compound-targets network and protein-protein interaction (PPI), respectively. Molecular docking results showed good binding affinity of the hub targets with their respective myco-metabolites. HFPO induced in-vitro anti-cancer activity by affecting the PI3K-AKT-mTOR pathway, besides time-dependent cell cytotoxicity and apoptotic cell body formation. Additionally, tumor volume reduction was observed in HFPO-treated Ehrlich ascites carcinoma (EAC) bearing Swiss albino mice. Overall, HFPO induces anti-cancer potential by modulating the PI3K-AKT-mTOR signaling pathway.

Chemometric-Based Analysis of Metabolomics Studies of Bioactive Fractions of Pleurotus osteratus and Their Correlation with In Vitro Anti-Cancer Activity.

Richness in nutrients with an ample of the myco-bioactive molecules makes Pleurotus osteratus preferential mushroom. In this paper, we conducted a preliminary study on bio-assay-guided fractionation of dichloromethane:ethanol crude extract (1:1, v/v) of P. osteratus (CD) against human breast cancer cell line (MDA-MB-231). Later, CD and its potent hexane (H) and ethyl acetate (EA) fraction were screened against a panel of a human cancer cell lines. H fraction possesses higher cytotoxicity followed by EA and CD. Literature review revealed that polyphenol and ergosterol are the biomarkers found in P. osteratus and could responsible for its cytotoxic potential. Accordingly, hyphenated liquid chromatography with tandem mass spectrometry (LC-MS/MS)-based polyphenol and ergosterol-targeted myco-metabolite profiling of CD, H, and EA fractions were carried out. Despite being significantly rich in polyphenol and ergosterol content, EA fraction showed moderate cytotoxicity. Considering this, liquid chromatography-hybrid quadrupole time-of-flight mass spectrometry (LC-QTOF/MS)-based untargeted myco-metabolite profiling of CD, H and EA fractions was further conducted to identify a new biomarker. Tentatively, 20 myco-metabolites were identified, belonging to the class of steroids, alkaloid, terpenoid, fatty alcohol, and polyketide. The myco-metabolite variabilities among potent samples in correlation to their in vitro anti-cancer activity was explored using the different chemometric tools: principal component analysis (PCA), hierarchical clustering analysis (HCA), and partial least square (PLS). A probable synergistic action among identified myco-metabolites (betulin, solanocapsine, ophiobolin F, linoleoyl ethanolamide, (13R,14R)-7-labdene-13,14,15-triol, asterosterol, cholest-5-ene, (3b,6b,8a,12a)-8,12-epoxy-7(11)-eremophilene-6,8,12-trimethoxy-3-ol, beta-obscurine, myxalamid B, momordol, and avocadyne 4-acetate) may be responsible for the observed cytotoxicity potential of H fraction of P. osteratus.