Applying quantitative and systems pharmacology to drug development and beyond: An introduction to clinical pharmacologists.

ABSTRACT: Quantitative and systems pharmacology (QSP) is an innovative and integrative approach combining physiology and pharmacology to accelerate medical research. This review focuses on QSP's pivotal role in drug development and its broader applications, introducing clinical pharmacologists/researchers to QSP's quantitative approach and the potential to enhance their practice and decision-making. The history of QSP adoption reveals its impact in diverse areas, including glucose regulation, oncology, autoimmune disease, and HIV treatment. By considering receptor-ligand interactions of various cell types, metabolic pathways, signaling networks, and disease biomarkers simultaneously, QSP provides a holistic understanding of interactions between the human body, diseases, and drugs. Integrating knowledge across multiple time and space scales enhances versatility, enabling insights into personalized responses and general trends. QSP consolidates vast data into robust mathematical models, predicting clinical trial outcomes and optimizing dosing based on preclinical data. QSP operates under a "learn and confirm paradigm," integrating experimental findings to generate testable hypotheses and refine them through precise experimental designs. An interdisciplinary collaboration involving expertise in pharmacology, biochemistry, genetics, mathematics, and medicine is vital. QSP's utility in drug development is demonstrated through integration in various stages, predicting drug responses, optimizing dosing, and evaluating combination therapies. Challenges exist in model complexity, communication, and peer review. Standardized workflows and evaluation methods ensure reliability and transparency.

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.

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.

Evaluation of the pharmacodynamic interaction effect of augmentation agents with clozapine in patients with treatment-resistant schizophrenia: A simulation study of clinical data.

INTRODUCTION: The aim of the study was to evaluate interaction effect of various augmentation strategies with clozapine in patients with Treatment-resistant schizophrenia. METHODS: Data was extracted for change in positive and negative syndrome scale (PANSS) or brief psychiatric rating scale (BPRS) scores for monotherapy with various antipsychotic agents alone and their combination with clozapine. Individual patient data was generated using simulation of data (factorial trial framework) from published clinical trials for sample sizes from eight to 400 to evaluate interaction effect through linear modeling. Dose equivalents were calculated, and best fit models were determined for simulated data. RESULTS: The polynomial model was found to be the best fit for the simulated data to determine interaction effect of combination. The clozapine augmentation with risperidone and ziprasidone was found to be antagonistic, whereas it was additive for haloperidol, aripiprazole, and quetiapine. A synergistic effect was observed for ECT combined with clozapine (Interaction effect: -7.62; p <0.001). A sample size of 250-300 may be sufficient to demonstrate a clinically significant interaction in future trials. CONCLUSION: Clozapine may be augmented with electroconvulsive therapy, leading to the enhancement of antipsychotic effect. Though some antipsychotics like aripiprazole demonstrate additive effects, they may also add to the adverse effects.

Efficacy and safety of dasotraline in attention-deficit hyperactivity disorder: A systematic review and meta-analysis.

Background and Aim: Pharmacotherapeutic options for attention-deficit hyperactivity disorder (ADHD) are limited due to adverse effects and inadequate efficacy of existing drugs. Clinical trials were conducted on dasotraline in search of a safer and more efficacious alternatives to stimulant agents. This meta-analysis was conducted to evaluate the efficacy and safety of dasotraline in ADHD compared to placebo. Methods: The reviewers extracted data from five relevant clinical trials after a literature search on Medline/PubMed, Embase, Scopus, Google Scholar, and 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 the effect size. Sub-group analysis, meta-regression, and sensitivity analysis were done as applicable. PRISMA guidelines were followed in the selection, analysis, and reporting of findings. Results: Dasotraline significantly reduced the ADHD total symptom score (SMD: -0.35; 95% CI: -0.55 to -0.15; P < 0.001), hyperactivity/impulsivity subscale score (SMD: -0.27; 95% CI: -0.44 to -0.11; P = 0.001), inattentiveness sub-scale score (SMD: -0.33; 95% CI: -0.53 to -0.14; P < 0.001), and CGI-S (SMD: -0.25; 95% CI: -0.42 to -0.08; P = 0.003). Sub-group analysis showed a significant reduction of ADHD symptoms in both pediatric and adult age groups. Meta-regression showed a significant association between SMD of ADHD symptom score reduction and the duration of dasotraline therapy. The incidence of decreased appetite showed dose dependence but not the incidence of insomnia. Conclusions: Dasotraline 4 mg (in children) and 6 mg (in adults) can improve the clinical outcome in patients with ADHD by improving symptoms and global functioning with acceptable tolerability.PROSPERO Registration number: CRD42022321979.

Augmentation Strategies for Partial or Non-responders to Clozapine in Patients with Schizophrenia: A Bayesian Network Meta-analysis of Randomized Controlled Trials.

Clozapine is the only approved drug for treatment-resistant schizophrenia, but the response to the drug is often inadequate. Augmentation with other antipsychotics, anticonvulsants, and antidepressants is recommended for such patients, but there is a lack of evidence regarding the most effective therapy. This network meta-analysis was conducted to evaluate the efficacy of pharmacological agents used in the augmentation strategies in patients who were partial/ non-responders to clozapine. Relevant data were extracted from 30 randomized controlled trials through searches of electronic databases (MEDLINE/PubMed, Embase, Cochrane, clinical trial registries). PRISMA guidelines were followed for the extraction, management, analysis, and reporting of the data. The outcome measure in this study was a reduction in symptom severity according to total PANSS/BPRS and was reported as the standardized mean difference with a 95% credible interval. Bayesian network meta-analysis with random effects model and uninformative priors was conducted, and the ranking probability of each intervention was done. Meta-regression was done to assess the effect of duration on the reduction in symptom severity scores. Mirtazapine (-5.2 [95%CrI: -7.7, -2.7]) and memantine (-2.1 [95%CrI: -4.0, -0.19]] were more efficacious than placebo for augmentation of clozapine in partial/non-responders and were the most effective adjunctive agents as per SUCRA scores. Both drugs did not cause a significant increase in frequency of adverse events compared to placebo. There was a significant effect of duration on the reduction in symptom severity. There was no evident publication bias. Mirtazapine and memantine may prove beneficial for augmentation of clozapine in non/partial responders to monotherapy.

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.

Efficacy and safety of low-dose amisulpride versus olanzapine-fluoxetine combination in post-schizophrenic depression: A randomized controlled trial.

Post-schizophrenic depression (PSD) increases the morbidity, mortality, and health burden in patients with schizophrenia. However, treatment of PSD is challenging due to the lack of substantial evidence of standard clinical practice. This study was aimed at comparing the efficacy and safety of low-dose amisulpride versus olanzapine-fluoxetine combination (OFC) in PSD. This was a randomized controlled trial conducted in sixty patients with PSD fulfilling the eligibility criteria. Recruited patients were randomized to receive either amisulpride at low dose (i.e., 100-300 mg/day) or OFC (5/10 mg + 20 mg) for eight weeks. The Calgary Depression Scale for Schizophrenia (CDSS), the Clinical Global Impression-Severity (CGI-S) and serum BDNF levels were assessed at baseline and after eight weeks of treatment. The change in the CDSS scores from baseline over eight weeks was significant in both the amisulpride and OFC groups. However, the changes were not significant when compared between the groups. Similarly, the changes in CGI-S scores and serum BDNF levels were significant in each group; but non-significant between the groups. A significant negative correlation was found between the changes in the CDSS scores and the serum BDNF levels in each group. No significant adverse events were noted in either group. Thus, to conclude, low-dose amisulpride can be a potential monotherapy in PSD with a favourable clinical outcome and safety profile (ClinicalTrials.gov ID: NCT04876521).

Total valproate versus free valproate in therapeutic drug monitoring for bipolar disorder: A cross-sectional study.

INTRODUCTION: The debate about observing total versus free serum valproate levels for therapeutic drug monitoring (TDM) has been unresolved for decades. This study was planned to assess the agreement between the total versus free valproate levels and the advantage of one method over the other in TDM. METHODS: The present cross-sectional study was done on 93 patients with bipolar disorder. The intraclass correlation coefficient, Bland Altman analysis, and Lin's concordance analysis were done to assess the agreement between the total and free valproate concentrations. Linear and polynomial models were constructed to evaluate the relation between the two measurements. Receiver operating characteristics analysis was done to compare the accuracy for differentiating remission from non-remission on Young's mania rating scale (YMRS). RESULTS: The intraclass correlation coefficient and Lin's concordance correlation coefficient were 0.491 (p = .002) and 0.055 (95% CI:0.037, 0.073), respectively. Bland Altman's analysis showed proportional bias. A polynomial model of second order was found to be the best fit for the prediction of free valproate from the data for total valproate, and 81.4% of the variability in free valproate could be explained when adjusted for albumin levels. The area under the curve for total valproate was 0.60 when compared to free valproate 0.56 for differentiating between remission and non-remission, but the comparison between the two ROC analyses was not statistically significant. CONCLUSION: Free valproate does not provide any added advantage over the total valproate levels; hence, total valproate levels may continue to be used as the marker for drug monitoring.

Efficacy and Safety of Fezolinetant for the Treatment of Menopause-Associated Vasomotor Symptoms: A Meta-analysis.

OBJECTIVE: To evaluate the efficacy and adverse events of fezolinetant for treating vasomotor symptoms (VMS) of menopause. DATA SOURCES: PubMed/MEDLINE, ClinicalTrials.gov , EMBASE, Cochrane Database, Scopus, and WHO International Clinical Trials Registry Platform were searched through June 2023 for publications and randomized controlled trials on fezolinetant compared with placebo in menopausal women who experienced moderate-to-severe VMS. METHODS OF STUDY SELECTION: Our literature search identified 330 articles, of which five studies with six reports were included in our meta-analysis per our eligibility criteria. TABULATION, INTEGRATION, AND RESULTS: The risk of bias was evaluated using Cochrane's RoB 2 (Risk of Bias version 2) tool, quality of evidence was graded using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach, and outcome measures data for effect size were pooled in random-effects model and rated. A total of 2,168 participants from five randomized clinical trials (six reports) were included. Fezolinetant significantly lowered VMS frequency, with pooled mean difference of 2.62 (95% CI, 1.84-3.41). The pooled mean difference for fezolinetant compared with placebo for the MENQOL (Menopause-Specific Quality of Life) measure was -0.60 (95% CI, -0.92 to -0.28), and the mean percentage improvement in VMS frequency was 22.51% (95% CI, 15.35-29.67). Fezolinetant was associated with improvement in sleep quality when compared with placebo. CONCLUSION: Fezolinetant is effective in lowering moderate-to-severe VMS frequency and sleep disturbances in postmenopausal women. SYSTEMATIC REVIEW REGISTRATION: PROSPERO, CRD42023427616.

Efficacy of pharmacological agents for the management of treatment-resistant schizophrenia: a network meta-analysis.

OBJECTIVE: The present network meta-analysis (NMA) was conducted to compare and generate evidence for the most efficacious treatment among available pharmacological interventions for treatment-resistant schizophrenia (TRS). METHODS: Reviewers extracted data from 47 studies screened from PubMed/MEDLINE, Embase, Cochrane databases and clinical trial registries fulfilling the eligibility criteria. Random effects Bayesian NMA was done with non-informative priors. Network geometry was visualized, and node splitting was done for the closed triangles. Standardized mean difference and 95% credible interval(95%CrI) were reported for the reduction in symptom severity scores. The probability of each intervention for each rank was plotted. Meta-regression was done for the duration of the therapy. RESULTS: Augmentation of antipsychotics with escitalopram (SMD: -1.7[95%CrI: -2.8, -0.70]), glycine (SMD: -1.2 [95%CrI: -2.2, -0.28]) and Yokukansan (SMD: -1.3 [95%CrI: -2.4, -0.24]) shows a statistically significant reduction in symptom severity when compared to clozapine. As per surface under cumulative ranking curve analysis, escitalopram in combination with antipsychotics appeared to be the best intervention with moderate certainty of evidence. There was no significant effect of the duration of therapy on the treatment effects. CONCLUSION: Escitalopram augmentation of antipsychotics appears to be the most efficacious treatment with moderate certainty of evidence among the available pharmacological interventions. PROSPERO REGISTRATION: CRD42022380292.

Efficacy and Safety of Anti-CGRP Monoclonal Antibodies in Prevention of Chronic Migraine: A Bayesian Network Meta-analysis.

Due to the unmet needs in the management of migraine, a primary headache, and disabling disorder, the past decade has focused on developing monoclonal antibodies (mAbs) against the calcitonin-gene-related peptide (CGRP) as migraine prophylactic agents. The objective of the study was to evaluate the efficacy and safety of various anti-CGRP mAbs in the prevention of chronic migraine. Network meta-analysis (NMA) was performed using the Bayesian framework to estimate the efficacy and safety of mAbs after performing a literature search in PubMed, MEDLINE, Cochrane database, and International Clinical Trial Registry Platform (ICTRP). The outcomes calculated were in terms of mean difference (MD) or odds ratio (OR) with a 95% credible interval (95%CrI). Network graphs were constructed and node-split analysis was done to analyze the inconsistency. The NMA included a total of 10 clinical trials. Galacanezumab (120 mg) (MD: -2.7; 95%CrI: -4.8 to -0.83) was found to be better than other mAbs in terms of the difference in mean migraine days (MMD). Fremanezumab quarterly dose administration showed the best response (OR: 2.9; 95%CrI: 1.9 to 4.6) in terms of responder rate. Eptinezumab was found to be safer (OR: 0.88; 95%CrI: 0.61-1.3) as compared to other mAbs in terms of the rate of adverse events. Fremanezumab (quarterly) ranked better in terms of response rate, and eptinezumab was found to be the safest in the prophylactic management of migraine. Galacenequmab was better at reducing MMD. Further studies are needed to evaluate the long-term safety, efficacy, and use of mAbs in migraine patients.

A Placebo-Controlled, Double-Blind Clinical Investigation to Evaluate the Efficacy of a Patented Trigonella foenum-graecum Seed Extract "Fenfuro®" in Type 2 Diabetics.

BACKGROUND: Trigonella foenum-graecum (Fenugreek) is an extensively researched phytotherapeutic for the management of Type 2 diabetes without any associated side effects. The major anti-diabetic bioactive constituents present in the plant are furostanolic saponins, which are more abundantly available in the seed of the plant. However, the bioavailability of these components depends on the method of extraction and hence formulation of the phytotherapeutic constitutes a critical step for its success. OBJECTIVE: The present study reports the efficacy of a novel, patented fenugreek seed extract, Fenfuro®, containing significant amount of furostanolic saponins, in an open-labelled, two-armed, single centric study on a group of 204 patients with Type 2 diabetes mellitus over a period of twelve consecutive weeks. RESULTS: Administration of Fenfuro® in the dosage of 500 mg twice daily along with metformin and/or sulfonylurea-based prescribed antidiabetic drug resulted in a reduction of post-prandial glucose by more than 33% along with significant reduction in fasting glucose, both of which were greater than what resulted for the patient group receiving only Metformin and/or Sulfonylurea therapy. Fenfuro® also resulted in reduction in mean baseline HOMA index from 4.27 to 3.765, indicating restoration of insulin sensitivity which was also supported by a significant decrease in serum insulin levels by >10% as well as slight reduction in the levels of C-peptide. However, in the case of the Metformin and/or Sulfonylurea group, insulin levels were found to increase by more than 14%, which clearly indicated that drug-induced suppression of glucose levels instead of restoration of glucose homeostasis. Administration of the formulation was also found to be free from any adverse side effects as there were no changes in hematological profile, liver function and renal function. CONCLUSION: The study demonstrated the promising potential of this novel phytotherapeutic, Fenfuro®, in long-term holistic management of type-2 diabetes.

Efficacy and safety of V1a receptor antagonists in autism spectrum disorder: A meta-analysis.

This meta-analysis has evaluated the efficacy and safety of V1a receptor antagonists in ASD compared to placebo. The reviewers extracted data from four relevant clinical trials after a literature search on 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. Subgroup analysis, meta-regression and sensitivity analysis were done. PRISMA guidelines were followed in the selection, analysis and reporting of findings. V1a receptor antagonists did not reduce Vineland II Adaptive behaviour composite score significantly (SMD: 0.14; 95% CI: -0.06-0.35; p = 0.16; PI: -0.44-0.73), communication domain subscale score and socialization domain subscale score. The change in daily living skills domain subscale score was significant and favourable for V1a receptor antagonists (SMD: 0.15; 95% CI: 0.03-0.26; p = 0.01). The subgroup analysis revealed a significant improvement in Vineland II Adaptive behaviour composite score with doses <10 mg (SMD: 0.45; 95% CI: 0.11-0.78; p = 0.009). Meta-regression does not show a significant association between SMD of ASD symptom score reduction with the duration and dose of V1a receptor antagonist therapy. Treatment-emergent adverse effects were not serious and dose dependent. Low doses (<10 mg) of V1a receptor antagonist may be effective in reducing the core symptoms of ASD compared to placebo; however, future active-controlled clinical trials are necessary to generate conclusive evidence.

Antigen loss following CAR-T cell therapy: Mechanisms, implications, and potential solutions.

Chimeric Antigen Receptor T-cell (CAR-T cell) therapy has emerged as a groundbreaking immunotherapeutic approach for treating various hematological malignancies. CAR-T cells are engineered to express synthetic receptors that target specific antigens on cancer cells, leading to their eradication. While the therapy has shown remarkable efficacy, a significant challenge that has been observed in 30%-70% of patients showing recurrent disease is antigen loss or downregulation. We searched PubMed/MEDLINE, EMBASE, and Google scholar for articles on antigen loss/escape following Chimeric antigen receptor T-cell therapy in malignancies. Antigen loss refers to the loss or reduction in the expression of the target antigen on cancer cells, rendering CAR-T cells ineffective. This phenomenon poses a significant clinical concern, as it can lead to disease relapse and limited treatment options. This review explores the mechanisms underlying antigen loss following CAR-T cell therapy, its implications on treatment outcomes, and potential strategies to overcome the problem.

Effect of Virgin Coconut Oil (VCO) on Cardiometabolic Parameters in Patients with Dyslipidemia: A Randomized, Add-on Placebo-Controlled Clinical Trial.

OBJECTIVE: Statin monotherapy for dyslipidemia is limited by adverse effects and limited effectiveness in certain subgroups like metabolic syndrome. Add-on therapy with an agent with a known safety profile may improve clinical outcomes, and virgin coconut oil (VCO) may be the candidate agent for improving the cardiometabolic profile. The present study was conducted to evaluate the effect of add-on VCO with atorvastatin in dyslipidemia in adults. METHODS: A randomized, double-blind clinical trial was conducted on 150 patients with dyslipidemia who were randomized into control and test groups. The control group received atorvastatin monotherapy, whereas the test group received add-on VCO with atorvastatin for 8 weeks. At baseline, demographic, clinical, and biochemical parameters were assessed and repeated after 8 weeks of therapy. The main outcome measures were lipid profile, cardiovascular risk indices, 10-year cardiovascular risk, body fat compositions, and thiobarbituric acid reactive substances (TBARS). RESULTS: The increase in HDL in the test group was significantly greater than in the control group (MD: 2.76; 95%CI: 2.43-3.08; p < 0.001). The changes in the atherogenic index (p = 0.003), coronary risk index (p < 0.001), cardiovascular risk index (p = 0.001), and TBARS (p < 0.001) were significantly greater in the test group. The decrease in LDL, total cholesterol and lipoprotein(a), were significantly higher in the control group. There were no significant differences between the groups with respect to the changes in triglyceride, VLDL, and 10-year cardiovascular risk. CONCLUSIONS: Add-on VCO (1000 mg/day) with atorvastatin (10 mg/day) can achieve a better clinical outcome in patients with dyslipidemia by increasing HDL and improving oxidative stress cardiovascular risk indices.

Dasiglucagon for the Treatment of Insulin-induced Hypoglycemia in Patients with Type 1 Diabetes Mellitus: A Meta-analysis

Background: The use of conventional glucagon for managing insulin-induced hypoglycemia is obscured by its chemical instability and the need for reconstitution of the lyophilized powder, leading to delayed rescue. Dasiglucagon, a glucagon analog, may potentially overcome these shortcomings. Aims: To evaluate the efficacy and safety of dasiglucagon in insulin-induced hypoglycemia in patients with type 1 diabetes mellitus (T1DM). Study Design: Meta-analysis. Methods: PubMed/MEDLINE, Scopus, Embase, and Cochrane databases along with clinical trial registries were searched to include data from five randomized controlled trials conducted using dasiglucagon for the treatment of insulin-induced hypoglycemia in T1DM patients published until May 2023. We performed a risk of bias assessment to determine the quality of the included studies and a random-effects model analysis for determining the effect size. Subgroup analysis and meta-regression were done as applicable. Results: The time to recovery (in minutes) with dasiglucagon was earlier than placebo [mean difference (MD): -24.73; 95% confidence interval (CI): -30.94 to -18.52; p < 0.00001) or oral glucose (MD: -15.00; 95% CI: -20.33 to -9.67; p < 0.00001); however, the difference between dasiglucagon and glucagon was not statistically significant (MD: -0.76; 95% CI: -2.19 to 0.66; p = 0.29). Conclusion: Dasiglucagon is safer and more effective than placebo or oral glucose for insulin-induced hypoglycemia in T1DM patients; however, it is not superior to conventional glucagon.

Efficacy and Safety of Azelnidipine as an Antihypertensive Compared to Amlodipine: A Systematic Review and Meta-analysis.

INTRODUCTION: Azelnidipine is one of the newer Calcium Channel Blockers (CCB) approved in China, Japan, and India. Some studies have found that the blood pressure-lowering effect of azelnidipine is more than amlodipine, and others found the effect similar. AIM: This meta-analysis was conducted to evaluate the efficacy of azelnidipine in managing hypertensive patients by lowering Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP), and Heart Rate (HR) as compared to amlodipine. METHODS: PubMed/MEDLINE, Google Scholar, PROQUEST, and International Clinical Trial Registry Platform (ICTRP) were searched for published articles to evaluate the clinical efficacy of azelnidipine in the management of hypertension patients. Data were extracted from the selected 11 randomized clinical trials (RCTs). The risk of bias 2 (RoB2) tool was used for the quality assessment of the included studies, and the random-effects model was used to estimate the effect size. RESULTS: There were no statistically significant differences in the reduction of SBP (Mean Difference, MD: - 1.07; 95% CI: - 4.10, 1.95, p-value: 0.49) and DBP (MD: 0.27; 95% CI: - 2.66, 3.20, p-value: 0.86) between both the drugs. In terms of HR reduction, there was a statistically significant difference (MD: - 3.63; 95% CI: - 5.27, - 2.00, p-value: < 0.0001) between both drugs. Egger's test excluded any publication bias for the included studies (p = 0.21). Meta-regression excluded the effect of the duration of treatment on outcome parameters. CONCLUSION: Though no significant difference between azelnidipine and amlodipine was found, in terms of reduction in SBP and DBP, azelnidipine reduced heart rate significantly compared to amlodipine. PROSPERO REGISTRATION: CRD42023390361.

Evaluation of Safety and Efficacy of Add-on Alpha-Lipoic Acid on Migraine Prophylaxis in an Adolescent Population: A Randomized Controlled Trial.

Nutraceuticals like alpha-lipoic acid (ALA) may have potential benefits as prophylactic agents for adolescent migraine, with fewer adverse events than existing medications. The present study was conducted to evaluate the safety and efficacy of add-on ALA for prophylaxis in adolescent migraine. A randomized, open-label, add-on clinical trial was conducted with 60 adolescent migraineurs, who were randomized to receive flunarizine or flunarizine with an add-on ALA. A clinical evaluation of the frequency and severity of migraine, responder rate, Pediatric Migraine Disability Assessment (PedMIDAS) scoring, serum thiol, and serum calcitonin gene-related peptide (CGRP) was performed both at baseline and following 12 weeks of treatment. The frequency of acute attacks of migraine decreased significantly (P = .001) in the test group compared with the control group. The responder rate was found to be significantly higher (80%) in the test group than in the control group (33.3%) (P = .001). The mean monthly migraine headache days in the test group showed a significant reduction (-7.7 days, 95%CI -9.1 to -6.3 days; P = .010). The severity of acute migraine attacks (mild, moderate, severe) also showed a significant reduction in the test group (P = .001). PedMIDAS scores showed significant improvement in the test group (P = .021), in comparison with the control group. Serum thiol levels were significantly increased in the test group (18 mmol/L, 95%CI 13.5 to 36.1 mmol/L; P = .001). Serum CGRP levels showed a significant reduction with adjunctive ALA therapy (-122.4 pg/mL, 95%CI -142.3 to -89.0 pg/mL; P = .006). Add-on ALA with flunarizine as a prophylactic agent for migraine in adolescents can improve clinical outcomes by improving clinical and biochemical parameters.