Clinical Pharmacology Studies Research Articles

α-Glucosidase inhibitory potential of Oroxylum indicum using molecular docking, molecular dynamics, and in vitro evaluation

BackgroundAccording to the International Diabetes Federation, there will be 578 million individuals worldwide with diabetes by 2030 and 700 million by 2045. One of the promising drug targets to fight diabetes is α-glucosidase (AG), and its inhibitors may be used to manage diabetes by reducing the breakdown of complex carbohydrates into simple sugars. The study aims to identify and validate potential AG inhibitors in natural sources to combat diabetes. MethodsComputational techniques such as structure-based virtual screening and molecular dyncamic simulation were employed to predict potential AG inhibitors from compounds of Oroxylum indicum. Finally, in silico results were validated by in vitro analysis using n-butanol fraction of crude methanol extracts. ResultsThe XP glide scores of top seven hits OI_13, OI_66, OI_16, OI_44, OI_43, OI_20, OI_78 and acarbose were –14.261, –13.475, –13.074, –13.045, –12.978, –12.659, –12.354 and –12.296 kcal/mol, respectively. These hits demonstrated excellent binding affinity towards AG, surpassing the known AG inhibitor acarbose. The MM-GBSA dG binding energies of OI_13, OI_66, and acarbose were −69.093, −62.950, and −53.055 kcal/mol, respectively. Most of the top hits were glycosides, indicating that active compounds lie in the n-butanol fraction of the extract. The IC50 value for AG inhibition by n-butanol fraction was 248.1 μg/ml, and for that of pure acarbose it was 89.16 μg/ml. The predicted oral absorption rate in humans for the top seven hits was low like acarbose, which favors the use of these compounds as anti-diabetes in the small intestine. ConclusionIn summary, the study provides promising insights into the use of natural compounds derived from O. indicum as potential AG inhibitors to manage diabetes. However, further research, including clinical trials and pharmacological studies, would be necessary to validate their efficacy and safety before clinical use.

State-of-the-Art Review on Botanical Hybrid Preparations in Phytomedicine and Phytotherapy Research: Background and Perspectives.

Despite some evidence supporting the synergy concept, the commonly known assumption that combinations of several herbs in one formulation can have better efficacy due to additive or synergistic effects has yet to be unambiguously and explicitly studied. The study aimed to reveal the molecular interactions in situ of host cells in response to botanical hybrid preparations (BHP) intervention and justify the benefits of implementing BHP in clinical practice. This prospective literature review provides the results of recent clinical and network pharmacology studies of BHP of Rhodiola rosea L. (Arctic root) with other plants, including Withania somnifera (L.) Dunal (ashwagandha), (Camellia sinensis (L.) Kuntze (green tea), Eleutherococcus senticosus (Rupr. and Maxim.) Maxim. (eleuthero), Schisandra chinensis (Turcz.) Baill. (schisandra), Leuzea carthamoides (Willd.) DC., caffeine, Cordyceps militaris L., Ginkgo biloba L.(ginkgo), Actaea racemosa L. (black cohosh), Crocus sativus L. (saffron), and L-carnosine. The most important finding from network pharmacology studies of BHP was the evidence supporting the synergistic interaction of BHP ingredients, revealing unexpected new pharmacological activities unique and specific to the new BHP. Some studies show the superior efficacy of BHP compared to mono-drugs. At the same time, some a priori-designed combinations can fail, presumably due to antagonistic interactions and crosstalk between molecular targets within the molecular networks involved in the cellular and overall response of organisms to the intervention. Network pharmacology studies help predict the results of studies aimed at discovering new indications and unpredicted adverse events.

Preventing CXCL12 elevation helps to reduce acute exacerbation of COPD in individuals co-existing type-2 diabetes: A bioinformatics and clinical pharmacology study

AimsTo investigate the immunology shared mechanisms underlying chronic obstructive pulmonary disease (COPD) and type 2 diabetes mellitus (T2DM) and examine the impact of anti-diabetic drugs on acute exacerbation of COPD (AECOPD). MethodsWe analyzed GSE76925, GSE76894, GSE37768, and GSE25724 to identify differentially expressed genes. Hub-genes were identified through protein–protein interaction network analysis and evaluated by the receiver operating characteristic curve. CXCL12 emerged as a robust biomarker, and its correlation with lung function and CD8+ T cells were further quantified and validated. The activated signaling pathways were inferred through Gene set enrichment analysis (GSEA). The retrospective clinical analysis was executed to identify the influence of dipeptidyl peptidase-4 inhibitors (DPP-4i) on CXCL12 and evaluate the drug’s efficacy in AECOPD. ResultsThe significant up-regulation of CXCL12 expression in patients with two diseases were revealed. CXCL12 exhibited a negative correlation with pulmonary function (r = -0.551, p < 0.05). Consistent with analysis in GSE76925 and GSE76894, the positive correlation between the proportion of CD8+ T cells was demonstrated(r=0.469, p<0.05). GSEA identified “cytokines interaction” as an activated signaling pathway, and the clinical study revealed the correlation between CXCL12 and IL-6 (r=0.668, p<0.05). In patients with COPD and T2DM, DDP-4i treatment exhibited significantly higher serum CXCL12, compared to GLP-1RA. Analysis of 187 COPD patients with T2DM indicated that the DPP-4i group had a higher frequency of AECOPD compared to the GLP-1RA group (OR 1.287, 95%CI [1.018–2.136]). ConclusionsCXCL12 may represent a therapeutic target for COPD and T2DM. GLP-1RA treatment may be associated with lower CXCL12 levels and a lower risk of AECOPD compared to DPP-4i treatment.Clinical Trial Registration: China Clinical Trial Registration Center（ChiCTR2200055611）.

Sources of pharmacokinetic and pharmacodynamic variability and clinical pharmacology studies of antiseizure medications in the pediatric population.

Multiple treatment options exist for children with epilepsy, including surgery, dietary therapies, neurostimulation, and antiseizure medications (ASMs). ASMs are the first line of therapy, and more than 30 ASMs have U.S. Food and Drug Administration (FDA) approval for the treatment of various epilepsy and seizure types in children. Given the extensive FDA approval of ASMs in children, it is crucial to consider how the physiological and developmental changes throughout childhood may impact drug disposition. Various sources of pharmacokinetic (PK) variability from different extrinsic and intrinsic factors such as patients' size, age, drug-drug interactions, and drug formulation could result in suboptimal dosing of ASMs. Barriers exist to conducting clinical pharmacological studies in neonates, infants, and children due to ethical and practical reasons, limiting available data to fully characterize these drugs' disposition and better elucidate sources of PK variability. Modeling and simulation offer ways to circumvent traditional and intensive clinical pharmacology methods to address gaps in epilepsy and seizure management in children. This review discusses various physiological and developmental changes that influence the PK and pharmacodynamic (PD) variability of ASMs in children, and several key ASMs will be discussed in detail. We will also review novel trial designs in younger pediatric populations, highlight the role of extrapolation of efficacy in epilepsy, and the use of physiologically based PK modeling as a tool to investigate sources of PK/PD variability in children. Finally, we will conclude with current challenges and future directions for optimizing the efficacy and safety of these drugs across the pediatric age spectrum.

Determination of glomerular filtration rate "en passant" after high doses of iohexol for computed tomography in intensive care medicine-a proof of concept.

Accurate assessment of renal function is of great clinical and scientific importance, as it is an important pharmacokinetic covariate of pivotal drugs. The iohexol clearance is nearly identical to the glomerular filtration rate, but its determination usually requires an intravenous injection and therefore bears intrinsic risks. This motivates to showcase an "en passant" approach to quantification of renal function without additional risk or blood sampling beyond routine care using real-world data. We enrolled 37 intensive care patients who received high doses of iohexol for computed tomography imaging, and quantified series of iohexol plasma concentrations by high-performance liquid chromatography (HPLC-UV). Iohexol clearance was derived by both log-linear regression and nonlinear least squares fitting and compared to glomerular filtration rate estimated by the CKD-EPI-2021 formulas. Nonlinear fitting not only turned out to be more accurate but also more robust in handling the irregularly timed data points. Concordance of iohexol clearance against estimations based on both creatinine and cystatin C showed a slightly higher bias (-3.44mL/min/1.73m2) compared to estimations based on creatinine alone (-0.76mL/min/1.73m2), but considerably narrower limits of agreement (±42.8 vs. 56mL/min/1.73m2) and higher Lin's correlation (0.84 vs. 0.72). In summary, we have demonstrated the feasibility and performance of the "en passant" variant of the iohexol method in intensive care medicine and described a working protocol for its application in clinical practice and pharmacologic studies.

Assessment of the CYP3A4 Induction Potential by Carbamazepine: Insights from Two Clinical DDI Studies and PBPK Modeling.

In the past, rifampicin was well-established as strong index CYP3A inducer in clinical drug-drug interaction (DDI) studies. However, due to identified potentially genotoxic nitrosamine impurities, it should not any longer be used in healthy volunteer studies. Available clinical data suggestcarbamazepine as an alternative to rifampicin as strong index CYP3A4 inducer in clinical DDI studies. Further, physiologically-based pharmacokinetic (PBPK) modeling is a tool with increasing importance to support the DDI risk assessment of drugs during drug development. CYP3A4 induction properties and the safety profile of carbamazepine were investigated in two open-label, fixed sequence, crossover clinical pharmacology studies in healthy volunteers using midazolam as a sensitive index CYP3A4 substrate. Carbamazepine was up-titrated from 100 mg twice daily (b.i.d.) to 200 mg b.i.d., and to a final dose of 300 mg b.i.d. for 10 consecutive days. Mean area under plasma concentration-time curve from zero to infinity (AUC(0-∞)) of midazolam consistently decreased by 71.8% (ratio: 0.282, 90% confidence interval (CI): 0.235-0.340) and 67.7% (ratio: 0.323, 90% CI: 0.256-0.407) in study 1 and study 2, respectively. The effect was adequately described by an internally developed PBPK model for carbamazepine which has been made freely available to the scientific community. Further, carbamazepine was safe and well-tolerated in the investigated dosing regimen in healthy participants. The results demonstrated that the presented design is appropriate for the use of carbamazepine as alternative inducer to rifampicin in DDI studies acknowledging its CYP3A4 inductive potency and safety profile.

Clinical Bridging Studies and Modeling Approach for Implementation of a Patient Centric Sampling Technique in Padsevonil Clinical Development

Volumetric absorptive microsampling (VAMS) techniques have gained popularity these last years as innovative tool for collection of blood pharmacokinetic (PK) samples in clinical trials as they offer many advantages over dried blood spot and conventional venous blood sampling. The use of Mitra®, a blood collection device based on volumetric absorptive microsampling (VAMS) technology, was implemented during clinical development of padsevonil (PSL), an anti-seizure medication (ASM) candidate. The present study describes the approach used to bridge plasma (obtained from conventional venous blood sampling) and blood exposures (obtained with Mitra®) to support the use of Mitra as sole blood PK sampling method in clinical trials. Paired blood (using Mitra®) and plasma samples (using conventional venous blood sampling) were collected in healthy volunteers as well as in patients with epilepsy. PSL concentration in plasma and blood were analyzed using different approaches which included evaluation of blood-to-plasma ratios (B/P) over time, linear regression, Bland-Altman analysis as well as development of a linear-mixed effect model based on clinical pharmacology studies. Results showed that the observed in vivo B/P and the measured bias between the 2 collection methods were consistent with the measured in vitro B/P. Graphical analysis demonstrated a clear time effect on the B/P which was confirmed in the linear mixed effect model with sampling time identified as significant covariate. Finally, the built-in model was validated using independent datasets and was shown to adequately predict plasma concentration based on blood concentration with a mean bias of less than 9% (predicted versus observed plasma concentration).Graphical

Rare oncology therapeutics: review of clinical pharmacology package of drug approvals (2019-2023) by US FDA, best practices and recommendations.

There are many challenges with rare diseases drug development and rare oncology indications are not different. To understand the regulatory landscape as it relates to application of clinical pharmacology principles in rare oncology product development, we reviewed publicly available information of 39 approvals by US FDA between January 2019 and March 2023. The objective was to understand the expected clinical pharmacology studies and knowledge base in such approvals. Model informed drug development (MIDD) applications were also reviewed, as such approaches are expected to play a critical role in filling clinical pharmacology gaps in rare oncology, where number of clinical trials and size of these trials will perhaps continue to be small. The findings highlighted how clinical pharmacology contributed to the evidence of effectiveness, dose optimization and elucidation of intrinsic and extrinsic factors affecting drug's behavior. Clinical pharmacology studies were often integrated with modeling in many of the NDAs/BLAs. Of the post marketing requirements (PMR) received, 18% were for dose optimization, 49% for DDI, 8% for QTc, 49% for specific population, and 5% for food effect. Two post marketing commitments (PMC) were issued for immunogenicity of the 11 biologics submissions. 15% (6 of 39) of the submissions used maximum tolerated dose (MTD) to advance their molecule into Phase 2 studies. Of them 3 approvals received PMR for dose optimization. 3 + 3 was the most prevalent Phase 1 design with use in 74% of the New Drug Applications (NDA)/Biologic License Applications (BLA) reviewed. Rest used innovative approaches such as BLRM, BOIN or mTPi, with BLRM being the most common. Seamless clinical pharmacology and MIDD approaches are paramount for rare oncology drug development.

Functional FDG-PET: Measurement of Task Related Neural Activity in Humans-A Compartment Model Approach and Comparison to fMRI.

Neuroimaging holds an essential position in global healthcare, as brain-related disorders are a substantial and growing burden. Non-degenerative disorders such as stress, depression and anxiety share common function related traits of diffuse and fluctuating changes, such as change in brain-based functions of mood, behavior and cognitive abilities, where underlying physiological mechanism remain unresolved. In this study we developed a novel application for studying intra-subject task-activated brain function by the quantitative physiological measurement of the change in glucose metabolism in a single scan setup. Data were acquired on a PET/MR-scanner. We implemented a functional [18F]-FDG PET-scan with double boli-tracer administration and finger-tapping activation, as proof-of-concept, in five healthy participants. The [18F]-FDG data were analyzed using a two-tissue compartment double boli kinetic model with an image-derived input function. For stand-alone visual reference, blood oxygenation level dependent (BOLD) functional MRI (fMRI) was acquired in the same session and analyzed separately. We were able to measure the cerebral glucose metabolic rate during baseline as well as activation. Results showed increased glucose metabolic rate during activation by 36.3-87.9% mean 62.0%, locally in the peak seed region of M1 in the brain, on an intra-subject level, as well as very good spatial accuracy on group level, and localization compared to the BOLD fMRI result at subject and group level. Our novel method successfully determined the relative increase in the cerebral metabolic rate of glucose on a voxel level with good visual association to fMRI at the subject-level, holding promise for future individual clinical application. This approach will be easily adapted in future clinical perspectives and pharmacological interventions studies.

Antioxidant, antidiabetic, antiglaucoma, and anticholinergic effects of Tayfi grape (Vitis vinifera): A phytochemical screening by LC-MS/MS analysis

Abstract Grapes (Vitis vinifera), grape extracts, and grape products are known to possess beneficial effects. Antioxidant activity and enzyme inhibition activities of Tayfi grape (Vitis vinifera) extracts were studied and compared to standards. The IC50 values of the ethanol extract of the Tayfi grape’s scavenging abilities for ABTS˙+ and DPPH˙ radicals were found to be 5.9 and 16.1 μg/mL, respectively, higher than those of positive controls. Also, the phenolic and flavonoid ingredients of the Tayfi grape seed ethanol extract were measured to be 82.8 mg GAE/g and 91 mg QE/g. The Tayfi grape seed water and ethanol extracts exhibited IC50 values of 5.3 and 5.8 μg/mL toward α-glycosidase, respectively; 385.2 and 567.6 μg/mL toward α-amylase; 27.1 and 13.8 μg/mL toward acetylcholinesterase (AChE); and 54.7 and 12.6 μg/mL toward CA II. Twenty-two biomolecules were detected by LC-MS/MS. The four types of conventional antibiotics utilized by hospitals proved ineffective against Staphylococcus aureus and Escherichia coli bacteria. The Tayfi grape ethanol and water extracts had high AChE, α-glycosidase, and CA II inhibitions in addition to having antioxidant activity. The use of Tayfi grape extracts for pharmacological purposes in individuals with the diseases mentioned above can be sustained by clinical pharmacology studies.

Patient Centric Microsampling to Support Paxlovid Clinical Development: Bridging and Implementation.

Nirmatrelvir is a potent and selective severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) main protease inhibitor. Nirmatrelvir co-packaged with ritonavir (as PAXLOVID) received US Food and Drug Administration (FDA) Emergency Use Authorization (EUA) on December 22, 2021, as an oral treatment for coronavirus disease 2019 (COVID-19) and subsequent new drug application approval on May 25, 2023. Pharmacokinetic (PK) capillary blood sampling at-home using Tasso-M20 micro-volumetric sampling device was implemented in the program, including three phase II/III outpatient and several clinical pharmacology studies supporting the EUA. The at-home sampling complemented venous blood sampling procedures to enrich the PK dataset, to decrease the need for patients' site visit for PK sampling, and to allow different sampling approaches for flexibility and convenience. To demonstrate concordance/equivalence, bridging between venous plasma and Tasso dried blood results was conducted by comparing concentrations and derived PK parameters from both sampling approaches. In addition, a two-compartment population PK model was utilized to bridge the plasma and Tasso data by estimating the PK parameters using blood-to-plasma ratio as a slope parameter. Operational challenges were successfully managed to implement at-home PK sampling in global phase II/III trials. Sample quality was generally very good with less than 3% samples deemed as "not usable" from over 800 samples collected in all the studies. Experience gained from sites and patients will guide future broader implementations.

Effect of Chinese patent medicine Kunling Pill on endometrial receptivity: A clinical trial, network pharmacology, and animal-based study.

Although pregnancy success rates are raised with assisted reproductive technology, it still cannot meet clinical demands. Kunling Pill (KLP), a traditional Chinese medicine, is widely used in various gynecological disorders, particularly in improving fertility and pregnancy rates. However, the underlying mechanism of how KLP affects pregnancy outcomes remains unclear. This study aimed to explore the effects and mechanisms of KLP on endometrial receptivity. Firstly, a retrospective trial was conducted to validate the efficacy of KLP on repeated implantation failure (RIF) patients. The result indicated a significant increase in the proportion of live birth in KLP group (30.56%) compared to the control group (16.89%). Secondly, network pharmacology methods predicted the active components and network targets of KLP. Endometrial receptivity is closely associated with the activation of inflammatory factors, predicting the function of KLP on the immune system. The estrogen and apoptotic signaling pathways were also highlighted in the gene ontology enrichment analysis. Thirdly, a decreased endometrial receptivity model was established by controlled ovarian hyperstimulation (COH) in female C57BL/6 mice, divided into the COH and KLP groups. Normal female mice are as control group. In vivo, KLP administration could increase endometrial thickness and the number of endometrial glands and pinopodes. In the endometrium, KLP supplementation upregulated the expressions of estrogen receptor α, progesterone receptor, endothelial nitric oxide synthase, and integrin αVβ3 in the murine uterus and reduced serum levels of estrogen and progesterone. KLP regulated the uterine immune cells and inhibited cell apoptosis in the ovary via Bcl-2/Bax/caspase-3 pathway. In conclusion, KLP administration raised the live birth rate in RIF patients to optimize medication regimens, mainly because KLP ameliorated impaired endometrial receptivity.

Safety of Lumason® (SonoVue®) in special populations and critically ill patients.

Evidence for the safe use of Lumason® (SonoVue®), an ultrasound enhancing agent (UEA), in special patient populations is critical to enable healthcare professionals to make informed decisions concerning its use in such patients. Herein, we provide insight on the safety and tolerability of Lumason® in special patient populations. Findings are presented from clinical pharmacology studies conducted in patients with compromised cardiopulmonary conditions, from a retrospective study performed in critically ill patients, and from post-marketing surveillance data from over 20 years of market use of Lumason® (SonoVue®). No detrimental effects of Lumason® on cardiac electrophysiology were observed in patients with coronary artery disease (CAD), and no significant effects on pulmonary hemodynamics were noted in patients with pulmonary hypertension or congestive heart failure. Similarly, no effects on several assessments of pulmonary function (e.g., FVC) were observed in patients with chronic obstructive pulmonary disease (COPD), and no clinically meaningful changes in O2 saturation or other safety parameters were observed after administration of Lumason® to patients with diffuse interstitial pulmonary fibrosis (DIPF). The retrospective study of critically ill patients revealed no significant difference for in-hospital mortality between patients administered Lumason® for echocardiography versus those who had undergone echocardiography without contrast agent. Post-marketing surveillance revealed very low reporting rates (RR) for non-serious and serious adverse events and that serious hypersensitivity reactions were rare. These findings confirm that Lumason® is a safe and well tolerated UEA for use in special populations and critically ill patients.

The new S7B/E14 Q&A document provides additional opportunities to replace the thorough QT study.

Since 2015, concentration-QTc analysis can be used to exclude that a drug has a concerning effect on the QTc interval. This has enabled replacing the designated TQT study by implementation of serial ECGs into routine clinical pharmacology studies, such as the First-in-Human (FIH) study. This has led to an increased proportion of FIH studies with this added objective of QT evaluation with the intention of replacing the TQT study. With the more recent, February 2022 revision of the S7B/E14 Q&A document, nonclinical assays/studies can be brought into the process of regulatory decisions at the time of marketing application. If the hERG and the non-rodent in vivo study are conducted according to described best practices, the previous requirement that a QTc effect > 10 ms must be excluded in healthy subjects at plasma concentrations 2-fold above what can be seen in patients can be reduced to covering concentrations seen in patients. For drugs that cannot be safely given in high doses to healthy subjects, ECG evaluation is often performed at the therapeutic dose in patients. If a QTc effect > 10 ms can be excluded, an argument can be made that the drug should be considered as having a low likelihood of proarrhythmic effects due to delayed repolarization. In this article, we describe what clinicians involved in early clinical development need to understand in terms of the hERG and in vivo studies to determine whether these meet best practices and therefore can be used in an integrated clinical/nonclinical QT/QTc risk assessment. This article is protected by copyright. All rights reserved.

Biodistribution of recombinant factor IX, extended half-life recombinant factor IX Fc fusion protein, and glycoPEGylated recombinant factor IX in hemophilia B mice.

Extended half-life recombinant FIX (rFIX) molecules have been generated to reduce the dosing burden and increase the protection of patients with hemophilia B. Clinical pharmacology studies with recombinant factor IX Fc fusion protein (rFIXFc) report a similar initial peak plasma recovery to that of rFIX, but with a larger volume of distribution. Although the pegylation of N9-GP results in a larger plasma recovery, there is a smaller volume of distribution, suggesting less extravasation of the latter drug. In this study, we set out to compare the biodistribution and tissue localization of rFIX, rFIXFc, and glycoPEGylated rFIX in a hemophilia B mouse model. Radiolabeled rFIX, rFIXFc, and rFIX-GP were employed in in vivo single-photon emission computed tomography imaging (SPECT/CT), microautoradiography (MARG), and histology to assess the distribution of FIX reagents over time. Immediately following injection, vascularized tissues demonstrated intense signal irrespective of FIX reagent. rFIX and rFIXFc were retained in joint and muscle areas through 5 half-lives, unlike rFIX-GP (assessed by SPECT). MARG and immunohistochemistry showed FIX agents localized at blood vessels among tissues, including liver, spleen, and kidney. Microautoradiographs, as well as fluorescent-labeled images of knee joint areas, demonstrated retention over time of FIX signal at the trabecular area of bone. Data indicate that rFIXFc is similar to rFIX in that it distributes outside the plasma compartment and is retained in certain tissues over time, while also retained at higher plasma levels. Overall, data suggest that Fc fusion does not impede the extravascular distribution of FIX.

Commentary on Improving the Efficiency of Clinical Pharmacology Studies.

Commentary on Improving the Efficiency of Clinical Pharmacology Studies.

Review: The use of functional magnetic resonance imaging (fMRI) in clinical trials and experimental research studies for depression.

Functional magnetic resonance imaging (fMRI) is a non-invasive technique that can be used to examine neural responses with and without the use of a functional task. Indeed, fMRI has been used in clinical trials and pharmacological research studies. In mental health, it has been used to identify brain areas linked to specific symptoms but also has the potential to help identify possible treatment targets. Despite fMRI's many advantages, such findings are rarely the primary outcome measure in clinical trials or research studies. This article reviews fMRI studies in depression that sought to assess the efficacy and mechanism of action of compounds with antidepressant effects. Our search results focused on selective serotonin reuptake inhibitors (SSRIs), the most commonly prescribed treatments for depression and ketamine, a fast-acting antidepressant treatment. Normalization of amygdala hyperactivity in response to negative emotional stimuli was found to underlie successful treatment response to SSRIs as well as ketamine, indicating a potential common pathway for both conventional and fast-acting antidepressants. Ketamine's rapid antidepressant effects make it a particularly useful compound for studying depression with fMRI; its effects on brain activity and connectivity trended toward normalizing the increases and decreases in brain activity and connectivity associated with depression. These findings highlight the considerable promise of fMRI as a tool for identifying treatment targets in depression. However, additional studies with improved methodology and study design are needed before fMRI findings can be translated into meaningful clinical trial outcomes.

Improving the Efficiency of Clinical Pharmacology Studies.

Improving the Efficiency of Clinical Pharmacology Studies.

Preclinical evaluation of antimalarial activity of CPF-1 formulation as an alternative choice for the treatment of malaria

BackgroundKheaw Hom remedy is a traditional Thai medicine used to treat fever. Some plants used in the Kheaw Hom remedy show promising in vitro antimalarial activity. This study prepared novel formulations of plants from the Kheaw Hom remedy and evaluated their antimalarial and toxicological activities.MethodsSeven new formulations were prepared by combining at least three herbs of six selected plants from the Kheaw Hom remedy, namely Mammea siamensis Kosterm., Mesua ferrea L., Dracaena loureiroi Gagnep., Pogostemon cablin (Blanco) Benth., Kaempferia galanga L, and Eupatorium stoechadosmum Hance. In vitro antimalarial activities of each formulation’s aqueous and ethanolic extracts were evaluated using the parasite lactate dehydrogenase (pLDH) assay. Cytotoxicity in Vero and HepG2 cells was assessed using the MTT assay. An extract with good antimalarial potency and selectivity index (SI) was selected for in vivo antimalarial activity using Peter’s 4-day suppressive test and acute oral toxicity test in mice. In addition, bioactive compounds were identified using Gas chromatography-mass spectrometry (GC-MS) analysis.ResultsAmong the seven new formulations, ethanolic extracts of CPF-1 (Formulation 1) showed the highest activity with an IC50 value of 1.32 ± 0.66 µg/ml, followed by ethanolic extracts of Formulation 4 and Formulation 6 with an IC50 value of 1.52 ± 0.28 µg/ml and 2.48 ± 0.34 µg/ml, respectively. The highest SI values were obtained for the ethanolic extract of CPF-1 that was selected to confirm its in vivo antimalarial activity and toxicity. The results demonstrated a significant dose-dependent reduction in parasitemia. Maximum suppressive effect of the extract (72.01%) was observed at the highest dose administered (600 mg/kg). No significant toxicity was observed after the administration of 2000 mg/kg. Using GC-MS analysis, the most abundant compound in the ethanolic extract of CPF-1 was ethyl p-methoxycinnamate (14.32%), followed by 2-propenoic acid, 3-phenyl-, ethyl ester, (E)- (2.50%), and pentadecane (1.85%).ConclusionThe ethanolic extract of CPF-1 showed promising in vitro and in vivo antimalarial efficacy, with no toxic effects at a dose of 2000 mg/kg, suggesting that the ethanolic extract of CPF-1 may serves as a new herbal formulation for the treatment of malaria. Additional research is required for safety and clinical pharmacology studies.

Updated Renal Dosage Recommendations for Rivaroxaban in Patients Experiencing or at Risk of Thromboembolic Disease

Patients with chronic kidney disease are at an increased risk of venous thromboembolism (VTE). The factor Xa inhibitor rivaroxaban has been shown to provide similar efficacy and a lower risk of bleeding compared with vitamin K antagonists for the treatment and prevention of VTE. Rivaroxaban has been studied in patients with varying degrees of renal impairment, and this review summarizes current knowledge supporting its use in patients with severe renal impairment (creatinine clearance [CrCl] of 15 to < 30 mL/min) for the prevention, treatment, or prophylaxis of VTE. Clinical pharmacology studies have demonstrated an increase in rivaroxaban systemic exposure, factor Xa inhibition, and prothrombin time with decreasing renal function. These changes reach a plateau with comparable increases in exposure among individuals with moderate or severe renal impairment and end-stage renal disease. The clinical development program for the treatment and prevention of VTE as well as prophylaxis of deep vein thrombosis (DVT) following orthopedic surgery excluded patients with CrCl < 30 mL/min; however, a limited number of patients with severe renal impairment were enrolled. Efficacy outcomes in these patients with severe renal impairment were not meaningfully different from those of patients with higher levels of renal function. There was also no increase in the incidence of major bleeding with rivaroxaban in patients with CrCl < 30 mL/min. Taken together, these pharmacological and clinical data suggest that in patients with severe renal impairment, the approved dosages of rivaroxaban can be used in the treatment and prevention of VTE and for prophylaxis of DVT after hip or knee replacement surgery.