Pharmacodynamic Studies Research Articles

FDA Approval Summary: Nalmefene Nasal Spray for the Emergency Treatment of Known or Suspected Opioid Overdose.

On May 22, 2023, the United States Food and Drug Administration approved the first nalmefene hydrochloride nasal spray for the emergency treatment of known or suspected opioid overdose in adults and pediatric patients 12 years of age and older. This approval of a new prescription nalmefene hydrochloride nasal spray adds to the available opioid reversal options for hospitals, communities, harm reduction groups, and emergency responders. Due to the life-threatening nature of opioid overdose, conducting randomized, well-controlled clinical efficacy trials in the target patient population is neither ethical nor feasible. Clinical investigations of nalmefene nasal spray consisted of two pharmacokinetic studies and one pharmacodynamic study. Approval of the new drug application was based on the scientific bridge established by the two pharmacokinetic studies to the Agency's previous efficacy and safety findings for the listed drug nalmefene hydrochloride injection. Additionally, the pharmacodynamic study conducted in an opioid-induced respiratory depression model in healthy volunteers established the onset of action of nalmefene administered as a nasal spray. A high-level summary of regulatory and scientific considerations during the development and approval of nalmefene nasal spray are presented.

Nanostructured Lipid Carrier-Mediated Transdermal Delivery System of Glibenclamide for Gestational Diabetes: Pharmacokinetic and Pharmacodynamic Evaluation.

Gestational diabetes mellitus (GDM) poses significant risks during pregnancy for both mother and fetus. Adherence to oral antidiabetic medications, like glibenclamide (GB), can be challenging, necessitating novel drug delivery methods. Nanostructured lipid carriers (NLC) offer a promising approach by efficiently permeating the skin due to their small size and lipid-based composition. This study aimed to develop and evaluate transdermal patches loaded with glibenclamide NLCs to treat GDM. Glibenclamide NLCs were prepared using hot homogenization with ultrasonication and melt dispersion method. A central composite design was utilized to optimize the formulations. Transdermal patches containing optimized NLCs were developed using HPMC K 100 and Eudragit L polymers. The patches were evaluated for various parameters, and their pharmacokinetic and pharmacodynamic studies were carried out to assess their safety and efficacy. Optimized NLCs efficiently permeated rat skin. Cell viability studies indicated the nontoxicity of the formulations. NLC-loaded transdermal patches (F2 and F7) showed drug release of 1098 μg/cm2 and 1001.83 μg/cm2 in 24 h, with a 2.5-fold higher flux and permeation coefficient than the GB patch. Pharmacokinetic analysis revealed Tmax of 8 and 10 h and Cmax of 7127 ng/ml and 7960 ng/ml for F2 and F7, respectively, ensuring sustained drug action. AUC0-α was 625681 ng/ml·h and 363625 ng/ml·h for F2 and F7, respectively, indicating improved bioavailability. Transdermal patches incorporating NLCs hold promise for enhancing glibenclamide's therapeutic efficacy in GDM treatment. Improved skin permeation, sustained drug release, and enhanced bioavailability make NLC-based transdermal patches a potential alternative with better patient compliance.

Transdermal Drug Delivery System of Linagliptin Sustained-release Microparticle Gels: In vitro Characterization and In vivo Evaluation.

Linagliptin (LNG) exhibits poor bioavailability and numerous side effects, significantly limiting its use. Transdermal drug delivery systems (TDDS) offer a potential solution to overcome the first-pass effect and gastrointestinal reactions associated with oral formulations. The aim of this study was to develop LNG microparticle gels to enhance drug bioavailability and mitigate side effects. Linagliptin hyaluronic acid (LNG-HA) microparticles were prepared by spray drying method and their formulation was optimized via a one-factor method. The solubility and release were investigated using the slurry method. LNG-HA microparticle gels were prepared and optimised using in vitro transdermal permeation assay. The hypoglycaemic effect of the LNG-HA microparticle gel was examined on diabetic mice. The results indicated that the LNG-HA microparticle encapsulation rate was 84.46%. Carbomer was selected as the gel matrix for the microparticle gels. Compared to the oral API, the microparticle gel formulation demonstrated a distinct biphasic release pattern. In the first 30 minutes, only 43.56% of the drug was released, followed by a gradual release. This indicates that the formulation achieved a slow-release effect from a dual reservoir system. Furthermore, pharmacodynamic studies revealed a sustained hypoglycemic effect lasting for 48 hours with the LNG microparticle gel formulation. These findings signify that the LNG microparticle gel holds significant clinical value for providing sustained release and justifies its practical application.

Population Pharmacokinetic and Pharmacodynamic Study of Palbociclib in Children and Young Adults with Recurrent, Progressive, or Refractory Brain Tumors

Population Pharmacokinetic and Pharmacodynamic Study of Palbociclib in Children and Young Adults with Recurrent, Progressive, or Refractory Brain Tumors

Alternatives to Injectable Adrenaline for Treating Anaphylaxis.

Adrenaline is the first line treatment for anaphylaxis and adrenaline auto-injectors (AAI) allow reliable, safe and ergonomic administration in the community. However, AAIs have significant limitations and adrenaline is often not used in anaphylaxis. Innovations to administer adrenaline via alternative routes may potentially improve usage rates and treatment effectiveness. Here, we describe the known limitations and barriers to AAI use in anaphylaxis. We then summarise current data for adrenaline devices which use alternative routes of administration for treating anaphylaxis. Several novel devices are in development, which deliver adrenaline via nasal, sublingual or transcutaneous routes. Pharmacokinetic, pharmacodynamic and safety studies have compared these treatments with AAI or intramuscular adrenaline via needle and syringe. The first non-injectable adrenaline delivery device for emergency treatment of anaphylaxis was approved in Europe and the United States. Neffy, an adrenaline nasal spray, is licensed for use in adult and paediatric patients who weigh at least 30 kg. In the near future, multiple alternatives to injectable adrenaline may be available for managing anaphylaxis, overcoming some, but not all of the limitations of AAIs.

Phase Ib pharmacodynamic study of the MNK inhibitor Tomivosertib (eFT508) combined with paclitaxel in patients with refractory metastatic breast cancer.

Preclinical data motivate clinical evaluation of inhibitors of mitogen-activated protein kinase-interacting kinases 1 and 2 (MNK1/2). We conducted a phase 1b clinical trial to study target engagement and safety of tomivosertib, a MNK1/2 inhibitor, alone and in combination with paclitaxel. Eligible patients had metastatic breast cancer resistant to standard of care treatments. Biopsies were obtained at baseline and during treatment with tomivosertib, and then tomivosertib was continued with addition of paclitaxel until disease progression or toxicity. Serum drug levels were measured, and pharmacodynamic endpoints included immunohistochemistry, proteomics, translatomics, and imaging mass cytometry. Tomivosertib alone and in combination with paclitaxel was well tolerated. There was no pharmacokinetic interaction between the drugs. We observed a clear reduction in phosphorylation of eIF4E at S209, a major substrate of MNK1/2, and identified tomivosertib-induced perturbations in the proteome, translatome, and cellular populations of biopsied metastatic breast cancer tissue. We conclude that tomivosertib effectively inhibits MNK1/2 activity in metastatic breast cancer tissue, and that it can safely be combined with paclitaxel in future phase II studies. We demonstrate feasibility of using proteomic profiles, translatomic profiles, and spatial distribution of immune cell infiltrates for clinical pharmacodynamic studies.

Aberrant activation of wound healing programs within the metastatic niche facilitates lung colonization by osteosarcoma cells.

Lung metastasis is responsible for most deaths caused by osteosarcoma. How malignant bone cells coerce the lung microenvironment to support metastatic growth remains unclear. We sought to identify metastasis-specific therapeutic vulnerabilities by delineating the cellular and molecular mechanisms essential to metastatic niche formation in the lung. We used single-cell transcriptomics (scRNA-seq) to characterize molecular changes induced within lung tissues by disseminated osteosarcoma cells. We then evaluated the ability of nintedanib to reverse metastasis-specific changes in both immunocompetent mouse and immunodeficient xenograft models. Molecular pharmacodynamic studies used single-nucleus and spatial transcriptomics to define the tumor-intrinsic and -extrinsic changes induced by the drug. Osteosarcoma cells induced acute alveolar epithelial injury upon lung dissemination. scRNA-seq demonstrated that the surrounding lung stroma adopts a chronic, non-resolving wound-healing phenotype similar to diseases associated with lung injury. Accordingly, metastasis-associated lung demonstrated marked fibrosis, likely due to the accumulation of pathogenic, pro-fibrotic, partially differentiated epithelial intermediates and macrophages. Our data suggested that nintedanib prevented metastatic progression in multiple murine and human xenograft models by inhibiting osteosarcoma-induced fibrosis. Fibrosis is essential to osteosarcoma lung metastasis and represents a targetable vulnerability. Our data support a model where interactions between osteosarcoma and epithelial cells induce the deposition of extracellular matrix proteins-a reaction disrupted by the anti-fibrotic TKI nintedanib. Our data shed light on the non-cell autonomous effects of TKIs on metastasis and provide a roadmap for using single-cell and spatial transcriptomics to define the mechanism of action of TKIs on metastases in animal models.

Targeting glutamine synthetase with AS1411-modified exosome-liposome hybrid nanoparticles for inhibition of choroidal neovascularization

Choroidal neovascularization (CNV) is a leading cause of visual impairment in wet age-related macular degeneration (wAMD). Recent investigations have validated the potential of reducing glutamine synthetase (GS) to inhibit neovascularization formation, offering prospects for treating various neovascularization-related diseases. In this study, we devised a CRISPR/Cas9 delivery system employing the nucleic acid aptamer AS1411 as a targeting moiety and exosome-liposome hybrid nanoparticles as carriers (CAELN). Exploiting the binding affinity between AS1411 and nucleolin on endothelial cell surfaces, the delivery system was engineered to specifically target the glutamine synthetase gene (GLUL), thereby attenuating GS levels and continuously suppressing CNV. CAELN exhibited spherical and uniform dispersion. In vitro cellular investigations demonstrated gene editing efficiencies of CAELN ranging from 42.05 to 55.02% and its capacity to inhibit neovascularization in HUVEC cells. Moreover, in vivo pharmacodynamic studies conducted in CNV rabbits revealed efficacy of CAELN in restoring the thickness of intra- and extranuclear tissues. The findings suggest that GS is a novel target for the inhibition of pathological CNV, while the development of AS1411-modified exosome-liposome hybrid nanoparticles represents a novel delivery method for the treatment of neovascular-related diseases.

Phase Ib clinical and pharmacodynamic study of the TIE2 kinase inhibitor rebastinib with paclitaxel or eribulin in HER2-negative metastatic breast cancer.

Breast cancer cells disseminate to distant sites via Tumor Microenvironment of Metastasis (TMEM) doorways. The TIE2 inhibitor rebastinib blocks TMEM doorway function in the PyMT mouse model of breast cancer. We aimed to assess the safety and pharmacodynamics of rebastinib plus paclitaxel or eribulin in patients with HER2-negative metastatic breast cancer (MBC). This phase Ib trial enrolled 27 patients with MBC who received 50 mg or 100 mg of rebastinib PO BID in combination with weekly paclitaxel 80 mg/m2 (if ≤ 2 prior non-taxane regimens) or eribulin 1.4 mg/m2 on days 1 & 8 (if ≥ 1 prior regimen). Safety, tolerability and pharmacodynamic parameters indicating TIE2 kinase inhibition and TMEM doorway function were evaluated. No dose-limiting toxicities in cycle 1 or 2 were observed among the first 12 patients at either rebastinib dose level. The most common treatment-emergent adverse events (AEs) were anemia (85%), fatigue (78%), anorexia (67%), leukopenia (67%), increased alanine aminotransferase (59%), hyperglycemia (56%), nausea (52%), and neutropenia (52%). AEs attributed to rebastinib include muscular weakness and myalgias. Intraocular pressure increased at the 100 mg rebastinib dose level, whereas angiopoietin-2 levels increased at both dose levels, providing pharmacodynamic evidence for TIE2 blockade. Circulating tumor cells decreased significantly with the combined treatment. Objective response occurred in 5/23 (22%) evaluable patients. In patients with MBC, the recommended phase 2 dose of rebastinib associated with pharmacodynamic evidence of TIE2 inhibition is either 50 or 100 mg PO BID in combination with paclitaxel or eribulin.

DDDR-04. PRECLINICAL INVESTIGATION OF A NOVEL BRAIN PENETRANT COMBINATION THERAPY TARGETING RAF AND MEK FOR MELANOMA BRAIN METASTASIS

Abstract INTRODUCTION Up to 75% of patients with advanced melanoma develop brain metastases. BRAF mutations are found in 50-55% of melanoma brain metastases. Current BRAF/MEK inhibitors, such as dabrafenib and vemurafenib, have shown responses on the order of 50-60% in patients with BRAF-mutant melanoma; however, responses are not durable. Better therapies are needed with improved penetration of the blood brain barrier. This study aims to evaluate the efficacy of two novel brain-penetrant inhibitors, KIN-7136 (MEK inhibitor) and KIN-8391 (RAF inhibitor), in preclinical mouse models of melanoma brain metastases driven by aberrant BRAF-MEK signaling. METHODS CellTiter-Glo® 2.0 Cell Viability Assay (Promega) was used for in vitro cell viability assays. Intracranial A375 melanoma models were generated in athymic nude mice to assess the pharmacodynamics, safety, and efficacy of combination therapy of KIN-7136 and KIN-8391. RESULTS In mice, the brain-to-plasma unbound partition coefficients (Kpuu) of KIN-7136 and KIN-8391 were 0.67 and 0.7 respectively, higher than the comparators binimetinib and belvarafenib, demonstrating improved brain exposure. The IC50s of KIN-7136/ KIN-8391 in melanoma cell lines were 27.0/36.5 nM in A375 (BRAF V600E), 78.6/35.4 nM in HMV2 (BRAF G469V), 183.0/699.0 nM in SK-MEL-2 (NRAS Q61R), and 53.9/110.0 nM in SK-MEL30 (BRAF D287H and E275K), respectively. KIN-7136 and KIN-8391 synergistically inhibited HMV2, SK-MEL-2, and SK-MEL-30 cells. Pharmacodynamic studies showed that both KIN-7136 and KIN-8391 suppressed phospho-ERK, a downstream component of BRAF-MEK signaling, in A375 xenografts in mice. Daily oral treatment with a combination of KIN-7136 and KIN-8391 was well-tolerated and extended overall survival to 64 days (median survival), compared to the vehicle control and monotherapies with KIN-7136 or KIN-8391 (28, 58, and 46.5, respectively) in the A375 intracranial tumor model. CONCLUSION These preclinical data confirm the synergistic effect of KIN-7136 and KIN-8391 in BRAF-mutant melanoma brain metastases models, supporting further research to advance its clinical translation.

Nanoformulations Insights: A Novel Paradigm for Antifungal Therapies and Future Perspectives.

Currently, fungal infections are becoming more prevalent worldwide. Subsequently, many antifungal agents are available to cure diseases like pemphigus, athlete's foot, acne, psoriasis, hyperpigmentation, albinism, and skin cancer. Still, they fall short due to pitfalls in physiochemical properties. Conventional medications like lotion, creams, ointments, poultices, and gels are available for antifungal therapy but present many shortcomings. They are associated with drug retention and poor penetration problems, resulting in drug resistance, hypersensitivity, and diminished efficacy. On the contrary, nanoformulations have gained tremendous potential in overcoming the drawbacks of conventional delivery. Furthermore, the potential breakthroughs of nanoformulations are site-specific targeting. It has improved bioavailability, patient-tailored approach, reduced drug retention and hypersensitivity, and improved skin penetration. Nowadays, nanoformulations are gaining popularity for antifungal therapy against superficial skin infections. Nanoformulations-based liposomes, niosomes, nanosponges, solid lipid nanoparticles, and potential applications have been explored for antifungal therapy due to enhanced activity and reduced toxicity. Researchers are now more focused on developing patient-oriented target-based nano delivery to cover the lacunas of conventional treatment with higher immune stimulatory effects. Future direction involves the construction of novel nanotherapeutic devices, nanorobotics, and robust methods. In addition, for the preparations of nanoformulations for clinical studies, animal modeling solves the problems of antifungal therapy. This review describes insights into various superficial fungal skin infections and their potential applications, nanocarrier-based drug delivery, and mechanism of action. In addition, it focuses on regulatory considerations, pharmacokinetic and pharmacodynamic studies, clinical trials, patents, challenges, and future inputs for researchers to improve antifungal therapy.

Exposure Matching-Based Pediatric Dose Selection for Drugs with Renal Excretion - Lessons Learned from Pediatric Development of Direct Oral Anticoagulants.

The pediatric clinical development programs of the direct oral anticoagulants (DOACs) edoxaban, rivaroxaban, and dabigatran have recently been completed, with apixaban close to the finish line. One common pharmacokinetic (PK) characteristic of these four DOACs is that renal excretion contributes 27% or more in their elimination, resulting in age-dependent drug clearance in both pediatric and adult subjects. Several lessons have been learned from adult exposure matching and pediatric dose selection for DOACs. The main goal of this tutorial is to provide an informed perspective on pediatric dose selection for renally excreted drugs, using these four DOACs as case examples. This tutorial is organized into seven steps: (1) consideration of age-related differences in disease and response to treatment; (2) consideration of age-related differences in drug absorption, distribution, metabolism, and excretion; (3) selection of the reference adult population and exposure for pediatric exposure matching; (4) prediction of pediatric clearance and pediatric dose selection based on data from young adults; (5) conduct and design of efficient pediatric PK and pharmacodynamic (PD) studies that inform dose selection; (6) assessment of exposure matching and dose adjustment using population PK simulation; (7) evaluation of the need for dose adjustment in pediatric sub-populations.

Ravulizumab for adults with generalized myasthenia gravis: a plain language summary of three studies.

Generalized myasthenia gravis (often shortened to gMG) is a rare health condition that causes muscular weakness. This summary gives an overview of three published articles that report the results of research studies of a medicine called ravulizumab, a treatment approved for adults with gMG. These studies are: The CHAMPION MG study. The CHAMPION MG extension study. A study of how the body processes and responds to ravulizumab (known as pharmacokinetics and pharmacodynamics). These studies looked at how effective and safe ravulizumab is for people with gMG. Overall, participants with gMG who received ravulizumab showed a significant and rapid improvement in their muscle strength and ability to do daily activities. These improvements were sustained for up to 60weeks of treatment. Ravulizumab was well-tolerated overall, and no-one in the study had a meningococcal infection (a type of bacterial infection preventable with vaccination). Results from the pharmacokinetic and pharmacodynamic study support the use of ravulizumab every 8weeks to maintain improvements in gMG. Ravulizumab can be considered as a treatment option for adults with gMG who are appropriately protected against meningococcal infection before starting treatment. The drug, administered every 8weeks, improves muscle strength and daily performance. These positive effects have been observed to persist over a long period of time.

Population Pharmacokinetic/Pharmacodynamic Study of Linezolid in Hospital-Acquired Pneumonia Patients with Renal Insufficiency.

The optimal treatment strategy in patients with hospital-acquired pneumonia (HAP) due to Gram-positive bacteria and renal insufficiency remains challenging. The objective of this study was to compare the outcomes of linezolid versus teicoplanin in HAP patients with renal insufficiency and to explore optimal dosage strategy for linezolid. The retrospective study enrolled adult patients treated with intravenous linezolid or teicoplanin at Suzhou Municipal Hospital between July 2018 and August 2023. For the comparative pharmacodynamic study, effectiveness, safety and target attainment of trough concentration (Cmin) for teicoplanin versus linezolid treatment in HAP patients with document Gram-positive bacteria and renal insufficiency were compared. For the population pharmacokinetics (PPK) analyses, linezolid concentrations collected exclusively from HAP patients with renal insufficiency were used and the optimal dosage strategy was investigated using Monte Carlo simulations. Linezolid-treated patients had a higher bacterial eradication rate than teicoplanin-treated patients (88.5% vs 63.4%, P < 0.001). A higher proportion of patients in the linezolid group experienced at least one adverse reaction (42.0% vs 25.0%, P = 0.025). Significantly more supratherapeutic Cmin, less therapeutic Cmin were achieved in the linezolid group (adjusted P < 0.05). A total of 207 linezolid concentrations from 166 patients with renal insufficiency were available for the PPK analysis. Age and creatinine clearance (CrCL) were identified as significant covariates that influenced clearance. Simulations show that 300 mg q12h provide the optimal exposure in patients with a CrCL of 60 or 45 mL/min, and 200 mg q12h was recommended for patients with a CrCL of 30 or 15 mL/min. Linezolid-treated patients with HAP and renal insufficiency had higher bacterial eradication rates, supratherapeutic exposure and adverse reactions than teicoplanin-treated patients. Linezolid dose reduction in patients with renal insufficiency improved the probability of achieving optimal exposure.

Structure‐Based Computational Approach in Search of the Potent Molecules Targeting Phosphoglycerate Dehydrogenase (PHGDH) Enzyme for Cancer Treatment

AbstractThis work aims to target phosphoglycerate dehydrogenase (PHGDH), a promising druggable target, that is overexpressed in various types of cancer. A structure‐based approach was employed to identify novel inhibitors against the enzyme. A common five‐feature pharmacophore model (RRHDA) was constructed using the active site co‐crystalized ligands. These chemical features were responsible for showing inhibition. The generated models were subsequently subjected to the validation method using a test set, receiver‐operator characteristic analysis, enrichment factor, and Güner–Henry studies. The validated models were subjected to the screening of a dataset of natural compounds. The screened unique natural compounds (1795) were further selected for the interaction analysis and study of ligand binding affinity considering the effect of the hydrogen bonding and desolvation and hydrophobic interactions contribution to the binding. The natural compounds which exhibited good ligand binding efficiency were selected and further subjected to pharmacokinetics and pharmacodynamic study. The natural compounds which exhibited good ligand binding efficiency were selected and further subjected to pharmacokinetics and pharmacodynamic study. The finalized complexes were selected for the simulation studies and MM/PBSA‐based binding free energy calculations. This study expands the possibilities for the development of shortlisted molecules as novel anti‐cancer compounds.

Species Differences in Ezetimibe Glucuronidation.

Peclinical and clinical studies have revealed that ezetimibe, an approved cholesterol-absorption inhibitor, is rapidly and extensively metabolized to a more potent metabolite, ezetimibe glucuronide. Since different species are commonly used in the pharmacokinetic and pharmacodynamic studies of ezetimibe, it is essential to determine the species difference in glucuronidation of ezetimibe in order to accurately evaluate ezetimibe's pharmacokinetics and pharmacodynamics. The purpose of the study was to compare species differences in ezetimibe glucuronidation rates using intestinal microsomes from humans, rats, mice, monkeys, and dogs. Intestinal microsomes from different species were used to assess the ezetimibe glucuronidation rates. Multiple substrate concentrations at 0.5, 2, 5, 10, 20, 30, 40, and 50 µM were tested and fitted into the Michaelis-Menten model to determine the enzyme kinetic parameters. The results showed that the glucuronidation rates with these tested species were significantly different. Kinetic studies revealed that the maximum metabolic rate (Vmax) was higher in monkeys (3.87 ± 0.22 nmol/mg/min) than that in rat (2.40 ± 0.148 nmol/mg/min) and mouse (2.23 ± 0.10 nmol/mg/min), and then human (1.90 ± 0.08 nmol/mg/min) and dog (1.19 ± 0.06 nmol/mg/min). The CLint was an 8.17-fold difference among these species, following the order of mouse > dog > human > rat = monkey. The study revealed that the rate of ezetimibe glucuronidation in the intestine was different in different species and has an impact on ezetimibe glucuronidation in the intestine. When analyzing the pharmacodynamics, pharmacokinetics, or toxicology of ezetimibe using different models, these species differences must be taken into consideration.

Lymphatic targeting of cilnidipine by designing and developing a nanostructured lipid carrier drug delivery system

Objective The objective of current research is to design, develop, and optimize a cilnidipine (CLN) nanostructured lipid carrier (NLC)-based drug delivery system for the effective treatment of hypertension (HT). Significance Oral administration of CLN-loaded NLC (CLN NLC) containing glyceryl monostearate (GMS) as a solid and isopropyl myristate (IPM) as a liquid lipid may show remarkable lymphatic uptake through payer patches. Methods The emulsification probe sonication technique was used followed by optimization using 32 factorial designs. Results The optimized batch showed a mean particle size of 115.4 ± 0.22 nm with encapsulation efficiency of 98.32 ± 0.23%, polydispersity index (PDI) of 0.342 ± 0.03, and zeta potential (ZP, ζ) was −60.5 ± 0.24 which indicate excellent physical stability. In vitro studies showed a controlled release of CLN NLCs. Pharmacokinetics studies determined the C max of NLCs (373.47 ± 15.1) indicates 2.3-fold enhancement compared with plain drug (160.64 ± 7.63). Pharmacodynamic studies indicated that CLN NLCs were maintaining systolic blood pressure in a controlled manner without any signs of side effects. Conclusion CLN NLCs significantly improved lymphatic delivery and proved to be effective in the treatment and management of HT. It has been proved that CLN NLCs are found to be better than any traditional CLN dosage form due to enhancement in solubility, absorption, bioavailability, intestinal permeability, avoidance of first-pass metabolism, P-glycoprotein efflux and reduction in dose-related side effects, achievement of controlled and sustained release action.

Nonclinical Profile of PF-06952229 (MDV6058), a Novel TGFβRI/Activin Like Kinase 5 Inhibitor Supports Clinical Evaluation in Cancer.

The development of transforming growth factor βreceptor inhibitors (TGFβRi) as new medicines has been affected by cardiac valvulopathy and arteriopathy toxicity findings in nonclinical toxicology studies. PF-06952229 (MDV6058) selected using rational drug design is a potent and selective TGFβRI inhibitor with a relatively clean off-target selectivity profile and good pharmacokinetic properties across species. PF-06952229 inhibited clinically translatable phospho-SMAD2 biomarker (≥60%) in human and cynomolgus monkey peripheral blood mononuclear cells, as well as in mouse and rat splenocytes. Using an optimized, intermittent dosing schedule (7-day on/7-day off/cycle; 5 cycles), PF-06952229 demonstrated efficacy in a 63-day syngeneic MC38 colon carcinoma mouse model. In the pivotal repeat-dose toxicity studies (rat and cynomolgus monkey), PF-06952229 on an intermittent dosing schedule (5-day on/5-day off cycle; 5 cycles, 28 doses) showed no cardiac-related adverse findings. However, new toxicity findings related to PF-06952229 included reversible hepatocellular (hepatocyte necrosis with corresponding clinically monitorable transaminase increases) and lung (hemorrhage with mixed cell inflammation) findings at ≥ targeted projected clinical efficacious exposures. Furthermore, partially reversible cartilage hypertrophy (trachea and femur in rat; femur in monkey) and partially to fully reversible, clinically monitorable decreases in serum phosphorus and urinary phosphate at ≥ projected clinically efficacious exposures were observed. Given the integral role of TGFβ in endochondral bone formation, cartilage findings in toxicity studies have been observed with other TGFβRi classes of compounds. The favorable cumulative profile of PF-06952229 in biochemical, pharmacodynamic, pharmacokinetic, and nonclinical studies allowed for its evaluation in cancer patients using the intermittent dosing schedule (7-day on/7-day off) and careful protocol-defined monitoring. SIGNIFICANCE STATEMENT: Only a few TGFβRi have progressed for clinical evaluation due to adverse cardiac findings in pivotal nonclinical toxicity studies. The potential translations of such findings in patients are of major concern. Using a carefully optimized intermittent dosing schedule, PF-06952229 has demonstrated impressive pharmacological efficacy in the syngeneic MC38 colon carcinoma mouse model. Additionally, a nonclinical toxicology package without cardiovascular liabilities and generally monitorable toxicity profile has been completed. The compound presents an acceptable International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use S9-compliant profile for the intended-to-treat cancer patients.

Pharmacodynamic and Clinical Effects of Ginkgo Biloba Extract EGb 761 and Its Phytochemical Components in Alzheimer's Disease.

Extracts made from plants are complex mixtures of substances with varying compositions depending on the plant material and method of manufacture. This complexity makes it difficult for scientists and clinicians to interpret findings from pharmacological and clinical research. We performed a narrative review summarizing information on ginkgo biloba leaf extract, its composition, pharmacological data and clinical evidence supporting its administration for the treatment of Alzheimer's disease (AD). Medicinal products containing ginkgo biloba leaf extract which are manufactured in compliance with the requirements of the European Pharmacopoeia are approved as medicinal products for the treatment of dementia and related conditions by drug regulatory agencies in Europe, Asia and South America. As multicomponent mixtures, they may affect various targets in the pathogenesis of AD, the most common form of dementia. Pharmacodynamic studies demonstrate the effects of EGb 761 and individual constituents on various pathophysiological features of experimentally induced cognitive impairment and neurodegeneration that could contribute to its clinical efficacy. The safety and efficacy in the treatment of AD and cognitive decline has been studied in randomized, placebo-controlled clinical trials. Most of the studies that investigate the effects of ginkgo biloba extract (GbE) used the special extract EGb 761, which makes it the best-researched plant preparation worldwide. It is therefore the only herbal alternative to standard-of-care anti-dementia drugs. However, the mechanism of action has not been fully elucidated yet, and the clinical studies in AD show heterogeneity.

A tailored phytosomes based nose-to-brain drug delivery strategy: Silver bullet for Alzheimer's disease

With the aging of the population, the incidence of Alzheimer's disease (AD) has increased dramatically, causing severe medical, care, and economic burdens on society and families. The efficacy of rivastigmine hydrogen tartrate (RHT), the first-line clinical treatment, is severely limited by the complex and multiple pathogenesis of AD and low brain bioavailability caused by the blood-brain barrier (BBB). Confronting such two bottlenecks, the development of multi-target agents encapsulated BBB-bypassing drug delivery systems offer tremendous therapeutics possibilities for AD. In this study, a tailored phytosomes based nose-to-brain drug delivery system with appropriate plume was successfully designed and developed. On the one hand, Ginseng RG3-based phytosomes loaded with RHT was designed for the co-delivery of GRg3 and RHT, achieving the multi-target pharmacology for AD treatment. On the other hand, a tailored nose-to-brain drug delivery system was established for the satisfactory nose-to-brain delivery efficiency, avoiding the obstacle of BBB through bypassing it. In the pharmacodynamic study based on AD rat model, GRg3@RHT exhibited obviously synergic effect, effectively break the vicious cycle of AD progression, ultimately markedly ameliorating learning and memory ability as well as behavioral dysfunctions, and delaying the neurodegenerative process associated with AD. In addition, the strong correlation of viscosity-droplet size-plume geometry-olfactory deposition was also established, and further proved by the in vivo pharmacokinetic study, which is proposed to provide evidence to enhance nose-to-brain delivery efficiency. This study is anticipated to provide novel insights into AD treatment strategies while offering innovative ideas for drug delivery approaches targeting nervous system disorders.