Current Research in Pharmacology and Drug Discovery最新文献

Neurodegeneration and synaptic loss in Alzheimer's disease (AD) lead to impairment in memory functions. Neuroinflammation causes activation of microglia and astrocytes cells that locally and systemically produces inflammatory cytokines which can serve as early diagnostic markers or therapeutic targets in AD. Pro-inflammatory cytokines (Interleukins (IL-1β, IL-6 and IL-10) and tumor necrosis factor (TNF α)) levels were estimated in serum, cerebral tissue, hepatic tissue, and renal tissue in treatment groups of scopolamine-induced amnesia mice model using ELISA protocol. The results showed that cerebral tissue of AD mice exhibited elevated levels of IL1β, IL6, IL10 and TNFα which indicate contribution of pro-inflammatory cytokines in the progression of AD. A significant reduction in the concentration of IL1β, IL-10 and TNF-α were noticed in serum, cerebral tissue and hepatic tissue of animal group treated with marketed memantine tablet (Admenta), pure memantine drug (MEMp), memantine-poly (lactic-co-glycolic acid) self-assembled nanoscaffolds (MEM-PLGA) SANs, Polyethylene Glycol coated memantine-poly (lactic-co-glycolic acid) self-assembled nanoscaffolds [(PEG-MEM-PLGA) SANs] and Polyethylene Glycol coated memantine-poly [(lactic-co-glycolic acid)] self-assembled nanoscaffolds grafted with Bone Marrow Derived Stem Cell ((PEG-MEM-PLGA) SANs-BMSc), whereas a high level of IL-6 was observed in hepatic tissue, cerebral tissue and renal tissues of normal and AD induced mice which showed the emerging potential of IL-6 cytokines that can trigger either neurons survival after injury or causing neurodegeneration and cell apoptosis. The Neuroregenerative potential of stem cells helps in the proliferation of neuronal cell and thus improves cognition in AD animal model.

Carnosine is a naturally occurring endogenous dipeptide composed by the ligation of β-alanine and L-histidine performed particularly by tissues with an increased oxidative metabolism such as muscles and brain. In the last 50 years different studies have assessed the role and function of carnosine through numerous in vitro, in vivo, and clinical studies, demonstrating the multimodal mechanism of action of this dipeptide that includes anti-aggregant, antioxidant, and anti-inflammatory activities. In particular its activity has been investigated in experimental models of cardiovascular disease (CVD), type 2 diabetes mellitus (T2DM), and neurodegenerative disorders, such as cerebral ischemia and Alzheimer's disease (AD). In the present review, we examined the protective role that carnosine could exert in the context of T2DM, CVD, and AD, which show common pathogenic mechanisms including oxidative stress, inflammation, and aggregation phenomena. Carnosine's pharmacodynamic profile is multimodal and combines the systemic anti-inflammatory and antioxidant activities with its anti-aggregant and neuroprotective efficacy in the central nervous system. This enlarged pharmacological activity opens a new path to explore the therapeutic potential of carnosine in all the three diseases, and in particular in patients with T2DM, who often show a history of CVD and also have an increased risk to develop mild cognitive impairment and AD.

α₁-Adrenergic Receptors (ARs) regulate the sympathetic nervous system by the binding of norepinephrine (NE) and epinephrine (Epi) through different subtypes (α_1A, α_1B, α_1D). α_1A-AR activation is hypothesized to be memory forming and cognitive enhancing but drug development has been stagnant due to unwanted side effects on blood pressure. We recently reported the pharmacological characterization of the first positive allosteric modulator (PAM) for the α_1A-AR with predictive pro-cognitive and memory properties. In this report, we now demonstrate the in vivo characteristics of Compound 3 (Cmpd-3) in two genetically-different Alzheimer’s Disease (AD) mouse models. Drug metabolism and pharmacokinetic studies indicate sufficient brain penetrance and rapid uptake into the brain with low to moderate clearance, and a favorable inhibition profile against the major cytochrome p450 enzymes. Oral administration of Cmpd-3 (3–9 mg/kg QD) can fully rescue long-term potentiation defects and AD biomarker profile (amyloid β-40, 42) within 3 months of dosing to levels that were non-significant from WT controls and which outperformed donepezil (1 mg/kg QD). There were also significant effects on paired pulse facilitation and cognitive behavior. Long-term and high-dose in vivo studies with Cmpd-3 revealed no effects on blood pressure. Our results suggest that Cmpd-3 can maintain lasting therapeutic levels and efficacy with disease modifying effects with a once per day dosing regimen in AD mouse models with no observed side effects.

The rationale for using thalidomide (THD) as a treatment for nausea and vomiting during pregnancy in the late 1950s appears to have been based on its sedative or hypnotic properties. In contrast to contemporaneous studies on the anti-emetic activity of phenothiazines, we were unable to identify publications reporting preclinical or clinical evaluation of THD as an anti-emetic. Our survey of the literature revealed a clinical study in 1965 showing THD reduced vomiting in cancer chemotherapy which was substantiated by similar studies from 2000, particularly showing efficacy in the delayed phase of chemotherapy-induced nausea and vomiting. To identify the mechanism(s) potentially involved in thalidomide's anti-emetic activity we reviewed its pharmacology in the light of nausea and vomiting mechanisms and their pharmacology with a particular emphasis on chemotherapy and pregnancy. The process identified the following potential mechanisms: reduced secretion of Growth Differentiation Factor 15, suppression of inflammation/prostaglandin production, downregulation of cytotoxic drug induced upregulation of iNOS, and modulation of BK (K_Ca1.1) channels and GABA_A/glutamate transmission at critical points in the emetic pathways (nucleus tractus solitarius, area postrema). We propose ways to investigate these hypothesized mechanisms and discuss the associated challenges (e.g., objective quantification of nausea) in addition to some of the more general aspects of developing novel drugs to treat nausea and vomiting.

Diabetes mellitus is a common disease affecting millions of people worldwide. This disease is not limited to metabolic disorders but also affects several vital organs in the body and can lead to major complications. People with diabetes mellitus are subjected to cardiovascular complications, such as cardiac myopathy, which can further result in major complications such as diabetes-induced cardiac failure. The mechanism underlying diabetes-induced cardiac failure requires further research; however, several contributing factors have been identified to function in tandem, such as reactive oxygen species production, inflammation, formation of advanced glycation end-products, altered substrate utilisation by mitochondria, activation of the renin–angiotensin–aldosterone system and lipotoxicity. Genetic factors such as microRNAs, long noncoding RNAs and circular RNAs, as well as epigenetic processes such as DNA methylation and histone modifications, also contribute to complications. These factors are potential targets for developing effective new therapies. This review article aims to facilitate in depth understanding of these contributing factors and provide insights into the correlation between diabetes mellitus and cardiovascular complications. Some alternative targets with therapeutic potential are discussed to indicate favourable targets for the management of diabetic cardiomyopathy.

Coronavirus disease (COVID-19) pandemic determined a 10 years-set back in tuberculosis (TB) control programs. Recent advances in available therapies may help recover the time lost. While Linezolid (LZD) and Bedaquiline (BDQ), previously Group D second line drugs (SLDs) for TB, have been relocated to Group A, other drugs are currently being studied in regimens for drug resistant TB (DR-TB). Among these, Pretomanid (PA), a recently introduced antimycobacterial drug derived from nitroimidazole with both solid bactericidal and bacteriostatic effect, and with an excellent effectiveness and tolerability profile, is in the spotlight. Following promising data obtained from recently published and ongoing randomized controlled trials (RCTs), the World Health Organization (WHO) determined to include PA in its guidelines for the treatment of rifampicin-resistant (RR), multi drug resistant (MDR) and pre-extensively drug resistant TB (pre-XDR-TB) with BDQ, LZD and Moxifloxacine (MFX) in a 6-month regimen. Although further studies on the subject are needed, PA may also represent a treatment option for drug-susceptible TB (DS-TB), latent TB infection (LTBI) and non tuberculous mycobacteria (NTM). This narrative review aims to examine current implementation options and future possibilities for PA in the never-ending fight against TB.

The rhizome of Microgramma vacciniifolia contains a lectin (carbohydrate-binding protein) called MvRL. Studies demonstrated that a MvRL-rich fraction did not show in vivo genotoxicity and acute toxicity in mice. This study aimed to evaluate the MvRL-rich fraction from M. vacciniifolia rhizome for antibacterial activity in vitro and in vivo as well as antitumor effect in vivo using the Ehrlich carcinoma model in mice. The fraction showed antibacterial activity against Acinetobacter baumannii, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Staphylococcus aureus with minimal inhibitory concentrations ranging from 31.2 to 125.0 ​μg/mL and minimal bactericidal concentrations from 62.5 to 200 ​μg/mL. The fraction was also effective in vivo against infection caused by these bacteria on Tenebrio molitor larvae considering the parameters evaluated. In regard to the antitumor activity, the treatments of Ehrlich carcinoma-bearing mice with the fraction at 100 and 200 ​mg/kg per os resulted in 62.58% and 75.43% of tumor inhibition, respectively. In conclusion, the MvRL-rich fraction showed in vivo antibacterial and antitumor activities and thus can be considered as an alternative of natural origin for the development of candidates for therapy.

The aim of the present study was to investigate the cytotoxicity induced by an omega-3 derivative, didocosahexaenoin (Dido) on human prostate carcinoma cells and to compare the cytotoxicity to that of docosahexaenoic acid (DHA). Different carcinoma- and non-carcinoma cells were exposed to various concentrations of omega-3 compounds at varying exposure times and the cytotoxicity was measured by MTT assay. The mechanism of Dido-induced apoptosis was investigated in prostate carcinoma cells. Dido induced stronger cytotoxicity than DHA in human prostate carcinoma cells in a dose- and time-dependent manner. Dido was also more selective and potent in inducing cytotoxicity in prostate carcinoma cells than other carcinoma cell lines tested. Pre-treatment with Dido increased the level of reactive oxygen species (ROS) in prostate carcinoma cells. Pre-treatment with various antioxidants reduced the cytotoxicity induced by Dido. Pre-treatment with Dido ≥30 ​μM also induced apoptosis which was suggested to involve an externalisation of phosphatidyl serine, a significant increase in the mitochondrial membrane potential (p ​< ​0.01) and the level of activated caspase 3/7 (p ​< ​0.05) in prostate carcinoma cells. This study is the first to show that Dido induced cytotoxicity with high selectivity and higher potency than DHA in human prostate carcinoma cells. The mechanism of action is likely to involve an increase in the level of ROS, loss in the mitochondrial membrane potential as well as externalisation of phosphatidyl serine and increase in the caspase 3/7 activity. Dido may have potential to be used for the adjuvant therapy or combination therapy with conventional chemotherapeutic drugs.

Within the IBD entity of Crohn's disease, there is currently no differentiation between ileal and colonic manifestation for recruitment of patients in clinical trials, well-powered analysis of study results or therapeutic decisions in daily clinical practice. However, there is accumulating evidence from epidemiological, genetic, microbial, immunological, and clinical characteristics that clearly indicate that ileal Crohn's disease represents a distinct disease entity, which differentiates itself from colonic Crohn's disease. This is also reflected by lower efficacy of targeted therapies in isolated ileal compared to colonic Crohn's disease. The distinct site-specific mechanisms that drive heightened non-response in ileal disease need to be analysed in-depth in the future, to enable optimized therapy in the individual Crohn's disease patient.

Diabetic retinopathy (DR) is a primary microvascular complication of diabetes mellitus and a vision-threatening condition. Vascular endothelial growth factor (VEGF) induces neovascularization and causes metabolic damage to the retinal and choroidal vasculature in diabetic patients. Existing drug screening models and treatment strategies for DR need to be refined through the establishment of relevant pre-clinical models, which may enable development of effective and safe therapies. The present study discusses the development of an in-vitro three-dimensional (3D) spheroid model, using RF/6A choroid-retinal vascular endothelial cells, to closely mimic the in-vivo disease condition. Compact, reproducibly-sized, viable and proliferating RF/6A spheroids were fabricated, as confirmed by microscopy, live/dead assay, cell proliferation assay and histological staining. In-vitro angiogenesis was studied by evaluating individual effects of VEGF and an anti-VEGF monoclonal antibody, Bevacizumab, and their combination on cellular proliferation and 3D endothelial sprout formation. VEGF stimulated angiogenic sprouting while Bevacizumab demonstrated a dose-dependent anti-angiogenic effect, as determined from the cellular proliferation observed and extent and length of sprouting. These investigations validated the potential of RF/6A spheroids in providing an alternative-to-animal, pathophysiologically-relevant model to facilitate pre-clinical and biomedical research related to DR.