Diminished Side Effects Research Articles

Synthesis, Molecular Docking Studies and Biological Evaluation of N-(α-Benzamido Cinnamoyl) Piperonal Hydrazones

Background: Nowadays, inflammation is recognized as the underlying cause of a number of diseases, but NSAIDs are the first drug of choice, having several side effects. Additionally, excessive cellular oxidative stress is often considered a major contributor to pathophysiological conditions, the development of cancer, and other diseases. Antimicrobial resistance is a global concern, hence, there is a critical need for the development of novel therapeutic agents to fight the emergence and increasing prevalence of resistant pathogens. This creates an initiation to introduce new molecules which act as efficient therapeutic agents with diminished side effects. Objective: As a part of our search for newer agents with enhanced activity profiles, it was planned to synthesize novel 2- (benzamido)-N-((benzo[d][1,3]dioxol-4-yl)methylene)-3-(substituted phenyl) acrylohydrazides and to investigate them for antiinflammatory, antioxidant, cytotoxic, antimicrobial activities. Furthermore, in silico studies were performed for title compounds to predict molecular properties, bioavailability, drug-likeness, and bioactivity scores, molecular docking studies were also performed against biological targets. Methods: The title compounds 1-14 were synthesized by nucleophilic addition of piperonal in ethanol, few drops of acetic acid to the intermediate 2-(benzamido)-3-(aryl)acrylohydrazides. The title compounds were tested for their antiinflammatory activity by in vivo carrageenan-induced rat paw edema method, in vitro COX-2 inhibition assay; in vitro cytotoxic activity evaluation by MTT assay; antioxidant activity by Lipid peroxidation, DPPH assay, Nitric Oxide scavenging assay and Hydrogen peroxide scavenging assay; and antimicrobial activity by cup plate method. Physicochemical properties and bioactive scores of title compounds were evaluated by in silico studies. Molecular docking studies were carried out for the title compounds against COX-2 (PDB: 5F19) and EGFR (PDB:1XKK). Results: Among the series, 4-Hydroxy-3,5-dimethoxy derivative (5) displayed good anti-inflammatory and antioxidant activities; Vanillinyl derivative (4) displayed good cytotoxicity and antimicrobial activity when compared to that of the respective standards. Compounds 5 & 4 also exhibited good docking scores with COX-2 and EGFR, respectively. All title compounds obeyed Lipinski’s rule of five and also exhibited acceptable molecular properties, drug-likeness properties, and moderate to good bioactivity scores in in silico studies. Conclusion: The study suggested that the title compounds showed notable pharmacological properties, could emerge as lead compounds, and be further explored as promising therapeutic agents.

Synthesis of Inonotus rickii metabolite-loaded chitosan nanoparticles and its biological activities

Inonotus rickii, a mushroom fungus classified as a Hyamenochetae, is commonly observed in the Western Ghats region of Maharashtra, India. The metabolites extracted from this mushroom exhibit various biological activities. On the other side, currently chitosan nanoparticles emerging as an effective nanocarrier for targeted treatments. Therefore in the present study nanoparticles from biopolymer chitosan loaded with I. rickii metabolites of different solvent extract were synthesized and their antioxidant, antibacterial and anticancer potential were evaluated. The synthesized NPs were spherical in shape, and the average size for pure chitosan nanoparticles (CHI-NPs) was 58.02 nm, I. rickii aqueous CHI-NPs (U2-Aq-CHI-NPs) 62.70 nm, I. rickii acetone CHI-NPs (U2-Ac-CHI-NPs) 17.11 nm, and I. rickii ethanol CHI-NPs (U2-Et-CHI-NPs) 27.05 nm. These I. rickii metabolite-loaded CHI-NPs exhibited antibacterial, antioxidant, and cytotoxic activities. The U2-Ac-CHI-NPs showed significant antibacterial actions against four bacterial strains such as E. coli, Bacillus cereus, Pseudomonas otitidis, and Chryseobacterium spp. It also showed significantly higher antioxidant activity (95.8±1.6 %). Moreover, a significant decrease in the cell viability of the HeLa cell line was noticed with a subsequent increase (1–1000 µg/mL) in the concentration of metabolite-loaded CHI-NPs. A U2-Aq-CHI-NPs lower concentration is also significant to decrease cell viability. The LC-MS analysis revealed the presence of different bioactive compounds like Hispolon, Inoscavins, Methyl inoscavins, and Phelligridins in all tested extracts of I. rickii supports the bioactivities. Therefore, the synergistic effect of I. rickii-derived metabolite-loaded CHI-NPs suggested a significant perspective for the targeted drug delivery-based treatment with diminished side effects.

Discovery of a mu-opioid receptor modulator that in combination with morphinan antagonists induces analgesia.

Morphinan antagonists, which block opioid effects at mu-opioid receptors, have been studied for their analgesic potential. Previous studies have suggested that these antagonists elicit analgesia with fewer adverse effects in the presence of the mutant mu-opioid receptor (MOR; S196A). However, introducing a mutant receptor for medical applications represents significant challenges. We hypothesize that binding a chemical compound to the MOR may elicit a comparable effect to the S196A mutation. Through high-throughput screening and structure-activity relationship studies, we identified a modulator, 4-(2-(4-fluorophenyl)-4-oxothiazolidin-3-yl)-3-methylbenzoic acid (BPRMU191), which confers agonistic properties to small-molecule morphinan antagonists, which induce G protein-dependent MOR activation. Co-application of BPRMU191 and morphinan antagonists resulted in MOR-dependent analgesia with diminished side effects, including gastrointestinal dysfunction, antinociceptive tolerance, and physical and psychological dependence. Combining BPRMU191 and morphinan antagonists could serve as a potential therapeutic strategy for severe pain with reduced adverse effects and provide an avenue for studying G protein-coupled receptor modulation.

Synthesis of Estrone Heterodimers and Evaluation of Their In Vitro Antiproliferative Activity.

Directed structural modifications of natural products offer excellent opportunities to develop selectively acting drug candidates. Natural product hybrids represent a particular compound group. The components of hybrids constructed from different molecular entities may result in synergic action with diminished side effects. Steroidal homo- or heterodimers deserve special attention owing to their potentially high anticancer effect. Inspired by our recently described antiproliferative core-modified estrone derivatives, here, we combined them into heterodimers via Cu(I)-catalyzed azide-alkyne cycloaddition reactions. The two trans-16-azido-3-(O-benzyl)-17-hydroxy-13α-estrone derivatives were reacted with 3-O-propargyl-D-secoestrone alcohol or oxime. The antiproliferative activities of the four newly synthesized dimers were evaluated against a panel of human adherent gynecological cancer cell lines (cervical: Hela, SiHa, C33A; breast: MCF-7, T47D, MDA-MB-231, MDA-MB-361; ovarian: A2780). One heterodimer (12) exerted substantial antiproliferative activity against all investigated cell lines in the submicromolar or low micromolar range. A pronounced proapoptotic effect was observed by fluorescent double staining and flow cytometry on three cervical cell lines. Additionally, cell cycle blockade in the G2/M phase was detected, which might be a consequence of the effect of the dimer on tubulin polymerization. Computational calculations on the taxoid binding site of tubulin revealed potential binding of both steroidal building blocks, mainly with hydrophobic interactions and water bridges.

PHARMACOLOGICAL INVESTIGATION IN ANTICANCER AND ANTIOXIDANT PROPERTY OF CHRYSANTHEMUM MORIFOLIUM RAMAT.

Chrysanthemum morifolium Ramat., commonly referred to as the decorative chrysanthemum or simply mum, has served ornamental and therapeutic objectives historically. Traditionally employed to assuage inflammation, fever, and hypertension, modern exploration has paid particular focus to its conceivable function as an antineoplastic and antioxidant ingredient. Its bioactive mixtures, incorporating flavonoids and polyphenols, have proven potential in discouraging malignant cell proliferation, stimulating apoptosis, and bettering antioxidant safeguards.Various tactics were utilized in the research to investigate CM's pharmacological impacts. Plant extracts were ready using methanol, and their cytotoxicity was evaluated using cell viability assays (MTT, Crystal Violet, Trypan Blue). IC50 values were calculated for HeLa and HepG2 cancerous cell lines. Moreover, antioxidant properties were assessed using catalase (CAT), ascorbate peroxidase (APOX), and glutathione reductase (GSH) assays. Enzyme-linked immunosorbent assays (ELISA) measured fluctuations in p53 and VEGF levels. CM revealed dose-dependently cytotoxic impacts against HeLa and HepG2 cells, with notably reductions in cell viability and heightened cell death seen at elevated concentrations. IC50 values indicated powerful antineoplastic action while sparing noncancerous 3T3 cells. Antioxidant assays uncovered enhanced CAT, APOX, and GSH activities in cancerous cells treated with CM, proposing a role in oxidative stress supervision.Chrysanthemum morifolium Ramat. puts forth encouraging anticancer properties through selective cytotoxicity and apoptotic induction in cancerous cells, backed by heightened antioxidant defenses. Its safety profile in normal cells emphasizes its potential as a therapeutic agent with diminished side effects. However, further exploration is necessary to elucidate the underlying molecular mechanisms and validate its efficacy in animal models and clinical trials. These discoveries underscore CM as a candidate for developing targeted cancer therapies and enhancing overall human health.

All-Hydrocarbon Stapled Peptide Multifunctional Agonists at Opioid and Neuropeptide FF Receptors: Highly Potent, Long-Lasting Brain Permeant Analgesics with Diminished Side Effects.

Our previous study reported the multifunctional agonist for opioid and neuropeptide FF receptors DN-9, along with its cyclic peptide analogues c[D-Cys2, Cys5]-DN-9 and c[D-Lys2, Asp5]-DN-9. These analogues demonstrated potent antinociceptive effects with reduced opioid-related side effects. To develop more stable and effective analgesics, we designed, synthesized, and evaluated seven hydrocarbon-stapled cyclic peptides based on DN-9. In vitro calcium mobilization assays revealed that most of the stapled peptides, except 3, displayed multifunctional agonistic activities at opioid and neuropeptide FF receptors. Subcutaneous administration of all stapled peptides resulted in effective and long-lasting antinociceptive activities lasting up to 360 min. Among these stapled peptides, 1a and 1b emerged as the optimized compounds, producing potent central antinociception following subcutaneous, intracerebroventricular, and oral administrations. Additionally, subcutaneous administration of 1a and 1b caused nontolerance antinociception, with limited occurrence of constipation and addiction. Furthermore, 1a was selected as the final optimized compound due to its wider safety window compared to 1b.

Integrin Facilitates the Internalization of TAT Peptide Conjugated to RGD Motif in Model Lipid Membranes.

In recent years, targeted drug delivery has attracted a great interest for enhanced therapeutic efficiency, with diminished side effects, especially in cancer therapy. Cell penetrating peptides (CPPs) like HIV1-TAT peptides, appear to be the perfect vectors for translocating drugs or other cargoes across the plasma membrane, but their application is limited mostly due to insufficient specificity for intended targets. Although these molecules were successfully used, the mechanism by which the peptides enter the cell interior still needs to be clarified. The tripeptide motif RGD (arginine-glycine-aspartate), found in extracellular matrix proteins has high affinity for integrin receptors overexpressed in cancer and it is involved in different phases of disease progression, including proliferation, invasion and migration. Discovery of new peptides with high binding affinity for disease receptors and permeability of plasma membranes is desirable for both, development of targeted drug delivery systems and early detection and diagnosis. To complement the TAT peptide with specific targeting ability, we conjugated it with an integrin-binding RGD motif. Although the idea of RGD-CPPs conjugates is not entirely new,[1] here we describe the permeability abilities and specificity of integrin receptors of RGD-TAT peptides in model membranes. Our findings reveal that this novel RGD sequence based on TAT peptide maintains its ability to permeate lipid membranes and exhibits specificity for integrin receptors embedded in giant unilamellar vesicles. This promising outcome suggests that the RGD-TAT peptide has significant potential for applications in the field of targeted drug delivery systems.

Treatment modalities for infantile spasms: current considerations and evolving strategies in clinical practice.

Infantile spasms, newly classified as infantile epileptic spasm syndrome (IESS), occur in children under 2 years of age and present as an occur as brief, symmetrical, contractions of the musculature of the neck, trunk, and extremities. When infantile spasms occur with a concomitant hypsarrhythmia on electroencephalogram (EEG) and developmental regression, it is known as West Syndrome. There is no universally accepted mainstay of treatment for this condition, but some options include synthetic adrenocorticotropic hormone (ACTH), repository corticotropin injection (RCI/Acthar Gel), corticosteroids, valproic acid, vigabatrin, and surgery. Without effective treatment, infantile spasms can cause an impairment of psychomotor development and/or cognitive and behavioral functions. The first-line treatment in the USA is ACTH related to high efficacy for cessation of infantile spasms long-term and low-cost profile. Acthar Gel is a repository corticotropin intramuscular injection that became FDA-approved for the treatment of IESS in 2010. Though it is believed that ACTH, Acthar Gel, and corticosteroids all work via a negative feedback pathway to decrease corticotropin-releasing hormone (CRH) release, their safety and efficacy profiles all vary. Vigabatrin and valproic acid are both anti-seizure medications that work by increasing GABA concentrations in the CNS and decreasing excitatory activity. Acthar Gel has been shown to have superior efficacy and a diminished side effect profile when compared with other treatment modalities.

Modification of N-hydroxycytidine yields a novel lead compound exhibiting activity against the Venezuelan equine encephalitis virus

Nucleoside and nucleobase analogs capable of interfering with nucleic acid synthesis have played essential roles in fighting infectious diseases. However, many of these agents are associated with important and potentially lethal off-target intracellular effects that limit their use. Based on the previous discovery of base-modified 2′-deoxyuridines, which showed high anticancer activity while exhibiting lower toxicity toward rapidly dividing normal human cells compared to antimetabolite chemotherapeutics, we hypothesized that a similar modification of the N4-hydroxycytidine (NHC) molecule would provide novel antiviral compounds with diminished side effects. This presumption is due to the substantial structural difference with natural cytidine leading to less recognizability by host cell enzymes. Among the 42 antimetabolite species that have been synthesized and screened against VEEV, one hit compound was identified. The structural features of the modifying moiety were similar to those of the anticancer lead 2′-deoxyuridine derivative reported previously, providing an opportunity to pursue further structure–activity relationship (SAR) studies directed to lead improvement, and obtain insight into the mechanism of action, which can lead to identifying drug candidates against a broad spectrum of RNA viral infections.

Orally Administered Amphotericin B Nanoformulations: Physical Properties of Nanoparticle Carriers on Bioavailability and Clinical Relevance.

Amphotericin B is an effective polyene antifungal considered as a “gold standard” in the management of fungal infections. Currently, it is administered mainly by IV due to poor aqueous solubility, which precludes its delivery orally. Paradoxically, IV administration is akin to side effects that have not been fully eliminated even with more recent IV formulations. Thus, the need for alternative formulations/route of administration for amphotericin B remains crucial. The oral route offers the possibility of delivering amphotericin B systemically and with diminished side effects; however, enterocyte permeation remains a constraint. Cellular phagocytosis of submicron particles can be used to courier encapsulated drugs. In this regard, nanoparticulate delivery systems have received much attention in the past decade. This review examines the trajectory of orally delivered amphotericin B and discusses key physical factors of nanoformulations that impact bioavailability. The review also explores obstacles that remain and gives a window into the possibility of realizing an oral nanoformulation of amphotericin B in the near future.

Physicochemical Insights on Terahertz Wave Diminished Side Effects of Drugs from Slow Dissociation.

Dopamine D2 receptors (D2Rs) are one of the most intensely investigated and well-established drug targets for neuropsychiatric disorders. Selective D2R antagonists have been developed as efficacious antipsychotic drugs. Nevertheless, the potent drugs with necessarily high affinity are prone to slow dissociation, which invokes a plethora of severe side effects such as extrapyramidal symptoms, substantial weight gain, associated diabetes, etc. This has become a major barrier in treating psychiatric patients. In this work, we propose a physical method, terahertz wave modulation, to promote the dissociation of high-affinity antipsychotics and thus diminish the side effects. We have proven that a 4.0 THz wave could reduce the affinity by 71% between the D2R and a risperidone ligand and meanwhile expand the exit via conformation modulation, which promises an accelerated dissociation of risperidone. In addition, it is estimated that the enhancement of the dissociation rate due to lowered binding by terahertz irritation could constitute up to 8 orders of magnitude, which is fairly impressive and resembles the enzyme's catalysis. Also, acceleration of the dissociation rate could be adjusted by the irritation strength. This work elaborates the terahertz wave-modulated noncovalent interactions critical in cell signaling pathways. Most importantly, it demonstrates the feasibility of terahertz technologies intervening in receptor-ligand complex regulated diseases such as neurodegenerative disorders, metabolic diseases, etc.

New techniques of regional anaesthesia for renal laparoscopic surgeries.

Renal procedures are performed within the realm of urology, general and transplant surgery. The implementation of new operating techniques imposes on anaesthetists the need to adapt their methods, aiming to improve the patient's perioperative comfort and safety. Laparoscopy is gaining increasing interest as a less invasive procedure; however clinical research shows that pain after the procedure is underestimated and therefore poorly controlled. Multimodal analgesia is very promising, though, as it allows better pain control, expedites discharge and enhances recovery. This is achieved through a combination of general and regional anaesthesia with administration of adjuvant drugs intraoperatively, resulting in reduced opioid requirements in the recovery room with diminished side effects of pain treatment. Good communication between the surgeon and the anaesthetist is the key to effective anaesthesia and analgesia.

Comparison of an Addictive Potential of μ-Opioid Receptor Agonists with G Protein Bias: Behavioral and Molecular Modeling Studies.

Among different approaches to the search for novel—safer and less addictive—opioid analgesics, biased agonism has received the most attention in recent years. Some μ-opioid receptor agonists with G protein bias, including SR compounds, were proposed to induce diminished side effects. However, in many aspects, behavioral effects of those compounds, as well as the mechanisms underlying differences in their action, remain unexplored. Here, we aimed to evaluate the effects of SR-14968 and SR-17018, highly G protein-biased opioid agonists, on antinociception, motor activity and addiction-like behaviors in C57BL/6J mice. The obtained results showed that the compounds induce strong and dose-dependent antinociception. SR-14968 causes high, and SR-17018 much lower, locomotor activity. Both agonists develop reward-associated behavior and physical dependence. The compounds also cause antinociceptive tolerance, however, developing more slowly when compared to morphine. Interestingly, SR compounds, in particular SR-17018, slow down the development of antinociceptive tolerance to morphine and inhibit some symptoms of morphine withdrawal. Therefore, our results indicate that SR agonists possess rewarding and addictive properties, but can positively modulate some symptoms of morphine dependence. Next, we have compared behavioral effects of SR-compounds and PZM21 and searched for a relationship to the substantial differences in molecular interactions that these compounds form with the µ-opioid receptor.

Development of Multifunctional and Orally Active Cyclic Peptide Agonists of Opioid/Neuropeptide FF Receptors that Produce Potent, Long-Lasting, and Peripherally Restricted Antinociception with Diminished Side Effects.

We previously reported that a multifunctional opioid/neuropeptide FF receptor agonist, DN-9, achieved peripherally restricted analgesia with reduced side effects. To develop stable and orally bioavailable analogues of DN-9, eight lactam-bridged cyclic analogues of DN-9 between positions 2 and 5 were designed, synthesized, and biologically evaluated. In vitro cAMP assays revealed that these analogues, except 7, were multifunctional ligands that activated opioid and neuropeptide FF receptors. Analogue 1 exhibited improved potency for κ-opioid and NPFF2 receptors. All analogues exhibited potent, long-lasting, and peripherally restricted antinociception in the tail-flick test without tolerance development after subcutaneous administration and produced oral analgesia. Oral administration of the optimized compound analogue 1 exhibited powerful, peripherally restricted antinociceptive effects in mouse models of acute, inflammatory, and neuropathic pain. Remarkably, orally administered analogue 1 had no significant side effects, such as tolerance, dependence, constipation, or respiratory depression, at effective analgesic doses.

Natural COX-2 Inhibitors as Promising Anti-inflammatory Agents: An Update

COX-2, a key enzyme that catalyzed the rate-limiting steps in the conversion of arachidonic acid to prostaglandins, played a pivotal role in the inflammatory process. Different from other family members, COX-2 was barely detectable in normal physiological conditions and highly inducible during the acute inflammatory response of human bodies to injuries or infections. Therefore, the therapeutic utilization of selective COX-2 inhibitors has already been considered as an effective approach for the treatment of inflammation with diminished side effects. Currently, both traditional and newer NSAIDs are the commonly prescribed medications that treat inflammatory diseases by targeting COX-2. However, due to the cardiovascular side-effects of the NSAIDs, finding reasonable alternatives for these frequently prescribed medicines are a hot spot in medicinal chemistry research. Naturallyoccurring compounds have been reported to inhibit COX-2, thereby possessing beneficial effects against inflammation and certain cell injury. The review mainly concentrated on recently identified natural products and derivatives as COX-2 inhibitors, the characteristics of their structural core scaffolds, their anti-inflammatory effects, molecular mechanisms for enzymatic inhibition, and related structure-activity relationships. According to the structural features, the natural COX-2 inhibitors were mainly divided into the following categories: natural phenols, flavonoids, stilbenes, terpenoids, quinones, and alkaloids. Apart from the anti-inflammatory activities, a few dietary COX-2 inhibitors from nature origin also exhibited chemopreventive effects by targeting COX-2-mediated carcinogenesis. The utilization of these natural remedies in future cancer prevention was also discussed. In all, the survey on the characterized COX-2 inhibitors from natural sources paves the way for the further development of more potent and selective COX-2 inhibitors in the future.

Progress in the development of human carbonic anhydraseinhibitors and their pharmacological applications: Where are we today?

Carbonic anhydrases (CAs, EC 4.2.1.1) are widely distributed metalloenzymes in both prokaryotes and eukaryotes. They efficiently catalyze the reversible hydration of carbon dioxide to bicarbonate and H+ ions and play a crucial role in regulating many physiological processes. CAs are well-studied drug target for various disorders such as glaucoma, epilepsy, sleep apnea, and high altitude sickness. In the past decades, a large category of diverse families of CA inhibitors (CAIs) have been developed and many of them showed effective inhibition towardspecific isoforms, and effectiveness in pathological conditions in preclinical and clinical settings. The discovery of isoform-selective CAIs in the last decade led to diminished side effects associated with off-target isoforms inhibition. The many new classes of such compounds will be discussed in the review, together with strategies for their development. Pharmacological advances of the newly emerged CAIs in diseases not usually associated with CA inhibition (neuropathic pain, arthritis, cerebral ischemia, and cancer) will also be discussed.

Current and Emerging Methods of Management of Ependymoma.

This review discusses the evidence base behind current and emerging strategies of management of intracranial and spinal ependymomas in children, with a particular focus on aspects of surgical techniques, challenges and complications. The cornerstone of management remains maximal safe resective surgery, which has repeatedly been shown to correlate with improved survival. This is followed by focal conformal radiotherapy, although good results using proton beam therapy, with the potential for diminished side effects, are emerging. The role of chemotherapy remains largely unproven for paediatric ependymoma. Despite optimal management strategies, many children with ependymoma suffer from tumour recurrence. The standard of care for paediatric ependymoma comprises surgery and radiotherapy. Results of ongoing clinical trials will help shape its management in order to leverage our increasingly sophisticated understanding of the genetic drivers behind these tumours into survival benefit for this challenging group of patients.

Positive allosteric modulators of nonbenzodiazepine γ-aminobutyric acidA receptor subtypes for the treatment of chronic pain.

Chronic neuropathic pain may be caused, in part, by loss of inhibition in spinal pain processing pathways due to attenuation of local GABAergic tone. Nociception and nocifensive behaviors are reduced after enhancement of tonically activated extrasynaptic GABAAR-mediated currents by agonist ligands for δ subunit-containing GABAARs. However, typical ligands that target δ subunit-containing GABAARs are limited due to sedative effects at higher doses. We used the spinal nerve ligation (SNL) and gp120 models of experimental neuropathic pain to evaluate compound 2-261, a nonbenzodiazepine site positive allosteric modulator of α4β3δ GABAARs optimized to be nonsedative by selective activation of β2/3-subunit-containing GABAARs over receptor subtypes incorporating β1 subunits. Similar levels of 2-261 were detected in the brain and plasma after intraperitoneal administration. Although systemic 2-261 did not alter sensory thresholds in sham-operated animals, it significantly reversed SNL-induced thermal and tactile hypersensitivity in a GABAAR-dependent fashion. Intrathecal 2-261 produced conditioned place preference and elevated dopamine levels in the nucleus accumbens of nerve-injured, but not sham-operated, rats. In addition, systemic pretreatment with 2-261 blocked conditioned place preference from spinal clonidine in SNL rats. Moreover, 2-261 reversed thermal hyperalgesia and partially reversed tactile allodynia in the gp120 model of HIV-related neuropathic pain. The effects of 2-261 likely required interaction with the α4β3δ GABAAR because 2-301, a close structural analog of 2-261 with limited extrasynaptic receptor efficacy, was not active. Thus, 2-261 may produce pain relief with diminished side effects through selective modulation of β2/3-subunit-containing extrasynaptic GABAARs.

Ascorbic Acid Chemosensitizes Colorectal Cancer Cells and Synergistically Inhibits Tumor Growth.

Colorectal cancer (CRC) is continuously classified as one of the most incidental and mortal types of cancer worldwide. The positive outcomes of the conventional chemotherapy are frequently associated with high toxicity, which often leads to the suspension of the treatment. Growing evidences consider the use of pharmacological concentrations of ascorbic acid (AA), better known as vitamin C, in the treatment of cancer. The use of AA in a clinical context is essentially related to the adoption of new therapeutic strategies based on combination regimens, where AA plays a chemosensitizing role. The reduced sensitivity of some tumors to chemotherapy and the highly associated adverse effects continue to be some of the major obstacles in the effective treatment of CRC. So, this paper aimed to study the potential of a new therapeutic approach against this neoplasia with diminished side effects for the patient. This approach was based on the study of the combination of high concentrations of AA with reduced concentrations of drugs conventionally used in CRC patients and eligible for first and second line chemotherapeutic regimens, namely 5-fluorouracilo (5-FU), oxaliplatin (Oxa) or irinotecan (Iri). The evaluation of the potential synergy between the compounds was first assessed in vitro in three CRC cell lines with different genetic background and later in vivo using one xenograft animal model of CRC. AA and 5-FU act synergistically in vitro just for longer incubation times, however, in vivo showed no benefit compared to 5-FU alone. In contrast to the lack of synergy seen in in vitro studies with the combination of AA with irinotecan, the animal model revealed the therapeutic potential of this combination. AA also potentiated the effect of Oxa, since a synergistic effect was demonstrated, in almost all conditions and in the three cell lines. Moreover, this combined therapy (CT) caused a stagnation of the tumor growth rate, being the most promising tested combination. Pharmacological concentrations of AA increased the efficacy of Iri and Oxa against CRC, with promising results in cell lines with more aggressive phenotypes, namely, tumors with mutant or null P53 expression and tumors resistant to chemotherapy.

Validation of Smart Nanoparticles as Controlled Drug Delivery Systems: Loading and pH-Dependent Release of Pilocarpine.

Micelles are good devices for use as controlled drug delivery systems because they exhibit the ability to protect the encapsulated substance from the routes of degradation until they reach the site of action. The present work assesses loading kinetics of a hydrophobic drug, pilocarpine, in polymeric micellar nanoparticles (NPs) and its pH-dependent release in hydrophilic environments. The trigger pH stimulus, pH 5.5, was the value encountered in damaged tissues in solid tumors. The new nanoparticles were prepared from an amphiphilic block copolymer, [(HEMA19%-DMA31%)-(FMA5%-DEA45%)]. For the present research, three systems were validated, two of them with cross-linked cores and the other without chemical stabilization. A comparison of their loading kinetics and release profiles is discussed, with the support of additional data obtained by scanning electron microscopy and dynamic light scattering. The drug was loaded into the NPs within the first minutes; the load was dependent on the degree of cross-linking. All of the systems experienced a boost in drug release at acidic pH, ranging from 50 to 80% within the first 48 h. NPs with the highest degree (20%) of core cross-linking delivered the highest percentage of drug at fixed times. The studied systems exhibited fine-tuned sustained release features, which may provide a continuous delivery of the drug at specific acidic locations, thereby diminishing side effects and increasing therapeutic rates. Hence, the studied NPs proved to behave as smart controlled drug delivery systems capable of responding to changes in pH.