Pharmaceuticals — Open Access Journal of Pharmaceutical Sciences

Many analgesics and their metabolites are renally excreted. The widely used Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI)-estimated glomerular filtration rate (eGFR) equations are not developed for use in the elderly, while the recent Berlin Initiative Study (BIS), Full Age Spectrum (FAS), and Lund-Malmö revised (LMR) equations are. This observational study investigated differences between creatinine-based eGFR equations and how the choice of equation influences dosage of analgesics in elderly (≥70 years) patients admitted with acute hip fracture. eGFR was calculated by the CKD-EPI, BIS, Cockcroft-Gault (CG), FAS, LMR, and Modification of Diet in Renal Disease (MDRD) equations. Standard daily dose for postoperative pain medications ibuprofen, morphine and gabapentin was simulated for each equation according to dosage recommendations in Renbase^®. For 118 patients, mean eGFR from the CKD-EPI, BIS, CG, FAS, LMR, and MDRD equations was 67.3 mL/min/1.73 m², 59.1 mL/min/1.73 m², 56.9 mL/min/1.73 m², 60.3 mL/min/1.73 m², 58.9 mL/min/1.73 m², and 79.1 mL/min/1.73 m², respectively (p < 0.0001). Mean difference to CKD-EPI was −10.4 mL/min/1.73 m² to 11.8 mL/min/1.73 m². Choice of eGFR equation significantly influenced the recommended dose (p < 0.0001). Shifting to BIS, FAS, or LMR equations led to a lower recommended dose in 20% to 31% of patients. Choice of eGFR equation significantly influenced dosing of ibuprofen, morphine, and gabapentin. Full article

Mitochondrial dysfunction has achieved an increasing interest in the field of neurodegeneration as a pathological hallmark for different disorders. The impact of mitochondria is related to a variety of mechanisms and several of them can co-exist in the same disease. The central role of mitochondria in neurodegenerative disorders has stimulated studies intended to implement therapeutic protocols based on the targeting of the distinct mitochondrial processes. The review summarizes the most relevant mechanisms by which mitochondria contribute to neurodegeneration, encompassing therapeutic approaches. Moreover, a new perspective is proposed based on the heme impact on neurodegeneration. The heme metabolism plays a central role in mitochondrial functions, and several evidences indicate that alterations of the heme metabolism are associated with neurodegenerative disorders. By reporting the body of knowledge on this topic, the review intends to stimulate future studies on the role of heme metabolism in neurodegeneration, envisioning innovative strategies in the struggle against neurodegenerative diseases. Full article

Cancer is the second leading cause of death worldwide. Researchers have been working hard on investigating not only improved therapeutics but also on early detection methods, both critical to increasing treatment efficacy, and developing methods for disease prevention. The use of nucleic acids, or aptamers, has emerged as more specific and accurate cancer diagnostic and therapeutic tools. Aptamers are single-stranded DNA or RNA molecules that recognize specific targets based on unique three-dimensional conformations. Despite the fact aptamer development has been mainly restricted to laboratory settings, the unique attributes of these molecules suggest their high potential for clinical advances in cancer detection. Aptamers can be selected for a wide range of targets, and also linked with an extensive variety of diagnostic agents, via physical or chemical conjugation, to improve previously-established detection methods or to be used as novel biosensors for cancer diagnosis. Consequently, herein we review the principal considerations and recent updates in cancer detection and imaging through aptamer-based molecules. Full article

Plasma non-transferrin-bound iron (NTBI) is potentially harmful due to the generation of free radicals that cause tissue damage in vascular and other diseases. Studies in iron-replete and iron-deficient subjects, receiving a single oral test dose of Fe(II)SO₄ or NaFe(III)EDTA with water, revealed that FeSO₄ was well absorbed when compared with NaFeEDTA, while only the Fe(II) compound showed a remarkable increase of NTBI. As NaFeEDTA is successfully used for food fortification, a double-blind randomized cross-over trial was conducted in 11 healthy women with uncomplicated iron deficiency. All subjects received a placebo, 6.5 mg FeSO₄, 65 mg FeSO₄, 6.5 mg NaFeEDTA, and 65 mg NaFeEDTA with a traditional Indonesian breakfast in one-week intervals. Blood tests were carried out every 60 min for five hours. NTBI detection was performed using the fluorescein-labeled apotransferrin method. Plasma iron values were highly increased after 65 mg NaFeEDTA, twice as high as after FeSO₄. A similar pattern was seen for NTBI. After 6.5 mg of NaFeEDTA and FeSO₄, NTBI was hardly detectable. NaFeEDTA was highly effective for the treatment of iron deficiency if given with a meal, inhibiting the formation of nonabsorbable Fe-complexes, while NTBI did not exceed the range of normal values for iron-replete subjects. Full article

Iron is an essential nutrient for almost all living organisms, but is not easily made available. Hosts and pathogens engage in a fight for the metal during an infection, leading to major alterations in the host’s iron metabolism. Important pathological consequences can emerge from the mentioned interaction, including anemia. Several recent reports have highlighted the alterations in iron metabolism caused by different types of infection, and several possible therapeutic strategies emerge, based on the targeting of the host’s iron metabolism. Here, we review the most recent literature on iron metabolism alterations that are induced by infection, the consequent development of anemia, and the potential therapeutic approaches to modulate iron metabolism in order to correct iron-related pathologies and control the ongoing infection. Full article

Several studies showed that [¹¹C]ABP688 binding is altered following drug-induced perturbation of glutamate levels in brains of humans, non-human primates and rats. We evaluated whether the fluorinated derivative [¹⁸F]PSS232 can be used to assess metabotropic glutamate receptor 5 (mGluR5) availability in rats after pharmacological challenge with ketamine, known to increase glutamate, or ceftriaxone, known to decrease glutamate. In vitro autoradiography was performed on rat brain slices with [¹⁸F]PSS232 to prove direct competition of the drugs for mGluR5. One group of rats were challenged with a bolus injection of either vehicle, racemic ketamine, S-ketamine or ceftriaxone followed by positron emission tomography PET imaging with [¹⁸F]PSS232. The other group received an infusion of the drugs during the PET scan. Distribution volume ratios (DVRs) were calculated using a reference tissue model. In vitro autoradiography showed no direct competition of the drugs with [¹⁸F]PSS232 for the allosteric binding site of mGluR5. DVRs of [¹⁸F]PSS232 binding in vivo did not change in any brain region neither after bolus injection nor after infusion. We conclude that [¹⁸F]PSS232 has utility for measuring mGluR5 density or occupancy of the allosteric site in vivo, but it cannot be used to measure in vivo fluctuations of glutamate levels in the rat brain. Full article

Iron is an essential trace mineral necessary for life, and iron deficiency anaemia (IDA) is one of the most common haematological problems worldwide, affecting a sixth of the global population. Principally linked to poverty, malnutrition and infection in developing countries, in Western countries the pathophysiology of IDA is primarily linked to blood loss, malabsorption and chronic disease. Oral iron replacement therapy is a simple, inexpensive treatment, but is limited by gastrointestinal side effects that are not inconsequential to some patients and are of minimal efficacy in others. Third generation intravenous (IV) iron therapies allow rapid and complete replacement dosing without the toxicity issues inherent with older iron preparations. Their characteristic, strongly-bound iron-carbohydrate complexes exist as colloidal suspensions of iron oxide nanoparticles with a polynuclear Fe(III)-oxyhydroxide/oxide core surrounded by a carbohydrate ligand. The physicochemical differences between the IV irons include mineral composition, crystalline structure, conformation, size and molecular weight, but the most important difference is the carbohydrate ligand, which influences complex stability, iron release and immunogenicity, and which is a unique feature of each drug. Recent studies have highlighted different adverse event profiles associated with third-generation IV irons that reflect their different structures. The increasing clinical evidence base has allayed safety concerns linked to older IV irons and widened their clinical use. This review considers the properties of the different IV irons, and how differences might impact current and future clinical practice. Full article

This work describes a novel screening strategy that implements small-scale spray-drying in early development of binary amorphous solid dispersions (ASDs). The proposed methodology consists of a three-stage decision protocol in which small batches (20–100 mg) of spray-dried solid dispersions (SDSDs) are evaluated in terms of drug–polymer miscibility, physical stability and dissolution performance in bio-predictive conditions. The objectives are to select the adequate carrier and drug-loading (DL) for the manufacturing of robust SDSD; and the appropriate stabilizer dissolved in the liquid vehicle of SDSD suspensions, which constitutes the common dosage form used during non-clinical studies. This methodology was verified with CDP146, a poorly water soluble (<2 µg/mL) API combined with four enteric polymers and four stabilizers. CDP146/HPMCAS-LF 40:60 (w/w) and 10% (w/v) PVPVA were identified as the lead SDSD and the best performing stabilizer, respectively. Lead SDSD suspensions (1–50 mg/mL) were found to preserve complete amorphous state during 8 h and maintain supersaturation in simulated rat intestinal fluids during the absorption window. Therefore, the implementation of spray-drying as a small-scale screening approach allowed maximizing screening effectiveness with respect to very limited API amounts (735 mg) and time resources (9 days), while removing transfer steps between screening and manufacturing phases. Full article

Aptamer binding has been used effectively for diagnostics, in-vivo targeting of therapeutics, and the construction and control of nanomachines. Nanostructures that respond to pH by releasing or changing affinity to a target have also been used for in vivo delivery, and in the construction of sensors and re-usable nanomachines. There are many applications that use aptamers together with pH-responsive materials, notably the targeted delivery of chemotherapeutics. However, the number of reported applications that directly use pH to control aptamer binding is small. In this review, we first discuss the use of aptamers with pH-responsive nanostructures for chemotherapeutic and other applications. We then discuss applications that use pH to denature or otherwise disrupt the binding of aptamers. Finally, we discuss motifs using non-canonical nucleic acid base pairing that can shift conformation in response to pH, followed by an overview of engineered pH-controlled aptamers designed using those motifs. Full article

Epigenetic mechanisms include DNA methylation, posttranslational modifications of histones, chromatin remodeling factors, and post transcriptional gene regulation by noncoding RNAs. All together, these processes regulate gene expression by changing chromatin organization and DNA accessibility. Targeting enzymatic regulators responsible for DNA and chromatin modifications hold promise for modulating the transcriptional regulation of genes that are involved in cancer, as well as in chronic noncommunicable metabolic diseases like obesity, diabetes, and cardiovascular diseases. Increasingly studies are emerging, leading to the identification of specific and effective molecules targeting epigenetic pathways involved in disease onset. In this regard, RNA interference, which uses small RNAs to reduce gene expression and nucleic acid aptamers are arising as very promising candidates in therapeutic approach. Common to all these strategies is the imperative challenge of specificity. In this regard, nucleic acid aptamers have emerged as an attractive class of carrier molecules due to their ability to bind with high affinity to specific ligands, their high chemical flexibility as well as tissue penetration capability. In this review, we will focus on the recent progress in the field of aptamers used as targeting moieties able to recognize and revert epigenetics marks involved in diseases onset. Full article

Prostate cancer is the most common cancer in men around the world. It is a complex and heterogeneous disease in which androgens and their receptors play a crucial role in the progression and development. The current treatment for prostate cancer is a combination of surgery, hormone therapy, radiation and chemotherapy. Therapeutic agents commonly used in the clinic include steroidal and non-steroidal anti-androgens, such as cyproterone acetate, bicalutamide and enzalutamide. These few agents have multiple adverse effects and are not 100% effective. Several plant compounds and mixtures, including grape seed polyphenol extracts, lycopene and tomato preparations, soy isoflavones, and green tea extracts, have been shown to be effective against prostate cancer cell growth. In vivo activity of some isolated compounds like capsaicin and curcumin was reported in prostate cancer murine models. We prepared a library of plant extracts from traditional Mayan medicine. These plants were selected for their use in the contemporaneous Mayan communities for the treatment of different diseases. The extracts were assessed in a phenotypic screening using LNCaP prostate cancer androgen sensitive cell line, with a fixed dose of 25 μg/mL. MTT assay identified seven out of ten plants with interesting anti-neoplastic activity. Extracts from these plants were subjected to a bioguided fractionation to study their major components. We identified three compounds with anti-neoplastic effects against LNCaP cells, one of which shows selectivity for neoplastic compared to benign cells. Full article

This study investigated the potential hepatoprotective effect of oligoribonucleotides-d-mannitol complexes (ORNs-d-M) against thioacetamide (TAA)-induced hepatotoxicity in mice. The hepatoprotective activity of ORNs-d-M was evaluated in thioacetamide (TAA)-treated C57BL/6J. Results indicate that treatment with ORNs-d-M displayed a protective effect at the TAA-induced liver injury. Treatment with ORNs-d-M, starting at 0 h after the administration of TAA, decreased TAA-elevated serum alanine aminotransferase (ALT) and γ-glutamyl transpeptidase (GGT). Activities of glutathione S-transferase (GST) and glutathione peroxidase (GPx), and levels of glutathione (GSH), were enhanced with ORNs-d-M administration, while the hepatic oxidative biomarkers (TBA-reactive substances, protein carbonyl derivatives, protein-SH group) and myeloperoxidase (MPO) activity were reduced. Furthermore, genetic analysis has shown that the ORNs-d-M decreases the expression of mRNA pro-inflammatory cytokines, such as tumor necrosis factor α (TNF-α) and interleukin-6 (IL-6), profibrogenic cytokine-transforming growth factor β1 (TGF-β1), as well as the principal protein of the extracellular matrix—collagen I. The present study demonstrates that ORNs-d-M exerts a protective effect against TAA-induced liver injury, which may be associated with its anti-inflammatory effects, inhibition of overexpression of mRNA cytokines, and direct effects on the metabolism of the toxin. Full article

Azadirachta indica A. Juss (neem) extracts have been used in pharmaceutical applications as antitumor agents, due to their terpenes and phenolic compounds. To obtain extracts from neem leaves with potential antiproliferative effect, a sequential process of pressurized liquid extraction was carried out in a fixed bed extractor at 25 °C and 100 bar, using hexane (SH), ethyl acetate (SEA), and ethanol (SE) as solvents. Extractions using only ethanol (EE) was also conducted to compare the characteristics of the fractionated extracts. The results obtained by liquid chromatography-electrospray ionization mass spectrometry suggested a higher concentration of terpenes in the SEA extract in comparison to SH, SE, and EE extracts. Therefore, antiproliferative activity showed that SEA extracts were the most efficient inhibitor to human tumor cells MCF-7, NCI-H460, HeLa, and HepG2. Hepatocellular cells were more resistant to SH, SEA, SE, and EE compared to breast, lung, hepatocellular, and cervical malignant cells. Neem fractioned extracts obtained in the present study seem to be more selective for malignant cells compared to the non-tumor cells. Full article

Polyethylene glycol (PEG) is an inert, water soluble polymer, used for decades in pharmaceuticals. Although PEG is considered safe, concerns persist about the potential adverse effects of long-term exposure to PEG-containing therapies, specifically in children, following the introduction of PEGylated recombinant factor products used for the treatment of hemophilia. Given the absence of long-term surveillance data, and to evaluate the potential risk, we estimated PEG exposure in the pediatric population receiving PEGylated therapies with pediatric indications administered intravenously or intramuscularly. We used a range of pediatric weights and doses based on prescribing information (PI) or treatment guidelines. PIs and reporting websites were searched for information about adverse events (AEs). For a child weighing 50 kg on the highest prophylactic dose of a FVIII product, the range of total PEG exposure was 40–21,840 mg/year; for factor IX (FIX) products, the range was 13–1342 mg/year; and for other products, the range was 383–26,743 mg/year, primarily as a derivative excipient. No AE patterns attributable to PEG were found for any of these products, including potential renal, neurological, or hepatic AEs. Our analyses suggest the pediatric population has had substantial exposure to PEG for several decades, with no evidence of adverse consequences. Full article

Malaysia is a multi-ethnic society whereby the impact of pharmacogenetic differences between ethnic groups may contribute significantly to variability in clinical therapy. One of the leading causes of mortality in Malaysia is cardiovascular disease (CVD), which accounts for up to 26% of all hospital deaths annually. Clopidogrel is used as an adjunct treatment in the secondary prevention of cardiovascular events. CYP2C19 plays an integral part in the metabolism of clopidogrel to the active metabolite clopi-H4. However, CYP2C19 genetic polymorphism, prominent in Malaysians, could influence target clopi-H4 plasma concentrations for clinical efficacy. This study addresses how inter-ethnicity variability within the Malaysian population impacts the attainment of clopi-H4 target plasma concentration under different CYP2C19 polymorphisms through pharmacokinetic (PK) modelling. We illustrated a statistically significant difference (P < 0.001) in the clopi-H4 C_max between the extensive metabolisers (EM) and poor metabolisers (PM) phenotypes with either Malay or Malaysian Chinese population groups. Furthermore, the number of PM individuals with peak clopi-H4 concentrations below the minimum therapeutic level was partially recovered using a high-dose strategy (600 mg loading dose followed by a 150 mg maintenance dose), which resulted in an approximate 50% increase in subjects attaining the minimum clopi-H4 plasma concentration for a therapeutic effect. Full article

Rapid replication of the influenza A virus and lung tissue damage caused by exaggerated pro-inflammatory host immune responses lead to numerous deaths. Therefore, novel therapeutic agents that have anti-influenza activities and attenuate excessive pro-inflammatory responses that are induced by an influenza virus infection are needed. Oligoribonucleotides-d-mannitol (ORNs-d-M) complexes possess both antiviral and anti-inflammatory activities. The current research was aimed at studying the ORNs-d-M effects on expression of innate immune genes in mice lungs during an influenza virus infection. Expression of genes was determined by RT-qPCR and Western blot assays. In the present studies, we found that the ORNs-d-M reduced the influenza-induced up-expression of Toll-like receptors (TLRs) (tlr3, tlr7, tlr8), nuclear factor NF-kB (nfkbia, nfnb1), cytokines (ifnε, ifnk, ifna2, ifnb1, ifnγ, il6, il1b, il12a, tnf), chemokines (ccl3, ccl4, сcl5, cxcl9, cxcl10, cxcl11), interferon-stimulated genes (ISGs) (oas1a, oas2, oas3, mx1), and pro-oxidation (nos2, xdh) genes. The ORNs-d-M inhibited the mRNA overexpression of tlr3, tlr7, and tlr8 induced by the influenza virus, which suggests that they impair the upregulation of NF-kB, cytokines, chemokines, ISGs, and pro-oxidation genes induced by the influenza virus by inhibiting activation of the TLR-3, TLR-7, and TLR-8 signaling pathways. By impairing activation of the TLR-3, TLR-7, and TLR-8 signaling pathways, the ORNs-d-M can modulate the innate immune response to an influenza virus infection. Full article

Reactive oxygen species (ROS) are continuously generated in the normal biological systems, primarily by enzymes as xanthine oxidase (XO). The inappropriate scavenging or inhibition of ROS has been considered to be linked with aging, inflammatory disorders, and chronic diseases. Therefore, many plants and their products have been investigated as natural antioxidants for their potential use in preventive medicine. The leaves and bark extracts of Curatella americana Linn. were described in scientific research as anti-inflammatory, vasodilator, anti-ulcerogenic, and hypolipidemic effects. So, the aim of this study was to evaluate the antioxidant potentials of leaf hydroalcoholic extract from C. americana (HECA) through the scavenging DPPH assay and their main chemical constituents, evaluated by the following quantum chemical approaches (DFT B3LYP/6-31G**): Maps of Molecular Electrostatic Potential (MEP), Frontier Orbital’s (HOMO and LUMO) followed by multivariate analysis and molecular docking simulations with the xanthine oxidase enzyme. The hydroalcoholic extract showed significant antioxidant activity by free radical scavenging probably due to the great presence of flavonoids, which were grouped in the PCA and HCA analysis with the standard gallic acid. In the molecular docking study, the compounds studied presented the binding free energy (ΔG) values close each other, due to the similar interactions with amino acids residues at the activity site. The descriptors Gap and softness were important to characterize the molecules with antioxidant potential by capturing oxygen radicals. Full article

Imaging is not only seeing, but also believing. For targeted imaging modalities, nucleic acid aptamers have features such as superior recognition of structural epitopes and quick uptake in target cells. This explains the emergence of an evolved new class of aptamers into a wide spectrum of imaging applications over the last decade. Genetically encoded biosensors tagged with fluorescent RNA aptamers have been developed as intracellular imaging tools to understand cellular signaling and physiology in live cells. Cancer-specific aptamers labeled with fluorescence have been used for assessment of clinical tissue specimens. Aptamers conjugated with gold nanoparticles have been employed to develop innovative mass spectrometry tissue imaging. Also, use of chemically conjugated cancer-specific aptamers as probes for non-invasive and high-resolution imaging has been transformative for in vivo imaging in multiple cancers. Full article

Background: New approaches based on the receptor-targeted molecular interaction have been recently developed with the aim to investigate specific probes for sentinel lymph nodes. In particular, the mannose receptors expressed by lymph node macrophages became an attractive target and different multifunctional mannose derivate ligands for the labeling with ^99mTc have been developed. In this study, we report the synthesis of a specific class of dextran-based, macromolecular, multifunctional ligands specially designed for labeling with the highly stable [^99mTc≡N]²⁺ core. Methods: The ligands have been obtained by appending to a macromolecular dextran scaffold pendant arms bearing a chelating moiety for the metallic group and a mannosyl residue for allowing the interaction of the resulting macromolecular ^99mTc conjugate with specific receptors on the external membrane of macrophages. Two different chelating systems have been selected, S-methyl dithiocarbazate [H₂N‒NH‒C(=S)SCH₃=HDTCZ] and a sequence of two cysteine residues, that in combination with a monophosphine coligand, are able to bind the [^99mTc≡N]²⁺ core. Conclusions: High-specific-activity labeling has been obtained by simple mixing and heating of the [^99mTc≡N]²⁺ group with the new mannose-dextran derivatives. Full article