Pharmaceuticals

Tuberculosis (TB) causes millions of deaths every year, ranking as one of the most dangerous infectious diseases worldwide. Because several pathogenic strains of M. tuberculosis (Mtb) have developed resistance against most of the established anti-TB drugs, new therapeutic options are urgently needed. An attractive target for the development of new anti-TB agents is the salicylate synthase MbtI, the first enzyme of the mycobacterial siderophore biochemical machinery, absent in human cells. In this work, a set of analogues of 5-(3-cyanophenyl)furan-2-carboxylic acid (I), the most potent MbtI inhibitor identified to date, was synthesized, characterized, and tested to further elucidate the structural requirements for achieving an efficient MbtI inhibition and potent antitubercular activity. The structure–activity relationships (SAR) discussed herein evidenced the importance of the side chain linked to the phenyl moiety to improve the in vitro antimycobacterial activity. In detail, 1f emerged as the most effective analogue against the pathogen, acting without cytotoxicity issues. To deepen the understanding of its mechanism of action, we established a fluorescence-based screening test to quantify the pathogen infectivity within host cells, using MPI-2 murine cells, a robust surrogate for alveolar macrophages. The set-up of the new assay demonstrates significant potential to accelerate the discovery of new anti-TB drugs. Full article

A popular and widely used combination therapy of leflunomide (LEF) and Tripterygium glycosides tablets (TGT_S) has become a valuable clinical tool in China for the treatment of rheumatoid arthritis. This regimen has not been evaluated either in terms of interaction or toxicity, even given the rising concerns about LEF’s prolonged elimination half-life and TGT’s narrow therapeutic index, in addition to the current trend of using high doses of LEF. Thus, this study determines the potential adverse drug reactions between these two medicines. Reliable validated LC-MS/MS methods were used for the determination of teriflunomide (TER, the only active metabolite of LEF), and the main components of TGT: wilforlide A, wilforgine, wilfortrine, wilfordine, and wilforine. The results obtained from this investigation, as paralleled with the control groups, revealed that the C_max and AUC_0-t of TER were significantly decreased with separate co-administration, as the C_max and AUC_0-t were 30.17 ± 1.55 μg/mL and 24.47 ± 2.50 μg/mL, 374.55 ± 15.54 μg h/mL and 336.94 ± 21.19 μg h/mL, respectively (p < 0.05). Meanwhile, the pharmacokinetic profiles of the main components of TGT have also been affected by separate co-administration in rats. Therefore, herb–drug interactions between LEF and TGT have been proven. Full article

Pediatric cancer treatment has evolved significantly in recent decades. The implementation of risk stratification strategies and the selection of evidence-based chemotherapy combinations have improved survival outcomes. However, there is large interindividual variability in terms of chemotherapy-related toxicities and, sometimes, the response among this population. This variability is partly attributed to the functional variability of drug-metabolizing enzymes (DME) and drug transporters (DTS) involved in the process of absorption, distribution, metabolism and excretion (ADME). The DTS, being ubiquitous, affects drug disposition across membranes and has relevance in determining chemotherapy response in pediatric cancer patients. Among the factors affecting DTS function, ontogeny or maturation is important in the pediatric population. In this narrative review, we describe the role of drug uptake/efflux transporters in defining pediatric chemotherapy-treatment-related toxicities and responses. Developmental differences in DTS and the consequent implications are also briefly discussed for the most commonly used chemotherapeutic drugs in the pediatric population. Full article

Intraocular pressure (IOP) is crucial to the well-being of eyes. During anesthesia, the administration of succinylcholine and endotracheal intubation are associated with an increase in IOP, which may be attenuated by short-acting opioids. However, the drug of choice among the commonly used short-acting opioids is unclear. This study aimed to evaluate the effects of fentanyl, sufentanil, alfentanil, and remifentanil on IOP measured after the administration of succinylcholine and after endotracheal intubation in patients undergoing general anesthesia. Five databases were searched. Randomized controlled trials (RCTs) that compared short-acting opioids and reported at least one of the clinical outcomes of interest were included. Nine RCTs with 357 patients were included. Remifentanil (1 μg kg⁻¹) more effectively alleviated the increase in IOP than the placebo after the administration of succinylcholine [mean difference (MD) of IOP, −3.64; confidence interval (CI), −5.47 to −1.81 and after endotracheal intubation (MD, −9.71; CI, −11.91 to −7.51). Remifentanil (1 μg kg⁻¹) ranked the best in terms of both attenuating the increase in IOP after the administration of succinylcholine [surface under the cumulative ranking curve (SUCRA), 0.91; normalized entropy (NE), 0.47; and after endotracheal intubation (SUCRA, 0.89; NE, 0.54) among all of the treatments. Remifentanil (1 μg kg⁻¹) should be considered the drug of choice in the circumstances where increased IOP is a great concern. Full article

Kleeb Bua Daeng (KBD) formula has long been used in Thailand as a traditional herbal medicine for promoting brain health. Our recent reports illustrated that KBD demonstrates multiple modes of action against several targets in the pathological cascade of Alzheimer’s disease (AD). The main purpose of the present study was to determine the protective effect and mechanism of KBD in amyloid beta (Aβ)-induced AD rats and its toxicity profiles. Pretreatment with the KBD formula for 14 days significantly improved the short- and long-term memory performance of Aβ-induced AD rats as assessed by the Morris Water Maze (MWM) and object-recognition tests. KBD treatment increased the activities of the antioxidant enzymes catalase, superoxide dismutase, and glutathione peroxidase; reduced the malondialdehyde content, and; decreased the acetylcholinesterase activity in the rat brain. An acute toxicity test revealed that the maximum dose of 2000 mg/kg did not cause any mortality or symptoms of toxicity. An oral, subchronic toxicity assessment of KBD at doses of 125, 250, and 500 mg/kg body weight/day for 90 days showed no adverse effects on behavior, mortality, hematology, or serum biochemistry. Our investigations indicate that KBD is a nontoxic traditional medicine with good potential for the prevention and treatment of AD. Full article

Sideritis sipylea Boiss. (Fam. Lamiaceae) is an endemic plant of the North Aegean Islands (Greece), commonly known as ironwort. Traditionally, its aerial parts have been used to relieve several ailments, especially gastrointestinal disorders, however, with scant knowledge about the pharmacological basis. In the present study, an endemic S. sipylea Greek species from Lesvos Island has been characterized for phytochemical composition and biological activities, in order to give a possible scientific basis to its traditional use and to highlight a further nutraceutical interest as a source of bioactive phytochemicals and extracts. Three different fractions obtained from a methanolic extract of S. sipylea aerial parts by using ethyl acetate with 10 (S10), 20 (S20), and 50% (S50) methanol as fractionation solvents were phytochemically characterized. Moreover, their antioxidant power and cytoprotective activity in different human cell lines were evaluated. The phytochemical analysis highlighted the presence of flavonoids, iridoids, and phenolic acids in all the tested samples. Particularly, the S10 fraction mainly contained iridoids, while S20 and S50 lavandulifolioside and chlorogenic acid, respectively. The fractions also showed antioxidant properties, S10 and S20 being the most potent. When assessed in human cholangiocytes, they counteracted the cytotoxicity of the tBOOH pro-oxidant agent, by reducing ROS levels and affecting GSH antioxidant system. The present findings highlight a possible interest in S10 and S20 fractions from S. sipylea as sources of bioactive molecules and stimulate further studies in order to characterize their possible application for nutraceutical and pharmaceutical purposes. Full article

The rapid emergence and spread of new variants of coronavirus type 2, as well as the emergence of zoonotic viruses, highlights the need for methodologies that contribute to the search for new pharmacological treatments. In the present work, we searched for new SARS-CoV-2 papain-like protease inhibitors in the PubChem database, which has more than 100 million compounds. Based on the ligand efficacy index obtained by molecular docking, 500 compounds with higher affinity than another experimentally tested inhibitor were selected. Finally, the seven compounds with ADME parameters within the acceptable range for such a drug were selected. Next, molecular dynamics simulation studies at 200 ns, ΔG calculations using molecular mechanics with generalized Born and surface solvation, and quantum mechanical calculations were performed with the selected compounds. Using this in silico protocol, seven papain-like protease inhibitors are proposed: three compounds with similar free energy (D28, D04, and D59) and three compounds with higher binding free energy (D60, D99, and D06) than the experimentally tested inhibitor, plus one compound (D24) that could bind to the ubiquitin-binding region and reduce the effect on the host immune system. The proposed compounds could be used in in vitro assays, and the described protocol could be used for smart drug design. Full article

Purposes: The aim of the study was to assess the efficacy of a treatment protocol that combines photodynamic therapy (PDT) and nitroglycerin (NG) on human retinoblastoma tumors xenografted on mice. We aimed to increase the PDT efficiency (in our least treatment-responsive retinoblastoma line) with better PS delivery to the tumor generated by NG, which is known to dilate vessels and enhance the permeability and retention of macromolecules in solid tumors. Methods: In vivo follow-up of the therapeutic effects was performed by sodium MRI, which directly monitors variations in sodium concentrations non-invasively and can be used to track the tumor response to therapy. NG ointment was applied one hour before PDT. The PDT protocol involves double-tumor targeting, i.e., cellular and vascular. The first PS dose was injected followed by a second one, separated by a 3 h interval. The timelapse allowed the PS molecules to penetrate tumor cells. Ten minutes after the second dose, the PS was red-light-activated. Results: In this study, we observed that the PDT effect was enhanced by applying nitroglycerin ointment to the tumor-bearing animal’s skin. PDT initiates the bystander effect on retinoblastomas, and NG increases this effect by increasing the intratumoral concentration of PS, which induces a higher production of ROS in the illuminated region and thus increases the propagation of the cell death signal deeper into the tumor (bystander effect). Full article

The continuous, worldwide spread of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB) endanger the World Health Organization’s (WHO) goal to end the global TB pandemic by the year 2035. During the past 50 years, very few new drugs have been approved by medical agencies to treat drug-resistant TB. Therefore, the development of novel antimycobacterial drug candidates to combat the threat of drug-resistant TB is urgent. In this work, we developed and optimized a total synthesis of the antimycobacterial natural flavonoid chlorflavonin by selective ruthenium(II)-catalyzed ortho-C(sp²)-H-hydroxylation of a substituted 3′-methoxyflavonoid skeleton. We extended our methodology to synthesize a small compound library of 14 structural analogs. The new analogs were tested for their antimycobacterial in vitro activity against Mycobacterium tuberculosis (Mtb) and their cytotoxicity against various human cell lines. The most promising new analog bromflavonin exhibited improved antimycobacterial in vitro activity against the virulent H37Rv strain of Mtb (Minimal Inhibitory Concentrations (MIC₉₀) = 0.78 μm). In addition, we determined the chemical and metabolic stability as well as the pK_a values of chlorflavonin and bromflavonin. Furthermore, we established a quantitative structure–activity relationship model using a thermodynamic integration approach. Our computations may be used for suggesting further structural changes to develop improved derivatives. Full article

Bone disorders affect millions of people worldwide and treatments currently available often produce undesirable secondary effects or have limited efficacy. It is therefore of the utmost interest for patients to develop more efficient drugs with reduced off-target activities. In the long process of drug development, screening and preclinical validation have recently gained momentum with the increased use of zebrafish as a model organism to study pathological processes related to human bone disorders, and the development of zebrafish high-throughput screening assays to identify bone anabolic compounds. In this review, we provided a comprehensive overview of the literature on zebrafish bone-related assays and evaluated their performance towards an integration into screening pipelines for the discovery of mineralogenic/osteogenic compounds. Tools available to standardize fish housing and feeding procedures, synchronize embryo production, and automatize specimen sorting and image acquisition/analysis toward faster and more accurate screening outputs were also presented. Full article

The demand for the development of novel medicines with few side effects and no proarrhythmic properties is increasing. Extensive research on herbal extracts has been conducted with the expectation that the compounds will exert precise effects without harmful side effects. Elsholtzia ciliata (Thunb.) Hyl. essential oil (EO) possesses antiarrhythmic properties similar to those of class 1B antiarrhythmics, such as prolonging myocardial activation of the QRS complex and shortening the QT interval. In this study, we determined the kinetic profile of EO phytocompounds and the effects of EO on heart electrical activity and arterial blood pressure. For this study, we chose to use local breed pigs that were anaesthetized. The effects of an intravenous bolus of EO on ECG parameters, arterial blood pressure, heart rate variability, and blood levels of haematological and biochemical parameters were registered and evaluated. Following an intravenous injection of a bolus, EO exerted a vasodilatory effect, resulting in significant reductions in arterial blood pressure. EO also increased the heart rate and altered ECG parameters. The bolus of EO prolonged the QRS complex, shortened the QT interval, and nonmonotonically altered the PQ interval. After the administration of a bolus of EO, the activity of the autonomic nervous system was altered. This study confirms that EO possesses similar properties to class 1B antiarrhythmics and exerts a hypotensive effect; it reduces arterial blood pressure possibly by modulating peripheral vascular resistance. Full article

Currently, gastro-retentive dosage forms achieved a remarkable position among the oral drug delivery systems. This is a broadly used technique to hold the drug delivery systems for a long duration in the gastro intestine (GI) region, slow drug delivery, and overcome other challenges related to typical oral delivery such as low bioavailability. The current work aimed to formulate and characterize a new expandable gastro-retentive system through Itopride Hydrochloride (IH)’s unfolding process for controlled release. The IH-loaded unfolding film formulation was optimized using the Box-Behnken design for folding endurance and length of tested layer (LTL). Initially, the formulation was made using several anti-adhesive additives to promote the unfolding mechanism. Citric acid and sodium bicarbonate were selected as anti-adhesives based on these results. The enfolded film in a capsule shell was shown to unroll in the stomach fluids and render drug delivery up to 12 h in acidic conditions. A fabricated system should have dimensions more than the size of the relaxed pyloric sphincter, and as required, >20 mm LTL was identified. This further confirms that the residence period in the stomach is irrelevant to the fed or fasted condition. Based on desirability criteria, the formulation containing 143.83, 0.7982, and 14.6096 Eudragit L100, PEG, and sodium bicarbonate are selected as optimized formulations (O-IH-UF). The optimized formulation was further analyzed for various parameters such as tensile strength, mechanical strength, unfolding nature, degradability, and in vitro release studies. The pharmacokinetic study revealed greater AUC (area under the curve) and long half-life with the designed O-IH-UF formulation, confirming that the unfolding film type can be a favorable drug system for enhancing the bioavailability of low soluble drugs. The results showed that unfolding types of gastro retentive systems could potentiate the drugs with stability issues in an alkaline medium or those with absorption in acidic conditions. Full article

The present study focused on the more detailed characterization of chitosan–carrageenan-based matrix tablets with respect to their potential utilization for drug targeting in the intestine. The study systematically dealt with the particular stages of the dissolution process, as well as with different views of the physico-chemical processes involved in these stages. The initial swelling of the tablets in the acidic medium based on the combined microscopy–calorimetry point of view, the pH-induced differences in the erosion and swelling of the tested tablets, and the morphological characterization of the tablets are discussed. The dissolution kinetics correlated with the rheological properties and mucoadhesive behavior of the tablets are also reported, and, correspondingly, the formulations with suitable properties were identified. It was confirmed that the formation of the chitosan–carrageenan polyelectrolyte complex may be an elegant and beneficial alternative solution for the drug targeting to the intestine by the matrix tablet. Full article

The complexation of biogenic molecules with metals is the widespread strategy in screening for new pharmaceuticals with improved therapeutic and physicochemical properties. This paper demonstrates the possibility of using simple QSAR modeling based on topological descriptors for chelates study. The presence of a relationship between the structure (J) and lipophilic properties (logP) of zinc complexes with amino acids, where two molecules coordinate the central atom through carboxyl oxygen and amino group nitrogen, and thus form a double ring structure, was predicted. Using a cellular biosensor model for Gly, Ala, Met, Val, Phe and their complexes Zn(AA)₂, we experimentally confirmed the existence of a direct relationship between logP and biological activity (Ea). The results obtained using topological analysis, Spirotox method and microbiological testing allowed us to assume and prove that the chelate complex of zinc with methionine has the highest activity of inhibiting bacterial biofilms, while in aqueous solutions it does not reveal direct antibacterial effect. Full article

Wound dressings created using nanotechnology are known as suitable substrates to speed up the healing of both acute and chronic wounds. Therapeutic substances can be delivered using these materials. In this study, a hydrogel loaded with Cu (II) Schiff base 8-hydroxy quinoline complex (CuSQ) solid lipid nanoparticles (SLN) was formulated to investigate its wound healing potential in an excision wound healing model in rats. The CuSQ SLN were spherical shaped with sizes ranging from 111 to 202 nm and a polydispersity index (PDI) ranging from 0.43 to 0.76, encapsulation efficiency (EE) % between 85 and 88, and zeta potential (ZP) of −11.8 to −40 mV. The formulated hydrogel showed good homogeneity, good stability, and a pH of 6.4 which indicates no skin irritation and had no cytotoxicity on the human skin fibroblast (HSF) cell line. In the in vivo study, animals were placed in five groups: control, standard, plain hydrogel, low dose, and high dose of CuSQ hydrogel. Both doses of CuSQ showed significantly faster healing rates compared to standard and control rats. In addition, the histopathology study showed more collagen, improved angiogenesis, and intact re-epithelization with less inflammation. A significant increase in transforming growth factor-beta1 (TGF-β1) level and increased immune expression of vascular endothelial growth factor (VEGF) by CuSQ treatment validates its role in collagen synthesis, proliferation of fibroblasts and enhancement of angiogenesis. Matrix metalloproteinase-9 (MMP-9) was found to be significantly reduced after CuSQ treatment. Immunohistochemistry of tumor necrosis factor alpha (TNF-α) revealed a marked decrease in inflammation. Thus, we concluded that CuSQ would be a beneficial drug for cutaneous wound healing since it effectively accelerated wound healing through regulation of various cytokines and growth factors. Full article

Through this structured review of the published literature, we aimed to provide an up-to-date description of strategies (human-related) and tools (mainly from the digital field) facilitating the appropriateness of drug use in older adults. The evidence of each strategy and tool’s effectiveness and sustainability largely derives from local and heterogeneous experiences, with contrasting results. As a general framework, three main steps should be considered in implementing measures to improve appropriateness: prescription, acceptance by the patient, and continuous monitoring of adherence and risk-benefit profile. Each step needs efforts from specific actors (physicians, patients, caregivers, healthcare professionals) and dedicated supporting tools. Moreover, how to support the appropriateness also strictly depends on the particular setting of care (hospital, ambulatory or primary care, nursing home, long-term care) and available economic resources. Therefore, it is urgent assigning to each approach proposed in the literature the following characteristics: level of effectiveness, strength of evidence, setting of implementation, needed resources, and issues for its sustainability. Full article

In this study, essential oils (EOs) and hydrolates (Hys) from Italian hemp (Cannabis sativa L. Kompolti cv.) and hop (Humulus Lupulus L., Chinook cv.) supply chains were chemically characterized and tested to investigate their apoptotic potential for the first time. Headspace–Gas Chromatography–Mass Spectrometry (HS-GC-MS) techniques were performed to describe their volatile chemical profile, highlighting a composition rich in terpene derivatives such as monoterpenes and sesquiterpenes among which β-myrcene, limonene, β-caryophyllene and α-humulene were the main constituents of EOs; in contrast, linalool, cis-p-menth-2,8-dien-1-ol, terpinen-4-ol, α-terpineol, caryophyllene oxide, and τ-cadinol were found in the Hys. The cytotoxicity activity on human leukemia cells (HL60), human neuroblastoma cells (SH-SY5Y), human metastatic adenocarcinoma breast cells (MCF7), human adenocarcinoma breast cells (MDA), and normal breast epithelial cell (MCF10A) for the EOs and Hys was studied by MTT assay and cytofluorimetric analysis and scanning and transmission electron microscopy were performed to define ultrastructural changes and the mechanism of cells death for HL 60 cells. An induction of the apoptotic mechanism was evidenced for hemp and hop EOs after treatment with the corresponding EC₅₀ dose. In addition, TEM and SEM investigations revealed typical characteristics induced by the apoptotic pathway. Therefore, thanks to the integration of the applied methodologies with the used techniques, this work provides an overview on the metabolomic profile and the apoptotic potential of hemp and hop EOs and, for the first time, also of Hys. The findings of this preliminary study confirm that the EOs and Hys from Cannabis and Humulus species are sources of bioactive molecules with multiple biological effects yet to be explored. Full article

The oral route is the most common and practical means of drug administration, particularly from a patient’s perspective. However, the pharmacokinetic profile of oral drugs depends on the rate of drug absorption through the intestinal wall before entering the systemic circulation. However, the enteric epithelium represents one of the major limiting steps for drug absorption, due to the presence of efflux transporters on the intestinal membrane, mucous layer, enzymatic degradation, and the existence of tight junctions along the intestinal linings. These challenges are more noticeable for hydrophilic drugs, high molecular weight drugs, and drugs that are substrates of the efflux transporters. Another challenge faced by oral drug delivery is the presence of first-pass hepatic metabolism that can result in reduced drug bioavailability. Over the years, a wide range of compounds have been investigated for their permeation-enhancing effect in order to circumvent these challenges. There is also a growing interest in developing nanocarrier-based formulation strategies to enhance the drug absorption. Therefore, this review aims to provide an overview of the challenges faced by oral drug delivery and selected strategies to enhance the oral drug absorption, including the application of absorption enhancers and nanocarrier-based formulations based on in vitro, in vivo, and in situ studies. Full article

(1) Background: To evaluate the clinical effects of leukocyte-rich platelet-rich plasma (LR-PRP) and hyaluronic acid (HA) injections in treating patients suffering from knee osteoarthritis (OA); (2) Methods: Randomized controlled trials (RCTs) were searched from PubMed, Web of Science, and Cochrane Library. Keywords were: platelet-rich plasma, LR-PRP, leukocyte-rich, hyaluronic acid, and knee osteoarthritis. The included RCTs were published between the 1st of November 2011 and the 3rd of February 2021. Western Ontario and McMaster Universities Arthritis Index (WOMAC) scores, visual analog scale (VAS) scores, International Knee Documentation Committee (IKDC) scores, and adverse events were used as outcomes for evaluation; (3) Results: A total of 14 RCTs were enrolled. At 6 months, revealed that the LR-PRP group was better than the HA group in WOMAC total, pain, and physical function scores. At 12 months, the LR-PRP group was better than the HA group in WOMAC stiffness and physical function scores. There was no significant difference in adverse events; (4) Conclusion: LR-PRP injection showed no significant pain relief effect as compared with HA injection. However, LR-PRP demonstrated better overall outcomes as compared to HA in knee OA patients at the follow-up periods of 3, 6, and 12 months. LR-PRP injection may be recommended as a feasible option in treating patients with knee OA. Full article