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Drugs and Drug Candidates

Drugs and Drug Candidates is an international, peer-reviewed, open access journal on drug discovery, development, and knowledge, published quarterly online by MDPI.

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Dr. Jean Jacques Vanden Eynde

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All Articles (170)

Review

Non-Pharmacological Activation of the Renal Kallikrein–Kinin System: Dietary Potassium as a Novel Renoprotective Approach

Leopoldo Ardiles and
Carlos D. Figueroa

Chronic kidney disease (CKD) has emerged as a pervasive global health concern, for which there are no known curative treatments. Consequently, there is an imperative for the implementation of preventive and kidney-protective strategies. The renal kallikrein–kinin system (KKS) is a vasodilator, anti-inflammatory, and antifibrotic pathway located in the distal nephron, whose decline contributes to hypertension and CKD progression. In this narrative, non-systematic review, a thorough evaluation of both experimental and clinical data was undertaken to ascertain the interactions between dietary potassium, renal KKS activity, and kidney protection. A particular emphasis was placed on animal models of proteinuria, tubulointerstitial damage, and salt-sensitive hypertension, in conjunction with human studies on potassium intake and renal outcomes. A body of experimental evidence suggests a relationship between potassium-rich diets and renal kallikrein synthesis, urinary kallikrein activity, and up-regulated kinin B2 receptor expression. Collectively, these factors have been shown to result in reduced blood pressure, oxidative stress, apoptosis, inflammation, and fibrosis, and these effects are counteracted by B2 receptor blockade. In humans, higher potassium intake has been shown to enhance kallikrein excretion and lower cardiovascular and renal risk, independently of aldosterone. Conversely, low potassium intake has the potential to exacerbate CKD progression. Notwithstanding the concerns that have been raised regarding the potential necessity of increasing potassium intake in cases of advanced CKD, extant evidence would appear to indicate that potassium excretion persists until late disease stages. The activation and preservation of the renal KKS through a potassium-rich diet is a rational, cost-effective strategy for renoprotection. When combined with sodium reduction and nutritional education, this approach has the potential to halt the progression of CKD and enhance cardiovascular health on a population scale.

2 February 2026

Schematic representation of the human nephron (right) and the major characteristics of the junction between the connecting tubule and the cortical collecting duct (left). A human nephron is represented, and its different segments are identified: G, glomerulus; EA, efferent arteriole; PT, proximal tubule; DCT, distal convoluted tubule; LH, loop of Henle; TAL, thick ascending limb of Henle; CNT, connecting tubule; CCD, cortical collecting duct. An anatomical relationship is established between the afferent arteriole (AA), the connecting tubule, and the macula densa (MD), labeled in blue at the end of the TAL; renin is synthesized in the muscular cells of the afferent arteriole (pink cells). In the distal nephron, cells of both CNT (CNTc, pale green cells) and CCD (orange cells known as collecting duct cells, CDc, or principal cells, PC) intermingle over a certain distance. CNTc produce and secrete renal kallikrein (KLK1) into the tubular lumen and the tubulointerstitium, and CDc/PC produce kininogens (KNGs), making kinin production feasible in both the urinary fluid and the interstitium. Both the CNT and CCD also have intercalated cells (gray cells), which are not involved in kallikrein or kininogen synthesis. It is still unknown whether kininogens are secreted by CDc/PC or are filtered from interstitial capillaries into the interstitium. Once formed, kinins may stimulate the release of prostaglandin E2 (PGE2) from CDc/PC that in turn inhibits sodium and water reabsorption, resulting in diuresis and natriuresis.

Article

Exploring the Chemical Space of Cephalosporins Across Generations

Henrique de Aguiar Mello and
Itamar Luís Gonçalves

Background/Objectives: Cephalosporins represent one of the most important classes of β-lactam antibiotics, widely used in clinical practice due to their broad-spectrum activity and favorable safety profile. As generations evolved, structural modifications were introduced to expand antimicrobial coverage and overcome β-lactamase resistance. This study aimed to analyze the drug-like properties of cephalosporins across different generations using molecular descriptors to identify structural and pharmacokinetic patterns influencing bioavailability and oral administration profiles. Methods: Thirty-eight cephalosporins representative of different generations were selected. Molecular data were obtained from PubChem, and SMILES were extracted and validated. Molecular descriptors (including MW, logP, TPSA, HBA, HBD, rotatable bonds, and global complexity indices) were calculated using the SwissADME and ChemDes platforms. Statistical analysis included ANOVA followed by post hoc tests, and principal component analysis (PCA). Results: A progressive increase in molecular weight, polarity, and TPSA was observed across generations, with fourth-generation cephalosporins showing significantly higher values compared to first-generation compounds (p < 0.0001). LogP decreased significantly in fourth-generation agents (p < 0.0001), reflecting increased polarity. PCA revealed that most compounds from generations 1–2 cluster in regions consistent with Lipinski’s and Veber’s rules, whereas fourth- and fifth generation - cephalosporins deviated substantially, prioritizing antimicrobial efficacy over oral bioavailability. Recurrent structural modifications such as oximes, tetrazoles, and aminothiazoles were identified, with increasing frequency in modern generations. Conclusions: The evolution of cephalosporins reflects a strategic shift toward enhanced antimicrobial potency and β-lactamase stability at the expense of oral bioavailability. Understanding these structural transitions provides valuable insights for rational drug design, aiming to balance antimicrobial effectiveness with favorable pharmacokinetic profiles essential for therapeutic success.

2 February 2026

Mean values of molecular weight (a), logP (b), TPSA (c), HBA (d), HBD (e), rotatable bonds (f), Csp3 (g), AHA (h), and HA (i), ECCEN (j), Zagreb index (k), and Bertz complexity index (l) across the four generations of cephalosporins (x-axis). The dataset (n = 38) is distributed as 1st Gen (n = 8; 50% oral, green points), 2nd Gen (n = 9; 33.33% oral, blue points), 3rd Gen (n = 13; 30.77% oral, purple points), and 4th/5th Gen (n = 8; 0% oral, yellow points). The fourth-generation group also included fifth-generation cephalosporins, due to the absence of a clear distinction between these generations and the limited number of cephalosporins classified as fifth generation. * indicates significant difference relative to the 4th generation: * p < 0.05, ** p < 0.01, *** p < 0.001, **** p < 0.0001; # indicates significant difference relative to the 3rd generation: # p < 0.05. All comparisons were performed using Tukey’s post hoc test, except for HBD and AHA, which were analyzed using Dunn’s test.

Article

Levamisole Potentiation via Thymol and Cinnamaldehyde: Assessment of Pharmacological Interactions in Sheep

María Victoria Miró,
Paula Ichinose and
Adrián Lifschitz
+ 3 authors

Background/Objectives: The widespread development of anthelmintic resistance in gastrointestinal nematodes constitutes a major production-limiting factor in grazing ruminants. Resistance mechanisms often involve drug efflux transporters like P-glycoprotein (P-gp). This study aimed to evaluate the potential of the phytochemicals cinnamaldehyde (CNM) and thymol (TML) to modulate P-gp activity and enhance the pharmacokinetic profile and efficacy of levamisole (LVM) in lambs. Methods: An ex vivo diffusion assay using sheep ileum was conducted to assess the influence of CNM, TML, and LVM on the transport of the P-gp substrate Rhodamine 123 (Rho123). Subsequently, a clinical trial was performed in lambs naturally infected with resistant nematodes. Animals received LVM (3.75 mg/kg) subcutaneously, either alone or co-administered with CNM or TML (80 mg/kg). Plasma LVM concentrations were analyzed by HPLC, and anthelmintic efficacy was determined via the Fecal Egg Count Reduction (FECR) test. Results: Ex vivo assays demonstrated that CNM, TML and LVM significantly reduced the efflux ratio of Rho123, confirming P-gp inhibition. The pharmacokinetic parameters of LVM did not differ significantly in the co-administered groups. However, the combination of LVM + TML tended to increase the total systemic exposure of LVM. Although all experimental groups showed a significant reduction in EPG between day 0 and day 7 (FECR 50–58%), the magnitude of this reduction did not differ significantly among treatments. Conclusions: While CNM and TML effectively inhibited P-gp activity ex vivo and slightly modified LVM pharmacokinetics, these effects were insufficient to yield clinically meaningful improvements in its efficacy against nematodes under the tested conditions. Future strategies should focus on optimizing delivery systems to maximize phytochemical–drug interactions.

31 January 2026

Comparative efflux ratio (%) (Peff S–M/Peff M-S) of rhodamine 123 (Rho123, 0.5 µM) across sheep ileum following its incubation either alone or in the presence of cinnamaldehyde (CNM), thymol (TML) (each at 1.5 mM) and levamisole (LVM, 5 µM). Values are expressed as percentage (%) relative to the control and showed the median (min–max) (n = 8–9 determinations). One-way ANOVA followed by Dunnett’s test was used to compare incubation with Rho123 alone against incubations with Rho123 in the presence of the modulators. Statistical differences relative to Rho123 alone were considered significant at * p < 0.05 and ** p < 0.01.

Article

Nanoencapsulated Cannabidiol–Cannabigerol Using Eudragit L100: In Vitro and In Vivo Evidence in Murine Colitis Model

K. Antonio Cárdenas-Noriega,
Joel H. Elizondo-Luévano and
Uziel Castillo-Velázquez
+ 6 authors

Background: Phytocannabinoids such as cannabidiol (CBD) and cannabigerol (CBG) have received increasing attention in the context of inflammatory and intestinal disorders. However, direct comparisons between their individual and combined effects, as well as the influence of delivery systems, remain limited. Objectives: This study evaluated the biological effects of free and nanoencapsulated CBD and CBG, including a cannabinoid–Eudragit L100 formulation, in an in vitro TNBS-treated intestinal cell model and an in vivo murine model of TNBS-induced colitis. Methods: Cytotoxicity and treatment-associated effects of CBD, CBG, their 1:1 combination, and a nanoencapsulated formulation were assessed in TNBS-exposed Caco-2 cells. In parallel, BALB/c mice with TNBS-induced colitis were evaluated for colonic damage and inflammatory markers. Results: CBD and CBG individually showed dose-dependent effects in Caco-2 cells, while their combined administration produced a greater effect than either compound alone at higher concentrations. The nanoencapsulated formulation preserved cellular metabolic activity following TNBS exposure. In vivo, both free combined and nanoencapsulated cannabinoids were associated with reduced epithelial damage and inflammatory alterations. Conclusions: Nanoencapsulation using Eudragit L100 modulated the biological effects of CBD and CBG in experimental models of TNBS-induced intestinal injury.

31 January 2026