Latest articles in this journal
Pharmaceutics, Volume 14; https://doi.org/10.3390/pharmaceutics14122762
Despite poor absorption properties, delivery to the colon of bioactive compounds administered by the oral route has become a focus of pharmaceutical research over the last few decades. In particular, the high prevalence of Inflammatory Bowel Disease has driven interest because of the need for improved pharmacological treatments, which may provide high local drug concentrations and low systemic exposure. Colonic release has also been explored to deliver orally biologics having gut stability and permeability issues. For colon delivery, various technologies have been proposed, among which time-dependent systems rely on relatively constant small intestine transit time. Drug delivery platforms exploiting this physiological feature provide a lag time programmed to cover the entire small intestine transit and control the onset of release. Functional polymer coatings or capsule plugs are mainly used for this purpose, working through different mechanisms, such as swelling, dissolution/erosion, rupturing and/or increasing permeability, all activated by aqueous fluids. In addition, enteric coating is generally required to protect time-controlled formulations during their stay in the stomach and rule out the influence of variable gastric emptying. In this review, the rationale and main delivery technologies for oral colon delivery based on the time-dependent strategy are presented and discussed.
Pharmaceutics, Volume 14; https://doi.org/10.3390/pharmaceutics14122761
The antineoplastic activity of the thioredoxin reductase 1 (TrxR) inhibitor, auranofin (AF), has already been investigated in various cancer mouse models as a single drug, or in combination with other molecules. However, there are inconsistencies in the literature on the solvent, dose and administration route of AF treatment in vivo. Therefore, we investigated the solvent and administration route of AF in a syngeneic SB28 glioblastoma (GBM) C57BL/6J and a 344SQ non-small cell lung cancer 129S2/SvPasCrl (129) mouse model. Compared to daily intraperitoneal injections and subcutaneous delivery of AF via osmotic minipumps, oral gavage for 14 days was the most suitable administration route for high doses of AF (10–15 mg/kg) in both mouse models, showing no measurable weight loss or signs of toxicity. A solvent comprising 50% DMSO, 40% PEG300 and 10% ethanol improved the solubility of AF for oral administration in mice. In addition, we confirmed that AF was a potent TrxR inhibitor in SB28 GBM tumors at high doses. Taken together, our results and results in the literature indicate the therapeutic value of AF in several in vivo cancer models, and provide relevant information about AF’s optimal administration route and solvent in two syngeneic cancer mouse models.
Pharmaceutics, Volume 14; https://doi.org/10.3390/pharmaceutics14122760
Cardiovascular disease (CVD) is a group of systemic disorders threatening human health with complex pathogenesis, among which mitochondrial energy metabolism reprogramming has a critical role. Mitochondria are cell organelles that fuel the energy essential for biochemical reactions and maintain normal physiological functions of the body. Mitochondrial metabolic disorders are extensively involved in the progression of CVD, especially for energy-demanding organs such as the heart. Therefore, elucidating the role of mitochondrial metabolism in the progression of CVD is of great significance to further understand the pathogenesis of CVD and explore preventive and therapeutic methods. In this review, we discuss the major factors of mitochondrial metabolism and their potential roles in the prevention and treatment of CVD. The current application of mitochondria-targeted therapeutic agents in the treatment of CVD and advances in mitochondria-targeted gene therapy technologies are also overviewed.
Pharmaceutics, Volume 14; https://doi.org/10.3390/pharmaceutics14122759
Probiotic bacteria are widely used to prepare pharmaceutical products and functional foods because they promote and sustain health. Nonetheless, probiotic viability is prone to decrease under gastrointestinal conditions. In this investigation, Lactiplantibacillus plantarum spp. CM-CNRG TB98 was entrapped in a gelatin–poly (vinyl alcohol) (Gel–PVA) hydrogel which was prepared by a “green” route using microbial transglutaminase (mTGase), which acts as a crosslinking agent. The hydrogel was fully characterized and its ability to entrap and protect L. plantarum from the lyophilization process and under simulated gastric and intestine conditions was explored. The Gel–PVA hydrogel showed a high probiotic loading efficiency (>90%) and survivability from the lyophilization process (91%) of the total bacteria entrapped. Under gastric conditions, no disintegration of the hydrogel was observed, keeping L. plantarum protected with a survival rate of >94%. While in the intestinal fluid the hydrogel is completely dissolved, helping to release probiotics. A Gel–PVA hydrogel is suitable for a probiotic oral administration system due to its physicochemical properties, lack of cytotoxicity, and the protection it offers L. plantarum under gastric conditions.
Pharmaceutics, Volume 14; https://doi.org/10.3390/pharmaceutics14122758
Diabetes mellitus is a metabolic disorder mainly characterized by obesity, hyperglycemia, altered lipid profile, oxidative stress, and vascular compromise. Physalis peruviana is a plant used in traditional Colombian medicine for its known activities of glucose regulation. This study aimed to evaluate the anti-diabetic activity of the butanol fraction from an extract of Physalis peruviana calyces in two doses (50 mg/kg and 100 mg/kg) in induced type 2 diabetic mice. Blood glucose levels were evaluated once a week, demonstrating that a dose of 100 mg/kg resulted in greater regulation of blood glucose levels in mice throughout the experiment. The same overall result was found for the oral glucose tolerance test (OGTT) and the homeostatic model assessment for insulin resistance (HOMA- IR). The lipid profile exhibited improvement compared to the non-treated group, a dose of 100 mg/kg having greater protection against oxidative stress (catalase, superoxide dismutase, and malondialdehyde levels). Histopathological findings in several tissues showed structure preservation in most of the animals treated. The butanol fraction from Physalis peruviana at 100 mg/kg showed beneficial results in improving hyperglycemia, lipidemia, and oxidative stress status, and can therefore be considered a beneficial coadjuvant in the therapy of diabetes mellitus.
Pharmaceutics, Volume 14; https://doi.org/10.3390/pharmaceutics14122757
VEGF is an important neurotrophic and vascular factor involved in mental disorders. The objective of this study was to verify the effect of genetic polymorphisms in the VEGF pathway on the risk for depression, symptom intensity, and suicide attempts. To examine the association between the VEGF pathway and depression, we genotyped polymorphisms and measured the plasma concentrations of VEGF, KDR, and FLT1 proteins. The participants were 160 patients with depression and 114 healthy controls. The questionnaires that assessed the clinical profile of the patients were the MINI-International Neuropsychiatric Interview, GRID-HAMD21, CTQ, BSI, and the number of suicide attempts. Genotyping of participants was performed using the real-time PCR and protein measurements were performed using the enzyme-linked immunosorbent assay (ELISA). VEGF and its inhibitors were reduced in depression. Individuals with depression and displaying the homozygous AA of the rs699947 polymorphism had higher plasma concentrations of VEGF (p-value = 0.006) and were associated with a greater number of suicide attempts (p-value = 0.041). Individuals with depression that were homozygous for the G allele of the FLT1 polymorphism rs7993418 were associated with lower symptom severity (p-value = 0.040). Our results suggest that VEGF pathway polymorphisms are associated with the number of suicide attempts and the severity of depressive symptoms.
Pharmaceutics, Volume 14; https://doi.org/10.3390/pharmaceutics14122756
In this article, nisin(N)-loaded poly lactic-co-glycolic acid (PLGA) nanoparticles (NPs) were prepared using the single-solvent evaporation method with a rhamnolipid(R) cosurfactant. The antibacterial–antibiofilm effects of the prepared formulation and free nisin were evaluated against S. aureus (ATCC 25923). The characterization of NPs was analyzed using scanning electron microscopy (SEM), Zetasizer and Fourier-transform infrared spectroscopy (FTIR). The drug encapsulation efficiency and loading capacity percentages of NPs were calculated by the spectrophotometric method. The drug release of N-loaded PVA-R-PLGA NPs was determined by the dialysis bag method. The antibacterial and antibiofilm activity of N-PVA-R-PLGA NPs was determined. PVA-R-PLGA-NPs were found to be spherical with sizes of ~140 nm, according to the SEM analysis and surface charge of N-PVA-R-PLGA NPs −53.23 ± 0.42 mV. The sustained release of N (≥72% after 6 h) was measured in PVA-R-PLGA-NPs. The encapsulation efficiency percentage of N-PVA-R-PLGA NP was 78%. The MIC values of free nisin and N-PVA-R-PLGA NPs were 256 μg/mL and 64 μg/mL, respectively. The antibiofilm inhibition percentages of free nisin and N-PVA-R-PLGA NPs were 28% and 72%, respectively. These results reveal that N-PVA-R-PLGA NPs are a promising formulation for use in infections caused by S. aureus compared to free nisin.
Pharmaceutics, Volume 14; https://doi.org/10.3390/pharmaceutics14122755
NOD2 is an innate immune receptor that constitutes an important target for the development of small molecule immunopotentiators with great potential to be used as vaccine adjuvants. We report here the results of an in vivo study of the adjuvant properties of a desmuramylpeptide NOD2 agonist SG29 and its lipidated analogs featuring an adamantyl moiety or a stearoyl group. These compounds have been synthesized, incorporated into liposomes, and evaluated for their in vivo adjuvant activity. The characterization of liposome formulations of examined compounds revealed that their size increased in comparison to that of empty liposomes. The introduction of a stearoyl or an adamantane lipophilic anchor into the structure of SG29, to produce SG115 and ZSB63, respectively, substantially improved the in vivo adjuvant activity. Of note, the attachment of the stearoyl moiety produced a Th2-biased immune response, while the incorporation of the adamantyl moiety greatly enhanced the production of total IgG but mostly augmented the production of IgG2a antibodies, which indicated a shift toward a Th1 immune response. The identified bona fide capacity of ZSB63 to initiate a cellular immune response thus highlights its untapped potential as an alternative vaccine adjuvant.
Pharmaceutics, Volume 14; https://doi.org/10.3390/pharmaceutics14122754
Alpha-1 antitrypsin (AAT) deficiency is a genetic disorder associated with pulmonary emphysema and bronchiectasis. Its management currently consists of weekly infusions of plasma-purified human AAT, which poses several issues regarding plasma supplies, possible pathogen transmission, purification costs, and parenteral administration. Here, we investigated an alternative administration strategy for augmentation therapy by combining recombinant expression of AAT in bacteria and the production of a respirable powder by spray drying. The same formulation approach was then applied to plasma-derived AAT for comparison. Purified, active, and endotoxin-free recombinant AAT was produced at high yields and formulated using L-leucine and mannitol as excipients after identifying compromise conditions for protein activity and good aerodynamic performances. An oxygen-free atmosphere, both during formulation and powder storage, slowed down methionine-specific oxidation and AAT inactivation. This work is the first peer-reviewed report of AAT formulated as a dry powder, which could represent an alternative to current treatments.
Pharmaceutics, Volume 14; https://doi.org/10.3390/pharmaceutics14122753
Despite the recent emergence of targeted therapeutic options, there are still unmet needs concerning moderate-to-severe atopic dermatitis treatment. This review aims to discuss the OX40-OX40L pathway as a therapeutic target for the treatment of atopic dermatitis. OX40 and OX40L are two checkpoint molecules that bind to potentiate pro-inflammatory T-cell responses that are pivotal to atopic dermatitis pathogenesis. Two OX40-OX40L inhibitors, rocatinlimab and amlitelimab, are being developed for the treatment of atopic dermatitis. Rocatinlimab, an anti-OX40 antibody, was evaluated in phase 2b, a randomized, placebo-controlled clinical trial. At week 16, rocatinlimab groups achieved a greater reduction in the EASI percentage change from the baseline (−48.3% to −61.1%) against the placebo (−15.0%; p < 0.001), and clinical response was maintained 20 weeks after the treatment had ceased. Amlitelimab, an anti-OX40L antibody, was studied in a 12-week treatment phase 2a clinical trial, with a significant efficacy response observed within 2 weeks. At week 16, amlitelimab groups reached the EASI mean percentage change from the baseline of −69.9% and −80.1% versus the placebo (−49.4%; p = 0.072 and p = 0.009). Among the responders, 68% of amlitelimab patients were sustained 24 weeks following the last dose. Both treatments were shown to be safe and well tolerated. Current evidence points to OX40-OX40L inhibitors as future options for atopic dermatitis treatment with potential disease-modifying effects.