Future Journal of Pharmaceutical Sciences最新文献

Background

The anti-diabetic drug, empagliflozin (EMPA), has many pleiotropic actions and is challenged recently to possess renoprotective properties. This renoprotective potential is proposed to be mediated via the activation of AMP-activated protein kinase (AMPK)/nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathways. This research investigated the renoprotective potential and the mechanistic pathway of EMPA against methotrexate (MTX)-induced nephrotoxicity and evaluated the role of AMPK by utilizing an AMPK inhibitor, dorsomorphin (Dorso).

Methods

Thirty male Wistar rats, weighing 180–200 g, were divided equally into five groups. Group I represented the control group. Nephrotoxicity was induced in the remaining rats through the administration of a single intraperitoneal injection of MTX (20 mg/kg). Rats were then randomly assigned to: Group 2 (received MTX injection only); Group 3 (received MTX and EMPA 30 mg/kg/day); Group 4 (received MTX and Dorso 0.2 mg/kg/day), Group 5 (received MTX, Dorso, EMPA). After one week, blood samples were collected, the rats were euthanized, and renal tissues were harvested for biochemical and histomorphometric assessments.

Results

MTX produced a significant rise in serum creatinine and tissue MDA levels; an increase in BAX, p53, cytochrome-c expression; a reduction in Bcl2 level; and disruption of renal microarchitecture. In contrast, EMPA therapy in group 3, resulted in a significant improvement of all these parameters, correlated with significant increase in AMPK phosphorylation and Nrf2 expression. Importantly, the co-administration of Dorso, in group 5, prevented EMPA’s beneficial effects.

Conclusion

EMPA has a potential protective effect against MTX-induced toxicity through the activation of the AMPK/Nrf2 signaling pathway.

Background

The RP-HPLC method has been established to simultaneous estimation of seven markers in polyherbal formulation JKC using the C₁₈ (25 × 0.46 cm, i.d,5 µm) column. The mobile phase consisted of methanol: water (80:20) at a flow rate of 1.0 mL/min and observed retention time at 2 to 11 min with sharp points. The marker compounds viz. Andrographolide (AG), Piperine (PP), Picroside-I (P-I), Picroside-II (P-II), α-Cyprone (AC), 6-Shogaol (6S), and 6-Gingerol (6G) were quantified in JKC formulations by HPLC method. Detection was performed at the wavelength (λ) of 229 nm for AG, 343 nm for PP, 279 nm for P-I, 264 nm for P-II, 254 nm for AC, and 280 nm for both 6S and 6G by HPLC–PDA detector.

Results

The marker compounds in JKC formulations were observed in different retention times (R_t) i.e. AG at 3.060 ± 0.01 min, PP at 5.460 ± 0.03 min, P-I at 2.789 ± 0.02 min, P-II at 2.553 ± 0.03 min, AC at 10.951 ± 0.02 min, 6S at 6.302 ± 0.03 min, and 6G at 4.111 ± 0.02 min respectively. The proposed method was validated with acceptable linearity (r² 0.9995–0.9999), precision, robustness, ruggedness, and accuracy (RSD < 2%) under optimum conditions. The limit of detection and quantification of bioactive markers were as: AG (1.386; 4.200 ppm), PP (2.033; 6.161 ppm), P-I (2.822; 8.553 ppm), P-II (2.538; 7.691 ppm), AC (0.269; 0.815 ppm), 6G (0.158; 0.480 ppm), 6S (0.188; 0.569 ppm). The amount (mg/g) of bioactive markers detected and estimated in plants and formulation were as: AG (41.282 ± 0.48; 10.06 ± 0.18), PP (53.81 ± 0.25, 13.82 ± 0.37 in PN, PL; 4.27 ± 0.07), P-I (15.97 ± 0.01; 0.48 ± 0.003), P-II (63.24 ± 0.35; 2.31 ± 0.006), AC (0.42 ± 0.01; 0.36 ± 0.006), 6G (0.71 ± 0.03; 0.16 ± 0.001), and 6S (2.64 ± 0.09; 0.12 ± 0.004) respectively. Method was found to be rugged and robust. The results found for all the validation parameters were within the limits according to ICH guidelines.

Conclusion

The proposed method is fast, precise, economic, and specific and used for the simultaneously quantifiable analysis of seven major bioactive markers in the ingredients (herbs) and the JKC formulations.

Background

In recent years, public awareness of healthy diets has significantly increased, leading to a rise in the consumption of nutritional supplements. Among these, omega-3 fatty acids have become particularly popular. n − 3 polyunsaturated fatty acids (PUFAs) are widely distributed in marine and terrestrial environments. The primary sources of marine n − 3 fatty acid supplements are oily fish, such as anchovies, sardines and mackerel. Recently, they have drawn considerable attention for their potential therapeutic benefits in treating a range of illnesses, including cancer, neurological disorders, cardiovascular diseases, immunological and reproductive diseases, respectively.

Main text

This study explores the many activities of n − 3 PUFAs, highlighting their importance in cellular processes that include signaling pathways, cell membrane integrity and structural maintenance. These fatty acids significantly regulate important physiological functions including the neurological system, blood pressure control, hematopoiesis, glucose metabolism and inflammatory responses. The latter highlights the wide therapeutic range of n − 3 PUFAs is especially notable considering the implications for controlling inflammatory disorders. Furthermore, the chemistry and dietary sources of omega-3 fatty acids are clarified in this review, which also sheds light on the complex molecular pathways that support the therapeutic efficacy of these fats and their bioavailability. The most recent information on the FDA's approval of omega-3 oils for use in formulation development highlights the compounds' adaptability and potential influence on the development of novel medications.

Conclusion

A thorough analysis of omega-3 polyunsaturated fatty acids reveals both their remarkable therapeutic potential against a variety of diseases and their essential place in a normal diet. This study adds to the increasing amount of data that supports the use of n − 3 PUFAs in preventative and therapeutic approaches that are meant to improve human health and well-being by clarifying their mechanisms of action and emphasizing their applicability in formulation and development.

Background

The human skin, as the body’s largest organ, is particularly sensitive to many chemical mutagens and carcinogens encountered in daily life. Skin cancer has become a notable global health concern, partly due to increased exposure to environmental pollutants and UV rays. Various treatments are available to treat skin cancer. Imiquimod is approved for the treatment of actinic keratosis and basal cell carcinoma. The present investigation aimed to develop nanoemulsion-based gel with imiquimod (2.5% w/w) and carbopol ultrez 10 NF using a modified method to enhance the solubility, permeation, and therapeutic effectiveness of imiquimod to treat skin cancer. Combinations of rose oil and oleic acid, with Tween 20/Propylene glycol as Smix, were used in the formulation. The formulation underwent evaluation for parameters such as % drug content, in vitro drug diffusion studies, viscosity, skin irritation, in vitro cytotoxicity assay (MTT assay) and the DMBA/ croton oil skin cancer in vivo model.

Results

The formulation showed a minimum globule size of 118 nm, a zeta potential– 56.26 mV, a PDI of 0.378 and a drug content of 99.77%. In vitro drug release exhibited 45.00% of imiquimod release within 8 h, while approximately 34.32% release was found from the commercial cream. The imiquimod-loaded nanoemulsion-based gel showed significant cytotoxicity (p < 0.001) against the A431 cell line compared to Imiquad cream. The IC₅₀ value of the imiquimod-loaded nanoemulsion-based gel was noted to be 10.76 ± 2.54 µg/mL. In vivo results showed a significant reduction in tumor incidence (16.66%), tumor volume (140.26 ± 3.48 mm³), tumor burden (5.50 mm³) and tumor mass (0.66 ± 0.05 g) compared with the DMBA/croton oil carcinogen treatment control group. Histopathological finding showed the absence of keratinized pearls, epidermal hyperplasia, and acanthosis in the formulation treated group.

Conclusion

The results revealed that the nanoemulsion-based gel, with half the IMQ concentration of the commercial cream and incorporating Carbopol Ultrez 10NF, is a promising method for treating skin carcinogenesis. It potentially reduces dose-dependent side effects and demonstrating enhanced efficacy.

Graphical abstract

Background

As per World Health Organization (WHO) database, neurological and psychiatric disorders constitute a significant and escalating source of morbidity, impacting over one billion lives with a staggering 9 million fatalities. Unfortunately, the magnitude of these disorders remains largely untreated, primarily due to the formidable challenge of the cerebrospinal fluid–brain barrier (CBB), blood–brain barrier (BBB), as well as the blood–cerebrospinal fluid barrier (BCSFB) compromising the central nervous system (CNS) therapies. Thus, there is a need to explore innovative drug delivery platforms capable of overcoming these barriers in order to facilitate effective delivery of therapeutic drugs.

Main body of abstract

Intranasal drug delivery (INDD) of nanoformulations has emerged as a promising approach, leveraging advantages such as a high surface area, nanoscale particle size, mucoadhesion, noninvasive administration with rapid, and greater drug bioavailability. In this, cubosomal drug delivery (DD) has emerged as a pivotal targeted drug delivery strategy, particularly in the therapy of neurological ailments. Nowadays, researchers and academicians have focused their efforts to tailor cubosomes (CBS) specifically for improving efficacy of central nervous system (CNS) therapies.

Conclusion

This review gives an idea about current status of neurological disorders (ND), the barriers that restricts CNS drug delivery (BBB), and possible nasal pathways of CBS for effective drug transport. A central focus is placed on intranasal (IN) cubosomal formulations for several NDs, elucidating their potential benefits while addressing existing challenges. In essence, this comprehensive review provides valuable insights into innovative approaches that hold promise for addressing the use and need of IN-CBS in the treatment of NDs.

Background

Cancer of unknown primary (CUP) is an orphan disease generally presented by undifferentiated and aggressive morphological phenotype. The treatment of CUP is solely dependent upon the origin of cancer. Despite extensive diagnostic testing, in most of the cases the primary site remains unidentifiable.

Case presentation

This case demonstrates a 75-year-old male patient, who initially presented with the complaints of swelling over right side of the neck since 2 months. A cervical lymph node biopsy was taken for immunohistochemistry, which revealed cytokeratin (CK) and CK7 markers to be positive. Computerized tomography (CT) of Thorax showed subcentimetric subpleural nodules in bilateral lungs fields, predominantly in lower lobes (metastatic in nature). A subsequent pulmoCORE 12 gene panel test was recommended, and patient was discharged with tablet gefitinib 250mg and capsule containing vitamins plus minerals. After one month, patient revisited with the pulmoCORE 12 gene test report which revealed polymorphism in TP53. A pathogenic variant of tumor protein p53 (TP53), i.e., p.Glu198Ter (amino acid alteration) and c.592G > T (coding) variant, was detected, which has 17.2% variant allele frequency. There are no treatment guidelines for TP53 mutation; therefore, the patient was treated with injection paclitaxel 70mg and carboplatin 100mg for 12 cycles along with palliative radiotherapy of 20 Gy for 5 fractions. The overall prognosis of patient was found to be favorable.

Conclusions

There is a need for development of comprehensive guidelines and new molecularly targeted therapies for treatment of CUP which can be tailored for each patient and achieve precise therapeutic outcome.

Background

Carbapenems are one of the most noteworthy choices for treating multidrug-resistant Acinetobacter baumannii (A. baumannii). Currently, carbapenem-resistant A. baumannii (CRAB) represents a healthcare problem worldwide, particularly among diabetic patients who are more susceptible to microbial infections. The aim of this study was to investigate the differences in antibiotic susceptibility profiles, the abundance of carbapenem resistance genes across A. baumannii-infected diabetic and non-diabetic patients, and the antimicrobial activity of different antibiotic combinations on highly resistant isolates.

Methods

Data of 99 A. baumannii-infected patients were collected during the period from 2018 to 2022 and categorized according to patients’ diabetes status into either diabetic or non-diabetic group. A total of 45 A. baumannii isolates were collected during 2021 and 2022 from the main hospital laboratory to be reidentified and genetically confirmed. Antibiotic susceptibility, including carbapenems, was determined using disc agar diffusion and broth microdilution methods. The isolates were screened for OXA-23, GES, VIM, and NDM carbapenem-resistant genes. Five antibiotic combinations were assessed using the double-disk synergy and checkerboard methods.

Results

The findings of the current study revealed that multidrug resistance increased gradually, from 56% in 2018 to 95.6% in 2022. Moreover, CRAB increased among diabetics and non-diabetics. Resistance rates of imipenem, meropenem, and doripenem reached 68.8%, 61.8%, and 47.4% in diabetics and 97.9%, 83.3%, and 50% in non-diabetics, respectively. The VIM gene was the most prevalent gene with prevalence rates of 100% and 96.15% in diabetics and non-diabetics, respectively. Moreover, all A. baumannii isolates carried at least two of the selected carbapenem-resistant genes. Across the different used combinations, only the tigecycline-meropenem combination showed synergistic activity in 50% of diabetic and 66.7% of non-diabetic isolates.

Conclusions

An increased carbapenem resistance was observed among A. baumannii-infected individuals, both diabetic and non-diabetic. The MEM/TCG combination was the only one that showed synergistic or additive effects against highly resistant isolates making it a viable alternative treatment option.

Background

To overcome the problem of side effects and toxicity, development of new anticancer agents is needed. Recently, piperidine salicylanilide derivatives with nanomolar epidermal growth factor receptor (EGFR) inhibitory and cytotoxicity activity have been reported. In the present study effect of replacing piperidine in reported piperidine salicylanilide with N-methyl piperazine and changing substituent’s of phenyl ring at other end on anticancer activity have been explored. A series of sixteen methyl piperazine incorporated phenyl benzamide and phenyl methanone derivatives have been synthesized and tested in a panel of three cancer cell lines (adenocarcinomic human alveolar basal epithelial cells (A-549), human colon carcinoma (HCT-116) and human pancreatic carcinoma (MIAPaCa-2)), using gefitinib as standard. Further, to study the probable mechanism, due to their structural similarity with EGFR inhibitors, docking interactions with EGFR active site were observed using Schrodinger suite.

Result

The results indicated that most of the compounds showed promising activity; out of which, compound A-11 was most active having cytotoxicity much better than that of gefitinib. It showed IC₅₀ value of 5.71 µM against A-549 cell line, 4.26 µM against HCT-116 colon cancer line and 31.36 µM against MIAPaCa-2 cell line.

Conclusion

It was found that these compounds fit well in the active site and may be exhibiting anticancer activity via EGFR inhibition.

Graphical Abstract

Background

This study aimed to formulate solid self-nanoemulsifying drug delivery systems (SNEDDS) for nimodipine (NIM). The selection of Cremophor RH 40, Lipoxol 300, and PEG 400 as oil, surfactant, and co-surfactant was based on solubility and self-emulsification assessments. A ternary phase diagram determined the optimal oil to Smix (surfactant/co-surfactant) ratio (40:60). By utilizing liquid SNEDDS (NIM-SNEDDS) as an adsorbate and chitosan EDTA microparticles, developed through spray drying (SD-CHEM) and solvent evaporation (SE-CHEM) as adsorbents, the solid SNEDDS were created (NIM-SD-SSNEDDS and NIM-SE-SSNEDDS, respectively).

Results

Both solid formulations exhibited favourable drug loading (NIM-SD-SSNEDDS = 79.67 ± 2.97%, NIM-SE-SSNEDDS = 77.76 ± 4.29%), excellent flowability, and drug amorphization as per XRD and DSC analysis. Scanning electron microscopy revealed smoothening and filling of adsorbent surfaces by adsorbate (with size range NIM-SD-SSNEDDS = 10–15 μm, NIM-SE-SSNEDDS = 20–25 μm). FTIR confirmed no interaction of drug and excipients. Stability studies demonstrated the physical and thermodynamic stability of reconstituted nanoemulsions with droplet size, PDI, zeta potential, emulsification time, % transmittance and cloud temperature for NIM-SD-SSNEDDS as 247.1 nm, PDI 0.620, 1.353 mV, 38–41 s, 94.64%, 54 °C and for NIM-SE-SSNEDDS as 399.6 nm, PDI 0.821, 1.351 mV, 40–48 s, 92.96%, 49 °C, respectively. FE-SEM images showed globules formed with small sizes, and there was no coalescence evidence, implying the reconstituted nanoemulsions' stability. In vitro dissolution studies revealed a fourfold increase in drug dissolution for NIM-SD-SSNEDDS (84.43%) and NIM-SE-SSNEDDS (76.68%) compared to pure drug (28%). Ex vivo permeation studies indicated almost similar profiles for NIM-SD-SSNEDDS (22.61%) and NIM-SE-SSNEDDS (21.93%) compared to NIM-SNEDDS (25.02%).

Conclusion

NIM-SD-SSNEDDS exhibited superior performance compared to NIM-SE-SSNEDDS, highlighting the efficacy of microparticles developed by the spray drying method (SD-CHEM) as adsorbents for solidification. These results suggest enhanced dissolution and permeation for nimodipine in both the solid SNEDDS.

Background

The Analytical Quality by Design (AQbD) methodology extends the application of Quality by Design (QbD) principles to the management of the analytical procedure life cycle, encompassing method creation, optimization, validation, and continuous improvement. AQbD assists in creating analytical procedures that are robust, reliable, precise, and cost-efficient. Opdualag™ is a combination of Nivolumab and Relatlimab, which are antibodies that block programmed death receptor-1 (PD-1) and lymphocyte-activation gene 3 (LAG-3) receptors, used to treat advanced melanoma. This work aims to develop and validate a reversed-phase ultra-performance liquid chromatography (RP-UPLC) method using AQbD principles to determine NLB and RTB in pharmaceutical products.

Results

A central composite design (CCD) comprising three factors arranged in five distinct levels was implemented via Design-expert® software to optimize the chromatographic conditions. A mathematical model was constructed and the effects of three independent factors namely flow rate (X₁), percentage of methanol in the mobile phase (X₂), and temperature (X₃) on responses including retention time (Y_1–2), resolution factor (Y₃), theoretical plates (Y_4–5), and tailing factor (Y_6–7) were investigated. The software determined the optimal chromatographic conditions for the separation of NLB and RTB, which were as follows: 32.80% methanol in the mobile phase, 0.272 mL/min flow rate, 29.42 °C column temperature, and 260 nm UV detection. The retention time for NLB and RTB were 1.46 and 1.88 min, respectively. The method exhibited linearity across the concentration ranges of 4–24 µg/mL for RTB and 12–72 µg/mL for NLB. The limits of detection (LOD) and limit of quantification (LOQ) for NLB and RTB, respectively, were 0.89 µg/mL, 2.69 µg/mL and 0.15 µg/mL and 0.46 µg/mL. The percentage relative standard deviation (%RSD) of intraday and interday precision for NLB and RTB was below 2. The recovery percentages for NLB and RTB were determined to be 99.57–100.43% and 99.59–100.61%, respectively. Both drugs were found to be susceptible to oxidative and photolytic degradation in forced degradation studies.

Conclusions

Employing the AQbD-based methodology, a straightforward, fast, accurate, precise, specific, and stability-indicating RP-UPLC method has been established for the quantitative analysis of NLB and its RTB in pharmaceutical formulations.