Effects of bisphosphonates on different zones of the epiphyseal growth plate of rats

Bisphosphonates (BIS) are indicated for several clinical disorders (e.g., osteoporosis). However, BIS has been associated with osteonecrosis and alterations in osteoclastogenesis and skeletal development. This study aimed to evaluate the effects of BIS (zoledronic acid - ZA and alendronate sodium - AS) on zones of the growth plate of rat femur. Animals (Wistar rats, n = 19) were divided into groups: 1) AS Group: animals received alendronate sodium orally (3 mg/kg per day); 2) ZA Group: ZA was administered intraperitoneally (0.2 mg/kg per week); and 3) Control Group (CG): a vehicle was administered. Animals were euthanized 21 days after the treatment, and femurs were collected for histological analysis. The images of all zones (resting, proliferative, hypertrophic, and calcified) were processed by the Qcapture® software providing a 40 and 400-fold increase. ZA decreased epiphyseal growth plate cell zones (ZA Group vs. CG) in most cases. Likewise, AS diminished the proliferative zone (AS Group vs. CG). Furthermore, ZA increased the calcified zone (ZA Group vs. CG). Previous works demonstrated that BIS decrease the epiphyseal disc. This reduction is probably due to the shortening of the cellular zones that undergoes calcification/ossification. The present results suggest that BIS should be carefully indicated because these drugs might accelerate epiphyseal closure.

Fabrication of Membrane Sensitive Electrodes for the Validated Electrochemical Quantification of Anti-Osteoporotic Drug Residues in Pharmaceutical Industrial Wastewater

Accurate and precise application of ion-selective electrodes (ISEs) in the quantification of environmental pollutants is a strenuous task. In this work, the electrochemical response of alendronate sodium trihydrate (ALN) was evaluated by the fabrication of two sensitive and delicate membrane electrodes, viz. polyvinyl chloride (PVC) and glassy carbon (GC) electrodes. A linear response was obtained at concentrations from 1 × 10−5 to 1 × 10−2 M for both electrodes. A Nernstian slope of 29 mV/decade over a pH range of 8–11 for the PVC and GC membrane electrodes was obtained. All assay settings were carefully adjusted to obtain the best electrochemical response. The proposed technique was effectively applied for the quantification of ALN in pure form and wastewater samples, acquired from manufacturing industries. The proposed electrodes were effectively used for the determination of ALN in real wastewater samples without any prior treatment. The current findings guarantee the applicability of the fabricated ISEs for the environmental monitoring of ALN.

Apamin-Conjugated Alendronate Sodium Nanocomplex for Management of Pancreatic Cancer

Pancreatic cancer has a low survival rate and has limited therapeutic options due to the peculiarity of the tumor tissue. Cancer nanotechnology provides several opportunities to resolve such difficulties as a result of the high surface-to-volume ratio of nanostructures. Peptide–drug nanocomplexes have proved to have immense potential in anticancer activity against pancreatic cancer cells. Thus, in the present study apamin (APA) and alendronate sodium (ALS) were combined to form nanocomplexes (APA-ALS-NC) against pancreatic cancer cells. Optimization of ALS, incubation time, and sonication time in terms of particle size of the nanocomplex was carried out. The optimized formulation was evaluated for anticancer activities in pancreatic cancer cells (PANC-1 cells). A Box–Behnken design using ALS, incubation time, and sonication time as independent factors and particle size as the response was chosen to optimize the APA-ALS-NC formulation. The optimized APA-ALS-NC had a particle size of 161.52 ± 8.4 nm. The evaluation of APA-ALS-NC in PANC-1 cells was carried out using various in vitro tests. The IC50 values were determined by MTT assay and found to be 37.6 ± 1.65, 13.4 ± 0.59, and 1.01 ± 0.04 µg/mL for ALS, APA, and APA-ALS-NC, respectively. The higher cytotoxicity activity of APA-ALS-NC was confirmed from the higher percentage of cells in the necrosis phase (apoptosis study) and the G2-M phase (cell cycle study) compared to that of ALS and APA. While the loss of mitochondrial membrane potential was less for APA-ALS-NC, the levels of IL-1β, TNF-α, caspase-3, ROS, IL-6, and NF-kB showed that APA-ALS-NC can significantly enhance apoptosis and cytotoxicity in PANC-1 cells. Moreover, Bax (10.87 ± 1.36), Bcl-2 (0.27 ± 0.02), and p53 (9.16 ± 1.22) gene expressions confirmed that APA-ALS-NC had a significant apoptotic effect compared to ALS and APA. In summary, the APA-ALS-NC had a more significant cytotoxic effect than ALS and APA. The results of the present study are promising for further evaluation in pre-clinical and clinical trials for arriving at a successful therapeutic strategy against pancreatic cancer.

Fabrication of Chemically Linked PEGylated Prodrugs for Hydrogel Carriers

Some hydrophilic drugs (e.g. anti-tumor drug of doxorubicin (DOX) and anti-osteoporosis drug of alendronate sodium (ALN)) have great toxic and adverse effects on the human body. In this paper, two kinds of drug-loaded composite gel systems were prepared via mild and efficient chemical reaction synthesis, hyaluronic acid-linked ALN (HA-ALN) hydrogel and polyethylene glycol-linked DOX (Tetra-PEG-DOX) hydrogel. By characterizing their chemical structures, morphological networks, and ultraviolet absorption behaviors, two different types of drug-loaded composite gels can be constructed well. It is expected to achieve effective drug loading and controlled release. The two drug-loaded gels are applied in the fields of antitumor and anti-osteoporosis and exert their application value in the field of biomedicine.

Clinical efficiency of combined pharmacotherapy of сoronary artery disease associated with postmenopausal osteoporosis

The aim of the study. To evaluate the clinical efficacy of combined pharmacotherapy with alendronate sodium and exogenous L-arginine on the background of basic treatment of patients with coronary artery disease (CAD) associated with postmenopausal osteoporosis (PMOP).Material and methods. A double open, prospective, monocentric clinical study in parallel groups involved 58 women in the postmenopausal period with a diagnosis of coronary artery disease: stable angina pectoris II-III FC, who had PMOP (age 71 (65; 77) years). By the method of block randomization, patients were divided into two groups: 1 group – 27 women who received standard basic therapy; 2 group – 31 women who were prescribed a combination of alendronate sodium and L-arginine hydrochloride according to the scheme on the background of basic treatment. The indices of daily ECG monitoring by Holter, structural and functional state of the heart and blood vessels assessment, levels of biomarkers (osteoprotegerin, osteocalcin, homocysteine, VEGF-A) assessment in patients were obtained at study entry and after 3 months of therapy.Results. According to the results of daily ECG monitoring in the dynamics of treatment in patients of both groups there was a significant decrease in the number of episodes of supraventricular arrhythmia per day (by 11.54% and 34.52%, respectively; p<0.05) and the ratio of LF / HF in active and passive period. In patients of group 2 in contrast to group 1, there was also a significant decrease in the number of episodes of tachycardia per day (1.8 times; p<0.05), an increase in RMSSD (by 74.36%; p<0.05), a decrease in LF (by 54.69%; p<0.05) and an increase in HF (by 73.71%; p<0.05) in both active and passive periods. After 3 months of treatment in patients of the 2nd group showed a significant decrease in the IMC thickness of the right CA by 7.95%, the size of the LP by 16.83% compared to baseline (p<0.05), while the 1st group no significant changes in these indicators were observed. Under the influence of treatment in patients of the 2nd group revealed a significant decrease in the level of VEGF-A (by 25.41%; p<0.05), homocysteine (by 10.72%; p<0.05), osteoprotegerin (2 times ; p<0.05), while in patients of the 1st group there was a significant decrease only in the level of VEGF-A (by 20.09%; p<0.05). In patients of group 2 compared with patients of group 1, after 3 months of treatment there were significantly fewer episodes of ventricular and supraventricular arrhythmias, smaller LF meaning, IMC, LA size and greater HF meaning, probably lower levels of osteocalcin, VEGF-A and osteoprotegerin.Conclusions. The use of combined therapy in patients with coronary artery disease, comorbid with PMOP, contributes to positive changes in the autonomic regulation of cardiac activity, structural adjustment of the heart and vascular endothelium, normalization of the balance of biomarkers of osteoreparation and bone resorption.