The effect of biocompatible carriers with vitamin D and platelet-rich plasma (PRP) on bone defects.

Introduction: In oral and maxillofacial surgery, hard tissue augmentation is provided by materials that accelerate the healing, act as a template for reconstructing bony defects, and stimulate bone production and growth. This study investigated the effects of biocompatible carriers containing active vitamin D and platelet-rich plasma (PRP) on bone defects created in rat calvaria. Material and Methods: This experimental animal study utilized fifty-two male Sprague Dawley rats divided into six groups and conducted histopathological, microtomographic, and biochemical comparisons by adding vitamin D, which has an accelerating effect on bone development. We examined the calvarial defects, sacrificing the rats in equal numbers (eight in each group and four to obtain PRP) at the first, second, fourth, and eighth weeks. The newly formed bone was assessed using histopathologic, microtomographic, and macroscopic methods as well as the biochemical analysis performed in the plasma samples. Expression of fibroblast growth factor 23 (FGF23), vitamin D receptor (VDR), and receptor activator of nuclear factor-kappa B (RANK), which determine bone formation, were investigated. The amounts of ossification, bone volume, and mineral densities were significantly higher in the fourth and eighth weeks as the biocompatible material was delivered with calcitriol. Results: The histological and macroscopic examinations revealed that the defect area shrank and was colonized with new cells in the "calcitriol + chitosan + PRP" group. The expression of RANK, FGF23, and VDR antibodies was more intense in the "calcitriol + chitosan + PRP" group than in other groups of the experiment and controls. Conclusion: Active vitamin D, PRP, and chitosan formulation positively contributed to the repair of bone defects and induced remarkable clinical improvement. This new delivery approach could be promising for healing bone defects following surgical operations in hard bony tissues. HIPPOKRATIA 2023, 27 (2):48-56.

Effects of atorvastatin on talinolol absorption: A potential drug-drug interaction.

In this study, we aimed to determine the drug-drug interaction potential between atorvastatin (ATOR), and talinolol (TAL). Concentration-dependent effects of ATOR on the intestinal permeability of TAL were investigated by an in situ intestinal perfusion method. Dose-dependent effects of ATOR on TAL exposure were evaluated by measuring plasma concentrations after oral administration in rats. ATOR slightly changed the intestinal secretion of TAL in jejunum but not in colon. Plasma AUC levels of TAL were elevated by co-administration of ATOR at low and high doses whereas medium doses of ATOR resulted in a decrease in TAL bioavailability. However, these changes were not statistically significant. In our study, the pharmacokinetics of TAL were not affected by the concurrent use of ATOR in rats. In conclusion, it should be considered that complex interplay between the efflux and uptake transporters in the tissues and inhibition of these transporters by modulating agents may overshadow individual effects of each other.

Pharmacokinetics of talinolol is modified by barnidipine: implication of P-glycoprotein modulation.

Concomitant administration of P-glycoprotein substrates and inhibitors may cause pharmacokinetic drug interactions leading to increased concentrations associated with serious side effects and toxicities. Barnidipine is a longacting calcium-channel blocker and potent inhibitor of P-glycoprotein in vitro, and talinolol is a beta-blocker and probe substrate of P-glycoprotein. This study was designed to investigate the effects of single and repeated oral doses of barnidipine on talinolol pharmacokinetics in rats. In the single-dose study, talinolol (20 mg/kg) alone and with barnidipine at low (1 mg/kg) and high doses (10 mg/kg) were orally administered to rats. In the repeated-dose study, rats were treated with barnidipine (1 mg/kg/day) or vehicle only for four days, then with talinolol (20 mg/kg, on day 5). Blood samples were collected at 0.5, 1, 2, 4, 6 h following last dose and plasma talinolol levels were determined by HPLC. Compared to the control, Cmax of talinolol elevated 10% (p=0.79) and 110% (p<0.05); plasma AUC0-6h increased 33% (p=0.41) and 46% (p<0.05) following low and high single doses of barnidipine co-administration, respectively. In the repeated-dose study, Cmax and AUC0-6h of talinolol increased 131% (p<0.05) and 130% (p<0.05) respectively, following co-administration of a low barnidipine dose. Double-peaks were observed when single or repeated low doses of barnidipine were co-administered. There may be coupling between occurrence of double-peak phenomenon and P-glycoprotein inhibition. Increment of talinolol bioavailability upon low and high doses of barnidipine co-administration may be due to P-glycoprotein inhibition. The higher increase of talinolol plasma AUC0-6h due to the repeated doses of barnidipine may be explained by downregulation of P-glycoprotein.

Implementation of boundary conditions in modeling the femur is critical for the evaluation of distal intramedullary nailing.

In previous numerical and experimental studies of the intramedullary nail-implanted human femur several simplifications to model the boundary and loading conditions during pre-clinical testing have been proposed. The distal end of the femur was fixed in the majority of studies dealing with the biomechanics of the lower extremity, be it numerical or experimental, which resulted in obviously non-physiological deflections. Per contra, Speirs et al. (2007) proclaimed physiological deflections as a result of constraining the femur in a novel statically determinate fashion in combination with using a complex set of muscle forces. In tandem with this, we have shown that not only the deflections but also the stress and strain predictions turn out to be much lower in magnitude, as a result of using the latter approach. To illustrate the dramatic change in results, we compared these results with those of two other models employing commonly used boundary and loading conditions in retrograde stabilization of a distal diaphyseal fracture. The model used herewith resulted in more realistic femoral cortical strains, lower stresses on both the nail and the screws, as well as such deflections in the overall structure.

The effect of loading in mechanical response predictions of bone lengthening.

Intramedullary (IM) distractor nails have become a viable alternative in bone-distraction operations. Upon stabilization of the fractured/dissected limb via the nail, the resulting construct accommodates the load bearing function of the otherwise healthy limb. In establishing design performance targets for these devices, in vitro test conditions are widely accepted leaving the in vivo conditions aside. However, in vivo device failures due to distraction forces necessitate novel modeling considerations. It is especially important to simulate the loads in limb distraction, as this brings the bone-implant construct to a totally different regime than the hip-joint contact force (Point-Force Model, PFM). In this work we used a simplified approach to incorporate ligament stretching due to limb distraction via self-equilibrating spring elements in a finite-element setting (spring-force model, SFM). We compared the effect of loading type on load transmission paths through the locking pins, for these two distinct loading modes, namely, SFM and PFM. The two modes illustrate entirely different load transfer regimes around the bone/nail interface region. In order to avoid high contact stresses between the nail and the bone segments, it is advisable to keep the osteotomy away from the mid-range between the pin connections. It was also seen for both loading modes that including an additional pin at a load transfer location does not significantly alter the load carried by a single pin (the additional pin rather acts as a geometric stabilizer).

Effect of Aloe vera leaves on blood glucose level in type I and type II diabetic rat models.

Aloe vera (L.) Burm. fil. (= A. barbadensis Miller) (Liliaceae) is native to North Africa and also cultivated in Turkey. Aloes have long been used all over the world for their various medicinal properties. In the past 15 years, there have been controversial reports on the hypoglycaemic activity of Aloe species, probably due to differences in the parts of the plant used or to the model of diabetes chosen. In this study, separate experiments on three main groups of rats, namely, non-diabetic (ND), type I (IDDM) and type II (NIDDM) diabetic rats were carried out. A. vera leaf pulp and gel extracts were ineffective on lowering the blood sugar level of ND rats. A. vera leaf pulp extract showed hypoglycaemic activity on IDDM and NIDDM rats, the effectiveness being enhanced for type II diabetes in comparison with glibenclamide. On the contrary, A. vera leaf gel extract showed hyperglycaemic activity on NIDDM rats. It may therefore be concluded that the pulps of Aloe vera leaves devoid of the gel could be useful in the treatment of non-insulin dependent diabetes mellitus

P-glycoprotein transporters and the gastrointestinal tract: evaluation of the potential in vivo relevance of in vitro data employing talinolol as model compound.

Among the different application routes peroral administration remains the one most widely used. Hence, mechanisms affecting p.o. bioavailability are of particular interest, also in drug development. In recent years, intestinal drug secretion mediated by the multi-drug resistance gene product P-glycoprotein (Pgp) has been discovered as a possible mechanism of low and erratic bioavailability. Due to the saturability of this process, a dose-dependent apparent oral clearance may be observed which decreases upon increasing dose. However, in vivo intestinal secretion might be revealed only in the lower or subtherapeutic dose range. In permeability studies with Caco-2 cell monolayers, the MDR-reversing agent verapamil inhibits secretion of P-glycoprotein substrates and, hence, increases apical-to-basolateral permeability. The aim of the rat studies with talinolol presented here was to test the relevance of the intestinal secretion process as well as the extent of inhibition by verapamil in ex vivo, in situ, and in vivo talinolol/verapamil drug-drug interaction studies. Intestinal secretion of talinolol was detected indirectly in ex vivo studies via transport inhibition with verapamil and directly in in situ intestinal perfusions in rats following a talinolol i.v. bolus. Both i.v. and p.o. verapamil appear to affect the concentration-time profiles of talinolol. Relevant observations with respect to drug absorption are the decreased apparent oral clearance upon verapamil coadministration as well as the decreased tmax and mean absorption times at high verapamil doses. Talinolol may be regarded as a potential model compound for mechanistic studies on Pgp interactions, including permeability as well as binding studies and the involvement of transporters other than Pgp.

Synthesis of new 2-arylidene-2H-1,4-benzoxazin-3(4H)-ones.

A number of 2-arylidene-2H-1,4-benzoxazin-3(4H)-ones were synthesized and evaluated for CNS activity. Some of the tested compounds exhibited marked CNS depressant activity in mice.