In vivo evaluation of a mucoadhesive polymeric caplet for intravaginal anti-HIV-1 delivery and development of a molecular mechanistic model for thermochemical characterization

Context and objective: The aim of this study was to develop, characterize and evaluate a mucoadhesive caplet resulting from a polymeric blend (polymeric caplet) for intravaginal anti-HIV-1 delivery.

Materials and methods: Poly(lactic-co-glycolic) acid, ethylcellulose, poly(vinylalcohol), polyacrylic acid and modified polyamide 6, 10 polymers were blended and compressed to a caplet-shaped device, with and without two model drugs 3′-azido-3′-deoxythymidine (AZT) and polystyrene sulfonate (PSS). Thermal analysis, infrared spectroscopy and microscopic analysis were carried out on the caplets employing temperature-modulated DSC (TMDSC), Fourier transform infra-red (FTIR) spectrometer and scanning electron microscope, respectively. In vitro and in vivo drug release analyses as well as the histopathological toxicity studies were carried out on the drug-loaded caplets. Furthermore, molecular mechanics (MM) simulations were carried out on the drug-loaded caplets to corroborate the experimental findings.

Results and discussion: There was a big deviation between the T_g of the polymeric caplet from the T_g's of the constituent polymers indicating a strong interaction between constituent polymers. FTIR spectroscopy confirmed the presence of specific ionic and non-ionic interactions within the caplet. A controlled near zero-order drug release was obtained for AZT (20 d) and PSS (28 d). In vivo results, i.e. the drug concentration in plasma ranged between 0.012–0.332?mg/mL and 0.009–0.256?mg/mL for AZT and PSS over 1–28 d.

Conclusion: The obtained results, which were corroborated by MM simulations, attested that the developed system has the potential for effective delivery of anti-HIV-agents.     

A hotel recommendation system based on customer location: a link prediction approach

Multimedia Tools and Applications - Hotel recommendation is one of the most used application areas in recommendation systems. So far, many hotel recommendation systems have been proposed. Most of...     

The effects of the pretreatment of intravenous high dose methylprednisolone on Na(+)-K(+)/Mg(+2) ATPase and lipid peroxidation and early ultrastructural findings following middle cerebral artery occlusion in the rat

The sodium-potassium activated and magnesium dependent adenosine-5'-triphosphatase (Na(+)-K(+)/Mg(+2) ATPase EC.3.6.1.3.) activity and lipid peroxidation and early ultrastructural findings were determined in rat brain at the acute stage of ischaemia produced by permanent unilateral occlusion of the middle cerebral artery (MCA). The effects of the pretreatment with intravenous high-dose methylprednisolone (MP) on these biochemical indices and ultrastructural findings were also evaluated in the same model. The rats were divided into four groups. In group I, 10 rats were used to determine Na(+)-K(+)/Mg(+2) ATPase activity and the extent of lipid peroxidation by measuring the malondialdehyde (MDA) content and normal ultrastructural findings. In group II on 20 rats, only subtemporal craniectomy was done in order to determine the effects of the surgical procedure on these indices and findings. This group was treated intravenously with saline solution before occlusion. In group III with MCA occlusion, saline solution was administered intravenously to 20 rats in the same amount of methylprednisolone used in group IV, ten minutes before the occlusion. In Group IV, a single high-dose (30 mg/kg) of methylprednisolone was administered intravenously, ten minutes before occlusion in 20 rats. After occlusion of the middle cerebral artery, Na(+)-K(+)/Mg(+2) ATPase activity was decreased promptly in the first ten minutes in the ischaemic hemisphere and remained at a lower level than the contralateral hemispheres in the same group and the normal levels in group I, during 120 minutes of ischaemia. A single dose methylprednisolone pretreatment prohibited the inactivation of Na(+)-K(+)/Mg(+2) ATPase. On the other hand, there was significant difference in malondialdehyde content between group I and group III. Malondialdehyde levels were significantly increased following ischaemia and a non-significant increase was observed in the contralateral hemisphere. Methylprednisolone treatment significantly decreased malondialdehyde content on the side of the ischaemic hemisphere. We conclude that there is a positive relationship between membrane-bound enzyme Na(+)-K(+)/Mg(+2) ATPase activity, malondialdehyde content and early ultrastructural changes in the treated group with MP. These data suggest that the pretreatment injection of high doses (30 mg/kg) methylprednisolone contribute to the protection of the brain from ischaemia with stabilization of the cell membrane by effecting the lipid peroxidation and the activation of Na(+)-K(+)/Mg(+2) ATPase.     

Isolated ovarian polyarteritis nodosa

Polyarteritis nodosa is a rare disorder and a form of systemic vasculitis. A 48 year-old female was admitted to the hospital because menorrhagia and pelvic pain in February 1993. The patient underwent exploratory laparotomy resulting in a total hysterectomy and bilateral salpingo-oophorectomy for myoma of uterus and a right adnexal cystic mass. Histopathologic examination revealed left ovarian periarteritis nodosa. Further investigation and 9 months follow-up failed to show any systemic involvement. To our knowledge the isolated ovarian polyarteritis nodosa is the first case in the literature.     

Different susceptibility to phospholipase A2 treatment of the fluorescence intensity changes in the vicinity of Cys-964 and Lys-501 in the alpha-chain of probe-labeled Na+,K(+)-ATPase

Phospholipase A2 [EC 3.1.1.4] treatment of pig kidney Na+,K(+)-ATPase [EC 3.6.1.3] labeled with fluorescence probes at the alpha-chain reduced the extent of the fluorescence intensity change of an N-[p-(2-benzimidazolyl)phenyl]maleimide (BIPM) probe at Cys-964 to below one-third of the control level accompanying the accumulation of phosphoenzymes. However, it only induced a slight decrease in that of a fluorescence isothiocyanate (FITC) probe at Lys-501 with a large decrease in the rate of change. The addition of phosphatidylserine (PS) or phosphatidylinositol (PI) to the phospholipase-treated BIPM-FITC-labeled enzyme increased the rate of the FITC fluorescence change. Phospholipase treatment of the BIPM-enzyme greatly reduced the Na+,K(+)-ATPase activity. The addition of PS or PI to the treated enzyme induced reactivation. These data and others suggest that Cys-964 and Glu-953 (Rb+ protectable dicyclohexyl carbodiimide binding site) are located in the vicinity of the surface area of the enzyme where hydrocarbon chains of phospholipids are present, and conserved H-bonding amino acids, Thr-955 and Ser-962, are located rather near the center of a domain forming a cation binding route or cage with other hydrophobic transmembrane segments. These data may indicate that the interaction between the BIPM probe and the hydrocarbon chains of phospholipids changes in such a way as to sense the change in the binding state of various ligands accompanying the sequential appearance of reaction intermediates of the enzyme.     

Influence of fretting on the fatigue strength at the vise clamp-specimen interface

Fretting fatigue is one of the most important phenomena for inducing a significant reduction of fatigue strength and consequently, leading to unexpected failure accidents of the engineering structures even at very low stresses. In the present study, both plain and fretting fatigue tests with zero mean stress were carried out on two different types of steel, low-carbon steel and martensitic stainless steel, by means of a reversed bending fatigue testing machine. The drop in the fatigue strengths through fretting at vise clamp-specimen interface were significant for both tested steels. The fretting processes produced a reduction in fatigue strength of about 27% for low-carbon steel and 16% for martensitic stainless steel.     

A new method for power generation planning and problems of uncertainty

This paper presents a new method for power system planning which considers uncertainties of various system parameters as a part of the criterion function. The criterion function involves both the expected values of total system costs and the cost variances of different power plants. Previously, the authors proposed that these cost variances be evaluated from the existing power system plans in the form of the solutions to the inverse optimization problem, and then applied this procedure to the planning of power systems in Japan. However, because of the correlation between fuel and facility costs, the cost variances could not be determined as specific values. Here, to overcome this difficulty, the authors now introduce hydropower plants into the model as the so-called nonrisky elements and focus on the expenditure shares rather than the plant capacity shares. As a result, more reasonable results are obtained. This improved methodology is applied and the derived cost variances are shown. Further, using the resultant cost variances, the authors make Pareto-optimal power generation plans and demonstrate also the robustness of the method to price fluctuations.