Aviva Ezra

Mode of administration-dependent pharmacokinetics of bisphosphonates and bioavailability determination

We investigated the influence of mode of administration on the pharmacokinetics of a clinically used bisphosphonate, pamidronate, and of suberoylbisphosphonate (SuBP), a novel bisacylphosphonate of the P-CO-(C)(n)-CO-P type, in rats. Serum drug levels and tissue disposition were determined following administration of the drugs by different modes: intravenous bolus (iso-osmotic and hypo-osmotic solutions), continuous intravenous infusion, and peroral administration. Results of the study indicate that the disposition of the bisphosphonates in soft tissue (liver, kidney and spleen) was dependent on route and rate of drug administration, and on the osmoticity of the vehicle. Consequently, main pharmacokinetic parameters (AUC, CL, and V(ss)) were influenced by the mode of drug administration, precluding accurate determination of bioavailability from AUC values. On the other hand, bone and urine bisphosphonate accumulation were considerably less dependent on mode of administration, and, therefore, are recommended for bioavailability calculation.

Synthesis and preclinical pharmacology of 2-(2-aminopyrimidinio) ethylidene-1,1-bisphosphonic acid betaine (ISA-13-1)-a novel bisphosphonate.

AbstractPurpose. To validate our hypothesis that a bisphosphonate (BP) having a nitrogen-containing heterocyclic ring on the side chain, and with no hydroxyl on the geminal carbon would possess increased activity, and better oral bioavailability due to enhanced solubility of its calcium complexes/salts and weaker Ca chelating properties. Methods. A novel BP, 2-(2-aminopyrimidinio)ethylidene-l,l-bisphosphonic acid betaine (ISA-13-1) was synthesized. The physicochemical properties and permeability were studied in vitro. The effects on macrophages, bone resorption (young growing rat model), and tumor-induced osteolysis (Walker carcinosarcoma) were studied in comparison to clinically used BPs. Results. The solubility of the Ca salt of ISA-13-1 was higher, and the log βCa: BP stability constant and the affinity to hydroxyapatite were lower than those of alendronate and pamidronate. ISA-13-1 exhibited effects similar to those of alendronate on bone volume, on bone osteolysis, and on macrophages, following delivery by liposomes. ISA-13-1 was shown to have 1.5−1.7 times better oral absorption than the other BPs with no deleterious effects on the tight junctions of intestinal tissue. Conclusions. The similar potency to clinically used BPs, the increased oral absorption as well as the lack of effect on tissue tight junction of ISA-13-1 warrant its further consideration as a potential drug for bone diseases.

Biodegradable Polymers in Clinical Use and Clinical Development: Domb/Biodegradable Polymers

CONTRIBUTORS. PREFACE. PART I GENERAL. 1 Biodegradable Polymers in Drug Delivery (Jay Prakash Jain, Wubante Yenet, Abraham J. Domb, and Neeraj Kumar). PART II BIODEGRADABLE POLYMERS OF NATURAL ORIGIN: PROTEIN-BASED POLYMERS. 2 Collagen (Wahid Khan, Deepak Yadav, Abraham J. Domb, and Neeraj Kumar). 3 Properties and Hemostatic Application of Gelatin (Jalindar Totre, Diana Ickowicz, and Abraham J. Domb). PART III BIODEGRADABLE POLYMERS OF NATURAL ORIGIN: POLYSACCHARIDES. 4 Chitosan and Its Derivatives in Clinical Use and Applications (Anuradha Subramanian, Kirthanashri Srinivasan Vasanthan, Uma Maheswari Krishnan, and Swaminathan Sethuraman). 5 Clinical Uses of Alginate (Udi Nussinovitch and Amos Nussinovitch). 6 Dextran and Pentosan Sulfate - Clinical Applications (Ramu Parthasarathi and Athipettah Jayakrishnan). 7 Arabinogalactan in Clinical Use (Rajendra P. Pawar, Babasaheb A. Kushekar, Bhaskar S. Jadhav, Kiran R. Kharat, Ravikumar M. Borade, and Abraham J. Domb). PART IV BIODEGRADABLE POLYMERS OF NATURAL ORIGIN: POLYESTERS. 8 Polyhydroxyalkanoate (Kesaven Bhubalan, Wing-Hin Lee, and Kumar Sudesh). PART V SYNTHETIC BIODEGRADABLE POLYMERS. 9 Lactide and Glycolide Polymers (Kevin Letchford, Anders Sodergard, David Plackett, Samuel Gilchrist, and Helen Burt). 10 Polyanhydrides Poly(CPP-SA), Fatty-Acid-Based Polyanhydrides (Ravikumar M. Borade, Abraham J. Domb, Archana A. Sawale, Rajendra P. Pawar, and Kiran R. Kharat). 11 Poly(e-Caprolactone-co-Glycolide): Biomedical Applications of a Unique Elastomer (Kevin Cooper, Aruna Nathan, and Murty Vyakarnam). 12 Medicinal Applications of Cyanoacrylate (Rajendra P. Pawar, Ashok E. Jadhav, Sumangala B. Tathe, Bhimrao C. Khade, and Abraham J. Domb). 13 Polyethylene Glycol in Clinical Application and PEGylated Drugs (Teerapol Srichana, and Tan Suwandecha). PART VI INORGANIC POLYMERS. 14 Calcium-Phosphate-Based Ceramics for Biomedical Applications (Qing Lv, Kevin W.-H. Lo, Lakshmi S. Nair, and Cato T. Laurencin). PART VII BIODEGRADABLE POLYMERS FOR EMERGING CLINICAL USES. 15 Biocompatible Polymers for Nucleic Acid Delivery (Jeff Sparks, and Khursheed Anwer). 16 Biodegradable Polymers for Emerging Clinical Use in Tissue Engineering (Shalini Verma, Kalpna Garkhal, Anupama Mittal, and Neeraj Kumar). 17 Injectable Polymers (Shimon A. Unterman, Norman A. Marcus, and Jennifer H. Elisseeff). PART VIII IPR ASPECTS OF BIODEGRADABLE POLYMERS. 18 Global Patent and Technological Status of Biodegradable Polymers in Drug Delivery and Tissue Engineering (Parikshit Bansal, Shalini Verma, Wahid Khan, and Neeraj Kumar). Index.

Cyclosporin pro-dispersion liposphere formulation

OBJECTIVE Preparation and characterization of an oral pro-dispersion liposphere formulation for cyclosporin, a water insoluble drug with limited bioavailability. METHODS Pro-dispersion formulation consisted of a solid fat, dispersing agents and amphiphilic solvents as the major components besides cyclosporin A (CsA) were prepared in the present work. For preparation of this formulation, phospholipid was dissolved in pharmaceutically acceptable water soluble organic solvent, thereafter CsA along with other components was added and formulation optimization was carried out. After formulation preparation, particle size determination and in vitro release study was carried out. Additionally, ultracentrifugation, TEM, Cryo-TEM and DSC techniques were used for in vitro characterization of formulation. The prepared system was also compared with marketed Neoral® microemulsion formulation. RESULTS Liposphere formulations were prepared and optimized as according to procedure. Though, determination of in vitro characteristics of such formulations is complex and difficult, yet selected and performed tests confirmed formation and existence of solid liposphere particles upon dispersion of formulation in water. It was also observed that particle size is influenced by the type of solid fat used and amphiphilic solvent present in the formulation. Prepared pro-dispersion was found to be stable for 2 years under normal storage conditions. CONCLUSION Prepared pro-dispersion liposphere formulation is a homogeneous solution of a lipophilic drug such as cyclosporin in a mixture of surfactants, lipids and ethyl lactate proved to spontaneously form dispersion when added to aqueous media. This formulation concept has a potential clinical use for improved bioavailability of water insoluble drugs.

Novel acylethanolamide derivatives that modulate body weight through enhancement of hypothalamic pro-opiomelanocortin (POMC) and/or decreased neuropeptide Y (NPY).

Newly synthesized acylethanolamide derivatives oleoyl-L-valinolamide (1), oleoyl-D-valinolamide (2), elaidoyl-L-valinolamide (3), elaidoyl-D-valinolamide (4) stearoyl-L-valinolamide (5), and palmitoyl-L-valinolamide (6) were investigated in mice as antiobesity compounds. Compounds 1, 2, 5, 6 significantly decreased body weight by 6.57% following eight injections of 1 mg/kg i.p. during 39 days, while 3 and 4 showed no such activity. Receptor binding indicated that no compound activated CB1, CB2, PPARα, or TRPV1 receptors. Hypothalamic RT-PCR showed that mRNA expression of the anorexigenic genes POMC and CART was up-regulated by 1, 2, 5 and 1, 2, respectively, while that of the orexigenic genes NPY and CaMKK2 was down-regulated by the respective compounds 1, 5, 6 and 1, 2, 5. Oleoyl-L-valinolamide enhances anorectic pathways and lead to decreased glucose levels, enhanced locomotor activity, and improved cognition. Effects of oleoyl-L-valinolamide on weight were dose-dependent, and it could be given orally. 1, 2, 4, 5 down-regulated FAAH mRNA expression.

Analytical Methods Applied to Characterization of Actinidia arguta, Actinidia deliciosa, and Actinidia eriantha Kiwi Fruit Cultivars

AbstractIn this research, eight kiwi fruit genotypes (six hardy kiwis (Actinidia arguta and their hybrids), one of Actinidia deliciosa ‘Hayward,’ and one of Actinidia eriantha ‘Bidan’ were examined and compared by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), Fourier transform infrared (FT-IR) spectra, and nuclear magnetic resonance (NMR) spectroscopy. Proteins were extracted from lyophilized fruits, flesh with seeds, grinded seeds, and singular seeds and then separated by SDS-PAGE. Matrix similarity and dendrogram was generated using Nei coefficient and Unweighted Pair Group Method with Arithmetic mean (UPGMA) algorithm. Based on protein patterns, Actinidia species were clearly distinguishable, whereas differences between hardy kiwi fruit cultivars were minor or nondetectable. The electrophoretical separations were able to distinguish a half of hardy kiwi fruit cultivars, so cluster analysis revealed a limited number of cultivar groups. Intervarietal polymorphism was low and this affected the results of similarity analysis. One distinct cluster, composed of two pairs of cultivars and identical by protein patterns, was obtained. Cultivars ‘Ananasnaya’ and ‘Weiki,’ according to the morphological description, were similar. Oppositely, ‘M1’ cultivar significantly differed from other hardy kiwi cultivars by densitometrical bands intensity. All examined singular seeds of ‘Ananasnaya’ cultivar possessed identical protein patterns. The protein patterns of ‘Bingo’ and ‘Ananasnaya’ hardy kiwi fruits harvested in 2011 and 2013 were identical. Three weeks storage after harvest did not affect the protein composition of these cultivars. FT-IR and NMR spectrum of hardy kiwi fruits were presented and compared with ‘Hayward’ and ‘Bidan’ and showed slight differences in comparison with the protein profiles. SDS-PAGE is more applicable than FT-IR and NMR for comparison of different kiwi fruit cultivars. The used analytical methods can be applied to any food analysis in order to distinguish the main compounds and to present fingerprints of different cultivars. Graphical AbstractA, Actinidia arguta kiwi fruit cultivars; B, Actinidia deliciosa kiwi fruit ‘Hayward’; C,Actinidia eriantha kiwi fruit ‘Bidan’; D, Electrophoretical patterns of proteins extracted with urea bufferfrom: 1, ‘Bingo’; 2, ‘M1’; 3, ‘Ananasnaya’; 4, ‘Weiki’; 5, ‘Jumbo’; 6, ‘Geneva’; 7, ‘Hayward’; 8,‘Bidan’; E, FT-IR spectra of extracted polyphenols. Curves from the top kiwi fruit ‘Ananasnaya,’‘Bingo,’ ‘M1’; F, 1H-NMR spectra from the top of DMSO extracts of ‘Bidan’; ‘Hayward’;‘Ananasnaya’.