stearates and Disease-Models--Animal

The commercially available alpha-asarone injections (CA-ARE) were frequently found to cause severe anaphylactic reactions by the solubilizer contained in the formulation such as polysorbate 80 and propylene glycol. This study aimed to develop a new ARE injection using Kolliphor HS 15 as solubilizing agent (HS 15-ARE) by the dissolution method to resolve its poor solubility problem and reduce the anaphylaxis of CA-AREs caused by Polysorbate 80. The HS 15-ARE micelle showed a homogeneous round shape with the mean particle size of around 13.73 ± 0.02 nm, polydisperse index (PDI) of 0.19 ± 0.01 and solubilizing efficiency of 95.7% ± 2.4%. In vitro and in vivo studies showed that HS 15-ARE is a stable injection presenting the same pharmacokinetic profile with CA-ARE. Moreover, improved therapeutic effect was observed for HS 15-ARE in treating asthma compared to CA-ARE (p < 0.05) with no anaphylactic reactions observed. These results demonstrate that the new formulation of ARE (HS 15-ARE) has a great potential for replacing CA-AREs injections.

Topics: Allylbenzene Derivatives; Anaphylaxis; Animals; Anisoles; Anti-Asthmatic Agents; Asthma; Biological Availability; Cells, Cultured; Chemistry, Pharmaceutical; Disease Models, Animal; Drug Stability; Erythrocytes; Guinea Pigs; Hemolysis; Histamine; Injections, Intravenous; Male; Molecular Structure; Particle Size; Polyethylene Glycols; Rats, Wistar; Sheep; Solvents; Stearates; Surface Properties; Tissue Distribution

CYP51 is a P450 enzyme involved in the biosynthesis of the sterol components of eukaryotic cell membranes. CYP51 inhibitors have been developed to treat infections caused by fungi, and more recently the protozoan parasite Trypanosoma cruzi, the causative agent of Chagas disease. To specifically optimize drug candidates for T. cruzi CYP51 (TcCYP51), we explored the structure-activity relationship (SAR) of a N-indolyl-oxopyridinyl-4-aminopropanyl-based scaffold originally identified in a target-based screen. This scaffold evolved via medicinal chemistry to yield orally bioavailable leads with potent anti-T. cruzi activity in vivo. Using an animal model of infection with a transgenic T. cruzi Y luc strain expressing firefly luciferase, we prioritized the biaryl and N-arylpiperazine analogues by oral bioavailability and potency. The drug-target complexes for both scaffold variants were characterized by X-ray structure analysis. Optimization of both binding mode and pharmacokinetic properties of these compounds led to potent inhibitors against experimental T. cruzi infection.

Topics: 14-alpha Demethylase Inhibitors; 4-Aminopyridine; Administration, Oral; Animals; Biological Availability; Chagas Disease; Chemistry Techniques, Synthetic; Crystallography, X-Ray; Cyclodextrins; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Humans; Luciferases, Firefly; Mice; Organisms, Genetically Modified; Polyethylene Glycols; Stearates; Structure-Activity Relationship; Tissue Distribution; Trypanocidal Agents; Trypanosoma cruzi

Hepatocellular carcinoma is the most common form of primary hepatic carcinoma. A new N(2)S(2) tetradentate ligand, N-[2-(triphenylmethyl)thioethyl]-3-aza-19-ethyloxycarbonyl-3-[2-(triphenylmethyl)thioethyl]octadecanoate (H(3)MN-16ET), was introduced and labeled with (188)Re to create (188)Re-MN-16ET in the Lipiodol phase. The potential of (188)Re-MN-16ET/Lipiodol for hepatoma therapy was evaluated in a hepatocellular carcinoma animal model of Sprague-Dawley rats implanted with the N1S1 cell line.. Synthesis of H(3)MN-16ET was described, and characterization was identified by infrared, nuclear magnetic resonance and mass spectra. We compared the effects of transchelating agents (glucoheptonate or tartaric acid) and a reducing agent (stannous chloride) on the complexing of (188)Re-perrhenate and H(3)MN-16ET. Twenty-four rats implanted with hepatoma were injected with 3.7 MBq/0.1 ml of (188)Re-MN-16ET/Lipiodol or (188)Re-MN-16ET via transcatheter arterial embolization. Biodistribution experiments and single-photon emission computed tomography imaging were performed to investigate tumor accumulation.. H(3)MN-16ET was proved to easily conjugate with the Re isotope and showed good solubility in Lipiodol. The radiochemical purity of (188)Re-MN-16ET/Lipiodol with 10 mg tartaric acid and stannous chloride was shown to be more than 90%. The major distribution sites of (188)Re-MN-16ET in Sprague-Dawley rats were hepatoma and the liver. However, the radioactivity at the tumor site postadministered with (188)Re-MN-16ET was quickly decreased from 9.15±0.23 (at 1 h) to 2.71%±0.18% of injected dose/g (at 48 h). The biodistribution and micro-single-photon emission computed tomography/computed tomography image data showed that (188)Re-MN-16ET/Lipiodol was selectively retained at the tumor site, with 11.55±1.44, 13.16±1.46 and 10.67%±0.95% of injected dose/g at 1, 24 and 48 h postinjection, respectively. The radioactivity in normal liver tissue was high but significantly lower than that of the tumors.. H(3)MN-16ET is a suitable tetradentate ligand for (188)Re labeling. From the animal data, we suggest that (188)Re-MN-16ET/Lipiodol has the potential to be a therapeutic radiopharmaceutical for hepatoma treatment.

Topics: Animals; Carcinoma, Hepatocellular; Cell Line, Tumor; Coordination Complexes; Disease Models, Animal; Ethiodized Oil; Glycine; Liver Neoplasms; Male; Palmitic Acids; Radiochemistry; Radioisotopes; Rats; Rhenium; Stearates; Tomography, Emission-Computed, Single-Photon

Four long-chain, linear fatty acid dopamides (N-acyldopamines) have been identified in nervous bovine and rat tissues. Two unsaturated members of this family of lipids, N-arachidonoyl-dopamine (NADA) and N-oleoyl-dopamine, were shown to potently activate the transient receptor potential channel type V1 (TRPV1), also known as the vanilloid receptor type 1 for capsaicin. However, the other two congeners, N-palmitoyl- and N-stearoyl-dopamine (PALDA and STEARDA), are inactive on TRPV1. We have investigated here the possibility that the two compounds act by enhancing the effect of NADA on TRPV1 ('entourage' effect). When pre-incubated for 5 min with cells, both compounds dose-dependently enhanced NADA's TRPV1-mediated effect on intracellular Ca(2+) in human embryonic kidney cells overexpressing the human TRPV1. In the presence of either PALDA or STEARDA (0.1-10 microm), the EC(50) of NADA was lowered from approximately 90 to approximately 30 nm. The effect on intracellular Ca(2+) by another endovanilloid, N-arachidonoyl-ethanolamine (anandamide, 50 nm), was also enhanced dose-dependently by both PALDA and STEARDA. PALDA and STEARDA also acted in synergy with low pH (6.0-6.7) to enhance intracellular Ca(2+) via TRPV1. When co-injected with NADA (0.5 micrograms) in rat hind paws, STEARDA (5 micrograms) potentiated NADA's TRPV1-mediated nociceptive effect by significantly shortening the withdrawal latencies from a radiant heat source. STEARDA (1 and 10 micrograms) also enhanced the nocifensive behavior induced by carrageenan in a typical test of inflammatory pain. These data indicate that, despite their inactivity per se on TRPV1, PALDA and STEARDA may play a role as 'entourage' compounds on chemicophysical agents that interact with these receptors, with possible implications in inflammatory and neuropathic pain.

Topics: Animals; Arachidonic Acids; Calcium; Carrageenan; Cell Line; Disease Models, Animal; Dopamine; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Drug Synergism; Drug Therapy, Combination; Endocannabinoids; Hindlimb; Humans; Hyperalgesia; Inflammation; Italy; Kidney; Male; Pain Measurement; Palmitates; Polyunsaturated Alkamides; Rats; Rats, Sprague-Dawley; Receptors, Drug; Stearates; TRPV Cation Channels

We prospectively studied the effect of a foam composite containing glycerin, propylene glycol, polyol, stearine, stearate and silicone oil, which is known to form a temporary barrier layer when applied to epithelial surface, on adhesion prevention in rats. The small intestine abrasion model was used for creation of adhesions. Sixty male Sabra rats of a mean weight of 295 +/- 23 g were randomly assigned into four groups: group 1 (n = 20) underwent laparotomy and abrasion; group 2 (n = 20) underwent laparotomy, abrasion and intraperitoneal instillation of the foam composite; group 3 (n = 10) underwent laparotomy with abrasion and a second laparotomy with adhesiolysis 2 weeks later; and group 4 (n = 10), was treated in the same way as group 3 but during the second laparotomy the foam composite was instilled intraperitoneally. All animals were relaparotomized 2 weeks (groups 1 and 2) and 4 weeks (groups 3 and 4) after the initial laparotomy for adhesion scoring performed by a blinded independent investigator using the standard 0-3 adhesion grading score. Representative specimens of small intestine and liver from animals in groups 2 and 4 were analyzed. A significantly lower mean adhesion score was noted in group 2 (1.15 +/- 0.3) compared with that of group 1 (2.65 +/- 0.1) or group 3 (2.60 +/- 0.1) (P < 0.01). Group 4 had a significantly lower score (1.4 +/- 0.3) than group 3 or group 1 (P < 0.05). There was no significant difference in the mean adhesion score between groups 1 and 3. Histological examination revealed no evidence of residual foam composite or adverse reaction to its use in the intestine and liver. The foam composite tested may reduce the severity of intestinal adhesions after laparotomy and may also reduce the severity of recurrent adhesions after adhesiolysis. Intraperitoneal use of this composite is safe in rats. The exact mechanism of action is unclear but may be related to the formation of a temporary microlayer that coats the injured surface of the intestine and facilitates healing without adhesion formation. Further investigation is needed to evaluate its full potential.

Topics: Animals; Disease Models, Animal; Glycerol; Injections, Intraperitoneal; Intestinal Diseases; Intestine, Small; Laparotomy; Lubrication; Male; Polymers; Propylene Glycol; Prospective Studies; Rats; Silicone Oils; Stearates; Tissue Adhesions