Study of the Interaction Between β-Cyclodextrin and Chlorhexidine

Pharmaceutical Research -     

Interaction of 5′-deoxy-5-fluorouridine and methotrexate

Methotrexate (MTX) toxicity is reduced significantly by a non-toxic dose of 5-deoxy-5-fluorouridine (5dFUr). Changes in the hematopoietic system (platelets, erythrocytes, leukocytes, and hematocrit), ileal tissue, and body weight were used as parameters to assess toxicity. MTX treatment alone resulted in: (a) a reduction of body weight; (b) significantly morphological changes in ileal tissue; and (c) a marked decrease in the hematopoietic parameters. Sequential treatment with MTX followed by 5dFUr resulted in reversal of MTX depression of animal body weight and ileal tissue necrosis, and partial reversal in MTX toxicity to the hematopoietic system. Also, for all parameters studied, there were no significant differences between scheduling of MTX after a priming dose of 5dFUr, 5dFUr alone, and control. Hence, this study suggests that 5dFUr is a pharmacological antidote for MTX toxicity, and, therefore, 5dFUr in combination with MTX may provide a basis whereby more intense and effective MTX therapy may be given.This research was supported by MBRS Grant 2S06RR0816-14     

Interaction of N-benzoyl-D-phenylalanine and related compounds with the sulphonylurea receptor of β-cells

1. The structure activity relationships for the insulin secretagogues N-benzoyl-D-phenylalanine (NBDP) and related compounds were examined at the sulphonylurea receptor level by use of cultured HIT-T15 and mouse pancreatic β-cells. The affinities of these compounds for the sulphonylurea receptor were compared with their potencies for K_ATP-channel inhibition. In addition, the effects of cytosolic nucleotides on K_ATP-channel inhibition by NBDP were investigated.
2. NBDP displayed a dissociation constant for binding to the sulphonylurea receptor (K_D value) of 11 μM and half-maximally effective concentrations of K_ATP-channel inhibition (EC₅₀ values) between 2 and 4 μM (in the absence of cytosolic nucleotides or presence of 0.1 mM GDP or 1 mM ADP).
3. In the absence of cytosolic nucleotides or presence of GDP (0.1 mM) maximally effective concentrations of NBDP (0.1–1 mM) reduced K_ATP-channel activity to 47% and 44% of control, respectively. In the presence of ADP (1 mM), K_ATP-channel activity was completely suppressed by 0.1 mM NBDP.
4. The L-isomer of N-benzoyl-phenylalanine displayed a 20 fold lower affinity and an 80 fold lower potency than the D-isomer.
5. Introduction of a p-nitro substituent in the D-phenylalanine moiety of NBDP did not decrease lipophilicity but lowered affinity and potency by more than 30 fold.
6. Introduction of a p-amino substituent in the D-phenylalanine moiety of NBDP (N-benzoyl-p-amino-D-phenylalanine, NBADP) reduced lipophilicity and lowered affinity and potency by about 10 fold. This loss of affinity and potency was compensated for by formation of the phenylpropionic acid derivative of NBADP. A similar difference in affinity was observed for the sulphonylurea carbutamide and its phenylpropionic acid derivative.
7. Replacing the benzene ring in the D-phenylalanine moiety of NBDP by a cyclohexyl ring increased lipophilicity, and the K_D and EC₅₀ values were slightly lower than for NBDP. Exchange of both benzene rings in NBDP by cyclohexyl rings further increased lipophilicity without altering affinity and potency.
8. This study shows that N-acylphenylalanines interact with the sulphonylurea receptor of pancreatic β-cells in a stereospecific manner. Their potency depends on lipophilic but not aromatic properties of their benzene rings. As observed for sulphonylureas, interaction of N-acylphenylalanines with the sulphonylurea receptor does not induce complete inhibition of K_ATP-channel activity in the absence of inhibitory cytosolic nucleotides.

     

The Effect of Hydrophobic Character of Drugs and Helix-coil Transition of κ-Carrageenan on the Polyelectrolyte-drug Interaction

Purpose. The extent of adsorption.of different drug molecules to -carrageenan was investigated in order to evaluate the effect of drug hydrophobicity on the adsorption isotherm. Methods. Dialysis experiments were used to determine the amount of drug adsorbed to the polyelectrolyte. The amount of drug on both sides of the membrane was determined spectrophotometrically after attaining equlibrium. CMC for the drugs were determined by the dye solubilisation method. Results. It is shown that the small differences in structure between the drug molecules used in this study still leads to considerable difference in adsorption properties, especially the onset of adsorption. It was also found that the slope of the adsorption isotherms among the drug molecules followed the same pattern as the CMC values for drugs. The extent of adsorption of drugs to the helix form of -carrageenan was much higher than to the coil form. Conclusions. These results suggest that the adsorption of charged drug molecules to an oppositely charged polymer is effected not only by the coulombic interactions, but also by the hydrophobicity of the drug. Furthermore, the adsorption of drug molecules to -carrageenan in the helix form is higher than for the coil form because of the shorter distance between the charges and the thereby enhanced hydrophobic interaction between bound drug molecules.     

Interaction between Δ 9-tetrahydrocannabinol and morphine on the motor activity of mice

The present experiments dealt the effects of ⁹-tetrahydrocannabinol (THC) on the locomotor activity stimulating action of morphine in mice. In the first series of experiments, the pretreatments of mice by THC in doses up to 20 mg/kg have been found to potentiate the morphine-induced hyperactivity in dose-dependent manner, but higher doses of THC did not produce such an action. In the second series of experiments the dose-response curve of morphine for the motor activity has been found to shift to the left by the pretreatment of mice with 10 mg/kg of THC. These results show a synergism between morphine and THC and suggest that both drugs may share some common site of action.     

Interaction between clopidogrel and proton-pump inhibitors

The American Heart Association/American College of Cardiology guidelines recommend initiating a proton-pump inhibitor (PPI) to prevent gastrointestinal bleeding if patients are receiving concomitant therapy with clopidogrel and aspirin. Recently, concern has been raised regarding the ability of PPIs to decrease the antiplatelet activity of clopidogrel. To date, there are 16 studies that evaluated the outcomes of using clopidogrel with a PPI. One of the studies has shown that adding lansoprazole to clopidogrel has no effect on the concentration of clopidogrel's inactive metabolite. The eight clinical trials that studied the effect of using PPIs and clopidogrel together on platelet function testing have shown differing effects between PPIs. Concurrent omeprazole and clopidogrel use was shown to decrease the antiplatelet effects of clopidogrel in three studies; whereas pantoprazole, lansoprazole and esomeprazole have been shown to have no significant effect on the antiplatelet response to clopidogrel. Six other studies showed that using PPIs and clopidogrel together led to adverse clinical outcomes; however, one study that did a separate analysis on pantoprazole, showed that using pantoprazole with clopidogrel had no significant impact on clinical outcomes. Post hoc analysis from a large randomized trial comparing prasugrel with clopidogrel indicated no clinically significant effects of PPIs in patients treated with either prasugrel or clopidogrel. Preliminary results from a prospective, randomized trial comparing cardiovascular clinical outcomes between omeprazole and placebo in clopidogrel-treated patients have been reported and suggest no interaction. However, the study was stopped prematurely secondary to loss of funding and follow-up limited to a median of 133 days so no firm conclusions were drawn. The data currently available regarding concurrent clopidogrel and PPI use are limited, so further studies are needed to provide a definite conclusion. Until additional prospective studies are available, the use of clopidogrel with a PPI should be avoided, if possible, and a H(2)-receptor antagonist be selected instead. Prasugrel may be administered safely with a PPI as there is currently no evidence of a pharmacokinetic, pharmacodynamic or adverse clinical effects.     

Interaction between Δ9-Tetrahydrocannabinol and d-amphetamine

d-Amphetamine increases the motor activity at a dose range of 0.5–4 mg/kg. ⁹-Tetrahydrocannabinol (THC) diminishes this effect dose-dependently. Also, the hyperthermia caused by 5 mg/kg d-amphetamine is antagonized by THC, whereas the d-amphetamine induced sterotype movements (above 4 mg/kg) are prolonged by the cannabinoid.THC and d-amphetamine both reduce the food and water intake and the normal development of body weight of rats. In combination the two substances have an additive effect.Rats treated with 5 mg/kg d-amphetamine show a significant enhancement of the dopamine (DA) concentration (26%) in the brain stem 2 h p.i. Pretreatment with 10 mg/kg THC, which also causes an increase of DA by 15%, raises the DA content by 50%. Norepinephrine (NE) in the brain stem and hypothalamus is reduced by d-amphetamine but THC has no effect on the concentration of this monoamine.After subchronical treatment with THC tolerance is demonstrable to all THC effects tested. But there is no cross tolerance between ⁹-THC and d-amphetamine since the pharmacological as well as the biochemical effects of d-amphetamine occur despite the subchronical treatment with THC.     

Nanoprobing of the Effect of Cu2+ Cations on Misfolding, Interaction and Aggregation of Amyloid β Peptide

Misfolding and aggregation of the amyloid β-protein (Aβ) are hallmarks of Alzheimer’s disease. Both processes are dependent on the environmental conditions, including the presence of divalent cations, such as Cu²⁺. Cu²⁺ cations regulate early stages of Aβ aggregation, but the molecular mechanism of Cu²⁺ regulation is unknown. In this study we applied single molecule AFM force spectroscopy to elucidate the role of Cu²⁺ cations on interpeptide interactions. By immobilizing one of two interacting Aβ42 molecules on a mica surface and tethering the counterpart molecule onto the tip, we were able to probe the interpeptide interactions in the presence and absence of Cu²⁺ cations at pH 7.4, 6.8, 6.0, 5.0, and 4.0. The results show that the presence of Cu²⁺ cations change the pattern of Aβ interactions for pH values between pH 7.4 and pH 5.0. Under these conditions, Cu²⁺ cations induce Aβ42 peptide structural changes resulting in N-termini interactions within the dimers. Cu²⁺ cations also stabilize the dimers. No effects of Cu²⁺ cations on Aβ-Aβ interactions were observed at pH 4.0, suggesting that peptide protonation changes the peptide-cation interaction. The effect of Cu²⁺ cations on later stages of Aβ aggregation was studied by AFM topographic images. The results demonstrate that substoichiometric Cu²⁺ cations accelerate the formation of fibrils at pH 7.4 and 5.0, whereas no effect of Cu²⁺ cations was observed at pH 4.0. Taken together, the combined AFM force spectroscopy and imaging analyses demonstrate that Cu²⁺ cations promote both the initial and the elongation stages of Aβ aggregation, but protein protonation diminishes the effect of Cu²⁺.     

Solubility and Permeability Improvement of Quercetin by an Interaction Between α-Glucosyl Stevia Nanoaggregates and Hydrophilic Polymer

The effect of composite formation between α-glucosyl stevia (Stevia-G) and hydrophilic polymers on solubility and permeability enhancement of quercetin hydrate (QUE) was evaluated. Polyvinylpyrrolidone K-30 (PVP), hydroxypropyl methylcellulose 2910-E (HPMC), and hydroxypropyl cellulose SSL (HPC) were selected as candidate hydrophilic polymers. Fluorescence studies with pyrene and curcumin suggested composite formation occurs between Stevia-G aggregate and polymers. Furthermore, the strength of interaction between Stevia-G aggregate and polymers was as follows: PVP > HPMC > HPC. Evaporated particles (EVPs) of QUE with Stevia-G and polymers showed synergic QUE solubility enhancement. Solubility of QUE from the EVPs was enhanced in the following order: Stevia-G/PVP > Stevia-G/HPMC > Stevia-G/HPC, in accordance with the degree of interaction. Enhanced membrane permeability of QUE from the EVPs of Stevia-G/PVP was confirmed using Caco-2 cells. The amount of QUE that permeated Caco-2 cells from the EVPs of Stevia-G/PVP was 13.7-, 4.7-, and 2.1-fold higher than that of the untreated QUE powder, EVPs of Stevia-G, and EVPs of PVP, respectively. These results indicated that the composite formed by Stevia-G and PVP can dramatically enhance the solubility and membrane permeability of QUE.     

Pharmacokinetic Drug–Drug Interaction of the Novel Anticancer Agent E7070 and Acenocoumarol

E7070 is a novel sulfonamide anticancer agent that arrests cancer cells at the G1/S boundary of the cell cycle. Three patients receiving chronic therapy with the oral anticoagulant acenocoumarol experienced bleeding and/or a prolonged prothrombin time after treatment with E7070 at a dose of 700mg/m² given as a 1-h infusion. In vitro studies have shown that E7070 has the potential to inhibit several cytochrome P450 (CYP)-enzymes, including CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4. The major enzyme involved in the metabolism of acenocoumarol in man is CYP2C9. This study was performed to investigate the interaction between E7070 and acenocoumarol.Blood samples were obtained from two patients receiving daily oral maintenance treatment with acenocoumarol both prior to and following treatment with E7070. In addition, we incubated acenocoumarol enantiomers with pooled human microsomes with and without E7070 and measured the in vitro plasma protein binding of acenocoumarol after incubation with E7070. Pharmacokinetic parameters of acenocoumarol were calculated by noncompartmental analysis and revealed that in both patients the area under the concentration–time curve up to 24h after the acenocoumarol administration was higher following E7070 (2.56 and 1.58h*mol/L) compared to the systemic exposure in the absence of E7070 (1.87 and 1.23h*mol/l). The formation of acenocoumarol metabolites was retarded by E7070 at already low concentrations (2.1M). The plasma protein binding of acenocoumarol was reduced at higher concentrations of E7070 (259M).These results indicate that E7070 may primarily interact with acenocoumarol by reducing its systemic clearance. Displacement of acenocoumarol's plasma protein binding by E7070 may also occur but to a minor extent. In the absence of careful monitoring this drug–drug interaction may result in hypoprothrombinemia and a hemorrhagic tendency.     

Interaction of lubricants with microcrystalline cellulose and anhydrous lactose — a solubility parameter approach

Based on a model involving the integrating of the Lennard-Jones pair potential function to predict the properties of a single and two component system it has been possible to predict the intensity of the molecular interactions between the excipients microcrystalline cellulose and anhydrous lactose and the lubricants magnesium stearate, stearic acid and polytetrafluoroethylene using literature values of their partial solubility parameters. In the case of magnesium stearate the lubricant-excipient interactions are higher than those of lubricant-lubricant while in the case of polytetrafluoroethylene the reverse is true. This is consistent with the generally held belief that magnesium stearate forms a monomolecular film around the excipient causing a decrease in tablet strength.     

Alginate-deoxycholic Acid Interaction and Its Impact on Pancreatic Β-Cells and Insulin Secretion and Potential Treatment of Type 1 Diabetes

Introduction

The secondary bile acid, deoxycholic acid (DCA), has been shown to exert membrane stabilising effects on a pH sensitive delivery system for the oral delivery of insulin. However, its potential applications in the microencapsulation of pancreatic β-cells using hydrogels and polyelectrolytes have not been investigated and may require refined microencapsulating methods. Thus, this study aimed to optimise a newly developed microencapsulating method for pancreatic β-cell delivery (Ionic-Gelation-Vibrational-Jet-Flow; IGVJF) and examine the effects of DCA incorporation on β-cells microcapsules, using various excipients.

Methods

Ten different formulations were prepared (five controls and five tests containing DCA) utilising different concentrations of water soluble gel, polystyrenes, sodium alginate (SA), polyallylamine, and poly-L-ornithine (PLO), and different microencapsulating methods were screened for most uniform microcapsules. The net flow nozzle size ratio of inner:outer flow through the concentric system was examined for best microcapsules. β-cell microcapsules for each formulation were analysed for cell biology and functions (insulin at 1 and 60 h), and microcapsules were examined for appearance.

Results

The used IGVJF method produced best microcapsules when the inner:outer flow nozzle size is 120/200 μm. In addition, deoxycholic acid addition produced higher cell biological activity and functions, postmicroencapsulation, regardless of excipients’ ratio used. DCA has inhibitory effects on pro-inflammatory cytokine secretion by the microencapsulated cells, while microcapsule size and strength remained similar. Microcapsule morphology and membrane surface characteristics were similar for all formulations with noticeable improvements by DCA addition occurring at the lowest PLO concentrations.

Conclusion

An inner:outer nozzle size of 120/200 μm, in the deployed microencapsulating method, in combination with the secondary bile acid deoxycholic acid, produced stable microcapsules with improved cell functionality, suggesting suitability for cell microencapsulation and transplantation.

     

Interaction of secreted phospholipase A2 and Pulmonary surfactant and its pathophysiological relevance in acute respiratory distress svndrome

Phospholipases A_2(PLA_2s)belong to a family of enzymes that hydrolyze phospholipids at the sn-2 position leading to the liberation of fatty acids and lysophospholipids(Fig 1). Mammaliall PLA_2s are divided into two major classes according to their location: high molecular mass intracellular PLA_2 and low molecular mass secreted PLA_2(sPLA_2)(Fig 2). There have been Substantial progresses in understanding the regulation of sPLA_2 expression. especiallv the type-ⅡA sPLA_2     

Interaction Between Bile Salts and β-Adrenoceptor Antagonists

The interactions between -adrenoceptor antagonists and bile salts were investigated by microcalorimetry. Nadolol and oxprenolol interactions with dihydroxy salts could be described by a 1:1 interaction model with the thermodynamic parameters indicating that the drugs were incorporated within the bile salt aggregates. This weak interaction was primarily hydrophobic although electrostatic attraction also played a role. Atenolol and metoprolol did not interact with the dihydroxy salts. None of the compounds interacted with trihydroxy bile salts or with salts below their aggregation concentration. Phase separation resulted when propranolol and alprenolol were present in dihydroxy salt solutions above a certain concentration with the interaction being of a hydrophobic and electrostatic nature. The implications of these results on in-vivo drug absorption are discussed.     

Interaction of ambient temperature with the effects of Δ 9 on brain catecholamine synthesis and plasma corticosterone levels

The effects of ⁹ (THC) on body temperature, catecholamine synthesis and plasma corticosteroid levels were examined in the mouse at ambient temperatures of 31°, 20° and 10°C in order to study the role of hypothermia in THC's other actions. THC produced hypothermia at 10° and 20°C, but not at 31°C. Dose related increases in dopamine and norepinephrine synthesis rates and plasma corticosterone levels were produced by THC at bot 31° and 20°C. The effects of THC at 10°C were biphasic. These data indicate that the effects of THC on brain catecholamines are not a result of drug induced hypothermia and may be a result of a direct action on neurons.     

Interaction of vascular endothelial cells with leukocytes, platelets and cancer cells in inflammation, thrombosis and cancer growth and metastasis

Adhesion and migration of mammalian cells are of crucial importance in a number of biological events, such as fertilization, embryogenesis, pattern, tissue and organ formation, and in a variety of physiological and pathological processes, including lymphocyte trafficking, leukocyte recruitment, hemostasis, wound healing, tumor angiogenesis and cancer metastasis. All these     

Interaction of Puerarin with Phospholipid in Solid Dispersion

Aim:To study the interaction of puerarin(PU) with phospholipid(PL)in solid dispersion.Methods:PU/PL solid dispersion was prepared with solvent evaporation and the interaction between PU and PL was studied by analysis of their ultraviolet spectra,infrared spectra,1H NMR spectra and thin layer chromatogram.Results:In chloroform the maximum absorption peak of pu in PU/PL mixture was located at 243nm,but 251nm for that of PU in solid dispersion.Howerver in methanol,QU in mixture or solid dispersion had the same maximum absorption peak location in ultraviolet spectra.Compared with the infrared spectra of mixture,that of solid dispersion showed the specific absorption peak location of berzene ring framework in PU molecule was markedly changed,the stretching vibration peak of P=O in PL molecule was shifted to high wavernumbers and the stretching vibration peak of C=C in PL molecule was disappeared.In 1H NMR spectra,most of the signals form PU in solid dispersion were weaken markedly or disappeared and the signals from the polar part of PL molecule were significantly changed.PU and PL in solid dispersion could be spearated on silica gel plate with the mixed solvent of chloroform,methanol and water (65:25:5)or ethyl acetate and methanol(10:1).Conclusion:In solid dispersion the benzene ring framework of PU molecule could act with the polar part and unsaturated part of PL molecule through charges transfer,and the interacted part could be surrounded by fat chains of PL molecule.     

Interaction of Omeprazole with a Methylated Derivative of β-Cyclodextrin: Phase Solubility,NMR Spectroscopy and Molecular Simulation

Purpose Cyclodextrins are known to be good solubility enhancers for several drugs, improving bioavailability when incorporated in pharmaceutical formulations. In this work we intend to assess and characterize the formation of inclusion complexes between omeprazole (OME) and a methylated derivative of β-cyclodextrin, methyl-β-cyclodextrin (MβCD). A comparison with results obtained from the most commonly used natural cyclodextrin, β-cyclodextrin (βCD) is also presented in most cases. Materials and Methods The interaction of OME with the mentioned cyclodextrins in aqueous solutions was studied by phase solubility studies, 1D ¹H and 2D rotating frame nuclear overhauser effect NMR spectroscopy (ROESY) and Molecular Dynamics. Results The solubility of OME was significantly increased by formation of inclusion complexes with each cyclodextrin. Phase solubility studies and continuous variation plots revealed that OME forms an inclusion complex in a stoichiometry of 1:1 with both cyclodextrins. ¹H NMR and ROESY spectra of the inclusion complexes indicated that the benzimidazole moiety is included within the cyclodextrins cavities. Molecular dynamics showed that OME is more deeply included in the MβCD than in βCD cavity, in agreement with a larger apparent stability constant (K _S) obtained for the inclusion complex with MβCD. Conclusions MβCD proved to be an efficient enhancer of OME solubility, thus possessing characteristics for being an useful excipient in pharmaceutical formulations of this drug.     

Discovery of Potent and Simplified Piperidinone-Based Inhibitors of the MDM2–p53 Interaction

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Drug–Drug Pharmacodynamic Interaction Detection by a Nonparametric Population Approach. Influence of Design and of Interindividual Variability

Population approaches are appealing methods for detecting then assessing drug–drug interactions mainly because they can cope with sparse data and quantify the interindividual pharmacokinetic (PK) and pharmacodynamic (PD) variability. Unfortunately these methods sometime fail to detect interactions expected on biochemical and/or pharmacological basis and the reasons of these false negatives are somewhat unclear. The aim of this paper is firstly to propose a strategy to detect and assess PD drug–drug interactions when performing the analysis with a nonparametric population approach, then to evaluate the influence of some design variates (i.e., number of subjects, individual measurements) and of the PD interindividual variability level on the performances of the suggested strategy. Two interacting drugs A and B are considered, the drug B being supposed to exhibit by itself a pharmacological action of no interest in this work but increasing the A effect. Concentrations of A and B after concomitant administration are simulated as well as the effect under various combinations of design variates and PD variability levels in the context of a controlled trial. Replications of simulated data are then analyzed by the NPML method, the concentration of the drug B being included as a covariate. In a first step, no model relating the latter to each PD parameter is specified and the NPML results are then proceeded graphically, and also by examining the expected reductions of variance and entropy of the estimated PD parameter distribution provided by the covariate. In a further step, a simple second stage model suggested by the graphic approach is introduced, the fixed effect and its associated variance are estimated and a statistical test is then performed to compare this fixed effect to a given value. The performances of our strategy are also compared to those of a non-population-based approach method commonly used for detecting interactions. Our results illustrate the relevance of our strategy in a case where the concentration of one of the two drugs can be included as a covariate and show that an existing interaction can be detected more often than with a usual approach. The prominent role of the interindividual PD variability level and of the two controlled factors is also shown.