Impact of Study Design on the Evaluation of Inhaled and Intranasal Corticosteroids' Effect on Hypothalamic–Pituitary–Adrenal Axis Function

In part I of this review, an overview of the designs of hypothalamic–pituitary–adrenal (HPA) axis studies in the setting of inhaled corticosteroids (ICS) or intranasal corticosteroids (INS) use was discussed. Part II provides detailed discussion on the HPA axis evaluation results for each common ICS and INS, and how these results are possibly affected by the factors of study design. Significant adrenal suppression at conventional ICS/INS doses appears to be rare in clinical settings. The magnitude of cortisol suppression varies widely among different study designs. Factors potentially impacting this variability include: the choice of dose, dosing duration, assay sensitivity, statistical methodology, study population, and compliance. All of these factors have the potential to affect the extent of HPA axis effects detected and should be considered when designing or interpreting the results of a HPA axis study. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:2963–2979, 2014     

Structure–effect relationships of amiodarone analogues on the inhibition of thyroxine deiodination

OBJECTIVES: Amiodarone (AMI) has proven to be a potent anti-arrhythmic compound. Due to the structural similarity between AMI and thyroid hormone, it is possible that the drug could inhibit the activity of the 5'-thyroxine-deiodinase. METHODS: AMI analogues resulting from (1) dealkylation, (2) deiodination and (3) deamination were synthesised and used as inhibitors in an in vitro biotransformation reaction of thyroxine (T4) to 3,3',5'-triiodothyronine (T3). Using high-performance liquid chromatography and ultraviolet detection for quantifying T3, it was found that the 5'-T4 deiodinase type I was involved in the reaction. On separate occasions, AMI or an AMI analogue was added to the reaction as an inhibitor. RESULTS: All studied AMI analogues inhibited 5'-T4 deiodination competitively (Ki value range 25-360 microM). In the concentration range of 1-1000 microM, AMI and its N-desethylated, deiodinated analogues inhibited 5'-T4 deiodination very weakly. AMI analogues with a hydroxyl group at the 4-position were strong inhibitors. Moreover, diiodo-AMI analogues inhibited 5'-T4 deiodination more strongly than their corresponding monoiodo- or deiodinated derivatives. CONCLUSION: It is likely that the degraded products of AMI could be responsible for thyroid dysfunction toxicosis in AMI therapy.     

Influence of continuous veno–venous haemodiafiltration and continuous veno–venous haemofiltration on the pharmacokinetics of fluconazole

OBJECTIVE: To compare the elimination of fluconazole by continuous veno-venous haemodiafiltration (CVVHD) and continuous veno-venous haemofiltration (CVVH) at different dosages. INTERVENTION: Patients received doses of 400 mg (n=3), 600 mg (n=1) or 800 mg (n=2) fluconazole as a short-time infusion once a day. Patients underwent CVVHD the first day and CVVH the second day. CVVHD and CVVH were performed using an acrylonitrile hollow-fibre filter at a constant blood flow of 90 ml/min and a substitution flow of 1000 ml/h (predilution). During CVVHD, the dialysate flow was 1000 ml/h. Ultrafiltration rates were 1158+/-90.5 ml/h during CVVHD and 1167+/-81.6 ml/h. Serum and ultrafiltrate/dialysate concentrations of fluconazole were determined on nine occasions over 24 h. PARTICIPANTS: Six critically ill patients with acute renal failure (ARF) and serious fungal infection. RESULTS: Extracorporeal clearance (CVVHD 30.5+/-6.0 ml/min, CVVH 17.5+/-4.0 ml/min) and total clearance of fluconazole (CVVHD 37.9+/-4.4 ml/min, CVVH 25.3+/-6.5 ml/min) were significantly higher during CVVHD (P < 0.05). During CVVHD, the sieving coefficient (S(CVVHD)) was 0.88 (range 0.54-1) and the elimination half-life (t1/2) was 14.8-35.1 h. During CVVH, the S(CVVH) was 0.96 (range 0.56-1.02) and t1/2 was 24.0-51.6 h. CONCLUSIONS: A daily dosage of 400-800 mg fluconazole is recommended in the treatment of life-threatening fungal infections in critically ill patients undergoing CVVHD since the clearance of CVVHD may considerably exceed the clearance in patients with normal renal function, which is about 20 ml/min. Drug monitoring is highly recommended for these patients.     

Effect of Chronic Hypertension on the Blood–Brain Barrier Permeability of Libenzapril

Very little information is available on the permeability of theblood–brain barrier (BBB) to small polar drugs inchronic hypertension. The blood and cerebrospinal fluid (CSF)pharmacokinetics of liben-zapril (LZP), a potentangiotensin converting enzyme inhibitor, were investigated inhypertensive (SH) and normotensive (SD) rats.Following intravenous bolus administration of this hydrophilic drug, theterminal rate constant for elimination (),steady-state volume of distribution ( ), and systemic clearance (CL) were similar in these two animalgroups. Other pharmacokinetic parameters (C_p°,, k _l2, and k ₂₁)were significantly (P < 0.05) greater in thehypertensive group, except for the volume of the central compartment(V_c) and ratio of V_c to , which were smaller in SH rats. The ratio ofarea under the concentration–time curve (AUC) in CSF toblood was about twofold higher in SH rats compared to normotensive rats,showing increased BBB permeability in hypertensive rats. An acute brainuptake study was also performed in SH, SD, and WK rats by intracarotidadministration of ¹⁴C-LZP along with³H₂O as a reference marker. Both LZP and watertransport was found to be significantly higher (about two-to five-fold) in six of the seven different brain regions inSH rats as compared to the normotensive (SD and WK) controls.Because of this simultaneous increase in concentrations of both the drugand the reference marker, BUI values were not affected. Regional brainconcentrations in SH rats were also linearly correlated with the meanarterial pressure (MAP) values, providing further evidence ofthe systemic pressure related increase in BBB permeability.     

Study on the quantitative structure–toxicity relationships of aconitine compounds basing on PCA-ANN method

Aconitine compounds are diterpenoid alkaloids found in the roots/rhizome of Aconitum napellus, Aconitum carmichaeli, and other Aconitum plants in the family of Ranunculanceae, which have beneficial pharmacological activity along with toxicity. The quantum chemistry parameters of thirty-six aconitine compounds were calculated using Gaussian software, and the quantitative structure–toxicity relationships of aconitine compounds were studied in mice via oral acute toxicity (LD₅₀). A model was built to more accurately predict the toxicity of aconitine compounds in mice versus oral LD₅₀. Twenty-seven aconitine compounds were used as a training dataset for building the principal component analysis combined with artificial neural network model and nine others as a forecasting dataset to test the prediction ability of the model using SAS 9.0 program software and Matlab 7.5 software. The model derived a good forecasting ability (MSE = 0.50, R ² = 0.9818 $ R_{\text{pred}}^{2} $  = 0.9457, $ r_{{{\text{m}}\left( {\text{test}} \right)}}^{2} $  = 0.9130, $ r_{{{\text{m}}\left( {\text{overal}} \right)}}^{2} $  = 0.9207, $ R_{\text{r}}^{2} $  = 0.6561, $ {\text{c}}R_{\text{r}}^{2} $  = 0.5655).     

Development of intravenous lipid emulsion of vinorelbine based on drug–phospholipid complex technique

In order to reduce the severe venous toxicity, we developed an intravenous lipid emulsion of vinorelbine and investigated its preclinical stability, toxicity and antitumor efficacy. Vinorelbine–phospholipid complex was prepared to enhance the lipophilicity of vinorelbine thus facilitating the encapsulation into lipid emulsion. After complexation more than 70% of vinorelbine was encapsulated into the oil phase. Meanwhile, the lipid emulsion showed good stability without drug leakage. Local irritation after injection of the lipid emulsion was investigated in rabbits and compared with Navelbine^® (the commercial product). The antitumor therapeutic efficacies were evaluated in tumor-bearing mouse models inoculated with A549 human lung cancer cells and BCAP-37 human breast cancer cells and compared as well. Results showed that the lipid emulsion significantly reduced the injection irritation compared with that of Navelbine^®, while maintained the antitumor activity in A549 and BCAP-37 cells xenograft tumor mouse models. Taken together, lipid emulsion loaded with vinorelbine–phospholipid complex is a promising vinorelbine intravenous injection with reduced venous irritation.     

Toxic effect of melanoidins from glucose–asparagine on trypsin activity

In this work the effect of the presence of the melanoidins from glucose–asparagine on the enzymatic activity of trypsin is studied. It was observed that an excess of Nα-benzoyl-l-arginine ethyl ester (BAEE) has an inhibiting effect on this enzyme activity. The maximum reaction rate was obtained for a 0.06 mN substrate concentration. It is also observed that the presence of melanoidin inhibits the enzymatic activity of trypsin. This inhibition can be described as a linear mixed type where the inhibition constant αK_i of the substrate–inhibitor complex is higher than the inhibition constant K_i of the complex enzyme–inhibitor with a α value of 1.88.     

Effects of cysteine on the pharmacokinetics of docetaxel in rats with protein–calorie malnutrition

1. The objective of this study is to report the effects of cysteine on the pharmacokinetics of intravenous and oral docetaxel in rats with protein–calorie malnutrition (PCM). The in vivo pharmacokinetics and in vitro hepatic/intestinal metabolism of docetaxel were assessed using control, CC (control with cysteine), PCM and PCMC (PCM with cysteine) rats. The effects of cysteine on the intestinal absorption of docetaxel were further investigated through in vitro transport studies using rat intestine and Caco-2 cell monolayers.

2. The AUCs (the areas under the plasma concentration-time curve from time zero to time infinity) of intravenous docetaxel in PCM rats were significantly greater than in the control rats because of the significant decrease in the hepatic CYP3A. In PCMC rats, the elevated AUCs in PCM rats returned to control levels. The AUC_{0–6 h}s of oral docetaxel in PCM rats were significantly smaller than that in the control rats, mainly due to the decrease in gastrointestinal absorption. In CC and PCMC rats, oral cysteine supplement enhanced the gastrointestinal absorption of docetaxel probably via intestinal P-gp inhibition.

3. If the present rat data could be expressed to humans, the alterations in docetaxel absorption and metabolism should be considered in designing a dosage regimen for cancer patients with PCM state after cysteine supplement.

     

Food–drug interactions: effect of capsaicin on the pharmacokinetics of galantamine in rats

1. Capsaicin (trans-8-methyl-N-vanillyl-6-nonenamide, CAP) is a naturally occurring alkaloid extracted from the fruit of Capsicum plant family. It represents an important ingredient in spicy foods consumed throughout the world. However, little is known about the metabolic interactions between CAP and clinically used drugs.

2. This study attempted to investigate the effect of CAP on the pharmacokinetics of galantamine, a competitive and reversible cholinesterase inhibitor. CAP, dexamethasone or sodium salt of carboxymethyl cellulose (CMC-Na) was given to rats for seven consecutive days and on the seventh day galantamine (10 mg/kg) was administered orally. Dexamethasone was used as a CYP inducer and CMC-Na was used as a vehicle.

3. The results showed that the pretreatment of rats with CAP resulted in a decrease in the AUC_0–∞ of galantamine of about 49.70% (p < 0.01) compared with the control group. After oral administration of galantamine (10 mg/kg), the apparent oral clearance of galantamine was raised by 2.05-fold by pretreatment with CAP (p < 0.05). These results demonstrate that the chronic ingestion of high doses of CAP will decrease the bioavailability of galantamine to a significant extent in rats.

     

Comparative examination of adsorption of serum proteins on HSA- and PLGA-based nanoparticles using SDS–PAGE and LC–MS

The behavior of nanosized drug carrier systems under cell culture conditions and therefore also the destiny in the body are highly influenced by the protein corona, which is formed upon entering a biological environment. Some of the adsorbed proteins, named opsonins, lead to a shortened plasma circulation half-life of the nanoparticles. Others are attributed to promote the transport of nanoparticles into other compartments of the body, just to mention two examples. Hence, detailed knowledge concerning the composition of the protein corona is of great importance. The aim of this work was to investigate the influence of the nanoparticle starting material and the surface modification on the composition of the adsorbed serum proteins in a cell culture environment. Therefore, positively charged nanoparticles based on the biodegradable polymer poly(dl-lactide-co-glycolide) (PLGA) stabilized with didodecyldimethylammonium bromide (DMAB) and negatively charged nanoparticles based on human serum albumin (HSA) were prepared and modified with hydrophilic polymers. By incubating the nanoparticles with fetal bovine serum (FBS) the adsorption of serum proteins on the colloidal system was investigated. Using sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS–PAGE) a semi-quantitative analysis of the protein corona was performed and after enzymatic in-solution-digestion the adsorbed proteins were identified using high resolution LC–MS. Our study accentuates the influence of the core material, surface charge, and surface modification on the amount and nature of the adsorbed proteins. The combination of SDS–PAGE and LC–MS turns out to be a simple and reliable method to investigate the protein corona of nanoparticles.     

Influence of the Polymer–Micelle Interaction on Micelle‐Substrate Binding

In an attempt to investigate how a nonionic polymer, hydroxypropyl methylcellulose (HPMC), interacts with a cationic surfactant, hexadecyltrimethylammonium bromide (CTAB), a dialysis method was employed for directly measuring the HPMC–CTAB interaction. The result showed that an interaction existed between CTAB and HPMC, and the higher the HPMC concentration the greater the fraction of CTAB bound. The shift in the UV spectra represents the change in the microenvironment. UV spectroscopy was employed to indicate the location of substrates, α‐NA, IBA, and oil red O, in the CTAB micelles. The study of solubility as a function of CTAB concentration was the method used for determining the binding constants of the substrates. The addition of HPMC decreased the binding constants of the substrates to the micelles. It implied that the HPMC‐CTAB interaction influenced the substrate binding regions. The IBA binding constant was also determined using a potentiometric titration method. The results agreed well between the two methods. © 2009 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 99: 1440–1451, 2010     

Mucoadhesive buccal patches based on interpolymer complexes of chitosan–pectin for delivery of carvedilol

The study was designed to develop bioadhesive patches of carvedilol hydrochloride using chitosan (CH) and pectin (PE) interpolymer complexes and to systematically evaluate their in vitro and in vivo performances. Mucoadhesive buccal patches of carvedilol were prepared using solvent casting method. The physicochemical interaction between CH and PE was investigated by FTIR and DSC studies. The patches were evaluated for their physical characteristics like mass variation, content uniformity, folding endurance, ex vivo mucoadhesion strength, ex vivo mucoadhesion time, surface pH, in vitro drug release, in situ release study, and in vivo bioavailability study. The swelling index of the patches was found to be proportional to the PE concentration. The surface pH of all the formulated bioadhesive patches was found to lie between 6.2 and 7.2. The optimized bioadhesive patch (C1, CH:PE 20:80) showed bioadhesive strength of 22.10 ± 0.20 g, in vitro release of 98.73% and ex vivo mucoadhesion time of 451 min with in a period of 8 h. The optimized patch demonstrated good in vitro and in vivo results. The buccal delivery of carvedilol in rabbits showed a significant improvement in bioavailability of carvedilol from patches when compared to oral route.     

Effects of sertraline on kinematic aspects of hand movements in patients with obsessive–compulsive disorder

Rationale Movement disorders such as disturbances of fine motor co-ordination are a frequent phenomenon in patients with obsessive–compulsive disorder (OCD).Objectives Our aim was to investigate changes of hand-motor dysfunction in OCD patients under the influence of 10-week treatment with sertraline and behaviour therapy.Methods We examined the performance of 40 patients satisfying DSM-IV criteria for OCD before and under this therapy using a digitising tablet and kinematic analysis of handwriting and drawing movements. Forty healthy controls were also tested (test–retest interval: 10 weeks).Results The speed of drawing was significantly lower in OCD patients than in controls (mean±standard deviation=197.03±113.26 mm/s for patients and 182.48±189.61 mm/s for controls; P=0.01). After 10 weeks of therapy, this parameter normalised in patients (from 197.03±113.26 mm/s to 163.66±101.92 mm/s; P=0.001).Conclusions Hand-motor dysfunction (especially bradykinesia) improves with a serotonin-enhancing therapy in OCD patients.     

Effects of peptidase inhibitors on anti-nociceptive action of dynorphin-(1–8) in rats

Previous in vitro studies showed that the degradation of dynorphin-(1-8) [dyn-(1-8)] by cerebral membrane preparations is almost completely prevented by a mixture of three peptidase inhibitors (PIs), amastatin, captopril and phosphoramidon. In the present investigations, effects of the three PIs on the anti-nociception induced by the intra-third-ventricular (i.t.v.) administration of dyn-(1-8) were examined. The inhibitory effect of dyn-(1-8) on the tail-flick response was increased more than 100-fold by the i.t.v. pretreatment of rats with the three PIs. The inhibition produced by dyn-(1-8) in rats pretreated with any combination of two PIs was significantly smaller than that in rats pretreated with three PIs, indicating that any residual single peptidase could inactivate significant amounts of dyn-(1-8). The antagonistic effectiveness of naloxone, a relatively selective mu-opioid antagonist, indicates that dyn-(1-8)-induced inhibition of tail-flick response in rats pretreated with three PIs is mediated by mu-opioid receptors. Furthermore, mu-receptor-mediated inhibition induced by dyn-(1-8) was significantly greater than that produced by [Met5]-enkephalin in rats pretreated with three PIs. The data obtained in the present investigations together with those obtained in previous studies strongly indicate that dyn-(1-8) not only has well-known kappa-agonist activity but also has high mu-agonist activity.     

Effectiveness of an educational intervention on health risks of vaping for high school–aged adolescents

ObjectiveThe primary objective of this research was to identify if an educational intervention increased the knowledge of high school adolescents on the social and health risks associated with vaping. The secondary objectives included measuring the prevalence of vaping habits and the attitudes of adolescents on the safety of vaping.MethodsThis research was conducted with adolescents at a single high school. An evidence-based educational intervention was provided on the health risks associated with vapingproductsData were collected using a pre- and postsurvey tool. The material presented was targeted on the basis of age and making the information relevant and easy to understand.ResultsA total of 235 participants showed a 14% increase in scores from the pre- to postsurvey, indicating an increase in knowledge (P < 0.001). Gender was not a predictor for vaping behavior, but grade level was. A significantly higher proportion of participants who vaped reported vaping being safer than smoking than those who did not vape (χ² = 13.31, P = 0.001). The most common reason for vaping was stress reduction. For the participants who reported vaping, the most common reason indicated that would motivate them to stop the use of vaping products was concern regarding the negative impact on personal or family health (n = 43).ConclusionAn educational intervention was successful in improving high school students’ knowledge on the risks associated with vaping. Knowledge on health risk was the most common reported reason for which students would stop vaping.     

The Study of the Influence of Formulation and Process Variables on the Functional Attributes of Simvastatin–Phospholipid Complex

Purpose

The aim of the present study was to examine the influence of the formulation and process variables on the entrapment efficiency of simvastatin–phospholipid complex (SPC), prepared with a goal of improving the solubility and permeability of simvastatin.

Methods

The SPC was prepared using a solvent evaporation method. The influence of formulation and process variables on simvastatin entrapment was assessed using a central composite design. An additional SPC was prepared using the optimized variables from the developed quadratic model. This formulation was characterized for its physical–chemical properties. The functional attributes of the optimized SPC formulation were analyzed by apparent aqueous solubility analysis, in vitro dissolution studies, dissolution efficiency analysis, and ex vivo permeability studies.

Results

The factors studied were found to significantly influence the entrapment efficiency. The developed model was validated using the optimized levels of formulation and process variables. The physical–chemical characterization confirmed a formation of the complex. The optimized SPC demonstrated over 25-fold higher aqueous solubility of simvastatin, compared to that of pure simvastatin. The optimized SPC exhibited a significantly higher rate and extent of simvastatin dissolution (>98 %), compared to that of pure simvastatin (～16 %). The calculated dissolution efficiency was also found to be significantly higher for the SPC (～54 %), compared to that of pure simvastatin (～8 %). Finally, the optimized SPC exhibited a significantly higher simvastatin permeability (>78 %), compared to that of pure simvastatin (～11 %).

Conclusion

The present study shows that SPC can be a promising strategy for improving the delivery of simvastatin and similar drugs with low aqueous solubility.

     

Effect of food restriction on cocaine locomotor sensitization in Sprague–Dawley rats

Rationale

The interaction between repeated cocaine exposure and food restriction on sensitization to the stimulatory effects of cocaine has not been characterized.

Objectives

To compare cocaine sensitization in rats free fed and food restricted, and begin to explore the role of the stress-responsive dynorphin/kappa opioid system.

Methods

Male rats were maintained for 10 days on two feeding conditions: free fed or food restricted (85 % of free fed weight). Test 1 of locomotor reactivity to cocaine (3, 9, or 15 mg/kg, IP) was followed by a sensitizing regimen of cocaine exposure (0 or 30 mg/kg/day × 5 days, IP), by a 10-day drug-free period, and by Test 2 of reactivity to the same cocaine dose. In a second experiment, rats received an injection of norbinaltorphimine (nor-BNI; 0, 5 or 20 mg/kg, SC) 10 days prior to each locomotion test, and plasma corticosterone (CORT) was assessed after Test 2.

Results

On Test 1, it was found that food restriction enhanced locomotor responses to all doses of cocaine. On Test 2, it was found that free fed and food restricted animals displayed similar sensitized responses to cocaine. This, however, was not observed in nor-BNI-treated rats. Furthermore, 20 mg/kg nor-BNI reduced both the locomotor response to cocaine on Test 2 and the effect of cocaine and food restriction on CORT plasma levels.

Conclusions

These results indicate that the interaction between cocaine sensitization and food restriction is not synergistic, and that it involves activation of kappa-opioid receptors.